# Clinicopathological Characteristics of Ovarian and Breast Cancer in PALB2, RAD51C, and RAD51D Germline Pathogenic Variant Carriers

## TL;DR

This study examines the cancer characteristics in women with genetic mutations in PALB2, RAD51C, and RAD51D, finding differences in age and type of breast and ovarian cancers compared to general population data.

## Contribution

The study provides new clinicopathological insights into cancers in carriers of PALB2, RAD51C, and RAD51D germline pathogenic variants.

## Key findings

- Breast cancer onset in PALB2 carriers was significantly earlier than in the general population.
- All ovarian cancers in RAD51D carriers were high-grade serous carcinoma, differing from national data.
- No breast cancers were observed in PALB2 carriers, but ovarian cancers occurred at a younger age in RAD51C and RAD51D carriers.

## Abstract

Background/Objectives: Germline pathogenic variants (GPVs) in PALB2, RAD51C, and RAD51D increase breast cancer (BC) and ovarian cancer (OC) risk. Limited data on clinicopathological characteristics of BC and OC in women with these GPVs hamper guideline development. Therefore, this study aims to describe these characteristics in a consecutive series of female PALB2, RAD51C, and RAD51D GPV carriers. Methods: Women with a PALB2, RAD51C, or RAD51D GPV determined before July 2023 at the University Medical Center Groningen were included. Cancer diagnoses were obtained through linkage with the Dutch Nationwide Pathology Databank (Palga). Median onset age and histopathological subtypes were compared to the data of The Netherlands Cancer Registry (NCR). Results: Among 164 GPV carriers (125 PALB2, 30 RAD51C, and 9 RAD51D), 54 BC and 6 OC cases were identified. The median BC onset age was 52 (n = 50), 71 (n = 3), and 43 years (n = 1) for PALB2, RAD51C, and RAD51D, respectively, compared with 62 years in the NCR. No BC histological subtype differences were observed in PALB2 carriers. The populations of RAD51C and RAD51D carriers were too small to compare to NCR data. No OC cases occurred in PALB2 carriers. The median OC onset age was 66 (n = 4) and 56 years (n = 2) for RAD51C and RAD51D carriers, respectively, versus 67 years in the NCR. All RAD51D carriers had high-grade serous carcinoma, compared to 51.5% in the NCR. Conclusions: Differences in onset age and histological subtypes were observed between GPV carriers and national data. Further research on cancer characteristics is needed to optimize counseling and cancer prevention in these women.