Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer

• Published in: JCO precision oncology 2023-09, Vol.7 (7), p.e2300338-e2300338
• Main Authors: Yndestad, Synnøve, Engebrethsen, Christina, Herencia-Ropero, Andrea, Nikolaienko, Oleksii, Vintermyr, Olav K, Lillestøl, Reidun K, Minsaas, Laura, Leirvaag, Beryl, Iversen, Gjertrud T, Gilje, Bjørnar, Blix, Egil S, Espelid, Helge, Lundgren, Steinar, Geisler, Jürgen, Aase, Hildegunn S, Aas, Turid, Gudlaugsson, Einar G, Llop-Guevara, Alba, Serra, Violeta, Janssen, Emiel A M, Lønning, Per E, Knappskog, Stian, Eikesdal, Hans P
• Format: Article
• Language: English
• Subjects: B7-H1 Antigen - genetics; Genes, BRCA2; Homologous Recombination - genetics; Humans; Mutation; Triple Negative Breast Neoplasms - genetics
• ISSN: 2473-4284; 2473-4284
• DOI: 10.1200/PO.23.00338

Homologous recombination deficiency (HRD) is highly prevalent in triple-negative breast cancer (TNBC) and associated with response to PARP inhibition (PARPi). Here, we studied the prevalence of HRD in non-TNBC to assess the potential for PARPi in a wider group of patients with breast cancer. HRD status was established using targeted gene panel sequencing (360 genes) and methylation analysis of pretreatment biopsies from 201 patients with primary breast cancer in the phase II PETREMAC trial (ClinicalTrials.gov identifier: NCT02624973). HRD was defined as mutations in , , , , and/or promoter methylation of (strict definition; HRD-S). In secondary analyses, a wider definition (HRD-W) was used, examining mutations in 20 additional genes. Furthermore, tumor ness (multiplex ligation-dependent probe amplification), PAM50 subtyping, RAD51 nuclear foci to test functional HRD, tumor-infiltrating lymphocyte (TIL), and PD-L1 analyses were performed. HRD-S was present in 5% of non-TNBC cases (n = 9 of 169), contrasting 47% of the TNBC tumors (n = 15 of 32). HRD-W was observed in 23% of non-TNBC (n = 39 of 169) and 59% of TNBC cases (n = 19 of 32). Of 58 non-TNBC and 30 TNBC biopsies examined for RAD51 foci, 4 of 4 (100%) non-TNBC and 13 of 14 (93%) TNBC cases classified as HRD-S had RAD51 low scores. In contrast, 4 of 17 (24%) non-TNBC and 15 of 19 (79%) TNBC biopsies classified as HRD-W exhibited RAD51 low scores. Of nine non-TNBC tumors with HRD-S status, only one had a basal-like PAM50 signature. There was a high concordance between HRD-S and either ness, high TIL density, or high PD-L1 expression (each < .001). The prevalence of HRD in non-TNBC suggests that therapy targeting HRD should be evaluated in a wider breast cancer patient population. Strict HRD criteria should be implemented to increase diagnostic precision with respect to functional HRD.