Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Dec 11:e255220.
doi: 10.1001/jamaoncol.2025.5220. Online ahead of print.

Cognitive Impairment and Chemoendocrine vs Endocrine Therapy in Pre- and Postmenopausal Women: A Secondary Analysis of the RxPONDER Randomized Clinical Trial

Irene M Kang  1 , Jamie K Forschmiedt  2 , Michelle M Loch  3 , Danika L Lew  4 , William E Barlow  4 , Julie R Gralow  5 , Funda Meric-Bernstam  6 , Kathy S Albain  7 , Daniel F Hayes  8 , Nancy U Lin  9 , Edith A Perez  10 , Lori J Goldstein  11 , Priya Rastogi  12 , Anne F Schott  8 , Rick Baehner  13 , Priyanka Sharma  14 , Debasish Tripathy  6 , Lajos Pusztai  15 , Gabriel N Hortobagyi  6 , Kevin Kalinsky  16 , N Lynn Henry  8
Affiliations

Cognitive Impairment and Chemoendocrine vs Endocrine Therapy in Pre- and Postmenopausal Women: A Secondary Analysis of the RxPONDER Randomized Clinical Trial

Irene M Kang et al. JAMA Oncol. .

Abstract

Importance: Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the association of endocrine therapy (ET) vs chemotherapy plus endocrine therapy (CET) with CRCI is poorly understood.

Objective: To compare patient-reported CRCI between women with breast cancer treated with ET vs CET and to consider whether menopausal status may be associated.

Design, settings, and participants: This was a prespecified secondary analysis of RxPONDER (SWOG S1007), a multinational phase 3 randomized clinical trial of more than 5000 women with hormone receptor-positive ERBB2-negative (formerly HER2-negative) breast cancer with 1 to 3 involved lymph nodes and Oncotype DX (21-gene recurrence score) of 25 or less. Participants were enrolled from February 2011 to September 2017, with results first reported in December 2020. Participants were randomly assigned to CET or ET, with ongoing follow-up. This secondary analysis assessed cognitive function using the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Data were analyzed from July 2022 to August 2025.

Intervention: Random assignment to CET or ET.

Main outcomes and measures: Mean PCF standardized (T) scores by menopausal status over time using generalized estimating equations analysis for continuous outcomes.

Results: Of the 568 patients who completed the baseline questionnaire and were included in the analysis, 139 (24%) were premenopausal (median [range] age, 47.8 [28.0-56.3] years) and 429 (76%) were postmenopausal (median [range] age, 62.3 [37.3-87.6] years). Among the 274 (48%) who received CET and the 294 (52%) who received ET alone, CET was determined to have a greater negative association with patient-reported CRCI in both the pre- and postmenopausal participants during the 36-month follow-up. In the ET alone group, PCF scores for premenopausal participants decreased from baseline to 6 and 12 months (53.53, 51.51, and 51.72, respectively) but recovered to baseline (54.36) at 36 months. For postmenopausal participants, mean PCF scores were essentially stable (51.72, 51.13, 51.11, and 51.70, respectively); however, in the CET group, PCF scores for both pre- and postmenopausal participants decreased from baseline to 6 and 12 months (premenopausal, 52.84, 49.27, 48.04; postmenopausal, 50.65, 48.39, 47.13, respectively) and did not return to baseline at 36 months (premenopausal, 49.25; postmenopausal, 48.44). The difference in longitudinal mean PCF scores over time between CET and ET groups was -3.02 (95% CI, -5.33 to -0.72; P = .01) for premenopausal and -2.37 (95% CI, -3.92 to -0.82; P = .003) for postmenopausal participants.

Conclusions and relevance: This secondary analysis of the RxPONDER found that CET had a greater negative association with patient-reported CRCI compared to ET alone in both pre- and postmenopausal participants over a 36-month follow-up period. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of these patients treated with chemotherapy.

