Women are reducing their risk of recurrence by extending their adjuvant therapy with an aromatase inhibitor (AI) to 10 years after treatment for their early-stage HR-positive breast cancer.
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, presented during 2016 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of over 30,000 oncology professionals in Chicago.
Patients receiving extended AI therapy of Femara (letrozole) versus placebo also 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.
This phase 3, randomized, double-blind, placebo-controlled 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 trial’s findings, reported by lead author Paul Goss at ASCO were published in the New England Journal of Medicine. This North American Cancer Group Trial, coordinated by the Canadian Cancer Clinical Trials Group, accrued participants over a five-year period beginning in October 2004, with the target enrollment of 1,918 patients reached in May 2009.
The total cohort included postmenopausal women with HR-positive breast cancer who had received 4.5 to six 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 two years after completing their prior AI therapy, but the majority began the trial within six months.
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 contralateral breast cancer (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 CBCs, 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 CBC 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 vs 37, respectively) and locoregional (19 vs 30, respectively). Thirteen CBC events occurred in the Femara arm and 31 in the placebo arm.
Patient-Reported Outcomes With Extended Femara
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, a researcher with the Centre Hospitalier Universitaire de Quebec in Canada. For this part of the study, women were asked to complete questionnaires at baseline and annually thereafter up to five years, using the SF-36 sexual health survey and MENQUOL, which measures menopause-specific quality of life. More than 85 percent of women completed the questionnaires.
The SF-36 assessment includes two physical and mental quality-of-life summary scores and eight subdomains. No differences between women taking Femara versus controls were seen in the women’s scores over the five years, on either the physical or mental components of the survey.
Lemieux said a difference between the two groups was reported on only one 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 Femara and placebo arms. Although statistically significant, it is below the five-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).
“For women who already tolerated five years of an aromatase inhibitor, extending Femara did not worsen their global or menopause-related quality of life compared to placebo,” said Lemieux, adding that the difference found on the role-function physical subscale was very small and unlikely to be significant for women. “It is very reassuring for those women who want longer duration of adjuvant endocrine therapy that they can expect a preserved QOL.”
Press panel moderator and ASCO President Julie Vose stressed the importance of capturing patient-reporting outcomes. “It’s very important that we consider what the patient is going through and that they can tolerate these sorts of treatments. Even if there is a small benefit, we want to make sure that there is not excess toxicity.”
One important limitation of the MR.17R study noted by both Goss and Lemieux 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,” Goss explained, “who are not having the severe symptoms,” which typically would prompt them to opt out of the therapy.
Overall Survival and Practice Implications
Goss said that he expected the DFS differences to widen over time between the Femara and placebo groups, and that the OS difference will 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,” he 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 Burstein.
“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.”