The largest genomic analysis ever conducted of small cell lung cancer tumors (SCLC) has identified genetic subtypes and provided insights into the mechanisms of this aggressive and deadly cancer.
The study, published recently in Cancer Discovery, reveals cues toward the development of personalized treatment approaches.
“On behalf of a wonderful multidisciplinary team of investigators, we are excited to share this study — the largest of its kind — on small cell lung cancer. Our study brings new insights into a tumor type for which advances in tumor genomics, personalized cancer medicine, and development of new treatments have been particularly difficult,” said the study’s co-corresponding author, Christine Lovly, MD, PhD, Ingram Associate Professor of Cancer Research and associate professor of Medicine in the Division of Hematology and Oncology at Vanderbilt-Ingram Cancer Center.
Small cell lung cancer is the most fatal type of lung cancer and has a five-year overall survival rate of about 6%. Treatment options have remained elusive, despite therapeutic advancements in recent years for the more common non-small cell lung cancer (NSCLC).
A barrier to research has been the limited availability of SCLC tumors for molecular analysis because the cancer is often diagnosed after it has already spread. Investigators in this study utilized the Foundation Medicine Clinico-Genomic and Flatiron Health Databases, which contain de-identified information from patient records and from genomic analysis of tumor samples obtained from patients across the United States.
The investigators analyzed genomic data from 3,600 SCLC tumors — far more than the number of tumors analyzed in the previous largest study. They made multiple discoveries.
- The identification of new recurrent alterations and genetic subtypes, including STK11-mutant tumors and TP53/RB1 double wild-type tumors as well as rare cases that were human papillomavirus positive.
- The association of gene amplifications on 4q12 with increased overall survival and the association of CCNE1 amplifications with decreased overall survival.
- The identification of more frequent alterations in the PTEN pathway in brain metastases, which are a common and potentially life-threatening site of SCLC spread.
- A better understanding of how NSCLC driver mutations, including EGFR, ALK, ROS1, RET, NTRK and KRAS, are recurrently detected in SCLC, suggesting that the transformation of NSCLC into the more aggressive type of lung cancer (SCLC) is more frequent that suspected.
Besides being the largest genomic analysis of SCLC, the study is also the most diverse. The patients included 7.1% who were of African ancestry, 4.2% who were Americans of mixed ancestry, 1.9% who were East Asian, and 0.3% who were South Asian. African ancestry was associated with decreased presence of TP53 or RB1 alterations. Young patients (age 50 and under) of all genetic ancestries had less frequent TP53 and RB1 alterations than older patients.
The study was published in Cancer Discovery simultaneously with a presentation by Lovly during the 2023 American Association for Cancer Research Annual Meeting in Orlando.
The study was done in conjunction with collaborators from Stanford University, led by co-corresponding author Julien Sage, PhD, professor of Genetics and Pediatrics, and from Foundation Medicine, led by first author Smruthy Sivakumar, PhD.
“New biological insights and novel treatment paradigms are desperately needed for patients with SCLC, where survival outcomes still remain too low. We hope that these data will provide more options for patients and catalyze further studies to ultimately advance towards a cure for SCLC,” Lovly said.