Trial registration: ClinicalTrials.gov Identifier: NCT01272037.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Kang reported personal fees from Pfizer, Daiichi Sankyo, Gilead, Caris Life Sciences, Novartis, and Menarini Stemline, and grants from Merck, all outside the submitted work. Dr Loch reported advisory board membership at AstraZeneca and Gilead, and speaking fees from Gilead, and Merck, outside the submitted work. Dr Barlow reported grants from US National Cancer Institute during the conduct of the study. Dr Meric-Bernstam reported consulting fees from AstraZeneca, Becton Dickinson, Biocartis NV, Calibr (Scripps Research Institute), Daiichi Sankyo, Dava Oncology, Debiopharm, EcoR1 Capital, Effector Therapeutics, Elevation Oncology, Exelixis, GT Aperion, Incyte, Jazz Pharmaceuticals, Ligochem Biosciences, Menarini Group, Molecular Templates, Protai Bio, Ribo Metrix, Syst Immune, Tallac Therapeutics, TEMPUS, Vir Biotechnology, and Zymeworks; advisory committee membership with Cybrexa, Go Therapeutics, Guardant Health, Harbinger Health, Illumen Therapeutics, Kivu Biosciences, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Sanofi Pharmaceuticals, Seagen, Thera Technologies, and Zentalis Pharmaceuticals, and nonfinancial support from Cholangiocarcinoma Foundation and Dava Oncology; and travel and/or nonfinancial support from European Organisation for Research and Treatment of Cancer, European Society for Medical Oncology, Physician Education Resource, and Dava Oncology Travel during the conduct of the study. Dr Albain reported institutional research support and drug supplies from Quantum Leap Healthcare Collaborative Research, and AstraZeneca; and being a member of an independent data monitoring committee at Seattle Genetics/Axio/Pfizer for a phase 3 trial outside the submitted work. Dr Hayes reported personal fees from Exact Sciences during the conduct of the study, and from Cepheid, Cellworks, BioVeca, Xilis, Centrix, Arvinas, BioTheranostics, Stratipath, Artera.AI, Delphi Diagnostics, Spotlight Diagnostics, Milagen, and Myriad outside the submitted work; reported a patent for Diagnosis and Treatment of Breast Cancer (US 8,790,878 B2); and being the Section Editor for UpToDate and being an expert panel member for CancerExpertNow outside the submitted work. Dr Lin reported institutional grants from Genentech, Pfizer, Seagen, Zion Pharmaceuticals, Olema, and AstraZeneca; personal fees from Seagen, Daiichi Sankyo, AstraZeneca, Olema, Janssen, Blueprint Medicines, Stemline/Menarini, Eisai, and Shorla Oncology; stock options from Artera; travel support from Olema, AstraZeneca, and Daiichi Sankyo; and UpToDate royalties, all outside the submitted work. Dr Goldstein reported grants from Eastern Cooperative Oncology Group-American College of Radiology Imaging Network during the conduct of the study; and advisory/speaking fees from Genomic Health outside the submitted work. Dr Baehner reported equity in Exact Sciences during the conduct of the study. Dr Sharma reported institutional grants from Novartis and Gilead; advisory board participation for Novartis, Gilead AstraZeneca, Menarini Stem , Daiichi Sankyo, Pfizer, Lilly, all outside the submitted work. Dr Kalinsky reported consulting fees from Genentech/Roche, Gilead, Seattle Genetics, AstraZeneca, Daiichi Sankyo, Puma Biotechnology, Mersana, Menarini Silicon Biosystems, Myovant Sciences, Merck, Eli Lilly, Pfizer, Novartis, Mersana, BioTheranostics, ProteinQure, Regor, and Relay Therapeutics; and spouse’s employment with ADC Therapeutics, all outside the submitted work. Dr Henry reported personal fees from AstraZeneca and Myovant Sciences outside the submitted work. No other disclosures were reported.

Comment in

References

    1. Early Breast Cancer Trialists’ Collaborative Group . Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717. doi: 10.1016/S0140-6736(05)66544-0 - DOI - PubMed
    1. Early Breast Cancer Trialists’ Collaborative Group . Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341-1352. doi: 10.1016/S0140-6736(15)61074-1 - DOI - PubMed
    1. Braybrooke J, Bradley R, Gray R, et al. ; Early Breast Cancer Trialists’ Collaborative Group . Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials. Lancet. 2023;401(10384):1277-1292. doi: 10.1016/S0140-6736(23)00285-4 - DOI - PMC - PubMed
    1. Harris LN, Ismaila N, McShane LM, et al. ; American Society of Clinical Oncology . Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(10):1134-1150. doi: 10.1200/JCO.2015.65.2289 - DOI - PMC - PubMed
    1. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi: 10.1056/NEJMoa1804710 - DOI - PMC - PubMed

Associated data