Therapeutic applications of germline testing for cancer predisposition genes in Asia in the real world.
Authors: Cheo Seng Wee , Ong Pei-Yi , Ow Samuel Guan Wei , Chan Gloria Hui Jia , Tan David Shao Peng , Lim Yi Wan , Kong Hwai L. , Wong Andrea , Lim Siew Eng , Walsh Robert John , Wong Alvin S.C. , Low Jeffrey , Ngoi Natalie Yl , Lim Joline Si Jing , Lee Soo-Chin 
Published: June 2023

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Background: Germline genetic testing is traditionally done in patients suspected with hereditary cancer syndrome for enhanced cancer surveillance and/or prevention. In recent years, germline genetic testing is increasingly performed for therapeutic indication, given the approval of PARP inhibitor in advanced cancer patients with germline BRCA1/2 or other homologous recombination repair (HRR) gene mutations, and immunotherapy for patients with mismatch repair gene mutations. We evaluated the clinical utility of actionable (treatable) pathogenic germline mutations (PGM) in a tertiary cancer center in Asia. Methods: We conducted a retrospective review of cancer patients who underwent germline genetic testing at the National University Cancer Institute, Singapore, Cancer Genetics Clinic. The primary objectives were to determine the prevalence of potentially actionable PGM in cancer predisposition genes and their therapeutic applications, with focus on BRCA, HRR and mismatch repair genes. Results: From 2000 till 2022, 1154 cancer patients underwent germline genetic testing, with the majority (81.9%) tested with multi-gene panels comprising 9-134 genes. 93% (n = 1069) fulfilled conventional criteria for genetic testing; 7% (n = 81) were tested specifically for treatment decisions. 411 (35.6%) patients tested positive for a PGM, of which 334 (81%) were potentially actionable. BRCA1/2 mutations accounted for 62.3% of actionable mutations, followed by mismatch repair (18%; MLH1 8.7%, MSH2 6%, MSH6 2.1%, PMS2 1.2%), and other HRR genes (19.7%: RAD51 6.3%, ATM 4.8%, PALB2 3%, BRIP1 2.4%, others 3.3%). Among patients with BRCA/HRR gene mutations, breast (60%) and ovarian cancer (26.7%) were the commonest primary cancer. 152 germline positive patients have advanced cancers, and 79 (52%) patients received germline directed therapies (PARP inhibitor: n = 75; immunotherapy: n = 4). Median duration of immunotherapy in the 4 mismatch repair gene carriers was 20.5 months (range 5-40). Among germline BRCA/HRR mutation carriers with advanced cancer who were treated with PARP inhibitor, ovarian cancer was the commonest (n = 49), followed by breast (n = 14) then prostate (n = 6). Median PARP inhibitor treatment duration was 8 months (range 1-76). Among germline BRCA/HRR mutation carriers who received platinum-based chemotherapy, pathological complete response rate in the neoadjuvant setting was 53% (n = 17 breast cancers; TNBC [n = 11], other subtypes [n = 6]) and objective response rate was > 80% in the advanced setting (n = 71; ovarian = 51, breast = 9, others = 11). Conclusions: About one-third of cancer patients tested in a high risk Cancer Genetics Clinic in a tertiary cancer centre in Asia carry PGM, of which ~80% are potentially actionable. > 50% advanced cancer patients with actionable PGM received germline directed therapies, confirming the clinical utility of germline testing in the real world.