Clinical utility of germline genetic testing in diverse cancer types.

10590 Background: Germline genetic testing (GGT) is often recommended for cancer patients with an estimated ≥10% risk of carrying a clinically actionable pathogenic germline variant (PGV). Clinical utility of GGT is understudied for many cancer types, making assessing risk challenging. Herein we describe interim results from a GGT study of diverse cancer types. Methods: The PROACTIVE (Profile And Cancer gene Testing for IndiVidual Evaluation) Study is an ongoing institute-wide study at Dana-Farber Cancer Institute through which participants may opt-in to blood- or saliva-based clinical GGT of 133-156 genes, with results returned. Participants were identified by their clinical program, mainly consisting of those who did not meet clinical criteria for GGT based on having cancers that are considered low-risk for hereditary cancer predisposition syndromes. Clinically actionable PGV were defined as those that conferred potential eligibility for clinical management guidelines, targeted therapies and/or clinical trials. Results: Between 03/15/2019 and 11/30/2024, 1569 participants completed GGT. PGV were identified in 437/1569 (27.9%) participants, however 285 (18.2%) had PGV associated only with autosomal recessive cancer risk or low penetrance. Clinically actionable PGV were identified in 152/1569 (9.7%) participants and made up one-third (152/437) of PGV results. Clinically actionable PGV were identified most frequently in ATM , CHEK2 , APC , BRCA2 , and TP53 , with the highest rates in gastric, central nervous system (CNS), and thyroid cancer (Table). High risk PGV were identified in 67/1569 (4.3%) participants, and were most frequent in the gastric, thyroid, and CNS cohorts (Table). Only 47/1569 (3.0%) participants had a PGV that was concordant with their cancer type. Conclusions: GGT identified clinically actionable findings in nearly 1 in 10 participants, most of whom were considered low-risk for hereditary cancer predisposition based on their personal cancer types. Most clinically actionable results were secondary findings unrelated to the presenting cancer type, but still impact cascade testing and screening for second primary cancers. This demonstrates the clinical utility of offering universal pan-cancer GGT to a broader range of cancer patients. Largest cohorts by cancer type. Cancer Type^ N Any PGV (%) Clinically Actionable PGV (%) High Risk PGV (%) PGV Concordance with Cancer Type (%) Lung 409 130 (32) 41 (10) 16 (4) 8 (2) Sarcoma* 229 59 (26) 19 (8) 9 (4) 6 (3) Endometrial (normal IHC) 206 52 (25) 13 (6) 6 (3) 5 (2) CNS* 125 37 (30) 15 (12) 6 (5) 3 (2) Renal* 121 27 (22) 8 (7) 5 (4) 2 (2) Bladder 77 13 (17) 5 (7) 2 (3) 0 (0) Thyroid* 56 14 (25) 6 (11) 4 (7) 2 (4) Cholangiocarcinoma 53 10 (19) 4 (8) 2 (4) 0 (0) Gastric 40 13 (33) 7 (18) 3 (8) 1 (3) *Includes adult and pediatric participants. ^Additional enrolled cancer types with fewer participants (N) include: melanoma, mesothelioma, multiple myeloma, therapy-associated polyposis, tongue, colon, breast.