Clinical Summary

• The final 15-year analysis of the phase 3 NRG Oncology/NSABP B-42 trial demonstrated a sustained disease-free survival benefit with 5 additional years of adjuvant letrozole in postmenopausal women with hormone receptor-positive early-stage breast cancer, with an absolute benefit of 5.1%.
• Extended letrozole therapy significantly improved breast cancer-free interval and reduced distant recurrence (HR, 0.72), with patients who had node-positive disease deriving greater absolute benefit than those with node-negative disease.
• Although extended letrozole did not significantly improve overall survival, investigators observed a trend toward fewer breast cancer-related deaths without a significant increase in osteoporotic fractures or arterial thrombotic events.

Eleftherios P. Mamounas, MD, MPH, FACS, medical director of the Breast Program at AdventHealth Cancer Institute in Orlando, Florida, discusses the final 15-year analysis of the phase 3 NRG Oncology/NSABP B-42 trial, presented at the 2026 ESMO Congress. The randomized, double-blind, placebo-controlled study evaluated whether 5 additional years of adjuvant letrozole improved long-term outcomes in postmenopausal women with stage I-III hormone receptor-positive breast cancer who remained disease-free after 5 years of prior endocrine therapy that included an aromatase inhibitor. The final analysis demonstrated a sustained disease-free survival benefit with extended letrozole, with an absolute improvement of 5.1% at 15 years compared with 2.8% at the previously reported 10-year analysis. Significant benefits were also observed for breast cancer-free interval, with an absolute improvement of 3.6%, and distant recurrence, with an absolute improvement of 2.8% (HR, 0.72).

Mamounas highlights that patients with node-positive disease experienced a greater absolute reduction in distant recurrence than those with node-negative disease (4.4% vs 1.6%). Although the overall survival difference remained statistically nonsignificant, the HR improved from 0.97 at 10 years to 0.92 at 15 years, with a trend toward fewer breast cancer-related deaths. Importantly, extended letrozole was not associated with a statistically significant increase in osteoporotic fractures or arterial thrombotic events. These long-term findings reinforce the potential value of extended aromatase inhibitor therapy in reducing late breast cancer recurrence, particularly among patients with node-positive disease, and provide additional evidence to support individualized decisions about endocrine therapy duration based on recurrence risk and treatment tolerability.

Transcript

Eleftherios P. Mamounas, MD, MPH, FACS: Hi, I'm Terry Mamounas. I'm medical director of the Breast Program at AdventHealth Cancer Institute in Orlando, Florida.

I'm here at the ESMO 2026 meeting, where I presented new results from the NSABP B-42 trial. This was the 15-year results, a final analysis of the trial.

As we know, the NSABP B-42 trial took patients with estrogen receptor-positive, progesterone receptor–positive, and HER2-positive or HER2-negative breast cancer—at the time, it was before we were testing for HER2—stage I to III, who were disease-free after 5 years of adjuvant endocrine therapy. Endocrine therapy could have been an aromatase inhibitor for 5 years or up to 3 years of tamoxifen, with the remaining duration of 5 years with an aromatase inhibitor, and then randomized patients to 5 years of extended letrozole therapy or 5 years of placebo.

The primary endpoint of the study was to see whether extended letrozole therapy improves disease-free survival. There were many secondary endpoints, such as breast cancer-free interval, which is recurrence and contralateral breast cancer, distant recurrence, overall survival, and also to look at potential side effects. In particular, we looked at osteoporotic fractures and arterial thrombotic events.

We had presented previously a couple of analyses of the study with 5-year follow-up and 10-year follow-up. At the ESMO meeting, we presented again the final analysis of the study with 15-year follow-up.

What the results show for the primary endpoint of disease-free survival is that the benefit of extended letrozole therapy seen before continues on the same path. It was about a 15% reduction in the odds of a disease-free survival event, but the absolute differences have increased now to about 5%, 5.1%, where it was about 2.8% at 10 years. Similarly, we saw a significant benefit for breast cancer-free interval, with about a 25% reduction in the odds of an event, with absolute benefit now at 15 years of 3.6%. We also saw significant benefit in distant recurrence, with a hazard ratio of 0.72, so a 28% reduction, and the absolute benefit was 2.8% at 15 years.

When we actually looked at node-negative patients versus node-positive patients, node-positive patients had much more absolute benefit. It was 4.4% versus 1.6% for node-negative patients, which wasn't even significant, although there was a trend toward benefit as well.

Finally, overall survival still is not statistically significant in the study, but the hazard ratio has started to drop a bit. At 10 years, the hazard ratio was like 0.97, with no significant difference. At 15 years, it dropped to 0.92, which is a little bit more, about a 1.5% difference.

Then, when we looked at the cause of death, letrozole appeared to have a trend in reducing breast cancer deaths, with a hazard ratio close to 0.8, with an absolute benefit of 1.7%, where there was no difference in deaths from other causes or unknown deaths. Essentially, there was a trend toward improving breast cancer deaths, but no adverse or no evidence of adverse outcomes for non-breast cancer deaths.

In summary, this study continues to show that 5 years of extended letrozole therapy significantly improved the main endpoints of the study: disease-free survival, breast cancer-free interval, and distant recurrence. Although there is no significant survival benefit, there is still a small benefit in breast cancer death reduction.

And by the way, the osteoporotic fractures or arterial thrombotic events, which are some of the concerns with aromatase inhibitor therapy, we don't see any significant difference. We didn't see it in the previous study at 10 years, and we don't see it now at 15 years again. It appears that there's no significant detriment of the aromatase inhibitor for these events.

Source

Mamounas EP, Bandos H, Geyer CE, et al. Final analysis of NRG Oncology/NSABP B-42, a randomized, double-blinded, placebo-controlled trial of extended letrozole in postmenopausal women with hormone-receptor positive breast cancer who have completed previous adjuvant therapy with an aromatase inhibitor. Presented at: ESMO Congress 2026; October 23-27, 2026; Madrid, Spain. Abstract LBA24.