Benefit of Extended Adjuvant Endocrine Therapy Not Upheld in Multiple Studies Reported in San Antonio

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Extended endocrine therapy with an aromatase inhibitor did not improve disease-free survival in patients with hormone receptor–positive breast cancer enrolled in three studies presented at the 2016 San Antonio Breast Cancer Symposium.

The results stand in contrast to the phase III National Cancer Institute of Canada (NCIC) MA.17R study, which showed benefit for the extended use of adjuvant letrozole beyond 5 years.1 While some experts maintained that extended endocrine therapy remains important in subsets of patients, the results came as a surprise to many attendees, who said they may re-think their recommendations.

John Cole, MD

John Cole, MD

John Cole, MD, a breast cancer specialist at Ochsner Medical Center in New Orleans, told The ASCO Post, “After MA.17R gave a positive signal for prolongation of aromatase inhibitor therapy, I think the expectation was that when these other studies came out, they would be supportive. In fact, none supported longer aromatase inhibitor therapy, and I think this was kind of shocking.”

He said that for many of his patients, extended treatment is “10 years of low-grade misery…. The important thing is that if your patient is really struggling, you don’t have enough data now to make them endure another 5 years of treatment.”

He continued, “For my patients with stage I disease who I’ve been keeping on treatment, I’ll stop. For my patients with heavier nodal burden who are tolerating the drugs, I will probably continue treatment.”

The studies’ invited discussant at the San Antonio meeting, ­Michael Gnant, MD, Professor of Surgery at the Medical University of Vienna in Austria and President of the Austrian Breast & Colorectal Cancer Study Group, concluded that none of these trials achieved adequate statistical levels to show that the extension of aromatase inhibitor therapy was clearly beneficial. However, he suggested that treatment decisions in this setting need to be made on a patient-by-patient basis (see Expert Point of View, below). 

Question to Be Answered

Despite the success of adjuvant endocrine therapy in early breast cancer, approximately half of the recurrences occur after the first 5 years of treatment. Extending adjuvant endocrine therapy after 5 years of tamoxifen with either tamoxifen or an aromatase inhibitor improves disease-free survival in early-stage breast cancer, but the optimal duration of adjuvant aromatase inhibitor use beyond these 5 years has not been established. In MA.17R, women who took letrozole for a total of 10 years (beyond 5 years of tamoxifen or an aromatase inhibitor) had a 34% lower risk of breast cancer recurrence and contralateral breast cancers, though survival was similar.

In contrast, the following findings were presented in San Antonio:

  • In the NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP) B-42 trial, 5 years of letrozole therapy after 5 years of endocrine treatment did not significantly improve disease-free survival or overall survival but did significantly improve the breast cancer–free interval event rate and distant recurrence rate.2
  • In the DATA study, 6 vs 3 additional years of anastrozole, after 2 to 3 years of adjuvant tamoxifen, did not improve rates of adapted disease-free survival.3
  • In the IDEAL trial, 5 vs 2.5 years of letrozole after 5 years of endocrine therapy failed to improve disease-free survival.4

NRG Oncology/NSABP B-42

The NRG Oncology/NSABP B-42 trial evaluated 5 years of letrozole (2.5 mg/d) vs placebo in 3,966 patients who had completed 5 years of hormonal therapy (aromatase inhibitor or tamoxifen followed by an aromatase inhibitor). Approximately one-third of patients were younger than 60 and almost half were node-positive. Overall, about 60% of both arms completed 5 years of additional treatment. The median follow-up for 3,923 patients included in the efficacy analysis was 6.9 years.

Our findings suggest that careful assessment of potential risks and benefits … is required before recommending extended aromatase inhibitor therapy.
— Eleftherios P. Mamounas, MD

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The randomized, placebo-controlled study showed a small but not statistically significant improvement in disease-free survival (the primary endpoint) and no improvement in overall survival, although a significant improvement was seen in the breast cancer–free interval and distant recurrence, reported Eleftherios P. Mamounas, MD, of the NSABP, now part of NRG Oncology. Dr. Mamounas is also Medical Director of the Comprehensive Breast Program at the University of Florida Health Cancer Center and Orlando Health.

Disease-free survival at approximately 7 years was 84.7% with extended letrozole vs 81.3% with placebo (hazard ratio [HR] = 0.85, P = .048). Overall survival was 91.8% with letrozole and 92.3% with placebo (HR = 1.15, P = .22).

“For the primary endpoint, we saw a 15% reduction in risk. You may think this looks statistically significant, but the level for statistical significance was set at P = .0418 (because of adjustments for four interim analyses), so technically this is not significant,” Dr. Mamounas reported.

Extended Adjuvant Endocrine Therapy

  • Three studies presented at the 2016 San Antonio Breast Cancer Symposium evaluating extended use of aromatase inhibitors in hormone receptor–positive postmenopausal patients failed to meet their primary endpoints.
  • Disease-free survival was not improved by the addition of 5 years of extended aromatase inhibitors after therapy with tamoxifen or an aromatase inhibitor.
  • NRG Oncology/NSABP B-42 evaluated 5 years of letrozole vs placebo in 3,966 patients, and the study showed a 15% (nonsignificant) reduction in risk.
  • Disease-free survival at 7 years was 84.7% with extended letrozole vs 81.3% with placebo (hazard ratio [HR] = 0.85, P = .048 [not significant]).
  • There were, however, significant improvements in distant metastases, contralateral breast cancer, and breast cancer–free interval events in B-42.
  • The European DATA and IDEAL studies also failed to show benefits for extended endocrine therapy.

