Paul Goss, MD, PhD
Women who extended their adjuvant therapy with an aromatase inhibitor (AI) to 10 years after treatment for their early-stage HR-positive breast cancer reduced their risk of recurrence by more than a third and experienced no new toxicities or worsening of quality of life, according to findings of the MA.17R trial.1
Patients receiving extended AI therapy of letrozole (Femara) versus placebo also experienced a significant reduction in the occurrence of contralateral breast cancer (CBC), but no statistically significant increase in 5-year overall survival (OS)—93% and 94%, respectively.
This phase III, randomized, double-blind, placebo-controlled trial marks the first to show a benefit with extending AI therapy beyond 5 years and is expected to provide direction for both patients and physicians worldwide.
The trial’s findings, reported at a press conference at the 2016 ASCO Annual Meeting by lead author Paul Goss, MD, PhD, were published simultaneously today in the New England Journal of Medicine.2
This North American Cancer Group Trial, coordinated by the Canadian Cancer Clinical Trials Group, accrued participants over a 5-year period beginning in October 2004, with the target enrollment of 1918 patients reached in May 2009. The total cohort included postmenopausal women with HR-positive breast cancer who had received 4.5-6 years of any adjuvant AI therapy—either as initial treatment or after any duration of prior tamoxifen. Eighty percent of the study participants had received prior tamoxifen. Patients were allowed to enroll up to 2 years after completing their prior AI therapy, but the majority (90%) began the trial within 6 months.
Women were evenly randomized to receive either 2.5 mg of oral AI letrozole 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 contralateral breast cancer (CBC). Goss noted that the precursor MA.17 trial reported a very significant 48% reduction in disease recurrence,3
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 CBCs, safety, and quality of life.
Goss, who is director of Breast Cancer Research at Massachusetts General Hospital, reported that women in the letrozole arm had a 34% reduction in recurrence (HR, 0.66; P
= .01), and a 58% reduction in CBC (HR, 0.42; P =
.007) compared with placebo controls. Investigators reported 165 disease-recurrence or CBC events, 67 with letrozole and 98 with placebo. The most common site of recurrence was distant: 42 in patients treated with letrozole versus 53 in the placebo arm, followed by bone (28 vs 37, respectively), and locoregional (19 vs 30, respectively). Thirteen CBC events occurred in the letrozole arm and 31 in the placebo arm.Patient-Reported Outcomes With Extended Letrozole
Given the known side effect profile of AI therapy, including arthralgia, hot flashes, and sexual symptoms like vaginal dryness, the results of a companion study looking at patient-reported outcomes in MA.17R were reported at the press conference by lead author Julie Lemieux, MD, a researcher with the Centre Hospitalier Universitaire de Quebec in Canada.4
For this part of the study, women were asked to complete questionnaires at baseline and annually thereafter up to 5 years, using the SF-36 sexual health survey and MENQUOL, which measures menopause-specific quality of life. More than 85% of women completed the questionnaires.
The SF-36 assessment includes two physical and mental quality-of-life summary scores and 8 subdomains. No differences between women taking letrozole versus controls were seen in the women’s scores over the 5 years, on either the physical (P
= .18) or mental (P
= .12) components of the survey.
Lemieux said a difference between the two groups was reported on only 1 of the subdomains, which assessed “role-function physical” (a measure of difficulty in accomplishing work or regular activities due to physical health). On this subscale, there was a 3.2 difference between the letrozole and placebo arms. Although statistically significant (P
= .009), it is below the 5-point difference deemed clinically important by the investigators, Lemieux noted.
Additionally, no difference was seen on any of the four domains of the MENQOL questionnaire (vasomotor, psychosocial, physical, and sexual).