SABCS 2015

SAN ANTONIO – A large randomized controlled trial of aspirin for breast cancer prevention is warranted in light of new evidence that aspirin use shows a strong independent inverse relationship with mammographic breast density, Dr. Marie E. Wood declared at the San Antonio Breast Cancer Symposium.

Breast density, she noted, is well accepted as a modifiable risk factor for both estrogen receptor–negative (ER–) and estrogren receptor–positive (ER+) breast cancer.

©Darren Hester/Fotolia.com

“Aspirin could be a promising breast cancer prevention therapy. It is cheap, safe, well tolerated, and there is strong biologic and epidemiologic evidence for a prevention effect for both ER– and ER+ breast cancers,” said Dr. Wood, professor of medicine and director of the familial cancer program at the University of Vermont in Burlington.

There is an unmet need for better chemoprevention agents for breast cancer. The current ones, such as tamoxifen and raloxifene (Evista), don’t prevent ER– breast cancer. Plus, they have substantial side effects leading to low utilization for primary prevention, she continued.

Dr. Wood presented a retrospective study of 26,000 women that demonstrated a dose-response relationship between aspirin use and lower mammographic breast density. The relationship was stronger in women under age 60 years and in African Americans. That’s an important finding because those two groups are at increased risk for developing ER– breast cancer.

She and her coinvestigators reviewed the electronic medical records of 26,000 women in 36 primary care and ob.gyn. practices. All had undergone routine screening mammography during 2012-2013 and had an office visit in the prior year that included gathering a confirmed list of medications.

The study group included 5,111 aspirin users and 20,889 nonusers. After performing logistic regression analysis to adjust for differences between the two groups in terms of age, ethnicity, and body mass index, the investigators examined the association between aspirin use and BI-RADS (Breast Imaging Reporting and Data System) breast density. The prevalence of low-risk, entirely fatty breasts was 9.6% in aspirin nonusers, compared with 16.9% in aspirin users, while extremely dense breasts were present in 5.1% of nonusers versus just 1.6% of aspirin users, Dr. Wood reported.

Women taking aspirin at 300 mg/day or less were 16% less likely to have mammographically dense breasts – that is, BIRADS 3 or 4 – than were aspirin nonusers. Women on more than 300 mg/day were 38% less likely to have dense breasts than nonusers.

Previous clinical trials looking at aspirin for breast cancer prevention have had design flaws that compromised the findings. Moreover, the several prior studies examining a link between aspirin use and mammographic breast density either lumped all NSAIDs together or were limited by small sample size, according to the oncologist.

As a next step in this project, Dr. Wood and her coinvestigators plan to examine duration of aspirin use and its relationship to mammographic breast density in this study population.

[email protected]

SAN ANTONIO – A large randomized controlled trial of aspirin for breast cancer prevention is warranted in light of new evidence that aspirin use shows a strong independent inverse relationship with mammographic breast density, Dr. Marie E. Wood declared at the San Antonio Breast Cancer Symposium.

Breast density, she noted, is well accepted as a modifiable risk factor for both estrogen receptor–negative (ER–) and estrogren receptor–positive (ER+) breast cancer.

©Darren Hester/Fotolia.com

“Aspirin could be a promising breast cancer prevention therapy. It is cheap, safe, well tolerated, and there is strong biologic and epidemiologic evidence for a prevention effect for both ER– and ER+ breast cancers,” said Dr. Wood, professor of medicine and director of the familial cancer program at the University of Vermont in Burlington.

There is an unmet need for better chemoprevention agents for breast cancer. The current ones, such as tamoxifen and raloxifene (Evista), don’t prevent ER– breast cancer. Plus, they have substantial side effects leading to low utilization for primary prevention, she continued.

Dr. Wood presented a retrospective study of 26,000 women that demonstrated a dose-response relationship between aspirin use and lower mammographic breast density. The relationship was stronger in women under age 60 years and in African Americans. That’s an important finding because those two groups are at increased risk for developing ER– breast cancer.

She and her coinvestigators reviewed the electronic medical records of 26,000 women in 36 primary care and ob.gyn. practices. All had undergone routine screening mammography during 2012-2013 and had an office visit in the prior year that included gathering a confirmed list of medications.

The study group included 5,111 aspirin users and 20,889 nonusers. After performing logistic regression analysis to adjust for differences between the two groups in terms of age, ethnicity, and body mass index, the investigators examined the association between aspirin use and BI-RADS (Breast Imaging Reporting and Data System) breast density. The prevalence of low-risk, entirely fatty breasts was 9.6% in aspirin nonusers, compared with 16.9% in aspirin users, while extremely dense breasts were present in 5.1% of nonusers versus just 1.6% of aspirin users, Dr. Wood reported.

Women taking aspirin at 300 mg/day or less were 16% less likely to have mammographically dense breasts – that is, BIRADS 3 or 4 – than were aspirin nonusers. Women on more than 300 mg/day were 38% less likely to have dense breasts than nonusers.

Previous clinical trials looking at aspirin for breast cancer prevention have had design flaws that compromised the findings. Moreover, the several prior studies examining a link between aspirin use and mammographic breast density either lumped all NSAIDs together or were limited by small sample size, according to the oncologist.

As a next step in this project, Dr. Wood and her coinvestigators plan to examine duration of aspirin use and its relationship to mammographic breast density in this study population.

[email protected]

SAN ANTONIO – A large randomized controlled trial of aspirin for breast cancer prevention is warranted in light of new evidence that aspirin use shows a strong independent inverse relationship with mammographic breast density, Dr. Marie E. Wood declared at the San Antonio Breast Cancer Symposium.

Breast density, she noted, is well accepted as a modifiable risk factor for both estrogen receptor–negative (ER–) and estrogren receptor–positive (ER+) breast cancer.

©Darren Hester/Fotolia.com

“Aspirin could be a promising breast cancer prevention therapy. It is cheap, safe, well tolerated, and there is strong biologic and epidemiologic evidence for a prevention effect for both ER– and ER+ breast cancers,” said Dr. Wood, professor of medicine and director of the familial cancer program at the University of Vermont in Burlington.

There is an unmet need for better chemoprevention agents for breast cancer. The current ones, such as tamoxifen and raloxifene (Evista), don’t prevent ER– breast cancer. Plus, they have substantial side effects leading to low utilization for primary prevention, she continued.

Dr. Wood presented a retrospective study of 26,000 women that demonstrated a dose-response relationship between aspirin use and lower mammographic breast density. The relationship was stronger in women under age 60 years and in African Americans. That’s an important finding because those two groups are at increased risk for developing ER– breast cancer.

She and her coinvestigators reviewed the electronic medical records of 26,000 women in 36 primary care and ob.gyn. practices. All had undergone routine screening mammography during 2012-2013 and had an office visit in the prior year that included gathering a confirmed list of medications.

The study group included 5,111 aspirin users and 20,889 nonusers. After performing logistic regression analysis to adjust for differences between the two groups in terms of age, ethnicity, and body mass index, the investigators examined the association between aspirin use and BI-RADS (Breast Imaging Reporting and Data System) breast density. The prevalence of low-risk, entirely fatty breasts was 9.6% in aspirin nonusers, compared with 16.9% in aspirin users, while extremely dense breasts were present in 5.1% of nonusers versus just 1.6% of aspirin users, Dr. Wood reported.

Women taking aspirin at 300 mg/day or less were 16% less likely to have mammographically dense breasts – that is, BIRADS 3 or 4 – than were aspirin nonusers. Women on more than 300 mg/day were 38% less likely to have dense breasts than nonusers.

Previous clinical trials looking at aspirin for breast cancer prevention have had design flaws that compromised the findings. Moreover, the several prior studies examining a link between aspirin use and mammographic breast density either lumped all NSAIDs together or were limited by small sample size, according to the oncologist.

As a next step in this project, Dr. Wood and her coinvestigators plan to examine duration of aspirin use and its relationship to mammographic breast density in this study population.

[email protected]

SAN ANTONIO – Dr. Hope S. Rugo shared her insights on breast cancer research presented at the San Antonio Breast Cancer Symposium, focusing particularly on neoadjuvant treatments and immunotherapy.

“It’s exciting to think we may be able to treat patients with ER-positive and HER2-negative disease with a relatively limited course of a well-tolerated therapy,” Dr. Rugo said when discussing the results of a phase II trial evaluating neoadjuvant therapy with the antibody-drug conjugate trastuzumab emtansine (T-DM1).

Furthermore, results from another arm within the same trial may help to identify which patients with triple-negative breast cancer can get by with less chemotherapy, and potentially avoid anthracyclines, said Dr. Rugo, professor of medicine at the University of California, San Francisco, in a video interview.

She also untangled the perplexing results from two trials presented evaluating neoadjuvant carboplatin, and discussed the highlights of immunotherapy research presented at the symposium.

[email protected]

SAN ANTONIO – Dr. Hope S. Rugo shared her insights on breast cancer research presented at the San Antonio Breast Cancer Symposium, focusing particularly on neoadjuvant treatments and immunotherapy.

“It’s exciting to think we may be able to treat patients with ER-positive and HER2-negative disease with a relatively limited course of a well-tolerated therapy,” Dr. Rugo said when discussing the results of a phase II trial evaluating neoadjuvant therapy with the antibody-drug conjugate trastuzumab emtansine (T-DM1).

Furthermore, results from another arm within the same trial may help to identify which patients with triple-negative breast cancer can get by with less chemotherapy, and potentially avoid anthracyclines, said Dr. Rugo, professor of medicine at the University of California, San Francisco, in a video interview.

She also untangled the perplexing results from two trials presented evaluating neoadjuvant carboplatin, and discussed the highlights of immunotherapy research presented at the symposium.

[email protected]

SAN ANTONIO – Dr. Hope S. Rugo shared her insights on breast cancer research presented at the San Antonio Breast Cancer Symposium, focusing particularly on neoadjuvant treatments and immunotherapy.

“It’s exciting to think we may be able to treat patients with ER-positive and HER2-negative disease with a relatively limited course of a well-tolerated therapy,” Dr. Rugo said when discussing the results of a phase II trial evaluating neoadjuvant therapy with the antibody-drug conjugate trastuzumab emtansine (T-DM1).

Furthermore, results from another arm within the same trial may help to identify which patients with triple-negative breast cancer can get by with less chemotherapy, and potentially avoid anthracyclines, said Dr. Rugo, professor of medicine at the University of California, San Francisco, in a video interview.

She also untangled the perplexing results from two trials presented evaluating neoadjuvant carboplatin, and discussed the highlights of immunotherapy research presented at the symposium.

[email protected]

SAN ANTONIO – Clinicians can expect tools to appear in the clinic in the very near future that will help define who will benefit from targeted therapy and who can get by with less therapy, Dr. William J. Gradishar asserted at the San Antonio Breast Cancer Symposium.

In particular, Dr. Gradishar cited BOLERO-2 and BELLE-2 results as evidence that evaluating the tumors of patients can lead to identifying those who will obtain benefit from targeted agents.

In a video interview, Dr. Gradishar also outlined where things stand on extended therapy for HER2-positive patients, and whether the use of osteoclast inhibitors is a new standard of care.

Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago.

[email protected]

SAN ANTONIO – Clinicians can expect tools to appear in the clinic in the very near future that will help define who will benefit from targeted therapy and who can get by with less therapy, Dr. William J. Gradishar asserted at the San Antonio Breast Cancer Symposium.

In particular, Dr. Gradishar cited BOLERO-2 and BELLE-2 results as evidence that evaluating the tumors of patients can lead to identifying those who will obtain benefit from targeted agents.

In a video interview, Dr. Gradishar also outlined where things stand on extended therapy for HER2-positive patients, and whether the use of osteoclast inhibitors is a new standard of care.

Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago.

[email protected]

SAN ANTONIO – Clinicians can expect tools to appear in the clinic in the very near future that will help define who will benefit from targeted therapy and who can get by with less therapy, Dr. William J. Gradishar asserted at the San Antonio Breast Cancer Symposium.

