Impact on Cognitive Function of Adding Chemotherapy to Endocrine Therapy for Breast Cancer

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Chemotherapy followed by endocrine therapy led to more cancer-related cognitive impairment compared with endocrine therapy alone in patients with hormone receptor–positive, HER2-negative breast cancer at 36 months, according to patient-reported responses. These findings—from a substudy of the phase III SWOG S1077 RxPONDER trial—were presented by Kang et al at the 2022 San Antonio Breast Cancer Symposium (Abstract GS1-04).

"Breast cancer treatment is associated with cancer-related cognitive impairment, and the effect of endocrine therapy vs chemotherapy followed by endocrine therapy is poorly understood,” said Irene Kang, MD, Medical Director of Women’s Health Breast Oncology at City of Hope Orange County, Irvine, California.

“Our analysis showed that cognitive impairment is experienced at a higher rate with chemoendocrine therapy rather than endocrine therapy alone and showed that in some patients, these symptoms persist even out to 36 months. I think these data highlight that using something like a molecular risk assay to avoid chemotherapy in patients who would otherwise not benefit is really important in preventing such a debilitating symptom,” Dr. Kang suggested.

Study Details

The RxPONDER trial enrolled more than 5,000 patients with HER2-negative breast cancer with one to three positive lymph nodes and an Oncotype DX recurrence score of 0 to 25. Participants were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The results of the substudy that Dr. Kang reported were based on patient-reported responses to health-related quality-of-life questionnaires from 139 premenopausal patients and 429 postmenopausal patients enrolled in RxPONDER. 

Following random assignment, English-speaking patients in the United States were asked to complete health-related quality-of-life questionnaires, which included an eight-item PROMIS Perceived Cognitive Function Concerns (PCF) Short Form questionnaire. This is an eight-item questionnaire that asked participants about memory and focus and related items on a five-point Likert scale. They also completed questionnaires at 6, 12, and 36 months. 

The study’s primary endpoint was to compare the mean PCF T-scores by treatment arm, as well as by patients’ menopausal status. Higher scores signified less cognitive impairment. 

Key Findings

For premenopausal patients, PCF T-scores were similar at 12 months, with both treatment arms reporting worsened cognitive function compared with baseline. However, at 36 months, 42% of patients given chemoendocrine therapy reported lower scores compared with 28% of patients given endocrine therapy alone. Among postmenopausal women, those who received chemoendocrine therapy had lower scores at 6 and 12 months, with recovery at 36 months, but not to baseline levels.

"Interestingly, in the endocrine therapy arm, the mean score stays essentially stable at the study follow-up timepoints,” Dr. Kang said.

Dr. Kang and coauthors calculated a longitudinal mean score difference between chemoendocrine therapy and endocrine therapy from both groups. In the premenopausal group, the score difference was –3.02, which Dr. Kang called “clinically meaningful.” The postmenopausal group had a mean score difference of –2.36, but according to Dr. Kang, this was statistically significant but not clinically meaningful.

The study’s limitations included a small sample size, especially for the premenopausal patients. Adherence data were lacking for endocrine therapy, and changes in menopausal status were also unknown. 

Dr. Kang said the implications of her study are that further research is needed to explore chemotherapy-related cognitive impairment in a more diverse population and to identify risk factors for developing cognitive impairment, as well as the ability to recover.

Commenting on the importance of this study, Neelima Vedula, MD, a medical oncologist at Mass General Cancer Center, said: “The take-home message of this study is that both chemoendocrine therapy and endocrine therapy can impact cognitive function. We need to be cognizant of this as an important part of survivorship. We need to be attentive to patients’ depression, anxiety, and sleep difficulties, all of which can impact cognition.”

Disclosure: Dr. Kang has served as an advisor or consultant to Caris Life Sciences and Puma Biotechnology. For full disclosures of the other study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.