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Oncotarget | Identification of biomarkers of immune checkpoint blockade efficacy in recurrent or refractory solid tumor malignancies


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2020-02-14

Oncotarget Volume 11, Issue 6 reported that multivariate regression analysis including the two variables of tumor mutation burden and ICB, and their interaction term, showed favorable survival associated with ICB, unfavorable survival associated with TMB without ICB treatment, and improved outcome with increasing TMB in ICB treated patients.

Tumor TP53 mutation was associated with worse survival, but these patients still benefited from ICB.

Dr. Russell R. Broaddus from the Department of Pathology and Laboratory Medicine at the University of North Carolina at Chapel Hill said, "Patients with advanced cancers who are initially resistant to frontline therapy or who develop recurrent disease have a finite survival [1], and choosing the right therapy within this window is crucial."

"Patients with advanced cancers who are initially resistant to frontline therapy or who develop recurrent disease have a finite survival [1], and choosing the right therapy within this window is crucial."

- Dr. Russell R. Broaddus, Department of Pathology and Laboratory Medicine at the University of North Carolina at Chapel Hill

When faced with patients with a variety of different advanced cancer types, it can be difficult to decide which specific patients should be treated with ICB. In a prospective trial reported previously, a large next-generation sequencing panel comprised of the entire coding regions of 409 cancer-related genes was employed to identify clinically actionable gene amplifications or mutations to help place patients onto matched targeted therapy trials.

Figure 1: Distribution of TMB (RMs /Mb) stratified by original histologic diagnosis and by gene mutation profile. (A) Dot plots with medians (blue) and interquartile ranges (red). Abbreviations: ADCA: Adenocarcinoma; ACC: Adrenal Cortical Carcinoma; ENT: Ear Nose Throat; GCT: Germ cell Tumor; LG: Low Grade; HG: High grade; IDC: Invasive Ductal Carcinoma; NEC: Neuroendocrine Carcinoma; NM: Non-Medullary Thyroid Carcinoma; NOS: Not Otherwise Specified; RCC: Renal Cell Carcinoma; SCC: Squamous Cell Carcinoma. Since response to ICB was not interrogated in these relationships, all 554 patients were included in this analysis, regardless of treatment status. (B) Distribution of TMB (RMs /Mb) stratified by individual somatic gene mutation. Tumors with somatic mutations within these genes or gene panels were plotted against a standardized TMB logarithmic scale with medians and interquartile ranges shown. The red arrow highlights the relatively high TMB seen in mismatch repair (MMR) gene mutated tumors. The blue arrows indicate tumors with mutations in other DNA repair pathways. The orange arrow indicates ATM mutated tumors. TP53 mutated tumors demonstrated relatively lower TMB (black arrows). Both stratifications yield a p < 0.0001 in one-way ANOVA analysis. TMB - Tumor Mutation Burden; RM - Reported Mutations; Mb – Megabase; DDR (DNA Damage Repair) = BER, CHEK, FA, MMR, NER, RER. MMR (Mismatch Repair) = MLH1, MSH2, MSH6, PMS1, PMS2; RER (Recombination Repair) = ATM, ATR, XRCC2, RAD50, WRN, PARP1, NBN, MRE11A; FA (Fanconi anemia pathway) = FANCA, FANCC, FANCD2, FANCF, FANCG, PALB2, BRIP1; NER (Nucleotide Excision Repair) = ERCC2, 4, 5, XPC, XPA; BER (Base Excision Repair) = SMUG1, MUTYH; CHEK (Checkpoint Kinases) = CHEK1, CHEK2. Since response to ICB was not interrogated in these relationships, all 554 patients were included in this analysis, regardless of treatment status.

TMB has been shown to predict response to ICB in patients with non-small cell lung carcinoma, melanoma, gastrointestinal and endometrial adenocarcinomas, as well as histology agnostic solid tumors .

Recently, patients with tumor mutations in certain DNA damage repair genes such as POLE, base excision repair genes, and mismatch repair genes have been shown to respond to ICB. However, the potential ICB response in patients with tumor mutations in other DDR pathway genes is not yet well characterized.

The Broaddus Research Team concluded in their Oncotarget Research Paper that a more complex multivariate analysis that included treatment type, cancer type, specific gene mutations, and TMB, treatment with ICB remained strongly associated with better overall survival. Tumor type and mutations in individual genes may be modifiers of the impact high TMB has on ICB treatment response.

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Full text - https://doi.org/10.18632/oncotarget.27466

Correspondence to - Russell R. Broaddus - rbroaddus@med.unc.edu

Keywords - biomarkers, immunotherapy, mutations, TMB, histology

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