Molecular Testing and Tumor Testing: Why is this important?
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Molecular Testing and Tumor Testing: Why is this important?

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Molecular testing and tumor testing. Have you ever been asked about it? Have you wondered the importance of it, as it relates to your particular cancer? Have you ever wondered if you should or ...

Molecular testing and tumor testing. Have you ever been asked about it? Have you wondered the importance of it, as it relates to your particular cancer? Have you ever wondered if you should or shouldn't have your tumor tested, and what that involves? Dr. Bekaii-Saab, MD will discuss the importance of testing the molecular biology of an individual patients tumor. How they do that and why it may or may not be important to have done. He will talk about how this is playing an even bigger role in choice of treatment options for patients now more than ever. And about the way physicians are making treatment choices based on each individuals molecular biology of their tumor.

Dr. Bekaii-Saab is the Section Chief, Gastrointestinal Oncology, James Cancer Hospital and Solove Research Institute. Dr. Bekaii-Saab is one of America’s Best Doctors. Additionally, he has been listed in U.S. News and World Report’s Top Doctors for multiple consecutive years. His research interests include experimental therapeutics/translational research focused on molecularly-targeted and immune-mediated therapies in gastrointestinal (GI) cancers. He is the principal investigator on numerous clinical trials, including studies supported through research grants from the National Cancer Institute (NCI) and the National Comprehensive Cancer Network (NCCN). Dr. Bekaii-Saab is the recipient of the prestigious NCI clinical investigator team leadership award and the ASCO leadership program development award.

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  • Graph explaining the concept of “All Three Drugs” in the era of cytotoxic chemotherapy – no targeted agents here. The median OS reported in phase III trials is correlated with percentage of patients with access to all active agents, fluoropyrimidine, irinotecan, and oxaliplatin, in the course of their disease. The analysis was performed without the FOLFOXIRI and CAIRO trial, but the treatment arms of these two studies project very nicely onto the graph and thus validate the analysis.

Molecular Testing and Tumor Testing: Why is this important? Molecular Testing and Tumor Testing: Why is this important? Presentation Transcript