In particular, Dr. Gradishar cited BOLERO-2 and BELLE-2 results as evidence that evaluating the tumors of patients can lead to identifying those who will obtain benefit from targeted agents.

In a video interview, Dr. Gradishar also outlined where things stand on extended therapy for HER2-positive patients, and whether the use of osteoclast inhibitors is a new standard of care.

Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago.

[email protected]

SAN ANTONIO – Twelve weeks of trastuzumab emtasine as single-agent neoadjuvant therapy in HER2-positive/hormone receptor–positive early-stage breast cancer achieved a pathologic complete response rate of 41%, underscoring the feasibility of therapeutic de-escalation in that patient subgroup, according to Dr. Nadia Harbeck.

jancin

Dr. Harbeck, head of the breast center at the Technical University of Munich, presented the final analysis of the phase II, 376-patient WSG-ADAPT HER2+/HR+ (Women’s Healthcare Study Group–Adjuvant Dynamic Marker–Adjusted Personalized Therapy HER2+/HR+ trial). The primary finding: The pathologic complete response (pCR) rate in the breast and lymph nodes after 12 weeks of neoadjuvant therapy with no systemic chemotherapy in this three-armed trial was 41% with trastuzumab emtasine (T-DM1) alone at 3.6 mg/kg every 3 weeks, 41.5% with T-DM1 plus endocrine therapy, and just 15.1% with tamoxifen plus endocrine therapy.

Adding in those patients with a near-pCR – that is, patients who were ypT1a, with very little remaining tumor burden of dubious clinical significance – the results looked even stronger: a pCR/near-pCR rate of 53% with neoadjuvant T-DM1 alone and 52.9% with T-DM1 and endocrine therapy, versus 19.3% with trastuzumab plus endocrine therapy, Dr. Harbeck said at the San Antonio Breast Cancer Symposium.

Thus, adding endocrine therapy to T-DM1 (Kadcyla) didn’t improve upon the effectiveness of T-DM1 alone in this updated and final WSG-ADAPT analysis. That’s an important difference from an earlier 130-patient prespecified interim analysis Dr. Harbeck presented at the 2015 ASCO meeting. At that point it seemed – incorrectly, as it turned out – that concurrent endocrine therapy and T-DM1 provided added benefit in premenopausal but not postmenopausal women.

“Single-agent T-DM1 therapy warrants further evaluation in early breast cancer, not just because of the efficacy, which I think is very impressive, but also because of the favorable safety profile,” she said.

Mild to moderate constipation, thrombocytopenia, dry mouth, fatigue, arthralgia, headache, and hot flushes were roughly twice as common in the combined T-DMI and T-DMI plus endocrine therapy arms, compared with the trastuzumab plus endocrine therapy arm. But the only grade 3 adverse event that was more frequent in the two T-DMI study arms was an elevation in liver enzymes, which occurred in 4.1% of those patients and none on trastuzumab and endocrine therapy.

WSG-ADAPT is actually an umbrella trial that to date has enrolled about 4,000 patients. An important goal of ADAPT is to identify and validate useful early biomarkers of clinical response. WSG-ADAPT HER2+/HR+ assessed two: a drop in Ki67 of 30% or greater or low cellularity as defined by fewer than 500 tumor cells in the biopsy taken at the 3-week point in neoadjuvant therapy, after one cycle of treatment had been completed. Patients with either marker of early response proved to be 2.2-fold more likely to have a pCR than women in whom the early biomarkers were absent.

Dr. Harbeck argued that the ADAPT findings make a cogent case for changing the current standard of care in treating HER2+ early breast cancer, which is chemotherapy plus anti-HER2 therapy regardless of the malignancy’s hormone receptor status.

“We don’t adjust for hormone receptor status in our standard treatment today, even though we know hormone receptor–positive disease is a distinct entity,” she said.

The study was sponsored by Roche. The presenter serves as a consultant to Roche, Celgene, and Genomic Health.

[email protected]

SAN ANTONIO – Twelve weeks of trastuzumab emtasine as single-agent neoadjuvant therapy in HER2-positive/hormone receptor–positive early-stage breast cancer achieved a pathologic complete response rate of 41%, underscoring the feasibility of therapeutic de-escalation in that patient subgroup, according to Dr. Nadia Harbeck.

jancin

Dr. Harbeck, head of the breast center at the Technical University of Munich, presented the final analysis of the phase II, 376-patient WSG-ADAPT HER2+/HR+ (Women’s Healthcare Study Group–Adjuvant Dynamic Marker–Adjusted Personalized Therapy HER2+/HR+ trial). The primary finding: The pathologic complete response (pCR) rate in the breast and lymph nodes after 12 weeks of neoadjuvant therapy with no systemic chemotherapy in this three-armed trial was 41% with trastuzumab emtasine (T-DM1) alone at 3.6 mg/kg every 3 weeks, 41.5% with T-DM1 plus endocrine therapy, and just 15.1% with tamoxifen plus endocrine therapy.

Adding in those patients with a near-pCR – that is, patients who were ypT1a, with very little remaining tumor burden of dubious clinical significance – the results looked even stronger: a pCR/near-pCR rate of 53% with neoadjuvant T-DM1 alone and 52.9% with T-DM1 and endocrine therapy, versus 19.3% with trastuzumab plus endocrine therapy, Dr. Harbeck said at the San Antonio Breast Cancer Symposium.

Thus, adding endocrine therapy to T-DM1 (Kadcyla) didn’t improve upon the effectiveness of T-DM1 alone in this updated and final WSG-ADAPT analysis. That’s an important difference from an earlier 130-patient prespecified interim analysis Dr. Harbeck presented at the 2015 ASCO meeting. At that point it seemed – incorrectly, as it turned out – that concurrent endocrine therapy and T-DM1 provided added benefit in premenopausal but not postmenopausal women.

“Single-agent T-DM1 therapy warrants further evaluation in early breast cancer, not just because of the efficacy, which I think is very impressive, but also because of the favorable safety profile,” she said.

Mild to moderate constipation, thrombocytopenia, dry mouth, fatigue, arthralgia, headache, and hot flushes were roughly twice as common in the combined T-DMI and T-DMI plus endocrine therapy arms, compared with the trastuzumab plus endocrine therapy arm. But the only grade 3 adverse event that was more frequent in the two T-DMI study arms was an elevation in liver enzymes, which occurred in 4.1% of those patients and none on trastuzumab and endocrine therapy.

WSG-ADAPT is actually an umbrella trial that to date has enrolled about 4,000 patients. An important goal of ADAPT is to identify and validate useful early biomarkers of clinical response. WSG-ADAPT HER2+/HR+ assessed two: a drop in Ki67 of 30% or greater or low cellularity as defined by fewer than 500 tumor cells in the biopsy taken at the 3-week point in neoadjuvant therapy, after one cycle of treatment had been completed. Patients with either marker of early response proved to be 2.2-fold more likely to have a pCR than women in whom the early biomarkers were absent.

Dr. Harbeck argued that the ADAPT findings make a cogent case for changing the current standard of care in treating HER2+ early breast cancer, which is chemotherapy plus anti-HER2 therapy regardless of the malignancy’s hormone receptor status.

“We don’t adjust for hormone receptor status in our standard treatment today, even though we know hormone receptor–positive disease is a distinct entity,” she said.

The study was sponsored by Roche. The presenter serves as a consultant to Roche, Celgene, and Genomic Health.

[email protected]

SAN ANTONIO – Twelve weeks of trastuzumab emtasine as single-agent neoadjuvant therapy in HER2-positive/hormone receptor–positive early-stage breast cancer achieved a pathologic complete response rate of 41%, underscoring the feasibility of therapeutic de-escalation in that patient subgroup, according to Dr. Nadia Harbeck.

jancin

Dr. Harbeck, head of the breast center at the Technical University of Munich, presented the final analysis of the phase II, 376-patient WSG-ADAPT HER2+/HR+ (Women’s Healthcare Study Group–Adjuvant Dynamic Marker–Adjusted Personalized Therapy HER2+/HR+ trial). The primary finding: The pathologic complete response (pCR) rate in the breast and lymph nodes after 12 weeks of neoadjuvant therapy with no systemic chemotherapy in this three-armed trial was 41% with trastuzumab emtasine (T-DM1) alone at 3.6 mg/kg every 3 weeks, 41.5% with T-DM1 plus endocrine therapy, and just 15.1% with tamoxifen plus endocrine therapy.

Adding in those patients with a near-pCR – that is, patients who were ypT1a, with very little remaining tumor burden of dubious clinical significance – the results looked even stronger: a pCR/near-pCR rate of 53% with neoadjuvant T-DM1 alone and 52.9% with T-DM1 and endocrine therapy, versus 19.3% with trastuzumab plus endocrine therapy, Dr. Harbeck said at the San Antonio Breast Cancer Symposium.

Thus, adding endocrine therapy to T-DM1 (Kadcyla) didn’t improve upon the effectiveness of T-DM1 alone in this updated and final WSG-ADAPT analysis. That’s an important difference from an earlier 130-patient prespecified interim analysis Dr. Harbeck presented at the 2015 ASCO meeting. At that point it seemed – incorrectly, as it turned out – that concurrent endocrine therapy and T-DM1 provided added benefit in premenopausal but not postmenopausal women.

“Single-agent T-DM1 therapy warrants further evaluation in early breast cancer, not just because of the efficacy, which I think is very impressive, but also because of the favorable safety profile,” she said.

Mild to moderate constipation, thrombocytopenia, dry mouth, fatigue, arthralgia, headache, and hot flushes were roughly twice as common in the combined T-DMI and T-DMI plus endocrine therapy arms, compared with the trastuzumab plus endocrine therapy arm. But the only grade 3 adverse event that was more frequent in the two T-DMI study arms was an elevation in liver enzymes, which occurred in 4.1% of those patients and none on trastuzumab and endocrine therapy.

WSG-ADAPT is actually an umbrella trial that to date has enrolled about 4,000 patients. An important goal of ADAPT is to identify and validate useful early biomarkers of clinical response. WSG-ADAPT HER2+/HR+ assessed two: a drop in Ki67 of 30% or greater or low cellularity as defined by fewer than 500 tumor cells in the biopsy taken at the 3-week point in neoadjuvant therapy, after one cycle of treatment had been completed. Patients with either marker of early response proved to be 2.2-fold more likely to have a pCR than women in whom the early biomarkers were absent.

Dr. Harbeck argued that the ADAPT findings make a cogent case for changing the current standard of care in treating HER2+ early breast cancer, which is chemotherapy plus anti-HER2 therapy regardless of the malignancy’s hormone receptor status.

“We don’t adjust for hormone receptor status in our standard treatment today, even though we know hormone receptor–positive disease is a distinct entity,” she said.

The study was sponsored by Roche. The presenter serves as a consultant to Roche, Celgene, and Genomic Health.

[email protected]

SAN ANTONIO – Women with estrogen receptor–positive advanced breast cancer who have common mutations of the estrogen receptor 1 (ESR1) gene detectable in plasma cell–free DNA have poorer overall survival, according to data presented at the San Antonio Breast Cancer Symposium.

Investigators led by Dr. Sarat Chandarlapaty, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, analyzed archival baseline plasma samples from 541 patients enrolled in the BOLERO-2 trial, which evaluated addition of everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin). They specifically looked for the D538G and Y537S mutations of the ESR1 gene, the two most commonly seen mutations in this setting and ones that lead to activation of the receptor even in the absence of estrogen.

Overall, nearly 29% of the women had either or both mutations, he reported in a session and related press briefing. “We think that is almost certainly an underestimate of the mutation rate, because there will be some other mutations … that we didn’t assay for here,” he commented. Of note, this prevalence using plasma was sharply higher than that found when analysis was instead performed on archival tumor tissue.

Patients with these ESR1 mutations had a 40% higher risk of death than counterparts who did not have them. And those with the D538G mutation (but not those with the Y537S mutation) had better progression-free survival if they were given everolimus.

