Susan London

Some women who have experienced a pregnancy loss can increase their odds of a live birth in the next pregnancy simply by taking aspirin, investigators reported at the Pregnancy Meeting, the annual meeting of the Society for Maternal-Fetal Medicine.

A team led by Enrique F. Schisterman, Ph.D., conducted a randomized trial of 1,228 healthy young women who had had up to two prior pregnancy losses, but did not have infertility and were attempting to conceive again.

©jimdeli/Fotolia.com

The women were assigned evenly to take low-dose aspirin (81 mg) or placebo daily, along with folic acid, for up to six menstrual cycles or, if they conceived, up to the 36th week of pregnancy.

Results showed that low-dose aspirin was associated with an absolute 9.2% increase in the rate of live birth among the subset of women who met restricted criteria for pregnancy loss, namely a single pregnancy loss before 20 weeks’ gestation in the past year, reported Dr. Schisterman, who is a senior investigator and chief of the epidemiology branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Rockville, Md.

The benefit was mainly due to early effects. "There was an effect on becoming pregnant and early pregnancy [maintenance], but there were no differences after that," he elaborated. "The implications of that are not only that aspirin will help women become pregnant, but if you start too late, then the effects of aspirin are not there any more."

Analyses in the group with restricted criteria suggested that only about 11 women would need to be treated with low-dose aspirin to achieve one additional live birth.

In contrast, there was no significant benefit of low-dose aspirin among the subset of women who met general criteria for pregnancy loss that required one or two pregnancy losses at any time in the past, but excluded those meeting restricted criteria.

Low-dose aspirin was associated with somewhat higher rates of minor vaginal bleeding and minor gastrointestinal upset, but the drug was not associated with pregnancy loss or with an increased risk of major fetal, neonatal, or maternal complications.

An attendee wondered about the difference between the two subsets of women having differing histories of pregnancy loss, saying, "You would expect more or less the same effect."

Dr. Schisterman maintained that the two groups were not all that similar. "I am not sure I would expect the same result, although when we did some analyses in which we compared those who had a single loss in the restricted stratum to those who had a single loss in the general stratum, we found attenuated but in a similar direction results in the general stratum," he commented. "So it seems that the number of losses is the driving force. But we are still analyzing that data."

Another attendee raised the issue of the timing of the previous pregnancy loss in the subset meeting restricted criteria. "Were you able to identify any influence of the gestational age of the previous loss on the effectiveness of aspirin in the next pregnancy, the randomized pregnancy?" he asked.

"Not yet," Dr. Schisterman replied, noting that all of the losses were fairly early. However, here too, analyses are still ongoing.

Giving some background to the trial, he noted, "We know that inflammation and abnormal blood flow, especially in the uterus, endometrium, ovaries, and placenta, ... are unifying features of outcomes like infertility, pregnancy loss, preeclampsia, preterm delivery, and small for gestational age. So clearly, an ideal therapy that would reduce inflammation and improve blood flow will be the one that we are looking for. Low-dose aspirin could be such a therapy."

The drug has seldom been studied when given in the preconceptional period, but there is a strong rationale for such use, he maintained.

"It impacts endometrial vascularization and placentation. It has very well documented anti-inflammatory effects. It has very few maternal and fetal side effects. It’s safe, widely available, and more importantly, it’s cheap – it costs $2 for the whole pregnancy to treat a woman," he elaborated.

Women enrolled in the trial, known as EAGeR (The Effects of Aspirin in Gestation and Reproduction), were aged 18-39 years. They were roughly evenly split between meeting the restricted criteria and the general criteria for previous pregnancy loss.

On average, the women were 29 years old and had a body mass index of about 27 kg/m². Most were married and white.

Overall, there was only a trend toward a higher rate of live births in the low-dose aspirin group compared with the placebo group (57.8% vs. 52.7%, P = .09), reported Dr. Schisterman.

In stratified analyses, there was a significant benefit of low-dose aspirin in the subset meeting the restricted pregnancy loss criteria (62.4% vs. 53.2%, P = .04) but not in the subset meeting the general pregnancy loss criteria (53.9% vs. 52.2%).

When the investigators more closely assessed the reason for benefit in the women meeting restricted criteria, they found a higher rate of achieving a positive pregnancy test with low-dose aspirin (70.5% vs. 61.7%, P = .03). Rates of progression thereafter to confirmed pregnancy by ultrasound at 6 weeks and ultimately to live birth were similar for the two treatment groups.

Dr. Schisterman disclosed no relevant conflicts of interest.

obnews@elsevier.com

Some women who have experienced a pregnancy loss can increase their odds of a live birth in the next pregnancy simply by taking aspirin, investigators reported at the Pregnancy Meeting, the annual meeting of the Society for Maternal-Fetal Medicine.

A team led by Enrique F. Schisterman, Ph.D., conducted a randomized trial of 1,228 healthy young women who had had up to two prior pregnancy losses, but did not have infertility and were attempting to conceive again.

©jimdeli/Fotolia.com

The women were assigned evenly to take low-dose aspirin (81 mg) or placebo daily, along with folic acid, for up to six menstrual cycles or, if they conceived, up to the 36th week of pregnancy.

Results showed that low-dose aspirin was associated with an absolute 9.2% increase in the rate of live birth among the subset of women who met restricted criteria for pregnancy loss, namely a single pregnancy loss before 20 weeks’ gestation in the past year, reported Dr. Schisterman, who is a senior investigator and chief of the epidemiology branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Rockville, Md.

The benefit was mainly due to early effects. "There was an effect on becoming pregnant and early pregnancy [maintenance], but there were no differences after that," he elaborated. "The implications of that are not only that aspirin will help women become pregnant, but if you start too late, then the effects of aspirin are not there any more."

Analyses in the group with restricted criteria suggested that only about 11 women would need to be treated with low-dose aspirin to achieve one additional live birth.

In contrast, there was no significant benefit of low-dose aspirin among the subset of women who met general criteria for pregnancy loss that required one or two pregnancy losses at any time in the past, but excluded those meeting restricted criteria.

Low-dose aspirin was associated with somewhat higher rates of minor vaginal bleeding and minor gastrointestinal upset, but the drug was not associated with pregnancy loss or with an increased risk of major fetal, neonatal, or maternal complications.

An attendee wondered about the difference between the two subsets of women having differing histories of pregnancy loss, saying, "You would expect more or less the same effect."

Dr. Schisterman maintained that the two groups were not all that similar. "I am not sure I would expect the same result, although when we did some analyses in which we compared those who had a single loss in the restricted stratum to those who had a single loss in the general stratum, we found attenuated but in a similar direction results in the general stratum," he commented. "So it seems that the number of losses is the driving force. But we are still analyzing that data."

Another attendee raised the issue of the timing of the previous pregnancy loss in the subset meeting restricted criteria. "Were you able to identify any influence of the gestational age of the previous loss on the effectiveness of aspirin in the next pregnancy, the randomized pregnancy?" he asked.

"Not yet," Dr. Schisterman replied, noting that all of the losses were fairly early. However, here too, analyses are still ongoing.

Giving some background to the trial, he noted, "We know that inflammation and abnormal blood flow, especially in the uterus, endometrium, ovaries, and placenta, ... are unifying features of outcomes like infertility, pregnancy loss, preeclampsia, preterm delivery, and small for gestational age. So clearly, an ideal therapy that would reduce inflammation and improve blood flow will be the one that we are looking for. Low-dose aspirin could be such a therapy."

The drug has seldom been studied when given in the preconceptional period, but there is a strong rationale for such use, he maintained.

"It impacts endometrial vascularization and placentation. It has very well documented anti-inflammatory effects. It has very few maternal and fetal side effects. It’s safe, widely available, and more importantly, it’s cheap – it costs $2 for the whole pregnancy to treat a woman," he elaborated.

Women enrolled in the trial, known as EAGeR (The Effects of Aspirin in Gestation and Reproduction), were aged 18-39 years. They were roughly evenly split between meeting the restricted criteria and the general criteria for previous pregnancy loss.

On average, the women were 29 years old and had a body mass index of about 27 kg/m². Most were married and white.

Overall, there was only a trend toward a higher rate of live births in the low-dose aspirin group compared with the placebo group (57.8% vs. 52.7%, P = .09), reported Dr. Schisterman.

In stratified analyses, there was a significant benefit of low-dose aspirin in the subset meeting the restricted pregnancy loss criteria (62.4% vs. 53.2%, P = .04) but not in the subset meeting the general pregnancy loss criteria (53.9% vs. 52.2%).

When the investigators more closely assessed the reason for benefit in the women meeting restricted criteria, they found a higher rate of achieving a positive pregnancy test with low-dose aspirin (70.5% vs. 61.7%, P = .03). Rates of progression thereafter to confirmed pregnancy by ultrasound at 6 weeks and ultimately to live birth were similar for the two treatment groups.

Dr. Schisterman disclosed no relevant conflicts of interest.

obnews@elsevier.com

Some women who have experienced a pregnancy loss can increase their odds of a live birth in the next pregnancy simply by taking aspirin, investigators reported at the Pregnancy Meeting, the annual meeting of the Society for Maternal-Fetal Medicine.

A team led by Enrique F. Schisterman, Ph.D., conducted a randomized trial of 1,228 healthy young women who had had up to two prior pregnancy losses, but did not have infertility and were attempting to conceive again.

©jimdeli/Fotolia.com

The women were assigned evenly to take low-dose aspirin (81 mg) or placebo daily, along with folic acid, for up to six menstrual cycles or, if they conceived, up to the 36th week of pregnancy.

Results showed that low-dose aspirin was associated with an absolute 9.2% increase in the rate of live birth among the subset of women who met restricted criteria for pregnancy loss, namely a single pregnancy loss before 20 weeks’ gestation in the past year, reported Dr. Schisterman, who is a senior investigator and chief of the epidemiology branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Rockville, Md.

The benefit was mainly due to early effects. "There was an effect on becoming pregnant and early pregnancy [maintenance], but there were no differences after that," he elaborated. "The implications of that are not only that aspirin will help women become pregnant, but if you start too late, then the effects of aspirin are not there any more."

Analyses in the group with restricted criteria suggested that only about 11 women would need to be treated with low-dose aspirin to achieve one additional live birth.

In contrast, there was no significant benefit of low-dose aspirin among the subset of women who met general criteria for pregnancy loss that required one or two pregnancy losses at any time in the past, but excluded those meeting restricted criteria.

Low-dose aspirin was associated with somewhat higher rates of minor vaginal bleeding and minor gastrointestinal upset, but the drug was not associated with pregnancy loss or with an increased risk of major fetal, neonatal, or maternal complications.

An attendee wondered about the difference between the two subsets of women having differing histories of pregnancy loss, saying, "You would expect more or less the same effect."

Dr. Schisterman maintained that the two groups were not all that similar. "I am not sure I would expect the same result, although when we did some analyses in which we compared those who had a single loss in the restricted stratum to those who had a single loss in the general stratum, we found attenuated but in a similar direction results in the general stratum," he commented. "So it seems that the number of losses is the driving force. But we are still analyzing that data."

Another attendee raised the issue of the timing of the previous pregnancy loss in the subset meeting restricted criteria. "Were you able to identify any influence of the gestational age of the previous loss on the effectiveness of aspirin in the next pregnancy, the randomized pregnancy?" he asked.

"Not yet," Dr. Schisterman replied, noting that all of the losses were fairly early. However, here too, analyses are still ongoing.

Giving some background to the trial, he noted, "We know that inflammation and abnormal blood flow, especially in the uterus, endometrium, ovaries, and placenta, ... are unifying features of outcomes like infertility, pregnancy loss, preeclampsia, preterm delivery, and small for gestational age. So clearly, an ideal therapy that would reduce inflammation and improve blood flow will be the one that we are looking for. Low-dose aspirin could be such a therapy."

The drug has seldom been studied when given in the preconceptional period, but there is a strong rationale for such use, he maintained.

"It impacts endometrial vascularization and placentation. It has very well documented anti-inflammatory effects. It has very few maternal and fetal side effects. It’s safe, widely available, and more importantly, it’s cheap – it costs $2 for the whole pregnancy to treat a woman," he elaborated.

Women enrolled in the trial, known as EAGeR (The Effects of Aspirin in Gestation and Reproduction), were aged 18-39 years. They were roughly evenly split between meeting the restricted criteria and the general criteria for previous pregnancy loss.

On average, the women were 29 years old and had a body mass index of about 27 kg/m². Most were married and white.

Overall, there was only a trend toward a higher rate of live births in the low-dose aspirin group compared with the placebo group (57.8% vs. 52.7%, P = .09), reported Dr. Schisterman.

In stratified analyses, there was a significant benefit of low-dose aspirin in the subset meeting the restricted pregnancy loss criteria (62.4% vs. 53.2%, P = .04) but not in the subset meeting the general pregnancy loss criteria (53.9% vs. 52.2%).

When the investigators more closely assessed the reason for benefit in the women meeting restricted criteria, they found a higher rate of achieving a positive pregnancy test with low-dose aspirin (70.5% vs. 61.7%, P = .03). Rates of progression thereafter to confirmed pregnancy by ultrasound at 6 weeks and ultimately to live birth were similar for the two treatment groups.

Dr. Schisterman disclosed no relevant conflicts of interest.

obnews@elsevier.com

LOS ANGELES – Use of lungs from donors who smoked heavily does not worsen lung transplantation outcomes including risk for lung cancer death, at least in the medium term.

At a median follow-up of 2 years for 5,900 adults who had double-lung transplants, those who received lungs from heavy smokers had an actuarial median overall survival of roughly 5.5 years, and their lung function was essentially the same as that of patients who received lungs from other donors, Dr. Sharven Taghavi reported at the annual meeting of the Society of Thoracic Surgeons.

The study data came from the United Network for Organ Sharing (UNOS) database. A team led by Dr. Taghavi, of Temple University Hospital in Philadelphia, compared data for double-lung transplants from 2005-2011, comparing donors with a history of smoking exceeding 20 pack-years with other donors.

About 13% of the study patients received lungs from donors who had smoked heavily. Compared with other recipients, these recipients were more likely to have a primary diagnosis of chronic obstructive pulmonary disease and less likely to have a diagnosis of idiopathic pulmonary fibrosis. Otherwise, they were similar.

The rate of deaths due to cancer was based on case reports, as UNOS does not capture this outcome. Cancer deaths were 5.8% among recipients of lungs from heavy smokers and 3.6% among other recipients.

"There is a fairly low capture rate for this field, so it’s difficult to draw significant conclusions from it," cautioned Dr. Taghavi.

Patients who received lungs from heavy smokers had a 1-day longer length of stay in the hospital (18 days vs. 17 days), which "may not really be clinically relevant." Rates of acute rejection during hospitalization were comparable (10.7% vs. 8.8%), as was post-transplant airway dehiscence (1.8% vs. 1.8%).

Post-transplant peak forced expiratory volume in 1 second (FEV₁) was the same (80% vs. 79%), as was decline in this measure over time. Median duration of freedom from bronchiolitis obliterans syndrome was 1,583 days vs. 1,827 days.

