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

Oncol Res Treat. 2022;45(5):248-253. doi: 10.1159/000523758. Epub 2022 Feb 25.

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 (chemo) 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 first-line (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 chemo, in 4/9 patients treated with chemo 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 chemo (0/9) compared to patients treated with chemo 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 hormone receptor positive and HER-2 negative disease treated with chemo or CDK4/6 inhibitors. These results should be confirmed in larger patient cohorts.

Keywords: Breast cancer; CDK4/6 therapy; Chemotherapy; Clonal evolution.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / pathology
  • Circulating Tumor DNA* / genetics
  • Clonal Evolution
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / therapeutic use
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Female
  • Humans
  • Receptor, ErbB-2 / genetics
  • Triple Negative Breast Neoplasms* / drug therapy

Substances

  • Circulating Tumor DNA
  • Receptor, ErbB-2
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6