Susan London

The following reports are based on presentations at the 2011 Breast Cancer Symposium, held September 8–10 in San Francisco. The symposium was sponsored in part by the American Society of Clinical Oncology.

Taxane-induced neuropathy gives no clue to breast cancer outcome
The development of taxaneinduced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data demonstrate.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial of 4,554 women, 13%–22% developed peripheral neuropathy, depending on which of four taxane regimens they received. Women who developed peripheral neuropathy did not have better recurrence- free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups.

Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received. The findings are important given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

“Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome,” he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that “at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points.”

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted. “The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients,” concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grades 2–4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio [HR], 1.47), and were marginally more likely if they were black, obese, or postmenopausal. Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel versus paclitaxel every 3 weeks (HR, 1.52), paclitaxel every 3 weeks versus weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks versus docetaxel every 3 weeks (HR, 1.91). In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence- free, disease-free, or overall survival.

The findings contrast with an earlier study in which women receiving paclitaxel-containing therapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Chemotherapy timing does not affect breast cancer recurrence

Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of The University of Texas MD Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987–2005. Results showed that with a median follow-up of 7–8 years, the rate of freedom from locoregional recurrence was high (≥ 90% at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

“For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy,” Dr. Mittendorf, a surgical oncologist, commented, adding, “It is important to obtain a negative margin at the time of surgery.”

“It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy,” she said. However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of “oversimplification of [a] complex issue … especially in the era of personalized therapy.”

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

“The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important,” commented Dr. Fowble. “Initial stage, molecular subtype, and response to therapy will impact on outcome.”

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor-negative disease, and to have multifocal disease.

Median durations of follow-up were 7.2 and 7.9 years. In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%; P < 0.001).

“Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy,” Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P < 0.001). For example, the 10-year rate was 90% with the former and 94% with the latter.

“Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors,” she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence. Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (HR, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor-negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor-positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence- free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

In the pipeline: entinostat may overcome AI resistance

Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase II trial suggest.

Investigators studied 130 women with estrogen receptor-positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

“The combination…is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy,” principal investigator Dr. Denise A. Yardley reported.

“These results support our plans for a global, pivotal phase III study due to begin enrollment in 2012,” added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy.

These data reveal “for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes,” she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as “very, very promising,” saying, “I agree that it’s time for a phase III” trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

The randomized phase II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor-positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values < 0.1 were considered statistically significant. Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs 2.27 months; HR, 0.73; P = 0.06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an abovemedian percent change in lysines that were acetylated during the first cycle of treatment.

These findings “suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment,” said Dr. Yardley.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs 20.3 months; HR, 0.56; P = 0.027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

Measure of bone metastases predicts breast cancer survival

The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at the symposium.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were “hotter” on a PET/CT—as assessed from maximum standardized uptake value (SUV-max)— had poorer overall survival. Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

“To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival,” said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not signifycant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness.

“So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index],” he said. “This gives us another tool to evaluate how patients are going to do,” he commented. “Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be—is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease.” The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information “is a little something extra you get from the test.”

Will these new findings be practice changing?

“I’ll start looking at SUV values in my patients with newly diagnosed metastasis,” said Dr. Kuske. “Yes, it will change my practice.”

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained. The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease. The median duration of followup was 40 months.

In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = 0.006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

“Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable,” Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

“Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer,” she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

Score predicts late recurrence in ER-positive breast cancer

A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor-positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor-positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole or placebo.

Study results, reported at the meeting, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled. The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor-positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

“If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component,” he explained.

“If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy,” he continued. “For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials.

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase- polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL- 17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

“We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually,” he noted. “In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence.”

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = 0.014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = 0.019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported.

In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = 0.037).

“Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = 0.02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I,” he said. “These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy.”

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

The following reports are based on presentations at the 2011 Breast Cancer Symposium, held September 8–10 in San Francisco. The symposium was sponsored in part by the American Society of Clinical Oncology.

Taxane-induced neuropathy gives no clue to breast cancer outcome
The development of taxaneinduced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data demonstrate.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial of 4,554 women, 13%–22% developed peripheral neuropathy, depending on which of four taxane regimens they received. Women who developed peripheral neuropathy did not have better recurrence- free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups.

Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received. The findings are important given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

“Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome,” he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that “at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points.”

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted. “The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients,” concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grades 2–4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio [HR], 1.47), and were marginally more likely if they were black, obese, or postmenopausal. Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel versus paclitaxel every 3 weeks (HR, 1.52), paclitaxel every 3 weeks versus weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks versus docetaxel every 3 weeks (HR, 1.91). In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence- free, disease-free, or overall survival.

The findings contrast with an earlier study in which women receiving paclitaxel-containing therapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Chemotherapy timing does not affect breast cancer recurrence

Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of The University of Texas MD Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987–2005. Results showed that with a median follow-up of 7–8 years, the rate of freedom from locoregional recurrence was high (≥ 90% at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

“For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy,” Dr. Mittendorf, a surgical oncologist, commented, adding, “It is important to obtain a negative margin at the time of surgery.”

“It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy,” she said. However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of “oversimplification of [a] complex issue … especially in the era of personalized therapy.”

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

“The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important,” commented Dr. Fowble. “Initial stage, molecular subtype, and response to therapy will impact on outcome.”

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor-negative disease, and to have multifocal disease.

Median durations of follow-up were 7.2 and 7.9 years. In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%; P < 0.001).

“Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy,” Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P < 0.001). For example, the 10-year rate was 90% with the former and 94% with the latter.

“Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors,” she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence. Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (HR, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor-negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor-positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence- free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

In the pipeline: entinostat may overcome AI resistance

Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase II trial suggest.

Investigators studied 130 women with estrogen receptor-positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

“The combination…is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy,” principal investigator Dr. Denise A. Yardley reported.

“These results support our plans for a global, pivotal phase III study due to begin enrollment in 2012,” added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy.

These data reveal “for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes,” she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as “very, very promising,” saying, “I agree that it’s time for a phase III” trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

The randomized phase II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor-positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values < 0.1 were considered statistically significant. Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs 2.27 months; HR, 0.73; P = 0.06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an abovemedian percent change in lysines that were acetylated during the first cycle of treatment.

These findings “suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment,” said Dr. Yardley.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs 20.3 months; HR, 0.56; P = 0.027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

Measure of bone metastases predicts breast cancer survival

The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at the symposium.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were “hotter” on a PET/CT—as assessed from maximum standardized uptake value (SUV-max)— had poorer overall survival. Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

“To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival,” said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not signifycant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness.

“So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index],” he said. “This gives us another tool to evaluate how patients are going to do,” he commented. “Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be—is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease.” The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information “is a little something extra you get from the test.”

Will these new findings be practice changing?

“I’ll start looking at SUV values in my patients with newly diagnosed metastasis,” said Dr. Kuske. “Yes, it will change my practice.”

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained. The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease. The median duration of followup was 40 months.

In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = 0.006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

“Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable,” Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

“Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer,” she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

Score predicts late recurrence in ER-positive breast cancer

A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor-positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor-positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole or placebo.

Study results, reported at the meeting, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled. The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor-positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

“If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component,” he explained.

“If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy,” he continued. “For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials.

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase- polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL- 17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

“We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually,” he noted. “In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence.”

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = 0.014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = 0.019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported.

In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = 0.037).

“Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = 0.02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I,” he said. “These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy.”

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

The following reports are based on presentations at the 2011 Breast Cancer Symposium, held September 8–10 in San Francisco. The symposium was sponsored in part by the American Society of Clinical Oncology.

Taxane-induced neuropathy gives no clue to breast cancer outcome
The development of taxaneinduced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data demonstrate.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial of 4,554 women, 13%–22% developed peripheral neuropathy, depending on which of four taxane regimens they received. Women who developed peripheral neuropathy did not have better recurrence- free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups.

Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received. The findings are important given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

“Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome,” he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that “at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points.”

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted. “The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients,” concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grades 2–4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio [HR], 1.47), and were marginally more likely if they were black, obese, or postmenopausal. Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel versus paclitaxel every 3 weeks (HR, 1.52), paclitaxel every 3 weeks versus weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks versus docetaxel every 3 weeks (HR, 1.91). In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence- free, disease-free, or overall survival.

The findings contrast with an earlier study in which women receiving paclitaxel-containing therapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

Chemotherapy timing does not affect breast cancer recurrence

Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of The University of Texas MD Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987–2005. Results showed that with a median follow-up of 7–8 years, the rate of freedom from locoregional recurrence was high (≥ 90% at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

“For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy,” Dr. Mittendorf, a surgical oncologist, commented, adding, “It is important to obtain a negative margin at the time of surgery.”

“It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy,” she said. However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of “oversimplification of [a] complex issue … especially in the era of personalized therapy.”

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

“The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important,” commented Dr. Fowble. “Initial stage, molecular subtype, and response to therapy will impact on outcome.”

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor-negative disease, and to have multifocal disease.

Median durations of follow-up were 7.2 and 7.9 years. In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%; P < 0.001).

“Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy,” Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P < 0.001). For example, the 10-year rate was 90% with the former and 94% with the latter.

“Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors,” she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence. Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (HR, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor-negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor-positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence- free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

In the pipeline: entinostat may overcome AI resistance

Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase II trial suggest.

Investigators studied 130 women with estrogen receptor-positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.

“The combination…is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy,” principal investigator Dr. Denise A. Yardley reported.

“These results support our plans for a global, pivotal phase III study due to begin enrollment in 2012,” added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.

In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy.

These data reveal “for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes,” she noted.

Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as “very, very promising,” saying, “I agree that it’s time for a phase III” trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.

The randomized phase II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor-positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.

The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values < 0.1 were considered statistically significant. Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.

With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs 2.27 months; HR, 0.73; P = 0.06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.

In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an abovemedian percent change in lysines that were acetylated during the first cycle of treatment.

These findings “suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment,” said Dr. Yardley.

In an analysis that was exploratory because follow-up is still short, entinostat was also associated with better overall survival (26.9 vs 20.3 months; HR, 0.56; P = 0.027). Additional data with longer follow-up will be reported at the San Antonio Breast Cancer Symposium later this year.

The combination of entinostat and exemestane was well tolerated, with no unexpected safety signals. The most common grade 3/4 adverse events in the entinostat group were fatigue (13%), neutropenia (13%), nausea (5%), and vomiting (5%). The rate of discontinuation because of adverse events was 1% in the placebo group and 11% in the entinostat group.

Dr. Yardley reported no relevant conflicts of interest. Syndax Pharmaceuticals, developer of entinostat, was not among Dr. O’Shaughnessy’s disclosures.

Measure of bone metastases predicts breast cancer survival

The more metabolically active a woman’s bone metastases of breast cancer are on imaging, the greater her risk of death, researchers reported at the symposium.

In a retrospective cohort study of 269 women with newly diagnosed metastatic breast cancer, those whose bone metastases were “hotter” on a PET/CT—as assessed from maximum standardized uptake value (SUV-max)— had poorer overall survival. Compared with their counterparts with values in the bottom tertile of SUV-max values, women with values in the middle and top tertiles were roughly two to three times more likely to die after other prognostic factors were taken into account.

“To our understanding, this is the first large retrospective series to correlate SUV-max at metastatic breast cancer diagnosis with overall survival,” said lead author Dr. Komal Jhaveri of Memorial Sloan-Kettering Cancer Center, New York.

The risk of death also rose with increasing tertile of SUV-max in liver, lung, and lymph node metastases, but those associations were not signifycant. Their nonsignificance may have been due to the smaller numbers of patients having metastases in those sites, she said.

Session chair Dr. Robert R. Kuske, a radiation oncologist with Arizona Breast Cancer Specialists in Scottsdale, noted that SUV-max is a surrogate for how rapidly the tumor cells are proliferating and, hence, the tumor’s aggressiveness.

“So there should be a strong correlation between this SUV on the PET and the Ki-67 [histologic proliferation index],” he said. “This gives us another tool to evaluate how patients are going to do,” he commented. “Now [oncologists] can look at a metastasis on PET, measure the SUV, and get a handle on what the future of that patient is going to be—is it going to be a rapid slide to death, or is it going to be a very slow, indolent progression maybe over 10 or 15 years. And they can tailor the therapy based on the aggressiveness of the disease.” The PET/CT is usually done to determine whether the patient has metastases, so this additional prognostic information “is a little something extra you get from the test.”

Will these new findings be practice changing?

“I’ll start looking at SUV values in my patients with newly diagnosed metastasis,” said Dr. Kuske. “Yes, it will change my practice.”

In the study, Dr. Jhaveri and her coinvestigators reviewed records for women with metastatic breast cancer diagnosed between 2001 and 2008 who had a PET/CT scan performed within 60 days of the detection of metastases; had at least one avid metastasis in bone, liver, lung, or lymph node; and had not received chemotherapy in the month before the scan. Prior or current hormonal therapy was permitted.

The investigators determined the SUV-max for individual metastatic sites. They compared values only within a given site because of known variation across sites such as liver and lung, Dr. Jhaveri explained. The women had a median age of 58 years. The median time elapsed between primary breast cancer diagnosis and PET/CT was 2.3 years. A fifth each had triple-negative disease and HER2-positive disease. The median duration of followup was 40 months.

In a multivariate analysis that included other prognostic factors (grade, tumor phenotype, and visceral metastases), overall survival differed across tertiles of SUV-max for bone metastases (P = 0.006). Women with values in the middle and top tertiles were 1.87 and 2.67 times more likely to die, respectively, than their counterparts with values in the bottom tertile.

“Given the variation in SUV and the differential impact on survival by site, it is possible that SUV-max may not be the most optimal PET variable,” Dr. Jhaveri commented. She proposed that an alternate variable, called total lesion glycolysis (TLG), which incorporates tumor lesion size, might perform better and be more informative.

