The landscape of secondary malignancies in cancer survivors and the susceptibility to hereditary multiple cancer syndrome: a Korean nationwide population-based study

Background Cancer survivors and secondary malignancy risk have increased following early diagnosis and advanced cancer treatments; however, secondary malignancy risk in cancer survivors and possibility of genetic susceptibility among young individuals with multiple cancers have scarcely been evaluated. We evaluated the risk of secondary malignancies in cancer survivors by primary cancer type, and the combination of cancer types frequently observed in young patients with multiple cancers. Methods and Findings Patients diagnosed with cancer, from Korea Health Insurance Review and Assessment database, between January 2009 and December 2010, were followed-up until December 2019. Cancer survivors and those with secondary cancers were defined as having lived >5 years without developing other cancers; and being newly diagnosed with cancer at another site, respectively. To identify possible hereditary multiple cancer syndrome (HMCS), combinations of multiple cancers frequently observed in young individuals compared to older adults were evaluated. Of the 371,181 patients in 3,008,274 person-years of follow-up, 266,241 were cancer survivors; of these 7,348 had secondary cancers (2.76%; 2,759.9 persons/100,000 population), higher than primary cancer risk in general population. The common primary cancer types were those mainly observed as secondary cancer in cancer survivors. Contrarily, higher-risk cancers among those with secondary cancers compared to those in the general population varied by sex and primary cancer type, suggesting the need for tailored cancer screening for cancer survivors. Combinations of well-known hereditary cancer syndrome-related cancer types were mainly observed in younger compared to older patients with multiple cancers, which could be HMCS, including cancer combinations those may be caused by a novel cancer predisposition gene. Conclusions Cancer survivors harbor high and distinctive secondary cancer risk than the general population, necessitating tailored cancer screening in survivors. Genetic screening should be considered for young patients with multiple cancers to validate genetic predisposition. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The author(s) received no specific funding for this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the research ethics committee of South Korea National Health Insurance Sharing Service (M20200902739) and the institutional review board of Severance Hospital (4-2020-0155). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Not Applicable All relevant data are within the manuscript and its Supporting Information files.