Risk-adjusted median all-cause survival – the study’s primary endpoint – did not differ significantly between the recipients given lungs from donors who smoked heavily and the other recipients (2,043 vs. 1,928 days).

The rate of cancer deaths did not differ significantly; however, the follow-up time is too short to address this concern in a meaningful way, Dr. Taghavi said.

"Currently, we recommend when evaluating a donor who has a heavy smoking history, that they undergo a thorough examination for lung tumors or evidence of cancer. This includes obtaining a chest x-ray, CT scans, and bronchoscopies. In addition, when the lungs are procured, they should undergo a very thorough visual inspection," he advised.

"Informed consent is very important. You have to discuss the donor’s smoking status with the recipient and explain the risks and the benefits," Dr. Taghavi said. Lung cancer risk, given the donor’s history, is about 1% to 2% annually, and that needs to be considered against the high likelihood of dying within 1 or 2 years without a transplant.

"One thing that is unquestionable is that survival will be better accepting these lungs than it will be sitting on a waiting list," he added. Only about half of the people listed for lung transplant in the United States each year actually undergo the surgery.

Recipients of lungs from heavy smokers do not need any extra follow-up or surveillance, as they are already diligently tested and monitored, according to Dr. Taghavi. The recipient’s immunosuppression does theoretically put one at additional risk for lung cancer.

Current guidelines of the International Society of Heart and Lung Transplantation advise against considering use of lungs from donors who have a smoking history of more than 20 pack-years, Dr. Taghavi noted. But he stopped short of saying that the study should prompt a formal revision of those guidelines.

"I think the findings start the conversation," he commented. "We should consider looking at these potential donors," especially when a recipient’s situation is dire.

Dr. Taghavi disclosed no conflicts of interest.

TOR@elsevier.com

LOS ANGELES – Use of lungs from donors who smoked heavily does not worsen lung transplantation outcomes including risk for lung cancer death, at least in the medium term.

At a median follow-up of 2 years for 5,900 adults who had double-lung transplants, those who received lungs from heavy smokers had an actuarial median overall survival of roughly 5.5 years, and their lung function was essentially the same as that of patients who received lungs from other donors, Dr. Sharven Taghavi reported at the annual meeting of the Society of Thoracic Surgeons.

The study data came from the United Network for Organ Sharing (UNOS) database. A team led by Dr. Taghavi, of Temple University Hospital in Philadelphia, compared data for double-lung transplants from 2005-2011, comparing donors with a history of smoking exceeding 20 pack-years with other donors.

About 13% of the study patients received lungs from donors who had smoked heavily. Compared with other recipients, these recipients were more likely to have a primary diagnosis of chronic obstructive pulmonary disease and less likely to have a diagnosis of idiopathic pulmonary fibrosis. Otherwise, they were similar.

The rate of deaths due to cancer was based on case reports, as UNOS does not capture this outcome. Cancer deaths were 5.8% among recipients of lungs from heavy smokers and 3.6% among other recipients.

"There is a fairly low capture rate for this field, so it’s difficult to draw significant conclusions from it," cautioned Dr. Taghavi.

Patients who received lungs from heavy smokers had a 1-day longer length of stay in the hospital (18 days vs. 17 days), which "may not really be clinically relevant." Rates of acute rejection during hospitalization were comparable (10.7% vs. 8.8%), as was post-transplant airway dehiscence (1.8% vs. 1.8%).

Post-transplant peak forced expiratory volume in 1 second (FEV₁) was the same (80% vs. 79%), as was decline in this measure over time. Median duration of freedom from bronchiolitis obliterans syndrome was 1,583 days vs. 1,827 days.

Risk-adjusted median all-cause survival – the study’s primary endpoint – did not differ significantly between the recipients given lungs from donors who smoked heavily and the other recipients (2,043 vs. 1,928 days).

The rate of cancer deaths did not differ significantly; however, the follow-up time is too short to address this concern in a meaningful way, Dr. Taghavi said.

"Currently, we recommend when evaluating a donor who has a heavy smoking history, that they undergo a thorough examination for lung tumors or evidence of cancer. This includes obtaining a chest x-ray, CT scans, and bronchoscopies. In addition, when the lungs are procured, they should undergo a very thorough visual inspection," he advised.

"Informed consent is very important. You have to discuss the donor’s smoking status with the recipient and explain the risks and the benefits," Dr. Taghavi said. Lung cancer risk, given the donor’s history, is about 1% to 2% annually, and that needs to be considered against the high likelihood of dying within 1 or 2 years without a transplant.

"One thing that is unquestionable is that survival will be better accepting these lungs than it will be sitting on a waiting list," he added. Only about half of the people listed for lung transplant in the United States each year actually undergo the surgery.

Recipients of lungs from heavy smokers do not need any extra follow-up or surveillance, as they are already diligently tested and monitored, according to Dr. Taghavi. The recipient’s immunosuppression does theoretically put one at additional risk for lung cancer.

Current guidelines of the International Society of Heart and Lung Transplantation advise against considering use of lungs from donors who have a smoking history of more than 20 pack-years, Dr. Taghavi noted. But he stopped short of saying that the study should prompt a formal revision of those guidelines.

"I think the findings start the conversation," he commented. "We should consider looking at these potential donors," especially when a recipient’s situation is dire.

Dr. Taghavi disclosed no conflicts of interest.

TOR@elsevier.com

LOS ANGELES – Use of lungs from donors who smoked heavily does not worsen lung transplantation outcomes including risk for lung cancer death, at least in the medium term.

At a median follow-up of 2 years for 5,900 adults who had double-lung transplants, those who received lungs from heavy smokers had an actuarial median overall survival of roughly 5.5 years, and their lung function was essentially the same as that of patients who received lungs from other donors, Dr. Sharven Taghavi reported at the annual meeting of the Society of Thoracic Surgeons.

The study data came from the United Network for Organ Sharing (UNOS) database. A team led by Dr. Taghavi, of Temple University Hospital in Philadelphia, compared data for double-lung transplants from 2005-2011, comparing donors with a history of smoking exceeding 20 pack-years with other donors.

About 13% of the study patients received lungs from donors who had smoked heavily. Compared with other recipients, these recipients were more likely to have a primary diagnosis of chronic obstructive pulmonary disease and less likely to have a diagnosis of idiopathic pulmonary fibrosis. Otherwise, they were similar.

The rate of deaths due to cancer was based on case reports, as UNOS does not capture this outcome. Cancer deaths were 5.8% among recipients of lungs from heavy smokers and 3.6% among other recipients.

"There is a fairly low capture rate for this field, so it’s difficult to draw significant conclusions from it," cautioned Dr. Taghavi.

Patients who received lungs from heavy smokers had a 1-day longer length of stay in the hospital (18 days vs. 17 days), which "may not really be clinically relevant." Rates of acute rejection during hospitalization were comparable (10.7% vs. 8.8%), as was post-transplant airway dehiscence (1.8% vs. 1.8%).

Post-transplant peak forced expiratory volume in 1 second (FEV₁) was the same (80% vs. 79%), as was decline in this measure over time. Median duration of freedom from bronchiolitis obliterans syndrome was 1,583 days vs. 1,827 days.

Risk-adjusted median all-cause survival – the study’s primary endpoint – did not differ significantly between the recipients given lungs from donors who smoked heavily and the other recipients (2,043 vs. 1,928 days).

The rate of cancer deaths did not differ significantly; however, the follow-up time is too short to address this concern in a meaningful way, Dr. Taghavi said.

"Currently, we recommend when evaluating a donor who has a heavy smoking history, that they undergo a thorough examination for lung tumors or evidence of cancer. This includes obtaining a chest x-ray, CT scans, and bronchoscopies. In addition, when the lungs are procured, they should undergo a very thorough visual inspection," he advised.

"Informed consent is very important. You have to discuss the donor’s smoking status with the recipient and explain the risks and the benefits," Dr. Taghavi said. Lung cancer risk, given the donor’s history, is about 1% to 2% annually, and that needs to be considered against the high likelihood of dying within 1 or 2 years without a transplant.

"One thing that is unquestionable is that survival will be better accepting these lungs than it will be sitting on a waiting list," he added. Only about half of the people listed for lung transplant in the United States each year actually undergo the surgery.

Recipients of lungs from heavy smokers do not need any extra follow-up or surveillance, as they are already diligently tested and monitored, according to Dr. Taghavi. The recipient’s immunosuppression does theoretically put one at additional risk for lung cancer.

Current guidelines of the International Society of Heart and Lung Transplantation advise against considering use of lungs from donors who have a smoking history of more than 20 pack-years, Dr. Taghavi noted. But he stopped short of saying that the study should prompt a formal revision of those guidelines.

"I think the findings start the conversation," he commented. "We should consider looking at these potential donors," especially when a recipient’s situation is dire.

Dr. Taghavi disclosed no conflicts of interest.

TOR@elsevier.com

LOS ANGELES – A novel genetic assay helps identify patients with early, aggressive lung cancer who might benefit from adjuvant therapy.

The assay, marketed as Pervino Lung RS by Life Technologies, is the only lung cancer signature to undergo blinded validation in two large cohorts from different countries, one in the United States and one in China (Lancet 2012;379:823-32).

It assesses expression of 14 genes involved in lung cancer tumorigenesis, including ones on the EGFR and KRAS signaling pathways. The assay provides considerably more prognostic information than do conventional criteria proposed by the National Comprehensive Cancer Network (NCCN) as defining high-risk tumors warranting treatment, according to Dr. Johannes R. Kratz, who reported the data at the annual meeting of the Society of Thoracic Surgeons.

The assay results were used to stratify the 269 study patients who had undergone resection of T1a node-negative and nonmetastatic, nonsquamous, non–small cell lung cancer (NSCLC) into groups with distinctly different 5-year survival rates.

Compared with their counterparts in the low-risk group, those in the intermediate- and high-risk groups had a respective doubling and more than tripling of the risk of death, said Dr. Kratz, who was the study’s lead investigator.

As a result of recommendations for CT screening in patients at high risk for lung cancer, resections of small node-negative tumors that are in fact deadly are likely to increase, he observed. Nearly 30% of all patients with stage IA tumors – the lowest level in the current classification system – will nonetheless die in the subsequent 5 years.

"These tumors with highly aggressive tumor biology can now be identified reliably with a prognostic gene signature. The identification of these small but deadly tumors may allow for personalized patient prognosis and could allow us to maximize the benefit of the early detection of these small but deadly tumors via low-dose CT screening," he added.

The current postoperative standard of care for stage IA disease is simply observation, according to Dr. Kratz, a former surgical resident at the Massachusetts General Hospital in Boston, and now a postdoctoral fellow at the University of California, San Francisco.

However, "we should strongly consider changing the way we think about patients with high-risk T1a tumors," he recommended. To that end, a randomized controlled trial of assay-guided adjuvant chemotherapy for early lung cancer is underway in China among roughly 1,000 patients.

Dr. Kratz said that studies to date have not examined a potential prognostic role of the assay in EGFR (epidermal growth factor receptor) mutations. "We haven’t performed an additional mutation analysis on these patients’ EGFR. The original assay was designed to work on patients with resected paraffin-embedded specimens and not fresh-frozen tissue specimens. As a result, it is difficult for us to do extensive EGFR mutation analysis. But that’s definitely something to consider, and it would be nice to explore that association."

It remains to be seen whether the assay, in fact, predicts chemotherapy benefit, he acknowledged in a related press conference. But research has suggested that such prognostic signatures in lung cancer are also predictive (J. Clin. Oncol. 2010;28:4417-24). "That is what we hope to show in the China trial as well," he said.

In the reported study, patients with T1a tumors were drawn from the initial validation cohorts. Fully 40% were under age 60. "This is important, because ... we’d like to be more aggressive in younger patients, both because they can tolerate it and we are more likely to treat them more aggressively," he noted.

The patients’ actual 5-year mortality rate was 32% overall, showing that "these tumors are as deadly as advertised."

The main study results, reported at the meeting and also published (JAMA 2012;308:1629-31), showed that the 5-year actuarial overall survival was 83%, 69%, and 52% among patients in assay-defined low-, medium-, and high-risk groups, respectively (P less than .0001).

In multivariate analyses, relative to their counterparts in the low-risk group, patients in the intermediate-risk group had a 2.0-fold higher risk of death (P = .04) and patients in the high-risk group had a 3.3-fold higher risk (P = .00).

The assay also showed good risk discrimination in analyses restricted to the smallest of tumors, those measuring 1.5 cm or less (P = .001 for difference across groups) and even those measuring 1.0 cm or less (P = .008).

And when compared with tumor size alone, the combination of the assay and tumor size significantly improved on the identification of patients who died (c-statistic, 0.68 vs. 0.57; P less than .0001).

Although these T1a tumors can be ablated nonoperatively, their genetic makeup offers a rich source of information about their subsequent behavior, Dr. Kratz said.

"Despite the popularity and endorsement of our radiology colleagues for techniques such as stereotactic radiation for small T1aN0M0 tumors, we should remember that these techniques don’t provide us with potentially important lung tissue that can provide prognostic and predictive information," he commented.

Dr. Kratz disclosed that he has been a consultant for Pinpoint Genomics, the company that developed the assay, and is a consultant for Life Technologies, which has acquired Pinpoint Genomics.

TOR@elsevier.com

LOS ANGELES – A novel genetic assay helps identify patients with early, aggressive lung cancer who might benefit from adjuvant therapy.

The assay, marketed as Pervino Lung RS by Life Technologies, is the only lung cancer signature to undergo blinded validation in two large cohorts from different countries, one in the United States and one in China (Lancet 2012;379:823-32).

It assesses expression of 14 genes involved in lung cancer tumorigenesis, including ones on the EGFR and KRAS signaling pathways. The assay provides considerably more prognostic information than do conventional criteria proposed by the National Comprehensive Cancer Network (NCCN) as defining high-risk tumors warranting treatment, according to Dr. Johannes R. Kratz, who reported the data at the annual meeting of the Society of Thoracic Surgeons.

The assay results were used to stratify the 269 study patients who had undergone resection of T1a node-negative and nonmetastatic, nonsquamous, non–small cell lung cancer (NSCLC) into groups with distinctly different 5-year survival rates.

Compared with their counterparts in the low-risk group, those in the intermediate- and high-risk groups had a respective doubling and more than tripling of the risk of death, said Dr. Kratz, who was the study’s lead investigator.

As a result of recommendations for CT screening in patients at high risk for lung cancer, resections of small node-negative tumors that are in fact deadly are likely to increase, he observed. Nearly 30% of all patients with stage IA tumors – the lowest level in the current classification system – will nonetheless die in the subsequent 5 years.

"These tumors with highly aggressive tumor biology can now be identified reliably with a prognostic gene signature. The identification of these small but deadly tumors may allow for personalized patient prognosis and could allow us to maximize the benefit of the early detection of these small but deadly tumors via low-dose CT screening," he added.

