157. Germline Mutations in High Penetrance Genes are Associated with Higher Pathologic Stage and Increased Cancer Recurrence in Patients with Non Small Cell Lung Cancer

Objective: To determine both the frequency of pathogenic mutations in high penetrance genes (HPGs) in patients with lung adeno or squamous cell carcinoma and whether the presence either HPGs or an elevated genetic risk score (GRS) is associated with different clinical phenotypes and oncologic outcomes.

Methods: Patients with NSCLC who had consented to participate in a prospectively collected linked clinical database and biorepository and had either a blood or tissue sample were included in the study. Their germline DNA was sequenced using a targeted next-generation sequencing panel that includes both cancer-associated HPGs genes and known lung cancer risk-associated SNPs to assess for the presence of HPGs and to calculate a GRS. This data was then linked to the corresponding clinical database to assess for association between germline mutations and clinical phenotype, including pathologic stage, tumor grade, and disease recurrence using Fisher's exact test and multivariable logistic regression.

Results: We analyzed 151 patients with either primary lung adenocarcinoma or squamous cell carcinoma. Pathologic stage breakdown was 96 (64%) stage I, 31 (20%) stage II, 17 (11%) stage III, and 7 (5%) stage IV. Fifty patients (33%) were carriers for any HPG mutation. GRS was missing in 5 patients. The GRS was >1.5 (23%) in 34 patients. The presence of an HPG mutation was strongly associated with higher pathologic stage and a higher risk of recurrence. Of patients with any HPG mutation 48% (24/50) were stage II or higher and 26% (13/50) were stage III or higher, compared to 31% (31/101, p=0.04) and 11% (11/101, p=0.02) of patients without an HPG mutation. For patients with both an HPG mutation and a GRS >1.5, 73% (8/11) were stage II or higher and 36% (4/11) were stage III or higher, compared to 33% (45/135, p=0.02) and 14% (19/135, p=0.07), respectively, of patients who did not have both an HPG mutation and an elevated GRS. Twenty-Two percent (11/50) of patients with an HPG mutation had cancer recurrence compared with 11% (11/101) of patients without (p=0.07). In multivariable analysis, the presence of a DNA repair HPG mutation was associated with higher stage (OR 3.34 for stage >1, p=0.02) and the presence of a cancer-related HPG mutation increased recurrence (OR 3.91, p=0.03) (Table 1). Higher tumor grade was not associated with the presence of an HPG mutation or an elevated GRS score.

Conclusion: The presence of mutations in HPGs is associated with presentation at higher pathologic stage and a higher risk of disease recurrence. Germline testing may be helpful in predicting who is at risk for recurrence, and therefore may eventually prove useful in appropriate delivery of adjuvant chemotherapy. Further large studies are needed to better delineate the role of HPGs in cancer recurrence and the potential benefit of adjuvant treatment in patients harboring such mutations.

Seth Krantz (1), Kanwal Zeeshan (1), Kristine Kuchta (2), Thomas Hensing (3), Siqun Zheng (4), Kathy Mangold (5), Jianfeng Xu (4), (1) Department of Surgery, NorthShore University HealthSystem, Evanston, IL, (2) Bioinformatics and Research Core, NorthShore University HealthSystem, Evanston, IL, (3) Department of Medicine, NorthShore University HealthSystem, Evanston, IL, (4) Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, (5) Department of Pathology, NorthShore University HealthSystem, Evanston, IL

Chuong Hoang

Invited Discussant

Dr. Hoang is a surgeon-scientist sub-specialized in Thoracic Surgical Oncology.  He heads the Molecular Therapeutics research section within the Thoracic Surgery Branch at NCI-NIH.  His research is focused on the comprehensive identification, understanding of mechanisms, innovating delivery methods, and preclinical development of nucleic acids (microRNA) against thoracic cancers.  His clinical expertise includes all the major aspects of thoracic surgery encompassing both complex open approaches as well as minimally invasive techniques.

Seth Krantz

Abstract Presenter

Dr. Krantz serves as the Chief of the Division of Thoracic Surgery and Chair of the Cancer Committee at Endeavor Health, formerly NorthShore-Edwards Elmhurst Health, a regional health system with a flagship teaching hosptial in Evanston, IL. Dr. Krantz is also a clinical associate professor within the Department of Surgery at the University of Chicago Pritzker School of Medicine. Dr. Krantz completed his undergraduate degree at the University of Michigan, medical school and general surgery residency at Northwestern University Feinberg School of Medicine, and completed his general thoracic training at Washington University in St. Louis. He has published on quality outcomes in lung cancer surgery, and has previously presented at the AATS a much cited paper assessing the quality of wedge resection with in the NCDB and the impotance of lymph node assessment in wedge resection. Current areas of research focus include understanding inherited risk in lung cancer and the impact of germline mutations on cancer outcomes. Work related to this was presented at the AATS in 2022 and received a Presidential Absctract Recognition Award. Dr. Krantz serves as the NorthShore site PI for the Thoracic Surgery Oncology Group of the AATS, is a member of the STS Workfoce on Health Policy, Reform, and Advocacy, and is a membrer of the American College of Surgeons Cancer Research Program Standards Investigation and Validation Committtee. Dr. Krantz's practice includes the breadth of general thoracic surgery with a focus on advanced robotic approaches for lung cancer including complex segmentectomy and minimally invasive resection for locally advanced cancer. Dr. Krantz lives in the Chicago area with his wife, Stephanie, and their two sons. Despite being a northsider, he is an avid White Sox fan and Michigan Wolverine through and through (Go Blue!).

Specialties: General Thoracic, Thoracic, Basic Science, Anatomy and Conditions, Lung--Basic Science, Lung--Cancer, Treatment/Procedure/Operation/Surgery, Lung--Cancer