ERCC2mutations as predictors of response to cisplatinin bladder cancer

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1 ERCC2mutations as predictors of response to cisplatinin bladder cancer Eliezer (Eli) Van Allen, MD Instructor, Harvard Medical School Dana-Farber Cancer Institute Broad Institute of MIT and Harvard August 8, 2015

2 Disclosures Advisory/Consultant role: Syapse Roche Ventana Third Rock Ventures

3 Outline Background Experimental design Genomic results Experimental validation Next steps

4 Outline Background Experimental design Genomic results Experimental validation Next steps

5 Clinical Computational Oncology Prospective clinical interpretation Clinical resistance to emerging therapies Responders and non-responders

6 Platinum chemotherapy as Imprecision Cancer Medicine Worldwide, estimated 750,000 patients receive a platinumbased chemotherapy each year Intrastrand Crosslink Wang & Lippard. Nat Rev Drug Discov : 307 Interstrand Crosslink

7 MIBC and neoadjuvant platinum-based chemotherapy Diagnosis Systemic treatment with cisplatin-based regimen Cystectomy Standard of care for ~ 20 years Cisplatin common to all regimens Some patients achieve pathologic complete response at cystectomy Improved OS Grossman et al NEJM2003

8 Low clinical uptake Regimen toxic Urologic management in community Genomic correlates of chemotherapy response lacking Hypothesis: Somatic alterations in DNA repair genes drive selective response to platinum-based chemotherapy David et al J Urol2007

9 Outline Background Experimental design Genomic results Experimental validation Next steps

10 Study design Jonathan Rosenberg Van Allen, Mouw et al Cancer Discovery 2014 dbgap; phs v1.p1

11 Outline Background Experimental design Genomic results Experimental validation Next steps

12 MutSigapproach

13 Case/controls studies with exomescale data All mutations + short indels Alteration subset Low Coverage/AF Low damaging score* (e.g. PPH2 < 0.5) Responders (n = 25) Non-responders (n = 25) Fishers exact test BH on genes with enough events for theoretical p < 0.01 *Hodis et al, Cell 2012

14 Responder enrichment

15 Responder enrichment

16 ERCC2and the nucleotide excision repair pathway Compe and Egly, Nature Reviews 2012

17 Helicase mutation selectivity Missense (Responders) Missense (Guo et al) Missense (TCGA) Y24C N238S V242F P463L E606G D609G D609E G665A Y72C S209C R286W P463S G607A H659Y G675S Q758E Y14C M42V E86Q S44L S246Y N238S T484A/M

18 Helicase mutation selectivity Conserved helicase motif Missense (Responders) Missense (Guo et al) Missense (TCGA) Y24C N238S V242F P463L E606G D609G D609E G665A 1 I IA II III IV V V Y72C S209C R286W P463S G607A H659Y G675S Q758E Y14C M42V E86Q S44L S246Y N238S T484A/M

19 Unique mutational signature Mutation Signatures in TCGA cohort C>A C>G C>T T>A T>C T>G APOBEC1 APOBEC2 C>T CpG Unknown Mutation Count A A A C A G A T C A C C C G C T G A G C G G G T T A T C T G T T A A A C A G A T C A C C C G C T G A G C G G G T T A T C T G T T A A A C A G A T C A C C C G C T G A G C G G G T T A T C T G T T A A A C A G A T C A C C C G C T G A G C G G G T T A T C T G T T A A A C A G A T C A C C C G C T G A G C G G G T T A T C T G T T A A A C A G A T C A C C C G C T G A G C G G G T T A T C T G T T Tri nucleotide Sequence Motifs JaegilKim, Paz Polak, Kent Mouw, Gad Getz

20 Unique mutational signature Log(P) TCGA DFCI/MSK BGI ERCC2 WDFY3 ERCC Median differences in No. Unknown Signature Mutations ERCC2 JaegilKim, Paz Polak, Kent Mouw, Gad Getz

21 Outline Background Experimental design Genomic results Experimental validation Next steps

22 Experimental work Use ERCC2null cell line derived from xerodermapigmentosumpatient Transfect with WT or mutants seen in patients Assess change in sensitivity to perturbation in different scenarios Kent Mouw Alan D Andrea

23 ERCC2and cisplatinsensitivity Kent Mouw Alan D Andrea

24 Outline Background Experimental design Genomic results Experimental validation Next steps

25 External Clinical Validation?

26 External Clinical Validation? Carbo< Cisclinically in bladder CA Carbo< Cispotency + DNA target Specifically excluded in our study Focusing on matching cohorts -> 6/16 vs. 0/16 Need larger sample size for wider application Still likely doesn t capture the full story

27 A window into broader DNA repair defects underlying response? Plimacket al Eur Urol2015

28 Next steps Expanding clinical validation Clonal v. subclonal effect? Towards development of genomic signature for platinum response 1 Metastatic cohorts Experimentally: What is the selective advantage of mutating ERCC2 for the tumor? Are other NER genes involved? Therapeutic potential? 1 Plimack et al Eur Urol2015

29 Let s work together! vanallenlab.dana-farber.org Clinical computational oncology team Broad Institute DFCI + Center for Cancer Precision Medicine MSKCC Ali Amin-Mansour Andrea Garofalo Diana Miao Travis Zack David Liu Alma Imamovic Brendan Reardon Daniel Keliher Genomics Platform Picard Team Firehose Team Gad Getz Gregory Kryukov Jill Mesirov Manaswi Gupta Jasmine Mu Kris Cibulskis Will Gibson Adam Keizun Scott Carter Many others Levi A. Garraway Joaquim Bellmunt Kent Mouw Alan D Andrea David Kwiatkowski Philip Kantoff Mary-Ellen Taplin GU Oncology team Judy Garber Many others Jonathan Rosenberg Gopa Iyer Hikmat Al-Ahmadie Many others Funding