The current postoperative standard of care for stage IA disease is simply observation, according to Dr. Kratz, a former surgical resident at the Massachusetts General Hospital in Boston, and now a postdoctoral fellow at the University of California, San Francisco.

However, "we should strongly consider changing the way we think about patients with high-risk T1a tumors," he recommended. To that end, a randomized controlled trial of assay-guided adjuvant chemotherapy for early lung cancer is underway in China among roughly 1,000 patients.

Dr. Kratz said that studies to date have not examined a potential prognostic role of the assay in EGFR (epidermal growth factor receptor) mutations. "We haven’t performed an additional mutation analysis on these patients’ EGFR. The original assay was designed to work on patients with resected paraffin-embedded specimens and not fresh-frozen tissue specimens. As a result, it is difficult for us to do extensive EGFR mutation analysis. But that’s definitely something to consider, and it would be nice to explore that association."

It remains to be seen whether the assay, in fact, predicts chemotherapy benefit, he acknowledged in a related press conference. But research has suggested that such prognostic signatures in lung cancer are also predictive (J. Clin. Oncol. 2010;28:4417-24). "That is what we hope to show in the China trial as well," he said.

In the reported study, patients with T1a tumors were drawn from the initial validation cohorts. Fully 40% were under age 60. "This is important, because ... we’d like to be more aggressive in younger patients, both because they can tolerate it and we are more likely to treat them more aggressively," he noted.

The patients’ actual 5-year mortality rate was 32% overall, showing that "these tumors are as deadly as advertised."

The main study results, reported at the meeting and also published (JAMA 2012;308:1629-31), showed that the 5-year actuarial overall survival was 83%, 69%, and 52% among patients in assay-defined low-, medium-, and high-risk groups, respectively (P less than .0001).

In multivariate analyses, relative to their counterparts in the low-risk group, patients in the intermediate-risk group had a 2.0-fold higher risk of death (P = .04) and patients in the high-risk group had a 3.3-fold higher risk (P = .00).

The assay also showed good risk discrimination in analyses restricted to the smallest of tumors, those measuring 1.5 cm or less (P = .001 for difference across groups) and even those measuring 1.0 cm or less (P = .008).

And when compared with tumor size alone, the combination of the assay and tumor size significantly improved on the identification of patients who died (c-statistic, 0.68 vs. 0.57; P less than .0001).

Although these T1a tumors can be ablated nonoperatively, their genetic makeup offers a rich source of information about their subsequent behavior, Dr. Kratz said.

"Despite the popularity and endorsement of our radiology colleagues for techniques such as stereotactic radiation for small T1aN0M0 tumors, we should remember that these techniques don’t provide us with potentially important lung tissue that can provide prognostic and predictive information," he commented.

Dr. Kratz disclosed that he has been a consultant for Pinpoint Genomics, the company that developed the assay, and is a consultant for Life Technologies, which has acquired Pinpoint Genomics.

TOR@elsevier.com

LOS ANGELES – A novel genetic assay helps identify patients with early, aggressive lung cancer who might benefit from adjuvant therapy.

The assay, marketed as Pervino Lung RS by Life Technologies, is the only lung cancer signature to undergo blinded validation in two large cohorts from different countries, one in the United States and one in China (Lancet 2012;379:823-32).

It assesses expression of 14 genes involved in lung cancer tumorigenesis, including ones on the EGFR and KRAS signaling pathways. The assay provides considerably more prognostic information than do conventional criteria proposed by the National Comprehensive Cancer Network (NCCN) as defining high-risk tumors warranting treatment, according to Dr. Johannes R. Kratz, who reported the data at the annual meeting of the Society of Thoracic Surgeons.

The assay results were used to stratify the 269 study patients who had undergone resection of T1a node-negative and nonmetastatic, nonsquamous, non–small cell lung cancer (NSCLC) into groups with distinctly different 5-year survival rates.

Compared with their counterparts in the low-risk group, those in the intermediate- and high-risk groups had a respective doubling and more than tripling of the risk of death, said Dr. Kratz, who was the study’s lead investigator.

As a result of recommendations for CT screening in patients at high risk for lung cancer, resections of small node-negative tumors that are in fact deadly are likely to increase, he observed. Nearly 30% of all patients with stage IA tumors – the lowest level in the current classification system – will nonetheless die in the subsequent 5 years.

"These tumors with highly aggressive tumor biology can now be identified reliably with a prognostic gene signature. The identification of these small but deadly tumors may allow for personalized patient prognosis and could allow us to maximize the benefit of the early detection of these small but deadly tumors via low-dose CT screening," he added.

The current postoperative standard of care for stage IA disease is simply observation, according to Dr. Kratz, a former surgical resident at the Massachusetts General Hospital in Boston, and now a postdoctoral fellow at the University of California, San Francisco.

However, "we should strongly consider changing the way we think about patients with high-risk T1a tumors," he recommended. To that end, a randomized controlled trial of assay-guided adjuvant chemotherapy for early lung cancer is underway in China among roughly 1,000 patients.

Dr. Kratz said that studies to date have not examined a potential prognostic role of the assay in EGFR (epidermal growth factor receptor) mutations. "We haven’t performed an additional mutation analysis on these patients’ EGFR. The original assay was designed to work on patients with resected paraffin-embedded specimens and not fresh-frozen tissue specimens. As a result, it is difficult for us to do extensive EGFR mutation analysis. But that’s definitely something to consider, and it would be nice to explore that association."

It remains to be seen whether the assay, in fact, predicts chemotherapy benefit, he acknowledged in a related press conference. But research has suggested that such prognostic signatures in lung cancer are also predictive (J. Clin. Oncol. 2010;28:4417-24). "That is what we hope to show in the China trial as well," he said.

In the reported study, patients with T1a tumors were drawn from the initial validation cohorts. Fully 40% were under age 60. "This is important, because ... we’d like to be more aggressive in younger patients, both because they can tolerate it and we are more likely to treat them more aggressively," he noted.

The patients’ actual 5-year mortality rate was 32% overall, showing that "these tumors are as deadly as advertised."

The main study results, reported at the meeting and also published (JAMA 2012;308:1629-31), showed that the 5-year actuarial overall survival was 83%, 69%, and 52% among patients in assay-defined low-, medium-, and high-risk groups, respectively (P less than .0001).

In multivariate analyses, relative to their counterparts in the low-risk group, patients in the intermediate-risk group had a 2.0-fold higher risk of death (P = .04) and patients in the high-risk group had a 3.3-fold higher risk (P = .00).

The assay also showed good risk discrimination in analyses restricted to the smallest of tumors, those measuring 1.5 cm or less (P = .001 for difference across groups) and even those measuring 1.0 cm or less (P = .008).

And when compared with tumor size alone, the combination of the assay and tumor size significantly improved on the identification of patients who died (c-statistic, 0.68 vs. 0.57; P less than .0001).

Although these T1a tumors can be ablated nonoperatively, their genetic makeup offers a rich source of information about their subsequent behavior, Dr. Kratz said.

"Despite the popularity and endorsement of our radiology colleagues for techniques such as stereotactic radiation for small T1aN0M0 tumors, we should remember that these techniques don’t provide us with potentially important lung tissue that can provide prognostic and predictive information," he commented.

Dr. Kratz disclosed that he has been a consultant for Pinpoint Genomics, the company that developed the assay, and is a consultant for Life Technologies, which has acquired Pinpoint Genomics.

TOR@elsevier.com

SAN ANTONIO – Some breast cancers categorized as HER2 negative by conventional testing harbor mutations that may still render them amenable to therapy targeting this receptor, researchers reported at the San Antonio Breast Cancer Symposium.

A team led by Dr. Ron Bose, of Washington University and the Siteman Cancer Center, St. Louis, compiled data from eight studies in which tissue from 1,499 breast cancers was sequenced.

Results showed that 25 cancers, or about 1.7%, had activating HER2 mutations. Most of these cancers did not have amplification of the HER2 gene and thus would be categorized as HER2 negative by conventional testing.

"We argue that mutation is an alternate mechanism to activate HER2 in breast cancer," he commented. "Patients with these mutations will be missed by current HER2 testing. Gene sequencing is required to identify these mutations."

The investigational tyrosine kinase inhibitor neratinib readily outperformed lapatinib (Tykerb) at inhibiting the growth of cells bearing the HER2 mutations, according to data presented at the meeting and recently published (Cancer Discov. 2012;3:1-14). The investigators are therefore planning a phase II trial of neratinib for metastatic HER2 gene amplification–negative, HER2 mutation–positive breast cancer.

"These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment," Dr. Bose maintained in a related press briefing. "If this trial is successful, we estimate that 4,000 women per year in the U.S. could benefit. Worldwide, that number could be five times as large."

He anticipates that the technological feasibility and cost of HER2 sequencing in clinical practice would be similar to those of sequencing for epidermal growth factor receptor (EGFR) mutations in lung cancer.

"Within the context of the clinical trial, we are specifically screening for HER2 mutations. But in the future, outside of a clinical trial setting, probably including HER2 in a panel of genes would be most cost effective," he elaborated. "If you compare to cost of treatment, a month of treatment with many of the chemotherapy drugs or with targeted inhibitors is in the thousands of dollars. So the cost of screening [for mutations] is much lower than that."

Dr. Kent Osborne, moderator of the press briefing and director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, characterized the research as "interesting" while adding that its usefulness may be limited at present.

"But what if these mutations occur in other cancers, now that Dr. Bose has identified them?" he said. "If you are a patient with that mutation, even though it’s pretty rare, that’s important to know for you. When we get into the era of personalized medicine, where we start doing these mutational analyses, ... there are going to be mutations that perhaps are contributing to the cancer and are pretty rare in the population, but are important for that particular patient."

"Some in the audience may remember the large trial in HER2-positive patients done by the National Surgical Adjuvant Breast and Bowel Project (NSABP). A few hundred of those patients on central review did not have HER2 amplification or overexpression, yet they seemed to have the same benefits from trastuzumab as did those [with HER2]," Dr. Osborne noted. "I guess at an incidence rate of 1% to 2%, [activating mutations don’t] explain all of those by any means, but I wonder if you could get those samples from the NSABP and screen them. They could be enriched for these mutations."

"That’s an excellent possibility," Dr. Bose replied. "We have had preliminary discussions with members of the NSABP. Now that the work is published, I think those discussions will go further."

When asked why neratinib was being used in the trial instead of trastuzumab (Herceptin), Dr. Bose said that in tissue culture, the former proved much more effective at inhibiting growth of cells harboring these mutations.

On a related note, a session attendee commented, "I am modestly concerned that you don’t have trastuzumab in your trial. And the reason is that I would expect trastuzumab to down-regulate this single-copy HER2 receptor and help neratinib. So have you done combinations of both preclinically to see whether it adds or not to neratinib?"

The investigators have done such in vitro work, Dr. Bose replied. "With trastuzumab alone, we see a partial growth suppression effect when you are looking at MCF-10A cells that bear these mutations. When we tried the combination, we did not see any benefit of adding trastuzumab on top of neratinib. But I would caution that this is with MCF-10A cells, and this is in tissue culture, where there are no immune effectors. We don’t know what the situation will be in actual patients."

Additional study results showed that all of the HER2 activating mutations were found only in the tumor and were thus somatic and not inherited, according to Dr. Bose, who disclosed having no conflicts of interest related to the research.

The mutations clustered in two areas of the HER2 gene: one area affecting the tyrosine kinase domain of the protein (seen in 68% of cases) and another area affecting the extracellular domain (seen in 20%).

Laboratory analyses indicated that the mutations were indeed being expressed at the RNA level, that those affecting the kinase domain of the protein were associated with increased kinase activity, and that the mutations spurred tumor growth in nude mice.

"The majority of these HER2 mutations are activating events that cause cancerous growth of the cells in the lab, meaning that they stimulate the function of HER2 or turn on HER2’s activity in an excessive or inappropriate manner," Dr. Bose summarized. "Thus, we feel they are highly likely to drive the growth of these human breast cancers in which they occur."

In sensitivity testing, the six cases having the L755S mutation were resistant to the tyrosine kinase inhibitor lapatinib but sensitive to neratinib, an irreversible pan-ErbB tyrosine kinase inhibitor.

In fact, neratinib showed greater effectiveness than lapatinib at inhibiting cell growth in all of the mutated tumors tested, with several hundred to several thousand times greater concentrations of lapatinib needed to achieve the same level of inhibition.

Dr. Bose disclosed having no relevant conflicts of interest.

SAN ANTONIO – Some breast cancers categorized as HER2 negative by conventional testing harbor mutations that may still render them amenable to therapy targeting this receptor, researchers reported at the San Antonio Breast Cancer Symposium.

A team led by Dr. Ron Bose, of Washington University and the Siteman Cancer Center, St. Louis, compiled data from eight studies in which tissue from 1,499 breast cancers was sequenced.

Results showed that 25 cancers, or about 1.7%, had activating HER2 mutations. Most of these cancers did not have amplification of the HER2 gene and thus would be categorized as HER2 negative by conventional testing.

"We argue that mutation is an alternate mechanism to activate HER2 in breast cancer," he commented. "Patients with these mutations will be missed by current HER2 testing. Gene sequencing is required to identify these mutations."

The investigational tyrosine kinase inhibitor neratinib readily outperformed lapatinib (Tykerb) at inhibiting the growth of cells bearing the HER2 mutations, according to data presented at the meeting and recently published (Cancer Discov. 2012;3:1-14). The investigators are therefore planning a phase II trial of neratinib for metastatic HER2 gene amplification–negative, HER2 mutation–positive breast cancer.

"These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment," Dr. Bose maintained in a related press briefing. "If this trial is successful, we estimate that 4,000 women per year in the U.S. could benefit. Worldwide, that number could be five times as large."

He anticipates that the technological feasibility and cost of HER2 sequencing in clinical practice would be similar to those of sequencing for epidermal growth factor receptor (EGFR) mutations in lung cancer.

"Within the context of the clinical trial, we are specifically screening for HER2 mutations. But in the future, outside of a clinical trial setting, probably including HER2 in a panel of genes would be most cost effective," he elaborated. "If you compare to cost of treatment, a month of treatment with many of the chemotherapy drugs or with targeted inhibitors is in the thousands of dollars. So the cost of screening [for mutations] is much lower than that."

Dr. Kent Osborne, moderator of the press briefing and director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, characterized the research as "interesting" while adding that its usefulness may be limited at present.

"But what if these mutations occur in other cancers, now that Dr. Bose has identified them?" he said. "If you are a patient with that mutation, even though it’s pretty rare, that’s important to know for you. When we get into the era of personalized medicine, where we start doing these mutational analyses, ... there are going to be mutations that perhaps are contributing to the cancer and are pretty rare in the population, but are important for that particular patient."

