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Biomarkers for the Immune Checkpoint Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Weijie Ma, Sixi Wei, Eddie C. Tian, Tianhong Li
Most recently, blood tumor mutational burden (bTMB) has been associated with clinical response to immune checkpoint inhibitor therapy. High bTMB is associated with prolonged PFS in patients treated with atezolizumab in individuals with previously treated NSCLC (POPLAR and OAK) (Table 14.2) [50, 111, 112].
Gastric Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Mark A. Baxter, Russell D. Petty
MSI and other deficits in DNA repair result in a higher tumor mutational burden (TMB). This in turn results in increased tumor antigens and increased immune cell infiltrate. As a result, TMB has also been proposed as another emerging biomarker,43 although it is yet to be validated in gastric cancer. As translational research on completed trials emerges, the role of biomarkers in prediction of response will become better defined.
Next-Generation Sequencing (NGS) for Companion Diagnostics (CDx) and Precision Medicine
Published in Il-Jin Kim, Companion Diagnostics (CDx) in Precision Medicine, 2019
Il-Jin Kim, Mendez Pedro, David Jablons
Before 2016, only a few NGS-based assays were FDA-approved. Two were for cystic fibrosis mutation career screening and the Illumina MiSeqDx Universal kit was approved for non-CDx purposes.19 By December 2017, four NGS tests were FDA-approved for oncology CDx testing (www.fda.gov). The first of these was the FoundationFocus CDxBRCA test (Foundation Medicine) for BRCA1 and BRCA2 mutation detection in ovarian cancer patients for PARP inhibitor treatment in December 2016 (PMA: P160018). The second NGS test was Oncomine Dx (ThermoFisher Scientific), a CDx assay for selecting inhibitors for EGFR, ALK, ROS1, MEK, and RAF, approved in June 2017. This assay can detect genetic alterations in 23 genes and provides additional genetic variations beyond the designated and approved mutations and fusions (PMA: P160045). The third NGS test is Illumina’s RAS extended panel analyzing 56 variants from KRAS and NRAS genes, which was approved by the FDA for Amgen’s Vectibix (panitumumab) treatment in metastatic colorectal cancer patients with wild-type RAS (PMA: P160038). The last NGS test is the FoundationOne CDx (Foundation Medicine Inc.). This assay detects mutations (substitutions, insertions, or deletions) and copy number alterations in 324 genes including EGFR, BRAF, HER2, KRAS, NRAS, and BRCA1/2. Fusions in selected genes, microsatellite instability, and tumor mutational burden can also be detected in this assay.
Response to systemic therapy in locally advanced and metastatic renal cell carcinoma: can it be predicted?
Published in Expert Review of Anticancer Therapy, 2021
Javier González, Jeffrey J Gaynor, Gaetano Ciancio
Tumor mutational burden (TMB) is based on the total number of mutations per encoding area of the tumor genome. A high-TMB profile results in an increase in the number of new neo-antigens that enhance immune response to the tumor. Therefore, clonal mutations are thought to be associated with neo-antigen abundance, and CD8 + T-cell activation. The activation of different endogenous retroviruses has been associated also with cytolytic activity and neo-antigen preservation in a number of tumors including RCC. However, the IMmotion-150 trial initially failed to demonstrate a difference in response to atezolizumab between patients exhibiting distinct TMB or neoantigen burden profiles. However, this biomarker is still under evaluation. Possible limitations in its use include lack of standardization, and technical issues regarding coverage, DNA amount, and analysis time [2,27].
Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538
Published in OncoImmunology, 2021
Oliver Klein, Clare Senko, Matteo S Carlino, Ben Markman, Louise Jackett, Bo Gao, Caroline Lum, Damien Kee, Andreas Behren, Jodie Palmer, Jonathan Cebon
Archival tumor tissue, or a fresh tumor biopsy during screening, were required for predictive biomarker analysis. Archival formalin-fixed paraffin-embedded tumor tissue was tested for PD-L1 expression by immunohistochemistry (IHC). The antibody used was Ventana PD-L1 (SP263) according to the ULTRA VENTANA PD-L1 (SP263) Assay (Roche diagnostics). A tumor was deemed PD-L1 positive if there was at least 1% expression on tumor cells. DNA was extracted from tumor tissue for gene sequencing and the tumor mutational burden (TMB) was determined by the Oncomine tumor mutation load assay (Thermo Fisher Scientific Ltd). The tumor microsatellite status was determined by examining the expression of mismatch repair proteins by immunohistochemistry. Genomic profiling has been performed by using multigene panel assays.11,12
A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma
Published in OncoImmunology, 2021
Jan Budczies, Martina Kirchner, Klaus Kluck, Daniel Kazdal, Julia Glade, Michael Allgäuer, Mark Kriegsmann, Claus-Peter Heußel, Felix J. Herth, Hauke Winter, Michael Meister, Thomas Muley, Stefan Fröhling, Solange Peters, Barbara Seliger, Peter Schirmacher, Michael Thomas, Petros Christopoulos, Albrecht Stenzinger
Hence, predictive biomarkers are urgently needed for identification of the most likely responding patients and to offer better suited treatment alternatives for the others. While numerous biomarkers were evaluated, PD-L1 protein expression analyzed by immunohistochemistry (IHC)9,10 and microsatellite instability (MSI)/mismatch repair deficiency are the only ones approved so far.11 However, both of them are far away from being perfect: PD-L1 IHC is limited in both sensitivity and specificity – as well as its heterogeneity, while MSI will identify only a very restricted subset of all ICB responders. In addition, in retrospective molecular analyses complementing clinical trials, tumor mutational burden (TMB) showed promising results as a predictive marker, 1–4,12 but so far this has not been validated in prospective trials. Furthermore, we and others delineated biological, technological, and bioinformatical parameters impairing correct measurement of TMB in a clinical setting.13–15 Hence, the suitability of TMB as a predictive marker is currently discussed controversially and remains practically challenging.