Partner and localizer of BRCA2 (PALB2) pathogenic variants and ovarian cancer: A systematic review and meta-analysis.

Abstract

e17597 Background: Approximately 20% of ovarian cancers are due to an underlying germline pathogenic variant. While several genes have been well-established in the development of hereditary ovarian cancer (e.g. BRCA1/2, RAD51C, RAD51D, BRIP1, mismatch repair genes), there are other genes for which the cancer risk is less certain and management recommendations remain controversial, including partner and localizer of BRCA 2 (PALB2). We sought to evaluate the association between PALB2 germline pathogenic mutations and ovarian cancer in the first meta-analysis on this topic. Methods: We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO no.: CRD42021281325). We searched key electronic databases to identify studies evaluating multigene panel testing in patients with ovarian cancer. Eligible trials were subjected to meta-analysis. Results: Thirty-seven studies met inclusion criteria. We found 55,137 cases of ovarian cancer with information available on germline PALB2 pathogenic variant status. Reported histological subtypes included serous adenocarcinoma (74.8%), endometroid (6.5%), clear cell (2.1%), mucinous (3.1%), and other (13.5%). Most ovarian cancers were stages III (73.5%) and IV (22.3%), followed by II (6.0%), and I (4.1%). Among ovarian cancer cases with PALB2 sequencing data available, 0.4% demonstrated a germline pathogenic variant in the PALB2 gene and the pooled odds ratio (OR) for having a PALB2 mutation was 2.31 (95% CI 0.89- 5.98). Among 94 patients with a germline PALB2 pathogenic variant, the pooled odds ratio (OR) for developing ovarian cancer was 2.85 (95% CI 1.58-5.15) relative to 33,855 patients without PALB2 mutations. Conclusions: Our meta-analysis demonstrates that the pooled OR for developing ovarian cancer with an underlying PALB2 germline pathogenic variant was 2.85 (95% CI 1.58-5.15). While this risk is lower than many of the well-established hereditary ovarian cancer genes, it does exceed the baseline population risk of 1-2%. Whether this meets the threshold to consider risk-reducing salpingo-oophorectomy is up for debate. Large population-based studies and evaluation of the combination of PALB2 mutations and cancer family history are needed to improve management recommendations for patients harboring pathogenic mutations in this gene.