“Patients with different mutations might end up having different responses to therapies in the future, and I think that’s what we are looking for in future research,” Dr. Chandarlapaty commented.

Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos L. Arteaga, a professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Breast Cancer Program, noted the high rate of discordance in mutation prevalence between the tumor tissue and the plasma. “Can you speculate about the reasons for that discordance?” he asked.

There are three possible explanations, Dr. Chandarlapaty replied. The archival tumor was often the primary tumor, whereas plasma samples were collected in the metastatic setting. Also, the tumor tissue was often obtained before any aromatase inhibitor therapy, which precipitates a low-estrogen environment that may promote emergence of resistance mutations. Finally, mutations detected in plasma likely reflect a summation of all mutations in the body in different sites. “I think for all these reasons, plasma may have certain advantages, especially for this alteration,” he said.

In the session, attendee Dr. Daniel F. Hayes of the University of Michigan Health System in Ann Arbor wondered whether the plasma samples were treated in any special way before the mutational testing.

“This trial started before we recognized the importance of plasma tumor DNA, so I’m pretty certain these samples were not handled in a way that we all believe they should be. The reason I’m asking this question is that if you did something special, the rest of us would love to know what it is because we are all sitting on samples like this that I’ve been told are worthless, but maybe I’m wrong,” he elaborated.

The plasma samples were collected in a routine manner, without any consideration of future genomic analysis and mutational testing, according to Dr. Chandarlapaty. “These were collected as a regular spin … and frozen at –70 [degrees],” he said. And they were stored that way, in some cases for many years, at various global sites. The investigators simply performed an additional hard spin before analyzing the samples. “So I think it does tell us that some of these archival samples that we have in our freezers may be usable for this type of analysis,” he said.

Attendee Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston said, “So on Monday morning, people can’t go home and order circulating tumor DNA in most centers. What studies need to be done and how long do you think it will be before this is something we should consider?”

Efforts are under way to try to rapidly make these assays available in the clinic, according to Dr. Chandarlapaty. “Actually, there are some that are not in the CLIA lab but sort of are available by different vendors,” he said. Additional studies still needed include validation of the observed findings in other cohorts, among others.

BOLERO-2 tested addition of the mTOR inhibitor everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin) in postmenopausal women with metastatic or locally advanced estrogen receptor–positive, HER2-negative breast cancer that had progressed despite treatment with other aromatase inhibitors.

Dr. Chandarlapaty and colleagues detected the D538G mutation in 15.3% of patients, the Y537S mutation in 7.8%, and both in 5.5% patients, for an overall prevalence of 28.8%.

In a subset of cases having both cell-free DNA and archival tumor tissue, the proportion of cases having these mutations was much higher in the former (28.4% vs. 1.3%).

Subgroup analyses showed mutations were more common for patients who had received prior aromatase therapy in the metastatic setting versus only in the adjuvant setting (P for difference less than .001).

In the study sample as a whole, median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both. Compared with patients having neither mutation, patients having either or both had an increased risk of death (hazard ratio, 1.40), as did those having the D538G mutation (1.25), the Y537S mutation (2.31), and both (1.77).

Additionally, exploratory analyses showed that adding everolimus to exemestane more than doubled median progression-free survival for patients with neither mutation (8.5 vs. 3.9 months; hazard ratio, 0.40) and for those with a D538G mutation (5.8 vs. 2.7 months; hazard ratio, 0.34). In contrast and unexpectedly, adding this drug did not improve the outcome for patients with a Y537S mutation.

Numbers of patients in the Y537S group were small, and a clear explanation for lack of benefit in that group is lacking, Dr. Chandarlapaty cautioned. “But it does tell us the biology, and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we are developing going forward,” he said.

SAN ANTONIO – Women with estrogen receptor–positive advanced breast cancer who have common mutations of the estrogen receptor 1 (ESR1) gene detectable in plasma cell–free DNA have poorer overall survival, according to data presented at the San Antonio Breast Cancer Symposium.

Investigators led by Dr. Sarat Chandarlapaty, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, analyzed archival baseline plasma samples from 541 patients enrolled in the BOLERO-2 trial, which evaluated addition of everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin). They specifically looked for the D538G and Y537S mutations of the ESR1 gene, the two most commonly seen mutations in this setting and ones that lead to activation of the receptor even in the absence of estrogen.

Overall, nearly 29% of the women had either or both mutations, he reported in a session and related press briefing. “We think that is almost certainly an underestimate of the mutation rate, because there will be some other mutations … that we didn’t assay for here,” he commented. Of note, this prevalence using plasma was sharply higher than that found when analysis was instead performed on archival tumor tissue.

Patients with these ESR1 mutations had a 40% higher risk of death than counterparts who did not have them. And those with the D538G mutation (but not those with the Y537S mutation) had better progression-free survival if they were given everolimus.

“Patients with different mutations might end up having different responses to therapies in the future, and I think that’s what we are looking for in future research,” Dr. Chandarlapaty commented.

Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos L. Arteaga, a professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Breast Cancer Program, noted the high rate of discordance in mutation prevalence between the tumor tissue and the plasma. “Can you speculate about the reasons for that discordance?” he asked.

There are three possible explanations, Dr. Chandarlapaty replied. The archival tumor was often the primary tumor, whereas plasma samples were collected in the metastatic setting. Also, the tumor tissue was often obtained before any aromatase inhibitor therapy, which precipitates a low-estrogen environment that may promote emergence of resistance mutations. Finally, mutations detected in plasma likely reflect a summation of all mutations in the body in different sites. “I think for all these reasons, plasma may have certain advantages, especially for this alteration,” he said.

In the session, attendee Dr. Daniel F. Hayes of the University of Michigan Health System in Ann Arbor wondered whether the plasma samples were treated in any special way before the mutational testing.

“This trial started before we recognized the importance of plasma tumor DNA, so I’m pretty certain these samples were not handled in a way that we all believe they should be. The reason I’m asking this question is that if you did something special, the rest of us would love to know what it is because we are all sitting on samples like this that I’ve been told are worthless, but maybe I’m wrong,” he elaborated.

The plasma samples were collected in a routine manner, without any consideration of future genomic analysis and mutational testing, according to Dr. Chandarlapaty. “These were collected as a regular spin … and frozen at –70 [degrees],” he said. And they were stored that way, in some cases for many years, at various global sites. The investigators simply performed an additional hard spin before analyzing the samples. “So I think it does tell us that some of these archival samples that we have in our freezers may be usable for this type of analysis,” he said.

Attendee Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston said, “So on Monday morning, people can’t go home and order circulating tumor DNA in most centers. What studies need to be done and how long do you think it will be before this is something we should consider?”

Efforts are under way to try to rapidly make these assays available in the clinic, according to Dr. Chandarlapaty. “Actually, there are some that are not in the CLIA lab but sort of are available by different vendors,” he said. Additional studies still needed include validation of the observed findings in other cohorts, among others.

BOLERO-2 tested addition of the mTOR inhibitor everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin) in postmenopausal women with metastatic or locally advanced estrogen receptor–positive, HER2-negative breast cancer that had progressed despite treatment with other aromatase inhibitors.

Dr. Chandarlapaty and colleagues detected the D538G mutation in 15.3% of patients, the Y537S mutation in 7.8%, and both in 5.5% patients, for an overall prevalence of 28.8%.

In a subset of cases having both cell-free DNA and archival tumor tissue, the proportion of cases having these mutations was much higher in the former (28.4% vs. 1.3%).

Subgroup analyses showed mutations were more common for patients who had received prior aromatase therapy in the metastatic setting versus only in the adjuvant setting (P for difference less than .001).

In the study sample as a whole, median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both. Compared with patients having neither mutation, patients having either or both had an increased risk of death (hazard ratio, 1.40), as did those having the D538G mutation (1.25), the Y537S mutation (2.31), and both (1.77).

Additionally, exploratory analyses showed that adding everolimus to exemestane more than doubled median progression-free survival for patients with neither mutation (8.5 vs. 3.9 months; hazard ratio, 0.40) and for those with a D538G mutation (5.8 vs. 2.7 months; hazard ratio, 0.34). In contrast and unexpectedly, adding this drug did not improve the outcome for patients with a Y537S mutation.

Numbers of patients in the Y537S group were small, and a clear explanation for lack of benefit in that group is lacking, Dr. Chandarlapaty cautioned. “But it does tell us the biology, and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we are developing going forward,” he said.

SAN ANTONIO – Women with estrogen receptor–positive advanced breast cancer who have common mutations of the estrogen receptor 1 (ESR1) gene detectable in plasma cell–free DNA have poorer overall survival, according to data presented at the San Antonio Breast Cancer Symposium.

Investigators led by Dr. Sarat Chandarlapaty, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, analyzed archival baseline plasma samples from 541 patients enrolled in the BOLERO-2 trial, which evaluated addition of everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin). They specifically looked for the D538G and Y537S mutations of the ESR1 gene, the two most commonly seen mutations in this setting and ones that lead to activation of the receptor even in the absence of estrogen.

Overall, nearly 29% of the women had either or both mutations, he reported in a session and related press briefing. “We think that is almost certainly an underestimate of the mutation rate, because there will be some other mutations … that we didn’t assay for here,” he commented. Of note, this prevalence using plasma was sharply higher than that found when analysis was instead performed on archival tumor tissue.

Patients with these ESR1 mutations had a 40% higher risk of death than counterparts who did not have them. And those with the D538G mutation (but not those with the Y537S mutation) had better progression-free survival if they were given everolimus.

“Patients with different mutations might end up having different responses to therapies in the future, and I think that’s what we are looking for in future research,” Dr. Chandarlapaty commented.

Press briefing moderator and codirector of the San Antonio Breast Cancer Symposium, Dr. Carlos L. Arteaga, a professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Breast Cancer Program, noted the high rate of discordance in mutation prevalence between the tumor tissue and the plasma. “Can you speculate about the reasons for that discordance?” he asked.

There are three possible explanations, Dr. Chandarlapaty replied. The archival tumor was often the primary tumor, whereas plasma samples were collected in the metastatic setting. Also, the tumor tissue was often obtained before any aromatase inhibitor therapy, which precipitates a low-estrogen environment that may promote emergence of resistance mutations. Finally, mutations detected in plasma likely reflect a summation of all mutations in the body in different sites. “I think for all these reasons, plasma may have certain advantages, especially for this alteration,” he said.

In the session, attendee Dr. Daniel F. Hayes of the University of Michigan Health System in Ann Arbor wondered whether the plasma samples were treated in any special way before the mutational testing.

“This trial started before we recognized the importance of plasma tumor DNA, so I’m pretty certain these samples were not handled in a way that we all believe they should be. The reason I’m asking this question is that if you did something special, the rest of us would love to know what it is because we are all sitting on samples like this that I’ve been told are worthless, but maybe I’m wrong,” he elaborated.

The plasma samples were collected in a routine manner, without any consideration of future genomic analysis and mutational testing, according to Dr. Chandarlapaty. “These were collected as a regular spin … and frozen at –70 [degrees],” he said. And they were stored that way, in some cases for many years, at various global sites. The investigators simply performed an additional hard spin before analyzing the samples. “So I think it does tell us that some of these archival samples that we have in our freezers may be usable for this type of analysis,” he said.

Attendee Dr. Eric P. Winer of the Dana-Farber Cancer Institute in Boston said, “So on Monday morning, people can’t go home and order circulating tumor DNA in most centers. What studies need to be done and how long do you think it will be before this is something we should consider?”

Efforts are under way to try to rapidly make these assays available in the clinic, according to Dr. Chandarlapaty. “Actually, there are some that are not in the CLIA lab but sort of are available by different vendors,” he said. Additional studies still needed include validation of the observed findings in other cohorts, among others.

BOLERO-2 tested addition of the mTOR inhibitor everolimus (Afinitor) to the aromatase inhibitor exemestane (Aromasin) in postmenopausal women with metastatic or locally advanced estrogen receptor–positive, HER2-negative breast cancer that had progressed despite treatment with other aromatase inhibitors.

