Susan London

CHICAGO – Homologous recombination (HR) deficiency is a biomarker for benefit from neoadjuvant chemotherapy in women with triple-negative breast cancer (TNBC), suggest data from the GeparSixto trial presented at the annual meeting of the American Society of Clinical Oncology.

Roughly two-thirds of women were found to have HR-deficient tumors, impairing their ability to repair DNA and thereby rendering them susceptible to DNA-damaging agents. These women had more than double the odds of a pathologic complete response (pCR).

“HR deficiency in triple-negative breast cancer appears to be an independent predictor of high pCR rates to the chemotherapies that were given in this study,” summarized Dr. Gunter von Minckwitz on behalf of the German Breast Group and Arbeitsgemeinschaft Gynakologische Onkologie-B (AGO-B) study group.

However, the findings were somewhat inconsistent. Additionally, although the highest pCR rate, at about 65%, was seen in women who had HR-deficient tumors and received carboplatin, women whose tumors were nondeficient also had some benefit from addition of this agent.

“This is why these data have to be confirmed by other studies, for example, the same measurements are currently ongoing in the CALGB 40603 study,” commented Dr. von Minckwitz, a senior physician at the University Women’s Hospital in Frankfurt. “And finally, they have to be set into the context with survival data that we expect at the end of 2015 or beginning of 2016.”

Invited discussant Dr. Pamela N. Munster, a professor at the University of California, San Francisco, noted, “Homologous recombination deficiency mediated through the host or tumor predicts for high responses to chemotherapy and platinum salts in early-stage triple-negative breast cancer.” However, “the role of carboplatin and its optimal setting remains complex.”

She asked about the prevailing clinical practice regarding this agent’s use. “Based on your presentation and your work, what’s the landscape in Europe on the incorporation of carboplatin in the neoadjuvant therapy in triple-negative breast cancer or a subselect group?”

“We made a survey in our group half a year ago, and all members said that they are using carboplatin in triple-negative disease when they get neoadjuvant treatment,” Dr. von Minckwitz replied. “I’m not sure if this was 100% of patients, but I believe it was a more general quote, and this is in concordance with our AGO guideline, which allows the use of carboplatin in general in triple-negative [breast cancer]. It still says in patients with germline mutations, there is a somewhat stronger recommendation to use it, but it’s of course not a must.”

Session attendee Dr. Rebecca Dent of the National Cancer Centre Singapore and the University of Toronto asked whether oncologists should begin clinically applying HR deficiency for patient selection.

“I don’t think that currently these data or the sample size is sufficient to support clinical use tomorrow. … We have to wait for a confirmative study,” Dr. von Minckwitz replied.

Dr. Munster, the discussant, agreed, saying, “I think the HRD percentage is actually quite high in [this] set, so the test may not be as robust as we like to see. So I think part of it is refinement of biomarkers has to be the focus of what we do in the next 10 years.”

Previous results of the randomized phase 2/3 GeparSixto trial have shown that adding carboplatin to a neoadjuvant chemotherapy backbone (paclitaxel, liposomal doxorubicin, and bevacizumab) improves the pCR rate in patients with triple-negative breast cancer, but at the cost of added toxicity (Lancet Oncol. 2014;15:747-56). “Therefore it is of importance to better define the group of patients that might have a higher benefit from the addition of carboplatin,” Dr. von Minckwitz explained.

“We know from previous studies that tumors with a decreased DNA repair capacity, for example, due to a mutation of the BRCA1 or BRCA2 gene are expected to have a higher sensitivity to DNA-damaging agents like platinum compounds. A more extensive way to measure DNA repair capacity is now possible using the HRD assay,” he noted.

The investigators assessed tumor HR deficiency among the 315 trial participants with triple-negative breast cancer. Overall, 70.5% had tumors that were HR deficient (meaning they had a high HRD score or a tumor BRCA mutation).

In the entire cohort, women with HR-deficient tumors were more likely to have a pCR, defined as absence of invasive residual disease in the breast or nodes (ypT0/is ypN0), than peers with HR-nondeficient tumors (55.9% vs. 29.8%). In multivariate analysis, HR deficiency independently predicted pCR (odds ratio, 2.51; P = .009).

Adding carboplatin improved the pCR rate significantly in women who had HR-deficient tumors (from 45.2% to 64.9%, P = .025) but also somewhat in women who had HR-nondeficient tumors (from 20.0% and 40.7%, P = .146). And there was no significant interaction between HR deficiency and carboplatin benefit.

In further analyses, carboplatin had a significant benefit in patients with a high HRD score but intact tumor BRCA, but not in patients with mutated tumor BRCA.

Findings differed slightly when the investigators repeated analyses but instead used a stricter definition of pCR that calls for absence of both invasive and noninvasive (ductal carcinoma in situ) residual disease in the breast and nodes (ypT0 ypN0), according to Dr. von Minckwitz.

Given that the majority of HR-deficient tumors did not have a BRCA mutation, the investigators plan to assess other drivers of HR deficiency, he said.

Dr. von Minckwitz disclosed employment, leadership, and stock ownership relationships with GBG Forschungs GmbH and research funding to his institution by Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi, and Teva. The trial was funded by Teva, Roche Pharma AG, and GlaxoSmithKline.

CHICAGO – Homologous recombination (HR) deficiency is a biomarker for benefit from neoadjuvant chemotherapy in women with triple-negative breast cancer (TNBC), suggest data from the GeparSixto trial presented at the annual meeting of the American Society of Clinical Oncology.

Roughly two-thirds of women were found to have HR-deficient tumors, impairing their ability to repair DNA and thereby rendering them susceptible to DNA-damaging agents. These women had more than double the odds of a pathologic complete response (pCR).

“HR deficiency in triple-negative breast cancer appears to be an independent predictor of high pCR rates to the chemotherapies that were given in this study,” summarized Dr. Gunter von Minckwitz on behalf of the German Breast Group and Arbeitsgemeinschaft Gynakologische Onkologie-B (AGO-B) study group.

However, the findings were somewhat inconsistent. Additionally, although the highest pCR rate, at about 65%, was seen in women who had HR-deficient tumors and received carboplatin, women whose tumors were nondeficient also had some benefit from addition of this agent.

“This is why these data have to be confirmed by other studies, for example, the same measurements are currently ongoing in the CALGB 40603 study,” commented Dr. von Minckwitz, a senior physician at the University Women’s Hospital in Frankfurt. “And finally, they have to be set into the context with survival data that we expect at the end of 2015 or beginning of 2016.”

Invited discussant Dr. Pamela N. Munster, a professor at the University of California, San Francisco, noted, “Homologous recombination deficiency mediated through the host or tumor predicts for high responses to chemotherapy and platinum salts in early-stage triple-negative breast cancer.” However, “the role of carboplatin and its optimal setting remains complex.”

She asked about the prevailing clinical practice regarding this agent’s use. “Based on your presentation and your work, what’s the landscape in Europe on the incorporation of carboplatin in the neoadjuvant therapy in triple-negative breast cancer or a subselect group?”

“We made a survey in our group half a year ago, and all members said that they are using carboplatin in triple-negative disease when they get neoadjuvant treatment,” Dr. von Minckwitz replied. “I’m not sure if this was 100% of patients, but I believe it was a more general quote, and this is in concordance with our AGO guideline, which allows the use of carboplatin in general in triple-negative [breast cancer]. It still says in patients with germline mutations, there is a somewhat stronger recommendation to use it, but it’s of course not a must.”

Session attendee Dr. Rebecca Dent of the National Cancer Centre Singapore and the University of Toronto asked whether oncologists should begin clinically applying HR deficiency for patient selection.

“I don’t think that currently these data or the sample size is sufficient to support clinical use tomorrow. … We have to wait for a confirmative study,” Dr. von Minckwitz replied.

Dr. Munster, the discussant, agreed, saying, “I think the HRD percentage is actually quite high in [this] set, so the test may not be as robust as we like to see. So I think part of it is refinement of biomarkers has to be the focus of what we do in the next 10 years.”

Previous results of the randomized phase 2/3 GeparSixto trial have shown that adding carboplatin to a neoadjuvant chemotherapy backbone (paclitaxel, liposomal doxorubicin, and bevacizumab) improves the pCR rate in patients with triple-negative breast cancer, but at the cost of added toxicity (Lancet Oncol. 2014;15:747-56). “Therefore it is of importance to better define the group of patients that might have a higher benefit from the addition of carboplatin,” Dr. von Minckwitz explained.

“We know from previous studies that tumors with a decreased DNA repair capacity, for example, due to a mutation of the BRCA1 or BRCA2 gene are expected to have a higher sensitivity to DNA-damaging agents like platinum compounds. A more extensive way to measure DNA repair capacity is now possible using the HRD assay,” he noted.

The investigators assessed tumor HR deficiency among the 315 trial participants with triple-negative breast cancer. Overall, 70.5% had tumors that were HR deficient (meaning they had a high HRD score or a tumor BRCA mutation).

In the entire cohort, women with HR-deficient tumors were more likely to have a pCR, defined as absence of invasive residual disease in the breast or nodes (ypT0/is ypN0), than peers with HR-nondeficient tumors (55.9% vs. 29.8%). In multivariate analysis, HR deficiency independently predicted pCR (odds ratio, 2.51; P = .009).

Adding carboplatin improved the pCR rate significantly in women who had HR-deficient tumors (from 45.2% to 64.9%, P = .025) but also somewhat in women who had HR-nondeficient tumors (from 20.0% and 40.7%, P = .146). And there was no significant interaction between HR deficiency and carboplatin benefit.

In further analyses, carboplatin had a significant benefit in patients with a high HRD score but intact tumor BRCA, but not in patients with mutated tumor BRCA.

Findings differed slightly when the investigators repeated analyses but instead used a stricter definition of pCR that calls for absence of both invasive and noninvasive (ductal carcinoma in situ) residual disease in the breast and nodes (ypT0 ypN0), according to Dr. von Minckwitz.

Given that the majority of HR-deficient tumors did not have a BRCA mutation, the investigators plan to assess other drivers of HR deficiency, he said.

Dr. von Minckwitz disclosed employment, leadership, and stock ownership relationships with GBG Forschungs GmbH and research funding to his institution by Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi, and Teva. The trial was funded by Teva, Roche Pharma AG, and GlaxoSmithKline.

CHICAGO – Homologous recombination (HR) deficiency is a biomarker for benefit from neoadjuvant chemotherapy in women with triple-negative breast cancer (TNBC), suggest data from the GeparSixto trial presented at the annual meeting of the American Society of Clinical Oncology.

Roughly two-thirds of women were found to have HR-deficient tumors, impairing their ability to repair DNA and thereby rendering them susceptible to DNA-damaging agents. These women had more than double the odds of a pathologic complete response (pCR).

“HR deficiency in triple-negative breast cancer appears to be an independent predictor of high pCR rates to the chemotherapies that were given in this study,” summarized Dr. Gunter von Minckwitz on behalf of the German Breast Group and Arbeitsgemeinschaft Gynakologische Onkologie-B (AGO-B) study group.

However, the findings were somewhat inconsistent. Additionally, although the highest pCR rate, at about 65%, was seen in women who had HR-deficient tumors and received carboplatin, women whose tumors were nondeficient also had some benefit from addition of this agent.

“This is why these data have to be confirmed by other studies, for example, the same measurements are currently ongoing in the CALGB 40603 study,” commented Dr. von Minckwitz, a senior physician at the University Women’s Hospital in Frankfurt. “And finally, they have to be set into the context with survival data that we expect at the end of 2015 or beginning of 2016.”

Invited discussant Dr. Pamela N. Munster, a professor at the University of California, San Francisco, noted, “Homologous recombination deficiency mediated through the host or tumor predicts for high responses to chemotherapy and platinum salts in early-stage triple-negative breast cancer.” However, “the role of carboplatin and its optimal setting remains complex.”

