Heterozygote Germline Mutations in Homologous Recombination Core Genes Can Predict for Pathologic Complete Response in Early Triple Negative Breast Cancer

Author(s): C Fontaine, S De Brakeleer, ETeugels, V Renard, H Van den Bulck, P Vuylsteke, P. Glorieux, C Dopchie, S Joris, L Decoster, A Awada, K Punie, H Wildiers, J De Grève, on behalf of the BSMO Breast cancer working group

Background: BSMO 2014-01 is a published prospective phase 2 study investigating neoadjuvant weekly paclitaxel and carboplatin, followed by epirubicin and cyclophosphamide in 63 patients with triple-negative breast cancer. Pathological complete response (pCR) was 54%. A secondary endpoint was to correlate pCR rate to the presence of germline pathogenic variants in DNA damage response (DDR) genes and in core genes involved in Homologous Recombination (HR).

Methods: Peripheral blood from 60 TNBC patients was collected for germline DNA analysis. Whole Exome Sequencing was performed; we considered only rare variants (minor allelic frequency < 0.01) in 276 DDR genes of which 88 HR and 21 HR core genes. The correlation between pCR rate and mutations in DDR or HR genes was analyzed using the Fisher's exact test. The same was done for the correlation between DDR gene mutations and the presence of hematologic toxicities.

Results: Thirty-five out of 60 patients (58.3%) carried a protein disrupting germline mutation in a DDR gene. Twenty-four of these 35 patients (68.6%) had a pCR, compared to 40% without a DDR mutation (p=0.026). In 14/15patients (93.3%) with a HR core gene mutation a pCR was obtained, while a pCR was present in 44.4% without a HR core gene mutation (p=0.0007). HR core gene mutations were detected in BRCA1 (5), BRCA2 (4), RAD52 (4), RAD50 (1), BARD1 (1) and EME1 (1).

Conclusions: This is the first study to demonstrate that germline pathogenic variants in genes involved in HR core genes predict for pCR after platinum-containing neoadjuvant chemotherapy.