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

Abstract

Background: Cancer survivors are developing more subsequent cancers. SIR analysis found lymphoma–lung, lymphoma–uterine, tumors. We sought to characterize patients with multiple (≥2) breast–brain, and melanoma–lung pairs in women and primary cancers (MPC) to assess associations and genetic prostate–mesothelioma, prostate–sarcoma, melanoma–stomach, mechanisms. and prostate–brain pairs in men in excess of expected after account-Methods: Patients were prospectively consented (01/2013–02/ ing for synchronous tumors, known inherited cancer syndromes, 2019) to tumor-normal sequencing via a custom targeted panel and environmental exposures. Of 1,580 (36%) patients who received (MSK-IMPACT). A subset consented to return of results of ≥76 germline results, 324 (21%) had 361 pathogenic/likely pathogenic cancer predisposition genes. International Agency for Research on variants (PV), 159 (44%) in high penetrance genes. Of tumor Cancer (IARC) 2004 rules for defining MPC were applied. Tumor samples analyzed, 55% exhibited loss of heterozygosity at the pairs were created to assess relationships between cancers. Age-germline variant. In those with negative germline findings, melaadjusted, sex-specific, standardized incidence ratios (SIR) for first to noma, prostate, and breast cancers were common. second cancer event combinations were calculated using SEER Conclusions: We identified tumor pairs without known predisrates, adjusting for confounders and time of ascertainment. Assoposing mutations that merit confirmation and will require novel ciations were made with germline and somatic variants. strategies to elucidate genetic mechanisms of shared susceptibilities. Results: Of 24,241 patients, 4,340 had MPC (18%); 20% were Impact: If verified, patients with MPC with novel phenotypes synchronous. Most (80%) had two primaries; however, 4% had ≥4 may benefit from targeted cancer surveillance.