BRCAness digitalMLPA profiling predicts benefit of intensified platinum-based chemotherapy in triple-negative and luminal-type breast cancer

Esther H Lips,Mark Opdam,Sabine C Linn,Suvi Savola,Frans B L Hogervorst,Anne Benard-Slagter,Petra M Nederlof,Jelle Wesseling,Caroline E Scheerman

doi:10.1186/s13058-020-01313-7

Abstract

BackgroundWe previously showed that BRCA-like profiles can be used to preselect individuals with the highest risk of carrying BRCA mutations but could also indicate which patients would benefit from double-strand break inducing chemotherapy. A simple, robust, and reliable assay for clinical use that utilizes limited amounts of formalin-fixed, paraffin-embedded tumor tissue to assess BRCAness status in both ER-positive and ER-negative breast cancer (BC) is currently lacking.MethodsA digital multiplex ligation-dependent probe amplification (digitalMLPA) assay was designed to detect copy number alterations required for the classification of BRCA1-like and BRCA2-like BC. The BRCA1-like classifier was trained on 71 tumors, enriched for triple-negative BC; the BRCA2-like classifier was trained on 55 tumors, enriched for luminal-type BC. A shrunken centroid-based classifier was developed and applied on an independent validation cohort. A total of 114 cases of a randomized controlled trial were analyzed, and the association of the classifier result with intensified platinum-based chemotherapy response was assessed.ResultsThe digitalMLPA BRCA1-like classifier correctly classified 91% of the BRCA1-like samples and 82% of the BRCA2-like samples. Patients with a BRCA-like tumor derived significant benefit of high-dose chemotherapy (adjusted hazard ratio (HR) 0.12, 95% CI 0.04–0.44) which was not observed in non-BRCA-like patients (HR 0.9, 95% CI 0.37–2.18) (p = 0.01). Analysis stratified for ER status showed borderline significance.ConclusionsThe digitalMLPA is a reliable method to detect a BRCA1- and BRCA2-like pattern on clinical samples and predicts platinum-based chemotherapy benefit in both triple-negative and luminal-type BC.

Highlights

We previously showed that BRCA-like profiles can be used to preselect individuals with the highest risk of carrying BRCA mutations but could indicate which patients would benefit from double-strand break inducing chemotherapy
Breast cancers arising in women with a BRCA1 or BRCA2 germline mutation are characterized by genomic instability
Training and validation of digitalMLPA-based BRCAness classifiers Table 1 gives an overview of the sample series used to develop and test the classifier

Summary

Introduction

We previously showed that BRCA-like profiles can be used to preselect individuals with the highest risk of carrying BRCA mutations but could indicate which patients would benefit from double-strand break inducing chemotherapy. Breast cancers arising in women with a BRCA1 or BRCA2 germline mutation are characterized by genomic instability. As both BRCA1 and BRCA2 play a role in the process of homologous recombination, non-functioning BRCA genes result in incorrect DNA repair, leading to gross genomic instability. Our group has shown that BRCA1- and BRCA2-mutated tumors have a specific pattern of chromosomal gains and losses [1,2,3]. These specific genomic regions were used to develop a BRCA1like and a BRCA2-like classifier. The classifiers have been used in the classification of BRCA1 variants of unknown significance (VUS) [2]

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Discussion

Conclusion