She asked about the prevailing clinical practice regarding this agent’s use. “Based on your presentation and your work, what’s the landscape in Europe on the incorporation of carboplatin in the neoadjuvant therapy in triple-negative breast cancer or a subselect group?”

“We made a survey in our group half a year ago, and all members said that they are using carboplatin in triple-negative disease when they get neoadjuvant treatment,” Dr. von Minckwitz replied. “I’m not sure if this was 100% of patients, but I believe it was a more general quote, and this is in concordance with our AGO guideline, which allows the use of carboplatin in general in triple-negative [breast cancer]. It still says in patients with germline mutations, there is a somewhat stronger recommendation to use it, but it’s of course not a must.”

Session attendee Dr. Rebecca Dent of the National Cancer Centre Singapore and the University of Toronto asked whether oncologists should begin clinically applying HR deficiency for patient selection.

“I don’t think that currently these data or the sample size is sufficient to support clinical use tomorrow. … We have to wait for a confirmative study,” Dr. von Minckwitz replied.

Dr. Munster, the discussant, agreed, saying, “I think the HRD percentage is actually quite high in [this] set, so the test may not be as robust as we like to see. So I think part of it is refinement of biomarkers has to be the focus of what we do in the next 10 years.”

Previous results of the randomized phase 2/3 GeparSixto trial have shown that adding carboplatin to a neoadjuvant chemotherapy backbone (paclitaxel, liposomal doxorubicin, and bevacizumab) improves the pCR rate in patients with triple-negative breast cancer, but at the cost of added toxicity (Lancet Oncol. 2014;15:747-56). “Therefore it is of importance to better define the group of patients that might have a higher benefit from the addition of carboplatin,” Dr. von Minckwitz explained.

“We know from previous studies that tumors with a decreased DNA repair capacity, for example, due to a mutation of the BRCA1 or BRCA2 gene are expected to have a higher sensitivity to DNA-damaging agents like platinum compounds. A more extensive way to measure DNA repair capacity is now possible using the HRD assay,” he noted.

The investigators assessed tumor HR deficiency among the 315 trial participants with triple-negative breast cancer. Overall, 70.5% had tumors that were HR deficient (meaning they had a high HRD score or a tumor BRCA mutation).

In the entire cohort, women with HR-deficient tumors were more likely to have a pCR, defined as absence of invasive residual disease in the breast or nodes (ypT0/is ypN0), than peers with HR-nondeficient tumors (55.9% vs. 29.8%). In multivariate analysis, HR deficiency independently predicted pCR (odds ratio, 2.51; P = .009).

Adding carboplatin improved the pCR rate significantly in women who had HR-deficient tumors (from 45.2% to 64.9%, P = .025) but also somewhat in women who had HR-nondeficient tumors (from 20.0% and 40.7%, P = .146). And there was no significant interaction between HR deficiency and carboplatin benefit.

In further analyses, carboplatin had a significant benefit in patients with a high HRD score but intact tumor BRCA, but not in patients with mutated tumor BRCA.

Findings differed slightly when the investigators repeated analyses but instead used a stricter definition of pCR that calls for absence of both invasive and noninvasive (ductal carcinoma in situ) residual disease in the breast and nodes (ypT0 ypN0), according to Dr. von Minckwitz.

Given that the majority of HR-deficient tumors did not have a BRCA mutation, the investigators plan to assess other drivers of HR deficiency, he said.

Dr. von Minckwitz disclosed employment, leadership, and stock ownership relationships with GBG Forschungs GmbH and research funding to his institution by Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi, and Teva. The trial was funded by Teva, Roche Pharma AG, and GlaxoSmithKline.

CHICAGO – Etirinotecan pegol is an efficacious treatment option for selected women with heavily pretreated advanced breast cancer, suggests the international phase III BEACON study (Breast Cancer Outcomes With NKTR-102).

Compared with a treatment of the physician’s choice, the novel drug – an encapsulated form of irinotecan that inhibits topoisomerase 1—did not significantly improve overall survival in the trial population as a whole, first author Dr. Edith A. Perez reported at the annual meeting of the American Society of Clinical Oncology. But it reduced the risk of death by nearly half for the subset of women with a history of brain metastases and by more than a quarter for the subset of women with a history of liver metastases, with less toxicity and better quality of life.

“Etirinotecan pegol … [has] clinical activity and good tolerability in patients with heavily pretreated advanced breast cancer,” summarized Dr. Perez, who is deputy director at large for the Mayo Clinic Cancer Center in Jacksonville, Florida, as well as director of the Mayo Clinic Breast Cancer Translational Genomics Program and chair of the Breast Cancer Specialty Council.

“The 2.1-month improvement in median survival favoring etirinotecan pegol did not reach statistical significance. However, provocative and potentially very important survival results in predefined subgroups of patients deserve further study, specifically, patients with brain metastases or liver metastases,” she said. “Exploration of potential predictive biomarkers is ongoing.”

The findings regarding brain metastases are “an intriguing nugget,” according to invited discussant Dr. Harold J. Burstein, a senior physician at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston. “I think these data and the growing literature on the effectiveness of systemic therapy for brain metastases … suggest that it’s time for us to be doing trials where we are comparing standards of care of radiotherapy against chemotherapy, trying to optimize our chemotherapy regimens for the palliation of metastatic disease of the brain.”

He pointed to a set of trials in patients with advanced lung cancer testing the benefits of early palliative care on outcomes and finding improvements in overall survival or in quality of life with no detriment to overall survival.

“I used to look at these and think this didn’t really speak to the breast cancer population. But when you start to see data in the heavily refractory patients as we have observed today, it turns out that their survival is unfortunately essentially the same as for all the patients who participated in these trials,” he said. “So when we think about what direction we should go for advanced breast cancer that’s heavily refractory to chemotherapy, in addition to exploring a variety of exciting new immunologic therapies, and targeted therapies … I think we need to begin to lean more on our palliation care specialists and colleagues to help us truly take optimal care of these patients.”

The 852 women studied in the BEACON trial had experienced progression after anthracycline, taxane, and capecitabine therapy and had received two to five prior therapies for their advanced disease. The trial, sponsored by Nektar Therapeutics, was unusual in that it allowed patients with stable brain metastases to enroll and set a high bar of overall survival as its primary endpoint, Dr. Perez noted.

The patients were randomized evenly to receive single-agent etirinotecan pegol or a single agent of the physician’s choice, which was most commonly eribulin.

Main results showed no significant improvement in overall survival among the entire trial population comparing etirinotecan pegol with physician’s choice (12.4 vs. 10.3 months; hazard ratio, 0.87; P = .08).

However, preplanned subgroup analyses showed that in the 8% of women who had a history of brain metastases, median overall survival was 10.0 months with the drug and 4.8 months with physician’s choice (HR, 0.51; P = .0099). The curves began to separate within 3 months of randomization, and the difference in the proportion of women alive at 12 months was “pretty amazing,” Dr. Perez noted, at 44% versus 19%.

There was a similar although smaller survival advantage of etirinotecan pegol among the 53% of patients with a history of liver metastases (10.9 vs. 8.3 months; HR, 0.73; P = .002).

A variety of biomarkers for etirinotecan benefit are still being analyzed, according to Dr. Perez. The most promising signal thus far has been a reduction in the number of topoisomerase 1–positive circulating tumor cells, with patients going from high (above the baseline median) to low (below the baseline median) numbers surviving significantly longer than peers having persistently high numbers (14.9 vs. 10.7 months; HR, 0.54; P = .007).

The rate of grade 3 or worse toxicity was lower with etirinotecan pegol than with physician’s choice (48% vs. 63%). The former was associated with a higher rate of diarrhea, whereas the latter was associated with higher rates of neutropenia and peripheral neuropathy.

Patients in the etirinotecan pegol group had a more favorable change from baseline in global health status and in physical functioning, reported Dr. Perez.

CHICAGO – Etirinotecan pegol is an efficacious treatment option for selected women with heavily pretreated advanced breast cancer, suggests the international phase III BEACON study (Breast Cancer Outcomes With NKTR-102).

Compared with a treatment of the physician’s choice, the novel drug – an encapsulated form of irinotecan that inhibits topoisomerase 1—did not significantly improve overall survival in the trial population as a whole, first author Dr. Edith A. Perez reported at the annual meeting of the American Society of Clinical Oncology. But it reduced the risk of death by nearly half for the subset of women with a history of brain metastases and by more than a quarter for the subset of women with a history of liver metastases, with less toxicity and better quality of life.

“Etirinotecan pegol … [has] clinical activity and good tolerability in patients with heavily pretreated advanced breast cancer,” summarized Dr. Perez, who is deputy director at large for the Mayo Clinic Cancer Center in Jacksonville, Florida, as well as director of the Mayo Clinic Breast Cancer Translational Genomics Program and chair of the Breast Cancer Specialty Council.

“The 2.1-month improvement in median survival favoring etirinotecan pegol did not reach statistical significance. However, provocative and potentially very important survival results in predefined subgroups of patients deserve further study, specifically, patients with brain metastases or liver metastases,” she said. “Exploration of potential predictive biomarkers is ongoing.”

The findings regarding brain metastases are “an intriguing nugget,” according to invited discussant Dr. Harold J. Burstein, a senior physician at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston. “I think these data and the growing literature on the effectiveness of systemic therapy for brain metastases … suggest that it’s time for us to be doing trials where we are comparing standards of care of radiotherapy against chemotherapy, trying to optimize our chemotherapy regimens for the palliation of metastatic disease of the brain.”

He pointed to a set of trials in patients with advanced lung cancer testing the benefits of early palliative care on outcomes and finding improvements in overall survival or in quality of life with no detriment to overall survival.

“I used to look at these and think this didn’t really speak to the breast cancer population. But when you start to see data in the heavily refractory patients as we have observed today, it turns out that their survival is unfortunately essentially the same as for all the patients who participated in these trials,” he said. “So when we think about what direction we should go for advanced breast cancer that’s heavily refractory to chemotherapy, in addition to exploring a variety of exciting new immunologic therapies, and targeted therapies … I think we need to begin to lean more on our palliation care specialists and colleagues to help us truly take optimal care of these patients.”

The 852 women studied in the BEACON trial had experienced progression after anthracycline, taxane, and capecitabine therapy and had received two to five prior therapies for their advanced disease. The trial, sponsored by Nektar Therapeutics, was unusual in that it allowed patients with stable brain metastases to enroll and set a high bar of overall survival as its primary endpoint, Dr. Perez noted.

The patients were randomized evenly to receive single-agent etirinotecan pegol or a single agent of the physician’s choice, which was most commonly eribulin.

Main results showed no significant improvement in overall survival among the entire trial population comparing etirinotecan pegol with physician’s choice (12.4 vs. 10.3 months; hazard ratio, 0.87; P = .08).

However, preplanned subgroup analyses showed that in the 8% of women who had a history of brain metastases, median overall survival was 10.0 months with the drug and 4.8 months with physician’s choice (HR, 0.51; P = .0099). The curves began to separate within 3 months of randomization, and the difference in the proportion of women alive at 12 months was “pretty amazing,” Dr. Perez noted, at 44% versus 19%.

There was a similar although smaller survival advantage of etirinotecan pegol among the 53% of patients with a history of liver metastases (10.9 vs. 8.3 months; HR, 0.73; P = .002).

A variety of biomarkers for etirinotecan benefit are still being analyzed, according to Dr. Perez. The most promising signal thus far has been a reduction in the number of topoisomerase 1–positive circulating tumor cells, with patients going from high (above the baseline median) to low (below the baseline median) numbers surviving significantly longer than peers having persistently high numbers (14.9 vs. 10.7 months; HR, 0.54; P = .007).

The rate of grade 3 or worse toxicity was lower with etirinotecan pegol than with physician’s choice (48% vs. 63%). The former was associated with a higher rate of diarrhea, whereas the latter was associated with higher rates of neutropenia and peripheral neuropathy.

