Extending Letrozole Therapy Beyond 5 Years in Early Breast Cancer Reduces Recurrence

August 2016, Vol 7, No 7, Special Issue: Payers’ Perspectives in Oncology

Extending aromatase inhibitor therapy with letrozole for an additional 5 years beyond standard treatment with letrozole improved disease-free survival (DFS) and reduced the rate of new contralateral breast cancer in postmenopausal women with estrogen receptor (ER)-positive breast cancer. Prolonged letrozole did not improve overall survival. These were the main findings of the large MA.17R trial, which were presented at the plenary session at ASCO 2016.

The results of the trial were simultaneously published in the New England Journal of Medicine (Goss PE, et al. 2016;375:209-219) to coincide with the ASCO presentation.

“This is the first large randomized study to show the benefit of extending aromatase inhibitor therapy beyond 5 years. An additional 5 years of letrozole resulted in a 34% reduction in risk for recurrence, with no worsening of quality of life,” said lead investigator Paul E. Goss, MD, PhD, FRCP, Director of Breast Cancer Research, Massachusetts General Hospital, and Professor of Medicine, Harvard Medical School, Boston.

“Women with early-stage hormone receptor–positive breast cancer face an indefinite risk of relapse. The study provides direction for many patients and their doctors, confirming that prolonged aromatase inhibitor therapy can further reduce the risk for breast cancer recurrences. Longer aromatase inhibitor therapy also showed a substantial breast cancer prevention effect in the opposite healthy breast,” Dr Goss said.

Experts suggested that the results of this trial were from women who already had 5 years of letrozole treatment (most of them after 5 years of tamoxifen), and that this was a select group of women who could tolerate the adverse events of aromatase inhibitor therapy.

Current practice for the treatment of patients with ER-positive postmenopausal early breast cancer is adjuvant therapy with an aromatase inhibitor for 5 years. The MA.17R trial was designed to determine if there is an additional benefit to extending letrozole therapy in this group of women, Dr Goss said.

Trial Results

The MA.17R trial included 1918 patients with hormone receptor–positive early breast cancer who had received 5 years of letrozole. Approximately 70% of the women had 5 years of tamoxifen therapy followed by 5 years of letrozole therapy before entering the trial.

The patients were randomized 1:1 to 5 additional years of letrozole treatment once daily or to placebo.

At a median follow-up of 6.3 years, a total of 165 events (disease recurrence or contralateral breast cancer) were reported, with 67 in the letrozole group and 98 in the placebo group. A total of 200 deaths were reported—100 deaths in each group.

The 5-year DFS rate was 95% for extended letrozole therapy and 91% for placebo (P = .01), a 34% improvement in DFS. This benefit was independent of nodal status, previous adjuvant chemotherapy, time since the last aromatase inhibitor dose, and duration of previous therapy with tamoxifen or an aromatase inhibitor.

The rate of contralateral breast cancer was 1.4% for letrozole and 3.2% for placebo, a significant (P = .007) 58% reduction. A consistent effect of letrozole therapy was observed across all prespecified subgroups.

Toxicities were mainly similar in the 2 cohorts, but more bone-related events (ie, bone pain, bone fracture, and new-onset osteoporosis) occurred in the letrozole group. Few treatment-related discontinuations were reported (5.4% with letrozole vs 3.7% in the placebo group).

There were 133 bone fractures in the letrozole group and 88 fractures in the placebo group. New-onset osteoporosis was found in 109 and 54 patients, respectively.

“Bone health remains an important consideration for risk versus benefit discussions with patients,” Dr Goss noted.

No worsening of quality of life was found in the letrozole group compared with the placebo group, according to the 36-Item Short Form Health Survey (SF-36) and the Menopausal Specific Quality of Life Questionnaire. Only 1 of 8 subscales of the SF-36 found a small difference favoring placebo (ie, the role-function physical subscale).

“Unlike many anticancer therapies, aromatase inhibitors are readily accessible around the world, and, therefore, our results will further improve the outcome of many women with breast cancer,” Dr Goss stated.

Expert Opinion

The formal discussant of this trial, Ian E. Smith, MD, of the Royal Marsden Hospital and the Institute of Cancer Research, London, England, said that these results are especially relevant for women who are at high risk for recurrence who can tolerate the side effects of aromatase inhibitor treatment. He does not believe, however, that these postmenopausal women should receive aromatase inhibitor therapy indefinitely.

“These data do not justify telling all our patients to continue endocrine therapy beyond 10 years,” Dr Smith said. “But in a patient with high-risk features who has thrown off unpleasant early side effects, I would discuss the data and help her make a choice.”

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