Dr. Chandarlapaty and colleagues detected the D538G mutation in 15.3% of patients, the Y537S mutation in 7.8%, and both in 5.5% patients, for an overall prevalence of 28.8%.

In a subset of cases having both cell-free DNA and archival tumor tissue, the proportion of cases having these mutations was much higher in the former (28.4% vs. 1.3%).

Subgroup analyses showed mutations were more common for patients who had received prior aromatase therapy in the metastatic setting versus only in the adjuvant setting (P for difference less than .001).

In the study sample as a whole, median overall survival was 32.1 months with neither ESR1 mutation, 26.0 months with only the D538G mutation, 20.0 months with only the Y537S mutation, and 15.2 months with both. Compared with patients having neither mutation, patients having either or both had an increased risk of death (hazard ratio, 1.40), as did those having the D538G mutation (1.25), the Y537S mutation (2.31), and both (1.77).

Additionally, exploratory analyses showed that adding everolimus to exemestane more than doubled median progression-free survival for patients with neither mutation (8.5 vs. 3.9 months; hazard ratio, 0.40) and for those with a D538G mutation (5.8 vs. 2.7 months; hazard ratio, 0.34). In contrast and unexpectedly, adding this drug did not improve the outcome for patients with a Y537S mutation.

Numbers of patients in the Y537S group were small, and a clear explanation for lack of benefit in that group is lacking, Dr. Chandarlapaty cautioned. “But it does tell us the biology, and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we are developing going forward,” he said.

SAN ANTONIO – The investigational oral tyrosine kinase inhibitor neratinib showed continued benefit in terms of reduced invasive disease-free survival at 3 years of follow-up in women with early-stage HER2-positive breast cancer in the randomized, double-blind ExteNET trial, Dr. Arlene Chan reported at the San Antonio Breast Cancer Symposium.

The 3-year analysis was not prespecified. It was performed because she and her coinvestigators were concerned that the previously reported benefit seen at 2 years might be lost with longer follow-up, as has occurred with trastuzumab (Herceptin) in the landmark HERA (HERceptin Adjuvant) trial. Reassuringly, however, the absolute 2.3% benefit for neratinib compared to placebo seen at 2 years in ExteNET was maintained at 3 years in the updated analysis, where the absolute difference remained essentially unchanged at 2.1%, according to Dr. Chan, vice chair of the Breast Cancer Research Center of Western Australia in Perth.

Bruce Jancin/Frontline Medical News

Moreover, most patients have reached the 4-year mark in follow-up, where the invasive disease-free survival benefit has remained significant in favor of neratinib at 90.5% versus 88.6% with placebo, she added.

ExteNET was a large international trial of 2,840 women with stage II-IIIc HER2-positive breast cancer with node-positive disease who were randomized to oral neratinib at 240 mg/day or placebo for 1 year beginning an average of 4.4 months after completing adjuvant chemotherapy and 1 year of trastuzumab.

The impetus for ExteNET was the well-established observation that relapse occurs in up to 26% of trastuzumab-treated patients at 8-plus years of follow-up. The study hypothesis is that neratinib, a tyrosine kinase inhibitor of HER1, –2, and –4, will prevent or delay disease recurrence because it attacks the cancer through a mechanism of action different from that of trastuzumab.

At 2 years of follow-up post neratinib, the invasive disease-free survival rate was 93.9% with active therapy and 91.6% with placebo, as previously reported by Dr. Chan. At 3 years in the roughly 85% of patients who remained in the study, which changed sponsors in the interim, the rates were 92% and 89.9%.

The 3-year outcomes were most robust in patients who began neratinib less than 1 year after completing trastuzumab and who were hormone receptor positive. In this subgroup, the 3-year invasive disease-free survival rate was 93.3% with neratinib versus 88.6% with placebo. That, Dr. Chan said, is the scenario where delayed adjuvant neratinib might prove beneficial in clinical practice.

Patients with hormone receptor–negative disease didn’t benefit from neratinib.

Forty percent of patients on neratinib developed grade 3 diarrhea, the agent’s major side effect and one that is a class effect with the tyrosine kinase inhibitors. Most cases occurred within the first 30 days of treatment and lasted for a median of 5 days, with 1.4% of neratinib-treated patients being hospitalized for this complication.

Dr. Chan noted that the study protocol precluded prophylaxis with loperamide during the first month of neratinib, which has been shown by other investigators to markedly reduce the frequency and severity of diarrhea.

Another ExteNET follow-up is planned at the 5-year mark.

Audience members asked how the Food and Drug Administration’s approval of pertuzumab (Perjeta) with indications for neoadjuvant treatment of HER2-positive breast cancer as well as for metastatic disease will change the prospects for neratinib.

Dr. Chan replied that, like other medical oncologists, she’s eagerly awaiting the results of the APHINITY trial, which is testing adjuvant pertuzumab versus placebo on top of chemotherapy plus trastuzumab in women with HER2-positive disease.

“I would suspect that even if APHINITY is positive, there will be patients who will still have a risk of relapse, so we still won’t be curing all HER2-positive patients,” she said, adding that a new clinical trial would be required in order to establish that neratinib is of benefit in such individuals.

[email protected]

SAN ANTONIO – The investigational oral tyrosine kinase inhibitor neratinib showed continued benefit in terms of reduced invasive disease-free survival at 3 years of follow-up in women with early-stage HER2-positive breast cancer in the randomized, double-blind ExteNET trial, Dr. Arlene Chan reported at the San Antonio Breast Cancer Symposium.

The 3-year analysis was not prespecified. It was performed because she and her coinvestigators were concerned that the previously reported benefit seen at 2 years might be lost with longer follow-up, as has occurred with trastuzumab (Herceptin) in the landmark HERA (HERceptin Adjuvant) trial. Reassuringly, however, the absolute 2.3% benefit for neratinib compared to placebo seen at 2 years in ExteNET was maintained at 3 years in the updated analysis, where the absolute difference remained essentially unchanged at 2.1%, according to Dr. Chan, vice chair of the Breast Cancer Research Center of Western Australia in Perth.

Bruce Jancin/Frontline Medical News

Moreover, most patients have reached the 4-year mark in follow-up, where the invasive disease-free survival benefit has remained significant in favor of neratinib at 90.5% versus 88.6% with placebo, she added.

ExteNET was a large international trial of 2,840 women with stage II-IIIc HER2-positive breast cancer with node-positive disease who were randomized to oral neratinib at 240 mg/day or placebo for 1 year beginning an average of 4.4 months after completing adjuvant chemotherapy and 1 year of trastuzumab.

The impetus for ExteNET was the well-established observation that relapse occurs in up to 26% of trastuzumab-treated patients at 8-plus years of follow-up. The study hypothesis is that neratinib, a tyrosine kinase inhibitor of HER1, –2, and –4, will prevent or delay disease recurrence because it attacks the cancer through a mechanism of action different from that of trastuzumab.

At 2 years of follow-up post neratinib, the invasive disease-free survival rate was 93.9% with active therapy and 91.6% with placebo, as previously reported by Dr. Chan. At 3 years in the roughly 85% of patients who remained in the study, which changed sponsors in the interim, the rates were 92% and 89.9%.

The 3-year outcomes were most robust in patients who began neratinib less than 1 year after completing trastuzumab and who were hormone receptor positive. In this subgroup, the 3-year invasive disease-free survival rate was 93.3% with neratinib versus 88.6% with placebo. That, Dr. Chan said, is the scenario where delayed adjuvant neratinib might prove beneficial in clinical practice.

Patients with hormone receptor–negative disease didn’t benefit from neratinib.

Forty percent of patients on neratinib developed grade 3 diarrhea, the agent’s major side effect and one that is a class effect with the tyrosine kinase inhibitors. Most cases occurred within the first 30 days of treatment and lasted for a median of 5 days, with 1.4% of neratinib-treated patients being hospitalized for this complication.

Dr. Chan noted that the study protocol precluded prophylaxis with loperamide during the first month of neratinib, which has been shown by other investigators to markedly reduce the frequency and severity of diarrhea.

Another ExteNET follow-up is planned at the 5-year mark.

Audience members asked how the Food and Drug Administration’s approval of pertuzumab (Perjeta) with indications for neoadjuvant treatment of HER2-positive breast cancer as well as for metastatic disease will change the prospects for neratinib.

Dr. Chan replied that, like other medical oncologists, she’s eagerly awaiting the results of the APHINITY trial, which is testing adjuvant pertuzumab versus placebo on top of chemotherapy plus trastuzumab in women with HER2-positive disease.

“I would suspect that even if APHINITY is positive, there will be patients who will still have a risk of relapse, so we still won’t be curing all HER2-positive patients,” she said, adding that a new clinical trial would be required in order to establish that neratinib is of benefit in such individuals.

[email protected]

SAN ANTONIO – The investigational oral tyrosine kinase inhibitor neratinib showed continued benefit in terms of reduced invasive disease-free survival at 3 years of follow-up in women with early-stage HER2-positive breast cancer in the randomized, double-blind ExteNET trial, Dr. Arlene Chan reported at the San Antonio Breast Cancer Symposium.

The 3-year analysis was not prespecified. It was performed because she and her coinvestigators were concerned that the previously reported benefit seen at 2 years might be lost with longer follow-up, as has occurred with trastuzumab (Herceptin) in the landmark HERA (HERceptin Adjuvant) trial. Reassuringly, however, the absolute 2.3% benefit for neratinib compared to placebo seen at 2 years in ExteNET was maintained at 3 years in the updated analysis, where the absolute difference remained essentially unchanged at 2.1%, according to Dr. Chan, vice chair of the Breast Cancer Research Center of Western Australia in Perth.

Bruce Jancin/Frontline Medical News

Moreover, most patients have reached the 4-year mark in follow-up, where the invasive disease-free survival benefit has remained significant in favor of neratinib at 90.5% versus 88.6% with placebo, she added.

ExteNET was a large international trial of 2,840 women with stage II-IIIc HER2-positive breast cancer with node-positive disease who were randomized to oral neratinib at 240 mg/day or placebo for 1 year beginning an average of 4.4 months after completing adjuvant chemotherapy and 1 year of trastuzumab.

The impetus for ExteNET was the well-established observation that relapse occurs in up to 26% of trastuzumab-treated patients at 8-plus years of follow-up. The study hypothesis is that neratinib, a tyrosine kinase inhibitor of HER1, –2, and –4, will prevent or delay disease recurrence because it attacks the cancer through a mechanism of action different from that of trastuzumab.

At 2 years of follow-up post neratinib, the invasive disease-free survival rate was 93.9% with active therapy and 91.6% with placebo, as previously reported by Dr. Chan. At 3 years in the roughly 85% of patients who remained in the study, which changed sponsors in the interim, the rates were 92% and 89.9%.

The 3-year outcomes were most robust in patients who began neratinib less than 1 year after completing trastuzumab and who were hormone receptor positive. In this subgroup, the 3-year invasive disease-free survival rate was 93.3% with neratinib versus 88.6% with placebo. That, Dr. Chan said, is the scenario where delayed adjuvant neratinib might prove beneficial in clinical practice.

Patients with hormone receptor–negative disease didn’t benefit from neratinib.

Forty percent of patients on neratinib developed grade 3 diarrhea, the agent’s major side effect and one that is a class effect with the tyrosine kinase inhibitors. Most cases occurred within the first 30 days of treatment and lasted for a median of 5 days, with 1.4% of neratinib-treated patients being hospitalized for this complication.

Dr. Chan noted that the study protocol precluded prophylaxis with loperamide during the first month of neratinib, which has been shown by other investigators to markedly reduce the frequency and severity of diarrhea.

Another ExteNET follow-up is planned at the 5-year mark.

Audience members asked how the Food and Drug Administration’s approval of pertuzumab (Perjeta) with indications for neoadjuvant treatment of HER2-positive breast cancer as well as for metastatic disease will change the prospects for neratinib.

