Abstract 472: Tumor mutational burden reveals tumor-specific patterns with intra-patient stability from multiple longitudinal tissue biopsies from 3,402 patients
Authors: Sivakumar Smruthy , Sokol Ethan S. , Frampton Garrett M. , Fabrizio David , Alexander Brian , Hegde Priti S. , Grothey Axel 
Published: July 2021

Abstract
Tumor mutational burden (TMB) continues to evolve as a predictive biomarker of immunotherapy response. The recent pan-tumor approval of pembrolizumab for solid tumors with high TMB (TMB-H), defined as ≥10 mutations/megabase (mut/Mb), offers a promising treatment option, especially in advanced tumors. Here, we sought to investigate genomic profiles in cancer patients with multiple longitudinal tissue biopsies to assess the prevalence and variability of TMB, and its relationship with other biomarkers.
We utilized pan-tumor comprehensive genomic profiling data from 246,806 patients, tested as part of routine clinical care (FoundationOne). High prevalence (&gt;30%) of TMB-H was observed in skin, lung and bladder tumors. In contrast, gastrointestinal (GI) tumors exhibited low prevalence of TMB-H (8.8%), with frequent co-occurrence of TMB-H with high microsatellite instability (TMB-H/MSI). Exclusive TMB-H represented only 4% of GI cases, with a median TMB of 12.2 mut/Mb, compared to a much higher median of 43.5 mut/Mb in the TMB-H/MSI subgroup. Uterus/endometrial tumors also displayed co-occurring TMB-H/MSI, however, unlike GI, exclusive TMB-H cases had a higher median of 16.3 mut/Mb.
3,402 patients with multiple longitudinal tissue biopsies across 38 tumor types were identified (median collection time difference, days (d): 472). Overall, largely stable patterns of TMB and MSI were observed. Only 234 cases (7%) showed a change in TMB status, of which 73% had a diagnostic status change from TMB-low to TMB-H. There was no significant correlation between change in TMB and time between tests. However, gliomas were a notable outlier with significant changes in TMB status. Breast, colorectal and ovarian tumors also showed evidence for a statistically significant TMB change (P &lt; 0.05), primarily in larger time points (&gt;3years). MSI tumors and cases with a DNA mismatch repair mutation signature (MMR+) showed a higher TMB change than MS-stable/MMR- tumors respectively, albeit limited by cohort size. 4.6% of MS-stable tumors shifted from TMB-low to TMB-H (median time difference: 658d), with a median TMB change of 7.5 mut/Mb. Of note, genomic loss of heterozygosity (gLOH)-high ovarian tumors showed a higher TMB change than gLOH-low tumors (P &lt; 0.05). These observed TMB changes, although rare, may, in part, result from intervening therapies or evolving mutational processes in these cases.
TMB is a continuous variable biomarker. Identifying a cutoff for clinical and analytical validation can be a challenge, particularly given the impact of underlying tumor heterogeneity on the diagnostic score. Our data suggest that TMB at the cutoff of 10 mut/Mb is stable across tumor types and potentially across treatment modalities. These results also shed light on the co-occurrence of TMB and MSI, particularly in GI tumors, which may further inform treatment decisions for patients.
Citation Format: Smruthy Sivakumar, Ethan S. Sokol, Garrett M. Frampton, David Fabrizio, Brian Alexander, Priti S. Hegde, Axel Grothey. Tumor mutational burden reveals tumor-specific patterns with intra-patient stability from multiple longitudinal tissue biopsies from 3,402 patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 472.