"Some in the audience may remember the large trial in HER2-positive patients done by the National Surgical Adjuvant Breast and Bowel Project (NSABP). A few hundred of those patients on central review did not have HER2 amplification or overexpression, yet they seemed to have the same benefits from trastuzumab as did those [with HER2]," Dr. Osborne noted. "I guess at an incidence rate of 1% to 2%, [activating mutations don’t] explain all of those by any means, but I wonder if you could get those samples from the NSABP and screen them. They could be enriched for these mutations."

"That’s an excellent possibility," Dr. Bose replied. "We have had preliminary discussions with members of the NSABP. Now that the work is published, I think those discussions will go further."

When asked why neratinib was being used in the trial instead of trastuzumab (Herceptin), Dr. Bose said that in tissue culture, the former proved much more effective at inhibiting growth of cells harboring these mutations.

On a related note, a session attendee commented, "I am modestly concerned that you don’t have trastuzumab in your trial. And the reason is that I would expect trastuzumab to down-regulate this single-copy HER2 receptor and help neratinib. So have you done combinations of both preclinically to see whether it adds or not to neratinib?"

The investigators have done such in vitro work, Dr. Bose replied. "With trastuzumab alone, we see a partial growth suppression effect when you are looking at MCF-10A cells that bear these mutations. When we tried the combination, we did not see any benefit of adding trastuzumab on top of neratinib. But I would caution that this is with MCF-10A cells, and this is in tissue culture, where there are no immune effectors. We don’t know what the situation will be in actual patients."

Additional study results showed that all of the HER2 activating mutations were found only in the tumor and were thus somatic and not inherited, according to Dr. Bose, who disclosed having no conflicts of interest related to the research.

The mutations clustered in two areas of the HER2 gene: one area affecting the tyrosine kinase domain of the protein (seen in 68% of cases) and another area affecting the extracellular domain (seen in 20%).

Laboratory analyses indicated that the mutations were indeed being expressed at the RNA level, that those affecting the kinase domain of the protein were associated with increased kinase activity, and that the mutations spurred tumor growth in nude mice.

"The majority of these HER2 mutations are activating events that cause cancerous growth of the cells in the lab, meaning that they stimulate the function of HER2 or turn on HER2’s activity in an excessive or inappropriate manner," Dr. Bose summarized. "Thus, we feel they are highly likely to drive the growth of these human breast cancers in which they occur."

In sensitivity testing, the six cases having the L755S mutation were resistant to the tyrosine kinase inhibitor lapatinib but sensitive to neratinib, an irreversible pan-ErbB tyrosine kinase inhibitor.

In fact, neratinib showed greater effectiveness than lapatinib at inhibiting cell growth in all of the mutated tumors tested, with several hundred to several thousand times greater concentrations of lapatinib needed to achieve the same level of inhibition.

Dr. Bose disclosed having no relevant conflicts of interest.

SAN ANTONIO – Some breast cancers categorized as HER2 negative by conventional testing harbor mutations that may still render them amenable to therapy targeting this receptor, researchers reported at the San Antonio Breast Cancer Symposium.

A team led by Dr. Ron Bose, of Washington University and the Siteman Cancer Center, St. Louis, compiled data from eight studies in which tissue from 1,499 breast cancers was sequenced.

Results showed that 25 cancers, or about 1.7%, had activating HER2 mutations. Most of these cancers did not have amplification of the HER2 gene and thus would be categorized as HER2 negative by conventional testing.

"We argue that mutation is an alternate mechanism to activate HER2 in breast cancer," he commented. "Patients with these mutations will be missed by current HER2 testing. Gene sequencing is required to identify these mutations."

The investigational tyrosine kinase inhibitor neratinib readily outperformed lapatinib (Tykerb) at inhibiting the growth of cells bearing the HER2 mutations, according to data presented at the meeting and recently published (Cancer Discov. 2012;3:1-14). The investigators are therefore planning a phase II trial of neratinib for metastatic HER2 gene amplification–negative, HER2 mutation–positive breast cancer.

"These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment," Dr. Bose maintained in a related press briefing. "If this trial is successful, we estimate that 4,000 women per year in the U.S. could benefit. Worldwide, that number could be five times as large."

He anticipates that the technological feasibility and cost of HER2 sequencing in clinical practice would be similar to those of sequencing for epidermal growth factor receptor (EGFR) mutations in lung cancer.

"Within the context of the clinical trial, we are specifically screening for HER2 mutations. But in the future, outside of a clinical trial setting, probably including HER2 in a panel of genes would be most cost effective," he elaborated. "If you compare to cost of treatment, a month of treatment with many of the chemotherapy drugs or with targeted inhibitors is in the thousands of dollars. So the cost of screening [for mutations] is much lower than that."

Dr. Kent Osborne, moderator of the press briefing and director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, characterized the research as "interesting" while adding that its usefulness may be limited at present.

"But what if these mutations occur in other cancers, now that Dr. Bose has identified them?" he said. "If you are a patient with that mutation, even though it’s pretty rare, that’s important to know for you. When we get into the era of personalized medicine, where we start doing these mutational analyses, ... there are going to be mutations that perhaps are contributing to the cancer and are pretty rare in the population, but are important for that particular patient."

"Some in the audience may remember the large trial in HER2-positive patients done by the National Surgical Adjuvant Breast and Bowel Project (NSABP). A few hundred of those patients on central review did not have HER2 amplification or overexpression, yet they seemed to have the same benefits from trastuzumab as did those [with HER2]," Dr. Osborne noted. "I guess at an incidence rate of 1% to 2%, [activating mutations don’t] explain all of those by any means, but I wonder if you could get those samples from the NSABP and screen them. They could be enriched for these mutations."

"That’s an excellent possibility," Dr. Bose replied. "We have had preliminary discussions with members of the NSABP. Now that the work is published, I think those discussions will go further."

When asked why neratinib was being used in the trial instead of trastuzumab (Herceptin), Dr. Bose said that in tissue culture, the former proved much more effective at inhibiting growth of cells harboring these mutations.

On a related note, a session attendee commented, "I am modestly concerned that you don’t have trastuzumab in your trial. And the reason is that I would expect trastuzumab to down-regulate this single-copy HER2 receptor and help neratinib. So have you done combinations of both preclinically to see whether it adds or not to neratinib?"

The investigators have done such in vitro work, Dr. Bose replied. "With trastuzumab alone, we see a partial growth suppression effect when you are looking at MCF-10A cells that bear these mutations. When we tried the combination, we did not see any benefit of adding trastuzumab on top of neratinib. But I would caution that this is with MCF-10A cells, and this is in tissue culture, where there are no immune effectors. We don’t know what the situation will be in actual patients."

Additional study results showed that all of the HER2 activating mutations were found only in the tumor and were thus somatic and not inherited, according to Dr. Bose, who disclosed having no conflicts of interest related to the research.

The mutations clustered in two areas of the HER2 gene: one area affecting the tyrosine kinase domain of the protein (seen in 68% of cases) and another area affecting the extracellular domain (seen in 20%).

Laboratory analyses indicated that the mutations were indeed being expressed at the RNA level, that those affecting the kinase domain of the protein were associated with increased kinase activity, and that the mutations spurred tumor growth in nude mice.

"The majority of these HER2 mutations are activating events that cause cancerous growth of the cells in the lab, meaning that they stimulate the function of HER2 or turn on HER2’s activity in an excessive or inappropriate manner," Dr. Bose summarized. "Thus, we feel they are highly likely to drive the growth of these human breast cancers in which they occur."

In sensitivity testing, the six cases having the L755S mutation were resistant to the tyrosine kinase inhibitor lapatinib but sensitive to neratinib, an irreversible pan-ErbB tyrosine kinase inhibitor.

In fact, neratinib showed greater effectiveness than lapatinib at inhibiting cell growth in all of the mutated tumors tested, with several hundred to several thousand times greater concentrations of lapatinib needed to achieve the same level of inhibition.

Dr. Bose disclosed having no relevant conflicts of interest.

SAN DIEGO – A new vaccine was safe and prompted a durable antibody response against pathogenic strains of Staphylococcus aureus, based on findings from a phase I trial conducted in 408 healthy adults.

The investigational three-antigen vaccine, known as SA3Ag, uses antigens that have established pathogenicity, Dr. Michael Nissen reported at IDWeek. "There was a rapid and robust functional antibody response to the vaccine antigens after a single dose and in all age groups," he said.

Analyses further suggested that a second (booster) dose of vaccine had only a modest additional effect on the immune response at 12 months. "High GMTs [geometric mean titers] for each antigen at 6 months, when the booster was administered, probably limited the booster response at this time," speculated Dr. Nissen, who is an associate professor with the Queensland Paediatric Infectious Diseases Laboratory in Brisbane, Australia.

He noted that a similar investigational four-antigen S. aureus vaccine is currently being tested in a pair of clinical trials (NCT 01364571 and NCT 01643941).

"Because of the high health care burden of S. aureus infections, there is an unmet need for an effective S. aureus vaccine," he commented. The new SA3Ag vaccine "has been developed based on known S. aureus virulence factors, namely capsular polysaccharides CP5 and CP8, and clumping factor A." The former are proteins that allow the pathogen to evade phagocytosis, whereas the latter enables it to adhere to host tissues.

Study participants were healthy adults aged 18-85 years. In a first randomization, they were assigned to receive a low, medium, or high dose of the vaccine, or a placebo; in a second randomization 6 months later, the initial vaccine groups were assigned to receive the same dose again (a booster) or a placebo.

Immunogenicity results showed that about 1 month after initial vaccination, there was a rise in titers of functional antibodies against the three vaccine antigens across all dose levels and across all age groups, Dr. Nissen reported.

After a single dose of the vaccine, the titers gradually waned over 12 months, but still remained well above those at baseline and well above those seen with placebo.

The booster dose of vaccine at 6 months only modestly improved on immunogenicity against one of the antigens, clumping factor A.

"Here, there was again a gradual decline in GMTs [of all antigens] through 12 months, but GMTs remained high at 12 months following booster, and again they were above placebo," Dr. Nissen commented. "Therefore, the timing of the booster dose warrants further investigation."

In terms of local reactions to the vaccine, the most common was pain at the injection site. Rates of pain, swelling, and redness all increased with dose, and were all higher after the booster dose than after the initial dose. Local reactions prompted a discontinuation of booster dosing.

In terms of systemic reactions, the overall rate was similar to that with placebo across the three vaccine dose levels. New or worsening muscle pain was more common after the vaccine than after placebo.

Fever developed after vaccination in 1%-2% of participants, regardless of vaccine dose. There were no vaccine-related serious adverse events or deaths during the 12-month study period.

IDWeek is the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society

Dr. Nissen disclosed that he has received travel grants from Wyeth and Pfizer, and has been the principal investigator on trials sponsored by Abbott, Baxter, CSL Behring, and other companies.

SAN DIEGO – A new vaccine was safe and prompted a durable antibody response against pathogenic strains of Staphylococcus aureus, based on findings from a phase I trial conducted in 408 healthy adults.

The investigational three-antigen vaccine, known as SA3Ag, uses antigens that have established pathogenicity, Dr. Michael Nissen reported at IDWeek. "There was a rapid and robust functional antibody response to the vaccine antigens after a single dose and in all age groups," he said.

Analyses further suggested that a second (booster) dose of vaccine had only a modest additional effect on the immune response at 12 months. "High GMTs [geometric mean titers] for each antigen at 6 months, when the booster was administered, probably limited the booster response at this time," speculated Dr. Nissen, who is an associate professor with the Queensland Paediatric Infectious Diseases Laboratory in Brisbane, Australia.

He noted that a similar investigational four-antigen S. aureus vaccine is currently being tested in a pair of clinical trials (NCT 01364571 and NCT 01643941).

"Because of the high health care burden of S. aureus infections, there is an unmet need for an effective S. aureus vaccine," he commented. The new SA3Ag vaccine "has been developed based on known S. aureus virulence factors, namely capsular polysaccharides CP5 and CP8, and clumping factor A." The former are proteins that allow the pathogen to evade phagocytosis, whereas the latter enables it to adhere to host tissues.

Study participants were healthy adults aged 18-85 years. In a first randomization, they were assigned to receive a low, medium, or high dose of the vaccine, or a placebo; in a second randomization 6 months later, the initial vaccine groups were assigned to receive the same dose again (a booster) or a placebo.

Immunogenicity results showed that about 1 month after initial vaccination, there was a rise in titers of functional antibodies against the three vaccine antigens across all dose levels and across all age groups, Dr. Nissen reported.

After a single dose of the vaccine, the titers gradually waned over 12 months, but still remained well above those at baseline and well above those seen with placebo.

The booster dose of vaccine at 6 months only modestly improved on immunogenicity against one of the antigens, clumping factor A.

"Here, there was again a gradual decline in GMTs [of all antigens] through 12 months, but GMTs remained high at 12 months following booster, and again they were above placebo," Dr. Nissen commented. "Therefore, the timing of the booster dose warrants further investigation."

In terms of local reactions to the vaccine, the most common was pain at the injection site. Rates of pain, swelling, and redness all increased with dose, and were all higher after the booster dose than after the initial dose. Local reactions prompted a discontinuation of booster dosing.

In terms of systemic reactions, the overall rate was similar to that with placebo across the three vaccine dose levels. New or worsening muscle pain was more common after the vaccine than after placebo.

Fever developed after vaccination in 1%-2% of participants, regardless of vaccine dose. There were no vaccine-related serious adverse events or deaths during the 12-month study period.

IDWeek is the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society

Dr. Nissen disclosed that he has received travel grants from Wyeth and Pfizer, and has been the principal investigator on trials sponsored by Abbott, Baxter, CSL Behring, and other companies.

SAN DIEGO – A new vaccine was safe and prompted a durable antibody response against pathogenic strains of Staphylococcus aureus, based on findings from a phase I trial conducted in 408 healthy adults.

The investigational three-antigen vaccine, known as SA3Ag, uses antigens that have established pathogenicity, Dr. Michael Nissen reported at IDWeek. "There was a rapid and robust functional antibody response to the vaccine antigens after a single dose and in all age groups," he said.

Analyses further suggested that a second (booster) dose of vaccine had only a modest additional effect on the immune response at 12 months. "High GMTs [geometric mean titers] for each antigen at 6 months, when the booster was administered, probably limited the booster response at this time," speculated Dr. Nissen, who is an associate professor with the Queensland Paediatric Infectious Diseases Laboratory in Brisbane, Australia.

He noted that a similar investigational four-antigen S. aureus vaccine is currently being tested in a pair of clinical trials (NCT 01364571 and NCT 01643941).

"Because of the high health care burden of S. aureus infections, there is an unmet need for an effective S. aureus vaccine," he commented. The new SA3Ag vaccine "has been developed based on known S. aureus virulence factors, namely capsular polysaccharides CP5 and CP8, and clumping factor A." The former are proteins that allow the pathogen to evade phagocytosis, whereas the latter enables it to adhere to host tissues.

Study participants were healthy adults aged 18-85 years. In a first randomization, they were assigned to receive a low, medium, or high dose of the vaccine, or a placebo; in a second randomization 6 months later, the initial vaccine groups were assigned to receive the same dose again (a booster) or a placebo.

