Extra Protection: Extended Hormone Therapy Can Reduce Breast Cancer Recurrence

Women with early-stage, hormone receptor (HR)- positive breast cancer who stayed on hormonal therapy for 10 years after initial treatment reduced their risk of recurrence by more than a third while experiencing no new side effects or worsening of quality of life, a study has found.

In the past, taking an aromatase inhibitor (AI) for five years was the standard of care. The phase 3, randomized, double-blind, placebocontrolled MA.17R trial marks the first to show a benefit with extending AI therapy beyond five years, and is expected to provide direction for both patients and physicians worldwide.

The study also found that patients receiving extended AI therapy of Femara (letrozole) versus placebo experienced a significant reduction in the occurrence of contralateral breast cancer (CBC), but no statistically significant increase in five-year overall survival (OS) — 93 percent and 94 percent, respectively. The trial’s findings, reported at a press conference at the 2016 annual meeting of the American Society of Clinical Oncology (ASCO) by lead author Paul Goss, M.D., Ph.D., were published simultaneously in the New England Journal of Medicine.

Over five years beginning in October 2004, the trial accrued 1,918 postmenopausal women with HR-positive breast cancer who had received four-anda- half to six years of any adjuvant (post-treatment) AI therapy — either as initial treatment or after any duration of prior tamoxifen.

Women were evenly randomized to receive either 2.5 mg of oral AI Femara or placebo daily with a median follow-up of 6.3 years. The study’s primary endpoint was disease-free survival (DFS), as measured from time of randomization to invasive breast cancer recurrence or development of CBC. Goss noted that the precursor MA.17 trial reported a very significant 48 percent reduction in disease recurrence, and these DFS results led to the approval of adjuvant endocrine therapies by regulatory agencies in more than 100 countries, a move that makes these drugs widely accessible in practice.

Secondary endpoints of MA.17R were OS, all contralateral breast cancers, safety and quality of life Goss, who is director of Breast Cancer Research at Massachusetts General Hospital, reported that women in the Femara arm had a 34 percent reduction in recurrence and a 58 percent reduction in CBCs compared with placebo controls. Investigators reported 165 disease-recurrence or CBC events, 67 with Femara and 98 with placebo. The most common site of recurrence was distant: 42 in patients treated with Femara versus 53 in the placebo arm, followed by bone (28 versus 37, respectively), and locoregional (19 versus 30, respectively). Thirteen CBC events occurred in the Femara arm and 31 in the placebo arm.

Overall Survival and Practice Implications

Goss said that he expected the DFS differences to widen over time between the Femara and placebo groups, and the OS difference to eventually become positive.

“Most of the endocrine therapies have a kind of ‘legacy effect’ after patients stop treatment. There is an improvement in disease-free survival during the course of the therapy — be it tamoxifen or an aromatase inhibitor. Thereafter, there is a persistent improvement. The FDA has taken the opinion that overall survival follows disease-free survival like night follows day for endocrine therapy, and I think they’re correct; that’s what we’ve seen in all the trials,” Goss said.

As a result of the clinical utility demonstrated with the MA.17R study, “there will be tremendous interest in longer durations of AI therapy, but also some tailoring of treatment based on how the patient has fared with the endocrine therapy and their baseline risk of recurrence,” noted press conference panelist and ASCO expert in breast cancer, Harold J. Burstein, M.D.

“Women who have less risky cancers will probably be less inclined to pursue these longer durations, and women who have higher-risk cancers will be more inclined,” he continued. “As the authors noted in their New England Journal of Medicine paper, women who have finished five years of AI therapy without any prior tamoxifen, I think, are going to be very compelled by these data; whereas, women who have had five years of tamoxifen, five years of an AI, and are already 10 years out will probably get less benefit numerically from the yet longer duration of therapy. We’re certainly not at the point of saying that women should be on these drugs for the rest of their lives or indefinitely.”

One important limitation of the MR.17R study noted by Goss is that it involved only participants who had already tolerated five years of an AI, and most had also received tamoxifen.

“These are highly selected patients who are not having the severe symptoms” that would typically prompt them to opt out of the therapy, Goss said.