Multi-gene panel testing of patients with multiple primary malignancies suspected with hereditary cancer syndrome.
1512 Background: Developing multiple primary cancers is an indicator of underlying hereditary cancer predisposition, but there is a paucity of data regarding the characteristics and clinical genetic testing outcome of these patients. Methods: We compared cancer index patients with 1 vs > 1 primary malignancy who underwent evaluation and clinical testing with multi-gene panels comprising up to 49 genes in a cancer genetics clinic in a tertiary cancer centre in Asia from 1998-2016. Results: Among 1191 cancer index patients, 960 (80.6%), 205 (17.2%), and 26 (2.2%) respectively had 1, 2, and ≥3 primary malignancies. Among patients with > 1 primary cancers (n = 231), the most common cancer pairs were breast-breast (35.4%), breast-ovary (12.1%), endometrium-ovary (8.2%), colon-colon (2.4%) and, colon-endometrium (2.4%). The mean age at diagnosis of the first, second and third cancers were 46.0 (21 to 87), 52.1 (21 to 89) and 57.7 (41 to 83) respectively. The mean duration between first and second cancers is 6.0 years (0 to 32). The most commonly suspected syndromes in patients with 1 vs > 1 primary cancer were hereditary breast and ovarian cancer 63.8% vs 53.6%, Lynch 24.8% vs 31.1%, Li-Fraumeni syndromes 1.8% vs 1.7%, and others 9.3% vs 13.4% (p = 0.03). Patients with > 1 primary cancer were more likely to have > 20% a priori risk of suspected hereditary cancer syndrome (42.8% vs. 26.5%; p < 0.001). 504/1191 (42.3%) patients underwent gene testing, including 394/960 (41.0%) and 110/231 (47.6%) patients with 1 vs > 1 cancer. Deleterious mutations were more likely to be identified in patients with > 1 vs 1 cancer (34.5% vs. 25.8%; p = 0.073), with causative genes being BRCA1 38.5%, BRCA2 17.9%, MLH1/MSH2/MSH6 20.5%, TP53 7.7%, and others (ATM [n = 2], MUTYH, APC, PALB2, RAD51 [n = 1 each]) for patients with > 1 cancer. VUS rates were 31.7% vs.31.8% in patients with 1 vs > 1 cancer, and were identified in genes including BRIP1, CHEK2, PALLD, POLE, PTEN, STK11, SMARCA4, and VHL. Conclusions: Patients with > 1 primary cancer comprised one-fifth of cancer index patients evaluated at a cancer genetics clinic, and were more likely to be found with deleterious mutations than patients with only 1 cancer on multi-gene panel testing.