Breast cancer post-ovarian cancer in germline non-BRCA homologous recombination (HR) gene pathogenic variant carriers.

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10607 Background: Ovarian cancer (OC) is characterized by deficiencies in homologous recombination (HR). Although germline and somatic BRCA1/2 pathogenic variants (PVs) play a critical role in HR and OC, germline PVs in other genes associated with HR, such as RAD51C, RAD51D, BRIP1 , and PALB2 , have also been linked to an increased risk of OC development. Most of these genes are also associated with increased risk of certain types of breast cancer (BC). However, little is known about risks of secondary BC after OC in this germline non-BRCA HR population. Methods: We identified patients with OC treated at a single institution undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015 to 12/31/2020. Germline assessment of ≥76 genes was performed, including HR genes ATM , BARD1 , BRIP1 , FANCA , FANCC , NBN , PALB2 , RAD50 , RAD51B , RAD51C , and RAD51D . Biallelic inactivation was assessed within tumors at the germline variant locus using the FACETS (fraction and allele-specific copy number estimates from tumor sequencing) algorithm. In this study, genes with high rates of biallelic inactivation (≥60%) were included based on role in OC tumorigenesis. Thus, we focused on patients with BRIP1 , PALB2 , and RAD51B/C/D PVs and further extracted clinical data including secondary BC screening patterns and rates. Results: Of the 882 patients with OC and germline assessment, 56 (6%) had germline PV in non-BRCA HR genes, and 35 (4%) patients had germline PV in BRIP1 (n = 13), PALB2 (n = 4) , RAD51B (n = 4), RAD51C (n = 4), or RAD51D (n = 10). With a median follow-up after OC diagnosis of 55.82 months, no metachronous BC diagnosis occurred in these 35 patients. Among this cohort, 23 (66%) patients received PARP inhibitor therapy for OC, and 17 (49%) patients died from OC. Three patients (9%) were diagnosed with BC before OC diagnosis (germline PALB2 , RAD51B, and RAD51D PV carriers). All 3 patients were BC disease-free at the time of data cutoff, and 2 died of their OC. Twenty-five patients (71%) underwent BC screening during OC treatment/follow-up with annual mammography, and 4 (16%) underwent additional annual magnetic resonance imaging. Only two patients were more intensively followed due to abnormal breast findings that were resolved during the follow-up. No patients underwent risk-reducing breast surgery. Interestingly, 30 patients (86%) had a family history of cancer: 12 (40%) with breast cancer, 6 (20%) with ovarian cancer, 8 (27%) with both breast and ovarian cancer, and 4 (13 %) with other cancers. Conclusions: BC incidence after OC diagnosis and treatment in non-BRCA HR germline PV carriers remains low, probably due to the poor prognosis of OC and the potential preventive effects of PARP inhibitor treatments on BC development. Further prospective studies are needed to address this question.

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