Distribution of homologous recombination deficiency (HRD) and BRCA mutations (m) detected by HRD-One test among Brazilian patients (pts) with newly diagnosed advanced epithelial ovarian, fallopian tube, or peritoneal cancer.
Authors: Scaranti Mariana , Lopes Yamamoto Guilherme , Guarischi Sousa Rodrigo , J Paniza Ana Carolina , Milanezi Fernanda , Scapulatempo-Neto Cristovam 
Published: June 2022

e17600

Background: In the Phase III PAOLA-1/ENGOT-ov25 (NCT02477644) and PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trials, the addition of a poly(ADP-ribose) polymerase (PARP) inhibitor as maintenance therapy led to a significant progression-free survival benefit in pts with newly diagnosed advanced ovarian cancer, particularly in those who were HRD positive, both including pts with BRCA1m and/or BRCA2m and pts without a BRCAm. Both trials used Myriad's myChoice to determine HRD status. However, this test is economically inaccessible for a significant fraction of the Brazilian population. Methods: We explored the prevalence and distribution of HRD and tumor (t) BRCAm in Brazilian pts using the HRD-One test that detects not only sequence variants in genes involved in homologous recombination repair (HRR) but also the genomic scars due to HRD that might be present even when a pathogenic variant in one of the HRR genes is not detected. Firstly, 59 high-grade serous epithelial ovarian cancer (HGSOC) samples were tested and the accuracy of the HRD-One score was established both by correlation with Myriad's myChoice score and an internal validation considering that most of the samples that carry a pathogenic variant in BRCA1 or BRCA2 should have HRD. HRD-One score of 2.0 or greater predicted HRD and correlated to Myriad's myChoice score of 42. HRD-One achieved an overall categorical concordance of 94.74% with the previously available commercial HRD test. We then tested stage III and IV HGSOC and high-grade endometrioid ovarian cancer pts’ tumor samples with HRD-One test only. Results: Of the 468 pts, 224 (47,9%) had HRD positive tumors, 213 (45,5%) were HRD negative, and 31 (6,6%) had inconclusive results. Ninety-six pts had t BRCAm, 95 (98.9%) of them had a genomic instability score compatible with HRD, and 59 (61%) had BRCA1m . BRCA1c.5266dupC was the most prevalent pathogenic variant in this population followed by BRCA1c.470_471del, c.5074+2T > C, c.5251C > T, and c.3331_3334del. The most prevalent BRCA2m were c.8488-1G > A, c.5216dupA, c.5073dupA, c.1796_1800del, c.8351G > A, c.2808_2811del, and c.9382C > T. Median age at diagnosis was 63 in the study population, 57 in the BRCA1m, and 60 in the BRCA2m group. 47,6% of the HGSOC were HRD positive, whereas 25% of the high-grade endometrioid ovarian cancer were HRD positive. Conclusions: This is the first study to report HRD prevalence in a cohort of Brazilian pts using HRD-One test validated to detect HRD genomic scars and t BRCAm. HRD was detected in approximately 50% of HGSOC pts which is in line with previous studies in different populations. HRD-One might help us select pts to receive PARP inhibitors in the front-line therapy noticeably in a low-resource setting where Myriad's myChoice is not widely available.