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

Abstract

Introduction Somatic evolution of the cancer genome resulting in genetically different subclones is thought to be involved in the development of treatment resistance but might also offer new therapeutic opportunities in metastatic breast cancer. No data are available if clonal evolution differs in patients treated with chemotherapy or CDK4/6 inhibitors given with endocrine treatment (CE treatment). Methods We performed a prospective analysis of circulating tumor DNA(ctDNA) by targeted next generation sequencing in 46 patients before the beginning of a systemic firstline (n=37) or second-line (n=9) treatment. Ct DNA was analyzed again upon disease progression. Results New mutations in ctDNA of patients with progressive disease were detected in 1/11 patients who started chemotherapy, in 4/9 patients treated with chemotherapy followed by CE maintenance treatment and in 9/26 patients receiving CE therapy. The number of acquired new mutations did not differ significantly between the three therapy cohorts (all p-values >0.05). However, in patients classified as secondary resistant (n=37), occurrence of new mutations significantly differed between patients who started chemotherapy (0/9) compared to patients treated with chemotherapy followed by CE (4/11; p=0.041) and patients receiving CE therapy (8/19; p=0.024), respectively. Conclusion Clonal evolution might differ significantly between metastatic breast cancer patients with HR positive and HER-2 negative disease treated with chemotherapy or CDK4/6 inhibitors. These results should be confirmed in larger patient cohorts.

Case report: From negative to positive: a remarkable journey of ER, PR and HER2 status in a patient with metastatic breast cancer

“…The occurrences of new mutations were 0% (0/9) for the chemotherapy group, 42.1% (8/19) for the CDK4/6 inhibitors plus endocrine treatment (CE group), and 36.3% (4/11) for the chemotherapy followed by CE group (p=0.024). The results strongly indicated that chemotherapy or CDK4/6 inhibitors may influence the change of clonal evolution among breast cancer patients (9). Liquid biopsy by Kujala J et al detected 56.2 ± 7.2% of somatic variants present both in the matched primary tumor and metastatic sites from breast cancer patients.…”