Molecular Pathology of Renal Cell Carcinoma: An Update

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1 Molecular Pathology of Renal Cell Carcinoma: An Update George J. Netto, M.D. Professor and Chair of Pathology Robert And Ruth Endowed Chair in Pathology University of Alabama at Birmingham

2 Enterprise Interest No disclosures.

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4 Overview Epidemiology Genomic Advances in CCRCC Targeted Rx ImmunoRx Genomics Advances in PRCC

5 CANCER STATISTICS 2018

6 Stage at Presentation DSS CANCER STATISTICS 2018

7 Renal Cell Carcinoma General Features Clinical Features: Symptoms Triad: Pain, Hematuria, Mass Paraneoplastic Syndromes: PTH, Erythropoitin, PG, ACTH Changing Presentation toward smaller incidental mass on imaging Watchful Waiting, Partial Nephrectomy, CryoRx, Targeted Rx Needle Bx & Frozen Section Dx

8 Renal Cell Carcinoma Genetics and Morphology Linehan W M et al. J Urol 2003

9 Genetics & Morphology SDHB Deficient RCC SDH FH Deficient RCC FH Cohen & McGovern, NEJM 2006

10 Cohen & McGovern, NEJM 2006

11 Cohen & McGovern, NEJM 2006

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13 Targeted Rx in ccrcc Tyrosine Kinase Inhibitor (Sunitinib) mtor Inhibitor (Evrolimus) Immune Checkpoint Inhibitors: anti PD1 + anti CTLA4

14 400 ccrcc analyzed by multiple genomic platforms Nature significantly mutated genes: VHL, PBRM1, SETD2, KDM5C, PTEN, BAP1, MTOR and TP53 Arm level chromosomal alterations: 3p21-25 loss (vhl, PBRM1, SETD2, BAP1) 5q35 gains (GNB2L1, SQSTM1) 14q loss (HIF1A) PI(3)K/AKT pathway: Rx target Widespread DNA hypomethylation associated with mutation of the H3K36 methyltransferase SETD2 Mutations in SWI/SNF chromatin remodeling complex (PBRM1, ARID1A, SMARCA4) far-reaching effects on other pathways

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17 Nature 2013 Metabolic Shift in Aggressive ccrcc Recurrent pattern of remodeling of cellular metabolism that correlates with stage and outcome: new Rx options? Downregulation of TCA cycle genes, decreased AMPK and PTEN protein levels Upregulation of pentose phosphate pathway and glutamine transporter genes, increased acetyl-coa carboxylase protein, Altered promoter methylation of mir-21

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19 Targeted Rx in ccrcc Nine FDA approved TKIs or mtor inhibitors First-line Rx for metastatic as well as high-risk RCC after nephrectomy TKI s (VEGFR/FGFR/ PDGFR ): Sorafenib, Sunitinib etc.. mtor inhibitors: Temsirolimus, Evrolimus etc..

20 S-TRAC Ravaud et al. NEJM 2018

21 Immune Checkpoint Pathways Nature Reviews CANCER 2016

22 9/33 RCC Responders

23 CheckMate 025 Motzer et al. NEJM 2015 (FDA approval)

24 European Journal of Cancer , 55-72

25 European Journal of Cancer , Less than 25% of all patients respond to anti PDL1/PD1 Resistance mechanisms: T-cell exhaustion, overexpression of caspase-8 and b-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations Novel inhibitory compounds targeting TIM-3, VISTA, LAG-3, IDO, KIR New co-stimulatory antibodies targeting CD40, GITR, CD137, ICOS Combining agonistic with antagonistic agents : step on the gas while cutting the brakes

26 European Journal of Cancer , 55-72

27 CheckMate 214 Motzer et al. NEJM 2018 First Line Rx

28 CheckMate 214 Motzer et al. NEJM 2018

29 CheckMate 214 Motzer et al. NEJM 2018 in intermediate and high risk ccrcc: OS and Objective response was higher in N+I regardless of PDL-1 expression level. Overall, PFS was higher with N+I only in PDL-1 1% group The favorable-risk group (IMDC) had a higher objective response rate and longer progression-free survival with sunitinib than N+I?TMB 9% complete response rate compared to 1% observed with sunitinib (and other TKIs)

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31 Immunologic Biomarkers IHC/Gene Expression: PDL-1 CD8+ Mechanisms Driven Predictive Biomarker for Immune Checkpoint Inhibitors CD8+/Ki67 TIM3, LAG3, IDO ICOS, GITR Chemokines Signature (Interferon ȣ) Tumor Mutational Load/Burden: NSCLC, Melanoma, BC Neoantigens dmmr/msi: e.g. CRCa, Endometrial Ca. Viral Oncoproteins: HTLV-1, HPV, EBV, KSV, MCPyV, HBV, HCV

32 ROC curves of checkpoint inhibitor response in melanoma and NSCLC studies identified cutoff of 192 NsM In 7,757 samples of TCGA: 16.2% exceeded the 192 NsM threshold > 30% of BC, CRCa, Gastric Ca. and Endometrial Ca. have NsM counts above 192

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34 TCGA PRCC NEJM 2016

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36 TCGA PRCC NEJM 2016

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38 MiTF Family Translocation RCC MiTF TFE3 TFEB TFEC

39 MiTF Family Translocation RCC ISUP Renal Tumor Consensus Conference, Vancouver 2012 t(6;11) translocation RCC Alpha-TFEB Xp11 translocation RCC ASPL-TFE3 PRCC-TFE3 PSF-TFE3 NonO-TFE3 CLTC-TFE3

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41 Conclusions Genomic advances in CCRCC are revolutionizing therapy for advanced disease. Immune-checkpoint inhibitors (ICI) is fast becoming a first line option for advanced CCRCC Future work should focus on refining biomarkers of response and best combination of targeted molecular and ICI agents THANK YOU! Increased understanding of key genomic alterations in PRCC should translate into better management

42 THANK YOU!

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