5 Additional Years of Letrozole Increased 15-Year Disease-Free Survival from 57% to 62% and Reduced Distant Recurrence by 28%
In this article
Extending Hormone Therapy by 5 More Years: Final 15-Year Results of NSABP B-42
After surgery for hormone receptor-positive breast cancer, hormone therapy usually lasts 5 years; yet these cancers can come back even 10 or 15 years later. So does continuing letrozole for 5 more years truly help postmenopausal women who have completed 5 years of aromatase inhibitor-based therapy? The answer with the longest follow-up comes from the US NRG Oncology/NSABP B-42 trial: the final analysis, after a median follow-up of 15.9 years, was presented at the ESMO Congress in October 2026 (LBA24). Extended letrozole significantly improved disease-free survival and distant recurrence, but did not change overall survival. We have previously covered the status of letrozole in Turkey, new options in hormone-positive breast cancer and the highlight trials of ESMO 2026.
- What was found? In 3,966 women who had completed 5 years of aromatase inhibitor-based therapy, 5 more years of letrozole raised the proportion of women alive and disease-free at 15 years from 56.5% to 61.6% (HR 0.85; P = 0.002). The absolute difference was 5.1 percentage points, meaning an additional benefit in about 1 in every 20 women.
- Breast cancer recurrence: Breast cancer events fell by 22% and distant recurrence by 28% (from 9.7% to 6.9%). The benefit was most evident in patients with node-positive disease.
- Length of life: The difference in overall survival was not significant (74.0% and 72.3%; P = 0.21). There was a trend toward less breast-cancer-related loss of life (5.0% and 6.5%; P = 0.08).
- Safety: Osteoporotic fractures (9.2% and 8.7%) and arterial thrombotic events (5.6% and 5.5%) were similar in the two arms. The decision to extend should weigh individual recurrence risk, side effects and bone health together.
Why does this matter?
About two-thirds of breast cancers are hormone receptor-positive. An important feature of these cancers is that the risk of recurrence persists over the years, even if it declines: in some patients the disease can return after the 5 years of treatment have ended, 10 or even 20 years later (breast cancer stages, resistance to hormone therapy). For this reason, continuing hormone therapy beyond 5 years has been one of the most debated topics of the past 20 years.
On the other hand, aromatase inhibitors can cause side effects such as joint pain, bone loss, hot flashes and sexual problems; extending treatment means living with these side effects for 5 more years (hormone therapy and sexual problems). Because earlier trials had short follow-up, it was unclear whether the benefit of extended treatment grows or fades over time. The 15-year results of B-42 provide an important answer to this question.
Does continuing letrozole after 5 years of hormone therapy help?
According to the 15-year results of NSABP B-42, continuing letrozole for 5 more years in postmenopausal women who have completed 5 years of aromatase inhibitor-based therapy increases disease-free survival by 5.1 percentage points and reduces distant recurrence by 28%. However, it does not significantly prolong overall survival; the benefit is most evident in women with lymph node involvement and a higher risk of recurrence.
How was the trial done?
Figure 1 · Design of the NSABP B-42 trial
Phase 3, randomized, double-blind, placebo-controlled
Of the patients, 34% were younger than 60, 57% had no lymph node involvement and 39% had previously received tamoxifen. One in four had markedly low bone density on bone density testing (T-score -2.0 or lower). Lymph node status, prior tamoxifen use and bone density were balanced at randomization. Since the 10-year analysis, 538 additional events have been recorded.
Results: the benefit grew over time
Disease-free survival over time
Percent. Colored bar: 5 more years of letrozole; grey bar: placebo.
The absolute difference was 3.4 percentage points at year 7, 2.8 at year 10 and 5.1 at year 15. Year 7 values are from the first analysis (2019); year 10 and year 15 values are from the final analysis presented at ESMO 2026. Disease-free survival includes recurrence, second cancers and loss of life from any cause.
In the trial's first analysis (2019), the 7-year difference in disease-free survival (84.7% and 81.3%) had not reached the prespecified statistical threshold. With longer follow-up the curves continued to separate: at 10 years the difference became significant, and at 15 years the absolute difference rose to 5.1 percentage points. This pattern suggests that the effect of hormone therapy persists even after the drug is stopped (a "carry-over effect").
