Cancer-predisposing germline variants and subsequent cancer risk

Childhood cancer survivors face an increased risk of new tumours, different from the initial disease, which persists throughout their life. The initial cancer treatment is a risk factor for these subsequent malignant neoplasms1Turcotte LM Neglia JP Reulen RC et al.Risk, risk factors, and surveillance of subsequent malignant neoplasms in survivors of childhood cancer: a review.J Clin Oncol. 2018; 36: 2145-2152Crossref PubMed Scopus (85) Google Scholar and it is becoming increasingly evident that germline genetic factors are also involved.2Kratz CP Jongmans MC Cavé H et al.Predisposition to cancer in children and adolescents.Lancet Child Adolesc Health. 2021; 5: 142-154Summary Full Text Full Text PDF PubMed Google Scholar In The Lancet Oncology, Cheng Chen and colleagues3Chen C Qin N Wang M et al.Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study.Lancet Oncol. 2023; 10: 1147-1156Google Scholar report on the role of high-penetrance cancer predisposing variants as a composite contributing factor to subsequent malignant neoplasm-associated mortality in childhood cancer survivors. Among more than 12 000 5-year survivors, 263 subsequent malignant neoplasm-related deaths occurred during follow-up. Cancer predisposing variant carriers (5% of the survivor cohort; n=28 subsequent malignant neoplasm-related deaths) were at a more than three-times higher subsequent malignant neoplasm-related mortality risk compared with non-carriers. Treatment-related factors were evaluated concurrently and relative risks for high-dose radiation exposure were similar to those for a positive cancer predisposing variant status. Despite the impressive cohort size, analyses by childhood cancer type, subsequent malignant neoplasm type, or specific genes were not feasible, as can be seen from our summary three-way classification table of the 28 subsequent malignant neoplasm-related deaths (table).3Chen C Qin N Wang M et al.Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study.Lancet Oncol. 2023; 10: 1147-1156Google Scholar Because of the focus on any lethal subsequent malignant neoplasm as an outcome, treatment factors were condensed, and thus nowhere near reflecting the true diversity in radiotherapy characteristics, chemotherapy agents, and hematopoietic stem-cell treatments, nor their effect on specific subsequent malignant neoplasm types.1Turcotte LM Neglia JP Reulen RC et al.Risk, risk factors, and surveillance of subsequent malignant neoplasms in survivors of childhood cancer: a review.J Clin Oncol. 2018; 36: 2145-2152Crossref PubMed Scopus (85) Google Scholar Approximately a third of cancer predisposing variant-positive patients with fatal subsequent malignant neoplasms had subsequent malignancies of the CNS (N=9). Analyses of subsequent neoplasm incidence in survivorship cohorts typically show a different distribution and are dominated by more prognostically favourable subsequent cancer types, such as non-melanoma skin cancer, thyroid cancer, breast cancer, and meningioma.1Turcotte LM Neglia JP Reulen RC et al.Risk, risk factors, and surveillance of subsequent malignant neoplasms in survivors of childhood cancer: a review.J Clin Oncol. 2018; 36: 2145-2152Crossref PubMed Scopus (85) Google ScholarTableCharacteristics of 28 cancer predisposing variant positive cohort members from the combined SJLIFE and CCSS cohort who died of subsequent malignant neoplasms, by childhood cancer typeCNS tumourNon-Hodgkin lymphomaSoft tissue sarcomaBone sarcomaLungBreastStomachBiliary or liverLarge intestineKidneyProstateOtherTotalAcute lymphoblastic leukaemiaTMEM127; PTPN11 and SMARCA4......................2Hodgkin lymphoma....SDHB......BRCA2PHOX2B; BRCA2......BRCA25Non-Hodgkin lymphoma..NF1................CDKN2ATP53; PMS24CNS tumourNF1; NF1 and NF2; NF1; NF1 and BRAF............NF1........5Wilms' tumourNRAS................WT1....2NeuroblastomaNF1......................1Retinoblastoma....RB1RB1................2Osteosarcoma..........TP53....TP53FH....3Soft tissue sarcomaTP53......TP53TP53..........NF14Total number of individuals91211213121428Each entry represents an individual cohort member; three individuals were affected by two different germline variants. Based on appendix (p 49).3Chen C Qin N Wang M et al.Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study.Lancet Oncol. 2023; 10: 1147-1156Google Scholar Open table in a new tab Each entry represents an individual cohort member; three individuals were affected by two different germline variants. Based on appendix (p 49).3Chen C Qin N Wang M et al.Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study.Lancet Oncol. 2023; 10: 1147-1156Google Scholar The authors concluded that testing survivors for highly penetrant cancer predisposing variants holds promise as a risk stratification factor to identify individuals at high risk of subsequent malignant neoplasms. We agree, but clinical recommendations for doing this need to bridge the somewhat distinct approaches taken by the current guidelines for cancer predisposition syndromes and survivorship and consider both the patients' cancer predisposing variant status and cancer treatment history. Clinical care for cancer predisposing variant carriers and their affected families by dedicated cancer predisposition syndrome care teams is increasingly focused on secondary prevention of syndrome-specific neoplasms with, at least in part, evidence-based cancer surveillance guidelines, including investigations such as whole-body imaging for early tumour detection.4Villani A Shore A Wasserman JD et al.Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study.Lancet Oncol. 2016; 17: 1295-1305Summary Full Text Full Text PDF PubMed Google Scholar The psychological benefits and drawbacks of genetic testing versus not testing deserve ample consideration, addressing issues such as so-called scanxiety4Villani A Shore A Wasserman JD et al.Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study.Lancet Oncol. 2016; 17: 1295-1305Summary Full Text Full Text PDF PubMed Google Scholar, 5Robson ME Bradbury AR Arun B et al.American Society of Clinical Oncology Policy statement update: genetic and genomic testing for cancer susceptibility.J Clin Oncol. 2015; 33: 3660-3667Crossref PubMed Scopus (417) Google Scholar and providing specialised genetic counselling to support informed decision making.5Robson ME Bradbury AR Arun B et al.American Society of Clinical Oncology Policy statement update: genetic and genomic testing for cancer susceptibility.J Clin Oncol. 2015; 33: 3660-3667Crossref PubMed Scopus (417) Google Scholar Ripperger and colleagues6Ripperger T Evans DG Malkin D Kratz CP Choose and stay on one out of two paths: distinction between clinical versus research genetic testing to identify cancer predisposition syndromes among patients with cancer.Fam Cancer. 2021; 20: 289-291Crossref PubMed Scopus (3) Google Scholar distinguished the clinical use of targeted genetic testing in specific high-risk groups and research-based broad-panel testing;3Chen C Qin N Wang M et al.Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study.Lancet Oncol. 2023; 10: 1147-1156Google Scholar they proposed rules for each of the two situations, including what to test, how to communicate results, and the need to provide psychological support. For most (>90%) paediatric cancer survivors not affected by known cancer predisposing variants, national and internationally harmonised guidelines on subsequent malignant neoplasm surveillance apply,7van Kalsbeek RJ van der Pal HJH Kremer LCM et al.European PanCareFollowUp recommendations for surveillance of late effects of childhood, adolescent, and young adult cancer.Eur J Cancer. 2021; 154: 316-328Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar which are increasingly implemented in survivorship care plans and routine late-effects care in resource-rich countries.8Haupt R Essiaf S Dellacasa C et al.The ‘Survivorship Passport’ for childhood cancer survivors.Eur J Cancer. 2018; 102: 69-81Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 9van Kalsbeek RJ Korevaar JC Rijken M et al.Evaluating the feasibility, effectiveness and costs of implementing person-centred follow-up care for childhood cancer survivors in four European countries: the PanCareFollowUp Care prospective cohort study protocol.BMJ Open. 2022; 12e063134Crossref PubMed Scopus (0) Google Scholar These guidelines emphasise: (1) the need to balance the benefits and side-effects of screening; (2) an organ-specific focus; (3) risk stratification mainly by previous treatment characteristics and age; and (4) increasingly, a focus on shared decision making by the patient and care provider for or against active surveillance.10Bowers DC Verbruggen LC Kremer LCM et al.Surveillance for subsequent neoplasms of the CNS for childhood, adolescent, and young adult cancer survivors: a systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.Lancet Oncol. 2021; 22: e196-e206Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar Childhood cancer survivors with a known positive cancer predisposing variant status are typically not covered by these cancer survivorship follow-up guidelines. Owing to their cancer treatment history and their underlying genetic risk, these childhood cancer survivors will also be at risk of a range of treatment-related health problems7van Kalsbeek RJ van der Pal HJH Kremer LCM et al.European PanCareFollowUp recommendations for surveillance of late effects of childhood, adolescent, and young adult cancer.Eur J Cancer. 2021; 154: 316-328Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar from a heterogeneous group of treatment exposures often specific to the type of childhood cancer and decade of diagnosis. Our table highlights the additional heterogeneity in the genetic effects. Therefore, a holistic model of care seems needed for childhood cancer survivors positive for cancer predisposing variants, integrating the respective branches of care, thereby uniting the expertise of the cancer predisposition experts with experience from survivorship care teams to ensure adequate attention to all aspects of health. An extended, integrated care passport,8Haupt R Essiaf S Dellacasa C et al.The ‘Survivorship Passport’ for childhood cancer survivors.Eur J Cancer. 2018; 102: 69-81Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar documenting previous cancer treatments, germline genetic details, and a combined set of care recommendations, might be helpful for practitioners, patients, and their families in these complex circumstances. We declare no competing interests. Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trialCadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. Full-Text PDF