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Cognitive function during endocrine treatment with or without cyclin-dependent kinase 4/6 inhibitors for advanced

Maryse J Luijendijk¹, Philippe R Lee Meeuw Kjoe¹, Noor Wortelboer²

¹Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

|December 10, 2025

Abstract

Background:

Endocrine treatment for breast cancer may adversely affect cognition. Given the widespread use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), assessing the cognitive effects of this combination is important.

Methods:

In the SONIA trial, patients with hormone receptor-positive, HER2-negative (HR⁺HER2^-) advanced breast cancer (ABC) starting first-line treatment with an aromatase inhibitor were randomized to treatment with (arm A) or without (arm B) CDK4/6i. Cognitive function was assessed at baseline and after 9 months with the online Amsterdam Cognition Scan. Standardized z scores at baseline and regression-based change scores at 9 months were computed on the basis of matched cancer-free controls. Rates of clinically meaningful decline were compared with estimated false-positive rates of observing decline by chance.

Results:

Altogether, 260 patients (arm A, N = 130; arm B, N = 130) and 130 matched controls participated at baseline; 199 patients (arm A, N = 108; arm B, N = 91) and 120 matched controls completed the follow-up. At baseline, patients performed significantly worse than controls across all cognitive domains. Over the course of 9 months, no group-level decline in cognitive function occurred in either treatment arm, with minimal differences between treatment arms. At the individual level, however, the rate of clinically meaningful decline in patients (arm A, 15.7%; arm B, 14.3%) but not in controls (6.7%) was significantly higher than the false-positive rate (7.5%), which indicates decline in a small subset of patients.

Conclusions:

Patients with HR⁺HER2^- ABC showed impaired cognitive function at initial diagnosis compared to cancer-free controls. During first-line endocrine treatment with aromatase inhibitors, cognitive function declined in a small group of patients, regardless of the addition of CDK4/6i.

Insights

Cognitive function in advanced breast cancer patients on endocrine therapy with or without CDK4/6 inhibitors showed no group decline, but a small subset experienced meaningful cognitive decline. This decline occurred regardless of CDK4/6 inhibitor use.

Area of Science:

Oncology
Neuroscience
Pharmacology

Background:

Endocrine therapy for breast cancer can negatively impact cognitive function.
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are widely used in breast cancer treatment.
Assessing the cognitive effects of endocrine therapy combined with CDK4/6i is crucial.

Purpose of the Study:

To evaluate the cognitive effects of first-line endocrine treatment with aromatase inhibitors, with or without CDK4/6 inhibitors, in patients with advanced breast cancer.
To compare cognitive function changes over 9 months between patients receiving aromatase inhibitors alone versus in combination with CDK4/6 inhibitors.
To determine if CDK4/6 inhibitors exacerbate cognitive decline in this patient population.

Main Methods:

The SONIA trial randomized patients with HR+/HER2- advanced breast cancer to aromatase inhibitor treatment with or without CDK4/6i.
Cognitive function was assessed at baseline and 9 months using the Amsterdam Cognition Scan.
Cognitive performance was compared to matched cancer-free controls, analyzing both group-level changes and individual clinically meaningful decline rates.

Main Results:

At baseline, patients performed significantly worse than controls across all cognitive domains.
Over 9 months, no significant group-level cognitive decline was observed in either treatment arm.
While group-level function remained stable, a small subset of patients (14-16%) experienced clinically meaningful cognitive decline, a rate significantly higher than in controls and exceeding the false-positive rate.

Conclusions:

Patients with HR+/HER2- advanced breast cancer exhibit cognitive impairment at diagnosis.
First-line endocrine treatment with aromatase inhibitors, with or without CDK4/6 inhibitors, did not cause group-level cognitive decline over 9 months.
A small proportion of patients experienced clinically meaningful cognitive decline, irrespective of CDK4/6 inhibitor addition, highlighting the need for individualized monitoring.

Read full analysis

Keywords:

cancer‐related cognitive impairment cognitive dysfunction endocrine treatment metastatic targeted therapy

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