Figure 2 · The absolute difference per 100 women: disease-free at 15 years
Illustrative; values are rounded
Cumulative event rates at 15 years
Percent; lower is better. Colored bar: letrozole; grey bar: placebo.
Breast cancer events: HR 0.78, P = 0.003; distant recurrence: HR 0.72, P = 0.005; breast-cancer-related loss of life: HR 0.78, P = 0.08 (not significant).
Looking at first events, distant recurrence (5.1% and 7.0%), second breast cancer (5.0% and 6.0%) and second cancers outside the breast (9.4% and 11.0%) were slightly less common in the letrozole arm. Local recurrence rates in the breast area were similar (3.2% and 3.6%). Loss of life as a first event was the same in the two arms (12.6% and 12.7%); this shows the weight of causes other than breast cancer during long follow-up in this postmenopausal age group.
Who benefits more?
The benefit in disease-free survival was similar across prespecified subgroups defined by lymph node status, prior tamoxifen use, bone density, age and type of surgery; no significant difference was found between the groups. However, the absolute benefit in distant recurrence was clearly larger in node-positive patients, who have a higher risk of recurrence (underarm lymph nodes and breast cancer).
Distant recurrence by lymph node status
Cumulative rate at 15 years, percent; lower is better. Colored bar: letrozole; grey bar: placebo.
Node-positive: absolute difference 4.4 percentage points, HR 0.69, P = 0.011. Node-negative: absolute difference 1.6 percentage points, HR 0.78, P = 0.22 (not significant). The benefit in disease-free survival, however, did not differ between subgroups.
An analysis of tumor samples from B-42 patients, published in the Journal of Clinical Oncology in 2024, also examined the 70-gene MammaPrint test. This analysis predates the final 15-year data and is exploratory:
| MammaPrint result | Number of patients | Disease-free survival (10 years) | Distant recurrence (10 years) |
|---|---|---|---|
| Low risk | 1,160 | HR 0.67; absolute benefit 7.8 points | HR 0.43; absolute benefit 3.7 points |
| High risk | 706 | HR 1.10; no benefit (-1.6 points) | HR 0.65; absolute benefit 2.4 points (not significant) |
A significant interaction between the test result and the treatment effect was found for disease-free survival (P = 0.015), but not for distant recurrence (P = 0.38). This finding, surprising at first glance, was interpreted as suggesting that a low-risk genomic profile may identify tumors that are more sensitive to hormone therapy. The results have not yet been validated to the level needed to guide clinical decisions (genomic tests and clinical risk, genomic tests and the chemotherapy decision).
Side effects and safety
Safety: cumulative rates at 15 years
Percent. Colored bar: letrozole; grey bar: placebo.
Fracture: HR 1.08, P = 0.47; arterial thrombotic events: HR 1.06, P = 0.68. No significant difference in either.
The most feared side effects of extended aromatase inhibitor therapy are bone loss and fractures. In B-42, the rates of osteoporotic fractures and arterial thrombotic events (such as heart attack and stroke) at 15 years were similar in the two arms. In the trial, patients were distributed evenly between the arms with bone density also taken into account. Because other trials reported somewhat more fractures and bone loss with extended therapy, monitoring bone health remains important (exercise and fracture risk, vitamin D).
Overall survival at 15 years
Percent. Colored bar: letrozole; grey bar: placebo.
HR 0.92, P = 0.21; no significant difference. Loss of life from causes other than breast cancer or from unknown causes was similar in the two arms (21.0% and 21.2%).
The lack of a significant difference in overall survival may be explained by the fact that, in this age group, most loss of life during long follow-up is due to causes other than breast cancer. Still, the reduction in distant recurrence matters: distant recurrence is the event that most affects quality of life and length of life in breast cancer.
Putting it together with other trials
| Trial | Question | Main result |
|---|---|---|
| MA.17R (2016) | 5 more years of letrozole or placebo after 5 years of aromatase inhibitor-based therapy | 5-year disease-free survival 95% and 91%; no difference in overall survival; bone side effects more common |
| ABCSG-16 (2021) | After 5 years, 2 or 5 more years of anastrozole? | No difference in disease-free survival; fractures more common in the longer arm (6% and 4%) |
| NSABP B-42 (2026) | 5 more years of letrozole or placebo after 5 years of aromatase inhibitor-based therapy | Disease-free survival at 15 years 61.6% and 56.5%; distant recurrence reduced by 28%; no difference in overall survival; no increase in fractures |
The trials differ in patient populations, prior treatments and follow-up times; the comparison is indirect.
