Genetic mutation profile of Chinese HER2-positive breast cancers and genetic predictors of responses to Neoadjuvant anti-HER2 therapy

Abstract

Purpose Despite the therapeutic success of existing HER2-targeted therapies, tumors respond quite differently to them. This study aimed at figuring out genetic mutation profile of Chinese HER2-positive patients and investigating predictive factors of neoadjuvant anti-HER2 responses. Methods We employed two cohorts. The first cohort was comprised of 181 HER2-positive patients treated at Guangdong Provincial People's Hospital from 2012 to 2018. The second cohort included 40 patients from the first cohort who underwent HER2-targeted neoadjuvant chemotherapy. Genetic mutations were characterized using next-generation sequencing. We employed the most commonly used definition of pathological complete response (pCR)-eradication of tumor from both breast and lymph nodes (ypT0/is ypN0). Results In Chinese HER2-positive breast cancer patients, TP53 (74.6%), CDK12 (64.6%) and PIK3CA (46.4%) have the highest mutation frequencies. In cohort 2, significant differences were found between pCR and non-pCR groups in terms of the initial Ki67 status, TP53 missense mutations, TP53 LOF mutations, PIK3CA mutations and ROS1 mutations (p = 0.028, 0.019, 0.005, 0.013, 0.049, respectively). Furthermore, TP53 LOF mutations and initial Ki67 status (OR 7.086, 95% CI 1.366-36.749, p = 0.020 and OR 6.007, 95% CI 1.120-32.210, p = 0.036, respectively) were found to be predictive of pCR status. Conclusion TP53 LOF mutations and initial Ki67 status in HER2-positive breast cancer are predictive of pCR status after HER2-targeted NACT.

Clinical implication of genetic composition and molecular mechanism on treatment strategies of HER2-positive breast cancers

“…The most frequently mutated genes were TP53 and PIK3CA, which were very often involved in cancer progression. TP53 mutation was reported in over 50% of cancers, but the rate was higher in another study analyzing cancers in Chinese patients (74.6%) (64). TP53-mutated cancers were associated with a poorer survival outcome (65).…”

“…Irrespective of hormonal receptor status, PI3KCA mutation rate of the primary cancers was similar in both pCR and non-pCR subgroups (27% vs. 28% respectively) in contrast to the earlier finding that PI3KCA and RhoA mutation were associated with higher pCR ( 63 , 72 ). Moreover, it was not found to be a predictive factor of pCR ( 64 ). Thus, PI3KCA mutation could merely be the genetic changes related to cancer progression instead of involving in treatment resistance.…”

“…This might be related to its induction of cell arrest and senescence instead of apoptosis as well as promoting production of cancer stem cells ( 66 , 67 ). Analysis of the pre-treatment samples of patients receiving neoadjuvant anti-HER2 treatment showed that TP53 mutation was commonly found in the pCR subgroup than non-pCR subgroup (67% vs 43%) and TP53 LOF mutation (and initial Ki67) was predictive of pCR status ( 63 , 64 ).…”

Exploring the effectiveness of molecular subtypes, biomarkers, and genetic variations as first-line treatment predictors in Asian breast cancer patients: A systematic review and meta-analysis

“…3D). Although all three and seven studies pooled in the two analyses were performed in the Chinese population, the primary outcome assessed in Li et al [45] and Xu et al [42] focused on the contribution of genetic mutations or long non-coding RNAs (lncRNAs) as a predictor of pCR status in the recruited population. Consequently, pooled analysis excluding Li et al eliminates the heterogeneity in the rst analysis revealing signi cant association (OR: 2.30; 95% CI: 1.66-3.19; p < 0.00001), while pooled analysis excluding Li et al and Xu et al in the second analysis decreased the heterogeneity, and maintaining the signi cant association (OR: 3.80; 95% CI: 2.02-7.13; p < 0.0001).…”

A Tale of Two Cancers: A Current Concise Overview of Breast and Prostate Cancer

“…Alterations in copy numbers are often observed at pre-malignant stages because 15 to 44% of atypical ductal hyperplasia are aneuploid [ 122 ]. The frequently mutated and/or amplified genes related to BC include phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), transcription factor tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), proto-oncogene myelocytomatosis (MYC), cyclin D1 (CCND1), human epidermal growth factor receptor 2/proto-oncogene C-ErbB-2/Erb-B2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 1 (FGFR1), and transcription factor GATA binding protein 3 (GATA3) [ 25 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 ]. To address the heterogeneity, classification systems have evolved to improve treatment choices and prognosis [ 134 ].…”