Dr. Chan replied that, like other medical oncologists, she’s eagerly awaiting the results of the APHINITY trial, which is testing adjuvant pertuzumab versus placebo on top of chemotherapy plus trastuzumab in women with HER2-positive disease.

“I would suspect that even if APHINITY is positive, there will be patients who will still have a risk of relapse, so we still won’t be curing all HER2-positive patients,” she said, adding that a new clinical trial would be required in order to establish that neratinib is of benefit in such individuals.

[email protected]

SAN ANTONIO – The antibody–drug conjugate trastuzumab emtansine (T-DM1) is safe and efficacious for treating heavily pretreated HER2-positive metastatic breast cancer, according to data from the randomized phase III TH3RESA trial reported at the San Antonio Breast Cancer Symposium.

“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival, compared to treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” first author Dr. Hans Wildiers, professor of medical oncology at KU Leuven (Belgium), commented in a related press briefing. “This result was reached despite about 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens,” he said.

T-DM1 is approved by the Food and Drug Administration for the treatment of less heavily pretreated advanced disease on the basis of findings from the EMILIA trial. In that trial (the results of which were updated at the symposium), T-DM1 outperformed the combination of lapatinib and capecitabine.

“The TH3RESA results together with the EMILIA overall survival benefit … further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer,” Dr. Wildiers said.

Press briefing moderator Dr. C. Kent Osborne, professor of medicine and molecular and cellular biology and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, asked about the durability of the T-DM1 benefit: “What is the longest patients who are still in remission have been on study?”

About a quarter of patients were still on the trial as of the data cutoff for the analysis, signifying longer-term benefit, according to Dr. Wildiers.

“Just to put this in perspective, we used to think, and still do in a way, that HER2-positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient who would come in with a HER2-positive tumor,” Dr. Osborne commented. “Now with our treatments, based on the HER2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. And this is just another example of the effectiveness of this drug.”

The 602 patients enrolled in TH3RESA had to have received at least two prior HER2-directed therapies for their advanced disease, although the majority had received four or more. They were randomized 2:1 to T-DM1 (brand name Kadcyla) or a treatment of the physician’s choice as a control.

The study was amended part way through when the EMILIA results became available so that patients in the control arm could cross over to T-DM1 at the time of progression, and about half did so.

The results of the second interim overall survival analysis reported at the symposium showed that T-DM1 prolonged overall survival by almost 7 months, compared with a treatment of the physician’s choice: 22.7 months vs.15.8 months (hazard ratio, 0.68; P = .0007).

“Subgroup analysis showed no clear differences in different subgroups, except for a possible trend toward greater benefit for patients outside the United States,” Dr. Wildiers commented, while cautioning that numbers of patients were small and that finding shouldn’t be overinterpreted.

The overall survival benefit was similar when patients in the control arm were censored at the time of progression and crossing over to T-DM1 (22.7 vs. 15.6 months; HR, 0.58; P = .0002).

Patients were on therapy about twice as long with T-DM1 as with the treatment of a physician’s choice (7.9 vs. 4.1 months). Even so, the agent had a favorable safety profile, he said.

The control group had higher rates of grade 3 or worse diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). The T-DM1 group had a higher rate of grade 3 or worse thrombocytopenia (6.0% vs. 2.7%). Reductions in ejection fraction were rare overall and no more common with T-DM1 than in the control arm, according to Dr. Wildiers.

Quality of life was not assessed in the trial. However, that outcome can be inferred from others, according to Dr. Osborne.

“You could estimate the difference in quality of life by looking at the side effects of the treatment, and this treatment [T-DM1] had far fewer side effects,” he said. “Most of the side effects come from the cancer anyway at this stage, and if you are putting patients into remission and they are staying there for long periods of time, those symptoms are markedly improved.”

SAN ANTONIO – The antibody–drug conjugate trastuzumab emtansine (T-DM1) is safe and efficacious for treating heavily pretreated HER2-positive metastatic breast cancer, according to data from the randomized phase III TH3RESA trial reported at the San Antonio Breast Cancer Symposium.

“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival, compared to treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” first author Dr. Hans Wildiers, professor of medical oncology at KU Leuven (Belgium), commented in a related press briefing. “This result was reached despite about 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens,” he said.

T-DM1 is approved by the Food and Drug Administration for the treatment of less heavily pretreated advanced disease on the basis of findings from the EMILIA trial. In that trial (the results of which were updated at the symposium), T-DM1 outperformed the combination of lapatinib and capecitabine.

“The TH3RESA results together with the EMILIA overall survival benefit … further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer,” Dr. Wildiers said.

Press briefing moderator Dr. C. Kent Osborne, professor of medicine and molecular and cellular biology and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, asked about the durability of the T-DM1 benefit: “What is the longest patients who are still in remission have been on study?”

About a quarter of patients were still on the trial as of the data cutoff for the analysis, signifying longer-term benefit, according to Dr. Wildiers.

“Just to put this in perspective, we used to think, and still do in a way, that HER2-positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient who would come in with a HER2-positive tumor,” Dr. Osborne commented. “Now with our treatments, based on the HER2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. And this is just another example of the effectiveness of this drug.”

The 602 patients enrolled in TH3RESA had to have received at least two prior HER2-directed therapies for their advanced disease, although the majority had received four or more. They were randomized 2:1 to T-DM1 (brand name Kadcyla) or a treatment of the physician’s choice as a control.

The study was amended part way through when the EMILIA results became available so that patients in the control arm could cross over to T-DM1 at the time of progression, and about half did so.

The results of the second interim overall survival analysis reported at the symposium showed that T-DM1 prolonged overall survival by almost 7 months, compared with a treatment of the physician’s choice: 22.7 months vs.15.8 months (hazard ratio, 0.68; P = .0007).

“Subgroup analysis showed no clear differences in different subgroups, except for a possible trend toward greater benefit for patients outside the United States,” Dr. Wildiers commented, while cautioning that numbers of patients were small and that finding shouldn’t be overinterpreted.

The overall survival benefit was similar when patients in the control arm were censored at the time of progression and crossing over to T-DM1 (22.7 vs. 15.6 months; HR, 0.58; P = .0002).

Patients were on therapy about twice as long with T-DM1 as with the treatment of a physician’s choice (7.9 vs. 4.1 months). Even so, the agent had a favorable safety profile, he said.

The control group had higher rates of grade 3 or worse diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). The T-DM1 group had a higher rate of grade 3 or worse thrombocytopenia (6.0% vs. 2.7%). Reductions in ejection fraction were rare overall and no more common with T-DM1 than in the control arm, according to Dr. Wildiers.

Quality of life was not assessed in the trial. However, that outcome can be inferred from others, according to Dr. Osborne.

“You could estimate the difference in quality of life by looking at the side effects of the treatment, and this treatment [T-DM1] had far fewer side effects,” he said. “Most of the side effects come from the cancer anyway at this stage, and if you are putting patients into remission and they are staying there for long periods of time, those symptoms are markedly improved.”

SAN ANTONIO – The antibody–drug conjugate trastuzumab emtansine (T-DM1) is safe and efficacious for treating heavily pretreated HER2-positive metastatic breast cancer, according to data from the randomized phase III TH3RESA trial reported at the San Antonio Breast Cancer Symposium.

“T-DM1 demonstrated a clinically meaningful and statistically significant improvement in overall survival, compared to treatment of physician’s choice in patients with HER2-positive metastatic breast cancer previously treated with a taxane, trastuzumab, and lapatinib,” first author Dr. Hans Wildiers, professor of medical oncology at KU Leuven (Belgium), commented in a related press briefing. “This result was reached despite about 50% crossover and about 80% of patients in the control arm receiving trastuzumab-containing regimens,” he said.

T-DM1 is approved by the Food and Drug Administration for the treatment of less heavily pretreated advanced disease on the basis of findings from the EMILIA trial. In that trial (the results of which were updated at the symposium), T-DM1 outperformed the combination of lapatinib and capecitabine.

“The TH3RESA results together with the EMILIA overall survival benefit … further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer,” Dr. Wildiers said.

Press briefing moderator Dr. C. Kent Osborne, professor of medicine and molecular and cellular biology and director of the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, asked about the durability of the T-DM1 benefit: “What is the longest patients who are still in remission have been on study?”

About a quarter of patients were still on the trial as of the data cutoff for the analysis, signifying longer-term benefit, according to Dr. Wildiers.

“Just to put this in perspective, we used to think, and still do in a way, that HER2-positive breast cancer was one of the more aggressive forms of the disease, and we hated to see a patient who would come in with a HER2-positive tumor,” Dr. Osborne commented. “Now with our treatments, based on the HER2 and the identification of targeted therapy, it’s actually turned out to be a good tumor to have. And this is just another example of the effectiveness of this drug.”

The 602 patients enrolled in TH3RESA had to have received at least two prior HER2-directed therapies for their advanced disease, although the majority had received four or more. They were randomized 2:1 to T-DM1 (brand name Kadcyla) or a treatment of the physician’s choice as a control.

The study was amended part way through when the EMILIA results became available so that patients in the control arm could cross over to T-DM1 at the time of progression, and about half did so.

The results of the second interim overall survival analysis reported at the symposium showed that T-DM1 prolonged overall survival by almost 7 months, compared with a treatment of the physician’s choice: 22.7 months vs.15.8 months (hazard ratio, 0.68; P = .0007).

“Subgroup analysis showed no clear differences in different subgroups, except for a possible trend toward greater benefit for patients outside the United States,” Dr. Wildiers commented, while cautioning that numbers of patients were small and that finding shouldn’t be overinterpreted.

The overall survival benefit was similar when patients in the control arm were censored at the time of progression and crossing over to T-DM1 (22.7 vs. 15.6 months; HR, 0.58; P = .0002).

Patients were on therapy about twice as long with T-DM1 as with the treatment of a physician’s choice (7.9 vs. 4.1 months). Even so, the agent had a favorable safety profile, he said.

The control group had higher rates of grade 3 or worse diarrhea (4.3% vs. 0.7%), neutropenia (15.8% vs. 2.5%), and febrile neutropenia (3.8% vs. 0.2%). The T-DM1 group had a higher rate of grade 3 or worse thrombocytopenia (6.0% vs. 2.7%). Reductions in ejection fraction were rare overall and no more common with T-DM1 than in the control arm, according to Dr. Wildiers.

Quality of life was not assessed in the trial. However, that outcome can be inferred from others, according to Dr. Osborne.

“You could estimate the difference in quality of life by looking at the side effects of the treatment, and this treatment [T-DM1] had far fewer side effects,” he said. “Most of the side effects come from the cancer anyway at this stage, and if you are putting patients into remission and they are staying there for long periods of time, those symptoms are markedly improved.”

SAN ANTONIO – Prophylactic beta-blockade with bisoprolol during adjuvant trastuzumab therapy for HER2-positive breast cancer prevented trastuzumab-induced decline in left ventricular ejection fraction in MANTICORE, a randomized trial presented at the San Antonio Breast Cancer Symposium.

“MANTICORE provides the first intervention proven in a randomized, double-blind, placebo-controlled, multicenter way to be an effective means of preventing trastuzumab-associated left ventricular dysfunction,” said Edith Pituskin, Ph.D., of the University of Alberta, Edmonton.

MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research) randomized 99 patients with HER2-positive early breast cancer and a normal-range left ventricular ejection fraction (LVEF) at baseline to bisoprolol (Zebeta), the ACE inhibitor perindopril (Aceon), or placebo shortly before starting a planned 1-year course of adjuvant trastuzumab (Herceptin). The patients had low background levels of cardiovascular risk factors. Roughly three-quarters of subjects were able to titrate up to the target dose of 10 mg once daily for bisoprolol or 8 mg once daily for perindopril.

Cardiac MRI assessments at baseline, 3, and 12 months – the point when trastuzumab and the cardioprotective medications were stopped – showed that neither bisoprolol nor perindopril prevented trastuzumab-related left ventricular remodeling, which was a disappointment, given that this was the prespecified primary endpoint.