Immunogenicity results showed that about 1 month after initial vaccination, there was a rise in titers of functional antibodies against the three vaccine antigens across all dose levels and across all age groups, Dr. Nissen reported.

After a single dose of the vaccine, the titers gradually waned over 12 months, but still remained well above those at baseline and well above those seen with placebo.

The booster dose of vaccine at 6 months only modestly improved on immunogenicity against one of the antigens, clumping factor A.

"Here, there was again a gradual decline in GMTs [of all antigens] through 12 months, but GMTs remained high at 12 months following booster, and again they were above placebo," Dr. Nissen commented. "Therefore, the timing of the booster dose warrants further investigation."

In terms of local reactions to the vaccine, the most common was pain at the injection site. Rates of pain, swelling, and redness all increased with dose, and were all higher after the booster dose than after the initial dose. Local reactions prompted a discontinuation of booster dosing.

In terms of systemic reactions, the overall rate was similar to that with placebo across the three vaccine dose levels. New or worsening muscle pain was more common after the vaccine than after placebo.

Fever developed after vaccination in 1%-2% of participants, regardless of vaccine dose. There were no vaccine-related serious adverse events or deaths during the 12-month study period.

IDWeek is the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society

Dr. Nissen disclosed that he has received travel grants from Wyeth and Pfizer, and has been the principal investigator on trials sponsored by Abbott, Baxter, CSL Behring, and other companies.

SAN DIEGO – Half of all HIV-positive inpatients experience antiretroviral medication errors during their stay, and these errors often go undetected and uncorrected, suggest a pair of studies reported in poster sessions at IDWeek 2012.

In the first study, a team led by Elizabeth A. Neuner, Pharm.D., of the Cleveland Clinic reviewed the electronic medical records of 162 HIV-positive adults admitted to the hospital during a 10-month period.

During a median hospital stay of 4 days, there were 126 medication errors, for a rate of 1.6 errors per admission. On a per-patient basis, 50% of patients had at least one medication error.

The most common medication errors were major drug interactions (26%), incorrect dosing (20%), and interactions involving contraindicated medications (12%).

Fully 65% of the errors were neither detected nor corrected during the patient’s stay, according to Dr. Neuner. Errors were significantly more likely to be detected and resolved if an infectious disease physician was consulted on the case (47% vs. 15%, P = .002), "so I think getting an ID consult can help with the resolution rate," she commented in an interview.

"We have focused a lot on quality improvement efforts in the hospital to try to reduce the number of errors that happen and also improve the resolution rate," she said. "It has really been a multidisciplinary approach. We have focused on education and transitions of care. We updated our electronic medication files to include common dose buttons and dose frequencies and removed buttons and frequencies that weren’t relevant anymore. And we have been doing some stewardship efforts in collaboration with the infectious disease physicians."

In the second study, a team led by Natasha N. Pettit, Pharm.D., of the University of Chicago began a program to evaluate the highly active antiretroviral therapy (HAART) regimens of HIV-positive inpatients within 12-24 hours of hospital admission or initiation of HAART regimens.

Given their complexity, "HAART regimens have a high potential for drug-drug interactions, adverse drug events, and dosing errors. Missed doses or inadvertent changes in therapy can quickly lead to resistance or toxicity," Dr. Pettit said in an interview.

Among the 155 patients whose regimens were evaluated in a 17-month period, 49% had a regimen containing some kind of error. Of these patients, 47% were errors related to drug dosage and 6% were related to drug interactions.

Protease inhibitors were significantly more often associated with errors, compared with other classes of antiretroviral medications, she said.

Interventions at or prior to the point of order entry, including providing resources to prescribers who may be less familiar with HAART regimens, can give some guidance while physicians are entering orders for these complex regimens, Dr. Pettit said. A process for reconciliation of HAART regimens before orders are placed also is recommended.

IDWeek is the combined annual meeting of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Dr. Neuner and Dr. Pettit disclosed no relevant conflicts of interest.

SAN DIEGO – Half of all HIV-positive inpatients experience antiretroviral medication errors during their stay, and these errors often go undetected and uncorrected, suggest a pair of studies reported in poster sessions at IDWeek 2012.

In the first study, a team led by Elizabeth A. Neuner, Pharm.D., of the Cleveland Clinic reviewed the electronic medical records of 162 HIV-positive adults admitted to the hospital during a 10-month period.

During a median hospital stay of 4 days, there were 126 medication errors, for a rate of 1.6 errors per admission. On a per-patient basis, 50% of patients had at least one medication error.

The most common medication errors were major drug interactions (26%), incorrect dosing (20%), and interactions involving contraindicated medications (12%).

Fully 65% of the errors were neither detected nor corrected during the patient’s stay, according to Dr. Neuner. Errors were significantly more likely to be detected and resolved if an infectious disease physician was consulted on the case (47% vs. 15%, P = .002), "so I think getting an ID consult can help with the resolution rate," she commented in an interview.

"We have focused a lot on quality improvement efforts in the hospital to try to reduce the number of errors that happen and also improve the resolution rate," she said. "It has really been a multidisciplinary approach. We have focused on education and transitions of care. We updated our electronic medication files to include common dose buttons and dose frequencies and removed buttons and frequencies that weren’t relevant anymore. And we have been doing some stewardship efforts in collaboration with the infectious disease physicians."

In the second study, a team led by Natasha N. Pettit, Pharm.D., of the University of Chicago began a program to evaluate the highly active antiretroviral therapy (HAART) regimens of HIV-positive inpatients within 12-24 hours of hospital admission or initiation of HAART regimens.

Given their complexity, "HAART regimens have a high potential for drug-drug interactions, adverse drug events, and dosing errors. Missed doses or inadvertent changes in therapy can quickly lead to resistance or toxicity," Dr. Pettit said in an interview.

Among the 155 patients whose regimens were evaluated in a 17-month period, 49% had a regimen containing some kind of error. Of these patients, 47% were errors related to drug dosage and 6% were related to drug interactions.

Protease inhibitors were significantly more often associated with errors, compared with other classes of antiretroviral medications, she said.

Interventions at or prior to the point of order entry, including providing resources to prescribers who may be less familiar with HAART regimens, can give some guidance while physicians are entering orders for these complex regimens, Dr. Pettit said. A process for reconciliation of HAART regimens before orders are placed also is recommended.

IDWeek is the combined annual meeting of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Dr. Neuner and Dr. Pettit disclosed no relevant conflicts of interest.

SAN DIEGO – Half of all HIV-positive inpatients experience antiretroviral medication errors during their stay, and these errors often go undetected and uncorrected, suggest a pair of studies reported in poster sessions at IDWeek 2012.

In the first study, a team led by Elizabeth A. Neuner, Pharm.D., of the Cleveland Clinic reviewed the electronic medical records of 162 HIV-positive adults admitted to the hospital during a 10-month period.

During a median hospital stay of 4 days, there were 126 medication errors, for a rate of 1.6 errors per admission. On a per-patient basis, 50% of patients had at least one medication error.

The most common medication errors were major drug interactions (26%), incorrect dosing (20%), and interactions involving contraindicated medications (12%).

Fully 65% of the errors were neither detected nor corrected during the patient’s stay, according to Dr. Neuner. Errors were significantly more likely to be detected and resolved if an infectious disease physician was consulted on the case (47% vs. 15%, P = .002), "so I think getting an ID consult can help with the resolution rate," she commented in an interview.

"We have focused a lot on quality improvement efforts in the hospital to try to reduce the number of errors that happen and also improve the resolution rate," she said. "It has really been a multidisciplinary approach. We have focused on education and transitions of care. We updated our electronic medication files to include common dose buttons and dose frequencies and removed buttons and frequencies that weren’t relevant anymore. And we have been doing some stewardship efforts in collaboration with the infectious disease physicians."

In the second study, a team led by Natasha N. Pettit, Pharm.D., of the University of Chicago began a program to evaluate the highly active antiretroviral therapy (HAART) regimens of HIV-positive inpatients within 12-24 hours of hospital admission or initiation of HAART regimens.

Given their complexity, "HAART regimens have a high potential for drug-drug interactions, adverse drug events, and dosing errors. Missed doses or inadvertent changes in therapy can quickly lead to resistance or toxicity," Dr. Pettit said in an interview.

Among the 155 patients whose regimens were evaluated in a 17-month period, 49% had a regimen containing some kind of error. Of these patients, 47% were errors related to drug dosage and 6% were related to drug interactions.

Protease inhibitors were significantly more often associated with errors, compared with other classes of antiretroviral medications, she said.

Interventions at or prior to the point of order entry, including providing resources to prescribers who may be less familiar with HAART regimens, can give some guidance while physicians are entering orders for these complex regimens, Dr. Pettit said. A process for reconciliation of HAART regimens before orders are placed also is recommended.

IDWeek is the combined annual meeting of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Dr. Neuner and Dr. Pettit disclosed no relevant conflicts of interest.

SAN ANTONIO – A variety of biomarkers failed to improve on the results of tumor HER2 status for predicting the benefits of therapy targeting HER2 signaling, based on an analysis of data from the CLEOPATRA trial.

In the trial, 808 patients with metastatic HER2-positive disease were given trastuzumab (Herceptin) and docetaxel (Taxotere) and evenly randomized to either pertuzumab (Perjeta) or placebo.

The main results, previously reported, showed that pertuzumab was significantly superior to placebo in terms of progression-free survival and overall survival.

In the new analysis, reported at the San Antonio Breast Cancer Symposium, a variety of protocol-predefined biomarkers of HER2 signaling in tumor tissue and in serum did not identify any patient subgroups that did better or worse on pertuzumab.

"Our analysis confirms that HER2 is the only marker for selecting patients for HER2-targeted therapy. This was despite a comprehensive exploration of a broad panel of candidate biomarkers," commented lead investigator Dr. Jose Baselga of the Memorial Sloan-Kettering Cancer Center in New York. "It is also consistent with the TRYPHAENA and NeoSphere studies, also presented here in San Antonio."

Discussing study limitations, Dr. Baselga said that "the lack of a HER2-naive treatment control arm may have resulted in the absence of a signal for other biomarkers in CLEOPATRA."

In additional findings, mutation of the gene for the catalytic subunit alpha of PI3 kinase (PIK3CA) in the tumor was associated with a poorer prognosis in the trial population as a whole. Patients whose tumors had the alternate, wildtype form of the gene were about one-fourth less likely to experience cancer progression or death.

"Mutations in PI3 kinase were not associated with resistance to pertuzumab, as patients derived similar additional benefit independent of PI3 kinase mutational status. However, the PI3 kinase mutational status may identify patients with poorer prognosis and particular unmet medical needs," Dr. Baselga commented. Prior studies have similarly shown mutant PI3 kinase to be associated with resistance to lapatinib (Tykerb), another HER2-targeted therapy and with a poorer prognosis after trastuzumab therapy.

"Clinical trials of HER2-targeted molecules in combination with PI3 kinase pathway–targeted agents may therefore be justified based on our findings," he added.

It would be interesting to see how a subset of untreated HER2-positive tumors behave as a function of PI3 kinase mutational status, Dr. Baselga said. "I think that will be what we need to know."

In the new analysis, the investigators evaluated a dozen biomarkers lying on the HER2 signaling pathway for both predictive and prognostic value. "From the cell surface down, we analyzed ligands, receptor tyrosine kinases, soluble HER2, and key intracellular pathway markers," Dr. Baselga explained. For most, they defined high and low levels as above- and below-median values, respectively.

In analyses of the predictive value of the biomarkers, the improvement in progression-free survival with pertuzumab relative to placebo was similar for patients having high versus low levels of all the biomarkers studied.

But in analyses of the prognostic value of the biomarkers in both trial arms pooled, patients had better progression-free survival if they had low serum levels of soluble HER2 (hazard ratio, 1.23; P = .04); in terms of ligands and receptor tyrosine kinases, if they had high levels of HER2 mRNA (0.77; P = .008) and HER3 mRNA (0.81; P = .03), and a high HER2 modified histoscore (0.83; P = .05); and in terms of tumor intracellular pathway markers, if they had mutation of the PIK3CA gene (0.83 for wild type; P = .0001).

The last "was by far our strongest prognostic marker," Dr. Baselga commented. Further analysis showed median progression-free survival was better with pertuzumab in both the mutant PIK3CA group (12.5 vs. 8.6 months) and in the wildtype PIK3CA group (21.8 vs. 13.8 months).

"Patients who harbor PI3 kinase mutations have clearly a worse prognosis. The treatment benefit, however, is maintained...the risk reduction is similar for mutants, for wild type, and for the whole study population," he noted.

In a final, longitudinal analysis to determine if serum biomarkers were early indicators of disease progression, levels of the biomarkers at baseline, week 9, and the time of disease progression showed no correlation with disease progression and did not differ between treatment arms.

Dr. Baselga disclosed that he is a consultant for Roche/Genentech and Sanofi. The trial was sponsored by Genentech.

SAN ANTONIO – A variety of biomarkers failed to improve on the results of tumor HER2 status for predicting the benefits of therapy targeting HER2 signaling, based on an analysis of data from the CLEOPATRA trial.

In the trial, 808 patients with metastatic HER2-positive disease were given trastuzumab (Herceptin) and docetaxel (Taxotere) and evenly randomized to either pertuzumab (Perjeta) or placebo.

The main results, previously reported, showed that pertuzumab was significantly superior to placebo in terms of progression-free survival and overall survival.

In the new analysis, reported at the San Antonio Breast Cancer Symposium, a variety of protocol-predefined biomarkers of HER2 signaling in tumor tissue and in serum did not identify any patient subgroups that did better or worse on pertuzumab.

"Our analysis confirms that HER2 is the only marker for selecting patients for HER2-targeted therapy. This was despite a comprehensive exploration of a broad panel of candidate biomarkers," commented lead investigator Dr. Jose Baselga of the Memorial Sloan-Kettering Cancer Center in New York. "It is also consistent with the TRYPHAENA and NeoSphere studies, also presented here in San Antonio."

Discussing study limitations, Dr. Baselga said that "the lack of a HER2-naive treatment control arm may have resulted in the absence of a signal for other biomarkers in CLEOPATRA."

In additional findings, mutation of the gene for the catalytic subunit alpha of PI3 kinase (PIK3CA) in the tumor was associated with a poorer prognosis in the trial population as a whole. Patients whose tumors had the alternate, wildtype form of the gene were about one-fourth less likely to experience cancer progression or death.

"Mutations in PI3 kinase were not associated with resistance to pertuzumab, as patients derived similar additional benefit independent of PI3 kinase mutational status. However, the PI3 kinase mutational status may identify patients with poorer prognosis and particular unmet medical needs," Dr. Baselga commented. Prior studies have similarly shown mutant PI3 kinase to be associated with resistance to lapatinib (Tykerb), another HER2-targeted therapy and with a poorer prognosis after trastuzumab therapy.

"Clinical trials of HER2-targeted molecules in combination with PI3 kinase pathway–targeted agents may therefore be justified based on our findings," he added.