Taken together, these trials show that the absolute benefit of extended therapy after an aromatase inhibitor is small but real, and is meaningful mainly in women at higher risk of recurrence. Today, CDK4/6 inhibitors (abemaciclib, ribociclib) are also added to hormone therapy in high-risk early-stage patients; the women enrolled in B-42 had not received these drugs (CDK4/6 inhibitors in early-stage disease, monarchE at 7 years, NATALEE at ESMO 2026). The added value of extended therapy in patients who have received a CDK4/6 inhibitor is unknown.
Figure 3 · What to consider in the extended letrozole decision
Topics for discussion, not fixed rules
Limitations
- Congress data: The 15-year results were presented at ESMO 2026; there is no full peer-reviewed publication yet. The 10-year rates differ slightly from those reported in the 2023 publication (75.9% and 72.6%); this difference may stem from the updated database.
- Overall survival: The difference is not significant; the trend in breast-cancer-related loss of life also remains at the borderline of significance.
- Subgroup details: Hazard ratios for subgroups were not given in detail in the presentation; the difference in distant recurrence in node-negative patients is not significant.
- Patient population: Only postmenopausal women who had completed 5 years of therapy without recurrence were enrolled; the results cannot be applied directly to premenopausal women or to patients who have received a CDK4/6 inhibitor. HER2 status was unknown in 8% of patients.
- Adherence: The proportion of patients who stopped the tablet during the 5 years, and its effect on the results, were not reported in detail in news sources (reading research correctly).
Letrozole is licensed in Turkey and widely used, including in equivalent (generic) forms; it is reimbursed for breast cancer. For extended therapy, it is advisable to check the current conditions of the SUT (Turkey's reimbursement regulation) separately (SGK (Turkish Social Security Institution) reimbursement guide). Bone density testing (DEXA) and, if needed, bone-protective treatments are accessible in our country. The decision to extend should be assessed together with the oncologist as the 5th year of treatment approaches.
Tips for patients and their families
- The year-5 conversation: As you approach the 5th year of your hormone therapy, talk openly with your doctor about whether to continue; ask about your own risk of recurrence and the expected benefit.
- Do not stop the drug on your own: If side effects are hard to cope with, tell your doctor; there are solutions for joint pain, hot flashes and sexual problems (menopause symptoms, menopause after cancer).
- Protect your bones: Regular bone density testing, enough calcium and vitamin D, regular exercise and, if needed, bone-protective drugs lower the risk of fractures (exercise in breast cancer).
- Keep up your check-ups: Because late recurrence can occur in hormone-positive breast cancer, your yearly check-ups remain important after year 5 (monitoring with tumor DNA in the blood).
- At the decision stage, do not hesitate to seek a second opinion.
Frequently asked questions
- What is the NSABP B-42 trial?
- NSABP B-42 is a double-blind, randomized phase 3 trial that compared 5 more years of letrozole with placebo in 3,966 postmenopausal women who had completed 5 years of aromatase inhibitor-based hormone therapy for hormone receptor-positive early-stage breast cancer. The final results after 15.9 years of follow-up were presented at the ESMO Congress in October 2026.
- How much does extending letrozole to 10 years help?
- At 15 years, the proportion of women alive and disease-free was 61.6% with letrozole and 56.5% with placebo; the absolute difference was 5.1 percentage points. Distant recurrence fell from 9.7% to 6.9%, and breast cancer events from 18.3% to 14.7%. No significant difference was seen in overall survival.
- Does extended letrozole increase bone fractures?
- In B-42, osteoporotic fractures at 15 years occurred in 9.2% of the letrozole arm and 8.7% of the placebo arm; the difference is not significant. Arterial thrombotic events were also similar. Still, because aromatase inhibitors can lower bone density, regular bone testing and, if needed, protective treatment are recommended.
- Should everyone extend hormone therapy to 10 years?
- No. The benefit is most evident in women with lymph node involvement and a high risk of recurrence. In women with a low risk of recurrence, bone loss or difficult side effects, the gain from extension may be limited. The decision should be made jointly by the doctor and the patient.