“We did see a major difference in the reduction of distant recurrence, however, and also in breast cancer–free interval events (which includes recurrences of breast cancer and cancers in the opposite breast), with extended letrozole,” he added, citing the following benefits for extended therapy:

breast cancer–free interval events: 6.7% vs 10.0% (HR = 0.71, P = .003); distant recurrence: 3.9% vs 5.8% (HR = 0.72, P = .03)

There was no significant difference in the incidence of osteoporotic fractures (5.4% vs 4.8%; HR = 1.19, P = .27) and occurrence of thrombotic events (4.0% vs 3.4%; HR = 1.21, P = .29), though a slight increase in thrombotic events occurred after 2.5 years of letrozole therapy.

Dr. Mamounas pointed out, however, that the results, while not statistically significant, would not be that different from those of MA.17R if the primary endpoint were defined the same. In B-42, disease-free survival included recurrence, contralateral breast cancer, nonbreast cancers, and deaths as first events. In MA.17R, disease-free survival included only recurrence and contralateral breast cancers. When disease-free survival in MA.17R was defined by adding deaths from any cause to recurrence and contralateral breast cancer, its hazard ratio was 0.80 (P = .06), similar to the 0.85 in B-42 (P = .048), he pointed out.

“Our findings suggest that careful assessment of potential risks and benefits, such as patient and tumor characteristics, comorbidities, information on bone mineral density, and tolerance of the initial 5 years of the aromatase inhibitor, is required before recommending extended aromatase inhibitor therapy,” Dr. Mamounas concluded.

DATA Study

Vivianne Tjan-Heijnen, MD, PhD

Vivianne Tjan-Heijnen, MD, PhD

The phase III DATA study randomly assigned 1,912 postmenopausal women who had received 2 to 3 years of adjuvant tamoxifen to either 3 or 6 years of anastrozole. Results of the study were reported by Vivianne Tjan-Heijnen, MD, PhD, of Maastricht University Medical Centre, Netherlands.

The primary endpoint was adapted disease-free survival, defined as disease-free survival beyond 3 years after randomization to aromatase inhibitor therapy (initially, all patients received the same aromatase inhibitor for 3 years). This included breast cancer recurrences, second primary breast cancers, and death from any cause.

The study was designed to detect an increase in the adapted disease-free survival for 6 years of anastrozole vs 3 years corresponding with a hazard ratio of 0.60. Instead, the hazard ratio was 0.79 (P = .07). Five-year adapted disease-free survival was 83.1% for patients receiving 6 additional years of anastrozole and 79.4% for those receiving 3 years, Dr. Tjan-Heijnen reported.


Erik Blok, MD

Erik Blok, MD

Erik Blok, MD, of Leiden University Medical Center, presented the results of the randomized phase III IDEAL trial, which compared a total of 7.5 years vs 10 years of endocrine therapy. Patients had received 5 years of adjuvant tamoxifen (10%), aromatase inhibitor (30%), or tamoxifen followed by an aromatase inhibitor (60%). The 1,824 patients were randomized to letrozole for 2.5 years or 5 more years of extended therapy. Also, this trial was designed to detect a hazard ratio of 0.6 in disease-free survival after the treatment arms diverged.

The 5-year disease-free survival rate was 88.4% in patients receiving 2.5 more years of treatment and 87.9% for those receiving 5 additional years (HR = .96, P = .70). Overall survival rates were 93.5% and 92.6%, respectively (HR = 1.08, P = .59). There was a significant difference in the prevention of second primary breast cancers (HR = 0.37, P = .008), but this represented a small (1%) absolute risk reduction. ■

Disclosure: Dr. Gnant has an immediate family member working for Sandoz; received honoraria from Roche, Novartis, AstraZeneca, Celgene, GSK; is a consultant for Accelsiors; has received research funding from AstraZeneca, Novartis, Roche, Pfizer, and travel expenses from Celgene, AstraZeneca, Novartis, Pfizer, and Eisai. Dr. Mamounas is a consultant for Pfizer, Genentech, Genomic Health, Biotheranostics, GRAIL, Macrogenics, Celcuity, and Bayer and a speaker for Genentech and Genomic Health. Dr. Tjan-Heijnen received research grants and speaker fees from AstraZeneca, Novartis, Pfizer, Roche, and Eisai. Dr. Blok reported no potential conflicts of interest.


1. Goss PE, Ingle JN, Pritchard KI, et al: A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. 2016 ASCO Annual Meeting. Abstract LBA1. Presented June 5, 2016.

2. Mamounas EP, Bandos H, Lembersky BC, et al: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy with letrozole in postmenopausal women with hormone-receptor-positive breast cancer who have completed previous adjuvant treatment with an aromatase inhibitor. 2016 San Antonio Breast Cancer Symposium. Abstract S1-05. Presented December 7, 2016.

3. Tjan-Heijnen VC, Van Hellemond IE, Peer PG, et al: First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer. 2016 San Antonio Breast Cancer Symposium. Abstract S1-03. Presented December 7, 2016.

4. Blok EJ, Van de Velde CJH, Meershoek-Klein Kranenbarg EM, et al: Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy. 2016 San Antonio Breast Cancer Symposium. Abstract S1-04. Presented December 7, 2016.

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Expert Point of View: Michael Gnant, MD

Clearly, decisions about extended treatment will now be individualized.
— Michael Gnant, MD

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Michael Gnant, MD, Professor of Surgery at the Medical University of Vienna in Austria and President of the Austrian Breast & Colorectal Cancer Study Group, ...