Extending Adjuvant Endocrine Therapy: 3 Trials, Few Answers

Kate Johnson

December 07, 2016

SAN ANTONIO — Despite three new trials examining the extension of adjuvant endocrine therapy in hormone-positive breast cancer, there were no easy answers here at the San Antonio Breast Cancer Symposium (SABCS) 2016. The trials were the NASPB B-42, IDEAL, and DATA studies.

"I was anticipating a new milestone of knowledge... [but] whether we like it or not, essentially these three trials did not reach statistical significance to demonstrate clear benefit for their respective aromatase inhibitor extensions," commented discussant Michael Gnant, MD, from the Medical University of Vienna, Austria.

In particular, the NASBP B-42 trial was much anticipated because it examined extending adjuvant therapy with the aromatase inhibitor (AI) letrozole (Femara, Novartis) for 5 years in patients who had initially received 5 years of adjuvant therapy with an AI (either alone or mixed sequentially with tamoxifen).

"The first extended adjuvant therapy trials (MA-17, NSABP-B33 and ABCSG-6a) investigated AIs after tamoxifen and demonstrated significant benefits for patients. However, those trials did not answer the question, should we also use extended AI treatment after AIs were used in initial adjuvant therapy? This is why NASBP B-42 is so important," said Dr Gnant.

 
This is why NASBP B-42 is so important Dr Michael Gnant
 

But the answer to that question is not a clear yes or no, reported NASBP B-42 investigator Terry Mamounas, MD, medical director of the Comprehensive Breast Program at the University of Florida Health Cancer Center at Orlando Health and chair of the NRG Oncology Breast Committee.

Although the trial did not show a statistically significant improvement in its primary endpoint of disease-free survival (DFS) or in overall survival (OS) with extended letrozole vs placebo, it did show a statistically significant reduction in the incidence of breast cancer–free interval (29%) and distant recurrence rates (28%).

The study randomly allocated 3923 patients with hormone receptor–positive disease who had completed 5 years of adjuvant AI or AI plus tamoxifen to receive an additional 5 years of either letrozole or placebo.The median follow-up was 6.9 years.

"At first glance, our results look discordant" to the very similar MA17-R trial, which showed a statistically significant benefit from extended adjuvant therapy with letrozole, said Dr Mamounas. However, after accounting for the studies' different definitions of DFS, "the results are very similar," he explained during a press conference.

Subgroup analyses of NSABP B-42 did not reveal statistically significant predictors of which patients might benefit from extended letrozole treatment. There is a suggestion that younger patients with few comorbidities and higher risk for recurrence, as determined on the basis of nodal status, might be the best candidates, he added.

Patients who had previously undergone tamoxifen therapy also saw greater benefit than those previously treated with an AI.

Both NSABP B-42 and MA17-R "are very similar," agreed press conference moderator Virginia Kaklamani, MD, codirector of the SABCS and professor of medicine at the University of Texas Health Science Center, San Antonio.

"Basically, there is a benefit, but it's really small. There will be women who won't have any benefit and some women who will. We just have to identify the women who have a high risk of recurrence after 10 years and offer it to them. To do that, we either have to use a genomic test or take tumor characteristics like size, lymph node positivity, and patient age, etc."

Results from the DATA and IDEAL trials were similarly murky.

Although both trials compared different durations of extended adjuvant AI (anastrozole [Arimedex, AstraZeneca] and letrozole, respectively), their major difference was in the initial adjuvant treatment, which was tamoxifen in DATA vs a mixture of any endocrine therapies in IDEAL, explained Dr Gnant.

Although neither trial showed overall benefit for extended adjuvant AI therapy, there was again a suggestion that prior tamoxifen treatment yielded greater benefit.

Although it is "difficult to draw overall conclusions on extended adjuvant endocrine therapy with an AI, one might argue to give additional therapy in patients who received first tamoxifen," agreed C. Kent Osborne, MD, director of the Dan L. Duncan Comprehensive Cancer Center at the Baylor College of Medicine in Houston, Texas, and an SABCS director. "The decision in those who received 5 years of an AI is more difficult given the lack of overall benefit in these studies."

 
The decision in those who received 5 years of an AI is more difficult. Dr C. Kent Osborne
 

For the latter patients, toxicity will be the guide, suggested Dr Gnant.

"In reality, the main trigger for the decision to extend an AI will be how you think your patient has tolerated it in the first years," he said. "Bone health is important — given the real fracture risk, we have to put this in the equation. This also means that younger age is a favoring factor. In several studies, classical risk factors as well as liminality have been proposed to favor treatment extension, and assessment with genomic assays remains an undecided issue at this point."

The NSABP B-42 study was funded by the National Cancer Institute and Novartis. DATA was funded by AstraZeneca. IDEAL was funded by Novartis. Dr Mamounas has been a consultant for Genentech, Genomic Health, GRAIL, Biotheranostics, Macrogenics, Pfizer, and Celcuity and has been on the speakers' bureaus for Genentech and Genomic Health. Dr Gnant has had consulting and advisory roles with Accelsiors. He has also received honoraria from Roche, Novartis, AstraZeneca, Celgene, and GlaxoSmithKline; research funding from AstraZeneca, Novartis, Roche, and Pfizer; travel, accommodation, and expenses from Celgene, AstraZeneca and Novartis; and employment of an immediate family member with Sandoz. Dr Kaklamani been a consultant for AstraZeneca, Myriad Genetics, Inc, and EISAI.

San Antonio Breast Cancer Symposium (SABCS) 2016. Abstracts S1-05, S1-03, and S1-04. Presented December 6, 2016.

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