Genentech Oncology
TRK=tropomyosin receptor kinase; NTRK=neurotrophic tyrosine receptor kinase.
Tumors that undergo MSI testing can be classified as7:
For colon cancer, NCCN Guidelines® consider IHC for mismatch repair (MMR) and DNA analysis for MSI to be different assays measuring different biological effects caused by deficient MMR function.8
PCR-based MSI testing can be conducted in combination with MMR IHC13
NGS-based MSI testing enables massive parallel sequencing of MMR genes8
Investigators identified over 386,000 microsatellite repeats in a recent study retrospectively analyzing 7,919 exomes and 1,000 whole genomes from The Cancer Genome Atlas (TCGA)12
The graph shows the frequency of MSI-H samples from the 16 most prevalent tumor types in the dataset.
*MSI-H predicted at a confidence level of 0.75.12
IHC=immunohistochemistry; MMR=mismatch repair; MSI=microsatellite instability; MSI-H=MSI-high; MSI-L=MSI-low; MSS=microsatellite stable; NCCN=National Comprehensive Cancer Network; NGS=next-generation sequencing; PCR=polymerase chain reaction.
TMB has been determined using both broad and targeted panels and detected by mutational load in cfDNA samples and liquid biopsies.17-20
TMB=tumor mutational burden.
The relationship between TMB and microsatellite instability (MSI), both markers of genetic instability, was evaluated for 62,150 tumor samples.15
Mb=megabases.
Republished with permission of Nature Publishing Group, from Lawrence MS, et al. Nature. 2013;499(7457):214-218; permission conveyed through Copyright Clearance Center, Inc.
High levels of somatic mutations within tumor cells may result in expression of neoantigens that can induce a T cell response.23
Increased mutation burden may be associated with a higher number of antigens, which may result in greater tumor immunogenicity.9,12,23,24
The biologic rationale behind TMB’s potential as a biomarker is that tumors with high TMB are likely to accumulate neoantigens, making the tumors susceptible to activated immune cells.9,24
cfDNA=circulating free DNA; NGS=next-generation sequencing; TMB=tumor mutational burden.
Murphy DA, et al. Detecting gene rearrangements in patient populations through a 2-step diagnostic test comprised of rapid IHC enrichment followed by sensitive next-generation sequencing. Appl Immunohistochem Mol Morphol. 2017;25(7):513-523. PMID: 27028240
Murphy DA, et al. Detecting gene rearrangements in patient populations through a 2-step diagnostic test comprised of rapid IHC enrichment followed by sensitive next-generation sequencing. Appl Immunohistochem Mol Morphol. 2017;25(7):513-523. PMID: 27028240
Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34. PMID: 25527197
Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34. PMID: 25527197
Su D, et al. High performance of targeted next generation sequencing on variance detection in clinical tumor specimens in comparison with current conventional methods. J Exp Clin Cancer Res. 2017;36(1):121. PMID: 28882180
Su D, et al. High performance of targeted next generation sequencing on variance detection in clinical tumor specimens in comparison with current conventional methods. J Exp Clin Cancer Res. 2017;36(1):121. PMID: 28882180
Hechtman JF, et al. Pan-Trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol. 2017;41(11):1547-1551. PMID: 28719467
Hechtman JF, et al. Pan-Trk immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol. 2017;41(11):1547-1551. PMID: 28719467
Stack EC, Wang C, Roman KA, Hoyt CC. Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of tyramide signal amplification, multispectral imaging and multiplex analysis. Methods. 2014;70(1):46-58. PMID: 25242720
Stack EC, Wang C, Roman KA, Hoyt CC. Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of tyramide signal amplification, multispectral imaging and multiplex analysis. Methods. 2014;70(1):46-58. PMID: 25242720
Rogers TM, et al. Multiplexed transcriptome analysis to detect ALK, ROS1 and RET rearrangements in lung cancer. Sci Rep. 2017;7:42259. PMID: 28181564
Rogers TM, et al. Multiplexed transcriptome analysis to detect ALK, ROS1 and RET rearrangements in lung cancer. Sci Rep. 2017;7:42259. PMID: 28181564
Richman S. Deficient mismatch repair: read all about it. Int J Oncol. 2015;47(4):1189-1202. PMID: 26315971
Richman S. Deficient mismatch repair: read all about it. Int J Oncol. 2015;47(4):1189-1202. PMID: 26315971