“Our results hint that, potentially, trastuzumab exposure–related left ventricular remodeling is not reversible,” Dr. Pituskin said.

The average reduction from baseline in LVEF over the course of a year of adjuvant trastuzumab therapy was 5% with placebo, 3% with perindopril, and 1% with bisoprolol, with the differences between bisoprolol and the other two study arms being highly statistically significant.

On the plus side, both of the once-daily cardiac medications displayed an important side benefit in MANTICORE: an eightfold reduction in the number of interruptions of trastuzumab therapy mandated by a significant drop in LVEF. There were eight such interruptions in the control group versus one each in the bisoprolol and perindopril arms. That’s of practical value in terms of patient convenience, cost of care, and possibly even the efficacy of the adjuvant cancer regimen, she noted.

Audience members raised several questions: what’s the clinical significance of the asymptomatic reduction in LVEF seen in the control group in MANTICORE? Does it place affected patients at risk for overt heart failure as time passes? And since LVEF is just one aspect of cardiac function, isn’t it possible that the cardiac medications were simply propping up LVEF while the underlying cardiotoxic effects of trastuzumab remained unchecked, such that the LVEF will drop once patients are off therapy?

Dr. Pituskin replied that these are good questions, the answers to which may be forthcoming at the planned follow-up cardiac MRI to be conducted at 24 months, a full year after discontinuation of the therapies.

Asked to compare the MANTICORE findings with those of the PRADA trial presented at this year’s annual meeting of the American Heart Association, in which an LVEF drop in breast cancer patients on adjuvant anthracycline and trastuzumab was prevented by prophylactic use of the angiotensin receptor blocker candesartan (Atacand) but not the beta-blocker metoprolol, Dr. Pituskin said she can’t make a definitive comparison until PRADA is published, but that it’s her understanding PRADA was a single-center trial without serial cardiac MRIs, and it included many more participants on an anthracycline-containing regimen, long recognized as a major hazard in terms of cardiotoxicity, and one thought to have a different cardiotoxic mechanism than trastuzumab.

By way of background, she noted that roughly 20% of women with breast cancer have HER2 receptor–overexpressing tumors. In such patients it’s well established that trastuzumab reduces mortality by one-third. However, it’s also well established that one in five patients on trastuzumab experience left ventricular dysfunction, and 1%-5% of patients develop heart failure, an “extremely devastating” complication carrying a 50% 5-year mortality. Beta-blockers and ACE inhibitors or angiotensin receptor blockers are standard, guideline-recommended treatments for patients with established heart failure.

[email protected]

SAN ANTONIO – Prophylactic beta-blockade with bisoprolol during adjuvant trastuzumab therapy for HER2-positive breast cancer prevented trastuzumab-induced decline in left ventricular ejection fraction in MANTICORE, a randomized trial presented at the San Antonio Breast Cancer Symposium.

“MANTICORE provides the first intervention proven in a randomized, double-blind, placebo-controlled, multicenter way to be an effective means of preventing trastuzumab-associated left ventricular dysfunction,” said Edith Pituskin, Ph.D., of the University of Alberta, Edmonton.

MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research) randomized 99 patients with HER2-positive early breast cancer and a normal-range left ventricular ejection fraction (LVEF) at baseline to bisoprolol (Zebeta), the ACE inhibitor perindopril (Aceon), or placebo shortly before starting a planned 1-year course of adjuvant trastuzumab (Herceptin). The patients had low background levels of cardiovascular risk factors. Roughly three-quarters of subjects were able to titrate up to the target dose of 10 mg once daily for bisoprolol or 8 mg once daily for perindopril.

Cardiac MRI assessments at baseline, 3, and 12 months – the point when trastuzumab and the cardioprotective medications were stopped – showed that neither bisoprolol nor perindopril prevented trastuzumab-related left ventricular remodeling, which was a disappointment, given that this was the prespecified primary endpoint.

“Our results hint that, potentially, trastuzumab exposure–related left ventricular remodeling is not reversible,” Dr. Pituskin said.

The average reduction from baseline in LVEF over the course of a year of adjuvant trastuzumab therapy was 5% with placebo, 3% with perindopril, and 1% with bisoprolol, with the differences between bisoprolol and the other two study arms being highly statistically significant.

On the plus side, both of the once-daily cardiac medications displayed an important side benefit in MANTICORE: an eightfold reduction in the number of interruptions of trastuzumab therapy mandated by a significant drop in LVEF. There were eight such interruptions in the control group versus one each in the bisoprolol and perindopril arms. That’s of practical value in terms of patient convenience, cost of care, and possibly even the efficacy of the adjuvant cancer regimen, she noted.

Audience members raised several questions: what’s the clinical significance of the asymptomatic reduction in LVEF seen in the control group in MANTICORE? Does it place affected patients at risk for overt heart failure as time passes? And since LVEF is just one aspect of cardiac function, isn’t it possible that the cardiac medications were simply propping up LVEF while the underlying cardiotoxic effects of trastuzumab remained unchecked, such that the LVEF will drop once patients are off therapy?

Dr. Pituskin replied that these are good questions, the answers to which may be forthcoming at the planned follow-up cardiac MRI to be conducted at 24 months, a full year after discontinuation of the therapies.

Asked to compare the MANTICORE findings with those of the PRADA trial presented at this year’s annual meeting of the American Heart Association, in which an LVEF drop in breast cancer patients on adjuvant anthracycline and trastuzumab was prevented by prophylactic use of the angiotensin receptor blocker candesartan (Atacand) but not the beta-blocker metoprolol, Dr. Pituskin said she can’t make a definitive comparison until PRADA is published, but that it’s her understanding PRADA was a single-center trial without serial cardiac MRIs, and it included many more participants on an anthracycline-containing regimen, long recognized as a major hazard in terms of cardiotoxicity, and one thought to have a different cardiotoxic mechanism than trastuzumab.

By way of background, she noted that roughly 20% of women with breast cancer have HER2 receptor–overexpressing tumors. In such patients it’s well established that trastuzumab reduces mortality by one-third. However, it’s also well established that one in five patients on trastuzumab experience left ventricular dysfunction, and 1%-5% of patients develop heart failure, an “extremely devastating” complication carrying a 50% 5-year mortality. Beta-blockers and ACE inhibitors or angiotensin receptor blockers are standard, guideline-recommended treatments for patients with established heart failure.

[email protected]

SAN ANTONIO – Prophylactic beta-blockade with bisoprolol during adjuvant trastuzumab therapy for HER2-positive breast cancer prevented trastuzumab-induced decline in left ventricular ejection fraction in MANTICORE, a randomized trial presented at the San Antonio Breast Cancer Symposium.

“MANTICORE provides the first intervention proven in a randomized, double-blind, placebo-controlled, multicenter way to be an effective means of preventing trastuzumab-associated left ventricular dysfunction,” said Edith Pituskin, Ph.D., of the University of Alberta, Edmonton.

MANTICORE (Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research) randomized 99 patients with HER2-positive early breast cancer and a normal-range left ventricular ejection fraction (LVEF) at baseline to bisoprolol (Zebeta), the ACE inhibitor perindopril (Aceon), or placebo shortly before starting a planned 1-year course of adjuvant trastuzumab (Herceptin). The patients had low background levels of cardiovascular risk factors. Roughly three-quarters of subjects were able to titrate up to the target dose of 10 mg once daily for bisoprolol or 8 mg once daily for perindopril.

Cardiac MRI assessments at baseline, 3, and 12 months – the point when trastuzumab and the cardioprotective medications were stopped – showed that neither bisoprolol nor perindopril prevented trastuzumab-related left ventricular remodeling, which was a disappointment, given that this was the prespecified primary endpoint.

“Our results hint that, potentially, trastuzumab exposure–related left ventricular remodeling is not reversible,” Dr. Pituskin said.

The average reduction from baseline in LVEF over the course of a year of adjuvant trastuzumab therapy was 5% with placebo, 3% with perindopril, and 1% with bisoprolol, with the differences between bisoprolol and the other two study arms being highly statistically significant.

On the plus side, both of the once-daily cardiac medications displayed an important side benefit in MANTICORE: an eightfold reduction in the number of interruptions of trastuzumab therapy mandated by a significant drop in LVEF. There were eight such interruptions in the control group versus one each in the bisoprolol and perindopril arms. That’s of practical value in terms of patient convenience, cost of care, and possibly even the efficacy of the adjuvant cancer regimen, she noted.

Audience members raised several questions: what’s the clinical significance of the asymptomatic reduction in LVEF seen in the control group in MANTICORE? Does it place affected patients at risk for overt heart failure as time passes? And since LVEF is just one aspect of cardiac function, isn’t it possible that the cardiac medications were simply propping up LVEF while the underlying cardiotoxic effects of trastuzumab remained unchecked, such that the LVEF will drop once patients are off therapy?

Dr. Pituskin replied that these are good questions, the answers to which may be forthcoming at the planned follow-up cardiac MRI to be conducted at 24 months, a full year after discontinuation of the therapies.

Asked to compare the MANTICORE findings with those of the PRADA trial presented at this year’s annual meeting of the American Heart Association, in which an LVEF drop in breast cancer patients on adjuvant anthracycline and trastuzumab was prevented by prophylactic use of the angiotensin receptor blocker candesartan (Atacand) but not the beta-blocker metoprolol, Dr. Pituskin said she can’t make a definitive comparison until PRADA is published, but that it’s her understanding PRADA was a single-center trial without serial cardiac MRIs, and it included many more participants on an anthracycline-containing regimen, long recognized as a major hazard in terms of cardiotoxicity, and one thought to have a different cardiotoxic mechanism than trastuzumab.

By way of background, she noted that roughly 20% of women with breast cancer have HER2 receptor–overexpressing tumors. In such patients it’s well established that trastuzumab reduces mortality by one-third. However, it’s also well established that one in five patients on trastuzumab experience left ventricular dysfunction, and 1%-5% of patients develop heart failure, an “extremely devastating” complication carrying a 50% 5-year mortality. Beta-blockers and ACE inhibitors or angiotensin receptor blockers are standard, guideline-recommended treatments for patients with established heart failure.

[email protected]

SAN ANTONIO – Should carboplatin be considered a routine part of neoadjuvant therapy in early stage triple negative breast cancer?

Not yet, Dr. Angela M. DeMichele declared at the San Antonio Breast Cancer Symposium.

“I would say it’s still an individualized decision. The hazard ratios suggest benefit, but currently there’s not enough data to be conclusive,” according to Dr. DeMichele, who served as discussant for two clinical trials with discordant results – GeparSixto and CALGB/Alliance 40603 – presented at the symposium.

She also addressed a second issue raised by the two studies: is a pathologic complete response a valid surrogate for event-free survival?

“I would say a qualified yes,” commented Dr. DeMichele, professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia.

In GeparSixto, the addition of weekly carboplatin to a neoadjuvant chemotherapy backbone comprised of an anthracycline, taxane, and bevacizumab in patients with triple negative breast cancer (TNBC) boosted the 3-year disease-free survival rate significantly, from 76.1% to 85.5%. This result prompted GeparSixto presenter Dr. Gunter von Minckwitz, president of the German Breast Group, to declare that the study supports incorporation of carboplatin as part of standard neoadjuvant therapy in TNBC.

In contrast, in CALGB/Alliance 40603, adding carboplatin to neoadjuvant chemotherapy didn’t result in a significant improvement in 3-year event-free or overall survival.

Dr. DeMichele noted that with just 3 years of followup to date in these trials, there isn’t any information yet about carboplatin’s added potential long-term bone marrow toxicity. That’s an important unanswered question. Nor is any quality of life data available from the two trials. These issues need clarification before broader use of carboplatin.

One possible explanation for the disparate results in the two studies lies in differences in the chemotherapy and carboplatin doses and treatment schedules used. Patients in GeparSixto received greater cumulative amounts of anthracycline and taxane, given over a longer time period. And if patients were randomized to receive carboplatin, they got it at area under the curve 1.5 or 2 weekly for the duration of chemotherapy, as compared to carboplatin dosed just four times at area under the curve 6 every 3 weeks in CALGB/Alliance 40603.

