State of the Art in Tumor Profiling
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1 State of the Art in Tumor Profiling Dora Dias-Santagata, PhD, FACMG Translational Research Laboratory Massachusetts General Hospital Harvard Medical School Boston, MA
2 Disclosures Intellectual Property Submission of a patent covering the SNaPshot genotyping methods US Patent and Trademark Office US/12/799,415 (pending) Consultant Bio Reference Laboratories, Inc.
3 State of the Art in Tumor Profiling Learning Objectives Describe the main goals of clinical molecular testing Understand some of the challenges facing the clinical implementation of tumor molecular profiling Identify examples of key tumor genetic changes, for which molecular testing is being performed, to assist in therapeutic decision making
4 Clinical Molecular Testing Diagnosis * Prognosis * Treatment Molecular Diagnostics / MGH Pathology Normal Sample Gene A Gene B Gene D Gene E Gene C Tumor Sample Mutation
5 Moving toward a genotype-based approach to guide cancer care Cancer Patient Clinical Information Therapeutic decisions Therapeutic *** decisions Targeted Therapies Surgical Specimen Histology-Based Diagnosis Molecular Analysis
6 Specific genetic changes & sensitivity to targeted therapies BCR-ABL Translocation: Imatinib 95% CML HER2 Amplification: Trastuzumab 20-30% IDC EGFR Mutation: Erlotinib/Gefitinib 20% Lung adenocarcinomas BRAF V600E: Vemurafenib 50-60% Melanoma ALK Translocation:Crizotinib 3-5% Lung adenocarcinoma BRAF 1799 T>A V600E
7 Oncogenic disruption of the EGFR RAS/MAPK pathway Oncogenic Mutations Targeted Therapies Growth factor-independent signaling EGFR inhibitors PI3K inhibitors BRAF inhibitors MEK inhibitors Uncontrolled cell proliferation
8 Establishing a Clinical Genotyping Platform Challenges and practical considerations Clinical Test Performed in a CLIA lab Archived FFPE tissue Analytical sensitivity Turnaround time (2 weeks) Report in medical record Actionable Targets Clinches diagnosis Yields prognosis Predicts response/resistance Stratify patients for trials Adaptability for new targets Logistics Clinical patient coordinator Accessioning Tracking Automation Scalable to test all tumors Other Economics Insurance and billing Translational research Bioinformatics
9 Translational Research Laboratory Directing patient therapy based on genetic fingerprinting Goal: To provide oncologists with real-time high-throughput tumor genotyping for: 1. Clinical decision making 2. Accelerated development of new cancer therapies Cancer Patients Oncology Treatment & Clinical Trials High-Throughput Genotyping Improved Clinical Use of Genotyping Translational Research Laboratory MGH Tissue Repository Basic Research Centers
10 New challenges in Molecular Pathology Which test is best? The problem: - multiple tumor types - many mutations - a growing number of targeted therapies Possible approach: Tumor A Test 1 Tumor B Test X Tumor C Test α Test 2 Test Y Test β Test 3 Test Z Test γ no more tissue? no more tissue? no more tissue? Other options: - multiple therapeutic options pose a new need multiplex testing Tumor A Test A Tumor B Test B Tumor C Test C Informed Therapeutic Decisions Tumor A Tumor B ONE Test Tumor C Informed Therapeutic Decisions