It would be interesting to see how a subset of untreated HER2-positive tumors behave as a function of PI3 kinase mutational status, Dr. Baselga said. "I think that will be what we need to know."

In the new analysis, the investigators evaluated a dozen biomarkers lying on the HER2 signaling pathway for both predictive and prognostic value. "From the cell surface down, we analyzed ligands, receptor tyrosine kinases, soluble HER2, and key intracellular pathway markers," Dr. Baselga explained. For most, they defined high and low levels as above- and below-median values, respectively.

In analyses of the predictive value of the biomarkers, the improvement in progression-free survival with pertuzumab relative to placebo was similar for patients having high versus low levels of all the biomarkers studied.

But in analyses of the prognostic value of the biomarkers in both trial arms pooled, patients had better progression-free survival if they had low serum levels of soluble HER2 (hazard ratio, 1.23; P = .04); in terms of ligands and receptor tyrosine kinases, if they had high levels of HER2 mRNA (0.77; P = .008) and HER3 mRNA (0.81; P = .03), and a high HER2 modified histoscore (0.83; P = .05); and in terms of tumor intracellular pathway markers, if they had mutation of the PIK3CA gene (0.83 for wild type; P = .0001).

The last "was by far our strongest prognostic marker," Dr. Baselga commented. Further analysis showed median progression-free survival was better with pertuzumab in both the mutant PIK3CA group (12.5 vs. 8.6 months) and in the wildtype PIK3CA group (21.8 vs. 13.8 months).

"Patients who harbor PI3 kinase mutations have clearly a worse prognosis. The treatment benefit, however, is maintained...the risk reduction is similar for mutants, for wild type, and for the whole study population," he noted.

In a final, longitudinal analysis to determine if serum biomarkers were early indicators of disease progression, levels of the biomarkers at baseline, week 9, and the time of disease progression showed no correlation with disease progression and did not differ between treatment arms.

Dr. Baselga disclosed that he is a consultant for Roche/Genentech and Sanofi. The trial was sponsored by Genentech.

SAN ANTONIO – A variety of biomarkers failed to improve on the results of tumor HER2 status for predicting the benefits of therapy targeting HER2 signaling, based on an analysis of data from the CLEOPATRA trial.

In the trial, 808 patients with metastatic HER2-positive disease were given trastuzumab (Herceptin) and docetaxel (Taxotere) and evenly randomized to either pertuzumab (Perjeta) or placebo.

The main results, previously reported, showed that pertuzumab was significantly superior to placebo in terms of progression-free survival and overall survival.

In the new analysis, reported at the San Antonio Breast Cancer Symposium, a variety of protocol-predefined biomarkers of HER2 signaling in tumor tissue and in serum did not identify any patient subgroups that did better or worse on pertuzumab.

"Our analysis confirms that HER2 is the only marker for selecting patients for HER2-targeted therapy. This was despite a comprehensive exploration of a broad panel of candidate biomarkers," commented lead investigator Dr. Jose Baselga of the Memorial Sloan-Kettering Cancer Center in New York. "It is also consistent with the TRYPHAENA and NeoSphere studies, also presented here in San Antonio."

Discussing study limitations, Dr. Baselga said that "the lack of a HER2-naive treatment control arm may have resulted in the absence of a signal for other biomarkers in CLEOPATRA."

In additional findings, mutation of the gene for the catalytic subunit alpha of PI3 kinase (PIK3CA) in the tumor was associated with a poorer prognosis in the trial population as a whole. Patients whose tumors had the alternate, wildtype form of the gene were about one-fourth less likely to experience cancer progression or death.

"Mutations in PI3 kinase were not associated with resistance to pertuzumab, as patients derived similar additional benefit independent of PI3 kinase mutational status. However, the PI3 kinase mutational status may identify patients with poorer prognosis and particular unmet medical needs," Dr. Baselga commented. Prior studies have similarly shown mutant PI3 kinase to be associated with resistance to lapatinib (Tykerb), another HER2-targeted therapy and with a poorer prognosis after trastuzumab therapy.

"Clinical trials of HER2-targeted molecules in combination with PI3 kinase pathway–targeted agents may therefore be justified based on our findings," he added.

It would be interesting to see how a subset of untreated HER2-positive tumors behave as a function of PI3 kinase mutational status, Dr. Baselga said. "I think that will be what we need to know."

In the new analysis, the investigators evaluated a dozen biomarkers lying on the HER2 signaling pathway for both predictive and prognostic value. "From the cell surface down, we analyzed ligands, receptor tyrosine kinases, soluble HER2, and key intracellular pathway markers," Dr. Baselga explained. For most, they defined high and low levels as above- and below-median values, respectively.

In analyses of the predictive value of the biomarkers, the improvement in progression-free survival with pertuzumab relative to placebo was similar for patients having high versus low levels of all the biomarkers studied.

But in analyses of the prognostic value of the biomarkers in both trial arms pooled, patients had better progression-free survival if they had low serum levels of soluble HER2 (hazard ratio, 1.23; P = .04); in terms of ligands and receptor tyrosine kinases, if they had high levels of HER2 mRNA (0.77; P = .008) and HER3 mRNA (0.81; P = .03), and a high HER2 modified histoscore (0.83; P = .05); and in terms of tumor intracellular pathway markers, if they had mutation of the PIK3CA gene (0.83 for wild type; P = .0001).

The last "was by far our strongest prognostic marker," Dr. Baselga commented. Further analysis showed median progression-free survival was better with pertuzumab in both the mutant PIK3CA group (12.5 vs. 8.6 months) and in the wildtype PIK3CA group (21.8 vs. 13.8 months).

"Patients who harbor PI3 kinase mutations have clearly a worse prognosis. The treatment benefit, however, is maintained...the risk reduction is similar for mutants, for wild type, and for the whole study population," he noted.

In a final, longitudinal analysis to determine if serum biomarkers were early indicators of disease progression, levels of the biomarkers at baseline, week 9, and the time of disease progression showed no correlation with disease progression and did not differ between treatment arms.

Dr. Baselga disclosed that he is a consultant for Roche/Genentech and Sanofi. The trial was sponsored by Genentech.

SAN ANTONIO – The results of a sentinel node biopsy performed after neoadjuvant chemotherapy for breast cancer are often unreliable, new data suggest.

Researchers with the German SENTINA trial prospectively analyzed the impact of the timing of sentinel lymph node (SLN) biopsy on the accuracy and feasibility of the procedure in 1,737 patients with early breast cancer who received neoadjuvant chemotherapy.

Patients with initial clinically node-negative disease (cN0) underwent SLN biopsy before chemotherapy. If biopsy results were positive, they underwent biopsy along with an axillary dissection after chemotherapy. Patients with clinically node-positive disease (cN1) underwent chemotherapy followed by SLN biopsy plus axillary dissection if they had a downstaging to clinically node-negative disease.

The SLN biopsy procedure was standardized according to interdisciplinary consensus (Cancer 2005;103:451-61); radiocolloid tracer with lymphoscintigraphy was mandatory for identifying sentinel nodes, whereas blue dye was optional.

Study results showed that the false-negative rate was 51.6% in patients with cN0 disease who had an initial SLN biopsy showing nodal involvement and therefore went on to have another SLN biopsy after the chemotherapy.

SLN biopsy had a false-negative rate of 14.2% when performed after the neoadjuvant chemotherapy in patients with initial cN1 disease who had downstaging to cN0 disease, lead author Dr. Thorsten Kuehn reported at the San Antonio Breast Cancer Symposium.

This rate was up to twice as high as that seen historically in patients instead having the SLN biopsy at the time of primary surgery, which has been on the order of 7%-10%.

"The SLN biopsy as a diagnostic procedure is not a reliable tool in patients who convert on neoadjuvant chemotherapy from cN1 to cN0 compared to SLN biopsy in primary surgery," he said.

Within this downstaged group, data showed that the odds of a false-negative result were reduced by half when patients had more than one sentinel node examined.

"It strikes me that your conclusion should have been, if you take two or more sentinel nodes, this is a safe procedure," one attendee noted during a discussion session. "But if you take less than that, it’s not safe. Is that true?"

The study biopsies were adequate in that all patients had lymphoscintigraphy, contended Dr. Kuehn, who is head of the breast center and chief of the gynecology and obstetrics clinic at Klinikum Esslingen in Germany. "I don’t think you necessarily always have two sentinel nodes – you may have one sentinel node. And every institution or every surgeon had to prove that the sentinel nodes that were shown on lymphoscintigraphy had to be removed."

Another attendee wondered about the extent of residual axillary disease in the patients having false-positive SLN results.

"As a radiation oncologist, I am seeing a lot of patients who have had sentinel node biopsies done after neoadjuvant chemotherapy without an axillary dissection, and I’m being asked to irradiate the patient, which makes me uncomfortable because I don’t know what the volume of disease left is," he explained. "Do you have a sense of what the volume of disease is – micrometastases, macrometastases, number of nodes – in the patients with false-negative sentinel nodes, and do you also have a sense of what that volume is in the axillary dissection specimen outside the true-positive sentinel nodes?"

"We don’t have information on the size of the metastases. We have information on the number of involved non–sentinel nodes, and these numbers are from 1 to 11," Dr. Kuehn replied.

"What we want to say is SLN biopsy is a diagnostic tool, and this tool is worse after previous treatment. I can say I work with this tool, but it is not a good diagnostic tool," he added.

In the study, SLN detection rates, a measure of feasibility, also differed significantly across groups. Surgeons were able to detect these nodes in 99% of all SLN biopsies performed before any treatment, but in only 80% of those performed after a downstaging of disease with the neoadjuvant chemotherapy and in only 61% of the repeated SLN biopsies. The pattern of nodal uptake of the radiocolloid tracer mirrored these findings.

"Previous local and systemic treatment significantly impairs the tracer uptake and the detection rate," concluded Dr. Kuehn, who disclosed no conflicts of interest related to the research.

In a multivariate analysis in the downstaged group, none of a variety of tumor characteristics significantly predicted the ability to detect an SLN.

SAN ANTONIO – The results of a sentinel node biopsy performed after neoadjuvant chemotherapy for breast cancer are often unreliable, new data suggest.

Researchers with the German SENTINA trial prospectively analyzed the impact of the timing of sentinel lymph node (SLN) biopsy on the accuracy and feasibility of the procedure in 1,737 patients with early breast cancer who received neoadjuvant chemotherapy.

Patients with initial clinically node-negative disease (cN0) underwent SLN biopsy before chemotherapy. If biopsy results were positive, they underwent biopsy along with an axillary dissection after chemotherapy. Patients with clinically node-positive disease (cN1) underwent chemotherapy followed by SLN biopsy plus axillary dissection if they had a downstaging to clinically node-negative disease.

The SLN biopsy procedure was standardized according to interdisciplinary consensus (Cancer 2005;103:451-61); radiocolloid tracer with lymphoscintigraphy was mandatory for identifying sentinel nodes, whereas blue dye was optional.

Study results showed that the false-negative rate was 51.6% in patients with cN0 disease who had an initial SLN biopsy showing nodal involvement and therefore went on to have another SLN biopsy after the chemotherapy.

SLN biopsy had a false-negative rate of 14.2% when performed after the neoadjuvant chemotherapy in patients with initial cN1 disease who had downstaging to cN0 disease, lead author Dr. Thorsten Kuehn reported at the San Antonio Breast Cancer Symposium.

This rate was up to twice as high as that seen historically in patients instead having the SLN biopsy at the time of primary surgery, which has been on the order of 7%-10%.

"The SLN biopsy as a diagnostic procedure is not a reliable tool in patients who convert on neoadjuvant chemotherapy from cN1 to cN0 compared to SLN biopsy in primary surgery," he said.

Within this downstaged group, data showed that the odds of a false-negative result were reduced by half when patients had more than one sentinel node examined.

"It strikes me that your conclusion should have been, if you take two or more sentinel nodes, this is a safe procedure," one attendee noted during a discussion session. "But if you take less than that, it’s not safe. Is that true?"

The study biopsies were adequate in that all patients had lymphoscintigraphy, contended Dr. Kuehn, who is head of the breast center and chief of the gynecology and obstetrics clinic at Klinikum Esslingen in Germany. "I don’t think you necessarily always have two sentinel nodes – you may have one sentinel node. And every institution or every surgeon had to prove that the sentinel nodes that were shown on lymphoscintigraphy had to be removed."

Another attendee wondered about the extent of residual axillary disease in the patients having false-positive SLN results.

"As a radiation oncologist, I am seeing a lot of patients who have had sentinel node biopsies done after neoadjuvant chemotherapy without an axillary dissection, and I’m being asked to irradiate the patient, which makes me uncomfortable because I don’t know what the volume of disease left is," he explained. "Do you have a sense of what the volume of disease is – micrometastases, macrometastases, number of nodes – in the patients with false-negative sentinel nodes, and do you also have a sense of what that volume is in the axillary dissection specimen outside the true-positive sentinel nodes?"

"We don’t have information on the size of the metastases. We have information on the number of involved non–sentinel nodes, and these numbers are from 1 to 11," Dr. Kuehn replied.

"What we want to say is SLN biopsy is a diagnostic tool, and this tool is worse after previous treatment. I can say I work with this tool, but it is not a good diagnostic tool," he added.

In the study, SLN detection rates, a measure of feasibility, also differed significantly across groups. Surgeons were able to detect these nodes in 99% of all SLN biopsies performed before any treatment, but in only 80% of those performed after a downstaging of disease with the neoadjuvant chemotherapy and in only 61% of the repeated SLN biopsies. The pattern of nodal uptake of the radiocolloid tracer mirrored these findings.

"Previous local and systemic treatment significantly impairs the tracer uptake and the detection rate," concluded Dr. Kuehn, who disclosed no conflicts of interest related to the research.

In a multivariate analysis in the downstaged group, none of a variety of tumor characteristics significantly predicted the ability to detect an SLN.

SAN ANTONIO – The results of a sentinel node biopsy performed after neoadjuvant chemotherapy for breast cancer are often unreliable, new data suggest.

Researchers with the German SENTINA trial prospectively analyzed the impact of the timing of sentinel lymph node (SLN) biopsy on the accuracy and feasibility of the procedure in 1,737 patients with early breast cancer who received neoadjuvant chemotherapy.

Patients with initial clinically node-negative disease (cN0) underwent SLN biopsy before chemotherapy. If biopsy results were positive, they underwent biopsy along with an axillary dissection after chemotherapy. Patients with clinically node-positive disease (cN1) underwent chemotherapy followed by SLN biopsy plus axillary dissection if they had a downstaging to clinically node-negative disease.

The SLN biopsy procedure was standardized according to interdisciplinary consensus (Cancer 2005;103:451-61); radiocolloid tracer with lymphoscintigraphy was mandatory for identifying sentinel nodes, whereas blue dye was optional.

Study results showed that the false-negative rate was 51.6% in patients with cN0 disease who had an initial SLN biopsy showing nodal involvement and therefore went on to have another SLN biopsy after the chemotherapy.

