Dataset Information

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

ABSTRACT:

Background

Triple-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.

Methods

Data 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.

Results

HRD 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).

Conclusions

These 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.

SUBMITTER: Liao G

PROVIDER: S-EPMC8408988 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Homologous recombination deficiency (HRD)-causing alterations have been reported in triple-negative breast cancer (TNBC). We hypothesized that TNBCs with HRD alterations might be more sensitive to anthracycline plus cyclophosphamide-based chemotherapy and report on HRD status and BRCA1 promoter methylation (PM) as prognostic markers in TNBC patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG9313. Patients and methods:In total, 425 TNBC patients were identified from S9313. HRD score, tumor BRCA1/2 sequencing, and BRCA1 PM were carried out on DNA isolated from formalin-fixed paraffin-embedded tissue. Positive HRD status was defined as either a deleterious tumor BRCA1/2 (tBRCA) mutation or a pre-defined HRD score ?42. Markers were tested for prognostic value on disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment and nodal status. Results:HRD status was determined in 89% (379/425) of cases. Of these, 67% were HRD positive (27% with tBRCA mutation, 40% tBRCA-negative but HRD score??42). HRD-positive status was associated with a better DFS [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.51-1.00; P?=?0.049] and non-significant trend toward better OS (HR?=?0.71; 95% CI 0.48-1.03; P?=?0.073). High HRD score (?42) in tBRCA-negative patients (n?=?274) was also associated with better DFS (HR?=?0.64; 95% CI 0.43-0.94; P?=?0.023) and OS (HR?=?0.65; 95% CI 0.42-1.00; P?=?0.049). BRCA1 PM was evaluated successfully in 82% (348/425) and detected in 32% of cases. The DFS HR for BRCA1 PM was similar to that for HRD but did not reach statistical significance (HR?=?0.79; 95% CI 0.54-1.17; P?=?0.25). Conclusions:HRD positivity was observed in two-thirds of TNBC patients receiving adjuvant AC and was associated with better DFS. HRD status may identify TNBC patients who receive greater benefit from AC-based chemotherapy and should be evaluated further in prospective studies. Clinical Trials Number:Int0137 (The trial pre-dates Clinicaltrial.Gov website establishment).