Clonal Evolution in Patients with Hormone Receptor Positive, HER-2 Negative Breast Cancer Treated with Chemotherapy or CDK4/6 Inhibitors

Area of Science:

• Oncology
• Genetics
• Genomics

Background:

• Somatic evolution of cancer genomes into distinct subclones is implicated in treatment resistance and potential therapeutic targets in metastatic breast cancer.
• Limited data exists on whether clonal evolution patterns vary between chemotherapy and CDK4/6 inhibitor plus endocrine treatment regimens.

Purpose of the Study:

• To investigate differences in clonal evolution patterns in metastatic breast cancer patients treated with chemotherapy versus CDK4/6 inhibitors plus endocrine therapy.
• To analyze circulating tumor DNA (ctDNA) for new mutations that arise during treatment progression.

Main Methods:

• Prospective analysis of ctDNA using targeted next-generation sequencing in 46 metastatic breast cancer patients.
• ctDNA samples collected at baseline and upon disease progression for first-line or second-line systemic treatments.

Main Results:

• New mutations were detected in ctDNA of progressing patients: 1/11 on chemotherapy, 4/9 on chemotherapy followed by CDK4/6 inhibitor plus endocrine therapy, and 9/26 on CDK4/6 inhibitor plus endocrine therapy.
• While the overall number of new mutations did not differ significantly across therapy groups, secondary resistant patients showed significantly more new mutations when treated with CDK4/6 inhibitor plus endocrine therapy compared to chemotherapy alone.

Conclusions:

• Clonal evolution patterns may differ significantly in hormone receptor-positive, HER2-negative metastatic breast cancer patients based on treatment with chemotherapy or CDK4/6 inhibitors.
• Further validation in larger patient cohorts is warranted to confirm these findings.