Patients in the etirinotecan pegol group had a more favorable change from baseline in global health status and in physical functioning, reported Dr. Perez.

CHICAGO – Etirinotecan pegol is an efficacious treatment option for selected women with heavily pretreated advanced breast cancer, suggests the international phase III BEACON study (Breast Cancer Outcomes With NKTR-102).

Compared with a treatment of the physician’s choice, the novel drug – an encapsulated form of irinotecan that inhibits topoisomerase 1—did not significantly improve overall survival in the trial population as a whole, first author Dr. Edith A. Perez reported at the annual meeting of the American Society of Clinical Oncology. But it reduced the risk of death by nearly half for the subset of women with a history of brain metastases and by more than a quarter for the subset of women with a history of liver metastases, with less toxicity and better quality of life.

“Etirinotecan pegol … [has] clinical activity and good tolerability in patients with heavily pretreated advanced breast cancer,” summarized Dr. Perez, who is deputy director at large for the Mayo Clinic Cancer Center in Jacksonville, Florida, as well as director of the Mayo Clinic Breast Cancer Translational Genomics Program and chair of the Breast Cancer Specialty Council.

“The 2.1-month improvement in median survival favoring etirinotecan pegol did not reach statistical significance. However, provocative and potentially very important survival results in predefined subgroups of patients deserve further study, specifically, patients with brain metastases or liver metastases,” she said. “Exploration of potential predictive biomarkers is ongoing.”

The findings regarding brain metastases are “an intriguing nugget,” according to invited discussant Dr. Harold J. Burstein, a senior physician at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston. “I think these data and the growing literature on the effectiveness of systemic therapy for brain metastases … suggest that it’s time for us to be doing trials where we are comparing standards of care of radiotherapy against chemotherapy, trying to optimize our chemotherapy regimens for the palliation of metastatic disease of the brain.”

He pointed to a set of trials in patients with advanced lung cancer testing the benefits of early palliative care on outcomes and finding improvements in overall survival or in quality of life with no detriment to overall survival.

“I used to look at these and think this didn’t really speak to the breast cancer population. But when you start to see data in the heavily refractory patients as we have observed today, it turns out that their survival is unfortunately essentially the same as for all the patients who participated in these trials,” he said. “So when we think about what direction we should go for advanced breast cancer that’s heavily refractory to chemotherapy, in addition to exploring a variety of exciting new immunologic therapies, and targeted therapies … I think we need to begin to lean more on our palliation care specialists and colleagues to help us truly take optimal care of these patients.”

The 852 women studied in the BEACON trial had experienced progression after anthracycline, taxane, and capecitabine therapy and had received two to five prior therapies for their advanced disease. The trial, sponsored by Nektar Therapeutics, was unusual in that it allowed patients with stable brain metastases to enroll and set a high bar of overall survival as its primary endpoint, Dr. Perez noted.

The patients were randomized evenly to receive single-agent etirinotecan pegol or a single agent of the physician’s choice, which was most commonly eribulin.

Main results showed no significant improvement in overall survival among the entire trial population comparing etirinotecan pegol with physician’s choice (12.4 vs. 10.3 months; hazard ratio, 0.87; P = .08).

However, preplanned subgroup analyses showed that in the 8% of women who had a history of brain metastases, median overall survival was 10.0 months with the drug and 4.8 months with physician’s choice (HR, 0.51; P = .0099). The curves began to separate within 3 months of randomization, and the difference in the proportion of women alive at 12 months was “pretty amazing,” Dr. Perez noted, at 44% versus 19%.

There was a similar although smaller survival advantage of etirinotecan pegol among the 53% of patients with a history of liver metastases (10.9 vs. 8.3 months; HR, 0.73; P = .002).

A variety of biomarkers for etirinotecan benefit are still being analyzed, according to Dr. Perez. The most promising signal thus far has been a reduction in the number of topoisomerase 1–positive circulating tumor cells, with patients going from high (above the baseline median) to low (below the baseline median) numbers surviving significantly longer than peers having persistently high numbers (14.9 vs. 10.7 months; HR, 0.54; P = .007).

The rate of grade 3 or worse toxicity was lower with etirinotecan pegol than with physician’s choice (48% vs. 63%). The former was associated with a higher rate of diarrhea, whereas the latter was associated with higher rates of neutropenia and peripheral neuropathy.

Patients in the etirinotecan pegol group had a more favorable change from baseline in global health status and in physical functioning, reported Dr. Perez.

CHICAGO – Women with breast cancer treated with neoadjuvant chemotherapy and surgery are more likely to have a recurrence in the breast, chest wall, or axilla or to die if they don’t receive adjuvant radiation therapy, even if they had a pathologic complete response to the chemotherapy, new data show.

In a meta-analysis of three Gepar trials conducted by the German Breast Group, radiation therapy was associated with a 38% lower multivariate risk of locoregional recurrence or death, investigators reported at the annual meeting of the American Society of Clinical Oncology. Significant benefit was seen regardless of pathologic complete response, although findings across other subgroups were not consistent, possibly due to selection bias or underlying confounders.

“Radiotherapy is an independent prognostic factor for locoregional recurrence–free survival after neoadjuvant chemotherapy in breast cancer. However, the optimal selection criteria remain unclear,” commented first author Dr. David Krug of University Hospital Heidelberg (Germany).

“We are eagerly awaiting the results of prospective studies that are currently recruiting patients,” he added, referring to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-51 trial and the Radiotherapy After Primary Chemotherapy for Breast Cancer (RAPCHEM) trial.

Findings of this meta-analysis are not practice changing, according to invited discussant Dr. Monica Morrow, chief of the breast service, department of surgery, and the Anne Burnett Windfohr Chair of Clinical Oncology at the Memorial Sloan Kettering Cancer Center in New York. “The Gepar data is not consistent enough across subsets to draw any different conclusions other than we need more data,” she said.

Focusing on the women who underwent mastectomy, she noted that only a small number who had a pathologic complete response did not receive radiation therapy, “so this study unfortunately lacks the power to tell us anything about the ability to eliminate radiation in this group.”

“What we’d really like to know about local control after neoadjuvant therapy is what’s the relative contribution of pretreatment stage and posttreatment stage to the risk of locoregional recurrence, especially in patients who achieve pathologic complete response? And if we try to address that question with this study, the results were a little murky,” Dr. Morrow further noted. For example, patients with higher–T stage primary tumors benefited from postmastectomy radiation, but patients who were clinically node positive did not.

“I think right now, what we have to say is we need to continue to do what we have been doing up until the present time, namely, patients whose presenting stage clearly indicates the need for radiotherapy should receive it, and patients who have lower-stage disease perhaps not,” she concluded, agreeing that the NSABP B-51 trial should help put this issue to rest.

Dr. Krug and his colleagues performed a pooled meta-analysis of data from the GeparTrio, GeparQuattro, and GeparQuinto trials of neoadjuvant chemotherapy, in which guidelines specified when adjuvant radiation therapy should be used. Those guidelines called for whole-breast radiation therapy with a boost after breast-conserving surgery (with omission of the boost in low-risk patients); radiation therapy after mastectomy for patients having more extensive disease before neoadjuvant chemotherapy; and radiation therapy for those with greater involvement of the regional lymphatics.

The meta-analysis was based on a total of 3,370 women. Overall, 94% received radiation therapy (99% of those who had undergone breast-conserving surgery and 85% of those who had undergone mastectomy).

With a median follow-up of 4.2 years, the 5-year rate of locoregional recurrence–free survival was 89.2% in the entire study population, according to Dr. Krug.

Women who did not receive radiation therapy had a significantly elevated risk of such recurrence or death compared with peers who received it. In subgroups analyses, benefit was significant whether women had had a pathologic complete response to neoadjuvant chemotherapy or not. Greatest absolute benefit was seen in those with a pathologic complete response, clinically positive nodes, or pathologically negative nodes.

The 5-year rate of disease-free survival was 74.0% in the entire study population. Here, there was only a trend toward a higher risk of events for women who did not receive radiation therapy.

In multivariate analyses, radiation therapy independently predicted better locoregional recurrence–free survival (hazard ratio, 0.62; P = .038) but not disease-free survival.

When analyses were restricted to women who had undergone mastectomy, radiation therapy was associated with significantly better locoregional recurrence–free survival among those with clinical stage T3/4 disease, pathologically negative nodes, a conversion from clinically positive to pathologically negative nodes, or hormone receptor–negative, HER2-positive disease.

It was associated with poorer disease-free survival for patients who did not achieve a pathologic complete response, had clinical stage T1/2 disease, or were clinically node negative.

Multivariate analysis here again showed that radiation therapy independently predicted better locoregional recurrence–free survival (HR, 0.56; P = .029) but not disease-free survival.

CHICAGO – Women with breast cancer treated with neoadjuvant chemotherapy and surgery are more likely to have a recurrence in the breast, chest wall, or axilla or to die if they don’t receive adjuvant radiation therapy, even if they had a pathologic complete response to the chemotherapy, new data show.

In a meta-analysis of three Gepar trials conducted by the German Breast Group, radiation therapy was associated with a 38% lower multivariate risk of locoregional recurrence or death, investigators reported at the annual meeting of the American Society of Clinical Oncology. Significant benefit was seen regardless of pathologic complete response, although findings across other subgroups were not consistent, possibly due to selection bias or underlying confounders.

“Radiotherapy is an independent prognostic factor for locoregional recurrence–free survival after neoadjuvant chemotherapy in breast cancer. However, the optimal selection criteria remain unclear,” commented first author Dr. David Krug of University Hospital Heidelberg (Germany).

“We are eagerly awaiting the results of prospective studies that are currently recruiting patients,” he added, referring to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-51 trial and the Radiotherapy After Primary Chemotherapy for Breast Cancer (RAPCHEM) trial.

Findings of this meta-analysis are not practice changing, according to invited discussant Dr. Monica Morrow, chief of the breast service, department of surgery, and the Anne Burnett Windfohr Chair of Clinical Oncology at the Memorial Sloan Kettering Cancer Center in New York. “The Gepar data is not consistent enough across subsets to draw any different conclusions other than we need more data,” she said.

Focusing on the women who underwent mastectomy, she noted that only a small number who had a pathologic complete response did not receive radiation therapy, “so this study unfortunately lacks the power to tell us anything about the ability to eliminate radiation in this group.”

“What we’d really like to know about local control after neoadjuvant therapy is what’s the relative contribution of pretreatment stage and posttreatment stage to the risk of locoregional recurrence, especially in patients who achieve pathologic complete response? And if we try to address that question with this study, the results were a little murky,” Dr. Morrow further noted. For example, patients with higher–T stage primary tumors benefited from postmastectomy radiation, but patients who were clinically node positive did not.

“I think right now, what we have to say is we need to continue to do what we have been doing up until the present time, namely, patients whose presenting stage clearly indicates the need for radiotherapy should receive it, and patients who have lower-stage disease perhaps not,” she concluded, agreeing that the NSABP B-51 trial should help put this issue to rest.

Dr. Krug and his colleagues performed a pooled meta-analysis of data from the GeparTrio, GeparQuattro, and GeparQuinto trials of neoadjuvant chemotherapy, in which guidelines specified when adjuvant radiation therapy should be used. Those guidelines called for whole-breast radiation therapy with a boost after breast-conserving surgery (with omission of the boost in low-risk patients); radiation therapy after mastectomy for patients having more extensive disease before neoadjuvant chemotherapy; and radiation therapy for those with greater involvement of the regional lymphatics.

The meta-analysis was based on a total of 3,370 women. Overall, 94% received radiation therapy (99% of those who had undergone breast-conserving surgery and 85% of those who had undergone mastectomy).

