Abstract 402P
Background
Alterations in tumor suppressor genes (TSG) affect the outcome of NSCLC. Their incidence in unselected or oncogene-addicted NSCLC, such as EGFR mutations, is 50% and 60%, respectively. However, their incidence in ALK+ or RET+ NSCLC has not been extensively investigated.
Methods
NSCLC patients (pts) with known genomic profiling before any treatments and with clinical data and tumor tissue availability were considered. Tissue samples were analyzed using a customized NGS Panel including a full coding sequence of ARID1A, ATM, BRCA1, NF1, PTEN, RB1, and TP53 genes. We evaluated that 78 pts could highlight a difference of at least 15% in the incidence of TSG alterations, at 5% 2-sided significance level and 80% power.
Results
Overall, 4185 pts were tested for ALK and ROS1 (from 2016 to 2024), and 2378 pts were tested for RET and NTRK (from 2020 to 2024). Among them, 225 had a gene fusion, including 168 ALK+ cases (4.8%), 34 RET+ cases (3.4%), 23 ROS1+ cases (0.5%), and 2 NTRK+ cases (0.1%). TSGs were analyzed in 78 cases. Fifty-eight were ALK+ and 20 were RET+. Pts characteristics reflected the known clinical profile of the diseases (adenocarcinoma 97%; F/M=52%/48%; smokers 30%; median age 60 years; stage IV at diagnosis 52.6%, and brain metastases 22%). Overall, TSG mutations occur in 17/78 (22%), a statistically lower proportion than in the historical control of unselected or EGFR mutant populations (p < 0.05). TP53 mutations were found in 8 (14%) and 5 (25%) ALK+ or RET+ NSCLC, respectively; variants of unknown significance (VUS) in BRCA1, ATM, or ARID1A genes were found in 3 ALK+ (5%) and 1 RET+ pts (5%), respectively. Interestingly, all but one ALK+ and 66% of RET+ pts harboring TSG mutations had their primary tumor located on the right side.
Conclusions
TSG mutations are present in a small fraction of ALK+ or RET+ NSCLC patients, preferentially in individuals with a primary tumor localized in the right lung. Our findings suggest that co-mutations are not equally distributed in oncogene-addicted NSCLC and primary cancer location influences tumor biology. Additional data in a larger cohort of ALK, RET, and ROS1 NSCLC will be presented at the meeting.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
L. Landi: Financial Interests, Personal, Advisory Board: Roche, Pfizer, Amgen, AstraZeneca, Eli Lilly, Johnson and Johnson; Financial Interests, Personal, Invited Speaker: Roche, Pfizer, Amgen, AstraZeneca, Eli Lilly, Novartis, Sanofi; Financial Interests, Personal, Other, Consultant: MSD; Financial Interests, Personal, Other, consultant: BMS, AbbVie. E. Melucci: Financial Interests, Personal, Invited Speaker: GSK, Incyte, Menarini, J&J. G. Minuti: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Novartis, Sanofi, Amgen, MSD, Johnson & Johnson, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Gilead, Novartis, BMS. F. Cappuzzo: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Mirati, PharmaMar, Novocure, Ose, Galecto and MSD; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Mirati, Novocure, Ose, and MSD. S. Buglioni: Financial Interests, Personal, Invited Speaker: Thermo Fisher, Lilly, Novartis, J&J, AstraZeneca, Roche; Financial Interests, Personal, Advisory Board: Novartis, J&J. All other authors have declared no conflicts of interest.