Item Details

title

The Usage of Clinicogenomics in Predicting Outcomes in Immunotherapy in Non-Small Cell Lung Cancer

author

Smith, Margaret Rose

abstract

The treatment of non-small cell lung cancer (NSCLC) patients is intricate, hinging on tumor stage and druggable mutations. Limited biomarkers for genetic background impact therapy decisions. In a study of 524 stage III and IV NSCLC patients at Atrium Wake Forest Baptist we correlated mutation profiles with treatment responses, employing mutation composite scores (MCS) through cox-proportional hazard regression for chemotherapy (Chemo), immune checkpoint inhibitor (ICI), and Chemo+ICI. MCS, specific to treatments, surpassed traditional ICI biomarkers in predicting response to immunotherapies. Additionally, the MCS were able to shed light upon co-occurring and mutually exclusive mutations that shed light upon the important of sequencing data in personalizing medicine. The use of MCS can be used in helping guide clinicians in patients that may have the highest benefit from treatment and help predict which patient may develop an adverse event from treatment. Despite the development of immune checkpoint inhibitors revolutionizing how we treat late-stage NSCLC patients, many patients will develop an immune related adverse event (irAE) from treatment. A retrospective study of 474 III and IV NSCLC patients on ICI revealed 15.2% high grade irAEs affecting primarily the respiratory and gastrointestinal tract. Analysis of sequencing data revealed specific tumor mutations correlated with high grade irAEs to help clinician with guidance of which patient to monitor closer. The development of ICI has improved survivorship in late-stage NSCLC patients, yet only 20% respond to treatment. Using a cohort of 424 patients, we identified a mutation in neurotrophic receptor tyrosine kinase 1 (NTRK1) as a beneficial mutation in ICI treatment. Though occurring in 6-7% of patients, NTRK1 mutation enhanced ICI efficacy by inducing T cell presence. In wildtype NTRK1-tumors, Entrectinib mimicked the mutations effects, causing a response to ICI treatment. RNA-Sequencing unveiled tumor-immune cell crosstalk, suggesting a therapeutic approach to overcome immune resistance. In summary, our integrated study shows the complex connections between genetic profiles, treatment responses, and adverse events. This comprehensive roadmap facilitates a personalized NSCLC treatment decision.

subject

Clinicogenomics

Immune Resistance

Immunotherapy

Non-Small Cell Lung Cancer

contributor

Xing, Fei (advisor)

Grayson, Jason M (committee member)

Miller, Lance (committee member)

Ruiz, Jimmy (committee member)

Lycan, Thomas (committee member)

date

2024-05-23T08:36:08Z (accessioned)

2024-11-22T09:30:09Z (available)

2024 (issued)

degree

Molecular Medicine and Translational Science (discipline)

embargo

2024-11-22 (terms)

identifier

http://hdl.handle.net/10339/109406 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation