Multiple Primary Cancers in Patients Undergoing Tumor-Normal Sequencing Define Novel Associations

Background: Cancer survivors are developing more subsequent tumors. We sought to characterize patients with multiple (>=2) primary cancers (MPC) to assess associations and genetic mechanisms. Methods: Patients were prospectively consented (01/2013-02/2019) to tumor-normal sequencing via a custom targeted panel (MSK-IMPACT). A subset consented to return of results of >=76 cancer predisposition genes. International Agency for Research on Cancer (IARC) 2004 rules for defining MPC were applied. Tumor pairs were created to assess relationships between cancers. Age-adjusted, sex-specific, standardized incidence ratios (SIR) for 1st-2nd cancer event combinations were calculated using SEER rates, adjusting for confounders and time of ascertainment. Associations were made with germline and somatic variants. Results: Of 24,241 patients, 4,340 had MPC (18%); 20% were synchronous. Most (80%) had 2 primaries; however, 4% had >=4 cancers. SIR analysis found lymphoma-lung, lymphoma-uterine, breast-brain, and melanoma-lung pairs in women and prostate-mesothelioma, prostate-sarcoma, melanoma-stomach, and prostate-brain pairs in men in excess of expected after accounting for synchronous tumors, known inherited cancer syndromes, and environmental exposures. Of 1580 (36%) patients who received germline results; 324 (21%) had 361 pathogenic/likely pathogenic variants (PV), 159 (44%) in high penetrance genes. Of tumor samples analyzed, 55% exhibited loss of heterozygosity at the germline variant. In those with negative germline findings, melanoma, prostate, and breast cancers were common. Conclusion: We identified tumor pairs without known predisposing mutations that merit confirmation and will require novel strategies to elucidate genetic mechanisms of shared susceptibilities. Impact: If verified, MPC patients with novel phenotypes may benefit from targeted cancer surveillance.