Abstract 4065: Prognostic and predictive role of tumor mutation burden and copy number alterations across metastatic cancer: Immunotherapeutic implications
Authors: Tang Xin-Ran , Dong Zhong Yi , Wu Dehua 
Published: August 2019

Background: Cancer immunotherapy has provided durable responses and improved survival in a subset of patients with advanced disease. Tumor mutation burden (TMB) and copy number alterations (CNA) have been shown to be associated with response to immune checkpoint inhibitors (ICI). However, the prognostic and predictive role of TMB and CNA across different types of advanced cancer has not yet been clarified.

Methods: We analyzed the prognostic value of TMB and CNA respectively and in combination across different types of advanced cancers from MSK-IMPACT sequencing cohort. For predictive analysis, non-small cell lung cancer (NSCLC, n=240) and skin cutaneous melanoma (SKCM, n=174) patients from previous studies were analyzed for efficacy to ICIs by TMB and CNA respectively and in combination. Kaplan-Meier curve and log-rank tests were used to estimate correlations of these molecular classifiers with progression-free survival (PFS), and overall survival (OS).

Findings: Patients with low TMB level had longer OS in most cancer types including NSCLC, head and neck squamous cell carcinoma (HNSCC), colon and rectal adenocarcinoma (COAD) and prostate adenocarcinoma (PRAD) compared with patients with high TMB level. Similarly, patients with low CNA level had longer OS in most cancer types including NSCLC, bladder urothelial carcinoma (BLCA), breast cancer (BRCA), PRAD and glioblastoma (GBM) compared with patients with high CNA level as well. Furthermore, the combination of TMB and CNA level could serve as a better prognosis biomarker in almost all of the cancer types above. In predictive cohort, high TMB (p=0.009) level and low SCNA (p=0.052) level was associated with longer PFS in NSCLC patients receiving anti-PD1/L1 treatment respectively. For SKCM cohort, patients with low CNA level (p&lt;0.001) had longer OS receiving anti-CTLA4 treatment, while TMB level was not associated with treatment outcome (p=0.272). More importantly, when we combined the TMB and CNA, those with TMBhigh CNAlow had the strongest objective response rates and favorable response in both NSCLC (ORR, 0.032; PFS, p=0.003) and SKCM (ORR, p&lt;0.001; OS, p=0.012) patients. Analysis of MSK-IMPACT database indicated that the joint stratification of TMB and CNA might be associated with diverse prognosis and potential sensitivity to ICIs across 24 cancer types.

Interpretation: This study shows that TMB and CNA represent both a prognostic and predictive factor of outcomes. Furthermore, the combination of TMB and CNA can jointly stratify metastatic cancers into groups with different prognosis and clinical responses to ICI treatment. It might guide immunotherapeutic decisions for patients with metastatic cancer.

Citation Format: Xin-Ran Tang, Zhong Yi Dong, Dehua Wu. Prognostic and predictive role of tumor mutation burden and copy number alterations across metastatic cancer: Immunotherapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4065.