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Randomized Controlled Trial
. 2018 Mar 1;29(3):654-660.
doi: 10.1093/annonc/mdx821.

Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with adjuvant doxorubicin and cyclophosphamide (SWOG S9313)

P Sharma  1 , W E Barlow  2 , A K Godwin  3 , H Pathak  3 , K Isakova  3 , D Williams  4 , K M Timms  4 , A R Hartman  4 , R J Wenstrup  4 , H M Linden  5 , D Tripathy  6 , G N Hortobagyi  6 , D F Hayes  7
Affiliations
Randomized Controlled Trial

Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with adjuvant doxorubicin and cyclophosphamide (SWOG S9313)

P Sharma et al. Ann Oncol. .

Abstract

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).

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Figures

Figure 1.
Figure 1.
(A) Disease-free survival (DFS) by homologous recombination deficiency (HRD) status. (B) Overall survival (OS) by HRD status. (C) DFS by HRD score for BRCA wild-type patients. (D) OS by HRD score for BRCA wild-type patients.
Figure 2.
Figure 2.
(A) Disease-free survival (DFS) by BRCA mutation status. (B) Overall survival (OS) by BRCA mutation status. (C) DFS by BRCA1 promoter methylation (PM) status. (D) OS by BRCA1 PM status. BRCA mutation information was available for 312 patients, and BRCA1 PM was available for 348 subjects.
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