  • Welcome! Molecular and Genetic Tumor Testing: Why is it Important? Part of Fight Colorectal Cancer’s Monthly Patient Webinar Series Our webinar will begin shortly www.FightColorectalCancer.org 877-427-2111
  • Fight Colorectal Cancer 1. Tonight’s speaker: Dr. Tanios Bekaii-Saab, MD 2. Archived webinars: Link.FightCRC.org/Webinars 3. Follow up survey to come via email. Get a free Blue Star of Hope pin when you tell us how we did tonight. 4. Ask a question in the panel on the right side of your screen and look for hyperlinks during throughout the presentation. 5. Or call the Fight Colorectal Cancer Answer Line at 877-427- 2111 www.FightColorectalCancer.org 877-427-2111
  • Fight Colorectal Cancer Disclaimer The information and services provided by Fight Colorectal Cancer are for general informational purposes only. The information and services are not intended to be substitutes for professional medical advice, diagnosis, or treatment. If you are ill, or suspect that you are ill, see a doctor immediately. In an emergency, call 911 or go to the nearest emergency room. Fight Colorectal Cancer never recommends or endorses any specific physicians, products or treatments for any condition. www.FightColorectalCancer.org 877-427-2111
  • Fight Colorectal Cancer Up coming webinars Wednesday, September 18th 8pm-9pm EST Pathways and Targets: How do these affect my treatment decisions? Wednesday, October 16th 8pm-9pm EST Peripheral Neuropathy: Will it ever go away? Problems, Causes, Solutions
  • Fight Colorectal Cancer www.FightColorectalCancer.org 877-427-2111 Dr. Tanios Bekaii-Saab, MD Section Chief , Gastrointestinal Oncology Program Associate Professor of Medicine and Pharmacology The Ohio State University – James Cancer Hospital
  • Molecular and Genetic Tumor Testing: Why is it Important? Tanios Bekaii-Saab, MD Section Chief , Gastrointestinal Oncology Program Associate Professor of Medicine and Pharmacology The Ohio State University – James Cancer Hospital
  • Colorectal Cancer as Worldwide Health Problem – 3rd highest incidence rate (~ 1,200,000/yr) – 4th highest mortality rate (~ 608,000/yr) CA: A Cancer Journal for Clinicians 2011;61:69-90 Worldwide Developed Developing
  • Sporadic Lynch Syndrome Familial Hereditary FAP; AFAP Mixed Polyposis Syndrome Ashkenazi I1307K CHEK2 (HBCC) MYH TGFBR1 PJS FJP CD BRRS = as yet undiscovered hereditary cancer variants Hamartomatous Polyposis Syndromes AC-1 without MMR (Familial CRC of syndrome “X”)
  • Colorectal Stage Distribution at Diagnosis (%) 19 % patients have Stage IV disease on diagnosis 5 year-survival of Stage IV disease is 12% Altekruse SF, Kosary CL, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010.
  • 10 Years No benefit of chemotherapy Cured by chemotherapy FluoroP + oxali Already cured by surgery Adjuvant Therapy for Colon Cancer Stage III 0 20 40 60 80 100 0 1 2 3 4 5 exposedtotoxicity Surgery alone Surgery plus Chemotherapy 20% % DiseaseFreeSurvival 60% 20% 20% 20% Moertel CG, N Engl J Med 1990 IMPACT investigators, Lancet 1995 André T, J Clin Oncol. 2009 Yothers G, J Clin Oncol 2011 Haller D, J Clin Oncol 2011
  • High-risk features Stage II colon cancer should be considered for adjuvant therapy • According to clinico-pathologic features: • Obstruction/perforation • T4 tumors • Less than 10/12 LN examined • Lymphatic or vascular invasion • Poorly differentiated histology • Molecular Biomarkers ? • Microsatellite instability (MSI) – Deficient Mismatch Repair as a Predictive Marker for Lack of Benefit from 5-FU based Chemotherapy in Adjuvant Colon Cancer (Sargent et al JCO 2010)
  • Microsatellite Instability • 4 MMR (mismatch repair) proteins: MLH1, MSH2, MSH6, and PMS2 • MSI is due to defects in MMR, resulting in the accumulation of nucleotide mutations and alteration in microsatellite length. • Genotyping: MSI-high versus MSS or MSI-low • IHC: deficient MMR versus proficient MMR • MSI tumors are due to: • Germline mutation of MMR proteins secondary to Lynch syndrome (5%) • Sporadic hypermethylation causing gene silencing of hMLH1 • Lynch syndrome screening: • IHC of MMR proteins • If missing MMR protein check BRAF mutation • If BRAF wild-type genetic testing for Lynch syndrome
  • Risk of recurrence • Adjuvant online: – Age – Co-morbidity – Tumor depth – # nodes positive – # nodes examined – Tumor Grade • Oncotype Dx – 12 gene recurrence score (8-24%) • Coloprint- 18 gene profile
  • Oncotype DX: Primary Analysis: Recurrence Score Predicts Recurrence Risk in Stage II Colon Cancer Patients in QUASAR
