Germline landscape of ovarian cancer across age groups: Spotlight on elderly patients.
Authors: Sia Tiffany Y. , Moufarrij Sara , Zhou Qin , Khurram Aliya , Kemel Yelena , Iasonos Alexia , Long Roche Kara , Stadler Zsofia Kinga , Tew William P. , Lichtman Stuart M. , Liu Ying L 
Published: June 2024

10583

Background: Genetic testing is recommended for all patients with ovarian cancer (OC), particularly high-grade serous OC (HGSOC). However, emphasis is often placed on younger patients, and the germline landscape of elderly patients with HGSOC is not well studied. We sought to define germline pathogenic variants (gPV) in patients with HGSOC by age. Methods: Patients with HGSOC treated at our institution who underwent clinical tumor-normal sequencing from 1/1/2015 – 3/31/2022, inclusive of germline analysis of ≥76 genes were included. Clinical variables including age at diagnosis were collected. OC-related genes were defined as BRCA1, BRCA2, BRIP1, RAD51B, RAD51C, RAD51D, PALB2, ATM, MLH1, MSH2, MSH6,and PMS2. Logistic regression models were built to examine associations between presence of gPV and clinical variables. In patients with new gPV findings, rates of genetics follow-up were calculated. Results: Of 1,231 patients with HGSOC, median age at diagnosis was 63 years (range 33-93) with 163 (13%) patients diagnosed age ≤49, 739 (60%) diagnosed ages 50-69, and 329 (27%) diagnosed age ≥70 years. Age-related differences were observed in primary treatment (neoadjuvant vs. primary debulking), genetic ancestry, marital status, insurance type, and National Cancer Institute (NCI) comorbidity index, p<0.01.We observed gPV in 68/163 (42%) patients diagnosed age ≤49, 200/739 (27%) patients diagnosed ages 50-69, and 52/329 (16%) patients diagnosed age ≥70 years, p<0.001. OC-related gPV were found in 59/163 (36%) patients diagnosed age ≤49, 132/739 (18%) patients diagnosed ages 50-69, and 26/329 (7.9%) patients diagnosed age ≥70 years, p<0.001. Age was associated with gPV in univariate and multivariable (MV) models, even after adjustment for genetic ancestry and NCI comorbidity index. Compared to patients diagnosed ages 50-69 years, those diagnosed age ≥70 were less likely to have gPV (OR 0.58 95% CI 0.38-0.86) and those diagnosed at age ≤49 were more likely to have a gPV (OR 1.78 95% CI 1.18-2.68) in MV models. Among the 67 patients diagnosed age ≥80 years, 7 (10%) had gPV with only 2/7 in OC-related gPV ( BRCA2and PALB2) and the rest being of low/recessive/uncertain penetrance (N=1 FANCC,N=2 APC,N=1 BLM,N=1 CHEK2).In contrast, in the 21 patients diagnosed age ≤39 years, 12 (57%) had gPV with 2 patients having 2 gPV. All 21 patients had gPV in OC-related genes with 1 patient having both a BRCA1 and BRCA2 gPV and another having a BRCA1 and ERCC3 gPV. No differences in genetics follow-up were observed by age group in those with new gPV with 65% of patients diagnosed age ≥70 years having genetics follow-up for a new gPV. Conclusions: Although gPV vary by age in those with HGSOC with highest rates in those diagnosed younger than 50 years, rates are high (≥10%) with good genetics follow-up in all age groups. Our findings support genetic testing in all patients with EOC regardless of age given implications for treatment and family members.