Glossary
- Aromatase inhibitor
- A group of drugs that reduce estrogen production in postmenopausal women; letrozole, anastrozole and exemestane.
- Extended endocrine therapy
- Continuing the standard 5-year hormone therapy beyond 5 years.
- Disease-free survival
- The time that passes without recurrence, a new cancer or loss of life.
- Distant recurrence
- The return of cancer in distant organs such as bone, liver or lung.
- Placebo
- A tablet that looks the same as the drug but contains no active substance.
- Carry-over effect
- Benefit that continues even after treatment is stopped.
- MammaPrint
- A genomic test that estimates the risk of recurrence by looking at the activity of 70 genes in the tumor.
DROZDOGAN Academy Commentary
The 15-year results of B-42 show the value of "data that takes patience" in hormone-positive breast cancer: a benefit that looked uncertain at 7 years became clearer at 15 years.
⚡ Why it matters
These are the longest-followed placebo-controlled data on extended aromatase inhibitor therapy. They show that the benefit does not fade over time but rather grows, and that it does so without an increase in fractures or vascular blockages.
✅ Strengths
Large, double-blind, placebo-controlled design; about 16 years of follow-up; detailed reporting of distant recurrence and safety endpoints.
⚠️ Limitations
No difference in overall survival; the absolute benefit is small. The results have not yet been published in a peer-reviewed journal. The trial does not represent today's high-risk patients, for whom CDK4/6 inhibitors have become routine.
🩺 In practice
In the 5th year of hormone therapy, we discuss extension with every patient. We recommend extension for women who are node-positive or at high risk of recurrence, who tolerate the drug well and whose bone health allows it; in low-risk patients, we discuss the small expected benefit alongside the side effects.
❓ Open questions
Is the ideal length of extension 2 years or 5 years? Does extension add anything in patients who have received a CDK4/6 inhibitor? Could genomic tests or tumor DNA in the blood better select the women who will benefit from extension?
Bottom line: Continuing letrozole for 5 more years after 5 years of aromatase inhibitor therapy is a safe option that reduces distant recurrence; but it is not for everyone, and it is a decision that should be made by weighing recurrence risk and quality of life together.
- This article was prepared in October 2026.
- The 15-year results are taken from news sources on the abstract presented at the ESMO 2026 Congress (LBA24); the full text of the presentation or of a peer-reviewed publication was not accessed. The 7- and 10-year results are based on publications in Lancet Oncology (2019) and the Journal of the National Cancer Institute (2023), respectively.
- The 10-year disease-free survival rates were reported as 75.9% and 72.6% in the 2023 publication and as 74.9% and 72.1% in the ESMO 2026 presentation; the chart uses the values from the final analysis.
- The MA.17R and ABCSG-16 results are summarized from their original publications; comparisons across trials are indirect.
- The reimbursement status in Turkey is general information; the current situation should be confirmed. This article is for general information and is not personal medical advice. The diagrams are derived from the text. The Academy commentary is our own.
References
- Mamounas EP, Bandos H, Geyer CE Jr, et al. NRG Oncology/NSABP B-42 final analysis (15 years). ESMO 2026 Congress, LBA24. News: Extended letrozole sustains DFS benefit at 15 years in HR+ breast cancer. CancerNetwork, October 23, 2026. cancernetwork.com
- Mamounas EP, Bandos H, Lembersky BC, et al. Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:88-99. doi:10.1016/S1470-2045(18)30621-1
- Mamounas EP, et al. Ten-year update: NRG Oncology/NSABP B-42 randomized trial: extended letrozole therapy in early-stage breast cancer. J Natl Cancer Inst 2023;115:1302-1309. PubMed
- Rastogi P, et al. 70-gene MammaPrint analysis in NRG Oncology/NSABP B-42. J Clin Oncol 2024. News: CancerNetwork, August 9, 2024. cancernetwork.com
- Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years (MA.17R). N Engl J Med 2016;375:209-219. doi:10.1056/NEJMoa1604700
- Gnant M, Fitzal F, Rinnerthaler G, et al. Duration of adjuvant aromatase-inhibitor therapy in postmenopausal breast cancer (ABCSG-16). N Engl J Med 2021;385:395-405. doi:10.1056/NEJMoa2104162
- NRG Oncology/NSABP B-42. ClinicalTrials.gov NCT00382070. clinicaltrials.gov
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