Chemotherapy Plus Endocrine Therapy Increases Cognitive Impairment in Breast Cancer


Patients with breast cancer may be at risk for more intense cognitive impairment following treatment with chemotherapy plus endocrine therapy.

Irene Kang, MD

Irene Kang, MD

Regardless of menopause status, women with breast cancer who receive chemotherapy followed by endocrine therapy may be at a greater risk of cancer-related cognitive impairment than those receiving endocrine therapy alone, according to patients-reported outcomes (PROs) from the RxPONDER PRO substudy.

Findings were presented at the 2022 San Antonio Breast Cancer Symposium.

“Cancer-related cognitive impairment seems to persist over time in a significant proportion of patients,” said Irene Kang, MD, medical director of women’s health breast oncology at City of Hope Orange County in Irvine, California, during the presentation of the data.

In the RxPONDER study, 5,083 women with HR-positive, HER2-negative breast cancer with 1 to 3 positive lymph nodes without distant metastasis were randomly assigned to either chemotherapy followed by endocrine therapy or endocrine therapy alone. The PRO substudy included 274 patients from the chemotherapy followed by endocrine therapy group and 294 patients from the endocrine monotherapy group.

In the substudy, patients completed an 8-item questionnaire on a 5-point Likert scale assessing cognitive function at baseline, 6 months, 12 months, and 36 months.

The primary end point of the RxPONDER PRO substudy was mean cognitive function score by treatment arm and menopausal status. In particular, 139 women were premenopausal (median age, 48 years) and 429 women were postmenopausal (median age, 62 years).

Scores indicating perceived cognitive function concerns were similar between both treatment groups at baseline. In patients assigned endocrine therapy alone, these scores decreased from baseline to 6 months and 12 months but recovered to baseline at 36 months, according to the abstract. In contrast, patients assigned chemotherapy and endocrine therapy also had the same decrease at 6 months and 12 months, although their scores did not return to baseline at 36 months.

The mean score difference between the chemotherapy and endocrine therapy group and the endocrine therapy alone group was -3.02 (P = .01) for premenopausal women and -2.36 for postmenopausal women (P = .003).

Of note, 42% of premenopausal women assigned chemotherapy followed by endocrine therapy experienced a sustained and clinically significant decline in cognitive function as opposed to 28% for endocrine therapy. For postmenopausal women, these declines were 41% and 36%, respectively.

During the presentation, Kang noted that these results differ from the findings of a similar trial, TAILORx, which used a different cognitive function scale. Results from that trial demonstrated that the differences in cancer-related cognitive impairment between chemotherapy followed by endocrine therapy and endocrine therapy alone “vanished” at 12-month follow-up, she said.

Limitations to the study, as acknowledged by Kang, included patient drop-off over time, small sample size particularly in the premenopausal group, and that patients in the premenopausal group could theoretically have begun menopause at any point during the study’s duration. Patients were also overwhelmingly White (84.2%) and non-Hispanic (91.6%).

“Our study highlights the need for future investigation of cancer-related cognitive impairment in a more diverse population, as well as understanding who will develop cognitive impairment and who will recover,” Kang said during the presentation.


Kang I, Forschmiedt J, Loch M, et al. Patient-reported cognitive impairment in women participating in the RxPONDER trial (SWOG S1007) by menopausal status. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS1-04.

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