Highlight
- Chemoendocrine therapy (CET) is associated with significantly greater patient-reported cancer-related cognitive impairment (CRCI) compared to endocrine therapy (ET) alone.
- Both pre- and postmenopausal women experience cognitive decline with CET that persists at 36 months.
- ET alone shows transient cognitive changes in premenopausal women, with recovery by 36 months, and stable cognitive scores in postmenopausal women.
- Findings highlight the need for CRCI prevention and management strategies in breast cancer care.
Background
Cancer-related cognitive impairment (CRCI) is a recognized sequela in breast cancer survivors, manifesting as memory deficits, executive dysfunction, and attention difficulties. These symptoms, often termed “chemobrain,” can markedly reduce quality of life and functional independence. While chemotherapy has been strongly linked to CRCI, the role of endocrine therapy in cognitive outcomes is less clear. Given the widespread use of these regimens in hormone receptor-positive breast cancer, delineating their impact is vital to improving survivorship care.
Study Design
This secondary analysis used data from the RxPONDER (SWOG S1007) trial, a multinational, randomized phase 3 study enrolling over 5000 women between February 2011 and September 2017. Eligible participants had hormone receptor-positive ERBB2-negative breast cancer with 1–3 involved lymph nodes and an Oncotype DX recurrence score ≤25. Patients were randomized to receive ET alone or CET (chemotherapy followed by ET), stratified by menopausal status.
Cognitive function was assessed via the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Statistical analysis employed generalized estimating equations for repeated measures to compare mean standardized PCF T-scores between groups.
Key Findings
Among 568 participants completing baseline PCF measures, 139 (24%) were premenopausal and 429 (76%) were postmenopausal. CET recipients accounted for 48% (n=274), while 52% (n=294) received ET alone.
Premenopausal Women
In the ET group, PCF scores dipped modestly from baseline (53.53) to 6 months (51.51) and 12 months (51.72), returning to baseline (54.36) at 36 months, suggesting a transient impact. Conversely, CET led to a sharper decline from baseline (52.84) to 6 months (49.27) and 12 months (48.04), with no recovery at 36 months (49.25). The longitudinal mean difference between CET and ET was -3.02 points (95% CI, -5.33 to -0.72; P=0.01).
Postmenopausal Women
ET patients maintained stable scores over time (baseline 51.72; 6 months 51.13; 12 months 51.11; 36 months 51.70). CET recipients showed steady deterioration starting at baseline (50.65), dropping to 48.39 at 6 months, 47.13 at 12 months, and remaining low at 36 months (48.44). The longitudinal difference versus ET was -2.37 points (95% CI, -3.92 to -0.82; P=0.003).
These results confirm a sustained negative association between CET and patient-reported cognitive function over a three-year follow-up, in both menopausal groups.
Expert Commentary
The pattern observed supports existing literature that chemotherapy’s neurotoxic effects can be prolonged, possibly due to direct CNS impact, inflammation, microvascular changes, or hormonal modulation. ET alone may lead to milder, predominantly reversible disruptions, especially in younger women. Clinicians should be mindful of CRCI risk when recommending CET, particularly in lower recurrence score patients who may derive limited survival benefit from chemotherapy. The need for proactive monitoring with cognitive screening tools, patient education, and neurorehabilitation interventions is underscored.
Limitations include reliance on patient-reported data without objective neuropsychological measures, possible selection bias given incomplete baseline questionnaire participation, and unmeasured confounding factors such as comorbidities or psychosocial stressors.
Conclusion
In hormone receptor-positive ERBB2-negative breast cancer, CET results in greater and longer-lasting cognitive impairment compared to ET alone, regardless of menopausal status. Survivorship protocols should integrate CRCI risk assessment and targeted interventions to support long-term functional outcomes.
Funding and ClinicalTrials.gov
Trial registration: ClinicalTrials.gov Identifier: NCT01272037.
References
Kang IM, Forschmiedt JK, Loch MM, Lew DL, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, Lin NU, Perez EA, Goldstein LJ, Rastogi P, Schott AF, Baehner R, Sharma P, Tripathy D, Pusztai L, Hortobagyi GN, Kalinsky K, Henry NL. Cognitive Impairment and Chemoendocrine vs Endocrine Therapy in Pre- and Postmenopausal Women: A Secondary Analysis of the RxPONDER Randomized Clinical Trial. JAMA Oncol. 2025 Dec 11:e255220. doi: 10.1001/jamaoncol.2025.5220. PMID: 41379459; PMCID: PMC12699395.