SLN biopsy had a false-negative rate of 14.2% when performed after the neoadjuvant chemotherapy in patients with initial cN1 disease who had downstaging to cN0 disease, lead author Dr. Thorsten Kuehn reported at the San Antonio Breast Cancer Symposium.

This rate was up to twice as high as that seen historically in patients instead having the SLN biopsy at the time of primary surgery, which has been on the order of 7%-10%.

"The SLN biopsy as a diagnostic procedure is not a reliable tool in patients who convert on neoadjuvant chemotherapy from cN1 to cN0 compared to SLN biopsy in primary surgery," he said.

Within this downstaged group, data showed that the odds of a false-negative result were reduced by half when patients had more than one sentinel node examined.

"It strikes me that your conclusion should have been, if you take two or more sentinel nodes, this is a safe procedure," one attendee noted during a discussion session. "But if you take less than that, it’s not safe. Is that true?"

The study biopsies were adequate in that all patients had lymphoscintigraphy, contended Dr. Kuehn, who is head of the breast center and chief of the gynecology and obstetrics clinic at Klinikum Esslingen in Germany. "I don’t think you necessarily always have two sentinel nodes – you may have one sentinel node. And every institution or every surgeon had to prove that the sentinel nodes that were shown on lymphoscintigraphy had to be removed."

Another attendee wondered about the extent of residual axillary disease in the patients having false-positive SLN results.

"As a radiation oncologist, I am seeing a lot of patients who have had sentinel node biopsies done after neoadjuvant chemotherapy without an axillary dissection, and I’m being asked to irradiate the patient, which makes me uncomfortable because I don’t know what the volume of disease left is," he explained. "Do you have a sense of what the volume of disease is – micrometastases, macrometastases, number of nodes – in the patients with false-negative sentinel nodes, and do you also have a sense of what that volume is in the axillary dissection specimen outside the true-positive sentinel nodes?"

"We don’t have information on the size of the metastases. We have information on the number of involved non–sentinel nodes, and these numbers are from 1 to 11," Dr. Kuehn replied.

"What we want to say is SLN biopsy is a diagnostic tool, and this tool is worse after previous treatment. I can say I work with this tool, but it is not a good diagnostic tool," he added.

In the study, SLN detection rates, a measure of feasibility, also differed significantly across groups. Surgeons were able to detect these nodes in 99% of all SLN biopsies performed before any treatment, but in only 80% of those performed after a downstaging of disease with the neoadjuvant chemotherapy and in only 61% of the repeated SLN biopsies. The pattern of nodal uptake of the radiocolloid tracer mirrored these findings.

"Previous local and systemic treatment significantly impairs the tracer uptake and the detection rate," concluded Dr. Kuehn, who disclosed no conflicts of interest related to the research.

In a multivariate analysis in the downstaged group, none of a variety of tumor characteristics significantly predicted the ability to detect an SLN.

SAN ANTONIO – Immunohistochemical expression of the proliferation marker Ki67 in a pretreatment biopsy of breast cancer is valid as both a positive predictive marker and a negative prognostic marker of response to neoadjuvant therapy, said Dr. Carsten Denkert, senior pathologist and head of the translational cancer research group at the Institute of Pathology, Charité University Hospital, Berlin.

The findings are based on an analysis of data from the GeparTrio trial of the German Breast Group.

Among the eight molecular subtypes of breast cancer (hormone receptor positive/negative, HER2 positive/negative, and four subtypes created by combining these features), Ki67 was a positive predictive marker in six subtypes and a negative prognostic marker in the three hormone receptor–positive subtypes, Dr. Denkert said at the San Antonio Breast Cancer Symposium.

Across cutpoints for Ki67 positivity ranging from 10% to 45%, women with Ki67-positive tumors were significantly more likely to have a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they also had significantly poorer disease-free and overall survival.

The analysis was unable to identify an optimal cutpoint for positivity, but the "results provide an explanation for the very different cutpoint results in various previous clinical studies," he said. As Ki67 is a continuous marker that measures tumor proliferation, cutpoints can be defined by the scientific community.

In the GeparTrio trial, the 1,166 patients all had tumors measuring at least 2 cm, underwent a core biopsy, received two cycles of neoadjuvant chemotherapy, underwent ultrasound assessment of response, and then received additional cycles of chemotherapy tailored to that response.

The research team led by Dr. Denkert performed immunohistochemical staining for Ki67 in the pretreatment core biopsy using the MIB-1 antibody and systematically assessed 94 cutpoints for Ki67 positivity between 0% and 100% for their association with outcomes.

Results showed that 93 of the cutpoints were significantly associated with pCR, 48 were significantly associated with disease-free survival, and 58 were significantly associated with overall survival. "So it is very difficult to decide which one is the optimal cutpoint," Dr. Denkert commented.

For further analyses, patients were split into three equal groups according to Ki67 cutpoint: low (less than or equal to 15%), intermediate (15.1%-35%), and high (greater than 35%).

In a multivariate analysis, these three groups differed significantly with respect to pCR rate (P less than .0005), median disease-free survival (P = .012), and median overall survival (P = .013).

In a discussion after the presentation, Dr. Steven Vogl of the Montefiore Medical Center, New York, referenced earlier reports from the same trial. "Getting a partial response for some of the hormone receptor–positive tumors was good in terms of prognosis, even though a pCR wasn’t achieved. Did you look at Ki67 in the non-pCR patients and see if that gave you any information as to their prognosis? That is, Ki67 at the time of the final surgical procedure."

"In fact, this was one of the aims of the large Ki67 program that we did on the core biopsies and also on the surgical tissues," Dr. Denkert replied. "So far, we have not yet been able to define Ki67 as a parameter for the effect observed with the hormone receptor–positive tumors in the GeparTrio trial. Very likely, we have to combine this parameter with other parameters, and we are currently working on this."

Although the 12th St. Gallen International Breast Cancer Conference (2011) Expert Panel has proposed that Ki67 may be able to differentiate between the luminal A and luminal B molecular subtypes of breast cancer (Ann. Oncol. 2011;22:1736-47), the optimal cutpoint of the percentage of positive cells for defining a tumor to be Ki67 positive is still debated, he noted.

Dr. Denkert disclosed that he receives research/grant support from Siemens Medical Solutions and Sividon Diagnostics; that he is a consultant for Celgene, Amgen, and Sividon Diagnostics; and that he is a shareholder in Sividon Diagnostics.

SAN ANTONIO – Immunohistochemical expression of the proliferation marker Ki67 in a pretreatment biopsy of breast cancer is valid as both a positive predictive marker and a negative prognostic marker of response to neoadjuvant therapy, said Dr. Carsten Denkert, senior pathologist and head of the translational cancer research group at the Institute of Pathology, Charité University Hospital, Berlin.

The findings are based on an analysis of data from the GeparTrio trial of the German Breast Group.

Among the eight molecular subtypes of breast cancer (hormone receptor positive/negative, HER2 positive/negative, and four subtypes created by combining these features), Ki67 was a positive predictive marker in six subtypes and a negative prognostic marker in the three hormone receptor–positive subtypes, Dr. Denkert said at the San Antonio Breast Cancer Symposium.

Across cutpoints for Ki67 positivity ranging from 10% to 45%, women with Ki67-positive tumors were significantly more likely to have a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they also had significantly poorer disease-free and overall survival.

The analysis was unable to identify an optimal cutpoint for positivity, but the "results provide an explanation for the very different cutpoint results in various previous clinical studies," he said. As Ki67 is a continuous marker that measures tumor proliferation, cutpoints can be defined by the scientific community.

In the GeparTrio trial, the 1,166 patients all had tumors measuring at least 2 cm, underwent a core biopsy, received two cycles of neoadjuvant chemotherapy, underwent ultrasound assessment of response, and then received additional cycles of chemotherapy tailored to that response.

The research team led by Dr. Denkert performed immunohistochemical staining for Ki67 in the pretreatment core biopsy using the MIB-1 antibody and systematically assessed 94 cutpoints for Ki67 positivity between 0% and 100% for their association with outcomes.

Results showed that 93 of the cutpoints were significantly associated with pCR, 48 were significantly associated with disease-free survival, and 58 were significantly associated with overall survival. "So it is very difficult to decide which one is the optimal cutpoint," Dr. Denkert commented.

For further analyses, patients were split into three equal groups according to Ki67 cutpoint: low (less than or equal to 15%), intermediate (15.1%-35%), and high (greater than 35%).

In a multivariate analysis, these three groups differed significantly with respect to pCR rate (P less than .0005), median disease-free survival (P = .012), and median overall survival (P = .013).

In a discussion after the presentation, Dr. Steven Vogl of the Montefiore Medical Center, New York, referenced earlier reports from the same trial. "Getting a partial response for some of the hormone receptor–positive tumors was good in terms of prognosis, even though a pCR wasn’t achieved. Did you look at Ki67 in the non-pCR patients and see if that gave you any information as to their prognosis? That is, Ki67 at the time of the final surgical procedure."

"In fact, this was one of the aims of the large Ki67 program that we did on the core biopsies and also on the surgical tissues," Dr. Denkert replied. "So far, we have not yet been able to define Ki67 as a parameter for the effect observed with the hormone receptor–positive tumors in the GeparTrio trial. Very likely, we have to combine this parameter with other parameters, and we are currently working on this."

Although the 12th St. Gallen International Breast Cancer Conference (2011) Expert Panel has proposed that Ki67 may be able to differentiate between the luminal A and luminal B molecular subtypes of breast cancer (Ann. Oncol. 2011;22:1736-47), the optimal cutpoint of the percentage of positive cells for defining a tumor to be Ki67 positive is still debated, he noted.

Dr. Denkert disclosed that he receives research/grant support from Siemens Medical Solutions and Sividon Diagnostics; that he is a consultant for Celgene, Amgen, and Sividon Diagnostics; and that he is a shareholder in Sividon Diagnostics.

SAN ANTONIO – Immunohistochemical expression of the proliferation marker Ki67 in a pretreatment biopsy of breast cancer is valid as both a positive predictive marker and a negative prognostic marker of response to neoadjuvant therapy, said Dr. Carsten Denkert, senior pathologist and head of the translational cancer research group at the Institute of Pathology, Charité University Hospital, Berlin.

The findings are based on an analysis of data from the GeparTrio trial of the German Breast Group.

Among the eight molecular subtypes of breast cancer (hormone receptor positive/negative, HER2 positive/negative, and four subtypes created by combining these features), Ki67 was a positive predictive marker in six subtypes and a negative prognostic marker in the three hormone receptor–positive subtypes, Dr. Denkert said at the San Antonio Breast Cancer Symposium.

Across cutpoints for Ki67 positivity ranging from 10% to 45%, women with Ki67-positive tumors were significantly more likely to have a pathologic complete response (pCR) to neoadjuvant chemotherapy, but they also had significantly poorer disease-free and overall survival.

The analysis was unable to identify an optimal cutpoint for positivity, but the "results provide an explanation for the very different cutpoint results in various previous clinical studies," he said. As Ki67 is a continuous marker that measures tumor proliferation, cutpoints can be defined by the scientific community.

In the GeparTrio trial, the 1,166 patients all had tumors measuring at least 2 cm, underwent a core biopsy, received two cycles of neoadjuvant chemotherapy, underwent ultrasound assessment of response, and then received additional cycles of chemotherapy tailored to that response.

The research team led by Dr. Denkert performed immunohistochemical staining for Ki67 in the pretreatment core biopsy using the MIB-1 antibody and systematically assessed 94 cutpoints for Ki67 positivity between 0% and 100% for their association with outcomes.

Results showed that 93 of the cutpoints were significantly associated with pCR, 48 were significantly associated with disease-free survival, and 58 were significantly associated with overall survival. "So it is very difficult to decide which one is the optimal cutpoint," Dr. Denkert commented.

For further analyses, patients were split into three equal groups according to Ki67 cutpoint: low (less than or equal to 15%), intermediate (15.1%-35%), and high (greater than 35%).

In a multivariate analysis, these three groups differed significantly with respect to pCR rate (P less than .0005), median disease-free survival (P = .012), and median overall survival (P = .013).

In a discussion after the presentation, Dr. Steven Vogl of the Montefiore Medical Center, New York, referenced earlier reports from the same trial. "Getting a partial response for some of the hormone receptor–positive tumors was good in terms of prognosis, even though a pCR wasn’t achieved. Did you look at Ki67 in the non-pCR patients and see if that gave you any information as to their prognosis? That is, Ki67 at the time of the final surgical procedure."

"In fact, this was one of the aims of the large Ki67 program that we did on the core biopsies and also on the surgical tissues," Dr. Denkert replied. "So far, we have not yet been able to define Ki67 as a parameter for the effect observed with the hormone receptor–positive tumors in the GeparTrio trial. Very likely, we have to combine this parameter with other parameters, and we are currently working on this."

Although the 12th St. Gallen International Breast Cancer Conference (2011) Expert Panel has proposed that Ki67 may be able to differentiate between the luminal A and luminal B molecular subtypes of breast cancer (Ann. Oncol. 2011;22:1736-47), the optimal cutpoint of the percentage of positive cells for defining a tumor to be Ki67 positive is still debated, he noted.

Dr. Denkert disclosed that he receives research/grant support from Siemens Medical Solutions and Sividon Diagnostics; that he is a consultant for Celgene, Amgen, and Sividon Diagnostics; and that he is a shareholder in Sividon Diagnostics.

A new multigene score called EndoPredict improves on clinical measures for predicting whether estrogen receptor–positive breast cancer will metastasize, especially in the long term. The score therefore may help identify patients who can skip extended antihormonal therapy.

Investigators with the Austrian Breast and Colorectal Cancer Study Group (ABCSG) studied more than 1,700 postmenopausal patients with early estrogen receptor (ER)-positive, HER2-negative breast cancer who underwent surgery and received hormonal therapy for 5 years.

Using formalin-fixed, paraffin-embedded tumor tissue, the team derived a pretreatment EndoPredict score (Sividon Diagnostics) for each patient. The score reflects expression levels of 12 genes involved in proliferation, ER signaling, and differentiation.

Patients with a low vs. high EndoPredict score were 20%-30% more likely to be free of distant metastases during the first 5 years of follow-up and also thereafter, lead investigator Dr. Peter Dubsky reported at the San Antonio Breast Cancer Symposium.

And an EndoPredict clinical score, which combined the score with clinical features, showed even better prediction, especially in the long term: Patients having a low vs. high EndoPredict clinical score at 5 years of follow-up were five times as likely to remain free of distant metastases thereafter. In absolute terms, more than 98% of this low-risk group was still metastasis free at 10 years.

"The EndoPredict score identifies early and late recurrences, and offers independent prognostic information beyond what can be achieved with all common clinical parameters," Dr. Dubsky maintained.

"Why would this data be important?" he asked. "We currently have around 20,000 women included in ongoing extended/late endocrine therapy clinical trials. Speaking from our trial, ABCSG-16, also known as SALSA [Secondary Adjuvant Long-Term Study With Arimidex], we see very low event rates, and the efficacy data of these trials is unlikely to make individual decisions for women very simple," he explained. "We believe that gene expression data may help establish patient subgroups with a very excellent prognosis and thus facilitate the therapeutic choice."

