Mixed Results on Benefit of Extending Letrozole Beyond 5 Years of Prior Endocrine Therapy

Terry Mamounas, MD

Extending letrozole therapy in women with early-stage, HR-positive breast cancer who completed 5 years of prior hormone therapy did not yield a statistically significant improvement in either disease-free or overall survival, but prolonged use of the aromatase inhibitor (AI) may be beneficial in some subgroups of women with a higher risk of recurrence, according to findings of the NSABP B-42 trial.

“To put our results in clinical perspective, our findings suggest that careful assessment of the potential risks and benefits is required before recommending extended letrozole therapy in patients with early-stage breast cancer,” said Terry Mamounas, MD, presenting the trial’s findings in a press briefing at the 2016 San Antonio Breast Cancer Symposium.

Research has shown that extending hormonal therapy beyond an initial 5-year course with either tamoxifen or an AI improves disease-free survival (DFS) in this patient population, but the optimal duration of additional AI therapy is unknown, explained Mamounas, medical director of the Comprehensive Breast Program at UF Health Cancer Center at Orlando Health and chair of the NRG Oncology Breast Committee.

Thus, the primary aim of this randomized, double-blind, placebo-controlled trial was to determine whether 5 years of letrozole would improve DFS, which investigators defined as a recurrence of the original breast cancer, cancer in the opposite breast, a non-breast malignancy, or death from any cause prior to the occurrence of one of the other DFS events.

Secondary endpoints included overall survival (OS), breast cancer—free interval (BCFI), defined as “recurrence or opposite breast cancer as a first event,” and incidence of osteoporotic fractures and arterial thrombotic events, eg, ischemia, infarction.

The trial enrolled nearly 4000 postmenopausal women from September 2006 to January 2010 and followed them for a median of 6.9 years. The participants, who were disease-free after 5 years of endocrine therapy for their stage I-IIIa HR-positive breast cancer, were assigned in a 1:1 ratio to either 2.5 mg letrozole or placebo daily for another 5 years. There were no significant differences in patient, tumor, and prior treatment characteristics between the 2 groups; approximately one-third of the participants were aged <60 years.

Sixty percent of patients completed the additional 5 years of letrozole, Mamounas reported. Primary reasons for discontinuation were patient withdrawal/refusal (13.8%), adverse event (9.6%), or disease progression (4.1%). Researchers set 631 DFS events as the requirement for definitive analysis, and this target was reached in August 2016.

Mamounas reported 292 DFS events in the letrozole arm and 339 in the placebo arm after the 7-year follow-up. The extended letrozole regimen resulted in a 15% reduction in the risk of a DFS event (hazard ratio [HR], 0.85; P = .048), but this finding did not reach the .0418 level of statistical significance preset by the investigators.

The main DFS event reductions occurring with letrozole involved distant recurrence: 87 of these events were reported in the placebo arm versus 61 with letrozole. Similarly, incidence of cancer in the opposite breast was higher with placebo—59 such events versus 30 in the letrozole group. No statistically significant differences in any of the other investigator-defined DFS events were observed.

Letrozole also did not improve OS; there were 164 deaths reported in the letrozole cohort versus 146 with placebo. However, there was a 29% statistically significant improvement in BCFI events (179 with placebo vs 127 with letrozole [HR, 0.71; P = .003]), as well as a 28% reduction in the cumulative risk of disease recurrence: 5.8% with placebo compared with 3.9% in the letrozole arm (HR, 0.72; P = .03).

The cumulative incidence of osteoporotic fractures did not differ significantly between the 2 arms (91 events in the letrozole group vs 78 with placebo); this was also true for arterial thrombotic events (71 vs 59, respectively).

Overall, he said, the NASBP B-42 results suggest that physicians take a number of factors into account when deciding whether to recommend that a patient extend adjuvant hormone therapy with letrozole. These factors include the patient’s age and nodal status, existing comorbidities, bone mineral density, and overall AI tolerance during her initial 5 years of therapy.

“Younger women, healthier patients with nonsignificant comorbidities, and also patients with high risk of recurrence, such as patients with positive nodes, large tumor size, high-grade tumors,” for example, are more likely to benefit from this approach, Mamounas said.

He hopes that genomic classifiers predictive of late recurrence and/or benefit from extended endocrine therapy may help to further guide clinicians in individualizing recommendations for extended AI therapy. Such studies are currently being planned in the B-42 cohort.

Mamounas EP, Bandos H, Lembersky BC, et al. A randomized, double-blinded, placebo-controlled clinical trial to evaluate extended adjuvant endocrine therapy (5 years of letrozole) in postmenopausal women with hormone-receptor positive breast cancer who have completed previous adjuvant endocrine therapy: Initial results of NRG oncology/NSABP B-42. Presented at: 2016 San Antonio Breast Cancer Symposium; San Antonio, TX; December 6-10, 2016. Abstract S1-05.

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“An interesting observation here is that during the first 2-and-a-half years, letrozole actually had a beneficial effect on arterial thrombotic events, and then there was an increase in these events after 2.5 years,” Mamounas remarked.