“Ultimately, prospective studies are required to further delineate the role of PET/CT as a prognostic tool in metastatic breast cancer,” she concluded.

Dr. Jhaveri and Dr. Kuske reported having no relevant conflicts of interest.

Score predicts late recurrence in ER-positive breast cancer

A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor-positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor-positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole or placebo.

Study results, reported at the meeting, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled. The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor-positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

“If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component,” he explained.

“If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy,” he continued. “For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials.

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase- polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL- 17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

“We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually,” he noted. “In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence.”

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = 0.014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = 0.019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported.

In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = 0.037).

“Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = 0.02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I,” he said. “These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy.”

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

CHICAGO – Compressing the usual 3-day course of intravenous azithromycin into a single high dose appears to be a safe, efficacious alternative for treating community-acquired pneumonia in adult outpatients.

In an open-label, randomized trial, investigators in Austria compared the same total dose of azithromycin either split over 3 days or given as a single infusion among 72 outpatients with community-acquired pneumonia (CAP).

Trial results, reported at the annual Interscience conference on Antimicrobial Agents and Chemotherapy, showed that the two regimens had similar efficacy and adverse effect profiles. In both groups, nearly 90% of patients were cured.

Photo: ©WILLSIE/iStockphoto.com

The single-dose strategy ensures high levels of the drug independent of patient compliance, according to presenting author Dr. Rainer Gattringer of the Elisabethinen Hospital and Analyse BioLab, both in Linz, Austria. Additionally, it may reduce treatment costs.

"I think maybe physicians are a little bit afraid because it’s not written in the description of the drug that you can use it at 1.5 g as a single dose," he proposed in an interview. "They say, I have no experience with it, and they don’t know about side effects and so on."

But the drug appeared safe and well tolerated with the protocol used in the trial: administration in a liter of infusion solution given over an extended period of 4 hours. "That [protocol] is I think the main thing," Dr. Gattringer said. "So don’t be afraid, try it."

The patients studied were 45 years old, on average, and 65% were men, according to data reported in a poster session. They were fairly healthy, Dr. Gattringer noted; the CRB-65 (confusion, respiratory rate, blood pressure, and age 65 years or older) score was 0, 1, and 2 in 33.3%, 51.4%, and 15.3%, respectively. Overall, 18% had previously received oral antibiotic therapy.

The most common pathogens identified were Streptococcus pneumoniae (22.2% of patients), Mycoplasma pneumoniae (6.9%), Legionella pneumophila (6.9%), Coxiella burnetii (1.4%), and Cytomegalovirus (1.4%). No pathogen was identified in 59.7% of cases.

The patients received either a single IV dose of 1.5 g azithromycin (diluted in 1 L of lactated Ringer solution and given as a 4-hour infusion) or the conventional dose schedule of 500 mg azithromycin IV once daily for 3 days.

Azithromycin is especially useful in patients who have an allergy to beta-lactam antibiotics, and the intravenous formulation is attractive given that oral macrolides, including azithromycin, have low bioavailability, Dr. Gattringer noted at the conference, which was sponsored by the American Society for Microbiology.

The rate of clinical cure – defined as resolution of fever within 72 hours; disappearance of other clinical and laboratory signs of inflammation, including achievement of C-reactive protein level of less than 1 mg/dL; and no need for additional antimicrobial therapy at 10 days – was statistically indistinguishable between the single-dose group and the conventional-regimen group (87.2% vs. 87.9%).

With the single-dose strategy, "you can send the patient home and you can achieve the right level of the drug in the patient," he concluded.

Dr. Gattringer reported having no conflicts of interest related to the trial. The trial was supported by a grant from Pfizer Research, manufacturer of Zithromax (azithromycin).

CHICAGO – Compressing the usual 3-day course of intravenous azithromycin into a single high dose appears to be a safe, efficacious alternative for treating community-acquired pneumonia in adult outpatients.

In an open-label, randomized trial, investigators in Austria compared the same total dose of azithromycin either split over 3 days or given as a single infusion among 72 outpatients with community-acquired pneumonia (CAP).

Trial results, reported at the annual Interscience conference on Antimicrobial Agents and Chemotherapy, showed that the two regimens had similar efficacy and adverse effect profiles. In both groups, nearly 90% of patients were cured.

Photo: ©WILLSIE/iStockphoto.com

The single-dose strategy ensures high levels of the drug independent of patient compliance, according to presenting author Dr. Rainer Gattringer of the Elisabethinen Hospital and Analyse BioLab, both in Linz, Austria. Additionally, it may reduce treatment costs.

"I think maybe physicians are a little bit afraid because it’s not written in the description of the drug that you can use it at 1.5 g as a single dose," he proposed in an interview. "They say, I have no experience with it, and they don’t know about side effects and so on."

But the drug appeared safe and well tolerated with the protocol used in the trial: administration in a liter of infusion solution given over an extended period of 4 hours. "That [protocol] is I think the main thing," Dr. Gattringer said. "So don’t be afraid, try it."

The patients studied were 45 years old, on average, and 65% were men, according to data reported in a poster session. They were fairly healthy, Dr. Gattringer noted; the CRB-65 (confusion, respiratory rate, blood pressure, and age 65 years or older) score was 0, 1, and 2 in 33.3%, 51.4%, and 15.3%, respectively. Overall, 18% had previously received oral antibiotic therapy.

The most common pathogens identified were Streptococcus pneumoniae (22.2% of patients), Mycoplasma pneumoniae (6.9%), Legionella pneumophila (6.9%), Coxiella burnetii (1.4%), and Cytomegalovirus (1.4%). No pathogen was identified in 59.7% of cases.

The patients received either a single IV dose of 1.5 g azithromycin (diluted in 1 L of lactated Ringer solution and given as a 4-hour infusion) or the conventional dose schedule of 500 mg azithromycin IV once daily for 3 days.

Azithromycin is especially useful in patients who have an allergy to beta-lactam antibiotics, and the intravenous formulation is attractive given that oral macrolides, including azithromycin, have low bioavailability, Dr. Gattringer noted at the conference, which was sponsored by the American Society for Microbiology.

The rate of clinical cure – defined as resolution of fever within 72 hours; disappearance of other clinical and laboratory signs of inflammation, including achievement of C-reactive protein level of less than 1 mg/dL; and no need for additional antimicrobial therapy at 10 days – was statistically indistinguishable between the single-dose group and the conventional-regimen group (87.2% vs. 87.9%).

With the single-dose strategy, "you can send the patient home and you can achieve the right level of the drug in the patient," he concluded.

Dr. Gattringer reported having no conflicts of interest related to the trial. The trial was supported by a grant from Pfizer Research, manufacturer of Zithromax (azithromycin).

CHICAGO – Compressing the usual 3-day course of intravenous azithromycin into a single high dose appears to be a safe, efficacious alternative for treating community-acquired pneumonia in adult outpatients.

In an open-label, randomized trial, investigators in Austria compared the same total dose of azithromycin either split over 3 days or given as a single infusion among 72 outpatients with community-acquired pneumonia (CAP).

Trial results, reported at the annual Interscience conference on Antimicrobial Agents and Chemotherapy, showed that the two regimens had similar efficacy and adverse effect profiles. In both groups, nearly 90% of patients were cured.

Photo: ©WILLSIE/iStockphoto.com

The single-dose strategy ensures high levels of the drug independent of patient compliance, according to presenting author Dr. Rainer Gattringer of the Elisabethinen Hospital and Analyse BioLab, both in Linz, Austria. Additionally, it may reduce treatment costs.

"I think maybe physicians are a little bit afraid because it’s not written in the description of the drug that you can use it at 1.5 g as a single dose," he proposed in an interview. "They say, I have no experience with it, and they don’t know about side effects and so on."

But the drug appeared safe and well tolerated with the protocol used in the trial: administration in a liter of infusion solution given over an extended period of 4 hours. "That [protocol] is I think the main thing," Dr. Gattringer said. "So don’t be afraid, try it."

The patients studied were 45 years old, on average, and 65% were men, according to data reported in a poster session. They were fairly healthy, Dr. Gattringer noted; the CRB-65 (confusion, respiratory rate, blood pressure, and age 65 years or older) score was 0, 1, and 2 in 33.3%, 51.4%, and 15.3%, respectively. Overall, 18% had previously received oral antibiotic therapy.

The most common pathogens identified were Streptococcus pneumoniae (22.2% of patients), Mycoplasma pneumoniae (6.9%), Legionella pneumophila (6.9%), Coxiella burnetii (1.4%), and Cytomegalovirus (1.4%). No pathogen was identified in 59.7% of cases.

The patients received either a single IV dose of 1.5 g azithromycin (diluted in 1 L of lactated Ringer solution and given as a 4-hour infusion) or the conventional dose schedule of 500 mg azithromycin IV once daily for 3 days.

Azithromycin is especially useful in patients who have an allergy to beta-lactam antibiotics, and the intravenous formulation is attractive given that oral macrolides, including azithromycin, have low bioavailability, Dr. Gattringer noted at the conference, which was sponsored by the American Society for Microbiology.

The rate of clinical cure – defined as resolution of fever within 72 hours; disappearance of other clinical and laboratory signs of inflammation, including achievement of C-reactive protein level of less than 1 mg/dL; and no need for additional antimicrobial therapy at 10 days – was statistically indistinguishable between the single-dose group and the conventional-regimen group (87.2% vs. 87.9%).

With the single-dose strategy, "you can send the patient home and you can achieve the right level of the drug in the patient," he concluded.

Dr. Gattringer reported having no conflicts of interest related to the trial. The trial was supported by a grant from Pfizer Research, manufacturer of Zithromax (azithromycin).

CHICAGO – Moxifloxacin works as well as the combination of amoxicillin and clavulanic acid in the treatment of acute exacerbations of complicated chronic obstructive pulmonary disease, new data show. But the former may have the edge in cases in which a bacterial pathogen is identified.

In a randomized, double-blind, noninferiority trial among 1,352 patients who had complicated COPD and an exacerbation, about a fifth of patients had a clinical failure of their antibiotic therapy, no matter which regimen they received, according to results reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

However, secondary analyses showed that in the subset of patients in whom a bacterial pathogen was identified in sputum before antibiotic therapy was started, clinical failure was significantly less likely for those who received moxifloxacin, which is a member of the fluoroquinolone class of antibiotics.

"I think, clinically, what this translates to is, yes, you can use either antibiotic in this group," lead investigator Dr. Sanjay Sethi said in an interview at the conference, which was sponsored by the American Society for Microbiology. But in patients in whom a bacterial pathogen is identified or strongly suspected, "Moxifloxacin does better in that subgroup."

The difference seems to be driven by better bacterial eradication with moxifloxacin, he added. "So when you have a well-defined pathogen, you eradicate the bacterium [and] you get a clinical difference in outcomes."

Both antibiotics were well tolerated, according to Dr. Sethi. Moxifloxacin may have a slight advantage in terms of convenience, as it was given once daily for 5 days, compared with twice daily for 7 days for the amoxicillin–clavulanic acid. Comparative costs will depend on the local market and availability of generic formulations.

Dr. Sethi uses the quinolones as well as amoxicillin plus clavulanic acid. When he is clinically sure that a patient has a predominant pathogen, or when a biomarker such as a C-reactive protein or procalcitonin level indicates "that this could very likely be bacterial, then I would tend to go for the ‘moxi,’ " based on such data, he added.

Some guidelines, such as the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, list the two antibiotic regimens as equal alternatives for patients with complicated COPD, such as those having underlying severe airflow obstruction, recurrent exacerbations, or comorbid cardiac disease, according to Dr. Sethi, chief of the division of pulmonary, critical care, and sleep medicine at the State University of New York at Buffalo.

"What this study tells me is, I think that we did that right," that is, listing the two regimens as alternatives, he commented. "These are secondary analyses, but there could be a subgroup with a predominant pathogen [in whom] there may be differences between the two."

In a novel finding, the study also showed that early bacterial eradication at the end of antibiotic therapy increased the likelihood of clinical cure at 8 weeks later, no matter which antibiotic the patients received. This association "has not been very well described in COPD exacerbations," Dr. Sethi noted.

Patients with COPD were eligible for the trial, called MAESTRAL (Moxifloxacin vs. Amoxicillin–Clavulanic Acid in Treatment of Acute Exacerbation of Chronic Bronchitis), if they were aged 60 years or older, had an Anthonisen type 1 exacerbation (with purulent sputum, increased sputum volume, and increased dyspnea), had an forced expiratory volume in 1 second (FEV₁) of less than or equal to 60% of predicted, and had experienced more than two exacerbations in the last year that required systemic antibiotics and/or systemic corticosteroids.

The subjects were randomized in equal numbers to receive moxifloxacin (400 mg orally once daily for 5 days), or amoxicillin plus clavulanic acid (875 and 125 mg orally twice daily for 7 days). Sputum samples were collected before start of therapy and serially thereafter for Gram staining and culture.

The trial’s primary end point was the rate of clinical failure (defined as the need for additional or alternative treatment for the exacerbation with systemic antibiotics, systemic corticosteroids, and/or hospitalization) within 8 weeks of the end of antibiotic therapy. The investigators defined noninferiority as a difference in the rate of this end point of no more than 6% between groups.

The patients studied were 70 years old on average, and 80% were men. Slightly more than a third used systemic corticosteroids. Their mean FEV₁ was about 980 mL, and their mean number of exacerbations in the previous year had been 2.5.

Study results, reported in a poster session, showed that the rate of clinical failure was noninferior with moxifloxacin, compared with amoxicillin–clavulanic acid, in both the intent-to-treat population (20.4% vs. 21.6%) and the per-protocol population (20.6% vs. 22.0%).

Slightly fewer than half of patients had at least one potentially pathogenic bacterium isolated from sputum before starting antibiotic therapy, most often Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus.

