Hepatocellular Carcinoma

New England Journal of Medicine, Journal Year: 2019, Volume and Issue: 380(15), P. 1450 - 1462

Published: April 10, 2019

Primary liver cancer is the fourth most common tumor worldwide. Hepatocellular carcinoma occurs mainly in context of cirrhosis, hepatitis B or C virus infection, nonalcoholic steatohepatitis. Underlying disease limits therapeutic efficacy.

Language: Английский

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Tumor mutational load predicts survival after immunotherapy across multiple cancer types

Nature Genetics, Journal Year: 2019, Volume and Issue: 51(2), P. 202 - 206

Published: Jan. 8, 2019

Language: Английский

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Oncogenic Signaling Pathways in The Cancer Genome Atlas

Cell, Journal Year: 2018, Volume and Issue: 173(2), P. 321 - 337.e10

Published: April 1, 2018

Highlights•Alteration map of 10 signaling pathways across 9,125 samples from 33 cancer types•Reusable, curated pathway templates that include a catalogue driver genes•57% tumors have at least one potentially actionable alteration in these pathways•Co-occurrence alterations suggests combination therapy opportunitiesSummaryGenetic control cell-cycle progression, apoptosis, and cell growth are common hallmarks cancer, but the extent, mechanisms, co-occurrence differ between individual tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions DNA methylation profiled by The Cancer Genome Atlas (TCGA), we analyzed mechanisms patterns somatic ten canonical pathways: cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 β-catenin/Wnt. We charted detailed landscape types, stratified into 64 subtypes, identified mutual exclusivity. Eighty-nine percent had pathways, 57% targetable currently available drugs. Thirty multiple alterations, indicating opportunities for therapy.Graphical abstract

Language: Английский

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Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

Annals of Oncology, Journal Year: 2018, Volume and Issue: 30(1), P. 44 - 56

Published: Nov. 1, 2018

Treatment with immune checkpoint blockade (ICB) agents such as anti-programmed cell death protein 1 (PD-1), death-ligand (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated 4 (CTLA-4) can result in impressive response rates and durable disease remission but only a subset of patients cancer. Expression PD-L1 has demonstrated utility selecting for to ICB proven be an important biomarker patient selection. Tumor mutation burden (TMB) is emerging potential biomarker. However, refinement interpretation contextualization required.

Language: Английский

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OncoKB: A Precision Oncology Knowledge Base

JCO Precision Oncology, Journal Year: 2017, Volume and Issue: 1, P. 1 - 16

Published: July 7, 2017

With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for support tool that distills the implications associated with specific mutation events into standardized and easily interpretable format. To this end, we developed OncoKB, expert-guided precision oncology knowledge base.

Language: Английский

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A view on drug resistance in cancer

Nature, Journal Year: 2019, Volume and Issue: 575(7782), P. 299 - 309

Published: Nov. 13, 2019

Language: Английский

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Patient-derived organoids model treatment response of metastatic gastrointestinal cancers

Science, Journal Year: 2018, Volume and Issue: 359(6378), P. 920 - 926

Published: Feb. 22, 2018

Cancer organoids to model therapy response are miniature, three-dimensional cell culture models that can be made from primary patient tumors and studied in the laboratory. Vlachogiannis et al. asked whether such “tumor-in-a-dish” approaches used predict drug responses clinic. They generated a live organoid biobank patients with metastatic gastrointestinal cancer who had previously been enrolled phase I or II clinical trials. This allowed authors compare how actually responded Encouragingly, similar molecular profiles those of tumor, reinforcing their value as platform for screening development. Science , this issue p. 920

Language: Английский

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STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma

Cancer Discovery, Journal Year: 2018, Volume and Issue: 8(7), P. 822 - 835

Published: May 17, 2018

Abstract KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine efficacy PD-1 inhibitors these subgroups. Objective response rates to blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) (P < 0.001) Stand Up To Cancer (SU2C) cohort (174 patients) with LUAC patients treated nivolumab CheckMate-057 phase III trial (0% vs. 57.1% 18.2%; P = 0.047). In SU2C cohort, exhibited shorter progression-free overall 0.0015) survival compared KRASMUT;STK11/LKB1WT Among 924 LUACs, alterations were only marker associated PD-L1 negativity TMBIntermediate/High The impact on clinical outcomes PD-1/PD-L1 extended PD-L1–positive non–small cell cancer. Kras-mutant murine models, Stk11/Lkb1 loss promoted inhibitor resistance, suggesting a causal role. Our results identify as major primary resistance Significance: This work identifies prevalent genomic axis adenocarcinoma. Genomic profiling may enhance predictive utility expression tumor mutation burden facilitate establishment personalized combination immunotherapy approaches for genomically defined subsets. Discov; 8(7); 822–35. ©2018 AACR. See related commentary by Etxeberria et al., p. 794. article highlighted Issue feature, 781

Language: Английский

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Molecular Determinants of Response to Anti–Programmed Cell Death (PD)-1 and Anti–Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non–Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing

Journal of Clinical Oncology, Journal Year: 2018, Volume and Issue: 36(7), P. 633 - 641

Published: Jan. 16, 2018

Purpose Treatment of advanced non-small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset patients. Clinically available tools to optimize use ICIs understand the molecular determinants response are needed. Targeted next-generation sequencing (NGS) increasingly routine, but its role identifying predictors not known. Methods Detailed clinical annotation data were collected for patients treated anti-programmed death-1 or death-ligand 1 [anti-programmed cell death (PD)-1] therapy profiled targeted NGS (MSK-IMPACT; n = 240). Efficacy was assessed Response Evaluation Criteria Solid Tumors (RECIST) version 1.1, benefit (DCB) defined as partial response/stable disease that lasted > 6 months. Tumor mutation burden (TMB), fraction copy number-altered genome, gene alterations compared among DCB no (NDB). Whole-exome (WES) performed 49 compare quantification TMB versus WES. Results Estimates correlated well WES (ρ 0.86; P < .001). greater than NDB ( .006). more common, progression-free longer at increasing thresholds above below 50th percentile (38.6% v 25.1%; .001; hazard ratio, 1.38; .024). The genome highest those NDB. Variants EGFR STK11 associated lack benefit. PD-L1 expression independent variables, composite plus further enriched ICIs. Conclusion accurately estimates elevated likelihood did correlate expression; both variables had similar predictive capacity. incorporation into multivariable models should result power.

Language: Английский

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Advances in epigenetics link genetics to the environment and disease

Nature, Journal Year: 2019, Volume and Issue: 571(7766), P. 489 - 499

Published: July 1, 2019

Language: Английский

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