11 SNaPshot Genotyping Assay 15 genes - 70 assays - >160 described mutations AKT1 E17-49G IDH1 R C PIK3CA R88-263G IDH1 R G PIK3CA E G APC APC APC APC R C Q C R C T1556fs* _4667insA KIT KRAS KRAS D A G12-34G G12-35G PIK3CA PIK3CA PIK3CA PIK3CA PIK3CA E G Q C Q A H C H A BRAF BRAF BRAF BRAF BRAF CTNNB1(b-Cat) CTNNB1(b-Cat) CTNNB1(b-Cat) CTNNB1(b-Cat) CTNNB1(b-Cat) G G G G L C V G V T D32-94G D32-95A S33-98C G34-101G S37-109T KRAS KRAS KRAS KRAS KRAS MAP2K1(MEK1) MAP2K1(MEK1) MAP2K1(MEK1) NOTCH1 NOTCH1 G13-37G G13-38G Q61-181C Q61-182A Q61-183A Q56-167A K57-171G D67-199G L T L T PIK3CA PTEN PTEN PTEN PTEN TP53 TP53 TP53 TP53 TP53 G G R C R C R C K267fs*- 800delA R G G G R C R G R C CTNNB1(b-Cat) CTNNB1(b-Cat) CTNNB1(b-Cat) CTNNB1(b-Cat) CTNNB1(b-Cat) EGFR EGFR S37-110C T41-121A T41-122C S45-133T S45-134C G G G G NRAS NRAS NRAS NRAS NRAS NRAS NRAS G12-34G G12-35G G13-37G G13-38G Q61-181C Q61-182A Q61-183A TP53 TP53 R G R C Multiplexed sizing assay: EGFR exon 19 EGFR exon 20 ERBB2 exon 20 EGFR T C EGFR L T EGFR L T EGFR E746_A _2249del EGFR E746_A _2250del
12
13 SNaPshot Overview Multiplex PCR Single Base Extension Reaction Capillary electrophoresis Loci of interest 1 2 ddntp ddntp 3 ddntp Electrophoretic Output Relative fluorescence Increasing molecular weight
14 SNaPshot Overview Single Base Extension Reaction G C 1 2 A T T A 3 C G Electrophoretic Output mut 1 2 3
15 MGH SNaPshot Testing Volume Brain n=24 Colorectal n=22 Breast n= Other n=25 GI, other n=32 Lung n= >4,500 clinical SNaPshot tests performed to date >200 clinical SNaPshot tests per month
16 3 years of mutational profiling LUNG cancer IDH1/AKT1/APC/PTEN/MEK1 <1% NRAS 1% BRAF 2% ALK rearrangement 4% CTNNB1 2% ROS rearrangement 2% PIK3CA 4% TP53 6% EGFR 14% Wild Type 40% KRAS 24% 1910 tumor specimens - 60% mutant
17 Overlap of Mutations - NSCLC B-cat (11 total) KRAS 129 isolated (134 total) 5 5 PIK3CA (22 total) EGFR 63 isolated (73 Total) (1) IDH BRAF TP53 (25 total) ALK 27 6 NRAS (2) HER2 Sequist et al., Annals of Oncology, 2011
18 Mechanisms of acquired drug resistance - NSCLC 37 patients w/ EGFR-mutant tumors responded to EGFR inhibitors and later relapsed Sequist et al., Science Translational Medicine, 2011
19 Case 1 NSCLC Presentation 61 y.o. Male never-smoker CT chest showed large right upper lobe mass and numerous bilateral pulmonary nodules (<5 mm) suspicious for metastasis Biopsy identified NSCLC, adenosquamous histology
20 Case 1 NSCLC Molecular Testing: EGFR gene mutation: EGFR L858R Normal Normal Tumor EGFR L858R (c.2573t>g) Tumor TP53 G245S (c.733g>a) Therapeutic implication: confers sensitivity to EGFR TKI
21 Case 1 NSCLC Pre-Treatment Therapeutic Response Acquired Resistance Erlotinib 1/30/08 3/31/08 (RUL 6.8x4.5 cm) (RUL 2.6x1.8 cm) 2/25/09 (RML 2 cm)
22 Case 1 NSCLC Molecular Testing Pre-Treatment 08 Resistant 09 Clinical Trial MET+EGFR inhibitor Engelman et al., Science, 2007 Bean et al., therapy PNAS, 2007 MET gene amplification response to therapy tumor mass reduced by ~30%
23 Case 2 NSCLC Genotype supports 2 independent primary tumors mutational profiling of bilateral tumor masses two distinct genotypes support the clinical suspicion that this was not metastatic disease but rather two synchronous lower stage primary tumors better prognosis and direct impact patient management (aggressive surgical therapy + adjuvant chemotherapy) Tumor #1 Tumor #1 KRAS G12C Tumor #2 Tumor #2 BRAF V600E Tumor #1 - Right upper lobe Adenocarcinoma (bronchioloalveolar) KRAS G12C (c.34g>t) Tumor #2 - Left upper lobe Adenocarcinoma (acinar subtype) BRAF V600E (c.1799t>a)
