A study presented by Nobuyuki Takahashi, MD, of the Center for Cancer Research at the National Cancer Institute, at the International Association for the Study of Lung Cancer (IASLC) 2020 World Conference on Lung Cancer (WCLC) Singapore (Abstract OA11.05) demonstrated that there may be an inherited predisposition for small cell lung cancer (SCLC). The findings lay the foundation for understanding the interaction between genotype and tobacco exposure in exacerbating SCLC risk, as well as potential therapeutic implications.
Because tobacco is the dominant carcinogen, secondary causes of lung cancer are often diminished in perceived importance, especially in SCLC, the most lethal lung cancer. SCLC is almost exclusively related to tobacco and comprises 15% to 20% of all lung cancers.
"The study opens new avenues for directed cancer screening for patients and their families, as well as subtyping and targeted therapies of SCLC, currently treated as a single entity."— Nobuyuki Takahashi, MD
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Genetic Findings
To explore the genetic basis of SCLC, researchers sequenced germline whole exomes of 87 patients (77 with SCLC, 10 with extrapulmonary small cell lung cancer) and compared these with an independent SCLC cohort and with cancer-free non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) cohort. They also evaluated clinical characteristics associated with the germline genotype.
Among 607 cancer predisposition and SCLC-related genes, the researchers discovered 42 deleterious variants in 35 genes among 38 (43.7%) of patients. Identification of variants influenced medical management and family member testing in nine (10.3%) patients. Six germline mutations were also found in the independent cohort of 79 patients with SCLC, including three of the same variants (MUTYH G386D, POLQ I421Rfs*7, and RNASEL E265X). By tumor whole-exome sequencing, the team confirmed loss of heterozygosity of the MLH1, BRCA2, and SMARCA4 genes.
Consistent with the contribution to potential cancer predisposition, patients with MLH1, BRCA2, and MUTYH germline mutations had multiple personal and family history of cancer and lung cancers, including SCLC. Unselected patients with SCLC in the cohort were more likely to carry germline RAD51D, CHEK1, BRCA2, and MUTYH mutations than healthy controls in the ExAC cohort. Pathogenic germline mutations were significantly associated with the likelihood of first-degree relatives with cancer or lung cancer (odds ratio = 1.82, 2.60, respectively) and longer recurrence-free survival following platinum-based chemotherapy (hazard ratio = 0.46, P = .002), independent of known prognostic factors including sex, stage, and age at diagnosis. Finally, the researchers tested therapeutic relevance of these observations in a patient with SCLC and a pathogenic BRIP1 mutation, who achieved a tumor response (–64% decrease in tumor size) with a combination treatment of a topoisomerase 1 inhibitor and a poly (ADP-ribose) polymerase inhibitor.
“The study opens new avenues for directed cancer screening for patients and their families, as well as subtyping and targeted therapies of SCLC, currently treated as a single entity”, reported Dr. Takahashi.
Disclosure: For full disclosures of the study authors, visit wclc2020.iaslc.org/disclosures.
