Middle-aged, not the youngest, patients have the worst independent survival in ER-negative metastatic breast cancer: a retrospective cohort study

Technical Summary: Age and Prognosis in ER-Negative Metastatic Breast Cancer

Problem Statement
The prognostic significance of age in metastatic breast cancer (MBC) remains an area of ongoing investigation, with evidence suggesting it may vary fundamentally based on tumor biology. While younger patients in early-stage disease often present with aggressive features (high-grade tumors, elevated Ki-67, triple-negative subtypes), the extent to which age independently influences survival in the metastatic setting—specifically when stratified by estrogen receptor (ER) status—is not fully elucidated. Furthermore, it is unclear whether the observed age-related survival differences are merely proxies for tumor proliferation (captured by Ki-67) or if age serves as an integrative marker reflecting broader biological complexities such as metastatic competence and host-tumor interactions. This study addresses the gap in understanding whether the impact of age on overall survival (OS) differs between ER-positive and ER-negative MBC and whether such associations persist after adjusting for proliferation indices.

Methodology
The authors conducted a retrospective cohort study involving 657 patients with MBC treated at a single tertiary center (Ewha Womans University Mokdong Hospital) between January 2000 and December 2022.

• Cohort Stratification: Patients were stratified by ER status (ER-positive, n=419; ER-negative, n=238) and categorized into three age groups at initial diagnosis: young (<35 years), middle-aged (35–50 years), and older (>50 years).
• Data Collection: Clinicopathologic data were extracted from electronic medical records, including hormone receptor status, HER2 status, Ki-67 proliferation index, histologic grade, and sites of metastasis. Tumor subtype was defined based on the most recent metastatic biopsy when available; otherwise, the primary tumor subtype was used.
• Outcomes: The primary endpoint was overall survival (OS), measured from initial diagnosis to death from any cause.
• Statistical Analysis: Survival was analyzed using Kaplan–Meier estimates and log-rank tests. Multivariable Cox proportional hazards models were employed to identify independent predictors of OS, adjusting for age group, time to first metastasis, site of first metastasis, and tumor subtype.
• Handling Missing Data: To address missing Ki-67 values (17.4% of the cohort), a sensitivity analysis was performed using multiple imputation by chained equations (MICE) with 20 imputed datasets. This allowed for the assessment of whether age effects were robust to Ki-67 adjustment.

Key Results

1. ER-Positive Cohort: Age was not associated with overall survival (log-rank p = 0.91). While the proportion of bone metastasis varied significantly across age groups (p = 0.007), this did not translate into survival differences. Multivariable analysis confirmed that age was not an independent predictor of OS in this group.
2. ER-Negative Cohort: Age was significantly associated with overall survival (log-rank p = 0.02).
   • Univariable Analysis: Young patients (<35) exhibited the lowest survival probabilities, with 100% high Ki-67 expression and a high rate of early relapse (6–24 months: 77.8%).
   • Multivariable Analysis: Contrary to the univariable trend, the middle-aged group (35–50 years) demonstrated the highest independent risk of death compared to older patients (>50 years) (Hazard Ratio [HR] 1.77, 95% CI 1.12–2.81; p = 0.015). The young group (<35) did not show a statistically significant independent risk difference compared to the older group (HR 1.15, p = 0.761), likely due to small sample size (n=18) and the fact that their poor univariable outcomes were mediated by concurrent aggressive tumor features (e.g., high proliferation, early metastasis) which were controlled for in the model.
3. Ki-67 Adjustment: In the sensitivity analysis using multiple imputation, the elevated risk for middle-aged patients in the ER-negative cohort persisted (HR 1.76, 95% CI 1.11–2.81; p = 0.017). Notably, Ki-67 status itself was not independently prognostic in either the ER-positive or ER-negative cohorts after multivariable adjustment.

Significance and Claims
The paper claims three principal findings that refine the understanding of age as a prognostic factor in MBC:

• ER-Dependent Prognostic Value: The prognostic impact of age is fundamentally different based on ER status. Age lacks prognostic significance in ER-positive disease, likely due to the efficacy of endocrine therapies and the indolent nature of bone-predominant metastases. Conversely, in ER-negative disease, age is an independent predictor of survival.
• The "Middle-Aged" Risk: In ER-negative MBC, the highest independent risk of death is concentrated in middle-aged patients (35–50 years), not the youngest. The study suggests that the poor survival observed in very young patients is largely a reflection of their aggressive tumor biology (high proliferation, early relapse), whereas the middle-aged group retains an independent risk that is not fully explained by these factors.
• Age as an Integrative Marker: The persistence of the age effect in ER-negative MBC after adjusting for Ki-67 suggests that age captures biological dimensions beyond simple proliferation. The authors propose that age may reflect complex factors such as metastatic competence, immune-stromal interactions, clonal heterogeneity, and treatment resistance, which are not captured by conventional proliferation markers.

Conclusion
The study concludes that chronological age alone is an insufficient risk descriptor and must be interpreted in the context of ER status. Specifically, middle-aged women with ER-negative metastatic breast cancer represent a clinically meaningful subgroup warranting heightened surveillance and prioritized trial enrollment, as they face an independent survival disadvantage that persists even when accounting for tumor proliferation indices.