In this subset of patients, the rate of clinical failure was lower with moxifloxacin than with amoxicillin–clavulanic acid in both the intent-to-treat population (19.0% vs. 25.4%; P = .02) and the per-protocol population (19.2% vs. 26.1%; P = .03). Further analysis showed higher rates of bacterial eradication with moxifloxacin, mainly driven by higher rates of eradication of H. influenzae (89.2% vs. 66.7%).

In the study population overall, patients who had bacteriologic eradication at the end of antibiotic therapy, compared with bacteriologic persistence or superinfection, were more likely to be cured 8 weeks later (79.7% vs. 54.7%; P less than .001). The finding was the same in the two treatment groups individually.

The rate of drug-related adverse events was 7.8% with moxifloxacin and 6.1% with amoxicillin–clavulanic acid. The most common events were headache, diarrhea, and fever.

Dr. Sethi reported that he is an investigator for and scientific advisor to Bayer HealthCare Pharmaceuticals, which manufactured the moxifloxacin, and has received speaker honoraria and consulting fees from the company. The trial was supported by Bayer HealthCare Pharmaceuticals.

CHICAGO – Moxifloxacin works as well as the combination of amoxicillin and clavulanic acid in the treatment of acute exacerbations of complicated chronic obstructive pulmonary disease, new data show. But the former may have the edge in cases in which a bacterial pathogen is identified.

In a randomized, double-blind, noninferiority trial among 1,352 patients who had complicated COPD and an exacerbation, about a fifth of patients had a clinical failure of their antibiotic therapy, no matter which regimen they received, according to results reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

However, secondary analyses showed that in the subset of patients in whom a bacterial pathogen was identified in sputum before antibiotic therapy was started, clinical failure was significantly less likely for those who received moxifloxacin, which is a member of the fluoroquinolone class of antibiotics.

"I think, clinically, what this translates to is, yes, you can use either antibiotic in this group," lead investigator Dr. Sanjay Sethi said in an interview at the conference, which was sponsored by the American Society for Microbiology. But in patients in whom a bacterial pathogen is identified or strongly suspected, "Moxifloxacin does better in that subgroup."

The difference seems to be driven by better bacterial eradication with moxifloxacin, he added. "So when you have a well-defined pathogen, you eradicate the bacterium [and] you get a clinical difference in outcomes."

Both antibiotics were well tolerated, according to Dr. Sethi. Moxifloxacin may have a slight advantage in terms of convenience, as it was given once daily for 5 days, compared with twice daily for 7 days for the amoxicillin–clavulanic acid. Comparative costs will depend on the local market and availability of generic formulations.

Dr. Sethi uses the quinolones as well as amoxicillin plus clavulanic acid. When he is clinically sure that a patient has a predominant pathogen, or when a biomarker such as a C-reactive protein or procalcitonin level indicates "that this could very likely be bacterial, then I would tend to go for the ‘moxi,’ " based on such data, he added.

Some guidelines, such as the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, list the two antibiotic regimens as equal alternatives for patients with complicated COPD, such as those having underlying severe airflow obstruction, recurrent exacerbations, or comorbid cardiac disease, according to Dr. Sethi, chief of the division of pulmonary, critical care, and sleep medicine at the State University of New York at Buffalo.

"What this study tells me is, I think that we did that right," that is, listing the two regimens as alternatives, he commented. "These are secondary analyses, but there could be a subgroup with a predominant pathogen [in whom] there may be differences between the two."

In a novel finding, the study also showed that early bacterial eradication at the end of antibiotic therapy increased the likelihood of clinical cure at 8 weeks later, no matter which antibiotic the patients received. This association "has not been very well described in COPD exacerbations," Dr. Sethi noted.

Patients with COPD were eligible for the trial, called MAESTRAL (Moxifloxacin vs. Amoxicillin–Clavulanic Acid in Treatment of Acute Exacerbation of Chronic Bronchitis), if they were aged 60 years or older, had an Anthonisen type 1 exacerbation (with purulent sputum, increased sputum volume, and increased dyspnea), had an forced expiratory volume in 1 second (FEV₁) of less than or equal to 60% of predicted, and had experienced more than two exacerbations in the last year that required systemic antibiotics and/or systemic corticosteroids.

The subjects were randomized in equal numbers to receive moxifloxacin (400 mg orally once daily for 5 days), or amoxicillin plus clavulanic acid (875 and 125 mg orally twice daily for 7 days). Sputum samples were collected before start of therapy and serially thereafter for Gram staining and culture.

The trial’s primary end point was the rate of clinical failure (defined as the need for additional or alternative treatment for the exacerbation with systemic antibiotics, systemic corticosteroids, and/or hospitalization) within 8 weeks of the end of antibiotic therapy. The investigators defined noninferiority as a difference in the rate of this end point of no more than 6% between groups.

The patients studied were 70 years old on average, and 80% were men. Slightly more than a third used systemic corticosteroids. Their mean FEV₁ was about 980 mL, and their mean number of exacerbations in the previous year had been 2.5.

Study results, reported in a poster session, showed that the rate of clinical failure was noninferior with moxifloxacin, compared with amoxicillin–clavulanic acid, in both the intent-to-treat population (20.4% vs. 21.6%) and the per-protocol population (20.6% vs. 22.0%).

Slightly fewer than half of patients had at least one potentially pathogenic bacterium isolated from sputum before starting antibiotic therapy, most often Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus.

In this subset of patients, the rate of clinical failure was lower with moxifloxacin than with amoxicillin–clavulanic acid in both the intent-to-treat population (19.0% vs. 25.4%; P = .02) and the per-protocol population (19.2% vs. 26.1%; P = .03). Further analysis showed higher rates of bacterial eradication with moxifloxacin, mainly driven by higher rates of eradication of H. influenzae (89.2% vs. 66.7%).

In the study population overall, patients who had bacteriologic eradication at the end of antibiotic therapy, compared with bacteriologic persistence or superinfection, were more likely to be cured 8 weeks later (79.7% vs. 54.7%; P less than .001). The finding was the same in the two treatment groups individually.

The rate of drug-related adverse events was 7.8% with moxifloxacin and 6.1% with amoxicillin–clavulanic acid. The most common events were headache, diarrhea, and fever.

Dr. Sethi reported that he is an investigator for and scientific advisor to Bayer HealthCare Pharmaceuticals, which manufactured the moxifloxacin, and has received speaker honoraria and consulting fees from the company. The trial was supported by Bayer HealthCare Pharmaceuticals.

CHICAGO – Moxifloxacin works as well as the combination of amoxicillin and clavulanic acid in the treatment of acute exacerbations of complicated chronic obstructive pulmonary disease, new data show. But the former may have the edge in cases in which a bacterial pathogen is identified.

In a randomized, double-blind, noninferiority trial among 1,352 patients who had complicated COPD and an exacerbation, about a fifth of patients had a clinical failure of their antibiotic therapy, no matter which regimen they received, according to results reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

However, secondary analyses showed that in the subset of patients in whom a bacterial pathogen was identified in sputum before antibiotic therapy was started, clinical failure was significantly less likely for those who received moxifloxacin, which is a member of the fluoroquinolone class of antibiotics.

"I think, clinically, what this translates to is, yes, you can use either antibiotic in this group," lead investigator Dr. Sanjay Sethi said in an interview at the conference, which was sponsored by the American Society for Microbiology. But in patients in whom a bacterial pathogen is identified or strongly suspected, "Moxifloxacin does better in that subgroup."

The difference seems to be driven by better bacterial eradication with moxifloxacin, he added. "So when you have a well-defined pathogen, you eradicate the bacterium [and] you get a clinical difference in outcomes."

Both antibiotics were well tolerated, according to Dr. Sethi. Moxifloxacin may have a slight advantage in terms of convenience, as it was given once daily for 5 days, compared with twice daily for 7 days for the amoxicillin–clavulanic acid. Comparative costs will depend on the local market and availability of generic formulations.

Dr. Sethi uses the quinolones as well as amoxicillin plus clavulanic acid. When he is clinically sure that a patient has a predominant pathogen, or when a biomarker such as a C-reactive protein or procalcitonin level indicates "that this could very likely be bacterial, then I would tend to go for the ‘moxi,’ " based on such data, he added.

Some guidelines, such as the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, list the two antibiotic regimens as equal alternatives for patients with complicated COPD, such as those having underlying severe airflow obstruction, recurrent exacerbations, or comorbid cardiac disease, according to Dr. Sethi, chief of the division of pulmonary, critical care, and sleep medicine at the State University of New York at Buffalo.

"What this study tells me is, I think that we did that right," that is, listing the two regimens as alternatives, he commented. "These are secondary analyses, but there could be a subgroup with a predominant pathogen [in whom] there may be differences between the two."

In a novel finding, the study also showed that early bacterial eradication at the end of antibiotic therapy increased the likelihood of clinical cure at 8 weeks later, no matter which antibiotic the patients received. This association "has not been very well described in COPD exacerbations," Dr. Sethi noted.

Patients with COPD were eligible for the trial, called MAESTRAL (Moxifloxacin vs. Amoxicillin–Clavulanic Acid in Treatment of Acute Exacerbation of Chronic Bronchitis), if they were aged 60 years or older, had an Anthonisen type 1 exacerbation (with purulent sputum, increased sputum volume, and increased dyspnea), had an forced expiratory volume in 1 second (FEV₁) of less than or equal to 60% of predicted, and had experienced more than two exacerbations in the last year that required systemic antibiotics and/or systemic corticosteroids.

The subjects were randomized in equal numbers to receive moxifloxacin (400 mg orally once daily for 5 days), or amoxicillin plus clavulanic acid (875 and 125 mg orally twice daily for 7 days). Sputum samples were collected before start of therapy and serially thereafter for Gram staining and culture.

The trial’s primary end point was the rate of clinical failure (defined as the need for additional or alternative treatment for the exacerbation with systemic antibiotics, systemic corticosteroids, and/or hospitalization) within 8 weeks of the end of antibiotic therapy. The investigators defined noninferiority as a difference in the rate of this end point of no more than 6% between groups.

The patients studied were 70 years old on average, and 80% were men. Slightly more than a third used systemic corticosteroids. Their mean FEV₁ was about 980 mL, and their mean number of exacerbations in the previous year had been 2.5.

Study results, reported in a poster session, showed that the rate of clinical failure was noninferior with moxifloxacin, compared with amoxicillin–clavulanic acid, in both the intent-to-treat population (20.4% vs. 21.6%) and the per-protocol population (20.6% vs. 22.0%).

Slightly fewer than half of patients had at least one potentially pathogenic bacterium isolated from sputum before starting antibiotic therapy, most often Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus.

In this subset of patients, the rate of clinical failure was lower with moxifloxacin than with amoxicillin–clavulanic acid in both the intent-to-treat population (19.0% vs. 25.4%; P = .02) and the per-protocol population (19.2% vs. 26.1%; P = .03). Further analysis showed higher rates of bacterial eradication with moxifloxacin, mainly driven by higher rates of eradication of H. influenzae (89.2% vs. 66.7%).

In the study population overall, patients who had bacteriologic eradication at the end of antibiotic therapy, compared with bacteriologic persistence or superinfection, were more likely to be cured 8 weeks later (79.7% vs. 54.7%; P less than .001). The finding was the same in the two treatment groups individually.

The rate of drug-related adverse events was 7.8% with moxifloxacin and 6.1% with amoxicillin–clavulanic acid. The most common events were headache, diarrhea, and fever.

Dr. Sethi reported that he is an investigator for and scientific advisor to Bayer HealthCare Pharmaceuticals, which manufactured the moxifloxacin, and has received speaker honoraria and consulting fees from the company. The trial was supported by Bayer HealthCare Pharmaceuticals.

Major Finding: Women who had anemia preoperatively were ninefold more likely to receive a transfusion than their nonanemic counterparts.

Data Source: A retrospective case-control study of 441 women who underwent hysterectomy for benign conditions.

Disclosures: Dr. Mangel reported that he had no relevant financial disclosures.

VANCOUVER, B.C. – Preoperative anemia sharply increases the odds that women undergoing elective hysterectomy for a benign condition will need a transfusion, according to a study of over 400 women.

In a retrospective cohort study of 441 women, those who were found to be anemic (defined as having a hematocrit of less than 30%) on their preoperative bloodwork were ninefold more likely to receive a transfusion intraoperatively or postoperatively after other factors were taken into account.

“Blood transfusion is a relatively safe intervention in the 21st century, but it's not without risks, such as the risk of infectious transmission or fluid overload, and blood supply is limited. So we don't want to give blood unless we have to give blood,” lead investigator Dr. Jeffrey Mangel commented in an interview.

“Anemia is a modifiable risk factor,” he added. “In a short period of time, you can't change a patient's weight or their prior surgical history or other things, but you certainly can change their preoperative hematocrit.”

For example, physicians can encourage anemic women to begin or better comply with iron therapy and start them on gonadotropin-releasing hormone (GnRH) agonist therapy to halt menstruation. Still, these interventions take approximately 2 to 3 months to restore red blood cell parameters to the normal range.

“The barriers to that might be more along the lines of convenience,” he noted, in that patients and physicians alike have already scheduled and prepared for the surgery. “So there is an element of inconvenience for the patient and the doctor that may prevent people from doing this.”

“But from the quality of care point of view, it's probably at least something that should be offered to patients before they have their surgery,” added Dr. Mangel, who is director of the division of urogynecology and pelvic surgery at MetroHealth Medical Center, and with the reproductive biology department at Case Western Reserve University, both in Cleveland. “Some patients might opt for the increased risk of getting blood if they don't choose to delay their surgery. But if I were advising women who were going to have this type of surgery, I would like them to minimize every possible risk of getting blood if they don't need to get it.”

For the study, he and his colleagues retrospectively queried the MetroHealth electronic medical record system to identify women who underwent an elective hysterectomy for a benign condition between 2000 and 2005. They compared characteristics between 137 women who received a perioperative transfusion and 304 women who did not.

