Phase III Trial Investigates Extended Adjuvant Endocrine Therapy for Postmenopausal Patients With Breast Cancer

Get Permission

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 and overall survival over the standard treatment of approximately 5 years of endocrine therapy. Results from the Italian phase III GIM4 trial were presented by Lucia Del Mastro, MD, and colleagues at the European Society for Medical Oncology (ESMO) Congress 2021 (Abstract 1180).

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), according to Dr. Del Mastro, of the IRCCS Ospedale Policlinico San Martino in Genoa, Italy. Dr. Del Mastro reported the final analysis at ESMO Congress 2021 on behalf of the Gruppo Italiano Mammela.

A previous analysis after 10 years of follow-up had suggested a trend toward better disease-free survival with the longer duration of letrozole. Here, Dr. Del Mastro reported the final analysis, with a median follow-up of 11.7 years.

Lucia Del Mastro, MD

Lucia Del Mastro, MD


“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.

GIM4 Details

The open-label phase III GIM4 trial compared extended therapy with letrozole for 5 years (for up to 7–8 years total) vs the standard duration of 2 to 3 years of letrozole (for up to 5 years total) in postmenopausal patients with stage I to III hormone receptor–positive breast cancer who remained recurrence-free after 2 to 3 years of tamoxifen. Patients were randomly assigned to the experimental or control arm of the study.

The primary endpoint was invasive disease–free survival in the intention-to-treat population of 2,056 patients, computed from the time of random assignment. A landmark analysis excluded patients with a disease-free survival event or those lost to follow-up before treatment divergence, yielding a population of 1,890 patients.

Approximately 41% had node-positive disease, 21% had grade 3 tumors, 6% had HER2-positive disease, 55% had received prior chemotherapy, and the median duration of prior tamoxifen treatment was about 2.5 years.

Treatment was completed by 80% of patients in the control arm and 63% of those in the extended arm. 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, as reported by 9% and 14%, respectively.  

Improvements 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, which included nodal status, tumor size, tumor grade, age, hormone receptor status, HER2 status, receipt of 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. 


  • 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.
  • Overall survival was also significantly improved at 12 years, with rates of 84% in the control arm vs 88% after extended letrozole therapy.

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).

Similarly, for overall survival, extended letrozole was associated with a statistically significant benefit, as 84% of patients in the control arm and 88% of those in the experimental arm were alive at 12 years (HR = 0.77, P = .036). Survival increased, therefore, by an absolute 4% with longer endocrine treatment.

Patients in the extended letrozole arm experienced more arthralgias (35% vs 29%), myalgia (11% vs 8%), hypertension (2% vs 1%), and osteoporosis (8% vs 5%), but these differences were not considered to be 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.

The study authors concluded: “In postmenopausal patients with breast cancer treated with 2 to 3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant and clinically meaningful improvement in both disease-free survival and overall survival compared to the duration of 2 to 3 years of letrozole.”

Disclosure: For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.