Chemotherapy followed by ET has a greater negative effect on cancer-related cognitive impairment vs. ET alone in both pre- and post-menopausal patients

Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). The RxPONDER PRO substudy analysed the effect of endocrine therapy (ET) vs. chemotherapy followed by ET (CET) on CRCI in HR+ HER2- breast cancer patients. The results suggest that CET has a greater negative effect on CRCI compared to ET alone in both pre- and post-menopausal women, and that CRCI persists over time in a significant proportion of patients.

Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). In this context, the effect of endocrine therapy (ET) vs. chemotherapy followed by endocrine therapy (CET) on CRCI is not well understood. Furthermore, whether menopausal status affects CRCI is also unknown. To shed light on this, a subgroup of patients from the RxPONDER trial, which enrolled women with HR+ HER2- breast cancer treated with CET or ET, was asked to fill in a Health-Related Quality of Life (HRQoL) questionnaire at different time points of the study. The results obtained from these questionnaires, specifically from the PROMIS Cognitive Function Concerns part, were presented at SABCS 2022.

Study design

The RxPONDER trial enrolled adult women with HR+ HER2- breast cancer with 1-3 positive lymph nodes, without distant metastasis and with a recurrence score of 0-25. In total, 5,083 patients were randomised 1:1 to CET or ET alone. In a subset of patients (N= 568), a patient-reported outcomes (PROs) study was performed, with HRQoL questionnaires given at baseline, 6, 12 and 36 months after randomisation. The questionnaires included PROMIS Cognitive Function Concerns (8 selected questions), PROMIS Anxiety and Fatigue forms, and EQ-5D. The RxPONDER PRO substudy invited consecutive English-speaking US patients to participate from February 2011 to December 2012. The primary endpoint was mean cognitive function score by treatment arm and menopausal status.

Results

In total, this study analysed 139 pre-menopausal (N= 65 and 74 in the CET and ET arms, respectively) and 429 post-menopausal women (N= 209 and 220) from the RxPONDER trial. In pre-menopausal women, the mean cognitive function score at baseline was similar between arms. With CET, the mean score decreased after 6 (49.27) and 12 months (47.95), and improved at 36 months (48.80) but did not reach baseline levels (52.84). In the ET arm, the mean score also decreased at 6 and 12 months (51.49 and 51.35) but in a lower magnitude compared to CET and improved reaching baseline levels at 36 months (53.50 vs. 53.23 at 36 months and baseline). The longitudinal mean score difference between CET and ET was -3.02 (p= 0.01). In post-menopausal women, baseline scores were also similar between both arms. In the CET group, a decline in score was seen again at 6 and 12 months (48.32 and 47.30), with an increase at 36 months but without reaching baseline levels (48.43 vs. 50.65 at 36 months and baseline). Interestingly, in the ET group, the mean score stays stable through the different time points (51.73, 51.35, 51.30 and 51.89 at baseline, 6, 12 and 36 months, respectively). The longitudinal mean score difference was -2.36 (p< 0.003). Changes in cognitive function score of 3 points from baseline were defined as clinically meaningful (increase ≥3 = better, decrease ≥ 3 worse, < 3 = no change). In the premenopausal group, a significant proportion of patients reported worse scores at each follow-up time point. Even after 36 months, 42% of patients in the CET and 28% in the ET reported worse scores. Findings were similar in the post-menopausal group, with a significant proportion of patients reporting worse cognitive function through the different time points (41% and 36% at 36 months in the CET and ET arms). The odds of having worse cognitive function were numerically higher with CET at each time point.

Conclusions

Results from the RxPONDER PRO substudy suggest that CET has greater negative effect on CRCI compared to ET alone in both pre- and post-menopausal women. Importantly, CRCI seems to persist over time in a significant proportion of patients. Some limitations of this study include the small sample size, particularly in the pre-menopausal group, and the unknown menopausal status change during follow-up. Future studies should include a bigger and more diverse population, and aim to unravel CRCI and cognitive function recovery predictors.

Reference

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 SABCS 2022; Abstract GS1-04.