Study results showed that the two groups were similar in terms of age (mean age was 45 years), race, body mass index (mean BMI was 31 kg/m

Many of the women who were transfused were anemic preoperatively (78%), compared with 25% of nonanemic women. The difference corresponded to ninefold higher odds of transfusion in adjusted analyses.

In addition, as might be expected, women were more likely to receive a transfusion if they had a greater estimated blood loss during the surgery. Age, body mass index, and prior history of surgeries did not influence this outcome, he said at the meeting.

Further analyses showed that the odds of transfusion were also higher for women whose indication for surgery was fibroids and/or menorrhagia versus prolapse, and for women having an abdominal hysterectomy versus women who had a transvaginal or laparoscopic procedure.

In the case of menorrhagia, women usually have a known history of anemia, according to Dr. Mangel. But the anemia can be much more severe preoperatively than anticipated, possibly related to a longer time between deciding to have the surgery and actually having it.

There are no formal guidelines when it comes specifically to managing anemia in patients undergoing hysterectomy, he said, but a general surgical principle is that the healthier a patient is going into surgery, the better the likelihood of a good outcome.

“I'm not advocating to have a hard and fast guideline published because I do think you need to leave room for patient counseling, discussion of what matters to the patient, and for there to be some physician judgment involved regarding the risks of postponing this person's surgery versus not,” he said. For instance, a patient who is unlikely to return for a rescheduled hysterectomy in 2 to 3 months may get into an emergent situation where, ironically, she needs a transfusion.

“But if given the opportunity, surgeons should consider intervening,” he recommended. “I think we are all a little bit guilty of this, that we have become a little bit lax with our concern about transfusing patients in general. … To the extent we don't have to give people blood, we are better off not giving them blood. And while this may pose inconvenience to patients and surgeons, if they are willing to consider doing this type of an intervention, blood transfusion rates will go down for hysterectomy. So sometimes, the right thing to do is not always the most convenient thing to do.”

Major Finding: Women who had anemia preoperatively were ninefold more likely to receive a transfusion than their nonanemic counterparts.

Data Source: A retrospective case-control study of 441 women who underwent hysterectomy for benign conditions.

Disclosures: Dr. Mangel reported that he had no relevant financial disclosures.

VANCOUVER, B.C. – Preoperative anemia sharply increases the odds that women undergoing elective hysterectomy for a benign condition will need a transfusion, according to a study of over 400 women.

In a retrospective cohort study of 441 women, those who were found to be anemic (defined as having a hematocrit of less than 30%) on their preoperative bloodwork were ninefold more likely to receive a transfusion intraoperatively or postoperatively after other factors were taken into account.

“Blood transfusion is a relatively safe intervention in the 21st century, but it's not without risks, such as the risk of infectious transmission or fluid overload, and blood supply is limited. So we don't want to give blood unless we have to give blood,” lead investigator Dr. Jeffrey Mangel commented in an interview.

“Anemia is a modifiable risk factor,” he added. “In a short period of time, you can't change a patient's weight or their prior surgical history or other things, but you certainly can change their preoperative hematocrit.”

For example, physicians can encourage anemic women to begin or better comply with iron therapy and start them on gonadotropin-releasing hormone (GnRH) agonist therapy to halt menstruation. Still, these interventions take approximately 2 to 3 months to restore red blood cell parameters to the normal range.

“The barriers to that might be more along the lines of convenience,” he noted, in that patients and physicians alike have already scheduled and prepared for the surgery. “So there is an element of inconvenience for the patient and the doctor that may prevent people from doing this.”

“But from the quality of care point of view, it's probably at least something that should be offered to patients before they have their surgery,” added Dr. Mangel, who is director of the division of urogynecology and pelvic surgery at MetroHealth Medical Center, and with the reproductive biology department at Case Western Reserve University, both in Cleveland. “Some patients might opt for the increased risk of getting blood if they don't choose to delay their surgery. But if I were advising women who were going to have this type of surgery, I would like them to minimize every possible risk of getting blood if they don't need to get it.”

For the study, he and his colleagues retrospectively queried the MetroHealth electronic medical record system to identify women who underwent an elective hysterectomy for a benign condition between 2000 and 2005. They compared characteristics between 137 women who received a perioperative transfusion and 304 women who did not.

Study results showed that the two groups were similar in terms of age (mean age was 45 years), race, body mass index (mean BMI was 31 kg/m

Many of the women who were transfused were anemic preoperatively (78%), compared with 25% of nonanemic women. The difference corresponded to ninefold higher odds of transfusion in adjusted analyses.

In addition, as might be expected, women were more likely to receive a transfusion if they had a greater estimated blood loss during the surgery. Age, body mass index, and prior history of surgeries did not influence this outcome, he said at the meeting.

Further analyses showed that the odds of transfusion were also higher for women whose indication for surgery was fibroids and/or menorrhagia versus prolapse, and for women having an abdominal hysterectomy versus women who had a transvaginal or laparoscopic procedure.

In the case of menorrhagia, women usually have a known history of anemia, according to Dr. Mangel. But the anemia can be much more severe preoperatively than anticipated, possibly related to a longer time between deciding to have the surgery and actually having it.

There are no formal guidelines when it comes specifically to managing anemia in patients undergoing hysterectomy, he said, but a general surgical principle is that the healthier a patient is going into surgery, the better the likelihood of a good outcome.

“I'm not advocating to have a hard and fast guideline published because I do think you need to leave room for patient counseling, discussion of what matters to the patient, and for there to be some physician judgment involved regarding the risks of postponing this person's surgery versus not,” he said. For instance, a patient who is unlikely to return for a rescheduled hysterectomy in 2 to 3 months may get into an emergent situation where, ironically, she needs a transfusion.

“But if given the opportunity, surgeons should consider intervening,” he recommended. “I think we are all a little bit guilty of this, that we have become a little bit lax with our concern about transfusing patients in general. … To the extent we don't have to give people blood, we are better off not giving them blood. And while this may pose inconvenience to patients and surgeons, if they are willing to consider doing this type of an intervention, blood transfusion rates will go down for hysterectomy. So sometimes, the right thing to do is not always the most convenient thing to do.”

Major Finding: Women who had anemia preoperatively were ninefold more likely to receive a transfusion than their nonanemic counterparts.

Data Source: A retrospective case-control study of 441 women who underwent hysterectomy for benign conditions.

Disclosures: Dr. Mangel reported that he had no relevant financial disclosures.

VANCOUVER, B.C. – Preoperative anemia sharply increases the odds that women undergoing elective hysterectomy for a benign condition will need a transfusion, according to a study of over 400 women.

In a retrospective cohort study of 441 women, those who were found to be anemic (defined as having a hematocrit of less than 30%) on their preoperative bloodwork were ninefold more likely to receive a transfusion intraoperatively or postoperatively after other factors were taken into account.

“Blood transfusion is a relatively safe intervention in the 21st century, but it's not without risks, such as the risk of infectious transmission or fluid overload, and blood supply is limited. So we don't want to give blood unless we have to give blood,” lead investigator Dr. Jeffrey Mangel commented in an interview.

“Anemia is a modifiable risk factor,” he added. “In a short period of time, you can't change a patient's weight or their prior surgical history or other things, but you certainly can change their preoperative hematocrit.”

For example, physicians can encourage anemic women to begin or better comply with iron therapy and start them on gonadotropin-releasing hormone (GnRH) agonist therapy to halt menstruation. Still, these interventions take approximately 2 to 3 months to restore red blood cell parameters to the normal range.

“The barriers to that might be more along the lines of convenience,” he noted, in that patients and physicians alike have already scheduled and prepared for the surgery. “So there is an element of inconvenience for the patient and the doctor that may prevent people from doing this.”

“But from the quality of care point of view, it's probably at least something that should be offered to patients before they have their surgery,” added Dr. Mangel, who is director of the division of urogynecology and pelvic surgery at MetroHealth Medical Center, and with the reproductive biology department at Case Western Reserve University, both in Cleveland. “Some patients might opt for the increased risk of getting blood if they don't choose to delay their surgery. But if I were advising women who were going to have this type of surgery, I would like them to minimize every possible risk of getting blood if they don't need to get it.”

For the study, he and his colleagues retrospectively queried the MetroHealth electronic medical record system to identify women who underwent an elective hysterectomy for a benign condition between 2000 and 2005. They compared characteristics between 137 women who received a perioperative transfusion and 304 women who did not.

Study results showed that the two groups were similar in terms of age (mean age was 45 years), race, body mass index (mean BMI was 31 kg/m

Many of the women who were transfused were anemic preoperatively (78%), compared with 25% of nonanemic women. The difference corresponded to ninefold higher odds of transfusion in adjusted analyses.

In addition, as might be expected, women were more likely to receive a transfusion if they had a greater estimated blood loss during the surgery. Age, body mass index, and prior history of surgeries did not influence this outcome, he said at the meeting.

Further analyses showed that the odds of transfusion were also higher for women whose indication for surgery was fibroids and/or menorrhagia versus prolapse, and for women having an abdominal hysterectomy versus women who had a transvaginal or laparoscopic procedure.

In the case of menorrhagia, women usually have a known history of anemia, according to Dr. Mangel. But the anemia can be much more severe preoperatively than anticipated, possibly related to a longer time between deciding to have the surgery and actually having it.

There are no formal guidelines when it comes specifically to managing anemia in patients undergoing hysterectomy, he said, but a general surgical principle is that the healthier a patient is going into surgery, the better the likelihood of a good outcome.

“I'm not advocating to have a hard and fast guideline published because I do think you need to leave room for patient counseling, discussion of what matters to the patient, and for there to be some physician judgment involved regarding the risks of postponing this person's surgery versus not,” he said. For instance, a patient who is unlikely to return for a rescheduled hysterectomy in 2 to 3 months may get into an emergent situation where, ironically, she needs a transfusion.

“But if given the opportunity, surgeons should consider intervening,” he recommended. “I think we are all a little bit guilty of this, that we have become a little bit lax with our concern about transfusing patients in general. … To the extent we don't have to give people blood, we are better off not giving them blood. And while this may pose inconvenience to patients and surgeons, if they are willing to consider doing this type of an intervention, blood transfusion rates will go down for hysterectomy. So sometimes, the right thing to do is not always the most convenient thing to do.”

Major Finding: Overall, 65.5% and 29.8% of breast cancers were detected by mammography and palpation, respectively. Among the women younger than age 50, the corresponding values were 48.3% and 46.1%.

Data Source: A retrospective cohort study of 5,628 women given a diagnosis of stage 0 to III breast cancer between 2006 and 2009.

Disclosures: Dr. Caughran and Dr. Seidman reported that they had no relevant conflicts of interest.

SAN FRANCISCO – Many breast cancer patients would have more advanced disease at diagnosis and face harsher treatment if recently updated screening guidelines of the U.S. Preventive Services Task Force were widely adopted, suggests the investigator of a retrospective cohort study of more than 5,000 women with breast cancer in Michigan.

Study results, being reported this week at the symposium, show that nearly a third of the women's cancers were detected by palpation. The guidelines do not advocate for self-exams at all and question the usefulness of clinical breast exams after age 40.

Additionally, nearly half of the cancers in women younger than 50 years were detected by mammography, while the guidelines now recommend against this practice in the 40- to 49-year age group.

Women with palpation-detected cancers had later-stage disease and were significantly more likely to undergo mastectomy and receive chemotherapy than were those with mammography-detected cancers.

“Annual screening mammograms and evaluation of palpable breast masses are important tools in breast cancer detection,” second author Dr. Jamie Caughran said during a premeeting press briefing from the American Society of Clinical Oncology (ASCO).

She declined to say whether the study's results contradict the U.S. Preventive Services Task Force (USPSTF) guidelines, as the investigators did not have adequate information on the women's screening history.

But “we take this data to conclude that you're better off if you can … have your cancer detected by mammography — that you are more likely to have options and less likely to need aggressive treatment. So … we would support the rest of the societies that continue to recommend annual screening mammography starting at age 40,” she said.

Additionally, this study “highlights the still-significant number of women who present with a palpable mass that shouldn't be overlooked by physicians even if they have a negative mammogram,” pointed out Dr. Caughran, medical director of the Comprehensive Breast Center at the Lacks Cancer Center in Grand Rapids, Mich. “So it just continues to reinforce what we believe is inherently true.”

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York City, commented that the appropriate age for starting screening mammography remains controversial.

“A lot of the debate and focus regarding the utility of mammography have been on overall survival and breast cancer—specific survival, and I certainly think that is the most important end point,” he said, noting that the study speaks to another important end point — reduced intensity of treatment.

“As a medical oncologist or chemotherapist, I think this is a very important gain, independent of any potential survival benefit,” he said. “Having less disfiguring surgery and the ability to deliver less chemotherapy based on the stage at diagnosis are for me a step forward.”

This newest study will not quell the debate, according to Dr. Seidman. “Undoubtedly, this area will continue to remain an area of controversy for some,” he said. “But certainly, women in this age group would be well served to know about this data.”

In the study, Dr. Caughran and her colleagues analyzed data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative, identifying 5,628 women who received a diagnosis of stage 0 to III breast cancer between 2006 and 2009. Their average age was 59.4 years.

In the cohort overall, 65.5% of breast cancers were detected by mammography, 29.8% by palpation, and 4.7% by other means.

Fully 90% of the cancers detected by palpation were detected by the patient herself, although “it's unclear if the patients … were practicing regular breast self-examination or if these were incidental findings,” noted Dr. Caughran.

When analyses were restricted to women younger than 50 years of age, 48.3% of breast cancers were detected by mammography, 46.1% by palpation, and 5.6% by other means.

Palpation-detected cancers were of later stages (P less than .0001) — two-thirds were stage II or higher — and were more often treated with mastectomy (45.8% vs. 27.1%, P less than .0001) and with chemotherapy (22.7% vs. 15.7%, P less than .0001).

