This article is more than 5 years old. Information may no longer be current.
Extended letrozole provides no significant benefit in subset of postmenopausal women with breast cancer
Click Here to Manage Email Alerts
SAN ANTONIO — Extended adjuvant endocrine therapy with letrozole conferred no significant survival benefit to postmenopausal women with hormone receptor–positive breast cancer who completed 5 years of hormonal therapy, according to results of the NRG Oncology/NSABP B-42 trial presented at San Antonio Breast Cancer Symposium.
Researchers also reported increased risk for arterial thrombotic events with letrozole after 2.5 years.
“We have to exercise caution as we discuss with our patients’ use of extended letrozole therapy,” Terry Mamounas, MD, MPH, medical director of the Comprehensive Breast Program at UF Health Cancer Center at Orlando Health, told HemOnc Today. “We need to look at the pros and cons. What is the risk for recurrence of the patient? What are the significant comorbidities? What is the age of the patient? How did they tolerate the primary aromatase inhibitor for the first 5 years, and what is the bone mineral density? All of these factors figure into the potential decision of [whether to extend] therapy beyond 5 years or to stop at 5 years.”
Extended adjuvant endocrine therapy after 5 years of tamoxifen with either an aromatase inhibitor or tamoxifen extends DFS in early-stage breast cancer. However, the optimal duration of adjuvant aromatase inhibitor therapy beyond 5 years has not been established.
In the randomized, double blind, placebo-controlled NSABP B-42 trial, Mamounas and colleagues sought to assess whether 5 years of letrozole extended DFS compared with placebo among patients who completed 5 years of hormonal therapy with either an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor.
The analysis included 3,923 women with ER– or PR–positive breast cancer, all of whom had stage I to stage IIIA disease at diagnosis and were disease free after 5 years of endocrine therapy.
Researchers randomly assigned patients to daily 2.5 mg letrozole (n = 1,959) or placebo (n = 1,964) for 5 years.
DFS served as the primary outcome. This encompassed local, regional, distant recurrence, cancer in the opposite breast, a second non-breast primary cancer, or death from any cause as first event.
Secondary outcomes included OS, breast cancer-free interval, distant recurrence, osteoporotic fractures and arterial thrombotic events.
Treatment groups were balanced with regard to tumor distribution, prior treatments, percentage of patients younger than 60 years, node positivity, prior tamoxifen treatment and receipt of breast-conserving surgery.
Median treatment duration was 59.8 months for both groups. A similar percentage of women in each group completed 5 years of therapy (62.5% for placebo, 60.3% for letrozole). The primary reasons for letrozole discontinuation were patient withdrawal/refusal (13.8%), adverse events (9.6%) and disease progression (4.1%).
Median follow-up for patients included in the efficacy analysis was 6.9 years.
At 7 years, Mamounas and colleagues reported no significant difference in DFS between patients assigned letrozole or placebo (87.4% vs. 81.3%; HR = 0.85; 95% CI, 0.73-0.99).
Although the P value was .048, the level of statistical significance was set at 0.418 because of adjustment for the preplanned interim analysis, Mamounas said.
When researchers analyzed DFS first events by treatment, they determined letrozole was associated with reduced incidence of distant recurrence (3.1% vs. 4.4%) and opposite breast cancer (1.5% vs. 3%) compared with placebo.
Results also revealed a 29% reduction in cumulative incidence of breast cancer–free interval events at 7 years among patients assigned letrozole (6.7% vs. 10%; HR = 0.71; 95% CI, 0.56-0.89).
Letrozole reduced cumulative incidence of distant recurrence by 28% (3.9% vs. 5.8%; HR = 0.72; 95% CI, 0.53-0.97).
Researchers reported no significant difference in OS at 7 years between the placebo group and letrozole group (92.3% vs. 91.8%; HR = 1.15; 95% CI, 0.99-1.44).
Cumulative incidence of osteoporotic fractures at 7 years was 5.4% with letrozole and 4.8% with placebo (HR = 1.19; 95% CI, 0.88-1.6). Cumulative incidence of arterial thrombotic events also was higher with letrozole at 7 years (4% vs. 3.4%; HR = 1.21; 95% CI, 0.85-1.7).
“We hope that genomic classifiers that predict risk of late recurrence and benefit from extended endocrine therapy may help to further individualize the recommendation for extended aromatase inhibitor therapy,” Mamounas said. “Additional studies are currently being planned in the NSABP B-42 cohort.” – by Jennifer Southall
Reference:
Mamounas P, et al. Abstract S1-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2016; San Antonio, Texas.
Disclosure: The NCI and Novartis funded this study. Mamounas reports consultant roles with Biotheranostics, Celcuity, Genentech, Genomic Health, GRAIL, Macrogenics and Pfizer, as well as speakers bureau roles with Genentech and Genomic Health.
Perspective
Back to Top
Sharon Wilks, MD, FACP
This trial was of particular interest for us because there have been numerous reports about tamoxifen and its value by being extended at least up to 10 years in individuals with hormone receptor–positive disease. Contemporary approaches now allow for patients who are postmenopausal to be on an aromatase inhibitor right from the get-go. So the question became, is there value and potentially were there some groups who might benefit if the individuals received treatment after 5 years with letrozole.
This trial did show some benefit for individuals in all groups that, if they extended aromatase inhibitor therapy, there was improvement in DFS. Unfortunately, we did not see any improvements in OS in this cohort. That does create some question about the value of the treatment vs. some of the side effects.
One of the biggest things we take home from this in that, in addition to the fact that there might be value, is that there is an extension of side effects, including bone defects, fracture risk, arthralgia, hot flashes and menopausal-like symptoms. Having women have that type of experience long term, countered by not showing a true benefit in OS, raises the question of whether we should adopt this practice in clinic.
That said, there may be some subgroups who might indeed benefit. If there is a patient who has good tolerance to an aromatase inhibitor who may have node-positive disease or a very large tumor burden at the outset of diagnosis, that may be the kind of individual who may be considered for this type of treatment.
Like with many other studies, there are a lot of questions about whether — from a molecular standpoint or through genomic-profiling tests — we might identify a cohort of patients more consistently and reliably that might benefit from extension of therapy.
Click Here to Manage Email Alerts