Contradictory Conclusions Reached in Extended Adjuvant Endocrine Therapy for Breast Cancer

After the MA.17 trial demonstrated that five years of letrozole improves disease-free survival (DFS) in breast cancer patients after five years of tamoxifen therapy, a question remained: Might longer treatment be better? The MA.17R trial sought to answer that question and, as reported in the New England Journal of Medicine in July, concluded that extension of treatment with an adjuvant aromatase inhibitor to 10 years significantly improved DFS in postmenopausal women.

Unfortunately, a phase III randomized, double-blind clinical trial, NSABP B-42, presented Dec. 7 at the 2016 San Antonio Breast Cancer Symposium, did not show similar benefit for extending adjuvant endocrine therapy beyond five years.

Results disappoint

“This study did not find benefit from a five-year extension of adjuvant endocrine treatment with letrozole in postmenopausal woman with hormone receptor (HR)-positive breast cancer,” says Jame Abraham, MD, Director of the Breast Oncology Program at Taussig Cancer Institute, and Co-director of the Cleveland Clinic Comprehensive Breast Cancer Program. The study was funded by the National Cancer Institute, National Institutes of Health.

According to Dr. Abraham, the discrepancy between the two studies might be due to how the disease-free survival was defined in these two studies. The NSABP B-42 study enrolled 3,996 women and the MA.17R study enrolled 1,918 women.

The secondary aims of the B-42 study were to examine whether letrozole improved overall survival, breast cancer-free interval, distant recurrence-free interval and if incidence of osteoporotic fractures or arterial thrombotic events increased. Potential side effects of AIs include fractures, osteoporosis and joint paint compared with tamoxifen’s (blood clots, endometrial cancer).

Patient selection and results

The B-42 study, which lasted nearly 10 years, included postmenopausal women with a primary stage I, II or IIIA invasive estrogen receptor-positive and/or progesterone receptor-positive carcinoma of the breast. Patients must have had a lumpectomy with axillary nodal staging followed by radiation or a total mastectomy and received adjuvant or neoadjuvant chemotherapy at the time of diagnosis for 75-63 months. Hormonal therapy must have been an AI or a combination of up to three years of tamoxifen followed by an AI.

Osteoporotic fractures and other malignancies were among exclusionary criteria. Patients were then randomized to receive placebo or letrozole 2.5 mg once daily for five years.

Median followup was 6.9 years. Patients were equally randomized between the letrozole and placebo arms of the trial. There was no statistically significant difference in DFS or overall survival in either arm. There was a minor improvement in survival of 15 percent in the letrozole arm.

Not the end of the story

“I wish that prolonged usage of aromatase inhibiters (AI) would have proven more beneficial for patients,” Dr. Abraham says. “We know that ER-positive patients can develop delayed recurrence, so prolonged anti-estrogen treatment may benefit some patients. I think we need longer followup before we draw final conclusions from this study. I don’t think this is the end of the story.”

Takeaway for physicians

“Molecular tests and other predictive markers will help us to identify the patients who will benefit from prolonged endocrine therapy,” Dr. Abraham predicts. In the meantime, he says, “My bottom line is that although this study didn’t show a significant advantage for letrozole beyond five years, I think the question is not completely answered. For high-risk patients, defined by clinical features or molecular tests, and those who are tolerating aromatase inhibitors, it may be reasonable to continue beyond five years. We need to learn from history. We prematurely concluded that five years of tamoxifen is optimal and prolonged use of tamoxifen is detrimental from NSABP B-4. But recent studies proved us wrong.”