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

Abstract

PurposeIn 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.MethodA 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.ResultsThe 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.ConclusionctDNA 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.

Longitudinal whole-exome sequencing of cell-free DNA unravels the metastatic evolutionary dynamics of BRCA2-mutated breast cancer

“…This mutation, was not detected in the PT and appears to be a sub-clonal mutation that resolved whilst the patient was on Pertuzumab, trastuzumab and docetaxel at time point B3. PIK3CA and FAT1 mutations are frequent in hormone receptor positive patients 28 , as in this case, where the PT was reported as ER+ (5+2). We also observed a mutation in TSC2 at B3 only, just prior to disease progression to her lung.…”

Problems to affect long-term survival for breast cancer patients

“…[ 41 ] BRCA1/2 mutation is related to both breast cancer and ovary cancer. [ 42 ] Breast cancer patients with a family history of breast or ovarian cancer also had an increased risk of subsequent leukemia. [ 43 ] BC survivors with ER-negative/HER2-positive and triple-negative BC (TNBC) had a significantly increased risk of developing a second primary asynchronous CBC.…”

PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis

“…They reported that PIK3CA mutations were frequently seen in tumors with normally expressed PTEN, ER, PR, and ERBB2 genes, as well as in tumors with nodal involvement. Studies demonstrated that mutations in PIK3CA were more common in hormone receptor-positive and HER2-positive breast cancers [25]. In a recent study by Wu et al, it was shown that PIK3CA mutations were positively associated with ER-positive, PR-positive, and low Ki67 labeling index, and negatively correlated with the triple-negative breast cancer subtype [26].…”

“…Colon Cancer [15] Nodal metastases, high pathological TNM stage, and lymphatic invasion [16] Decreased risk of peritoneal metastases [17,18] Diffuse-type and poorly differentiated gastric cancers and peritoneal recurrence Not associated with patient outcomes such as survival [19,20] Not associated with the overall survival [21] Increased five-year relapse-free interval [22,23] Against anti-EGFR antibodies [24] Poor prognosis Breast Cancer [14] Nodal involvement [25] Hormone receptor positive and HER2-positive status [26,27] ER-positive, PR-positive, low Ki67 labeling index and negatively correlated with triple-negative breast cancer subtype [28,29] Poor survival rates [30] Mutations in exon 9 are associated with poor prognosis but mutations in exon 20 are associated with better prognosis [31] Reduced disease-free survival [32] Risk factors for progression-free survival [33] Poor survival [34][35][36][37] Better survival [30] Exon 9 mutations are independently associated with early recurrence and death, whereas exon 20 PIK3CA mutations are associated with optimal prognosis [38][39][40][41] Resistant to antibody-based therapeutic therapy and chemotherapy Saal et al were the first to report a definite clinicopathological correlate of PIK3CA mutations in breast cancer [14]. They reported that PIK3CA mutations were frequently seen in tumors with normally expressed PTEN, ER, PR, and ERBB2 genes, as well as in tumors with nodal involvement.…”