Guan‐Tian Lang

To characterize the prevalence of BRCA mutations and characteristics of BRCA carriers in China and to update the clinical recommendations for BRCA testing, we conducted a wide screen for BRCA mutations using next-generation sequencing (NGS). A total of 4,034 Chinese subjects were screened for germline BRCA1/2 mutations, including 2,991 breast cancer patients and 1,043 healthy individuals from the community enrolled as controls. We developed an NGS-based approach to perform BRCA1/2 screening. BRCA mutations were identified in 9.1% (232/2,560) of cases with at least one risk factor, in 3.5% (15/431) of sporadic patients and in 0.38% (4/1,043) of healthy controls. The mutation frequency ranged from 8.9 to 15.2% in cohorts with a single risk factor to 16.6-100% in groups with multiple risk factors. We identified 70 novel BRCA mutations. A high frequency of BRCA1 c.5470_5477del was detected, accounting for 13.9% (16/115) of the BRCA1 mutations detected in our study. Clinical characteristics such as family history, invasive carcinoma, negative human epidermal growth factor receptor 2 (HER2), high Ki67 index, lymph node status, and high tumour grade were closely related to BRCA mutations. BRCA2 carriers had poorer disease-free survival among HER2- or hormone receptor-positive patients (hazard ratio = 1.892; 95% confidence interval: 1.132-3.161; p = 0.013). This study shows that BRCA mutation carriers could be frequently identified among breast cancer patients with multiple risk factors. Importantly, we established an NGS-based pipeline for BRCA1/2 testing in clinical practice and strongly suggest that breast cancer patients of premier- and moderate-grade risks receive BRCA1/2 mutations testing in China.

The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.

// He-Sheng Jiang 1,2,* , Xia-Ying Kuang 1,5,* , Wei-Li Sun 2,* , Yan Xu 4 , Yi-Zi Zheng 1,2 , Yi-Rong Liu 1,2 , Guan-Tian Lang 1,2 , Feng Qiao 2 , Xin Hu 2 and Zhi-Ming Shao 1,2,3 1 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China 3 Institutes of Biomedical Science, Fudan University, Shanghai, China 4 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China 5 Department of Breast Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China * These authors have contributed equally to this article Correspondence to: Zhi-Ming Shao, email: // Xin Hu, email: // Keywords : breast cancer; TNBC; androgen receptor; BRCA1; hormone receptor Received : February 26, 2016 Accepted : May 20, 2016 Published : June 07, 2016 Abstract In this study we sought to correlate androgen receptor (AR) expression with tumor progression and disease-free survival (DFS) in breast cancer patients. We investigated AR expression in 450 breast cancer patients. We found that breast cancers expressing the estrogen receptor (ER) are more likely to co-express AR compared to ER-negative cancers (56.0% versus 28.1%, P < 0.001). In addition, we found that AR expression is correlated with increased DFS in patients with luminal breast cancer ( P < 0.001), and decreased DFS in TNBC (triple negative breast cancer, P = 0.014). In addition, patients with HR+ tumors (Hormone receptor positive tumors) expressing low levels of AR have the lowest DFS among all receptor combinations. We also propose a novel prognostic model using AR receptor status, BRCA1, and present data showing that our model is more predictive of disease free survival compared to the traditional TMN staging system.

Our findings advance the understanding of tumor heterogeneity regulation in APA and yield new insights into therapeutic target identification in TNBC.

Glutathione S-transferase M (GSTM) family is concerned with oxidative stress, which is associated with breast carcinogenesis and chemotherapy response. The null polymorphism of GSTM1 gene results in a thorough absence of the enzyme function. Our study was to evaluate the association between GSTM1 null/present polymorphism and chemotherapy treatment outcome in breast cancer patients. A total of unrelated 714 patients with a histologically confirmed breast cancer were randomly selected from two independent cancer centers. Polymerase chain reaction was performed to analyze null/present genotypes of GSTM1 in our study. Our study found that the present genotype of GSTM1 was associated with a better relapse-free survival (RFS) (P = .03) with adjusted hazard ratio (HR) [95% confidence interval (CI)] of 0.63 (95% CI: 0.42-0.93). The present genotype of GSTM1 was significantly correlated with a better RFS compared with the null genotype in the nonchemotherapy group (HR = 0.17, 95% CI: 0.06-0.50; P = 0.001), but no effect was observed in the chemotherapy group (HR = 0.81, 95% CI: 0.52-1.26; P = 0.35). Moreover, the interaction between the GSTM1-null/present genotype and adjuvant chemotherapy was significant (P = 0.04) in further analysis. Our study suggests that the GSTM1 polymorphism plays a complex role in influencing the chemotherapy response and breast cancer survival. It is suggested that the GSTM1-present genotype might prevent progression in breast cancer patients. In the meanwhile, it could damage the benefit of adjuvant chemotherapy as well in certain ways.