“Cognitive Impairment and Chemoendocrine vs Endocrine Therapy in Pre- and Postmenopausal Women: A Secondary Analysis of the RxPONDER Randomized Clinical Trial” by Irene M. Kang, MD; Jamie K. Forschmiedt, BS; Michelle M. Loch, MD; Danika L. Lew, MA; William E. Barlow, PhD; Julie R. Gralow, MD, et al.
This secondary analysis of the RxPONDER clinical trial for women with breast cancer published in JAMA Oncology provides important new insights into cancer-related cognitive impairment (CRCI) among women with hormone receptor–positive, HER2-negative breast cancer treated with endocrine therapy (ET) alone versus chemotherapy followed by endocrine therapy (CET). While chemotherapy decisions in early breast cancer are traditionally driven by recurrence risk and survival benefit, this study highlights that long-term cognitive outcomes represent a clinically meaningful trade-off that deserves explicit consideration in shared decision-making
.The investigators analyzed patient-reported cognitive function in 568 women enrolled in a prespecified patient-reported outcomes substudy of RxPONDER. Cognitive function was assessed using the PROMIS Perceived Cognitive Function Concerns questionnaire at baseline and at 6, 12, and 36 months after treatment initiation. Participants were stratified by menopausal status, given the known interaction between menopause, chemotherapy benefit, and treatment toxicity. Approximately one-quarter of participants were premenopausal and three-quarters postmenopausal, with roughly equal distribution between CET and ET treatment arms.
The study’s central finding is that CET was associated with significantly worse patient-reported cognitive function than ET alone in both premenopausal and postmenopausal women, and that this difference persisted over three years of follow-up. In the ET group, premenopausal women experienced a modest early decline in cognitive scores that recovered to baseline by 36 months, while postmenopausal women had largely stable cognitive function throughout follow-up. In contrast, women treated with CET experienced larger declines in cognitive scores at 6 and 12 months that did not return to baseline at 36 months, regardless of menopausal status. The longitudinal mean difference between CET and ET was clinically meaningful, exceeding the predefined threshold for important change.
For clinicians, these findings have direct implications for treatment counseling. RxPONDER established that postmenopausal women with low recurrence scores can safely omit chemotherapy without compromising invasive disease-free survival. This cognitive outcome analysis strengthens that recommendation by demonstrating a sustained quality-of-life advantage with ET alone. In premenopausal women—where chemotherapy does improve cancer outcomes—the results underscore the importance of proactively discussing potential long-term cognitive effects, monitoring symptoms over time, and integrating supportive interventions when chemotherapy is indicated.
Importantly, the study also clarifies that CRCI does not appear to be strongly associated with survival outcomes. Neither baseline cognitive function nor worsening cognitive scores at 12 months predicted invasive disease-free survival or overall survival. This distinction is reassuring for patients who experience cognitive symptoms and reinforces that CRCI is primarily a survivorship and quality-of-life issue rather than a marker of cancer prognosis.
The authors further identified significant correlations between baseline anxiety, fatigue, and worse perceived cognitive function, highlighting the multifactorial nature of CRCI. These findings emphasize the need for holistic symptom assessment and management strategies that address mood, fatigue, sleep, and stress alongside cognitive concerns.
For patients, this study validates lived experiences often described as “chemo brain” and confirms that cognitive changes can be real, persistent, and treatment related. It also offers reassurance that cognitive recovery is more likely with endocrine therapy alone and that cognitive symptoms do not imply poorer cancer outcomes. For both patients and clinicians, the results reinforce the importance of individualized treatment decisions that balance cancer control with long-term cognitive and functional well-being.
Overall, this analysis extends the impact of RxPONDER beyond survival endpoints and highlights CRCI as a critical consideration in modern breast cancer care.
Exercise Oncology Programs providing both aerobic and resistance exercise interventions have been associated with improvements in both objective cognitive performance and patient-reported cognitive function during and after chemotherapy. Proposed mechanisms include enhanced cerebral blood flow, increased neurotrophic factors such as brain-derived neurotrophic factor (BDNF), reduced systemic inflammation, improved insulin sensitivity, and attenuation of cancer- and treatment-related fatigue and depression—each of which independently contributes to CRCI. Exercise may also counteract treatment-related hormonal changes, particularly relevant for women on endocrine therapies such as aromatase inhibitors or tamoxifen, which are linked to cognitive complaints and mood disturbance.
Importantly, supervised Exercise Oncology Programs provide individualized, safe, and progressive training that accommodates treatment-related side effects, improving adherence and clinical effectiveness compared with unsupervised activity. Trials incorporating moderate-intensity aerobic exercise combined with resistance training show the most consistent cognitive benefits, especially when initiated during chemotherapy and continued into survivorship.
For patients, these programs offer a non-pharmacologic, empowering strategy to preserve cognitive health while simultaneously improving fatigue, physical function, and emotional well-being. For clinicians, exercise oncology represents a low-risk, evidence-based adjunct to standard breast cancer care with the potential to address CRCI—a symptom for which few effective treatments currently exist. As survivorship continues to expand, integrating exercise oncology into routine breast cancer treatment pathways may be a critical step toward protecting long-term cognitive function and overall quality of life.
Reference: JAMA Oncol. doi:10.1001/jamaoncol.2025.5220 Published online December 11, 2025.