Nearly half of the cancers in women younger than 50 years were detected by mammography.

Source © KSASS/ISTOCKPHOTO.COM

View on The News

Study Does Not Invalidate the Guidelines

You might imagine that as an advocate of breast cancer screening for women ages 40–49 years, I would be dancing in the streets as a result of this report.

Sadly, I am not.

To say that this research invalidates the guidelines from the U.S. Preventive Services Task Force is a stretch.

There is nothing wrong with research itself. It's the interpretation of the research that is problematic. Headlines stating that this study validates screening mammography in women under age 50 simply are not supported by the data.

Here's what is supported by the study findings:

Focusing solely on the question of how cancers were diagnosed in women between the ages of 40 to 49, the researchers reported that 48.3% of the breast cancers were found by mammograms and 46.1% by palpation (which means someone — we don't know whether it was the woman, her physician or another health professional — felt the lump). It turns out that in press reports there were comments that in this group 90% of the lumps were felt first by the women, and 10% by their doctors).

Importantly, compared with women ages 50 and older, the younger women had a greater percentage of their cancers found by palpation.

According to the abstract, there is a slightly greater percentage of lesions found at stage 1 versus stage 2 when detection was made by mammography compared with palpation. That is an interesting and statistically significant finding, but it's not surprising and it doesn't relate specifically to women under the age of 50.

Finally, all the cancer diagnoses in the study were made prior to the 2009 USPSTF guidelines. Cancer detection rates in the study therefore reflect usual care at the time of the investigation and are not a demonstration of practice and outcomes under the guideline.

I do believe in the value of screening mammography for women ages 40 to 49 years. However, this debate about screening women in their forties that has been going for several years needs to be supported by research that is specific to the question being asked.

Let's be wary of headlines that extrapolate and draw conclusions about specific issues on which the research was not designed to address in the first place.

J. LEONARD LICHTENFELD, M.D., is deputy chief medical officer for the American Cancer Society. His remarks were summarized, with permission, from his blog,

cancer.org/AboutUs/DrLensBlog

Major Finding: Overall, 65.5% and 29.8% of breast cancers were detected by mammography and palpation, respectively. Among the women younger than age 50, the corresponding values were 48.3% and 46.1%.

Data Source: A retrospective cohort study of 5,628 women given a diagnosis of stage 0 to III breast cancer between 2006 and 2009.

Disclosures: Dr. Caughran and Dr. Seidman reported that they had no relevant conflicts of interest.

SAN FRANCISCO – Many breast cancer patients would have more advanced disease at diagnosis and face harsher treatment if recently updated screening guidelines of the U.S. Preventive Services Task Force were widely adopted, suggests the investigator of a retrospective cohort study of more than 5,000 women with breast cancer in Michigan.

Study results, being reported this week at the symposium, show that nearly a third of the women's cancers were detected by palpation. The guidelines do not advocate for self-exams at all and question the usefulness of clinical breast exams after age 40.

Additionally, nearly half of the cancers in women younger than 50 years were detected by mammography, while the guidelines now recommend against this practice in the 40- to 49-year age group.

Women with palpation-detected cancers had later-stage disease and were significantly more likely to undergo mastectomy and receive chemotherapy than were those with mammography-detected cancers.

“Annual screening mammograms and evaluation of palpable breast masses are important tools in breast cancer detection,” second author Dr. Jamie Caughran said during a premeeting press briefing from the American Society of Clinical Oncology (ASCO).

She declined to say whether the study's results contradict the U.S. Preventive Services Task Force (USPSTF) guidelines, as the investigators did not have adequate information on the women's screening history.

But “we take this data to conclude that you're better off if you can … have your cancer detected by mammography — that you are more likely to have options and less likely to need aggressive treatment. So … we would support the rest of the societies that continue to recommend annual screening mammography starting at age 40,” she said.

Additionally, this study “highlights the still-significant number of women who present with a palpable mass that shouldn't be overlooked by physicians even if they have a negative mammogram,” pointed out Dr. Caughran, medical director of the Comprehensive Breast Center at the Lacks Cancer Center in Grand Rapids, Mich. “So it just continues to reinforce what we believe is inherently true.”

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York City, commented that the appropriate age for starting screening mammography remains controversial.

“A lot of the debate and focus regarding the utility of mammography have been on overall survival and breast cancer—specific survival, and I certainly think that is the most important end point,” he said, noting that the study speaks to another important end point — reduced intensity of treatment.

“As a medical oncologist or chemotherapist, I think this is a very important gain, independent of any potential survival benefit,” he said. “Having less disfiguring surgery and the ability to deliver less chemotherapy based on the stage at diagnosis are for me a step forward.”

This newest study will not quell the debate, according to Dr. Seidman. “Undoubtedly, this area will continue to remain an area of controversy for some,” he said. “But certainly, women in this age group would be well served to know about this data.”

In the study, Dr. Caughran and her colleagues analyzed data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative, identifying 5,628 women who received a diagnosis of stage 0 to III breast cancer between 2006 and 2009. Their average age was 59.4 years.

In the cohort overall, 65.5% of breast cancers were detected by mammography, 29.8% by palpation, and 4.7% by other means.

Fully 90% of the cancers detected by palpation were detected by the patient herself, although “it's unclear if the patients … were practicing regular breast self-examination or if these were incidental findings,” noted Dr. Caughran.

When analyses were restricted to women younger than 50 years of age, 48.3% of breast cancers were detected by mammography, 46.1% by palpation, and 5.6% by other means.

Palpation-detected cancers were of later stages (P less than .0001) — two-thirds were stage II or higher — and were more often treated with mastectomy (45.8% vs. 27.1%, P less than .0001) and with chemotherapy (22.7% vs. 15.7%, P less than .0001).

Nearly half of the cancers in women younger than 50 years were detected by mammography.

Source © KSASS/ISTOCKPHOTO.COM

View on The News

Study Does Not Invalidate the Guidelines

You might imagine that as an advocate of breast cancer screening for women ages 40–49 years, I would be dancing in the streets as a result of this report.

Sadly, I am not.

To say that this research invalidates the guidelines from the U.S. Preventive Services Task Force is a stretch.

There is nothing wrong with research itself. It's the interpretation of the research that is problematic. Headlines stating that this study validates screening mammography in women under age 50 simply are not supported by the data.

Here's what is supported by the study findings:

Focusing solely on the question of how cancers were diagnosed in women between the ages of 40 to 49, the researchers reported that 48.3% of the breast cancers were found by mammograms and 46.1% by palpation (which means someone — we don't know whether it was the woman, her physician or another health professional — felt the lump). It turns out that in press reports there were comments that in this group 90% of the lumps were felt first by the women, and 10% by their doctors).

Importantly, compared with women ages 50 and older, the younger women had a greater percentage of their cancers found by palpation.

According to the abstract, there is a slightly greater percentage of lesions found at stage 1 versus stage 2 when detection was made by mammography compared with palpation. That is an interesting and statistically significant finding, but it's not surprising and it doesn't relate specifically to women under the age of 50.

Finally, all the cancer diagnoses in the study were made prior to the 2009 USPSTF guidelines. Cancer detection rates in the study therefore reflect usual care at the time of the investigation and are not a demonstration of practice and outcomes under the guideline.

I do believe in the value of screening mammography for women ages 40 to 49 years. However, this debate about screening women in their forties that has been going for several years needs to be supported by research that is specific to the question being asked.

Let's be wary of headlines that extrapolate and draw conclusions about specific issues on which the research was not designed to address in the first place.

J. LEONARD LICHTENFELD, M.D., is deputy chief medical officer for the American Cancer Society. His remarks were summarized, with permission, from his blog,

cancer.org/AboutUs/DrLensBlog

Major Finding: Overall, 65.5% and 29.8% of breast cancers were detected by mammography and palpation, respectively. Among the women younger than age 50, the corresponding values were 48.3% and 46.1%.

Data Source: A retrospective cohort study of 5,628 women given a diagnosis of stage 0 to III breast cancer between 2006 and 2009.

Disclosures: Dr. Caughran and Dr. Seidman reported that they had no relevant conflicts of interest.

SAN FRANCISCO – Many breast cancer patients would have more advanced disease at diagnosis and face harsher treatment if recently updated screening guidelines of the U.S. Preventive Services Task Force were widely adopted, suggests the investigator of a retrospective cohort study of more than 5,000 women with breast cancer in Michigan.

Study results, being reported this week at the symposium, show that nearly a third of the women's cancers were detected by palpation. The guidelines do not advocate for self-exams at all and question the usefulness of clinical breast exams after age 40.

Additionally, nearly half of the cancers in women younger than 50 years were detected by mammography, while the guidelines now recommend against this practice in the 40- to 49-year age group.

Women with palpation-detected cancers had later-stage disease and were significantly more likely to undergo mastectomy and receive chemotherapy than were those with mammography-detected cancers.

“Annual screening mammograms and evaluation of palpable breast masses are important tools in breast cancer detection,” second author Dr. Jamie Caughran said during a premeeting press briefing from the American Society of Clinical Oncology (ASCO).

She declined to say whether the study's results contradict the U.S. Preventive Services Task Force (USPSTF) guidelines, as the investigators did not have adequate information on the women's screening history.

But “we take this data to conclude that you're better off if you can … have your cancer detected by mammography — that you are more likely to have options and less likely to need aggressive treatment. So … we would support the rest of the societies that continue to recommend annual screening mammography starting at age 40,” she said.

Additionally, this study “highlights the still-significant number of women who present with a palpable mass that shouldn't be overlooked by physicians even if they have a negative mammogram,” pointed out Dr. Caughran, medical director of the Comprehensive Breast Center at the Lacks Cancer Center in Grand Rapids, Mich. “So it just continues to reinforce what we believe is inherently true.”

Dr. Andrew Seidman, moderator of the press briefing and a medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York City, commented that the appropriate age for starting screening mammography remains controversial.

“A lot of the debate and focus regarding the utility of mammography have been on overall survival and breast cancer—specific survival, and I certainly think that is the most important end point,” he said, noting that the study speaks to another important end point — reduced intensity of treatment.

“As a medical oncologist or chemotherapist, I think this is a very important gain, independent of any potential survival benefit,” he said. “Having less disfiguring surgery and the ability to deliver less chemotherapy based on the stage at diagnosis are for me a step forward.”

This newest study will not quell the debate, according to Dr. Seidman. “Undoubtedly, this area will continue to remain an area of controversy for some,” he said. “But certainly, women in this age group would be well served to know about this data.”

In the study, Dr. Caughran and her colleagues analyzed data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative, identifying 5,628 women who received a diagnosis of stage 0 to III breast cancer between 2006 and 2009. Their average age was 59.4 years.

In the cohort overall, 65.5% of breast cancers were detected by mammography, 29.8% by palpation, and 4.7% by other means.

Fully 90% of the cancers detected by palpation were detected by the patient herself, although “it's unclear if the patients … were practicing regular breast self-examination or if these were incidental findings,” noted Dr. Caughran.

When analyses were restricted to women younger than 50 years of age, 48.3% of breast cancers were detected by mammography, 46.1% by palpation, and 5.6% by other means.

Palpation-detected cancers were of later stages (P less than .0001) — two-thirds were stage II or higher — and were more often treated with mastectomy (45.8% vs. 27.1%, P less than .0001) and with chemotherapy (22.7% vs. 15.7%, P less than .0001).

Nearly half of the cancers in women younger than 50 years were detected by mammography.

Source © KSASS/ISTOCKPHOTO.COM

View on The News

Study Does Not Invalidate the Guidelines

You might imagine that as an advocate of breast cancer screening for women ages 40–49 years, I would be dancing in the streets as a result of this report.

Sadly, I am not.

To say that this research invalidates the guidelines from the U.S. Preventive Services Task Force is a stretch.

There is nothing wrong with research itself. It's the interpretation of the research that is problematic. Headlines stating that this study validates screening mammography in women under age 50 simply are not supported by the data.

Here's what is supported by the study findings:

Focusing solely on the question of how cancers were diagnosed in women between the ages of 40 to 49, the researchers reported that 48.3% of the breast cancers were found by mammograms and 46.1% by palpation (which means someone — we don't know whether it was the woman, her physician or another health professional — felt the lump). It turns out that in press reports there were comments that in this group 90% of the lumps were felt first by the women, and 10% by their doctors).

Importantly, compared with women ages 50 and older, the younger women had a greater percentage of their cancers found by palpation.

According to the abstract, there is a slightly greater percentage of lesions found at stage 1 versus stage 2 when detection was made by mammography compared with palpation. That is an interesting and statistically significant finding, but it's not surprising and it doesn't relate specifically to women under the age of 50.

Finally, all the cancer diagnoses in the study were made prior to the 2009 USPSTF guidelines. Cancer detection rates in the study therefore reflect usual care at the time of the investigation and are not a demonstration of practice and outcomes under the guideline.

I do believe in the value of screening mammography for women ages 40 to 49 years. However, this debate about screening women in their forties that has been going for several years needs to be supported by research that is specific to the question being asked.

Let's be wary of headlines that extrapolate and draw conclusions about specific issues on which the research was not designed to address in the first place.

J. LEONARD LICHTENFELD, M.D., is deputy chief medical officer for the American Cancer Society. His remarks were summarized, with permission, from his blog,

cancer.org/AboutUs/DrLensBlog

CHICAGO – Escherichia coli O26 does not appear to cause severe disease in children, according to an epidemiologic study of a recent outbreak in an Oregon child care center.

In all, 60% of 10 infected children and staff were asymptomatic, and none developed illness more serious than diarrhea, investigators reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Shedding in the stool of infected children was prolonged, lasting up to 46 days, but there was no secondary transmission of the pathogen to household members.

Laboratory testing showed that the pathogen produced type 1 Shiga toxin but not type 2 Shiga toxin, which is seen in some other E. coli serotypes and carries a higher risk of hemolytic uremic syndrome.

