Background: Tumor mutational burden (TMB) has been associated with efficacy of immune checkpoint therapy and is being investigated as a potential biomarker in several tumor types. The foundational studies evaluating TMB in clinical trials have not examined factors that may affect TMB estimates in real-world practice, such as the site of biopsy relative to the tumor tissue of origin.

Methods: We used the Flatiron Health/Foundation Medicine Clinico-Genomic Database (Presley CJ, et al. JAMA 2018; Singal G, et al. JAMA 2019), which contains deidentified patient-level clinical records from Flatiron Health (New York, NY), combined with genomic sequencing test results of tissue TMB from Foundation Medicine (Cambridge, MA). We examined patient records from 7 advanced cancer types: non-small cell lung cancer (NSCLC), breast cancer (BC), gastric/esophageal cancer (G/EC), melanoma (MEL), metastatic castration-resistant prostate cancer (CRPC), head and neck cancer (H&N), and small cell lung cancer (SCLC). We performed a multivariate mixed-model linear regression to test for associations between the site of tissue biopsy and TMB measurement. We used a cutoff of 10 mutations per megabase (mut/Mb) to classify specimens as high TMB.

Results: TMB data were available for 11,928 biopsy specimens from 11,567 patients: NSCLC, n = 5556; BC, n = 3381; G/EC, n = 1335; MEL, n = 528; CRPC, n = 506; H&N, n = 342; SCLC, n = 280. In multiple cancer types, we found that TMB estimates were significantly associated with the biopsied site. For example, brain metastasis specimens from patients with NSCLC had higher TMB (median 11.3 mut/Mb) than specimens collected from primary lung tissue (median 7.0 mut/Mb) or from pleura or pleural fluid (median 3.5 mut/Mb). TMB measurements were higher in brain metastases than in samples from the primary tissue across multiple cancer types. In contrast, biopsies from lymph nodes showed different TMB patterns depending on the cancer type. Consistent with those results, the proportion of patients with high TMB differed significantly by biopsied site.

Conclusion: We used a real-world database of clinical data linked with genomic tests to evaluate TMB values across tissue biopsy sites for multiple cancer types. Our results highlight the biopsied site as a potential source of variation for TMB results measurements in a cancer type–specific manner. This will be important to consider when performing research in heterogenous data sets.

Citation Format: Simon Papillon-Cavanagh, Chuan Gao, G. Celine Han, Alice M. Walsh. Pan-cancer profiling of the effect of biopsied site on tumor mutational burden measurements in a real-world data cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2008.