Combined homologous recombination repair deficiency and immune activation analysis for predicting intensified responses of anthracycline, cyclophosphamide and taxane chemotherapy in triple-negative breast cancer

BMC Medicine

Yiran Yang¹  Yunpeng Zhang¹  Liwen Xu¹  Zedong Jiang¹  Min Yan¹  Aimin Xie¹  Jiali Zhu¹  Gaoming Liao¹  Xia Li²  Yun Xiao²  Cong Zhang³  Meiting Jiang⁴ 

[1] College of Bioinformatics Science and Technology, Harbin Medical University, 150081, Harbin, Heilongjiang, China;College of Bioinformatics Science and Technology, Harbin Medical University, 150081, Harbin, Heilongjiang, China;Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, 150081, Harbin, Heilongjiang, China;Department of Ultrasonic Medicine, The First Affiliated Hospital of Harbin Medical University, 150010, Harbin, Heilongjiang, China;Key Laboratory of University in Heilongjiang Province, Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, 150086, Harbin, China;

关键词: Triple-negative breast cancer;    ACT chemotherapy;    Homologous recombination repair deficiency;    Failure-free interval;    Immune checkpoint;   

DOI  :  10.1186/s12916-021-02068-4

来源: Springer

【 摘 要 】

BackgroundTriple-negative breast cancer (TNBC) is a clinically aggressive disease with abundant variants that cause homologous recombination repair deficiency (HRD). Whether TNBC patients with HRD are sensitive to anthracycline, cyclophosphamide and taxane (ACT), and whether the combination of HRD and tumour immunity can improve the recognition of ACT responders are still unknown.MethodsData from 83 TNBC patients in The Cancer Genome Atlas (TCGA) was used as a discovery cohort to analyse the association between HRD and ACT chemotherapy benefits. The combined effects of HRD and immune activation on ACT chemotherapy were explored at both the genome and the transcriptome levels. Independent cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) were adopted to validate our findings.ResultsHRD was associated with a longer ACT chemotherapy failure-free interval (FFI) with a hazard ratio of 0.16 (P = 0.004) and improved patient prognosis (P = 0.0063). By analysing both HRD status and ACT response, we identified patients with a distinct TNBC subtype (ACT-S&HR-P) that showed higher tumour lymphocyte infiltration, IFN-γ activity and NK cell levels. Patients with ACT-S&HR-P had significantly elevated immune inhibitor levels and presented immune activation associated with the increased activities of both innate immune cells and adaptive immune cells, which suggested treatment with immune checkpoint blockade as an option for this subtype. Our analysis revealed that the combination of HRD and immune activation enhanced the efficiency of identifying responders to ACT chemotherapy (AUC = 0.91, P = 1.06e−04) and synergistically contributed to the clinical benefits of TNBC patients. A transcriptional HRD signature of ACT response-related prognostic factors was identified and independently validated to be significantly associated with improved survival in the GEO cohort (P = 0.0038) and the METABRIC dataset (P < 0.0001).ConclusionsThese findings highlight that HR deficiency prolongs FFI and predicts intensified responses in TNBC patients by combining HRD and immune activation, which provides a molecular basis for identifying ACT responders.

【 授权许可】

CC BY