In all, 60% of 10 infected children and staff were asymptomatic, and none developed illness more serious than diarrhea, investigators reported

"This study raised more questions than it answered," acknowledged lead investigator Dr. Mathieu Tourdjman, a Centers for Disease Control and Prevention Epidemic Intelligence Service officer with the Oregon Health Authority in Portland. But taken together, the findings generally point to a low-virulence pathogen.

This new information does not warrant any change to Oregon’s policy for child care settings when O26 is detected, according to Dr. Tourdjman. That policy requires that infected children be excluded until they have two consecutive negative stool samples, but allows the local health department to waive the exclusion at its discretion.

"In the context of an O26 Shiga toxin 1–only outbreak in a child care center, we continue to recommend that symptomatic children be excluded at least until symptoms resolve, and that the incidence of infection should be closely monitored," he said. "Routine hand washing before meals and before and after changing diapers and toileting should be emphasized."

And restriction criteria should remain flexible. "In the absence of severe disease, requiring two consecutive negative stool samples to lift the exclusion might not be justifiable," Dr. Tourdjman commented. "And routine testing of asymptomatic children should not be recommended."

Public health officials agree that children with E. coli O157 (the most common serotype) should be excluded from child care until two consecutive negative stool samples are obtained, he noted by way of background. But because of a lack of data, there is no consensus when it comes to restrictions for children with E. coli O26, the second most common serotype.

The Oregon outbreak occurred in October 2010 at a child care center having 76 attendees aged 6 weeks to 12 years, Dr. Tourdjman reported at the conference, which was sponsored by the American Society for Microbiology.

Overall, 61 people – all 13 staff, all 41 attendees in four of five preschool classrooms, and all 7 school-aged siblings of those attendees – provided stool samples for testing.

Results showed that nine of the children and one of the staff were positive for Shiga toxin–producing E. coli O26, as determined by initial polymerase chain reaction for the toxin and confirmed by subsequent stool culture for typing.

Four of the 10 positive individuals, all children, had diarrhea, which was bloody in one case. But none experienced hemolytic uremic syndrome or other serious illness. Laboratory tests showed that all isolates matched and all produced only Shiga toxin type 1.

Of the nine infected children, two had consistently negative test results after their initial positive result. Among the other seven, the median duration of shedding in stool was 25 days, with a maximum of 46 days.

Half of the households of infected children agreed to testing to assess possible secondary transmission, and 14 of 17 household members provided stool samples. None were positive by polymerase chain reaction for Shiga toxin.

In the wake of the outbreak, the child care center was thoroughly cleaned and staff were trained in hygiene practices, according to Dr. Tourdjman. The children with diarrhea were excluded from the center, and the asymptomatic positive children were cohorted (separated from other children in a single classroom).

However, the cohorting was discontinued after 3 weeks given that all factors pointed to a low-virulence pathogen and there was strict compliance with the hygiene practices. "The decision to stop cohorting was not based on the results of the shedding study," he noted. "No symptoms were reported at the center after the discontinuation of cohorting."

Dr. Tourdjman did not report any relevant financial conflicts of interests.

CHICAGO – Escherichia coli O26 does not appear to cause severe disease in children, according to an epidemiologic study of a recent outbreak in an Oregon child care center.

In all, 60% of 10 infected children and staff were asymptomatic, and none developed illness more serious than diarrhea, investigators reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Shedding in the stool of infected children was prolonged, lasting up to 46 days, but there was no secondary transmission of the pathogen to household members.

Laboratory testing showed that the pathogen produced type 1 Shiga toxin but not type 2 Shiga toxin, which is seen in some other E. coli serotypes and carries a higher risk of hemolytic uremic syndrome.

In all, 60% of 10 infected children and staff were asymptomatic, and none developed illness more serious than diarrhea, investigators reported

"This study raised more questions than it answered," acknowledged lead investigator Dr. Mathieu Tourdjman, a Centers for Disease Control and Prevention Epidemic Intelligence Service officer with the Oregon Health Authority in Portland. But taken together, the findings generally point to a low-virulence pathogen.

This new information does not warrant any change to Oregon’s policy for child care settings when O26 is detected, according to Dr. Tourdjman. That policy requires that infected children be excluded until they have two consecutive negative stool samples, but allows the local health department to waive the exclusion at its discretion.

"In the context of an O26 Shiga toxin 1–only outbreak in a child care center, we continue to recommend that symptomatic children be excluded at least until symptoms resolve, and that the incidence of infection should be closely monitored," he said. "Routine hand washing before meals and before and after changing diapers and toileting should be emphasized."

And restriction criteria should remain flexible. "In the absence of severe disease, requiring two consecutive negative stool samples to lift the exclusion might not be justifiable," Dr. Tourdjman commented. "And routine testing of asymptomatic children should not be recommended."

Public health officials agree that children with E. coli O157 (the most common serotype) should be excluded from child care until two consecutive negative stool samples are obtained, he noted by way of background. But because of a lack of data, there is no consensus when it comes to restrictions for children with E. coli O26, the second most common serotype.

The Oregon outbreak occurred in October 2010 at a child care center having 76 attendees aged 6 weeks to 12 years, Dr. Tourdjman reported at the conference, which was sponsored by the American Society for Microbiology.

Overall, 61 people – all 13 staff, all 41 attendees in four of five preschool classrooms, and all 7 school-aged siblings of those attendees – provided stool samples for testing.

Results showed that nine of the children and one of the staff were positive for Shiga toxin–producing E. coli O26, as determined by initial polymerase chain reaction for the toxin and confirmed by subsequent stool culture for typing.

Four of the 10 positive individuals, all children, had diarrhea, which was bloody in one case. But none experienced hemolytic uremic syndrome or other serious illness. Laboratory tests showed that all isolates matched and all produced only Shiga toxin type 1.

Of the nine infected children, two had consistently negative test results after their initial positive result. Among the other seven, the median duration of shedding in stool was 25 days, with a maximum of 46 days.

Half of the households of infected children agreed to testing to assess possible secondary transmission, and 14 of 17 household members provided stool samples. None were positive by polymerase chain reaction for Shiga toxin.

In the wake of the outbreak, the child care center was thoroughly cleaned and staff were trained in hygiene practices, according to Dr. Tourdjman. The children with diarrhea were excluded from the center, and the asymptomatic positive children were cohorted (separated from other children in a single classroom).

However, the cohorting was discontinued after 3 weeks given that all factors pointed to a low-virulence pathogen and there was strict compliance with the hygiene practices. "The decision to stop cohorting was not based on the results of the shedding study," he noted. "No symptoms were reported at the center after the discontinuation of cohorting."

Dr. Tourdjman did not report any relevant financial conflicts of interests.

CHICAGO – Escherichia coli O26 does not appear to cause severe disease in children, according to an epidemiologic study of a recent outbreak in an Oregon child care center.

In all, 60% of 10 infected children and staff were asymptomatic, and none developed illness more serious than diarrhea, investigators reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Shedding in the stool of infected children was prolonged, lasting up to 46 days, but there was no secondary transmission of the pathogen to household members.

Laboratory testing showed that the pathogen produced type 1 Shiga toxin but not type 2 Shiga toxin, which is seen in some other E. coli serotypes and carries a higher risk of hemolytic uremic syndrome.

In all, 60% of 10 infected children and staff were asymptomatic, and none developed illness more serious than diarrhea, investigators reported

"This study raised more questions than it answered," acknowledged lead investigator Dr. Mathieu Tourdjman, a Centers for Disease Control and Prevention Epidemic Intelligence Service officer with the Oregon Health Authority in Portland. But taken together, the findings generally point to a low-virulence pathogen.

This new information does not warrant any change to Oregon’s policy for child care settings when O26 is detected, according to Dr. Tourdjman. That policy requires that infected children be excluded until they have two consecutive negative stool samples, but allows the local health department to waive the exclusion at its discretion.

"In the context of an O26 Shiga toxin 1–only outbreak in a child care center, we continue to recommend that symptomatic children be excluded at least until symptoms resolve, and that the incidence of infection should be closely monitored," he said. "Routine hand washing before meals and before and after changing diapers and toileting should be emphasized."

And restriction criteria should remain flexible. "In the absence of severe disease, requiring two consecutive negative stool samples to lift the exclusion might not be justifiable," Dr. Tourdjman commented. "And routine testing of asymptomatic children should not be recommended."

Public health officials agree that children with E. coli O157 (the most common serotype) should be excluded from child care until two consecutive negative stool samples are obtained, he noted by way of background. But because of a lack of data, there is no consensus when it comes to restrictions for children with E. coli O26, the second most common serotype.

The Oregon outbreak occurred in October 2010 at a child care center having 76 attendees aged 6 weeks to 12 years, Dr. Tourdjman reported at the conference, which was sponsored by the American Society for Microbiology.

Overall, 61 people – all 13 staff, all 41 attendees in four of five preschool classrooms, and all 7 school-aged siblings of those attendees – provided stool samples for testing.

Results showed that nine of the children and one of the staff were positive for Shiga toxin–producing E. coli O26, as determined by initial polymerase chain reaction for the toxin and confirmed by subsequent stool culture for typing.

Four of the 10 positive individuals, all children, had diarrhea, which was bloody in one case. But none experienced hemolytic uremic syndrome or other serious illness. Laboratory tests showed that all isolates matched and all produced only Shiga toxin type 1.

Of the nine infected children, two had consistently negative test results after their initial positive result. Among the other seven, the median duration of shedding in stool was 25 days, with a maximum of 46 days.

Half of the households of infected children agreed to testing to assess possible secondary transmission, and 14 of 17 household members provided stool samples. None were positive by polymerase chain reaction for Shiga toxin.

In the wake of the outbreak, the child care center was thoroughly cleaned and staff were trained in hygiene practices, according to Dr. Tourdjman. The children with diarrhea were excluded from the center, and the asymptomatic positive children were cohorted (separated from other children in a single classroom).

However, the cohorting was discontinued after 3 weeks given that all factors pointed to a low-virulence pathogen and there was strict compliance with the hygiene practices. "The decision to stop cohorting was not based on the results of the shedding study," he noted. "No symptoms were reported at the center after the discontinuation of cohorting."

Dr. Tourdjman did not report any relevant financial conflicts of interests.

Car crashes are the leading cause of death among teens, accounting for one-third of deaths in this age group in the United States.

The good news is that the rate of motor vehicle deaths among adolescents has been on the decline over the past decade in most U.S. states. The success of efforts by state and local governments in bringing down traffic deaths, especially among teens, is rated among the top 10 public health achievements of the past decade, according to the Centers for Disease Control and Prevention (MMWR, 2011;60:619-23).

Photo (c) Rich Legg/iStock.com

The CDC analyzed data from the Fatality Analysis Report System to assess crash death risk among teens. The rate for drivers aged 16 or 17 years involved in a fatal car accident declined approximately 38%, from 27.1 per 100,000 population in 2004 to 16.7 in 2008 (MMWR 2010;59:1329-34). The decline as been attributed to a variety of factors including increased use of seat belts and decreased rates of drunk driving among teens, but also changing driver behavior brought about by training and other public health interventions.

Several innovative approaches hold promise for making teens safer drivers, according to Dr. Beth Ebel, director of the Harborview Injury Prevention & Research Center and a physician at Seattle Children’s Hospital, Seattle.

"We know that learning to drive is risky," she commented. Despite the decline in fatal crashes among teens, "this still remains such a high risk for kids that we really need to consider how we can do better."

Research is helping to sort out what works – and what doesn’t – for reducing teen drivers’ risk to themselves and others. For example, "policy and frameworks that work for adults work for kids, and more so with seat belt and alcohol and texting laws," said Dr. Ebel.

Driver education has been found ineffective, Dr. Ebel said. In fact, a 1999 study associated such education with an increased risk of motor vehicle crashes (Am. J. Prev. Med. 1999;16:40-6).

"This isn’t because driver’s ed is teaching you to drive in a risky way," she explained. "Driver’s ed gives you early exposure to a vehicle before your frontal lobe and everything else has fully matured. So it basically gets you in the vehicle at a younger age."

On the other hand, graduated driver licensing (GDL), in which teens’ driving privileges are slowly expanded, has been a success. This legislation has three components – a restriction on passengers in the vehicle, a restriction on nighttime driving, and a zero-tolerance policy for the combination of alcohol and driving – the specifics of which vary by state.

Implementation of GDL has been associated with a 25% reduction in numbers of crashes (JAMA 2001;286:1593-8), "so we should do this," Dr. Ebel recommended. "It gives parents some guidance on what to advise their kids. GDL’s effect isn’t that it really makes you a safer driver; it tends to reduce driving exposure."

It is difficult to enforce because law enforcement officers can’t reliably identify teen drivers by appearance. "So GDL is working primarily through parents and kids knowing what the law is and being willing to implement that," she said. "And that’s of course not always going to work for some of the kids at highest risk."

Parent-teen driving contracts, such as one used in the Checkpoints Program, an education-based intervention, also have shown promise. It’s a chance to sit down with your kids, like in other areas ... and discuss what your expectations are when they are in the vehicle, Dr. Ebel commented at the annual meeting of the Society for Adolescent Health and Medicine in Seattle.

Parents participating in the program put more limits on their teens’ driving privileges, although risky driving and rates of violations and crashes are not reduced (J. Safety Res. 2006;37:9-15). "But I think having that discussion is probably a good starting point," she said.

Additional help in improving the safety of teen drivers may come from several novel technologies. One is event-triggered video, in which a camera installed on the rearview mirror captures data both inside and outside the car if, for example, the driver slams on the brakes or swerves. It is available free through some auto insurance companies.

"[Driving] still remains such a high risk for kids that we really need to consider how we can do better."

