medwireNews: Extending adjuvant aromatase inhibitor (AI) therapy with letrozole to 5 years improves survival among women with hormone receptor-positive breast cancer who have already received 2 to 3 years of tamoxifen, shows the phase 3 GIM4 trial.
“Sequential endocrine therapy with tamoxifen for 2–3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer,” write Lucia Del Mastro (University of Genoa, Italy) and co-authors in The Lancet Oncology.
The GIM-4 study, which was also presented at the ESMO Congress 2021, included 2056 postmenopausal women with stage I–III hormone receptor-positive breast cancer, who had received 2 to 3 years of adjuvant tamoxifen therapy with no signs of disease recurrence.
They were randomly assigned to receive a further 2–3 years of treatment with letrozole 2.5 mg/day, to give a maximum adjuvant treatment time of 5 years (control group), or an additional 5 years of letrozole, giving them up to 8 years of adjuvant treatment in total (extended group).
Del Mastro and team report that, during a median 11.7 years of follow-up, 20.7% of 1026 patients in the extended arm and 25.4% of 1030 patients in the control arm experienced recurrence or died.
The estimated 12-year invasive disease-free survival rates were 67% and 62%, respectively, corresponding to a significant 22% lower risk for recurrence or death in favor of the extended regimen.
In addition, the risk for death was a significant 23% lower in the extended arm relative to the control arm, with corresponding estimated 12-year overall survival rates of 88% and 84%.
The investigators note that the study “confirmed the poor adherence to adjuvant endocrine therapy in women with breast cancer, with a high discontinuation rate in both groups.” Specifically, 37.1% of participants in the extended group and 19.5% of those in the control group discontinued letrozole before the end of treatment, mainly due to toxicity or patient refusal.
The most common grade 3 or 4 adverse events were arthralgia (3.0% of 977 patients in the extended group vs 2.2% of 983 in the control group) and myalgia (0.9 vs 0.7%). There were no treatment-related deaths.
“To our knowledge, GIM4 is the clinical trial of extended aromatase inhibitor therapy with the longest follow-up and the first study showing an overall survival benefit by extending aromatase inhibitor treatment beyond 5 years, which strongly supports the use of extended endocrine therapy with aromatase inhibitors in postmenopausal patients,” Del Mastro et al remark.
They also point out that the survival curves only began to separate, in favor of letrozole, after around 9.5 years of follow-up, which “underscores the importance of adequate follow-up length in hormone receptor-positive early breast cancer to assess the effect of treatments and is consistent with the previously reported carryover effect of aromatase inhibitors.”
The authors add: “The absence of a difference in disease-free survival and overall survival at 5 years and 10 years suggests that the effect of letrozole takes several years to be seen.”
And this observation may also explain results of previous studies with shorter follow-up, including the SALSA trial, that found no benefit with extended letrozole.
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ESMO Congress 2021; 16–21 September
Lancet Oncol 2021; doi:10.1016/S1470-2045(21)00352-1