24 Tumor Genotyping to Resolve Staging Questions Genotype YR Location Clinical questions/staging Informative? Answer KRAS 35G>A, G12D 2011 RUL T3N0 vs T1aN0 x2 lesions Y T1 x 2 KRAS 182A>T, Q61L, BRAF 1798G>T, V600L 2011 RUL KRAS 35G>T, G12V 2011 RLL T1aN0 vs T4N0 Y T1 x 2 EGFR 2582T>A, L861Q 2011 RUL No mutation 2011 RML T1aN0 vs T4N0 Y T1 x 2 KRAS 34G>C, gly12arg 2011 RUL KRAS 34G>T, G12C 2010 RLL T4N0 vs T1aN0 x2 lesion Y T1 x 2 BRAF 1397G>T, G466V, KRAS 37G>T, G13C 2010 RUL KRAS 34G>T, G12C 2009a RUL T1aN0M1a vs T1aN0 x2 lesions Y T1 x 2 KRAS 35G>C, G12A 2009a LUL KRAS 34G>T, G12C 2009b adrenal KRAS 34G>C, G12R 2008 LLL Met vs. metachronous 2 primaries Y 2 primaries No mutation 2010 RLL No mutation 2008 LLL Met vs. metachronous 2 primaries Y 2 primaries KRAS 34G>T, G12C 2010 RML EGFR 2573T>G, L858R 2009 LLL Met vs. metachronous 2 primaries Y Metastases EGFR 2573T>G, L858R 2011 RUL No mutation 2007 RML Met vs. metachronous 2 primaries N - No mutation 2010 RML KRAS 35G>C, G12A 2011 RUL Met vs. metachronous 2 primaries Y 2 primaries EGFR exon 19 (18bp) deletion 2011 LUL No mutation 2009 LUL Met vs. metachronous 2 primaries Y 2 primaries KRAS 34G>T, G12C 2010 RLL KRAS 34G>T, G12C 2010 RML T1aN0 x2 vs T4N0 Y T1 x 2 BRAF 1799T>A, V600E 2010 RLL TP53 742C>T, R248W; KRAS 35G>C, G12A 2010 LUL Met vs. metachronous 2 primaries Y 2 primaries KRAS 37G>T, G13C 2010 RUL 12/13 staging dilemmas solved! 92%!
25 ALK Rearrangements in NSCLC Rapid integration of FISH PF : Potent & selective ATP competitive oral inhibitor of MET and ALK kinases and their Telomere 2p23 region 3 5 t(2;5) ALK gene breakpoint region Centromere oncogenic variants ~250 kb ~300 kb
26 Case 3 NSCLC Dramatic Improvement Following Targeted ALK Inhibition Pre-Treatment After 2 cycles PF yr-old Female
27 Tumor Responses to Crizotinib by Patient Decrease or increase from baseline (%) % reduction PD SD PR CR Best Percent Change in Tumor Size (n=105 evaluable patients) Camidge R et al. Poster 366 presented at the 35 th ESMO, 2010
28 Crizotinib & ALK: Targeted Treatment of NSCLC Timeline for approval PF activity in cells exhibiting ALK fusion in broad screen (McDermott et al., Canc Res, 2008) FDA Approval: ALK-positive NSCLC Discovery of EML4-ALK fusions in NSCLC (Soda et al., Nature) MGH clinical study of PF in ALK-positive NSCLC starts
29 Genotype-based clinical trial enrollment of advanced disease NSCLC patients Mutant gene and targeted agents Mutation-positive patients Clinical trial with metastatic disease enrollment ALK (73%) crizotinib (ALK inhibitor ) Hsp-90 inhibitor BRAF 7 3 (43%) MEK inhibitor EGFR (63%) erlotinib+met inhibitor erlotinib+pi3k inhibitor erlotinib+her3 MAb 2 nd gen EGFR inhibitors STAT3 inhibitor HER2 7 1 (14%) 2 nd gen EGFR inhibitor + mtor inhibitor HER3 MAb KRAS (8%) MEK inhibitor + chemotherapy MEK inhibitor + PI3K inhibitor Hsp-90 inhibitor PIK3CA 16 2 (13%) PI3K inhibitors Total (35%) 540 mut+ (expanded) Sequist et al., Annals of Oncology, 2011
30 Tumor genetic profiling in the clinic Breast Cancer PTEN 2% KRAS 2% BRAF 2% TP53 4% PIK3CA 33% Wild Type 58% 130 cases HER2 amplification ~ 20-30% IDC PIK3CA mutant Breast Cancer favorable prognosis improved OS decreased response to treatment with HER2 inhibitors (trastuzumab, lapatinib)? PI3K/mTOR inhibitors (actively pursued, encouraging data) KRAS / BRAF mutant Breast Cancer? MEK inhibitors? /? BRAF inhibitors?