With a median follow-up of 4.2 years, the 5-year rate of locoregional recurrence–free survival was 89.2% in the entire study population, according to Dr. Krug.

Women who did not receive radiation therapy had a significantly elevated risk of such recurrence or death compared with peers who received it. In subgroups analyses, benefit was significant whether women had had a pathologic complete response to neoadjuvant chemotherapy or not. Greatest absolute benefit was seen in those with a pathologic complete response, clinically positive nodes, or pathologically negative nodes.

The 5-year rate of disease-free survival was 74.0% in the entire study population. Here, there was only a trend toward a higher risk of events for women who did not receive radiation therapy.

In multivariate analyses, radiation therapy independently predicted better locoregional recurrence–free survival (hazard ratio, 0.62; P = .038) but not disease-free survival.

When analyses were restricted to women who had undergone mastectomy, radiation therapy was associated with significantly better locoregional recurrence–free survival among those with clinical stage T3/4 disease, pathologically negative nodes, a conversion from clinically positive to pathologically negative nodes, or hormone receptor–negative, HER2-positive disease.

It was associated with poorer disease-free survival for patients who did not achieve a pathologic complete response, had clinical stage T1/2 disease, or were clinically node negative.

Multivariate analysis here again showed that radiation therapy independently predicted better locoregional recurrence–free survival (HR, 0.56; P = .029) but not disease-free survival.

CHICAGO – Women with breast cancer treated with neoadjuvant chemotherapy and surgery are more likely to have a recurrence in the breast, chest wall, or axilla or to die if they don’t receive adjuvant radiation therapy, even if they had a pathologic complete response to the chemotherapy, new data show.

In a meta-analysis of three Gepar trials conducted by the German Breast Group, radiation therapy was associated with a 38% lower multivariate risk of locoregional recurrence or death, investigators reported at the annual meeting of the American Society of Clinical Oncology. Significant benefit was seen regardless of pathologic complete response, although findings across other subgroups were not consistent, possibly due to selection bias or underlying confounders.

“Radiotherapy is an independent prognostic factor for locoregional recurrence–free survival after neoadjuvant chemotherapy in breast cancer. However, the optimal selection criteria remain unclear,” commented first author Dr. David Krug of University Hospital Heidelberg (Germany).

“We are eagerly awaiting the results of prospective studies that are currently recruiting patients,” he added, referring to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-51 trial and the Radiotherapy After Primary Chemotherapy for Breast Cancer (RAPCHEM) trial.

Findings of this meta-analysis are not practice changing, according to invited discussant Dr. Monica Morrow, chief of the breast service, department of surgery, and the Anne Burnett Windfohr Chair of Clinical Oncology at the Memorial Sloan Kettering Cancer Center in New York. “The Gepar data is not consistent enough across subsets to draw any different conclusions other than we need more data,” she said.

Focusing on the women who underwent mastectomy, she noted that only a small number who had a pathologic complete response did not receive radiation therapy, “so this study unfortunately lacks the power to tell us anything about the ability to eliminate radiation in this group.”

“What we’d really like to know about local control after neoadjuvant therapy is what’s the relative contribution of pretreatment stage and posttreatment stage to the risk of locoregional recurrence, especially in patients who achieve pathologic complete response? And if we try to address that question with this study, the results were a little murky,” Dr. Morrow further noted. For example, patients with higher–T stage primary tumors benefited from postmastectomy radiation, but patients who were clinically node positive did not.

“I think right now, what we have to say is we need to continue to do what we have been doing up until the present time, namely, patients whose presenting stage clearly indicates the need for radiotherapy should receive it, and patients who have lower-stage disease perhaps not,” she concluded, agreeing that the NSABP B-51 trial should help put this issue to rest.

Dr. Krug and his colleagues performed a pooled meta-analysis of data from the GeparTrio, GeparQuattro, and GeparQuinto trials of neoadjuvant chemotherapy, in which guidelines specified when adjuvant radiation therapy should be used. Those guidelines called for whole-breast radiation therapy with a boost after breast-conserving surgery (with omission of the boost in low-risk patients); radiation therapy after mastectomy for patients having more extensive disease before neoadjuvant chemotherapy; and radiation therapy for those with greater involvement of the regional lymphatics.

The meta-analysis was based on a total of 3,370 women. Overall, 94% received radiation therapy (99% of those who had undergone breast-conserving surgery and 85% of those who had undergone mastectomy).

With a median follow-up of 4.2 years, the 5-year rate of locoregional recurrence–free survival was 89.2% in the entire study population, according to Dr. Krug.

Women who did not receive radiation therapy had a significantly elevated risk of such recurrence or death compared with peers who received it. In subgroups analyses, benefit was significant whether women had had a pathologic complete response to neoadjuvant chemotherapy or not. Greatest absolute benefit was seen in those with a pathologic complete response, clinically positive nodes, or pathologically negative nodes.

The 5-year rate of disease-free survival was 74.0% in the entire study population. Here, there was only a trend toward a higher risk of events for women who did not receive radiation therapy.

In multivariate analyses, radiation therapy independently predicted better locoregional recurrence–free survival (hazard ratio, 0.62; P = .038) but not disease-free survival.

When analyses were restricted to women who had undergone mastectomy, radiation therapy was associated with significantly better locoregional recurrence–free survival among those with clinical stage T3/4 disease, pathologically negative nodes, a conversion from clinically positive to pathologically negative nodes, or hormone receptor–negative, HER2-positive disease.

It was associated with poorer disease-free survival for patients who did not achieve a pathologic complete response, had clinical stage T1/2 disease, or were clinically node negative.

Multivariate analysis here again showed that radiation therapy independently predicted better locoregional recurrence–free survival (HR, 0.56; P = .029) but not disease-free survival.

CHICAGO – Oral and intravenous bisphosphonates have similar efficacy and safety when used in the adjuvant breast cancer setting, but patients prefer the former, finds a phase III trial conducted by the Southwest Oncology Group (SWOG) and reported at the annual meeting of the American Society of Clinical Oncology.

Nearly 90% of the 6,097 women studied were alive and free of breast cancer at 5 years, whether they had been randomized to intravenous zoledronic acid (currently approved in the United States for treatment of multiple myeloma and cancer-related hypercalcemia) or to oral clodronate or oral ibandronate (neither of which is available in the United States). Side effect profiles differed somewhat, but three-fourths of patients indicated that they preferred oral formulations.

“SWOG S0307 shows no evidence of differences in efficacy by the type of bisphosphonate, either in an intent-to-treat analysis or based on age or tumor subtype. Overall toxicity of bisphosphonates as given in S0307 is low, and toxicity grade differed little across arms,” said Dr. Julie Gralow, director of breast medical oncology at the Seattle Cancer Care Alliance and a professor in the medical oncology division, University of Washington, both in Seattle. “Given that these oral bisphosphonates are preferred by patients and approved elsewhere, efforts to make them available in the U.S. should be considered.”

Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England noted that the findings are consistent with a meta-analysis recently reported (San Antonio Breast Cancer Symposium 2013, abstract S4-07) and being published (Coleman R et al., Lancet 2015, in press), which shows that postmenopausal women had reductions in bone recurrences and breast cancer mortality with use of adjuvant bisphosphonates, irrespective of the agent.

“We are left now with the dilemma that the opportunity for patients to access adjuvant bisphosphonates is hampered by the lack of regulatory approval and of course the lack of interest, now that these agents have become generic, from the pharmaceutical companies” he said.

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, New York, posed a question to Dr. Gralow: “Your statistics looked at two-sided tests to find the superior outcome. You found no difference. Could you tell us how it works if you are looking at this as a noninferiority test, because practically, what we’d like to do if we are going to give a bisphosphonate, we’d like to give oral clodronate. And I’d really like to know it’s not inferior to Zometa [zoledronic acid] by your study.”

“My statistician isn’t here to speak to the exact details of that analysis,” Dr. Gralow replied. “But I think it’s pretty clear with this huge study that there was absolutely no hint of a difference in absolute number between any of the arms, and no matter how we would do an analysis, I don’t think we could pull out – with exactly the same numbers of recurrences – anything that would be more statistically significant. I think that between the meta-analysis, which looks at clodronate, zoledronic acid, ibandronate across trials, and this trial, I would have complete confidence if clodronate were available in this country in using that if that were my patient’s choice. I’m left with intravenous zoledronic acid as the only one of these three drugs in S0307 available, and that is what I will offer my patients.”

Another attendee noted that whereas these data and those of the forthcoming meta-analysis suggest bisphosphonates should be used as therapy to prevent recurrence, other data also being presented at the meeting suggest adjuvant denosumab should be used to reduce fracture risk (Gnant et al., abstract 504). “This creates somewhat of a dilemma. So tomorrow morning, if I have to treat a patient with an antiresorptive agent, which should I choose?” he asked.

Dr. Gralow said that the reduction in fracture risk was comparable for the two studies. “I think [Dr. Gnant] made the statement that if you are most worried about the bone health and the bone density, then denosumab is reasonable. To date, with respect to reducing bone recurrences and death, we have the most data for the bisphosphonates,” she noted.

In the trial, Dr. Gralow and her colleagues randomized patients to 3 years of treatment with intravenous zoledronic acid, oral clodronate, or oral ibandronate. Zoledronic acid was given at 4 mg monthly for six doses, then every 3 months out to 3 years; clodronate and ibandronate were given at doses approved in other countries for the treatment of bone metastases.

The trial’s fourth preplanned interim analysis suggested that the differences in outcomes between groups would not become statistically significant, so the data safety monitoring committee recommended early reporting of the findings, according to Dr. Gralow.

At the time of analysis, the median follow-up was 5.4 years. Fifty-nine percent of the patients studied were postmenopausal at baseline.

The rate of 5-year disease-free survival, the trial’s primary endpoint, was 88% overall, with no significant difference across the three arms. Findings were the same in subgroups having different tumor types (hormone receptor positive, HER2 positive, and triple negative) and in different age groups (younger than 60 and older than 60). Five-year overall survival was 93% and likewise statistically indistinguishable across arms.

Roughly 8%-10% of patients in each arm had grade 3 or 4 toxicities. Pain was more commonly reported in the zoledronic acid and ibandronate arms, and gastrointestinal issues were more commonly reported with clodronate and ibandronate. Patients in the zoledronic acid arm had a higher rate of osteonecrosis of the jaw.

The arms were statistically indistinguishable with respect to rates of both all fractures and traumatic fractures, reported Dr. Gralow.

Overall, 76% of patients expressed a preference for oral agents at baseline as did 75% at the completion of therapy, although there was some switching between preference.

CHICAGO – Oral and intravenous bisphosphonates have similar efficacy and safety when used in the adjuvant breast cancer setting, but patients prefer the former, finds a phase III trial conducted by the Southwest Oncology Group (SWOG) and reported at the annual meeting of the American Society of Clinical Oncology.

Nearly 90% of the 6,097 women studied were alive and free of breast cancer at 5 years, whether they had been randomized to intravenous zoledronic acid (currently approved in the United States for treatment of multiple myeloma and cancer-related hypercalcemia) or to oral clodronate or oral ibandronate (neither of which is available in the United States). Side effect profiles differed somewhat, but three-fourths of patients indicated that they preferred oral formulations.

“SWOG S0307 shows no evidence of differences in efficacy by the type of bisphosphonate, either in an intent-to-treat analysis or based on age or tumor subtype. Overall toxicity of bisphosphonates as given in S0307 is low, and toxicity grade differed little across arms,” said Dr. Julie Gralow, director of breast medical oncology at the Seattle Cancer Care Alliance and a professor in the medical oncology division, University of Washington, both in Seattle. “Given that these oral bisphosphonates are preferred by patients and approved elsewhere, efforts to make them available in the U.S. should be considered.”

Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England noted that the findings are consistent with a meta-analysis recently reported (San Antonio Breast Cancer Symposium 2013, abstract S4-07) and being published (Coleman R et al., Lancet 2015, in press), which shows that postmenopausal women had reductions in bone recurrences and breast cancer mortality with use of adjuvant bisphosphonates, irrespective of the agent.

“We are left now with the dilemma that the opportunity for patients to access adjuvant bisphosphonates is hampered by the lack of regulatory approval and of course the lack of interest, now that these agents have become generic, from the pharmaceutical companies” he said.

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, New York, posed a question to Dr. Gralow: “Your statistics looked at two-sided tests to find the superior outcome. You found no difference. Could you tell us how it works if you are looking at this as a noninferiority test, because practically, what we’d like to do if we are going to give a bisphosphonate, we’d like to give oral clodronate. And I’d really like to know it’s not inferior to Zometa [zoledronic acid] by your study.”

“My statistician isn’t here to speak to the exact details of that analysis,” Dr. Gralow replied. “But I think it’s pretty clear with this huge study that there was absolutely no hint of a difference in absolute number between any of the arms, and no matter how we would do an analysis, I don’t think we could pull out – with exactly the same numbers of recurrences – anything that would be more statistically significant. I think that between the meta-analysis, which looks at clodronate, zoledronic acid, ibandronate across trials, and this trial, I would have complete confidence if clodronate were available in this country in using that if that were my patient’s choice. I’m left with intravenous zoledronic acid as the only one of these three drugs in S0307 available, and that is what I will offer my patients.”

Another attendee noted that whereas these data and those of the forthcoming meta-analysis suggest bisphosphonates should be used as therapy to prevent recurrence, other data also being presented at the meeting suggest adjuvant denosumab should be used to reduce fracture risk (Gnant et al., abstract 504). “This creates somewhat of a dilemma. So tomorrow morning, if I have to treat a patient with an antiresorptive agent, which should I choose?” he asked.

Dr. Gralow said that the reduction in fracture risk was comparable for the two studies. “I think [Dr. Gnant] made the statement that if you are most worried about the bone health and the bone density, then denosumab is reasonable. To date, with respect to reducing bone recurrences and death, we have the most data for the bisphosphonates,” she noted.

In the trial, Dr. Gralow and her colleagues randomized patients to 3 years of treatment with intravenous zoledronic acid, oral clodronate, or oral ibandronate. Zoledronic acid was given at 4 mg monthly for six doses, then every 3 months out to 3 years; clodronate and ibandronate were given at doses approved in other countries for the treatment of bone metastases.

The trial’s fourth preplanned interim analysis suggested that the differences in outcomes between groups would not become statistically significant, so the data safety monitoring committee recommended early reporting of the findings, according to Dr. Gralow.

At the time of analysis, the median follow-up was 5.4 years. Fifty-nine percent of the patients studied were postmenopausal at baseline.

The rate of 5-year disease-free survival, the trial’s primary endpoint, was 88% overall, with no significant difference across the three arms. Findings were the same in subgroups having different tumor types (hormone receptor positive, HER2 positive, and triple negative) and in different age groups (younger than 60 and older than 60). Five-year overall survival was 93% and likewise statistically indistinguishable across arms.

Roughly 8%-10% of patients in each arm had grade 3 or 4 toxicities. Pain was more commonly reported in the zoledronic acid and ibandronate arms, and gastrointestinal issues were more commonly reported with clodronate and ibandronate. Patients in the zoledronic acid arm had a higher rate of osteonecrosis of the jaw.

The arms were statistically indistinguishable with respect to rates of both all fractures and traumatic fractures, reported Dr. Gralow.

Overall, 76% of patients expressed a preference for oral agents at baseline as did 75% at the completion of therapy, although there was some switching between preference.

CHICAGO – Oral and intravenous bisphosphonates have similar efficacy and safety when used in the adjuvant breast cancer setting, but patients prefer the former, finds a phase III trial conducted by the Southwest Oncology Group (SWOG) and reported at the annual meeting of the American Society of Clinical Oncology.

Nearly 90% of the 6,097 women studied were alive and free of breast cancer at 5 years, whether they had been randomized to intravenous zoledronic acid (currently approved in the United States for treatment of multiple myeloma and cancer-related hypercalcemia) or to oral clodronate or oral ibandronate (neither of which is available in the United States). Side effect profiles differed somewhat, but three-fourths of patients indicated that they preferred oral formulations.

“SWOG S0307 shows no evidence of differences in efficacy by the type of bisphosphonate, either in an intent-to-treat analysis or based on age or tumor subtype. Overall toxicity of bisphosphonates as given in S0307 is low, and toxicity grade differed little across arms,” said Dr. Julie Gralow, director of breast medical oncology at the Seattle Cancer Care Alliance and a professor in the medical oncology division, University of Washington, both in Seattle. “Given that these oral bisphosphonates are preferred by patients and approved elsewhere, efforts to make them available in the U.S. should be considered.”

Invited discussant Dr. Robert E. Coleman of the University of Sheffield and Weston Park Hospital in England noted that the findings are consistent with a meta-analysis recently reported (San Antonio Breast Cancer Symposium 2013, abstract S4-07) and being published (Coleman R et al., Lancet 2015, in press), which shows that postmenopausal women had reductions in bone recurrences and breast cancer mortality with use of adjuvant bisphosphonates, irrespective of the agent.

“We are left now with the dilemma that the opportunity for patients to access adjuvant bisphosphonates is hampered by the lack of regulatory approval and of course the lack of interest, now that these agents have become generic, from the pharmaceutical companies” he said.

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, New York, posed a question to Dr. Gralow: “Your statistics looked at two-sided tests to find the superior outcome. You found no difference. Could you tell us how it works if you are looking at this as a noninferiority test, because practically, what we’d like to do if we are going to give a bisphosphonate, we’d like to give oral clodronate. And I’d really like to know it’s not inferior to Zometa [zoledronic acid] by your study.”

“My statistician isn’t here to speak to the exact details of that analysis,” Dr. Gralow replied. “But I think it’s pretty clear with this huge study that there was absolutely no hint of a difference in absolute number between any of the arms, and no matter how we would do an analysis, I don’t think we could pull out – with exactly the same numbers of recurrences – anything that would be more statistically significant. I think that between the meta-analysis, which looks at clodronate, zoledronic acid, ibandronate across trials, and this trial, I would have complete confidence if clodronate were available in this country in using that if that were my patient’s choice. I’m left with intravenous zoledronic acid as the only one of these three drugs in S0307 available, and that is what I will offer my patients.”

Another attendee noted that whereas these data and those of the forthcoming meta-analysis suggest bisphosphonates should be used as therapy to prevent recurrence, other data also being presented at the meeting suggest adjuvant denosumab should be used to reduce fracture risk (Gnant et al., abstract 504). “This creates somewhat of a dilemma. So tomorrow morning, if I have to treat a patient with an antiresorptive agent, which should I choose?” he asked.

Dr. Gralow said that the reduction in fracture risk was comparable for the two studies. “I think [Dr. Gnant] made the statement that if you are most worried about the bone health and the bone density, then denosumab is reasonable. To date, with respect to reducing bone recurrences and death, we have the most data for the bisphosphonates,” she noted.

In the trial, Dr. Gralow and her colleagues randomized patients to 3 years of treatment with intravenous zoledronic acid, oral clodronate, or oral ibandronate. Zoledronic acid was given at 4 mg monthly for six doses, then every 3 months out to 3 years; clodronate and ibandronate were given at doses approved in other countries for the treatment of bone metastases.

The trial’s fourth preplanned interim analysis suggested that the differences in outcomes between groups would not become statistically significant, so the data safety monitoring committee recommended early reporting of the findings, according to Dr. Gralow.

At the time of analysis, the median follow-up was 5.4 years. Fifty-nine percent of the patients studied were postmenopausal at baseline.

The rate of 5-year disease-free survival, the trial’s primary endpoint, was 88% overall, with no significant difference across the three arms. Findings were the same in subgroups having different tumor types (hormone receptor positive, HER2 positive, and triple negative) and in different age groups (younger than 60 and older than 60). Five-year overall survival was 93% and likewise statistically indistinguishable across arms.

Roughly 8%-10% of patients in each arm had grade 3 or 4 toxicities. Pain was more commonly reported in the zoledronic acid and ibandronate arms, and gastrointestinal issues were more commonly reported with clodronate and ibandronate. Patients in the zoledronic acid arm had a higher rate of osteonecrosis of the jaw.

The arms were statistically indistinguishable with respect to rates of both all fractures and traumatic fractures, reported Dr. Gralow.

Overall, 76% of patients expressed a preference for oral agents at baseline as did 75% at the completion of therapy, although there was some switching between preference.

CHICAGO – Extending adjuvant targeted therapy for HER2-positive early breast cancer by a year with neratinib further protects against recurrence, suggest primary results of the phase III randomized ExteNET trial (Study Evaluating the Effects of Neratinib After Adjuvant Trastuzumab in Women With Early-Stage Breast Cancer).

At 2 years of follow-up, women assigned to receive neratinib, an investigational pan-HER tyrosine kinase inhibitor, had a one-third reduction in the risk of invasive breast cancer or death relative to counterparts assigned to receive placebo, with an absolute difference between groups of 2.3%, investigators reported at the annual meeting of the American Society of Clinical Oncology. Benefit was even greater among the subset whose tumor had hormone receptors.

“The ExteNET study, utilizing 12 months of neratinib therapy, is the first study … to demonstrate a significant improvement in invasive disease–free survival at 2 years. The underlying [molecular] cross-talk mechanism, which may explain the observed greater benefit in the hormone receptor–positive cohort, clearly requires further evaluation in other studies,” said Dr. Arlene Chan, a medical oncologist at the Breast Cancer Research Centre of Western Australia and Mount Medical Centre, both in Perth.

Grade 3 or 4 diarrhea was problematic, however, occurring in 40% of the neratinib group and often leading to dose reductions and discontinuations. “Studies have shown that the incidence of diarrhea can be attenuated with the use of an intensive loperamide prophylaxis regimen, and we believe that by adopting this approach, it will make this treatment far more tolerable for all our patients,” she noted.

Invited discussant Dr. Shanu Modi of Memorial Sloan Kettering Cancer Center, New York, noted that there are factors weighing both for and against making extended therapy with neratinib a new standard of care.

“On the one hand, the absolute disease-free survival gain is real, and if you recall, these results are similar to what we saw with the 2-year data for the original adjuvant trastuzumab studies,” she elaborated. “But on the other hand, we don’t have overall survival data, and that is something we did have with the trastuzumab trials. Additionally, from a practical perspective, to which population do we apply these results? In the U.S., pertuzumab is an option for our high-risk HER2-positive patients, so would the benefit seen with neratinib persist in these pertuzumab-pretreated patients? For our lower-risk patients, stage 1 patients, for whom we have very effective taxane-based therapies, how do we justify the risks of treatment for the potential small benefits expected in this group that already does very well?”

“We await the longer follow-up and FDA deliberations to determine how and whether to offer neratinib as extended therapy to our early-stage patients,” Dr. Modi concluded. “How will these ExteNET data apply to patients who have received pertuzumab? This is an area where further clinical research could guide us forward.”

Session attendee Richard Gelber, Ph.D., of the Dana-Farber Cancer Institute, Boston, agreed with Dr. Chan that the trial’s short follow-up is a limitation. “I would hypothesize that it’s actually a fatal limitation for the results we saw today. I would consider the results nonactionable. In fact, the early results of ALTTO done at about that time showed an even larger advantage than we saw here today,” he said, referring to an adjuvant trial of lapatinib that was ultimately negative. “Similar pathway, and I would propose that the longer-term follow-up would likely prove a negative result.”

