Tumor mutational burden as a potential biomarker for PD1/PD-L1 therapy in colorectal cancer.
2016; Lippincott Williams & Wilkins; Volume: 34; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2016.34.15_suppl.3587
ISSN1527-7755
AutoresThomas J. George, Garrett M. Frampton, James Sun, Kyle Gowen, Mark Kennedy, Joel Greenbowe, Alexa B. Schrock, Siraj M. Ali, Samuel J. Klempner, Aram F. Hezel, Jeffrey S. Ross, Phil Stephens, Vincent A. Miller, David Fabrizio,
Tópico(s)Radiomics and Machine Learning in Medical Imaging
Resumo3587 Background: Biomarkers capable of predicting response to checkpoint inhibitor therapies represent a significant clinical need. Increased tumor neo-antigenic burden has been linked to PD1/PD-L1 therapeutic response in several conditions including metastatic melanoma, non-small cell lung carcinoma and microsatellite instable (MSI-H) colorectal cancer (CRC). However, the challenges and high cost associated with neo-antigen discovery has shifted focus towards more efficient methods of response stratification. As such, mutational burden determination from whole exome sequencing and comprehensive genomic profiling (CGP) has emerged as a potential solution. In CRC, MSI-H may serve as a predictive biomarker for activity of PD1/PD-L1 therapy, reflecting an unquantified immunogenic mutational burden. Herein, we explore the ability to quantify tumor mutational burden (TMB) as a potential predictive biomarker of PD1/PD-L1 therapy in CRC. Methods: Formalin-fixed, paraffin embedded tissue sections from 2013 cases of CRC were sequenced with CGP (FoundationOne assay). MSI status and PD-L1 gene amplification were determined as previously described. TMB was calculated by counting mutations across a 1.25Mb region spanning 315 genes. Patients were classified as TMB high or low using the top quartile threshold and microsatellite instable (MSI-H) or stable (MSS) using a computational algorithm developed by Foundation Medicine. Results: MSS tumors were observed in 1934 of 2013 (95.2%) cases and MSI-H tumors were observed in 79 of 2013 (3.9%) cases. 79 of 79 (100%) MSI-H cases were TMB high (range 16.8-72.7 mut./Mb) and 1510 of 1934 (78.1%) MSS cases were TMB low (range 0.0-8.0 mut./Mb). Consequently, 424 of 1934 (21.9%) MSS cases were confirmed as TMB high (range 8.8-43.1 mut./Mb). Of note, less than 0.1% of cases featured PD-L1 gene amplifications. Conclusions: Tumor mutational burden as estimated by CGP, as opposed to MSI assessment alone, significantly increases the number of patients with metastatic CRC who may benefit from checkpoint inhibitor based therapeutic approaches. Investigations to validate this biomarker are ongoing.
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