Dr. Laura Esserman of the University of California, San Francisco, asked how EndoPredict might stack up against other similar tools, such as the sensitivity to endocrine therapy (SET) index.

"I’d love to run this side by side in the same biomarker sample. That would be great," Dr. Dubsky commented. "We have had a fantastic presentation on the BCI (Breast Cancer Index), but this is a score that runs only in node-negative. And I think what is similar between the EndoPredict score and the BCI is that the BCI also has the ER signaling incorporated in the algorithm of genes."

Another attendee likewise asked whether the investigators had compared EndoPredict with tools such as Adjuvant Online.

"I’d be very careful with prediction power and comparing, because this is always going to depend on the biomarkers that you are using," Dr. Dubsky replied. "We have a fantastic sensitivity with this test, but how would another test from another company perform in the same biomarker sample, I cannot say."

"Would you not enrich your gene signature for late recurrence by simply examining patients who recurred late, and compare them with those that did not?" a third attendee wondered.

"The women assigned to the low-risk group have a very, very low incidence of both early and late recurrence; the high-risk group has a high risk of both early and late recurrence. The signature does in no way select specifically for the late recurrence," Dr. Dubsky explained. "I think what is special about the signature is that it can predict the late recurrences better than others do because it is not relying solely on proliferation."

Giving some background to the study, he noted, "The first-generation multigene signatures have largely been trained to predict early recurrences and not late recurrences, and commonly fail to identify the late events."

EndoPredict may be the first multigene test for breast cancer that can be used in a decentralized setting. The test has recently received the European CE mark as an in vitro diagnostic test, and is being used in Germany, Austria, and Switzerland.

The 1,702 postmenopausal women studied were participants in a pair of randomized trials (ABCSG-6 and ABCSG-8). One-third had node-positive disease. None received adjuvant chemotherapy, but all received hormonal therapy (tamoxifen alone or some sequence of tamoxifen and an aromatase inhibitor) for 5 years. Their median age was 64 years.

"This is a very homogeneously treated cohort with low to intermediate risk," Dr. Dubsky summarized.

A total of 998 women were still at risk for distant metastases after 5 years, and their median duration of follow-up was 7.1 years.

Overall, 49% of all patients had a low-risk EndoPredict score. After multivariate adjustment, these patients were significantly more likely to be free of distant metastases in the first 5 years of follow-up (hazard ratio, 1.20; P less than .001) and thereafter (HR, 1.28; P = .001). Fully 96.3% of patients with a low-risk score were metastasis free between 5 and 10 years.

"The EndoPredict is clearly an independent prognostic parameter both in the years 0 to 5 and after 5 years," Dr. Dubsky maintained.

When the C-index for discrimination was calculated, EndoPredict significantly improved on prediction of distant metastases after 5 years of follow-up when combined with the Adjuvant Online score (P less than .001) and other factors.

However, the best prediction was achieved with the predefined EndoPredict clinical score, which combined the EndoPredict score, nodal status, and tumor size, and achieved a C-index of nearly 0.8.

Fully 64% of patients still at risk for distant metastases after 5 years of follow-up had a low EndoPredict clinical score. These patients were dramatically more likely to remain free of distant metastases thereafter (HR, 5.11; P less than .001). In absolute terms, 98.2% were free of distant metastasis at 10 years.

"Risks and side effects of extended therapy should be weighed against this outcome," Dr. Dubsky recommended.

In a final analysis teasing apart the role of various genes included in the EndoPredict score, the proliferation genes added independent negative prognostic information for early recurrence, whereas the genes associated with ER signaling added independent positive prognostic information for late recurrence.

Dr. Dubsky disclosed that he is an adviser to Sividon, Agendia, Genomic Health, and AstraZeneca; receives grant support from Sividon and Agendia; and is on the speakers bureau for Sividon.

A new multigene score called EndoPredict improves on clinical measures for predicting whether estrogen receptor–positive breast cancer will metastasize, especially in the long term. The score therefore may help identify patients who can skip extended antihormonal therapy.

Investigators with the Austrian Breast and Colorectal Cancer Study Group (ABCSG) studied more than 1,700 postmenopausal patients with early estrogen receptor (ER)-positive, HER2-negative breast cancer who underwent surgery and received hormonal therapy for 5 years.

Using formalin-fixed, paraffin-embedded tumor tissue, the team derived a pretreatment EndoPredict score (Sividon Diagnostics) for each patient. The score reflects expression levels of 12 genes involved in proliferation, ER signaling, and differentiation.

Patients with a low vs. high EndoPredict score were 20%-30% more likely to be free of distant metastases during the first 5 years of follow-up and also thereafter, lead investigator Dr. Peter Dubsky reported at the San Antonio Breast Cancer Symposium.

And an EndoPredict clinical score, which combined the score with clinical features, showed even better prediction, especially in the long term: Patients having a low vs. high EndoPredict clinical score at 5 years of follow-up were five times as likely to remain free of distant metastases thereafter. In absolute terms, more than 98% of this low-risk group was still metastasis free at 10 years.

"The EndoPredict score identifies early and late recurrences, and offers independent prognostic information beyond what can be achieved with all common clinical parameters," Dr. Dubsky maintained.

"Why would this data be important?" he asked. "We currently have around 20,000 women included in ongoing extended/late endocrine therapy clinical trials. Speaking from our trial, ABCSG-16, also known as SALSA [Secondary Adjuvant Long-Term Study With Arimidex], we see very low event rates, and the efficacy data of these trials is unlikely to make individual decisions for women very simple," he explained. "We believe that gene expression data may help establish patient subgroups with a very excellent prognosis and thus facilitate the therapeutic choice."

Dr. Laura Esserman of the University of California, San Francisco, asked how EndoPredict might stack up against other similar tools, such as the sensitivity to endocrine therapy (SET) index.

"I’d love to run this side by side in the same biomarker sample. That would be great," Dr. Dubsky commented. "We have had a fantastic presentation on the BCI (Breast Cancer Index), but this is a score that runs only in node-negative. And I think what is similar between the EndoPredict score and the BCI is that the BCI also has the ER signaling incorporated in the algorithm of genes."

Another attendee likewise asked whether the investigators had compared EndoPredict with tools such as Adjuvant Online.

"I’d be very careful with prediction power and comparing, because this is always going to depend on the biomarkers that you are using," Dr. Dubsky replied. "We have a fantastic sensitivity with this test, but how would another test from another company perform in the same biomarker sample, I cannot say."

"Would you not enrich your gene signature for late recurrence by simply examining patients who recurred late, and compare them with those that did not?" a third attendee wondered.

"The women assigned to the low-risk group have a very, very low incidence of both early and late recurrence; the high-risk group has a high risk of both early and late recurrence. The signature does in no way select specifically for the late recurrence," Dr. Dubsky explained. "I think what is special about the signature is that it can predict the late recurrences better than others do because it is not relying solely on proliferation."

Giving some background to the study, he noted, "The first-generation multigene signatures have largely been trained to predict early recurrences and not late recurrences, and commonly fail to identify the late events."

EndoPredict may be the first multigene test for breast cancer that can be used in a decentralized setting. The test has recently received the European CE mark as an in vitro diagnostic test, and is being used in Germany, Austria, and Switzerland.

The 1,702 postmenopausal women studied were participants in a pair of randomized trials (ABCSG-6 and ABCSG-8). One-third had node-positive disease. None received adjuvant chemotherapy, but all received hormonal therapy (tamoxifen alone or some sequence of tamoxifen and an aromatase inhibitor) for 5 years. Their median age was 64 years.

"This is a very homogeneously treated cohort with low to intermediate risk," Dr. Dubsky summarized.

A total of 998 women were still at risk for distant metastases after 5 years, and their median duration of follow-up was 7.1 years.

Overall, 49% of all patients had a low-risk EndoPredict score. After multivariate adjustment, these patients were significantly more likely to be free of distant metastases in the first 5 years of follow-up (hazard ratio, 1.20; P less than .001) and thereafter (HR, 1.28; P = .001). Fully 96.3% of patients with a low-risk score were metastasis free between 5 and 10 years.

"The EndoPredict is clearly an independent prognostic parameter both in the years 0 to 5 and after 5 years," Dr. Dubsky maintained.

When the C-index for discrimination was calculated, EndoPredict significantly improved on prediction of distant metastases after 5 years of follow-up when combined with the Adjuvant Online score (P less than .001) and other factors.

However, the best prediction was achieved with the predefined EndoPredict clinical score, which combined the EndoPredict score, nodal status, and tumor size, and achieved a C-index of nearly 0.8.

Fully 64% of patients still at risk for distant metastases after 5 years of follow-up had a low EndoPredict clinical score. These patients were dramatically more likely to remain free of distant metastases thereafter (HR, 5.11; P less than .001). In absolute terms, 98.2% were free of distant metastasis at 10 years.

"Risks and side effects of extended therapy should be weighed against this outcome," Dr. Dubsky recommended.

In a final analysis teasing apart the role of various genes included in the EndoPredict score, the proliferation genes added independent negative prognostic information for early recurrence, whereas the genes associated with ER signaling added independent positive prognostic information for late recurrence.

Dr. Dubsky disclosed that he is an adviser to Sividon, Agendia, Genomic Health, and AstraZeneca; receives grant support from Sividon and Agendia; and is on the speakers bureau for Sividon.

A new multigene score called EndoPredict improves on clinical measures for predicting whether estrogen receptor–positive breast cancer will metastasize, especially in the long term. The score therefore may help identify patients who can skip extended antihormonal therapy.

Investigators with the Austrian Breast and Colorectal Cancer Study Group (ABCSG) studied more than 1,700 postmenopausal patients with early estrogen receptor (ER)-positive, HER2-negative breast cancer who underwent surgery and received hormonal therapy for 5 years.

Using formalin-fixed, paraffin-embedded tumor tissue, the team derived a pretreatment EndoPredict score (Sividon Diagnostics) for each patient. The score reflects expression levels of 12 genes involved in proliferation, ER signaling, and differentiation.

Patients with a low vs. high EndoPredict score were 20%-30% more likely to be free of distant metastases during the first 5 years of follow-up and also thereafter, lead investigator Dr. Peter Dubsky reported at the San Antonio Breast Cancer Symposium.

And an EndoPredict clinical score, which combined the score with clinical features, showed even better prediction, especially in the long term: Patients having a low vs. high EndoPredict clinical score at 5 years of follow-up were five times as likely to remain free of distant metastases thereafter. In absolute terms, more than 98% of this low-risk group was still metastasis free at 10 years.

"The EndoPredict score identifies early and late recurrences, and offers independent prognostic information beyond what can be achieved with all common clinical parameters," Dr. Dubsky maintained.

"Why would this data be important?" he asked. "We currently have around 20,000 women included in ongoing extended/late endocrine therapy clinical trials. Speaking from our trial, ABCSG-16, also known as SALSA [Secondary Adjuvant Long-Term Study With Arimidex], we see very low event rates, and the efficacy data of these trials is unlikely to make individual decisions for women very simple," he explained. "We believe that gene expression data may help establish patient subgroups with a very excellent prognosis and thus facilitate the therapeutic choice."

Dr. Laura Esserman of the University of California, San Francisco, asked how EndoPredict might stack up against other similar tools, such as the sensitivity to endocrine therapy (SET) index.

"I’d love to run this side by side in the same biomarker sample. That would be great," Dr. Dubsky commented. "We have had a fantastic presentation on the BCI (Breast Cancer Index), but this is a score that runs only in node-negative. And I think what is similar between the EndoPredict score and the BCI is that the BCI also has the ER signaling incorporated in the algorithm of genes."

Another attendee likewise asked whether the investigators had compared EndoPredict with tools such as Adjuvant Online.

"I’d be very careful with prediction power and comparing, because this is always going to depend on the biomarkers that you are using," Dr. Dubsky replied. "We have a fantastic sensitivity with this test, but how would another test from another company perform in the same biomarker sample, I cannot say."

"Would you not enrich your gene signature for late recurrence by simply examining patients who recurred late, and compare them with those that did not?" a third attendee wondered.

"The women assigned to the low-risk group have a very, very low incidence of both early and late recurrence; the high-risk group has a high risk of both early and late recurrence. The signature does in no way select specifically for the late recurrence," Dr. Dubsky explained. "I think what is special about the signature is that it can predict the late recurrences better than others do because it is not relying solely on proliferation."

Giving some background to the study, he noted, "The first-generation multigene signatures have largely been trained to predict early recurrences and not late recurrences, and commonly fail to identify the late events."

EndoPredict may be the first multigene test for breast cancer that can be used in a decentralized setting. The test has recently received the European CE mark as an in vitro diagnostic test, and is being used in Germany, Austria, and Switzerland.

The 1,702 postmenopausal women studied were participants in a pair of randomized trials (ABCSG-6 and ABCSG-8). One-third had node-positive disease. None received adjuvant chemotherapy, but all received hormonal therapy (tamoxifen alone or some sequence of tamoxifen and an aromatase inhibitor) for 5 years. Their median age was 64 years.

"This is a very homogeneously treated cohort with low to intermediate risk," Dr. Dubsky summarized.

A total of 998 women were still at risk for distant metastases after 5 years, and their median duration of follow-up was 7.1 years.

Overall, 49% of all patients had a low-risk EndoPredict score. After multivariate adjustment, these patients were significantly more likely to be free of distant metastases in the first 5 years of follow-up (hazard ratio, 1.20; P less than .001) and thereafter (HR, 1.28; P = .001). Fully 96.3% of patients with a low-risk score were metastasis free between 5 and 10 years.

"The EndoPredict is clearly an independent prognostic parameter both in the years 0 to 5 and after 5 years," Dr. Dubsky maintained.

When the C-index for discrimination was calculated, EndoPredict significantly improved on prediction of distant metastases after 5 years of follow-up when combined with the Adjuvant Online score (P less than .001) and other factors.

However, the best prediction was achieved with the predefined EndoPredict clinical score, which combined the EndoPredict score, nodal status, and tumor size, and achieved a C-index of nearly 0.8.

Fully 64% of patients still at risk for distant metastases after 5 years of follow-up had a low EndoPredict clinical score. These patients were dramatically more likely to remain free of distant metastases thereafter (HR, 5.11; P less than .001). In absolute terms, 98.2% were free of distant metastasis at 10 years.

"Risks and side effects of extended therapy should be weighed against this outcome," Dr. Dubsky recommended.

In a final analysis teasing apart the role of various genes included in the EndoPredict score, the proliferation genes added independent negative prognostic information for early recurrence, whereas the genes associated with ER signaling added independent positive prognostic information for late recurrence.

Dr. Dubsky disclosed that he is an adviser to Sividon, Agendia, Genomic Health, and AstraZeneca; receives grant support from Sividon and Agendia; and is on the speakers bureau for Sividon.