Dr. Chan replied: “I think that in terms of the absolute benefit derived from our study, we need to take it in the context that this is added upon a treatment intervention with trastuzumab, which has already provided an enormous benefit for our patients,” so it may be unreasonable to expect another large gain; furthermore, the MA.17 trial, which investigated extended adjuvant hormonal therapy, had an even smaller benefit at the 2-year mark, but eventually concluded in favor of the therapy. She added that the ExteNET trial will continue to follow patients out to 5 years.

Dr. Steven Vogl, an oncologist in the Bronx, New York, didn’t mince words about the observed toxicity, saying, “This neratinib sounds like a terrible drug. How many people were still taking it after 6 months and how many actually finished a year of the stuff?”

The relative dose intensity was 81% in the neratinib arm, compared with 98% in the placebo arm, according to Dr. Chan. Only 61% of patients in the former were able to complete the full year of planned treatment.

“Seeing an impressive response with that degree of noncompliance suggests that maybe you don’t need as much drug as you gave,” Dr. Vogl proposed.

ExteNET, sponsored by Puma Biotechnology, enrolled 2,840 women who had completed adjuvant chemotherapy and trastuzumab (Herceptin) for early breast cancer that was HER2 positive by local assessment. The women were randomized evenly to neratinib – an oral irreversible inhibitor of HER 1, 2, and 4 shown to be active in trastuzumab-pretreated patients – or placebo.

The study had a complex evolution, with several major amendments of the protocol due to new results from other trials and changes in sponsorship, Dr. Chan noted. Initially, women were required to have stage 1 to 3c disease with receipt of the last trastuzumab dose no more than 2 years earlier; later, that was modified to stage 2 to 3 disease and receipt of the last trastuzumab dose no more than 1 year earlier. Also, the duration of follow-up was temporarily shortened from 5 years to 2 years.

In intention-to-treat analyses, the 2-year rate of invasive disease–free survival was 93.9% with neratinib and 91.6% with placebo (hazard ratio, 0.67; P = .009), reported Dr. Chan, who disclosed that she has a consulting or advisory role with Pfizer, and that she is on the speakers’ bureau and is provided with travel, accommodation, and expenses by Pierre Fabre.

In some noteworthy subgroup findings, benefit was even greater among women with hormone receptor–positive disease (hazard ratio, 0.51; P = .001) or centrally confirmed HER2-positive disease (hazard ratio, 0.51; P = .002).

The neratinib group also had a significantly better rate of survival with freedom from invasive and in situ disease combined (93.9% vs. 91.0%; hazard ratio, 0.63; P = .002).

In terms of adverse events of special interest, neratinib was associated with a sharply higher rate of grade 3 or 4 diarrhea when compared to placebo (40% vs. 2%), as expected from its mechanism of action, Dr. Chan said. But rates of cardiac toxicity and interstitial lung disease did not differ between groups.

CHICAGO – Extending adjuvant targeted therapy for HER2-positive early breast cancer by a year with neratinib further protects against recurrence, suggest primary results of the phase III randomized ExteNET trial (Study Evaluating the Effects of Neratinib After Adjuvant Trastuzumab in Women With Early-Stage Breast Cancer).

At 2 years of follow-up, women assigned to receive neratinib, an investigational pan-HER tyrosine kinase inhibitor, had a one-third reduction in the risk of invasive breast cancer or death relative to counterparts assigned to receive placebo, with an absolute difference between groups of 2.3%, investigators reported at the annual meeting of the American Society of Clinical Oncology. Benefit was even greater among the subset whose tumor had hormone receptors.

“The ExteNET study, utilizing 12 months of neratinib therapy, is the first study … to demonstrate a significant improvement in invasive disease–free survival at 2 years. The underlying [molecular] cross-talk mechanism, which may explain the observed greater benefit in the hormone receptor–positive cohort, clearly requires further evaluation in other studies,” said Dr. Arlene Chan, a medical oncologist at the Breast Cancer Research Centre of Western Australia and Mount Medical Centre, both in Perth.

Grade 3 or 4 diarrhea was problematic, however, occurring in 40% of the neratinib group and often leading to dose reductions and discontinuations. “Studies have shown that the incidence of diarrhea can be attenuated with the use of an intensive loperamide prophylaxis regimen, and we believe that by adopting this approach, it will make this treatment far more tolerable for all our patients,” she noted.

Invited discussant Dr. Shanu Modi of Memorial Sloan Kettering Cancer Center, New York, noted that there are factors weighing both for and against making extended therapy with neratinib a new standard of care.

“On the one hand, the absolute disease-free survival gain is real, and if you recall, these results are similar to what we saw with the 2-year data for the original adjuvant trastuzumab studies,” she elaborated. “But on the other hand, we don’t have overall survival data, and that is something we did have with the trastuzumab trials. Additionally, from a practical perspective, to which population do we apply these results? In the U.S., pertuzumab is an option for our high-risk HER2-positive patients, so would the benefit seen with neratinib persist in these pertuzumab-pretreated patients? For our lower-risk patients, stage 1 patients, for whom we have very effective taxane-based therapies, how do we justify the risks of treatment for the potential small benefits expected in this group that already does very well?”

“We await the longer follow-up and FDA deliberations to determine how and whether to offer neratinib as extended therapy to our early-stage patients,” Dr. Modi concluded. “How will these ExteNET data apply to patients who have received pertuzumab? This is an area where further clinical research could guide us forward.”

Session attendee Richard Gelber, Ph.D., of the Dana-Farber Cancer Institute, Boston, agreed with Dr. Chan that the trial’s short follow-up is a limitation. “I would hypothesize that it’s actually a fatal limitation for the results we saw today. I would consider the results nonactionable. In fact, the early results of ALTTO done at about that time showed an even larger advantage than we saw here today,” he said, referring to an adjuvant trial of lapatinib that was ultimately negative. “Similar pathway, and I would propose that the longer-term follow-up would likely prove a negative result.”

Dr. Chan replied: “I think that in terms of the absolute benefit derived from our study, we need to take it in the context that this is added upon a treatment intervention with trastuzumab, which has already provided an enormous benefit for our patients,” so it may be unreasonable to expect another large gain; furthermore, the MA.17 trial, which investigated extended adjuvant hormonal therapy, had an even smaller benefit at the 2-year mark, but eventually concluded in favor of the therapy. She added that the ExteNET trial will continue to follow patients out to 5 years.

Dr. Steven Vogl, an oncologist in the Bronx, New York, didn’t mince words about the observed toxicity, saying, “This neratinib sounds like a terrible drug. How many people were still taking it after 6 months and how many actually finished a year of the stuff?”

The relative dose intensity was 81% in the neratinib arm, compared with 98% in the placebo arm, according to Dr. Chan. Only 61% of patients in the former were able to complete the full year of planned treatment.

“Seeing an impressive response with that degree of noncompliance suggests that maybe you don’t need as much drug as you gave,” Dr. Vogl proposed.

ExteNET, sponsored by Puma Biotechnology, enrolled 2,840 women who had completed adjuvant chemotherapy and trastuzumab (Herceptin) for early breast cancer that was HER2 positive by local assessment. The women were randomized evenly to neratinib – an oral irreversible inhibitor of HER 1, 2, and 4 shown to be active in trastuzumab-pretreated patients – or placebo.

The study had a complex evolution, with several major amendments of the protocol due to new results from other trials and changes in sponsorship, Dr. Chan noted. Initially, women were required to have stage 1 to 3c disease with receipt of the last trastuzumab dose no more than 2 years earlier; later, that was modified to stage 2 to 3 disease and receipt of the last trastuzumab dose no more than 1 year earlier. Also, the duration of follow-up was temporarily shortened from 5 years to 2 years.

In intention-to-treat analyses, the 2-year rate of invasive disease–free survival was 93.9% with neratinib and 91.6% with placebo (hazard ratio, 0.67; P = .009), reported Dr. Chan, who disclosed that she has a consulting or advisory role with Pfizer, and that she is on the speakers’ bureau and is provided with travel, accommodation, and expenses by Pierre Fabre.

In some noteworthy subgroup findings, benefit was even greater among women with hormone receptor–positive disease (hazard ratio, 0.51; P = .001) or centrally confirmed HER2-positive disease (hazard ratio, 0.51; P = .002).

The neratinib group also had a significantly better rate of survival with freedom from invasive and in situ disease combined (93.9% vs. 91.0%; hazard ratio, 0.63; P = .002).

In terms of adverse events of special interest, neratinib was associated with a sharply higher rate of grade 3 or 4 diarrhea when compared to placebo (40% vs. 2%), as expected from its mechanism of action, Dr. Chan said. But rates of cardiac toxicity and interstitial lung disease did not differ between groups.

CHICAGO – Extending adjuvant targeted therapy for HER2-positive early breast cancer by a year with neratinib further protects against recurrence, suggest primary results of the phase III randomized ExteNET trial (Study Evaluating the Effects of Neratinib After Adjuvant Trastuzumab in Women With Early-Stage Breast Cancer).

At 2 years of follow-up, women assigned to receive neratinib, an investigational pan-HER tyrosine kinase inhibitor, had a one-third reduction in the risk of invasive breast cancer or death relative to counterparts assigned to receive placebo, with an absolute difference between groups of 2.3%, investigators reported at the annual meeting of the American Society of Clinical Oncology. Benefit was even greater among the subset whose tumor had hormone receptors.

“The ExteNET study, utilizing 12 months of neratinib therapy, is the first study … to demonstrate a significant improvement in invasive disease–free survival at 2 years. The underlying [molecular] cross-talk mechanism, which may explain the observed greater benefit in the hormone receptor–positive cohort, clearly requires further evaluation in other studies,” said Dr. Arlene Chan, a medical oncologist at the Breast Cancer Research Centre of Western Australia and Mount Medical Centre, both in Perth.

Grade 3 or 4 diarrhea was problematic, however, occurring in 40% of the neratinib group and often leading to dose reductions and discontinuations. “Studies have shown that the incidence of diarrhea can be attenuated with the use of an intensive loperamide prophylaxis regimen, and we believe that by adopting this approach, it will make this treatment far more tolerable for all our patients,” she noted.

Invited discussant Dr. Shanu Modi of Memorial Sloan Kettering Cancer Center, New York, noted that there are factors weighing both for and against making extended therapy with neratinib a new standard of care.

“On the one hand, the absolute disease-free survival gain is real, and if you recall, these results are similar to what we saw with the 2-year data for the original adjuvant trastuzumab studies,” she elaborated. “But on the other hand, we don’t have overall survival data, and that is something we did have with the trastuzumab trials. Additionally, from a practical perspective, to which population do we apply these results? In the U.S., pertuzumab is an option for our high-risk HER2-positive patients, so would the benefit seen with neratinib persist in these pertuzumab-pretreated patients? For our lower-risk patients, stage 1 patients, for whom we have very effective taxane-based therapies, how do we justify the risks of treatment for the potential small benefits expected in this group that already does very well?”

“We await the longer follow-up and FDA deliberations to determine how and whether to offer neratinib as extended therapy to our early-stage patients,” Dr. Modi concluded. “How will these ExteNET data apply to patients who have received pertuzumab? This is an area where further clinical research could guide us forward.”

Session attendee Richard Gelber, Ph.D., of the Dana-Farber Cancer Institute, Boston, agreed with Dr. Chan that the trial’s short follow-up is a limitation. “I would hypothesize that it’s actually a fatal limitation for the results we saw today. I would consider the results nonactionable. In fact, the early results of ALTTO done at about that time showed an even larger advantage than we saw here today,” he said, referring to an adjuvant trial of lapatinib that was ultimately negative. “Similar pathway, and I would propose that the longer-term follow-up would likely prove a negative result.”

Dr. Chan replied: “I think that in terms of the absolute benefit derived from our study, we need to take it in the context that this is added upon a treatment intervention with trastuzumab, which has already provided an enormous benefit for our patients,” so it may be unreasonable to expect another large gain; furthermore, the MA.17 trial, which investigated extended adjuvant hormonal therapy, had an even smaller benefit at the 2-year mark, but eventually concluded in favor of the therapy. She added that the ExteNET trial will continue to follow patients out to 5 years.

