Pan-cancer analysis of tumor mutation burden and other key ICI biomarkers in the Indian cohort.
Authors: Vaid Ashok Kumar , Batra Sandeep , Gupta Sachin , Shreenivas Aditya V. , Rohatgi Nitesh , Singhal Manish Kumar , Kurzrock Razelle , Limited Datar , Akolkar Dadasaheb B. , Patil Darshana , Datta Vineet , Syed Nelofer , Plowman Nick , Limaye Sewanti Atul 
Published: June 2023

e18872

Background: Tumor Mutation Burden has been correlated with therapy outcomes in patients receiving immune checkpoint inhibitors (ICI). However, tumor specific TMB cut-offs are not well established in the Indian cohort. Genomic alterations are shown to be vital determinants of response, resistance, and hyper-progression post-ICI administration and information about these alterations in Indian patients is scarce. Further, there is limited evidence of reliable predictive biomarkers in ‘immunologically cold’ tumors representing a crucial challenge in this setting. Uncovering key molecular alterations along with TMB and other genomic signatures can aid in selecting potential candidates for immunotherapy. Methods: The study cohort comprised 1383 tumor tissue specimens from solid tumors across twenty three organs including the bladder, breast, lung, ovary, colon, stomach, esophagus, kidney, liver, pancreas, etc. Targeted next-generation sequencing was carried out for more than 400 genes. dMMR/MSI status was evaluated in a subset of samples. Results: Of the 1383 tumor samples analyzed, 81.6% showed TMB-Low ( < 10 mut/Mb), while 18.4% samples had TMB-High (≥10 mut/Mb) and 6.1% had TMB ≥16 mut/Mb. Bladder and cervical cancer sub-cohorts showed the highest median TMB of 8. Breast cancer was the largest subcohort comprising 255 samples with a median TMB of 5. The lowest median TMB of 4 was seen in thyroid cancer. Highest degree of variability was observed within cervical cancer subcohort with TMBs ranging from 1 – 39 mut/Mb, followed by thyroid (1 – 29 mut/Mb), prostate (2 – 31 mut/Mb), and breast (1 – 88 mut/Mb) subcohorts. The least variation in TMB was observed in tumors of the pancreaticobiliary tract (1- 12 m/Mb) and small intestine (3 – 12 m/Mb). Among TMB-H tumors, markers of potential hyper-progression were analyzed. MDM2 amplification (CNV ≥8 copies) was detected in 2.4% (6/254) and MYC amplification (CNV ≥6 copies) was detected in 7.1% (18/254) cases. In a breast cancer subcohort, PIK3CA mutation-linked immune-cold tumor microenvironment was detected in 36% of TMB-H tumors against 29% of TMB-L tumors. Only 0.8% (6/751) samples were diagnosed as MSI-H/dMMR, at a significantly lower incidence against the reported incidence in the western population. All 6 MSI-H patients were also TMB-H; while 95.9% (139/145) patients with TMB-H were found to be MSI-stable. Conclusions: This study gives insights into key ICI biomarkers with TMB profiles of Indian patients and reinforces the varied range of TMB depending on tumor type. The incidence of key genes involved in hyper-progression may support active disease monitoring on ICI therapy in such patients and co-application of multi-pathway therapies to address these resistant pathways. These findings suggest that wider prospective studies to establish cancer-specific thresholds concerning tumor type and patient outcomes should be undertaken.