Abstract 5785: Tumors with higher heterogeneity were associated with poorer survival outcome in early stage lung adenocarcinoma cancer patients with low tumor mutational burden

Abstract

Abstract Background: Response to immune checkpoint inhibitors is associated with tumor mutational burden (TMB). Pembrolizumab has recently been approved by the FDA for use in patients with high TMB. However low TMB patients are not considered good responders and could benefit from stratification. The predictive value of other biomarkers such as intratumor heterogeneity (ITH) has been studied across a range of cancer indications. The utility of ITH in Lung Adenocarcinoma (LUAD) has not been established. Here we evaluate the relationship between ITH and outcome in early stage low TMB patients and explore differences in immune cell enrichment and predicted driver genes. Stratifying early stage patients may yield an opportunity to improve Recurrence Free Survival (RFS) and lower the risk of progression to late stage disease. Methods: All molecular data was obtained from the Tumor Cancer Genome Atlas via the GDC Data Portal. Clinical data was from the PanCancer Atlas dataset through cBioPortal. We estimated ITH using PyClone, an algorithm that estimates the number of tumor clones. We generated our ITH values in triplicate across 3 separate days, yielding an average PyClone clone number. Clones with >2 mutations were counted. We used p-value minimization to choose 1.4 for the TMB cutoff and 2.6 for the PyClone cutoff. We generated 4 groups: HTHI, HTLI, LTHI, and LTLI, where H - high, L- low, T-TMB, and I-ITH. Immune cell enrichment analysis was obtained from the xCell webtool. Driver gene prediction was performed with OncoDriveClust via the R package maftools. Results: We found a statistically significant difference in RFS between early stage (Stage I and Stage II) LTHI (N = 18) and LTLI (N = 40) patients (16.69 months vs. 33.27 months, p-value = 0.0056). Interestingly the predicted driver genes did not significantly differ between these two groups. One driver (EGFR) and two drivers (EGFR and TP53) genes were predicted for LTHI and LTLI, respectively. Gene set enrichment analysis showed statistically significant differences in key immune subtypes. B-cells were depressed and Th1 cells were elevated in LTHI, both of which are associated with poorer survival outcomes. Conclusion: We found an association between high ITH and poor survival in low TMB early stage LUAD patients. Early stage patients can be stratified using heterogeneity metrics like PyClone. Given the presence of immune subtypes known to associate with poorer outcomes, early stage LTHI patients may benefit from additional adjuvant therapies. Citation Format: Stanislav Fridland, Young Kwang Chae. Tumors with higher heterogeneity were associated with poorer survival outcome in early stage lung adenocarcinoma cancer patients with low tumor mutational burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5785.