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Life sciences · Journal article
JAMA Network Open · November 6, 2026
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Importance As the population of older women with breast cancer grows, an increasing number are considered for primary endocrine therapy (pET), yet clinicians lack a framework for identifying which patients are appropriate candidates, resulting in reliance on chronologic age and life expectancy rather than tumor biology. Objective To evaluate survival and variables associated with response duration for patients treated with pET. Data Sources PubMed, MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials were searched from inception through March 26, 2026. Study Selection Randomized clinical trials (RCTs) and non-RCT (observational) cohorts comparing pET with surgery in operable, nonmetastatic, estrogen receptor (ER)–positive breast cancer. Data Extraction and Synthesis Data were extracted independently by 2 reviewers per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Hazard ratios (HRs) not directly reported were reconstructed from Kaplan-Meier curves. Randomized clinical trial–derived HRs for overall survival (OS) and breast cancer–specific survival (BCSS) were pooled using a random-effects model, given anticipated heterogeneity across trials spanning 5 decades and differing tumor biology criteria. Observational cohorts were analyzed descriptively, not pooled for comparative survival, given susceptibility to confounding by indication. Main Outcomes and Measures The main outcomes were OS and BCSS (RCTs) assessed using meta-analysis. Time to progression, salvage intervention rates, and variables associated with progression and mortality (observational cohorts) were assessed using descriptive analyses. Results Twenty-nine studies (6 RCTs and 23 observational cohorts; 22 821 patients; overall median [IQR] age, 83.1 [77.0-85.0] years) met the inclusion criteria. Patients from RCTs were generally younger (median [IQR] age, 77.0 [75.8-78.0] years) than those from the observational studies (median [IQR] age, 84.0 [81.5-86.0] years). Treatment with pET was not associated with a statistically significant OS difference vs surgery (HR, 1.14; 95% CI, 0.98-1.33), though the point estimate favored surgery. Median time to progression ranged from 19.7 months (range, 13.5-26.0 months) in tumor biology–unselected, tamoxifen-era cohorts to more than 50 months in ER-selected and aromatase inhibitor–treated cohorts. Tumor biology was consistently associated with progression risk. Conclusions and Relevance This systematic review and meta-analysis of more than 22 000 patients with ER-positive breast cancer found no statistically significant survival difference between pET and upfront surgery. Durable disease control under pET seemed to be concentrated in patients with favorable biology. These findings support a framework incorporating tumor biology and frailty, rather than age alone, to identify candidates for pET.