Tumor Biology and Frailty May Guide Selection for Primary Endocrine Therapy in ER-Positive Breast Cancer: JAMA
USA: A systematic review and meta-analysis involving over 22,000 patients with ER-positive breast cancer has found no statistically significant difference in survival between primary endocrine therapy (pET) and upfront surgery. Durable disease control with pET appeared more likely in patients with favorable tumor biology. The findings suggest that treatment selection should consider tumor characteristics, frailty, and comorbidities rather than relying on chronological age alone. Prospective studies are needed to validate this approach.
The study was published in JAMA Network Open by Neil Carleton, MD, PhD, of the Women’s Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, and colleagues.
As the number of older women diagnosed with breast cancer increases, primary endocrine therapy is increasingly being considered as an alternative to surgery. However, treatment decisions have traditionally relied heavily on age and estimated life expectancy, with limited guidance on identifying patients whose tumor characteristics may favor endocrine therapy.
To address this gap, researchers reviewed evidence from PubMed, MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials through March 26, 2026. The analysis included randomized clinical trials and observational studies comparing pET with surgery in women with operable, nonmetastatic, estrogen receptor-positive breast cancer.
The review included 29 studies involving 22,821 patients, comprising six randomized trials and 23 observational cohorts. The median age across the study population was 83.1 years.
The findings revealed the following:
- Primary endocrine therapy was not associated with a statistically significant difference in overall survival compared with surgery (hazard ratio [HR], 1.14; 95% CI, 0.98–1.33), although the results numerically favored surgery.
- Breast cancer-specific survival findings did not establish a consistent survival advantage for surgery.
- Disease progression under pET varied considerably according to tumor characteristics, with median progression times ranging from approximately 20 months in biologically unselected cohorts to more than 50 months in selected patients receiving aromatase inhibitors.
- Tumors with favorable biological characteristics, including higher estrogen receptor expression and lower proliferation, were associated with more prolonged disease control.
- Surgery generally provided better local disease control, but this advantage did not consistently translate into improved survival, particularly among patients with competing health risks.
The researchers acknowledged that the randomized evidence was limited to six trials involving 813 patients, reducing the ability to detect modest survival differences. Differences in tumor biology assessment and the retrospective nature of several studies also limited comparisons.
Overall, the findings suggest that pET may be a reasonable treatment option for carefully selected older women with favorable tumor biology, particularly when frailty and comorbidities influence treatment decisions. The researchers emphasised that prospective studies are needed to validate a framework integrating tumor biology and physiological vulnerability before its widespread clinical implementation.
Reference:
Carleton N, Zou J, Mu Y, et al. Primary Endocrine Therapy vs Upfront Surgery for Older Women With Estrogen Receptor–Positive Breast Cancer: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2026;9(11):e2643218. doi:10.1001/jamanetworkopen.2026.43218
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