The Role of US in Depicting Axillary Metastasis in High-Risk Breast Cancer Patients

Purpose: The aim of this study is to evaluate the role of US in depicting axillary nodal disease in high-risk patients with and without pathogenic mutations. Methods: The retrospective study included consecutive high-risk breast cancer (BC) patients who underwent a multigene testing panel for hereditary cancers, pre-operative axillary US and breast/axillary surgery. The group was divided into patients with pathogenic mutations (PM group) and patients without PM. Statistical analyses were performed using GraphPad Prism by applying Chi-square and Fisher exact tests, with a reference p-value < 0.05 and a CI of 95%. Results: Out of 190 patients with BC, 96 (51%) were negative and 94 (49%) were positive for PM as follows: 28 (25.5%) BRCA1, 16 (17%) BRCA2, 15 (16%) CHECK2, 14 (14%) RAD Group, 7 (7%) PALB, 6 (6%) NBN, 3 (3%) TP53 and ATM and 2 (2%) BARD1. US was positive in 88 of the patients, 36 with PM and 52 without PM. US and surgery (>= N1 stage) were both positive in 31 (62%) of PM patients and 44 (88%) of patients without genetic changes. There were 19 (61%) false negative US examinations in the PM group and 6 (13%) in the group without genetic changes, respectively. If the US is positive, there is a 2.6 times greater risk of positive nodes in PM patients (p-value < 0.000, 95% CI = 4.2–37.9), and a 6.2 times greater risk of positive nodes in patients without genetic changes (p-value < 0.000, 95%CI = 8.4–37.4). In the PM group, US compared to surgery reached a sensitivity = 62, with PPV = 86 and NPV = 67. In the BRCA1/2 subgroup, there is 2.5 greater times risk of nodal disease if the US is positive (p-value = 0.001, 95%CI = 2.6–76). In patients without PM, US compared to surgery reached a sensitivity = 88, PPV = 84 and NPV = 86. Conclusion: US is more sensitive in depicting axillary nodal disease in high-risk patients without PM compared to PM patients. Furthermore, there are more false negative US examinations in PM patients, compared to surgery patients.

Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions

Background:Expert consensus on BRCA1/2 genetic testing and clinical application in Chinese breast cancer patients recommends that BRCA1/2 testing should be performed in those with clinical risk factors, such as an early onset, triple-negative breast cancer (TNBC) or family history of cancer. With the increasing application of multigene panels, testing for genes beyond BRCA1/2 has become more prevalent. However, the non-BRCA mutation status of Chinese high-risk breast cancer patients has not been fully explored.Methods: A total of 230 high-risk breast cancer patients from Fudan University Shanghai Cancer Center who had undergone peripheral blood germline 72 genes next-generation sequencing (NGS) from June 2018 to June 2020 were enrolled for retrospective analysis. The 72 genes include common hereditary breast cancer genes, such as homologous recombination repair (HRR) genes and other DNA damage repair genes. High-risk factors included: 1) TNBC; 2) male breast cancer; 3) primary bilateral breast cancer; 4) diagnosed with breast cancer at age less than or equal to 40 years; or 5) at least one first- and/or second-degree relative with BRCA-related cancer (breast or ovarian or prostate or pancreatic cancer).Results: The germline pathogenic or likely pathogenic mutation rate was 29.6% (68/230) in high-risk breast cancer patients. Among them, 44 (19.1%, 44/230) were identified as harboring BRCA1/2 mutation, and 28 (12.2%, 28/230) patients carried non-BRCA germline variants. Variants were detected in 16 non-BRCA genes, including PALB2 (5, 2.2%), ATM (4, 1.7%), RAD51D (3, 1.3%), TP53 (3, 1.3%), CHEK2 (2, 0.9%), FANCA (2, 0.9%) and ATR, BARD1, BRIP1, ERCC3, HOXB13, MLH1, MRE11, PMS2, RAD51C, RAD54L (1, 0.4%). Besides, 22 (9.6%, 22/230) patients were non-BRCA HRR gene mutation (including ATM, ATR, BARD1, BRIP1, CHEK2, FANCA, MRE11, PALB2, RAD51C RAD51D and RAD54L) carriers. Among high-risk factors, family history showed a correlation with both BRCA (p = 0.005) and non-BRCA HRR gene mutation status (p = 0.036). In addition, TNBC showed a correlation with BRCA1 gene mutation status (p = 0.038). However, other high-risk factors have not shown significantly related to BRCA1/2, non-BRCA genes and non-BRCA HRR gene mutations (p &gt; 0.05). In addition, 312 unique variants of uncertain significance (VUS) were identified among 175 (76.1%, 175/230) patients and 65 different genes.Conclusions: Non-BRCA gene mutations are frequently identified in breast cancer patients with high risk factors. Family history showed a correlation with both BRCA (p = 0.005) and non-BRCA HRR gene mutation status (p = 0.036), so we strongly suggest that breast cancer patients with a BRCA-related family history receive comprehensive gene mutation testing in China, especially HRR genes, which are not only related to high risk of breast cancer, but also potentially related to poly ADP ribose polymerase inhibitor (PARPi) targeted therapy. The exact relationship of rare gene mutations to breast cancer predisposition and the pathogenicity of VUS need to be further investigated.