From the Journals

Better survival with extended letrozole in early-stage breast cancer



Long-term survival outcomes are better when postmenopausal women are on an aromatase inhibitor for 5 years, instead of the usual 2-3 years, following tamoxifen for hormone receptor–positive breast cancer, according to a randomized, open-label trial from Italy with over 2,000 women.

The approach “should be considered among the optimal standard endocrine treatments for postmenopausal patients with hormone receptor–positive breast cancer, regardless of the nodal status at diagnosis,” concluded investigators led by Lucia Del Mastro, MD, a medical oncologist at the University of Genoa, Italy.

Clinical practice guidelines recommend an individualized approach to decide the duration of treatment based on relapse risk and tolerability because no study until now has shown an overall survival benefit with extended aromatase inhibitor therapy. Based on “our results ... this statement is no longer supported by the evidence and should be updated,” they wrote.

The optimal duration or type of endocrine therapy has been uncertain; the team sought to bring more clarity to the issue.

Following 2-3 years of adjuvant tamoxifen, they randomized evenly 2,056 women at 69 hospitals in Italy to either 2-3 years or letrozole 2.5 mg once daily – the usual care control group – or 5 years. Women in the trial, dubbed GIM4, had stage I-III histologically proven and operable invasive cancer, with no signs of disease recurrence.

Twelve-year overall survival was 88% with extended letrozole, but 84% in the control arm (HR 0.77, 95% confidence interval, 0.60-0.98; P = 0.036).

Twelve-year disease-free survival was 67% in the extended group versus 62% in the control arm (HR 0.78, 95% CI, 0.65-0.93; P = 0.0064).

At a median follow-up of 11.7 years, disease-free survival (DFS) events occurred in 25.4% of control patients, but only 20.7% with extended aromatase inhibitor treatment.

It took 9.5 years for the survival curves to separate, suggesting “that the effect of letrozole takes several years to be seen,” the investigators said.

With the disease-free survival benefits shown in earlier trials and now better overall survival as well, it’s looking like “7-8 years of adjuvant therapy, including at least 5 years with an aromatase inhibitor, could be the optimal duration of adjuvant endocrine therapy in postmenopausal patients with breast cancer.” It probably represents “the best compromise between efficacy and side-effects,” they said.

Breast cancer oncologists Rachel L. Yung, MD, and Nancy E. Davidson, MD, both of the Fred Hutchinson Cancer Research Center, Seattle, agreed in an editorial.

For now, “the currently available data seem to recommend 5 years of aromatase inhibitor for postmenopausal women who have already completed 2-3 years of tamoxifen,” they said.

However, with 19.5% of control patients and 37.1% in the extended stopping treatment early, “GIM4 highlights that early therapy discontinuation remains a crucial issue ... better ways to promote adherence are sorely needed. Another area of focus is the identification of biomarkers that could [better] inform the optimal duration of therapy,” they said.

Longer duration of letrozole was associated with an increased incidence of arthralgia, myalgia, hypertension, and osteoporosis; however, there was no difference in the incidence of bone fractures.

There was also a slightly higher number of cardiovascular events (1% in the extended group, but fewer in the control arm) which is a known issue with aromatase inhibitors. There were three serious treatment-related adverse events in the control arm and eight in the extended group, but no deaths. The Italian investigators noted that because they enrolled only patients free of recurrence after 2-3 years of tamoxifen, the population with early relapse who were likely to be node-positive, was excluded, leaving only patients with a better prognosis. “On the other hand, patients with node-negative disease relapse later and are therefore captured by this trial with a long follow-up.”

The work was funded by Novartis and the Italian Ministry of Health. The investigators had numerous industry ties, including Dr. Del Mastro, who reported honoraria and nonfinancial support from Novartis, Roche, Pfizer, and others. The editorialists didn’t have any competing interests.

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