Identification of mutation patterns and circulating tumour DNA-derived prognostic markers in advanced breast cancer patients

Abstract

Background The correlations between circulating tumour DNA (ctDNA)-derived genomic markers and treatment response and survival outcome in Chinese patients with advanced breast cancer (ABC) have not been extensively characterized. Methods Blood samples from 141 ABC patients who underwent first-line standard treatment in Peking University Cancer Hospital were collected. A next-generation sequencing based liquid biopsy assay (PredicineCARE) was used to detect somatic mutations and copy number variations (CNVs) in ctDNA. A subset of matched blood samples and tumour tissue biopsies were compared to evaluate the concordance. Results Overall, TP53 (44.0%) and PIK3CA (28.4%) were the top two altered genes. Frequent CNVs included amplifications of ERBB2 (24.8%) and FGFR1 (8.5%) and deletions of CDKN2A (3.5%). PIK3CA/TP53 and FGFR1/2/3 variants were associated with drug resistance in hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-positive (HER2 +) patients. The comparison of genomic variants across matched tumour tissue and ctDNA samples revealed a moderate to high concordance that was gene dependent. Triple-negative breast cancer (TNBC) patients harbouring TP53 or PIK3CA alterations had a shorter overall survival than those without corresponding mutations (P = 0.03 and 0.008). A high ctDNA fraction was correlated with a shorter progression-free survival (PFS) (P = 0.005) in TNBC patients. High blood-based tumor mutation burden (bTMB) was associated with a shorter PFS for HER2 + and TNBC patients (P = 0.009 and 0.05). Moreover, disease monitoring revealed several acquired genomic variants such as ESR1 mutations, CDKN2A deletions, and FGFR1 amplifications. Conclusions This study revealed the molecular profiles of Chinese patients with ABC and the clinical validity of ctDNA-derived markers, including the ctDNA fraction and bTMB, for predicting treatment response, prognosis, and disease progression. Trial registration: ClinicalTrials.gov ID: NCT03792529. Registered January 3rd 2019, https://clinicaltrials.gov/ct2/show/NCT03792529.

Genomic analysis of plasma circulating tumor DNA in patients with heavily pretreated HER2 + metastatic breast cancer

“…Consistent with previous studies 22 , 23 , TP53 and PIK3CA mutations were the two most altered genes. It is well known that the frequency of TP53 mutation is especially high in HER2 + breast cancer, and TP53 mutation per se is associated with early onset breast cancer and poor prognosis 24 .…”

“…ctDNA is assumed to reflect the tumor burden and has been suggested as a tool for prognostication and follow-up in patients with advanced cancers 30 , 31 . Several studies have shown the prognostic ability of ctDNA fractions in patients with MBC 22 , 23 , and a recent study advocated its role as a pragmatic, independent prognostic biomarker across the four most common advanced cancer types, including MBC, in real-world settings 32 . Moreover, although not addressed in our study, several studies have found that early on-treatment ctDNA dynamics were a surrogate for treatment outcomes 33 , 34 .…”

Prolactin-induced protein (PIP) increases the sensitivity of breast cancer cells to drug-induced apoptosis

“…They also found that PIP-positive cells were characterized by increased expression of several genes with the pro-apoptotic function ( BAD , CDKN2A , PRAME ), but also concomitant up-regulation of genes involved in the inhibition of cell growth and proliferation, and down-regulation of genes promoting cell proliferation. Two of these pro-apoptotic genes ( BAD and CDKN2A ) were also associated with drug resistance of BC cells 49 – 52 . However, they were different from the genes that we identified.…”

Circulating tumour DNA dynamics for assessment of molecular residual disease and for intercepting resistance in breast cancer

“…Observational studies evaluating the clinical validity of ctDNA dynamics for intercepting resistance are reported in Table 3 [28][29][30][31][32][33][34][35][36][37][38][39][40][41]. Most of them evaluated ctDNA through a targeted approach, confirming the known evidences about resistance to endocrine therapy, CDK4/6-inhibitors, PIK3CAinhibitors and antihuman epidermal growth factor receptor 2 (HER2) drugs.…”