For patients with early-stage hormone receptor–positive breast cancer, extending the duration of letrozole after tamoxifen—for up to 8 years of total endocrine therapy—significantly improved invasive disease–free survival over the standard 5 or so years, according to the final analysis of the Italian phase III GIM4 trial.1
At 12 years, the invasive disease–free survival rates were 62% in the control arm and 67% with extended letrozole, a statistically significant relative risk reduction of 22% and an absolute improvement of 5% (P = .006), as reported by Lucia Del Mastro, MD, of the IRCCS Ospedale Policlinico San Martino, Genoa, Italy, at the European Society for Medical Oncology (ESMO) Congress 2021, on behalf of the Gruppo Italiano Mammela. The study was simultaneously published in The Lancet Oncology.2
“Putting results in context with other trials…, we can consider a duration of 7 to 8 years total as the optimal duration of extended endocrine therapy. It’s a good compromise between efficacy and toxicity,” she commented.
We can consider a duration of 7 to 8 years total as the optimal duration of extended endocrine therapy. It’s a good compromise between efficacy and toxicity.— Lucia Del Mastro, MD
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Dr. Del Mastro said her opinion is based on a constellation of findings from GIM4 and the DATA,3 NSABP B42,4 IDEAL,5 and ABCSG-166 trials. They all showed a benefit to extending treatment beyond 5 years but not necessarily to 10 years.
A previous analysis performed at a median follow-up of 10 years found a trend toward better disease-free survival with extended letrozole.7 Here, Dr. Del Mastro reported the final analysis of the GIM4 trial, performed at a median follow-up of 11.7 years.
Background for GIM4
As Dr. Del Mastro pointed out, the benefit of extending endocrine therapy beyond a patient’s initial treatment with tamoxifen or an aromatase inhibitor is now well established. However, in patients treated with the switch strategy—ie, tamoxifen for 2 to 3 years followed by an aromatase inhibitor for 2 to 3 years—the value of going beyond 5 years remains controversial. Several large studies evaluating various schemas and durations of endocrine agents have yielded discordant findings.2-5
The open-label GIM4 trial compared extended therapy with letrozole for 5 years (for up to 7 to 8 years total) vs the standard duration of 2 to 3 years of (for up to 5 years total) in postmenopausal patients whose endocrine therapy began with 2 to 3 years of tamoxifen. The study explored the long-term outcomes in 2,056 postmenopausal patients with hormone receptor–positive, stage I–III breast cancer who were free of recurrence after 2 to 3 years of tamoxifen and thus were randomly assigned to the experimental or control arm of the study.
Study Details
The primary endpoint was invasive disease–free survival in the intention-to-treat population of 2,056 patients, computed from the time of randomization. The landmark analysis excluded patients with a disease-free survival event, or those lost to follow-up, before treatment divergence, yielding a final population of 1,890 patients.
Approximately 41% had node-positive disease, 21% had grade 3 tumors, 6% had HER2-positive disease, 55% had prior chemotherapy, and the median duration of prior tamoxifen was about 2.5 years.
Treatment was completed by 80% of the control arm and 63% of the extended arm. The median duration of letrozole was 2.4 years and 5.0 years, respectively. Early treatment discontinuation was observed for 19% of the control arm and 37% of the extended arm, primarily because of toxicity, which was reported as the reason by 9% and 14%, respectively.
KEY POINTS
- The phase III GIM4 trial enrolled 2,056 patients with hormone receptor–positive early breast cancer treated for 2 to 3 years with tamoxifen, without experiencing recurrence. Patients were randomly assigned to receive the standard 2 to 3 years of more letrozole or 5 years of “extended” letrozole therapy.
- In the final analysis at 12 years, the invasive disease–free survival rates were 62% in the control arm and 67% with extended letrozole, translating into a statistically significant 5% absolute improvement (hazard ratio [HR] = 0.78; P = .006).
- Overall survival was also significantly improved at 12 years, with rates of 84% in the control arm vs 88% after extended letrozole therapy (HR = 0.77; P = .036).
Improvement in Disease-Free and Overall Survival
At 12 years, the invasive disease–free survival rates were 62% in the control arm and 67% with extended letrozole, resulting in a statistically significant 5% absolute improvement (hazard ratio [HR] = 0.78; P = .006). This effect did not change in the multivariate model that included nodal status, tumor size, tumor grade, age, hormone receptor status, HER2 status, previous chemotherapy, and body mass index. There was a suggestion that patients with node-negative disease may obtain an exceptional benefit (HR = 0.626; P = .026); however, this was not a preplanned analysis and “should be interpreted with caution,” Dr. Del Mastro said.
The landmark analysis confirmed this benefit, showing a 10-year estimated disease-free survival of 59% with standard treatment and 68% with extended letrozole (HR = 0.73; P = .002), she reported. Similarly, for overall survival, extended letrozole was associated with a statistically significant benefit based on 12-year survival rates of 84% in the control arm and 88% with extended-duration letrozole (HR = 0.77; P = .036).
Longer treatment was associated with more arthralgias (35% vs 29%), myalgias (11% vs 8%), hypertension (2% vs 1%), and osteoporosis (8% vs 5%), but these differences were not statistically significant. Cardiovascular events were recorded for six patients (1%) in the extended arm and one patient (< 1%) in the control arm. Hematologic malignancies, including myelodysplastic syndrome, acute myeloid leukemia, and others, were rare and did not significantly differ between the arms.
DISCLOSURE: Dr. Del Mastro has served on the advisory board of speakers bureaus of Roche, Novartis, Pfizer, Merck Sharpe & Dohme, Genomic Health, Takeda, Ipsen, Eisai, Eli Lilly, and Celgene.
REFERENCES
1. Del Mastro L, Mansutti M, Bisagni G, et al: Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: A randomised, phase III trial of the Gruppo Italiano Mammella. ESMO Congress 2021. Abstract 118O. Presented September 17, 2021.
2. Del Mastro L, Mansutti M, Bisagni G, et al: Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. September 17, 2021 (early release online).
3. Tjan-Heijnen VCG, van Hellemond IEG, Peer PGM, et al: Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): A randomised, phase 3 trial. Lancet Oncol 18:1502-1511, 2017.
4. Mamounas EP, Bandos H, Lembersky BC, et al: Ten-year results from NRG Oncology/NSABP B-42: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy with letrozole in postmenopausal women with hormone-receptor+ breast cancer who have completed previous adjuvant therapy with an aromatase inhibitor. 2019 San Antonio Breast Cancer Symposium. Abstract GS4-01. Presented December 12, 2019.
5. Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, et al: Optimal duration of extended adjuvant endocrine therapy for early breast cancer: Results of the IDEAL trial (BOOG 2006-05). J Natl Cancer Inst 110(1), 2018.
6. Gnant M, Fitzal F, Rinnerthaler G, et al: Duration of adjuvant aromatase-inhibitor therapy in postmenopausal breast cancer. N Engl J Med 385:395-405, 2021.
7. Del Mastro L, Mansutti M, Bisagni G, et al: Benefit from letrozole as extended adjuvant therapy after sequential endocrine therapy: A randomized, phase III study of Gruppo Italiano Mammella (GIM). 2019 ASCO Annual Meeting. Abstract 504. Presented June 3, 2019.