"Effectively, the trigger camera is there to basically extend this parent-in-the-vehicle concept when the parent is no longer in the vehicle," Dr. Ebel explained. The data are transmitted to a central server, collated, and e-mailed back to parents and their teens so that they can be used as an educational tool.

Research that she and her colleagues have done has found event-triggered video to be acceptable to teens, eventually. "Kids of course hated it at first, but at the end they saw a lot of value and they learned a lot about how to reduce their [event] scores," she said. And a study looking at quantitative impact has found a 61% reduction in the so-called coachable events when this technology is used (Am. J. Public Health 2010;100:1101-6).

"This is worth thinking about," Dr. Ebel asserted. "But it definitely has implications for privacy, and I think basically from a broader information perspective, who is going to take this up."

A second new technology, an electronics-disabling device, ironically uses cell phone technology to reduce the distraction of mobile devices in the car. This is important given that evidence shows, for example, that texting drivers are 23 times more likely to have a crash or near-crash than are their nondistracted counterparts (Virginia Tech Transportation Institute, July 2009).

"These are basically devices that stop your cell phone and text message service while you are in the car," she explained. "They can tell that you are moving, so it activates at 10 mph. They can send a message to your buddies, so you don’t feel like they are just hanging there."

Additional features include the ability to generate reports about driving parameters such as speed, according to Dr. Ebel. And drivers can still make emergency calls and use navigation systems.

A third technology, being introduced by auto manufacturers, is making it possible to tailor the vehicle environment depending on who’s driving, for example, through development of cars that recognize different keys used by parents and their teens.

The car key that you hand your kid could limit the vehicle speed and the audio volume, as well, she explained, thereby favoring safer driving conditions.

Dr. Ebel said that she had no relevant financial disclosures.

Therese Borden contributed to this article.

Car crashes are the leading cause of death among teens, accounting for one-third of deaths in this age group in the United States.

The good news is that the rate of motor vehicle deaths among adolescents has been on the decline over the past decade in most U.S. states. The success of efforts by state and local governments in bringing down traffic deaths, especially among teens, is rated among the top 10 public health achievements of the past decade, according to the Centers for Disease Control and Prevention (MMWR, 2011;60:619-23).

Photo (c) Rich Legg/iStock.com

The CDC analyzed data from the Fatality Analysis Report System to assess crash death risk among teens. The rate for drivers aged 16 or 17 years involved in a fatal car accident declined approximately 38%, from 27.1 per 100,000 population in 2004 to 16.7 in 2008 (MMWR 2010;59:1329-34). The decline as been attributed to a variety of factors including increased use of seat belts and decreased rates of drunk driving among teens, but also changing driver behavior brought about by training and other public health interventions.

Several innovative approaches hold promise for making teens safer drivers, according to Dr. Beth Ebel, director of the Harborview Injury Prevention & Research Center and a physician at Seattle Children’s Hospital, Seattle.

"We know that learning to drive is risky," she commented. Despite the decline in fatal crashes among teens, "this still remains such a high risk for kids that we really need to consider how we can do better."

Research is helping to sort out what works – and what doesn’t – for reducing teen drivers’ risk to themselves and others. For example, "policy and frameworks that work for adults work for kids, and more so with seat belt and alcohol and texting laws," said Dr. Ebel.

Driver education has been found ineffective, Dr. Ebel said. In fact, a 1999 study associated such education with an increased risk of motor vehicle crashes (Am. J. Prev. Med. 1999;16:40-6).

"This isn’t because driver’s ed is teaching you to drive in a risky way," she explained. "Driver’s ed gives you early exposure to a vehicle before your frontal lobe and everything else has fully matured. So it basically gets you in the vehicle at a younger age."

On the other hand, graduated driver licensing (GDL), in which teens’ driving privileges are slowly expanded, has been a success. This legislation has three components – a restriction on passengers in the vehicle, a restriction on nighttime driving, and a zero-tolerance policy for the combination of alcohol and driving – the specifics of which vary by state.

Implementation of GDL has been associated with a 25% reduction in numbers of crashes (JAMA 2001;286:1593-8), "so we should do this," Dr. Ebel recommended. "It gives parents some guidance on what to advise their kids. GDL’s effect isn’t that it really makes you a safer driver; it tends to reduce driving exposure."

It is difficult to enforce because law enforcement officers can’t reliably identify teen drivers by appearance. "So GDL is working primarily through parents and kids knowing what the law is and being willing to implement that," she said. "And that’s of course not always going to work for some of the kids at highest risk."

Parent-teen driving contracts, such as one used in the Checkpoints Program, an education-based intervention, also have shown promise. It’s a chance to sit down with your kids, like in other areas ... and discuss what your expectations are when they are in the vehicle, Dr. Ebel commented at the annual meeting of the Society for Adolescent Health and Medicine in Seattle.

Parents participating in the program put more limits on their teens’ driving privileges, although risky driving and rates of violations and crashes are not reduced (J. Safety Res. 2006;37:9-15). "But I think having that discussion is probably a good starting point," she said.

Additional help in improving the safety of teen drivers may come from several novel technologies. One is event-triggered video, in which a camera installed on the rearview mirror captures data both inside and outside the car if, for example, the driver slams on the brakes or swerves. It is available free through some auto insurance companies.

"[Driving] still remains such a high risk for kids that we really need to consider how we can do better."

"Effectively, the trigger camera is there to basically extend this parent-in-the-vehicle concept when the parent is no longer in the vehicle," Dr. Ebel explained. The data are transmitted to a central server, collated, and e-mailed back to parents and their teens so that they can be used as an educational tool.

Research that she and her colleagues have done has found event-triggered video to be acceptable to teens, eventually. "Kids of course hated it at first, but at the end they saw a lot of value and they learned a lot about how to reduce their [event] scores," she said. And a study looking at quantitative impact has found a 61% reduction in the so-called coachable events when this technology is used (Am. J. Public Health 2010;100:1101-6).

"This is worth thinking about," Dr. Ebel asserted. "But it definitely has implications for privacy, and I think basically from a broader information perspective, who is going to take this up."

A second new technology, an electronics-disabling device, ironically uses cell phone technology to reduce the distraction of mobile devices in the car. This is important given that evidence shows, for example, that texting drivers are 23 times more likely to have a crash or near-crash than are their nondistracted counterparts (Virginia Tech Transportation Institute, July 2009).

"These are basically devices that stop your cell phone and text message service while you are in the car," she explained. "They can tell that you are moving, so it activates at 10 mph. They can send a message to your buddies, so you don’t feel like they are just hanging there."

Additional features include the ability to generate reports about driving parameters such as speed, according to Dr. Ebel. And drivers can still make emergency calls and use navigation systems.

A third technology, being introduced by auto manufacturers, is making it possible to tailor the vehicle environment depending on who’s driving, for example, through development of cars that recognize different keys used by parents and their teens.

The car key that you hand your kid could limit the vehicle speed and the audio volume, as well, she explained, thereby favoring safer driving conditions.

Dr. Ebel said that she had no relevant financial disclosures.

Therese Borden contributed to this article.

Car crashes are the leading cause of death among teens, accounting for one-third of deaths in this age group in the United States.

The good news is that the rate of motor vehicle deaths among adolescents has been on the decline over the past decade in most U.S. states. The success of efforts by state and local governments in bringing down traffic deaths, especially among teens, is rated among the top 10 public health achievements of the past decade, according to the Centers for Disease Control and Prevention (MMWR, 2011;60:619-23).

Photo (c) Rich Legg/iStock.com

The CDC analyzed data from the Fatality Analysis Report System to assess crash death risk among teens. The rate for drivers aged 16 or 17 years involved in a fatal car accident declined approximately 38%, from 27.1 per 100,000 population in 2004 to 16.7 in 2008 (MMWR 2010;59:1329-34). The decline as been attributed to a variety of factors including increased use of seat belts and decreased rates of drunk driving among teens, but also changing driver behavior brought about by training and other public health interventions.

Several innovative approaches hold promise for making teens safer drivers, according to Dr. Beth Ebel, director of the Harborview Injury Prevention & Research Center and a physician at Seattle Children’s Hospital, Seattle.

"We know that learning to drive is risky," she commented. Despite the decline in fatal crashes among teens, "this still remains such a high risk for kids that we really need to consider how we can do better."

Research is helping to sort out what works – and what doesn’t – for reducing teen drivers’ risk to themselves and others. For example, "policy and frameworks that work for adults work for kids, and more so with seat belt and alcohol and texting laws," said Dr. Ebel.

Driver education has been found ineffective, Dr. Ebel said. In fact, a 1999 study associated such education with an increased risk of motor vehicle crashes (Am. J. Prev. Med. 1999;16:40-6).

"This isn’t because driver’s ed is teaching you to drive in a risky way," she explained. "Driver’s ed gives you early exposure to a vehicle before your frontal lobe and everything else has fully matured. So it basically gets you in the vehicle at a younger age."

On the other hand, graduated driver licensing (GDL), in which teens’ driving privileges are slowly expanded, has been a success. This legislation has three components – a restriction on passengers in the vehicle, a restriction on nighttime driving, and a zero-tolerance policy for the combination of alcohol and driving – the specifics of which vary by state.

Implementation of GDL has been associated with a 25% reduction in numbers of crashes (JAMA 2001;286:1593-8), "so we should do this," Dr. Ebel recommended. "It gives parents some guidance on what to advise their kids. GDL’s effect isn’t that it really makes you a safer driver; it tends to reduce driving exposure."

It is difficult to enforce because law enforcement officers can’t reliably identify teen drivers by appearance. "So GDL is working primarily through parents and kids knowing what the law is and being willing to implement that," she said. "And that’s of course not always going to work for some of the kids at highest risk."

Parent-teen driving contracts, such as one used in the Checkpoints Program, an education-based intervention, also have shown promise. It’s a chance to sit down with your kids, like in other areas ... and discuss what your expectations are when they are in the vehicle, Dr. Ebel commented at the annual meeting of the Society for Adolescent Health and Medicine in Seattle.

Parents participating in the program put more limits on their teens’ driving privileges, although risky driving and rates of violations and crashes are not reduced (J. Safety Res. 2006;37:9-15). "But I think having that discussion is probably a good starting point," she said.

Additional help in improving the safety of teen drivers may come from several novel technologies. One is event-triggered video, in which a camera installed on the rearview mirror captures data both inside and outside the car if, for example, the driver slams on the brakes or swerves. It is available free through some auto insurance companies.

"[Driving] still remains such a high risk for kids that we really need to consider how we can do better."

"Effectively, the trigger camera is there to basically extend this parent-in-the-vehicle concept when the parent is no longer in the vehicle," Dr. Ebel explained. The data are transmitted to a central server, collated, and e-mailed back to parents and their teens so that they can be used as an educational tool.

Research that she and her colleagues have done has found event-triggered video to be acceptable to teens, eventually. "Kids of course hated it at first, but at the end they saw a lot of value and they learned a lot about how to reduce their [event] scores," she said. And a study looking at quantitative impact has found a 61% reduction in the so-called coachable events when this technology is used (Am. J. Public Health 2010;100:1101-6).

"This is worth thinking about," Dr. Ebel asserted. "But it definitely has implications for privacy, and I think basically from a broader information perspective, who is going to take this up."

A second new technology, an electronics-disabling device, ironically uses cell phone technology to reduce the distraction of mobile devices in the car. This is important given that evidence shows, for example, that texting drivers are 23 times more likely to have a crash or near-crash than are their nondistracted counterparts (Virginia Tech Transportation Institute, July 2009).

"These are basically devices that stop your cell phone and text message service while you are in the car," she explained. "They can tell that you are moving, so it activates at 10 mph. They can send a message to your buddies, so you don’t feel like they are just hanging there."

Additional features include the ability to generate reports about driving parameters such as speed, according to Dr. Ebel. And drivers can still make emergency calls and use navigation systems.

A third technology, being introduced by auto manufacturers, is making it possible to tailor the vehicle environment depending on who’s driving, for example, through development of cars that recognize different keys used by parents and their teens.

The car key that you hand your kid could limit the vehicle speed and the audio volume, as well, she explained, thereby favoring safer driving conditions.

Dr. Ebel said that she had no relevant financial disclosures.

Therese Borden contributed to this article.

SAN FRANCISCO – Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987-2005.

Results showed that with a median follow-up of 7-8 years, the rate of freedom from locoregional recurrence was high (90% or greater at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

"For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy," Dr. Mittendorf, a surgical oncologist, commented, adding, "It is important to obtain a negative margin at the time of surgery."

"It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy," she said.

However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of "oversimplification of [a] complex issue ... especially in the era of personalized therapy."

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

"The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important," commented Dr. Fowble. "Initial stage, molecular subtype, and response to therapy will impact on outcome."

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor–negative disease, and to have multifocal disease. Median durations of follow-up were 7.2 and 7.9 years.

In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%) (P less than .001).

"Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy," Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P less than .001). For example, the 10-year rate was 90% with the former and 94% with the latter.

"Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors," she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence.

Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (hazard ratio, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor–negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor–positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence–free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

SAN FRANCISCO – Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987-2005.

Results showed that with a median follow-up of 7-8 years, the rate of freedom from locoregional recurrence was high (90% or greater at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

"For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy," Dr. Mittendorf, a surgical oncologist, commented, adding, "It is important to obtain a negative margin at the time of surgery."

"It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy," she said.

However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of "oversimplification of [a] complex issue ... especially in the era of personalized therapy."

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

"The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important," commented Dr. Fowble. "Initial stage, molecular subtype, and response to therapy will impact on outcome."

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor–negative disease, and to have multifocal disease. Median durations of follow-up were 7.2 and 7.9 years.

In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%) (P less than .001).

"Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy," Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P less than .001). For example, the 10-year rate was 90% with the former and 94% with the latter.

"Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors," she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence.

Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (hazard ratio, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor–negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor–positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence–free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

SAN FRANCISCO – Women with early breast cancer who are treated with breast-conserving therapy have similar rates of freedom from locoregional recurrence whether chemotherapy is given before or after surgery, based on the experience of the University of Texas M.D. Anderson Cancer Center in Houston.

Investigators led by Dr. Elizabeth A. Mittendorf compared outcomes with these two approaches among nearly 3,000 women who had a segmental mastectomy plus whole-breast irradiation at the center in 1987-2005.

Results showed that with a median follow-up of 7-8 years, the rate of freedom from locoregional recurrence was high (90% or greater at 10 years) and did not differ significantly between the neoadjuvant and adjuvant chemotherapy groups after multiple potential confounders were taken into account.

"For appropriately selected patients, we can achieve high rates of locoregional control with breast-conserving therapy," Dr. Mittendorf, a surgical oncologist, commented, adding, "It is important to obtain a negative margin at the time of surgery."

"It appears that locoregional recurrence after breast-conserving therapy is driven primarily by [biological] factors and not by the timing of chemotherapy," she said.

However, discussant Dr. Barbara Fowble, a professor of clinical radiation oncology at the University of California San Francisco, said that the study was an example of "oversimplification of [a] complex issue ... especially in the era of personalized therapy."

She noted that factors such as breast cancer subtype (luminal A, luminal B, HER2 positive, or basal) can influence locoregional control after neoadjuvant chemotherapy with breast-conserving therapy.

"The identification of patients receiving neoadjuvant chemotherapy for whom mastectomy with or without radiation may result in a decreased risk of locoregional failure [when compared with breast-conserving therapy] is very important," commented Dr. Fowble. "Initial stage, molecular subtype, and response to therapy will impact on outcome."

Of the 2,984 women studied, 22% received neoadjuvant chemotherapy and 78% received adjuvant chemotherapy. Those in the former group were significantly more likely to have higher clinical stage and tumor grade, to have estrogen receptor–negative disease, and to have multifocal disease. Median durations of follow-up were 7.2 and 7.9 years.

In the neoadjuvant group, one-fifth of women had a pathological complete response, and there was a significant difference between the proportion having clinical stage II or III disease (93%) and the proportion having pathological stage II or III disease (46%) (P less than .001).

"Neoadjuvant chemotherapy downstages a significant number of patients with clinical stage II or III disease, presumably facilitating breast-conserving therapy," Dr. Mittendorf said.

In an unadjusted analysis, the rate of freedom from locoregional recurrence was lower with neoadjuvant chemotherapy than with adjuvant chemotherapy (P less than .001). For example, the 10-year rate was 90% with the former and 94% with the latter.

"Although the difference is statistically significant, I would suggest that these are excellent rates of locoregional control in our neoadjuvant chemotherapy patients, particularly considering that they presented with higher-stage disease, higher grade, and [more] ER-negative tumors," she maintained.

In a multivariate analysis that took into account clinical and disease factors, the timing of chemotherapy was no longer significantly associated with the risk of locoregional recurrence.

Eight factors conferred an elevated risk of such recurrence in this analysis: age younger than 50 years (hazard ratio, 1.9), clinical stage III disease (HR, 2.5), a grade 3 tumor (HR, 1.9), estrogen receptor–negative disease (HR, 2.4), multifocal disease (HR, 1.9), lymphovascular invasion (HR, 1.5), close or positive margins (HR, 2.5), and failure to receive hormone therapy in the context of estrogen receptor–positive disease (HR, 2.8).

When women were stratified according to the number of factors they had, there was still no significant difference in the rate of locoregional, recurrence–free survival between neoadjuvant and adjuvant chemotherapy, noted Dr. Mittendorf.

Dr. Mittendorf and Dr. Fowble reported no relevant conflicts of interest.

SAN FRANCISCO – A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor–positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor–positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole (Femara) or placebo.

Study results, reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled.

The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor–positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

"If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component," he explained.

"If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy," he continued. "For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials."

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase–polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

"We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually," he noted. "In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence."

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = .014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = .019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported. In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = .037).

"Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = .02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I," he said. "These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy."

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

SAN FRANCISCO – A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor–positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor–positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole (Femara) or placebo.

Study results, reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled.

The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor–positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

"If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component," he explained.

"If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy," he continued. "For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials."

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase–polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

"We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually," he noted. "In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence."

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = .014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = .019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported. In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = .037).

"Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = .02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I," he said. "These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy."

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

SAN FRANCISCO – A new gene-based biomarker assay may help to estimate prognosis and make decisions about extended endocrine therapy in women with estrogen receptor–positive early breast cancer, new data suggest.

Researchers tested the biomarker, the Breast Cancer Index (BCI), among 249 women with estrogen receptor–positive early breast cancer from the MA.17 trial, in which women received 5 years of adjuvant tamoxifen therapy and, if still disease free, were then randomized to an additional 5 years of either letrozole (Femara) or placebo.

Study results, reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology, showed that with each 5-unit increase in the 10-unit BCI score, women’s odds of late recurrence nearly tripled.

The index as a whole was not helpful in predicting the benefit of added letrozole therapy in reducing recurrence risk. But one of its components, called H/I, was helpful: Women having a high H/I were about half as likely to have a recurrence if they received letrozole instead of placebo.

In the future, these findings might be used to develop a management algorithm for women with estrogen receptor–positive breast cancer, according to lead investigator Dr. Dennis C. Sgroi, director of breast pathology at the Massachusetts General Hospital in Boston.

"If patients are disease free after 5 years of adjuvant endocrine therapy, we might be able to then test them with the BCI. If this assay identifies these patients to be at low risk, there will be no further therapy for these patients. However, if they are at high risk by BCI, we can then explore the H/I component," he explained.

"If they have high H/I, that indicates that these patients are likely to benefit from extended adjuvant therapy," he continued. "For patients who have low H/I, one might consider using extended adjuvant therapy, or these patients might be considered as a future focus for research in clinical trials."

The investigators identified 83 women from the MA.17 trial who had had a recurrence and had primary tumor tissue available. They then matched the women by age, N stage, T stage, and prior receipt of chemotherapy in a 1:2 ratio with 166 women who had not had a recurrence and had primary tumor tissue available. Tissue was analyzed by reverse transcriptase–polymerase chain reaction to determine the BCI.

The BCI has two components, Dr. Sgroi explained. The HOXB13/IL17BR (H/I) component is based on expression of two genes regulated by estradiol. The molecular grade index (MGI) component is based on five genes related to pathological grade.

"We have shown in the past that these two biomarkers are complementary, as the combination of the two biomarkers outperforms each individually," he noted. "In addition, we have shown that the combination biomarker outperforms standard clinicopathological parameters currently used to predict disease recurrence."

In a multivariate analysis, with each 5-unit increase in the BCI score, women’s odds of recurrence increased 2.91-fold (P = .014). The findings were similar when categories were used: Women with high or intermediate scores had 2.21-fold higher odds of recurrence than did their counterparts with low scores (P = .019).

The BCI as a whole did not predict the benefit of extended therapy with letrozole, but the H/I component did, Dr. Sgroi reported. In a multivariate analysis, women who had a high H/I had a 58% reduction in the odds of recurrence if they received letrozole instead of placebo (P = .037).

"Most notably, there was a statistically significant interaction between the H/I biomarker and treatment (P = .02), indicating that the magnitude of letrozole benefit depends on the expression level of H/I," he said. "These results suggest that patients with tumors expressing high H/I will benefit from extended endocrine therapy."

Dr. Sgroi reported receiving research funding from bioTheranostics Inc. The study was supported in part by Novartis, the manufacturer of letrozole.

SAN FRANCISCO – The development of taxane-induced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data show.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial involving 4,554 women, 13%-22% developed peripheral neuropathy, depending on which of four taxane regimens they received.

The women who developed peripheral neuropathy did not have better recurrence-free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups. Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received.

He noted that the findings are important, given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

"Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome," he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that "at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points."

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted.

"The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients," concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel (Taxol) every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel (Taxotere) every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grade 2-4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio, 1.47), and were marginally more likely if they were black, obese, or postmenopausal.

Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel vs. paclitaxel every 3 week (HR, 1.52), paclitaxel every 3 weeks vs. weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks vs. docetaxel every 3 weeks (HR, 1.91).

In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence-free, disease-free, or overall survival.

The findings contrast with those of an earlier study in which women receiving paclitaxel-containing chemotherapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

"Every-3-week docetaxel and weekly paclitaxel are viable therapeutic options for breast cancer," commented Dr. Schneider. The former is associated with more grade 3/4 toxicity in general, whereas the latter is associated with more peripheral neuropathy.

"Our goal is to study SNPs that have previously been shown to predict neuropathy in E1199," he concluded. "We hope to validate those top SNPs and ultimately identify which therapy has the optimal risk-benefit ratio for a given subgroup based on genotype."

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

SAN FRANCISCO – The development of taxane-induced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data show.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial involving 4,554 women, 13%-22% developed peripheral neuropathy, depending on which of four taxane regimens they received.

The women who developed peripheral neuropathy did not have better recurrence-free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups. Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received.

He noted that the findings are important, given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

"Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome," he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that "at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points."

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted.

"The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients," concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel (Taxol) every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel (Taxotere) every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grade 2-4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio, 1.47), and were marginally more likely if they were black, obese, or postmenopausal.

Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel vs. paclitaxel every 3 week (HR, 1.52), paclitaxel every 3 weeks vs. weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks vs. docetaxel every 3 weeks (HR, 1.91).

In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence-free, disease-free, or overall survival.

The findings contrast with those of an earlier study in which women receiving paclitaxel-containing chemotherapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

"Every-3-week docetaxel and weekly paclitaxel are viable therapeutic options for breast cancer," commented Dr. Schneider. The former is associated with more grade 3/4 toxicity in general, whereas the latter is associated with more peripheral neuropathy.

"Our goal is to study SNPs that have previously been shown to predict neuropathy in E1199," he concluded. "We hope to validate those top SNPs and ultimately identify which therapy has the optimal risk-benefit ratio for a given subgroup based on genotype."

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.

SAN FRANCISCO – The development of taxane-induced peripheral neuropathy does not appear to be a marker for better outcomes in women with early breast cancer, new data show.

In a secondary analysis of the Eastern Cooperative Oncology Group E1199 trial involving 4,554 women, 13%-22% developed peripheral neuropathy, depending on which of four taxane regimens they received.

The women who developed peripheral neuropathy did not have better recurrence-free, disease-free, or overall survival than did their counterparts who escaped this toxicity, lead investigator Dr. Bryan P. Schneider reported on behalf of several North American breast cancer groups. Results were the same regardless of tumor type (estrogen receptor positive, HER2 positive, or triple negative) and the taxane regimen received.

He noted that the findings are important, given recent identification of six single-nucleotide polymorphisms (SNPs) predicting the likelihood of peripheral neuropathy in women receiving paclitaxel-containing chemotherapy (ASCO 2011, abstract 1000).

"Neuropathy did not correlate with outcome in E1199. The relevance is that SNPs or biomarkers that predict a subgroup protected from neuropathy are thus unlikely to enrich for inferior outcome," he explained.

Discussant Dr. William J. Gradishar, director of the center for women’s cancer care at Northwestern University in Chicago, said that "at the end of the day, at least with the present data we have, it doesn’t appear that the presence of neuropathy has any bearing on overall clinical outcome from those end points."

Trials thus far have failed to identify effective agents for preventing peripheral neuropathy in this setting, but there are some new agents on the horizon, he noted.

"The hope will be, because these [chemotherapy drugs] are such a mainstay of our therapies in both the adjuvant and metastatic disease setting, that one or a few of [the new agents] may ultimately prove to be fruitful for our patients," concluded Dr. Gradishar.

Women participating in the E1199 trial all received four cycles of doxorubicin and cyclophosphamide. They then received one of four taxane regimens: paclitaxel (Taxol) every 3 weeks for 4 cycles (control), paclitaxel weekly for 12 cycles, docetaxel (Taxotere) every 3 weeks for 4 cycles, or docetaxel weekly for 12 cycles. Median follow-up was 95.5 months.

Peripheral neuropathy (grade 2-4, either sensory or motor) was the most common nonhematologic toxicity seen in the trial, according to Dr. Schneider of Indiana University in Indianapolis. It occurred in 22.0% of women treated with weekly paclitaxel, in 17.5% of women treated with paclitaxel every 3 weeks, in 14.7% of women treated with docetaxel every 3 weeks, and in 13.4% of women treated with weekly docetaxel.

In a multivariate model, women were significantly more likely to develop peripheral neuropathy if they had treatment-associated hyperglycemia (hazard ratio, 1.47), and were marginally more likely if they were black, obese, or postmenopausal.

Risk also varied by taxane regimen. It was higher for women who received weekly paclitaxel vs. paclitaxel every 3 week (HR, 1.52), paclitaxel every 3 weeks vs. weekly docetaxel (HR, 3.00), or paclitaxel every 3 weeks vs. docetaxel every 3 weeks (HR, 1.91).

In several types of analyses including multivariate models, the development of peripheral neuropathy was not significantly associated with recurrence-free, disease-free, or overall survival.

The findings contrast with those of an earlier study in which women receiving paclitaxel-containing chemotherapy without trastuzumab did have better outcomes if they developed peripheral neuropathy (SABCS 2009, abstract A-2100).

"Every-3-week docetaxel and weekly paclitaxel are viable therapeutic options for breast cancer," commented Dr. Schneider. The former is associated with more grade 3/4 toxicity in general, whereas the latter is associated with more peripheral neuropathy.

"Our goal is to study SNPs that have previously been shown to predict neuropathy in E1199," he concluded. "We hope to validate those top SNPs and ultimately identify which therapy has the optimal risk-benefit ratio for a given subgroup based on genotype."

Dr. Schneider reported that he had no relevant conflicts of interest. Dr. Gradishar had relationships with several companies that make taxanes.