31 Case 2 Breast Cancer Therapeutic Application 65yo Female with : 2005: ER+ breast cancer (localized) 2009: Disease recurrence (bone and liver): - Started endocrine therapy - Progressed on various endocrine therapies 2011: SNaPshot revealed: - PIK3CA E542K mutation - Enrolled on PI3K-alpha inhibitor trial
32 Case 2 Breast Cancer Therapeutic Application Marked PET response with PIK3CA-directed Rx Pre-Therapy Post-Therapy
33 PIK3CA Mutation Distribution Across Tumor Types % Percentage of each tumor type demonstrating PIK3CA mutation Number of cases % 16% 7% 33% 2% 5% 0 # cases # mutant cases S# PIK3CA mutant cases
34 Orphan Diseases Broad based Tumor Genotyping applied to ALL tumors in a CLINICAL setting identify new targets for rare/poorly studied malignancies enable rapid translation to patient care (genotype-driven clinical trials) BRAF V600E mutations are common in a subset of pediatric brain tumors Dias-Santagata et al., PLoS ONE, 2011 Activating mutations in PIK3CA in a rare and very aggressive skin malignancy Nardi et al., Clin Cancer Res, 2012
35 Future Goals Moving toward a more comprehensive tumor genetic fingerprint wild type Sanger Sequencing one exon SNaPshot >160 hotspot mutations 15 cancer genes Next Generation Sequencing all exons hundreds of cancer genes
36 Tumor Genetic Changes Drive Cancer Development copy number NexGen indels proteomics point mutations rearrangements FISH non-coding RNAs epigenetics gene expression
37 The Next Generation of Clinical Cancer Genotyping Clinical targeted sequencing of FFPE DNA Goals * * genes (5 Mb) X coverage 5 Gb data per tumor-normal pair 3-4 week turnaround time $ raw reagent cost Tumor vs. normal SNV, indel, copy number
38 Clinical Application of Tumor Genotyping Biological/Clinical Tumor Heterogeneity Tumor Evolution Practical/Logistical Data Management How to interpret data and deliver results quickly Maximum Sensitivity Resistance mechanisms Rapid Evolution of Knowledge and Clinical Indications Cost and Reimbursement Challenges
39 Conclusions Prospective, multiplexed genotyping can be efficiently incorporated into clinical practice to aid clinical decision-making and to accelerate stratified clinical trial enrollment. Broad-based tumor genotyping can identify new prognostic/therapeutic markers not previously identified in a specific cancer type. Emerging tumor genotyping technologies including Next Generation Sequencing will be an important tool in expanding our efforts to: identify novel therapeutic targets understand differential response to treatment discover additional mechanisms of acquired resistance
40 MGH Translational/MolDx Laboratory John Iafrate Leif Ellisen Darrell Borger Long Phi Le Lindsay Bernardo A. Bernard Collins Jae Han Taylor Johnson Quynh Lam Daniel Lara Hector Lopez Julie Miller Anhthu Nguyen Divya Panditi Joseph Parziale Amanda Pawlak Hayley Robinson Uma Saxena Kathy Vernovsky Boryana Zhelyazkova Zongli Zheng MGH Clinical Translational Collaborators Daniel Haber (Director) Jose Baselga (Phase I/Director) David Louis (Director) Jeffrey Engelman (Lung Cancer) Rebecca Heist (Lung Cancer) Ignatius Ou (Lung Cancer) Lecia Sequist (Lung Cancer) Alice Shaw (Lung Cancer) Mari Mino-Kenudson (Pathology) Jeffrey Clark (GI Cancer) Eunice Kwak (Phase I/GI Cancer) David Ryan (GI Cancer) Kenneth Tanabe (GI Cancer) Andrew Zhu (GI Cancer) Tracy Batchelor (Neuro-Onc) Daniel Cahill (Neuro-Onc) Andrew Chi (Neuro-Onc) Theodore Hong (Rad-Onc) Keith Flaherty (Phase I/Melanoma) Steven Isakoff (Breast Cancer) Thank you to the PATIENTS and their Families!
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