“Could the weekly carboplatin in GeparSixto have provided less time for DNA repair in the tumor?,” she speculated.

Dr. William M. Sikov, who presented the CALGB/Alliance 40603 findings, found this quite plausible.

“We know treatment schedule and dose are important with anthracyclines, they’re important with taxanes, and it’s certainly not far fetched to propose that they may be important for carboplatin as well. Might that have made a difference? Can’t say,” observed Dr. Sikov of Women and Infants Hospital of Rhode Island in Providence.

In any case, Dr. DeMichele said neither GeparSixto, with its 315 patients with TNBC, nor CALGB/Alliance 40603, with 443, was adequately powered to prove or disprove a therapeutic advantage for the addition of neoadjuvant carboplatin.

“This is the 50th anniversary of the discovery of carboplatin. Yet despite all of our advancements in breast cancer, we’re still trying to figure out the role of platinum-containing agents in our armamentarium for breast cancer,” she observed.

During this period of what she termed clinical equipoise regarding carboplatin, she said it’s reasonable to consider using the agent outside of a clinical trial in selected circumstances: namely, when it’s important to gain rapid control of locoregional disease in order to improve operability or reduce morbidity, or in patients at the highest risk of relapse, mainly those who are very young or have stage III disease.

The issue of the validity of pathologic complete response (pCR) as a surrogate endpoint for event-free survival was raised by the GeparSixto and CALGB/Alliance 40603 investigators. In CALGB/Alliance 40603 only 9% of patients who had a pCR developed a distant recurrence and 3-year mortality was just 6%, compared with a 27% distant recurrence rate and 25% mortality in those without a pCR. Patients with a pCR had a 70% improvement in event-free survival and an 80% improvement in overall survival compared to those without a pCR, Dr. Sikov reported.

Similarly, in GeparSixto disease relapse occurred in only 5 of 129 TNBC patients with a pCR, compared with 50 of 162 without a pCR.

Dr. DeMichele said that while these are encouraging results, neither trial was designed to evaluate pCR as a predictor of improved event-free survival in accord with the Food and Drug Administration’s formal written guidance for attaining recognition of pCR as a surrogate endpoint. The studies were underpowered for this purpose. And a pooled analysis of 12 international trials totaling nearly 12,000 patients that was led by FDA investigators concluded that the data couldn’t validate pCR as a surrogate endpoint for event-free and overall survival (Lancet. 2014 Jul 12;384[9938]:164-72).

However, four studies adequately powered to detect improvement in event-free survival in conjunction with a carboplatin-induced benefit in terms of pCR are underway, including the NRG-BR-003 trial in the U.S. and the BrighTNess study in China.

In addition, a study with an innovative post-neoadjuvant design for platinum-based therapy is underway. The ECOG-ACRIN 1131 study is a Phase III randomized postoperative trial of four rounds of carboplatin or cisplatin versus observation in patients with residual TNBC following an anthracycline-based neoadjuvant regimen. This strategy limits exposure to the toxicities of platinum-based compounds to those patients in need of additional therapy. The planned 558-patient trial is powered to detect a 33% improvement in event-free survival.

[email protected]

SAN ANTONIO – Should carboplatin be considered a routine part of neoadjuvant therapy in early stage triple negative breast cancer?

Not yet, Dr. Angela M. DeMichele declared at the San Antonio Breast Cancer Symposium.

“I would say it’s still an individualized decision. The hazard ratios suggest benefit, but currently there’s not enough data to be conclusive,” according to Dr. DeMichele, who served as discussant for two clinical trials with discordant results – GeparSixto and CALGB/Alliance 40603 – presented at the symposium.

She also addressed a second issue raised by the two studies: is a pathologic complete response a valid surrogate for event-free survival?

“I would say a qualified yes,” commented Dr. DeMichele, professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia.

In GeparSixto, the addition of weekly carboplatin to a neoadjuvant chemotherapy backbone comprised of an anthracycline, taxane, and bevacizumab in patients with triple negative breast cancer (TNBC) boosted the 3-year disease-free survival rate significantly, from 76.1% to 85.5%. This result prompted GeparSixto presenter Dr. Gunter von Minckwitz, president of the German Breast Group, to declare that the study supports incorporation of carboplatin as part of standard neoadjuvant therapy in TNBC.

In contrast, in CALGB/Alliance 40603, adding carboplatin to neoadjuvant chemotherapy didn’t result in a significant improvement in 3-year event-free or overall survival.

Dr. DeMichele noted that with just 3 years of followup to date in these trials, there isn’t any information yet about carboplatin’s added potential long-term bone marrow toxicity. That’s an important unanswered question. Nor is any quality of life data available from the two trials. These issues need clarification before broader use of carboplatin.

One possible explanation for the disparate results in the two studies lies in differences in the chemotherapy and carboplatin doses and treatment schedules used. Patients in GeparSixto received greater cumulative amounts of anthracycline and taxane, given over a longer time period. And if patients were randomized to receive carboplatin, they got it at area under the curve 1.5 or 2 weekly for the duration of chemotherapy, as compared to carboplatin dosed just four times at area under the curve 6 every 3 weeks in CALGB/Alliance 40603.

“Could the weekly carboplatin in GeparSixto have provided less time for DNA repair in the tumor?,” she speculated.

Dr. William M. Sikov, who presented the CALGB/Alliance 40603 findings, found this quite plausible.

“We know treatment schedule and dose are important with anthracyclines, they’re important with taxanes, and it’s certainly not far fetched to propose that they may be important for carboplatin as well. Might that have made a difference? Can’t say,” observed Dr. Sikov of Women and Infants Hospital of Rhode Island in Providence.

In any case, Dr. DeMichele said neither GeparSixto, with its 315 patients with TNBC, nor CALGB/Alliance 40603, with 443, was adequately powered to prove or disprove a therapeutic advantage for the addition of neoadjuvant carboplatin.

“This is the 50th anniversary of the discovery of carboplatin. Yet despite all of our advancements in breast cancer, we’re still trying to figure out the role of platinum-containing agents in our armamentarium for breast cancer,” she observed.

During this period of what she termed clinical equipoise regarding carboplatin, she said it’s reasonable to consider using the agent outside of a clinical trial in selected circumstances: namely, when it’s important to gain rapid control of locoregional disease in order to improve operability or reduce morbidity, or in patients at the highest risk of relapse, mainly those who are very young or have stage III disease.

The issue of the validity of pathologic complete response (pCR) as a surrogate endpoint for event-free survival was raised by the GeparSixto and CALGB/Alliance 40603 investigators. In CALGB/Alliance 40603 only 9% of patients who had a pCR developed a distant recurrence and 3-year mortality was just 6%, compared with a 27% distant recurrence rate and 25% mortality in those without a pCR. Patients with a pCR had a 70% improvement in event-free survival and an 80% improvement in overall survival compared to those without a pCR, Dr. Sikov reported.

Similarly, in GeparSixto disease relapse occurred in only 5 of 129 TNBC patients with a pCR, compared with 50 of 162 without a pCR.

Dr. DeMichele said that while these are encouraging results, neither trial was designed to evaluate pCR as a predictor of improved event-free survival in accord with the Food and Drug Administration’s formal written guidance for attaining recognition of pCR as a surrogate endpoint. The studies were underpowered for this purpose. And a pooled analysis of 12 international trials totaling nearly 12,000 patients that was led by FDA investigators concluded that the data couldn’t validate pCR as a surrogate endpoint for event-free and overall survival (Lancet. 2014 Jul 12;384[9938]:164-72).

However, four studies adequately powered to detect improvement in event-free survival in conjunction with a carboplatin-induced benefit in terms of pCR are underway, including the NRG-BR-003 trial in the U.S. and the BrighTNess study in China.

In addition, a study with an innovative post-neoadjuvant design for platinum-based therapy is underway. The ECOG-ACRIN 1131 study is a Phase III randomized postoperative trial of four rounds of carboplatin or cisplatin versus observation in patients with residual TNBC following an anthracycline-based neoadjuvant regimen. This strategy limits exposure to the toxicities of platinum-based compounds to those patients in need of additional therapy. The planned 558-patient trial is powered to detect a 33% improvement in event-free survival.

[email protected]

SAN ANTONIO – Should carboplatin be considered a routine part of neoadjuvant therapy in early stage triple negative breast cancer?

Not yet, Dr. Angela M. DeMichele declared at the San Antonio Breast Cancer Symposium.

“I would say it’s still an individualized decision. The hazard ratios suggest benefit, but currently there’s not enough data to be conclusive,” according to Dr. DeMichele, who served as discussant for two clinical trials with discordant results – GeparSixto and CALGB/Alliance 40603 – presented at the symposium.

She also addressed a second issue raised by the two studies: is a pathologic complete response a valid surrogate for event-free survival?

“I would say a qualified yes,” commented Dr. DeMichele, professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia.

In GeparSixto, the addition of weekly carboplatin to a neoadjuvant chemotherapy backbone comprised of an anthracycline, taxane, and bevacizumab in patients with triple negative breast cancer (TNBC) boosted the 3-year disease-free survival rate significantly, from 76.1% to 85.5%. This result prompted GeparSixto presenter Dr. Gunter von Minckwitz, president of the German Breast Group, to declare that the study supports incorporation of carboplatin as part of standard neoadjuvant therapy in TNBC.

In contrast, in CALGB/Alliance 40603, adding carboplatin to neoadjuvant chemotherapy didn’t result in a significant improvement in 3-year event-free or overall survival.

Dr. DeMichele noted that with just 3 years of followup to date in these trials, there isn’t any information yet about carboplatin’s added potential long-term bone marrow toxicity. That’s an important unanswered question. Nor is any quality of life data available from the two trials. These issues need clarification before broader use of carboplatin.

One possible explanation for the disparate results in the two studies lies in differences in the chemotherapy and carboplatin doses and treatment schedules used. Patients in GeparSixto received greater cumulative amounts of anthracycline and taxane, given over a longer time period. And if patients were randomized to receive carboplatin, they got it at area under the curve 1.5 or 2 weekly for the duration of chemotherapy, as compared to carboplatin dosed just four times at area under the curve 6 every 3 weeks in CALGB/Alliance 40603.

“Could the weekly carboplatin in GeparSixto have provided less time for DNA repair in the tumor?,” she speculated.

Dr. William M. Sikov, who presented the CALGB/Alliance 40603 findings, found this quite plausible.

“We know treatment schedule and dose are important with anthracyclines, they’re important with taxanes, and it’s certainly not far fetched to propose that they may be important for carboplatin as well. Might that have made a difference? Can’t say,” observed Dr. Sikov of Women and Infants Hospital of Rhode Island in Providence.

In any case, Dr. DeMichele said neither GeparSixto, with its 315 patients with TNBC, nor CALGB/Alliance 40603, with 443, was adequately powered to prove or disprove a therapeutic advantage for the addition of neoadjuvant carboplatin.

“This is the 50th anniversary of the discovery of carboplatin. Yet despite all of our advancements in breast cancer, we’re still trying to figure out the role of platinum-containing agents in our armamentarium for breast cancer,” she observed.

During this period of what she termed clinical equipoise regarding carboplatin, she said it’s reasonable to consider using the agent outside of a clinical trial in selected circumstances: namely, when it’s important to gain rapid control of locoregional disease in order to improve operability or reduce morbidity, or in patients at the highest risk of relapse, mainly those who are very young or have stage III disease.

The issue of the validity of pathologic complete response (pCR) as a surrogate endpoint for event-free survival was raised by the GeparSixto and CALGB/Alliance 40603 investigators. In CALGB/Alliance 40603 only 9% of patients who had a pCR developed a distant recurrence and 3-year mortality was just 6%, compared with a 27% distant recurrence rate and 25% mortality in those without a pCR. Patients with a pCR had a 70% improvement in event-free survival and an 80% improvement in overall survival compared to those without a pCR, Dr. Sikov reported.