Referenced from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.4.2020. © National Comprehensive Cancer Network, Inc 2020. All rights reserved. Accessed June 15, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Referenced from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.4.2020. © National Comprehensive Cancer Network, Inc 2020. All rights reserved. Accessed June 15, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Le DT, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520. PMID: 26028255
Le DT, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520. PMID: 26028255
Peltomäki P. Update on Lynch syndrome genomics. Fam Cancer. 2016;15(3):385-393. PMID: 26873718
Peltomäki P. Update on Lynch syndrome genomics. Fam Cancer. 2016;15(3):385-393. PMID: 26873718
Vilar E, et al. Microsatellite instability in colorectal cancer—the stable Evidence. Nat Rev Clin Oncol. 2010;7(3):153–162. PMID: 20142816
Vilar E, et al. Microsatellite instability in colorectal cancer—the stable Evidence. Nat Rev Clin Oncol. 2010;7(3):153–162. PMID: 20142816
Cortes-Ciriano I, et al. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;8:15180. PMID: 28585546
Cortes-Ciriano I, et al. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;8:15180. PMID: 28585546
Boyle TA, Bridge JA, Sabatini LM, et al. Summary of microsatellite instability test results from laboratories participating in proficiency surveys: proficiency survey results from 2005 to 2012. Arch Pathol Lab Med. 2014;138(3):363-370. PMID: 24576032
Boyle TA, Bridge JA, Sabatini LM, et al. Summary of microsatellite instability test results from laboratories participating in proficiency surveys: proficiency survey results from 2005 to 2012. Arch Pathol Lab Med. 2014;138(3):363-370. PMID: 24576032
US Food and Drug Administration. https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019C.pdf. Accessed December 12, 2019.
US Food and Drug Administration. https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019C.pdf. Accessed December 12, 2019.
Chalmers ZR, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34. PMID: 28420421
Chalmers ZR, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34. PMID: 28420421
Tran E, et al. ‘Final common pathway’ of human cancer immunotherapy: targeting random somatic mutations. Nat Immunol. 2017;18(3):255-262. PMID: 28198830
Tran E, et al. ‘Final common pathway’ of human cancer immunotherapy: targeting random somatic mutations. Nat Immunol. 2017;18(3):255-262. PMID: 28198830
Roszik J, et al. Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set. BMC Med. 2016;14(1):168. PMID: 27776519
Roszik J, et al. Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set. BMC Med. 2016;14(1):168. PMID: 27776519
Clinical implications of circulating tumor DNA tumor mutational burden (ctDNA TMB) in non-small cell lung cancer. Oncologist. 2019;24(6):820-828. PMID: 30867242
Clinical implications of circulating tumor DNA tumor mutational burden (ctDNA TMB) in non-small cell lung cancer. Oncologist. 2019;24(6):820-828. PMID: 30867242
Measuring tumor mutational burden (TMB) in plasma from mCRPC patients using two commercial NGS assays. Sci Rep. 2019:14;9(1):114. doi: 10.1038/s41598-018-37128-y. PMID: 30643180
Measuring tumor mutational burden (TMB) in plasma from mCRPC patients using two commercial NGS assays. Sci Rep. 2019:14;9(1):114. doi: 10.1038/s41598-018-37128-y. PMID: 30643180
Koeppel F, et al. Whole exome sequencing for determination of tumor mutation load in liquid biopsy from advanced cancer patients. PLoS One. 2017;12:e0188174. PMID: 29161279
Koeppel F, et al. Whole exome sequencing for determination of tumor mutation load in liquid biopsy from advanced cancer patients. PLoS One. 2017;12:e0188174. PMID: 29161279
Lawrence MS, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-218. PMID: 23770567
Lawrence MS, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-218. PMID: 23770567
Rizvi NA, et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science. 2015;348(6230):124-128. PMID: 25765070
Rizvi NA, et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science. 2015;348(6230):124-128. PMID: 25765070
Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504. PMID: 27207108
Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504. PMID: 27207108
Goodman AM, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598-2608. PMID: 28835386
Goodman AM, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598-2608. PMID: 28835386
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