Practicing Pathology in the Era of. Molecular Classification and Precision Medicine. Molecular Classification

Transcription

1 Practicing Pathology in the Era of Molecular Classification August 18, 2016 Molecular Classification and Precision Medicine Liang Cheng, MD Indiana University Indianapolis, IN Sept 13, 2017 Biankin Nature Alexandrov et al Nature 500:415 Based on 4,938,362 mutations from 7,042 cancers Molecular signatures provide a distinct taxonomy relative to the currently used tissue-oforigin based classification. Approximately 10% of cases were reclassified by the molecular taxonomy. The newly defined integrated subtypes providing a significant increase in the accuracy for the prediction of clinical outcomes. The Cancer Genome Atlas Research Network TCGA TCGA NEJM 372:2481; 2015 Ledford Nature Aug 14,

2 Eckel-Passow et al. NEJM 372:2499 Ellison NEJM 2015 IDH: isocitrate dehydrogenase Survival (yr) TERT mutation is BAD! Northcott Nature July 20, 2017 Louis et al Acta Neuropathol 131:803, medulloblastoma patients WHO Classification, 2016 Melanoma Leads Precision Medicine Aug 18, 2011 BRAF inhibitor Sept 4, 2014 FDA Approval of PD1 inhibitor Keytruda Mack JCO July

3 BRAF Kinase: An Important Mediator of Cellular Proliferation Superior Combined BRAF and MEK Inhibition Ascierto et al Lancet Oncol 17:1248, Sept 2016 Mod Pathol (in press, 2017) 495 patients Median survival: 22 vs 17 months Hyman et al NEJM 2373:726, 2015 Calio et al Oncotarget (in press) Location and Pathology Matter! Acinar pattern Lung (20): Response rate: 42% Median PFS: 7.3 months Lung Other tumors Planchard Lancet Oncol 17:984, 2016 BRAF + MEK inhibition for Lung Cancer June 22, 2017 BRAF+ MEK: 9.7 mo BRAF: 5.5 mo Chemo: 3.1 mo 3

4 July 14, 2017 Release Lung Cancer in the Era of Precision Medicine Politi CCR Cheng et al Modern Pathology 25:347 Mok et al NEJM 2009 Maemondo et al NEJM 2010 Median PFS: 10.8 vs 5.4 mo Barlesi Lancet 2016; 387:1415 Lee JNCI 2017,109 n= 17,664 N=1231 Median PFS: 11 vs 5.6 month 4

5 Cheng et al J Pathol Clin Res 3:73, 2017 Mano Cancer Discov 2:495 EML4-ALK in Lung Cancer ALK FISH vs IHC Disconcordance Normal Blackhall J Clin Oncol 32:2780 EML4-ALK fusion 5 yr OS: 54% vs 73% N=1281 Cheng et al J Pathol Clin Res 3:73, 2017 Yoshida J Clin Oncol 2016 Cancer Discov vs 4.2 months Variant 1: exon 13 of EML4 fused to exon 20 of ALK 5

6 Robison et al. NEJM Aug Poly(adenosine diphosphate ribose) polymerase inhibitor April 10, 2017 The risk of disease progression or death was 42% lower with olaparib monotherapy Median PFS: 7.0 vs 4.2 months N=302 Katona & Cheng Am J Surg Pathol 31:1029, 2007 Meacham Nature 501:328 BRAF Discrepancy in Primary vs Metastatic Melanoma Bradish & Cheng Modern Pathology April 2015 Bradish & Cheng Modern Pathology 28:480,

7 Wang et al J Natl Cancer Inst Indiana University Wang et al. J Natl Cancer Inst 101:560 Major Challenge: Drug Resistance Wan Nature Review Cancer 2017 Science 331:1542 Oxnard J Clin Oncol 34:2275; 2016 Kato et al. Aug 15, vs 3.4 months N=308 Patients positive for T790M in plasma have outcomes with osimertinib that are equivalent to patients positive by a tissue-based assay N= /442 (66%) patients harboring genomic alterations, distinct genomic profiles were observed in 88% of CUP cases, with 99.7% exhibiting targetable alterations. 7

8 Phallen et al. Sci Transl Med August 16, 2017 Smit Nature Review Clin Oncol 2016 Reck NEJM Epub Oct 9, 2016 N= healthy Johnson NEJM 2016 PFS: 10.3 vs 6.0 months 20% OS difference AACR Meeting, April 3, 2017 Nasser Hana et al J Clin Oncol August 15, 2017 (Epub) First Line Therapy PDL1 TPS >50% Estimated five-year overall survival rate in previously treated advanced NSCLC patients who received Opdivo was 16% (vs 5%) Gettinger JCO 2015 Topalian 2016 Nature Review Cancer Ledford Nature 2016 Mlecnik 2016 Immunity 8

9 Precision Immunotherapy 60% versus 0% ORR Le & Diaz New Engl J Med May 30, 2015 Epub 12 different tumor types Objective response: 53% Complete response: 21% Le et al. Science Epub June 8, 2017 May 23, 2017 Hause et al. Nature Med 22:1342, 2016 Uhlen Science Aug 18, cancer exome from 18 cancer types at >200,000 microsatellite site We used systems level approaches to analyze the genome wide transcriptome of the protein-coding genes of 17 major cancer types from >8000 patients. Shorter patient survival was associated with up regulation of genes involved in cell growth and with down regulation of genes involved in cellular differentiation. Contact Information Liang Cheng, MD Virgil H. Moon Professor of Pathology Director of Molecular Diagnostics Laboratory Chief of Genitourinary Pathology Division Director, Fellowship in Urologic Pathology Indiana University School of Medicine Indianapolis, Indiana Tel: liang_cheng@yahoo.com 9