Similarly, in GeparSixto disease relapse occurred in only 5 of 129 TNBC patients with a pCR, compared with 50 of 162 without a pCR.

Dr. DeMichele said that while these are encouraging results, neither trial was designed to evaluate pCR as a predictor of improved event-free survival in accord with the Food and Drug Administration’s formal written guidance for attaining recognition of pCR as a surrogate endpoint. The studies were underpowered for this purpose. And a pooled analysis of 12 international trials totaling nearly 12,000 patients that was led by FDA investigators concluded that the data couldn’t validate pCR as a surrogate endpoint for event-free and overall survival (Lancet. 2014 Jul 12;384[9938]:164-72).

However, four studies adequately powered to detect improvement in event-free survival in conjunction with a carboplatin-induced benefit in terms of pCR are underway, including the NRG-BR-003 trial in the U.S. and the BrighTNess study in China.

In addition, a study with an innovative post-neoadjuvant design for platinum-based therapy is underway. The ECOG-ACRIN 1131 study is a Phase III randomized postoperative trial of four rounds of carboplatin or cisplatin versus observation in patients with residual TNBC following an anthracycline-based neoadjuvant regimen. This strategy limits exposure to the toxicities of platinum-based compounds to those patients in need of additional therapy. The planned 558-patient trial is powered to detect a 33% improvement in event-free survival.

[email protected]

SAN ANTONIO – The immunologic checkpoint inhibitor avelumab showed only modest single-digit efficacy in an unselected group of metastatic breast cancer patients, but the results were sevenfold better in the subset of JAVELIN trial participants with strong expression of PD-L1 by immune cells within the tumor, Dr. Luc Y. Dirix reported at the San Antonio Breast Cancer Symposium.

Avelumab is an investigational fully human IgG1 monoclonal antibody that selectively binds to PD-L1 (programmed death–ligand 1). In addition, it’s believed that avelumab elicits antibody-dependent cellular cytotoxicity as a secondary mechanism for its antitumor activity, according to Dr. Dirix of the University of Antwerp, Belgium.

JAVELIN is a multipronged phase Ib clinical trial which to date has enrolled more than 1,000 participants with various types of advanced cancer. Avelumab has shown antitumor activity in patients with lung, gastric, bladder, ovarian, and other cancers. Phase III randomized trials are underway evaluating avelumab in patients with advanced non–small cell lung cancer and gastric cancer.

Dr. Dirix reported on the 168 JAVELIN participants with locally advanced or metastatic breast cancer refractory to standard therapy, including anthracycline and a taxane. Their median time since diagnosis of metastatic disease was 21.6 weeks at the time they went on avelumab at 10 mg/kg every 2 weeks until disease progression occurred. Roughly half of participants had already undergone three or more regimens for their advanced malignancy.

At a median duration of 10 months follow-up, 1 of the 168 patients had shown a complete response and 7 others had a partial response, for an overall response rate of 4.8%. Of note, 5 of the 8 responders were among the 58 women with triple-negative breast cancer (TNBC). Median time to response was 11.4 weeks, with a relatively long 28.7-week median duration of response. The response was ongoing in 5 of 8 patients at the time of Dr. Dirix’s presentation.

Of the 136 patients for whom data on PD-L1 expression level was available, 4 of the 12 with PD-L1 expression by at least 10% of immune cells within the tumor had a clinical response, for a 33% rate. Nine patients with TNBC had a PD-L1 response which rose to this level, and 4 of these 9 (44%) had a clinical response.

In contrast, patients whose immune cells within the tumor were PD-L1–negative had a clinical response rate of less than 3%. But expression of PD-L1 by tumor cells was not predictive of benefit from avelumab; indeed, even when 25% or more of a patient’s tumor cells expressed PD-L1, the clinical response rate was in the single digits.

Ten of 58 patients with TNBC (17%) experienced tumor shrinkage by 30% or more during the course of treatment.

Dr. Dirix characterized avelumab’s safety profile as acceptable for patients with metastatic breast cancer. Only 8 patients (4.8%) discontinued participation because of treatment-related adverse events. Potentially treatment-related immune toxicity occurred in 8 patients who became hypothyroid, 3 with autoimmune hepatitis, 3 with pneumonia, and 2 with thrombocytopenia. Three-quarters of these complications were Grade 1/2.

Far more common treatment-related adverse events included Grade 1/2 fatigue, which occurred in 19% of patients, nausea in 13%, and diarrhea in 9%. Infusion reactions occurred in 14% of patients; however, the incidence was halved after mandatory pretreatment with an antihistamine and antipyretic was instituted.

Session moderator Dr. Nicholas Turner of Royal Marsden Hospital in London observed that in lung cancer and other malignancies included in the JAVELIN program, PD-L1 expression by tumor cells predicted benefit with avelumab. “Why not in metastatic breast cancer?” he asked.

Dr. Dirix replied that he and his coinvestigators are looking into that question but don’t have an answer yet.

[email protected]

SAN ANTONIO – The immunologic checkpoint inhibitor avelumab showed only modest single-digit efficacy in an unselected group of metastatic breast cancer patients, but the results were sevenfold better in the subset of JAVELIN trial participants with strong expression of PD-L1 by immune cells within the tumor, Dr. Luc Y. Dirix reported at the San Antonio Breast Cancer Symposium.

Avelumab is an investigational fully human IgG1 monoclonal antibody that selectively binds to PD-L1 (programmed death–ligand 1). In addition, it’s believed that avelumab elicits antibody-dependent cellular cytotoxicity as a secondary mechanism for its antitumor activity, according to Dr. Dirix of the University of Antwerp, Belgium.

JAVELIN is a multipronged phase Ib clinical trial which to date has enrolled more than 1,000 participants with various types of advanced cancer. Avelumab has shown antitumor activity in patients with lung, gastric, bladder, ovarian, and other cancers. Phase III randomized trials are underway evaluating avelumab in patients with advanced non–small cell lung cancer and gastric cancer.

Dr. Dirix reported on the 168 JAVELIN participants with locally advanced or metastatic breast cancer refractory to standard therapy, including anthracycline and a taxane. Their median time since diagnosis of metastatic disease was 21.6 weeks at the time they went on avelumab at 10 mg/kg every 2 weeks until disease progression occurred. Roughly half of participants had already undergone three or more regimens for their advanced malignancy.

At a median duration of 10 months follow-up, 1 of the 168 patients had shown a complete response and 7 others had a partial response, for an overall response rate of 4.8%. Of note, 5 of the 8 responders were among the 58 women with triple-negative breast cancer (TNBC). Median time to response was 11.4 weeks, with a relatively long 28.7-week median duration of response. The response was ongoing in 5 of 8 patients at the time of Dr. Dirix’s presentation.

Of the 136 patients for whom data on PD-L1 expression level was available, 4 of the 12 with PD-L1 expression by at least 10% of immune cells within the tumor had a clinical response, for a 33% rate. Nine patients with TNBC had a PD-L1 response which rose to this level, and 4 of these 9 (44%) had a clinical response.

In contrast, patients whose immune cells within the tumor were PD-L1–negative had a clinical response rate of less than 3%. But expression of PD-L1 by tumor cells was not predictive of benefit from avelumab; indeed, even when 25% or more of a patient’s tumor cells expressed PD-L1, the clinical response rate was in the single digits.

Ten of 58 patients with TNBC (17%) experienced tumor shrinkage by 30% or more during the course of treatment.

Dr. Dirix characterized avelumab’s safety profile as acceptable for patients with metastatic breast cancer. Only 8 patients (4.8%) discontinued participation because of treatment-related adverse events. Potentially treatment-related immune toxicity occurred in 8 patients who became hypothyroid, 3 with autoimmune hepatitis, 3 with pneumonia, and 2 with thrombocytopenia. Three-quarters of these complications were Grade 1/2.

Far more common treatment-related adverse events included Grade 1/2 fatigue, which occurred in 19% of patients, nausea in 13%, and diarrhea in 9%. Infusion reactions occurred in 14% of patients; however, the incidence was halved after mandatory pretreatment with an antihistamine and antipyretic was instituted.

Session moderator Dr. Nicholas Turner of Royal Marsden Hospital in London observed that in lung cancer and other malignancies included in the JAVELIN program, PD-L1 expression by tumor cells predicted benefit with avelumab. “Why not in metastatic breast cancer?” he asked.

Dr. Dirix replied that he and his coinvestigators are looking into that question but don’t have an answer yet.

[email protected]

SAN ANTONIO – The immunologic checkpoint inhibitor avelumab showed only modest single-digit efficacy in an unselected group of metastatic breast cancer patients, but the results were sevenfold better in the subset of JAVELIN trial participants with strong expression of PD-L1 by immune cells within the tumor, Dr. Luc Y. Dirix reported at the San Antonio Breast Cancer Symposium.

Avelumab is an investigational fully human IgG1 monoclonal antibody that selectively binds to PD-L1 (programmed death–ligand 1). In addition, it’s believed that avelumab elicits antibody-dependent cellular cytotoxicity as a secondary mechanism for its antitumor activity, according to Dr. Dirix of the University of Antwerp, Belgium.

JAVELIN is a multipronged phase Ib clinical trial which to date has enrolled more than 1,000 participants with various types of advanced cancer. Avelumab has shown antitumor activity in patients with lung, gastric, bladder, ovarian, and other cancers. Phase III randomized trials are underway evaluating avelumab in patients with advanced non–small cell lung cancer and gastric cancer.

Dr. Dirix reported on the 168 JAVELIN participants with locally advanced or metastatic breast cancer refractory to standard therapy, including anthracycline and a taxane. Their median time since diagnosis of metastatic disease was 21.6 weeks at the time they went on avelumab at 10 mg/kg every 2 weeks until disease progression occurred. Roughly half of participants had already undergone three or more regimens for their advanced malignancy.

At a median duration of 10 months follow-up, 1 of the 168 patients had shown a complete response and 7 others had a partial response, for an overall response rate of 4.8%. Of note, 5 of the 8 responders were among the 58 women with triple-negative breast cancer (TNBC). Median time to response was 11.4 weeks, with a relatively long 28.7-week median duration of response. The response was ongoing in 5 of 8 patients at the time of Dr. Dirix’s presentation.

Of the 136 patients for whom data on PD-L1 expression level was available, 4 of the 12 with PD-L1 expression by at least 10% of immune cells within the tumor had a clinical response, for a 33% rate. Nine patients with TNBC had a PD-L1 response which rose to this level, and 4 of these 9 (44%) had a clinical response.

In contrast, patients whose immune cells within the tumor were PD-L1–negative had a clinical response rate of less than 3%. But expression of PD-L1 by tumor cells was not predictive of benefit from avelumab; indeed, even when 25% or more of a patient’s tumor cells expressed PD-L1, the clinical response rate was in the single digits.

Ten of 58 patients with TNBC (17%) experienced tumor shrinkage by 30% or more during the course of treatment.

Dr. Dirix characterized avelumab’s safety profile as acceptable for patients with metastatic breast cancer. Only 8 patients (4.8%) discontinued participation because of treatment-related adverse events. Potentially treatment-related immune toxicity occurred in 8 patients who became hypothyroid, 3 with autoimmune hepatitis, 3 with pneumonia, and 2 with thrombocytopenia. Three-quarters of these complications were Grade 1/2.

Far more common treatment-related adverse events included Grade 1/2 fatigue, which occurred in 19% of patients, nausea in 13%, and diarrhea in 9%. Infusion reactions occurred in 14% of patients; however, the incidence was halved after mandatory pretreatment with an antihistamine and antipyretic was instituted.

Session moderator Dr. Nicholas Turner of Royal Marsden Hospital in London observed that in lung cancer and other malignancies included in the JAVELIN program, PD-L1 expression by tumor cells predicted benefit with avelumab. “Why not in metastatic breast cancer?” he asked.

Dr. Dirix replied that he and his coinvestigators are looking into that question but don’t have an answer yet.

[email protected]