Dr. Steven Vogl, an oncologist in the Bronx, New York, didn’t mince words about the observed toxicity, saying, “This neratinib sounds like a terrible drug. How many people were still taking it after 6 months and how many actually finished a year of the stuff?”

The relative dose intensity was 81% in the neratinib arm, compared with 98% in the placebo arm, according to Dr. Chan. Only 61% of patients in the former were able to complete the full year of planned treatment.

“Seeing an impressive response with that degree of noncompliance suggests that maybe you don’t need as much drug as you gave,” Dr. Vogl proposed.

ExteNET, sponsored by Puma Biotechnology, enrolled 2,840 women who had completed adjuvant chemotherapy and trastuzumab (Herceptin) for early breast cancer that was HER2 positive by local assessment. The women were randomized evenly to neratinib – an oral irreversible inhibitor of HER 1, 2, and 4 shown to be active in trastuzumab-pretreated patients – or placebo.

The study had a complex evolution, with several major amendments of the protocol due to new results from other trials and changes in sponsorship, Dr. Chan noted. Initially, women were required to have stage 1 to 3c disease with receipt of the last trastuzumab dose no more than 2 years earlier; later, that was modified to stage 2 to 3 disease and receipt of the last trastuzumab dose no more than 1 year earlier. Also, the duration of follow-up was temporarily shortened from 5 years to 2 years.

In intention-to-treat analyses, the 2-year rate of invasive disease–free survival was 93.9% with neratinib and 91.6% with placebo (hazard ratio, 0.67; P = .009), reported Dr. Chan, who disclosed that she has a consulting or advisory role with Pfizer, and that she is on the speakers’ bureau and is provided with travel, accommodation, and expenses by Pierre Fabre.

In some noteworthy subgroup findings, benefit was even greater among women with hormone receptor–positive disease (hazard ratio, 0.51; P = .001) or centrally confirmed HER2-positive disease (hazard ratio, 0.51; P = .002).

The neratinib group also had a significantly better rate of survival with freedom from invasive and in situ disease combined (93.9% vs. 91.0%; hazard ratio, 0.63; P = .002).

In terms of adverse events of special interest, neratinib was associated with a sharply higher rate of grade 3 or 4 diarrhea when compared to placebo (40% vs. 2%), as expected from its mechanism of action, Dr. Chan said. But rates of cardiac toxicity and interstitial lung disease did not differ between groups.

SEATTLE – The pain of knee osteoarthritis is not exacerbated by regular exercise such as walking and may actually be relieved by it, according to several findings presented at the World Congress on Osteoarthritis.

“Physical activity is important for the reduction of knee pain and the prevention of functional limitation in knee osteoarthritis,” Daniel White, Sc.D., said.

“We should be recommending walking to people with painful knee osteoarthritis. Just as a preliminary goal, we can start with 3,000 steps per day and ultimately progress people to at least 6,000 steps per day,” he added.

National guidelines issued in 2008 for the general population call for at least 150 minutes per week of moderate to vigorous–intensity physical activity, according to Dr. White of the department of physical therapy at the University of Delaware in Newark. When that recommendation is applied to walking, which is the most common physical activity among older adults (Arthritis Care Res. 2014;66:139-46), it translates to a brisk pace that permits conversation but is exertional enough to cause sweating. Meeting the goal would mean approximately 100 steps per minute (Am. J. Prev. Med. 2009;36:410-5).

“The clinical hypothesis is that osteoarthritis pain is limiting your physical activity, but whether that has been empirically [established] has yet to be seen,” Dr. White said. For example, investigators for an Osteoarthritis Initiative study found that only 13% of men and 8% of women with knee osteoarthritis met the criteria for the national guideline (Arthritis Rheum. 2011;63:3372-82), but also noted that these values differed little from those of the general population. Data from the Multicenter Osteoarthritis Study found similarly low proportions, regardless of the presence of radiographic disease and the severity of knee pain (Arthritis Rheum. 2013;65:139-47). In a cohort that underwent total knee replacement, patients had more than 180% improvements in subjective pain and function at 6 months, yet their objectively measured time spent walking increased by only 5% (Clin. Orthop. Relat. Res. 2008;466:2201-8).

These findings suggest that osteoarthritis and pain may have a limited role in explaining physical inactivity, according to Dr. White. “An implication of this is that improvements in disease and pain may not lead to more physical activity; in other words, the pills you give to people to make them feel better or the exercises that they may do to improve their knee pain may not necessarily increase the amount of unstructured physical activity that people do on a day-to-day basis. Also, physical activity specifically may need to be targeted; you need to increase physical activity in a specific way rather than just expecting it to happen once the barriers of pain and disease are removed.”

Recommendations for physical activity must consider both potential risks and benefits, he noted. Data regarding its impact on structural changes in the knee are mixed. Conversely, there is substantial evidence that physical activity moderately reduces knee pain (Cochrane Database Syst Rev. 2015;1:CD004376) and lowers the likelihood of developing functional limitations in a dose-response manner (Arthritis Care Res. 2014;66:1328-36). And there are a variety of other health benefits, some of which may affect osteoarthritis, such as weight maintenance.

“In my mind, the benefits outweigh the risks for promoting physical activity in this patient population. And specifically, given that walking is the most common physical activity, from a clinical perspective, there is very strong evidence to recommend walking to this patient population,” Dr. White said at the meeting sponsored by the Osteoarthritis Research Society International.

He further endorsed use of a pedometer as a practical, objective way to measure this activity. “Regardless of what instrument or device you use, they all measure steps, and that is sort of the common denominator which is a very understandable outcome that patients can relate to, that clinicians understand,” he elaborated. Moreover, a meta-analysis has shown that interventions using pedometers achieve greater increases in walking (JAMA 2007;298:2296-304).

The above analysis of impact on functional limitations in people with knee osteoarthritis also helps to define target walking goals, according to Dr. White, who disclosed that he had no relevant conflicts of interest. The study showed that 95% of people who did not develop functional limitations walked at least 3,000 steps per day, and that 6,000 steps per day best discriminated between those who did and did not develop functional limitations.

Assuming that a moderate intensity of walking is 100 steps per minute, this step range translates to 30-60 minutes of walking per day, he said. As half of 60-year-olds in the general population already walk approximately 40-50 minutes daily as part of their usual activities (J. Gerontol. A Biol. Sci. Med. Sci. 2013;68:1426-32), they may need to add only 10 more minutes. And a recent report suggests that even people with severe knee osteoarthritis find this amount to be safe and feasible (Osteoarthritis Cartilage 2015 April 14 [doi:10.1016/j.joca.2015.04.001]).

SEATTLE – The pain of knee osteoarthritis is not exacerbated by regular exercise such as walking and may actually be relieved by it, according to several findings presented at the World Congress on Osteoarthritis.

“Physical activity is important for the reduction of knee pain and the prevention of functional limitation in knee osteoarthritis,” Daniel White, Sc.D., said.

“We should be recommending walking to people with painful knee osteoarthritis. Just as a preliminary goal, we can start with 3,000 steps per day and ultimately progress people to at least 6,000 steps per day,” he added.

National guidelines issued in 2008 for the general population call for at least 150 minutes per week of moderate to vigorous–intensity physical activity, according to Dr. White of the department of physical therapy at the University of Delaware in Newark. When that recommendation is applied to walking, which is the most common physical activity among older adults (Arthritis Care Res. 2014;66:139-46), it translates to a brisk pace that permits conversation but is exertional enough to cause sweating. Meeting the goal would mean approximately 100 steps per minute (Am. J. Prev. Med. 2009;36:410-5).

“The clinical hypothesis is that osteoarthritis pain is limiting your physical activity, but whether that has been empirically [established] has yet to be seen,” Dr. White said. For example, investigators for an Osteoarthritis Initiative study found that only 13% of men and 8% of women with knee osteoarthritis met the criteria for the national guideline (Arthritis Rheum. 2011;63:3372-82), but also noted that these values differed little from those of the general population. Data from the Multicenter Osteoarthritis Study found similarly low proportions, regardless of the presence of radiographic disease and the severity of knee pain (Arthritis Rheum. 2013;65:139-47). In a cohort that underwent total knee replacement, patients had more than 180% improvements in subjective pain and function at 6 months, yet their objectively measured time spent walking increased by only 5% (Clin. Orthop. Relat. Res. 2008;466:2201-8).

These findings suggest that osteoarthritis and pain may have a limited role in explaining physical inactivity, according to Dr. White. “An implication of this is that improvements in disease and pain may not lead to more physical activity; in other words, the pills you give to people to make them feel better or the exercises that they may do to improve their knee pain may not necessarily increase the amount of unstructured physical activity that people do on a day-to-day basis. Also, physical activity specifically may need to be targeted; you need to increase physical activity in a specific way rather than just expecting it to happen once the barriers of pain and disease are removed.”

Recommendations for physical activity must consider both potential risks and benefits, he noted. Data regarding its impact on structural changes in the knee are mixed. Conversely, there is substantial evidence that physical activity moderately reduces knee pain (Cochrane Database Syst Rev. 2015;1:CD004376) and lowers the likelihood of developing functional limitations in a dose-response manner (Arthritis Care Res. 2014;66:1328-36). And there are a variety of other health benefits, some of which may affect osteoarthritis, such as weight maintenance.

“In my mind, the benefits outweigh the risks for promoting physical activity in this patient population. And specifically, given that walking is the most common physical activity, from a clinical perspective, there is very strong evidence to recommend walking to this patient population,” Dr. White said at the meeting sponsored by the Osteoarthritis Research Society International.

He further endorsed use of a pedometer as a practical, objective way to measure this activity. “Regardless of what instrument or device you use, they all measure steps, and that is sort of the common denominator which is a very understandable outcome that patients can relate to, that clinicians understand,” he elaborated. Moreover, a meta-analysis has shown that interventions using pedometers achieve greater increases in walking (JAMA 2007;298:2296-304).

The above analysis of impact on functional limitations in people with knee osteoarthritis also helps to define target walking goals, according to Dr. White, who disclosed that he had no relevant conflicts of interest. The study showed that 95% of people who did not develop functional limitations walked at least 3,000 steps per day, and that 6,000 steps per day best discriminated between those who did and did not develop functional limitations.

Assuming that a moderate intensity of walking is 100 steps per minute, this step range translates to 30-60 minutes of walking per day, he said. As half of 60-year-olds in the general population already walk approximately 40-50 minutes daily as part of their usual activities (J. Gerontol. A Biol. Sci. Med. Sci. 2013;68:1426-32), they may need to add only 10 more minutes. And a recent report suggests that even people with severe knee osteoarthritis find this amount to be safe and feasible (Osteoarthritis Cartilage 2015 April 14 [doi:10.1016/j.joca.2015.04.001]).

SEATTLE – The pain of knee osteoarthritis is not exacerbated by regular exercise such as walking and may actually be relieved by it, according to several findings presented at the World Congress on Osteoarthritis.

“Physical activity is important for the reduction of knee pain and the prevention of functional limitation in knee osteoarthritis,” Daniel White, Sc.D., said.

“We should be recommending walking to people with painful knee osteoarthritis. Just as a preliminary goal, we can start with 3,000 steps per day and ultimately progress people to at least 6,000 steps per day,” he added.

National guidelines issued in 2008 for the general population call for at least 150 minutes per week of moderate to vigorous–intensity physical activity, according to Dr. White of the department of physical therapy at the University of Delaware in Newark. When that recommendation is applied to walking, which is the most common physical activity among older adults (Arthritis Care Res. 2014;66:139-46), it translates to a brisk pace that permits conversation but is exertional enough to cause sweating. Meeting the goal would mean approximately 100 steps per minute (Am. J. Prev. Med. 2009;36:410-5).

