Mutation Spectrum of Homologous Recombination Repair Genes and Other Cancer Predisposition Genes in Early Triple-Negative Breast Cancer Association with Clinicopathological Factors, Immune Infiltration, and Prognosis

Abstract

Background: The frequency and clinical relevance of tumor mutations in homologous recombination repair (HRR) and other cancer predisposition genes in early triple-negative breast cancer (TNBC) are not well established. Furthermore, the association between HRR mutation, immune infiltration, and prognosis in TNBC is unknown. The aim of this study was to evaluate the mutation spectrum of HRR and other cancer predisposition genes and its association with clinicopathological factors, immune infiltration, and prognosis in TNBC.

Methods: TNBC patients (434 patients from Ruijin cohort) were evaluated with targeted next-generating sequencing for mutations in HRR and other cancer predisposition genes. The frequencies of mutations were compared with public reference cohorts (320 TNBC patients from METABRIC, 105 from TCGA, and 225 from MSKCC 2018). Associations between mutation status and clinicopathological factors, immune infiltration, and prognosis were analyzed.

Results: HRR genes mutations were seen in 21.89% of 434 patients, with BRCA1/2 mutations significantly enriched in tumors with breast/ovarian cancer family history (P = 0.025) and high Ki-67 levels (P = 0.018), while mutations in other cancer predisposition genes were found in 59.91% of patients. The pathological variation (PV) prevalence of BRCA1 was higher in Ruijin cohort (10.60%), than other public cohorts (2.67% to 2.86%), whereas the PV prevalence of BRCA2 in our study (3.92%) and MSKCC 2018 (4.44%) outnumbered that of TCGA (0.95%) and METABRIC (0.63%). HRR genes mutations were not related with recurrence-free survival (RFS) (adjusted P = 0.070) and overall survival (OS) (adjusted P = 0.318) for TNBC patients, regardless of carboplatin treatment or not (P > 0.05). Moreover, immune infiltration and PD-L1 expression was positively associated with HRR or BRCA1/2 mutation (all P < 0.001). Patients with both HRR mutation and high CD8+ T cell counts had the best RFS and OS compared with other groups, whereas patients with no HRR mutation and low CD8+ T cell counts had the worst outcomes (P < 0.001 for RFS and P = 0.019 for OS).

Conclusion: High frequency of tumor mutations in HRR genes and other cancer predisposition genes was found in early TNBC patients, but showed no significant association with survival outcome. Immune infiltration and PD-L1 expression was positively associated with HRR mutation, and both HRR mutation and high CD8+ T cell infiltration levels were associated with superior disease outcome.

Funding: This work was supported by the National Natural Science Foundation of China (82002773, 82072937 and 82072897), Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20212200), and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20172007).

Declaration of Interest: The authors have declared no conflict of inter

Ethical Approval: All patients were given informed consent and our study was approved by the Ethical Committees of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (Clinical Trial Ethics Approval Number: 2016; 5-3). All procedures were in accordance with the 1964 Helsinki declaration and its later amendment.

Keywords: triple negative breast cancer, homologous recombination repair genes, mutation spectrum, clinicopathological factors, immune infiltration, prognosis