Identifying Circulating Tumor DNA Mutation Profiles in Metastatic Breast Cancer Patients with Multiline Resistance

Purpose In cancer patients, tumor gene mutations contribute to drug resistance and treatment failure. In patients with metastatic breast cancer (MBC), these mutations increase after multiline treatment, thereby decreasing treatment efficiency. The aim of this study was to evaluate gene mutation patterns in MBC patients to predict drug resistance and disease progression. Method A total of 68 MBC patients who had received multiline treatment were recruited. Circulating tumor DNA (ctDNA) mutations were evaluated and compared among hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) subgroups. Results The baseline gene mutation pattern (at the time of recruitment) varied among HR/HER2 subtypes. BRCA1 and MED12 were frequently mutated in triple negative breast cancer (TNBC) patients, PIK3CA and FAT1 mutations were frequent in HR+ patients, and PIK3CA and ERBB2 mutations were frequent in HER2+ patients. Gene mutation patterns also varied in patients who progressed within either 3 months or 3–6 months of chemotherapy treatment. For example, in HR+ patients who progressed within 3 months of treatment, the frequency of TERT mutations significantly increased. Other related mutations included FAT1 and NOTCH4. In HR+ patients who progressed within 3–6 months, PIK3CA, TP53, MLL3, ERBB2, NOTCH2, and ERS1 were the candidate mutations. This suggests that different mechanisms underlie disease progression at different times after treatment initiation. In the COX model, the ctDNA TP53 + PIK3CA gene mutation pattern successfully predicted progression within 6 months. Conclusion ctDNA gene mutation profiles differed among HR/HER2 subtypes of MBC patients. By identifying mutations associated with treatment resistance, we hope to improve therapy selection for MBC patients who received multiline treatment.
Highlights • Doctors felt difficult to design effective regimen for MBC patients after multi-line treatment. • ctDNA testing provide potential treatment targets and reflect treatment response of tumors. • ctDNA gene mutation pattern varies among four HR/HER2 subgroups. • The gene mutation patterns also varied between resistant patients and sensitive patients. • In COX model, ctDNA gene mutation pattern could successfully predict progression within 6 months. In this study, we clarified the baseline ctDNA mutation pattern for metastatic breast cancer patients. We also selected out treatment-resistance related mutations by ctDNA testing. Here, we showed that PIK3CA were significantly related to HR+. Moreover, in this study, we also showed a plenty of other rare mutations, including DDR2, CDK12, etc. For different HR/HER2 subtypes, MED12 was frequent in TNBC samples, FAT1 was frequent in HR+ samples, and DDR2 was frequent in HER2+ samples. These findings need further intensive investigations in larger samples.