“The clinical hypothesis is that osteoarthritis pain is limiting your physical activity, but whether that has been empirically [established] has yet to be seen,” Dr. White said. For example, investigators for an Osteoarthritis Initiative study found that only 13% of men and 8% of women with knee osteoarthritis met the criteria for the national guideline (Arthritis Rheum. 2011;63:3372-82), but also noted that these values differed little from those of the general population. Data from the Multicenter Osteoarthritis Study found similarly low proportions, regardless of the presence of radiographic disease and the severity of knee pain (Arthritis Rheum. 2013;65:139-47). In a cohort that underwent total knee replacement, patients had more than 180% improvements in subjective pain and function at 6 months, yet their objectively measured time spent walking increased by only 5% (Clin. Orthop. Relat. Res. 2008;466:2201-8).

These findings suggest that osteoarthritis and pain may have a limited role in explaining physical inactivity, according to Dr. White. “An implication of this is that improvements in disease and pain may not lead to more physical activity; in other words, the pills you give to people to make them feel better or the exercises that they may do to improve their knee pain may not necessarily increase the amount of unstructured physical activity that people do on a day-to-day basis. Also, physical activity specifically may need to be targeted; you need to increase physical activity in a specific way rather than just expecting it to happen once the barriers of pain and disease are removed.”

Recommendations for physical activity must consider both potential risks and benefits, he noted. Data regarding its impact on structural changes in the knee are mixed. Conversely, there is substantial evidence that physical activity moderately reduces knee pain (Cochrane Database Syst Rev. 2015;1:CD004376) and lowers the likelihood of developing functional limitations in a dose-response manner (Arthritis Care Res. 2014;66:1328-36). And there are a variety of other health benefits, some of which may affect osteoarthritis, such as weight maintenance.

“In my mind, the benefits outweigh the risks for promoting physical activity in this patient population. And specifically, given that walking is the most common physical activity, from a clinical perspective, there is very strong evidence to recommend walking to this patient population,” Dr. White said at the meeting sponsored by the Osteoarthritis Research Society International.

He further endorsed use of a pedometer as a practical, objective way to measure this activity. “Regardless of what instrument or device you use, they all measure steps, and that is sort of the common denominator which is a very understandable outcome that patients can relate to, that clinicians understand,” he elaborated. Moreover, a meta-analysis has shown that interventions using pedometers achieve greater increases in walking (JAMA 2007;298:2296-304).

The above analysis of impact on functional limitations in people with knee osteoarthritis also helps to define target walking goals, according to Dr. White, who disclosed that he had no relevant conflicts of interest. The study showed that 95% of people who did not develop functional limitations walked at least 3,000 steps per day, and that 6,000 steps per day best discriminated between those who did and did not develop functional limitations.

Assuming that a moderate intensity of walking is 100 steps per minute, this step range translates to 30-60 minutes of walking per day, he said. As half of 60-year-olds in the general population already walk approximately 40-50 minutes daily as part of their usual activities (J. Gerontol. A Biol. Sci. Med. Sci. 2013;68:1426-32), they may need to add only 10 more minutes. And a recent report suggests that even people with severe knee osteoarthritis find this amount to be safe and feasible (Osteoarthritis Cartilage 2015 April 14 [doi:10.1016/j.joca.2015.04.001]).

SEATTLE – C-reactive protein is associated with the presence and progression of bone marrow lesions in patients with osteoarthritis of the knee, according to data from a cohort study of 192 patients that were reported at the World Congress on Osteoarthritis.

“Osteoarthritis has predominantly been viewed as a degenerative joint disease driven by continued and irreversible deterioration of joints,” said lead investigator Zhaohua (Alex) Zhu, a PhD candidate at the Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. “However, current studies suggest a different way of understanding this disease, showing that the development of osteoarthritis may be in great part driven by a low-grade inflammatory process.”

He and his colleagues analyzed data from the randomized phase III VIDEO trial (Vitamin D Effect on Osteoarthritis), which enrolled patients aged 50-79 years who had symptomatic knee osteoarthritis and vitamin D deficiency. Analyses were based on 192 patients who had measurement of high-sensitivity C-reactive protein (CRP) and resistin (a proinflammatory cytokine secreted by adipose tissue) at baseline and again 2 years later.

Bone marrow lesions also were assessed at both time points with a modified version of the whole-organ magnetic resonance imaging score (WORMS). “Bone marrow lesions may represent areas of edema, inflammation, and remodeling,” Mr. Zhu explained. “Plenty of studies have shown that bone marrow lesions are linked to knee pain, cartilage volumes, and cartilage defect changes, so it’s a very important subchondral feature in knee osteoarthritis. But so far, the cause of bone marrow lesions remains unclear.”

Multivariate analyses showed that, as patients’ baseline CRP quartile increased, so did their odds of having total knee bone marrow lesions at that time (odds ratio, 1.45) and worsening of these lesions during follow-up (odds ratio, 1.56), according to data reported at the meeting, which was sponsored by the Osteoarthritis Research Society International. Additionally, the absolute change in CRP level during follow-up was positively associated with a worsening of lesions.

Associations for resistin were generally weaker or absent, with the only significant one seen between baseline quartile of that marker and bone marrow lesions at that time, reported Dr. Zhu.

In an interview, Dr. Timothy McAlindon, one of the session’s comoderators and professor of medicine at Tufts University in Boston, said that the study helps elucidate a possible role for adipose tissue, overweight, and adipocytokines in one subphenotype of osteoarthritis. “They found some associations, and I think those associations are probably the basis for further study and hopefully more understanding of what they mean,” he commented.

Dr. Rik Lories, the other session comoderator and professor at the University of Leuven (Belgium), noted that research on this topic is complicated. “You can ask questions about the chicken and the egg in this case because, if you are obese, you have a higher fat mass, so you are more likely to produce proinflammatory mediators, which can then induce your CRP. The fact that you have more inflammatory mediators could also contribute to the fact that you get these bone marrow lesions,” he elaborated. “But on the other hand, if you put more weight on your knees, the impact may also play a role. So it remains a very, very difficult thing to study and to come up with clear answers.”

Dr. Zhu disclosed no relevant conflicts of interest.

SEATTLE – C-reactive protein is associated with the presence and progression of bone marrow lesions in patients with osteoarthritis of the knee, according to data from a cohort study of 192 patients that were reported at the World Congress on Osteoarthritis.

“Osteoarthritis has predominantly been viewed as a degenerative joint disease driven by continued and irreversible deterioration of joints,” said lead investigator Zhaohua (Alex) Zhu, a PhD candidate at the Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. “However, current studies suggest a different way of understanding this disease, showing that the development of osteoarthritis may be in great part driven by a low-grade inflammatory process.”

He and his colleagues analyzed data from the randomized phase III VIDEO trial (Vitamin D Effect on Osteoarthritis), which enrolled patients aged 50-79 years who had symptomatic knee osteoarthritis and vitamin D deficiency. Analyses were based on 192 patients who had measurement of high-sensitivity C-reactive protein (CRP) and resistin (a proinflammatory cytokine secreted by adipose tissue) at baseline and again 2 years later.

Bone marrow lesions also were assessed at both time points with a modified version of the whole-organ magnetic resonance imaging score (WORMS). “Bone marrow lesions may represent areas of edema, inflammation, and remodeling,” Mr. Zhu explained. “Plenty of studies have shown that bone marrow lesions are linked to knee pain, cartilage volumes, and cartilage defect changes, so it’s a very important subchondral feature in knee osteoarthritis. But so far, the cause of bone marrow lesions remains unclear.”

Multivariate analyses showed that, as patients’ baseline CRP quartile increased, so did their odds of having total knee bone marrow lesions at that time (odds ratio, 1.45) and worsening of these lesions during follow-up (odds ratio, 1.56), according to data reported at the meeting, which was sponsored by the Osteoarthritis Research Society International. Additionally, the absolute change in CRP level during follow-up was positively associated with a worsening of lesions.

Associations for resistin were generally weaker or absent, with the only significant one seen between baseline quartile of that marker and bone marrow lesions at that time, reported Dr. Zhu.

In an interview, Dr. Timothy McAlindon, one of the session’s comoderators and professor of medicine at Tufts University in Boston, said that the study helps elucidate a possible role for adipose tissue, overweight, and adipocytokines in one subphenotype of osteoarthritis. “They found some associations, and I think those associations are probably the basis for further study and hopefully more understanding of what they mean,” he commented.

Dr. Rik Lories, the other session comoderator and professor at the University of Leuven (Belgium), noted that research on this topic is complicated. “You can ask questions about the chicken and the egg in this case because, if you are obese, you have a higher fat mass, so you are more likely to produce proinflammatory mediators, which can then induce your CRP. The fact that you have more inflammatory mediators could also contribute to the fact that you get these bone marrow lesions,” he elaborated. “But on the other hand, if you put more weight on your knees, the impact may also play a role. So it remains a very, very difficult thing to study and to come up with clear answers.”

Dr. Zhu disclosed no relevant conflicts of interest.

SEATTLE – C-reactive protein is associated with the presence and progression of bone marrow lesions in patients with osteoarthritis of the knee, according to data from a cohort study of 192 patients that were reported at the World Congress on Osteoarthritis.

“Osteoarthritis has predominantly been viewed as a degenerative joint disease driven by continued and irreversible deterioration of joints,” said lead investigator Zhaohua (Alex) Zhu, a PhD candidate at the Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. “However, current studies suggest a different way of understanding this disease, showing that the development of osteoarthritis may be in great part driven by a low-grade inflammatory process.”

He and his colleagues analyzed data from the randomized phase III VIDEO trial (Vitamin D Effect on Osteoarthritis), which enrolled patients aged 50-79 years who had symptomatic knee osteoarthritis and vitamin D deficiency. Analyses were based on 192 patients who had measurement of high-sensitivity C-reactive protein (CRP) and resistin (a proinflammatory cytokine secreted by adipose tissue) at baseline and again 2 years later.

Bone marrow lesions also were assessed at both time points with a modified version of the whole-organ magnetic resonance imaging score (WORMS). “Bone marrow lesions may represent areas of edema, inflammation, and remodeling,” Mr. Zhu explained. “Plenty of studies have shown that bone marrow lesions are linked to knee pain, cartilage volumes, and cartilage defect changes, so it’s a very important subchondral feature in knee osteoarthritis. But so far, the cause of bone marrow lesions remains unclear.”

Multivariate analyses showed that, as patients’ baseline CRP quartile increased, so did their odds of having total knee bone marrow lesions at that time (odds ratio, 1.45) and worsening of these lesions during follow-up (odds ratio, 1.56), according to data reported at the meeting, which was sponsored by the Osteoarthritis Research Society International. Additionally, the absolute change in CRP level during follow-up was positively associated with a worsening of lesions.

Associations for resistin were generally weaker or absent, with the only significant one seen between baseline quartile of that marker and bone marrow lesions at that time, reported Dr. Zhu.

In an interview, Dr. Timothy McAlindon, one of the session’s comoderators and professor of medicine at Tufts University in Boston, said that the study helps elucidate a possible role for adipose tissue, overweight, and adipocytokines in one subphenotype of osteoarthritis. “They found some associations, and I think those associations are probably the basis for further study and hopefully more understanding of what they mean,” he commented.

Dr. Rik Lories, the other session comoderator and professor at the University of Leuven (Belgium), noted that research on this topic is complicated. “You can ask questions about the chicken and the egg in this case because, if you are obese, you have a higher fat mass, so you are more likely to produce proinflammatory mediators, which can then induce your CRP. The fact that you have more inflammatory mediators could also contribute to the fact that you get these bone marrow lesions,” he elaborated. “But on the other hand, if you put more weight on your knees, the impact may also play a role. So it remains a very, very difficult thing to study and to come up with clear answers.”

Dr. Zhu disclosed no relevant conflicts of interest.