  • Oncotype DX: Primary Analysis: Recurrence Score Predicts Recurrence Risk in Stage II & III Colon Cancer Patients in NSABP C-07 (n=892) Solid: 5FU Dashed: 5FU+Ox Stage III C Stage III A/B Stage II • With similar relative benefit of oxaliplatin added to adjuvant 5FU across the range of RS, absolute benefit of oxaliplatin increases with increasing RS, most apparently in stage II and stage IIIA/B patients p<0.001 Solid: 5FU Dashed: 5FU+Ox O’Connell, ASCO 2012
  • Summary: Stages II and III • Stage II colon cancer – look at high-risk features, MSI status to help decide whether to offer adjuvant chemotherapy • Stage III colon cancer – Offer adjuvant 5FU/Xeloda or FOLFOX • Stage II and III rectal cancer – Neoadjuvant chemoradiation surgery adjuvant chemotherapy
  • Stage IV Colorectal Cancer (mCRC): Which biologic agent and for whom?
  • A high number of agents is currently available for the treatment of mCRC 5-FU Capecitabine Irinotecan Oxaliplatin Bevacizumab Panitumumab Cetuximab AfliberceptRegorafenib
  • Concept of “All-3-Drugs” : 11 Phase III Trials; 5,768 Patients OS (mos) = 13.2 + (% 3 drugs x 0.1), R^2 = 0.85 0 10 20 30 40 50 60 70 80 Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5-FU2 FOLFOXIRI CAIRO 22 21 20 19 18 17 16 15 14 13 12 MedianOS(mos) Patients With 3 Drugs (%) p = .0001 First-Line Therapy LV = leucovorin. Grothey et al, 2004; Grothey & Sargent, 2005; Koopman et al, 2007; Falcone et al, 2007.
  • Murine Ab “momab” Chimeric Mouse-Human Ab “ximab” Humanized Ab “zumab” Fc Fab Human Ab “mumab” Biologic Agents in CRC =MoAbs (17-1A) Cetuximab Bevacizumab Panitumumab EGFR VEGFMoAbs = monoclonal antibodies. McRee & Goldberg, 2011; Eng, 2010.
  • Extracellular Intracellular Ligand EGFR PI3K Akt Raf MEK MAPK Cell Motility MetastasisAngiogenesis Proliferation Cell Survival DNA PTEN Ras Fakih & Wong, 2010; Williams & Lockhart, 2009. KRAS WT = Wild Type KRAS MT = Mutant ( codons 12 and 13)
  • VEGF-A VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R3 (Flt-4) Lymphangiogenesis VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability PlGF VEGF-B VEGF-C, VEGF-D Functions Bevacizumab Ramucirumab Aflibercept (VEGF Trap) PIGF = placental growth factor. Holash et al, 2002; Roy et al, 2006; Ghosh et al, 2000. Large Molecule VEGF Inhibitors
  • Regorafenib (BAY 73-4506), an oral multikinase inhibitor targeting multiple tumor pathways1-3 KIT PDGFR RET 1. Wilhelm SM et al. Int J Cancer 2011. 2. Mross K et al. Clin Cancer Research 2012. 3. Strumberg D et al. Expert Opin Invest Drugs 2012. PDGFR-β FGFR VEGFR1-3 TIE2 Regorafenib Inhibition of neoangiogenesis Inhibition of neoangiogenesis Inhibition of tumor microenvironment signaling Inhibition of tumor microenvironment signaling Inhibition of proliferation Inhibition of proliferation Biochemical activity Regorafenib IC50 mean ± SD nmol/l (n) VEGFR1 13 ± 0.4 (2) Murine VEGFR2 4.2 ± 1.6 (10) Murine VEGFR3 46 ± 10 (4) TIE2 311 ± 46 (4) PDGFR-β 22 ± 3 (2) FGFR1 202 ± 18 (6) KIT 7 ± 2 (4) RET 1.5 ± 0.7 (2) RAF-1 2.5 ± 0.6 (4) B-RAF 28 ± 10 (6) B-RAFV600E 19 ± 6 (6)
  • Treatment Paradigms for mCRC • NCCN guidelines are a great resource to help see the “trees in the forest” • Some patients with stage IV disease are cured by an interdisciplinary approach • FOLFOX = CAPOX = FOLFIRI (XELIRI has problems with toxicity) • Most patients tolerate a chemotherapy doublet (but not all need it) • The addition of biologics to chemotherapy has improved outcomes • We are on the verge of individualized therapy based on molecular predictive factors mCRC = metastatic CRC; FOLFOX = oxaliplatin, 5-FU, leucovorin; CAPOX = capecitabine, oxaliplatin; FOLFIRI = irinotecan, infusional 5-FU; XELIRI = capecitabine, irinotecan. Aranda et al, 2011; Eadens & Grothey, 2011; NCCN, 2011.
  • Current Biologic Landscape in mCRC • Bevacizumab and EGFR mAbs competing for first-line patients in KRAS WT CRC • Bevacizumab (TML) and ziv-Aflibercept(VELOUR) competing for second-line and with EGFR mAbs in KRAS Wt CRC • Best sequence of therapies (VEGFi vs EGFRi) still to be established • Regorafenib as salvage therapy option (CORRECT)
  • mab: 40 mg m i.v. 120min initial dose 250 mg/m2 i.v. 60min q 1w Bevacizumab: 5 mg/kg i.v. 30-90min q 2w /0i FIRE-3 Phase III study design Cetux 2 FOLFIRI + Cetuximab FOLFIRI + Bevacizumab Bevacizumab: 5 mg/kg i.v. 30-90min q 2w mCRC 1st-line therapy KRAS wild-type N= 592 Randomize 1:1 Cetuximab: 400 mg/m2 i.v. 120min initial dose 250 mg/m2 i.v. 60min q 1w • Primary objective: Overall response rate (ORR) (inv assessed) • Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%) • 284 evaluable patients per arm needed to achieve 80% power for an one-sided Fisher‘s exact test at an alpha level of 2.5% FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2 irinotecan: 180 mg/m2 5-FU: 2,400 mg/m2 (i.v. 46h) Heinemann et al., ASCO 2013
  • Predictive Biomarkers For the Use of Anti-EGFR Antibodies in mCRC 79% 18% 3% MT BRAF 5-10% Other - PTEN LOE - NRAS MT - PIK3CA ex 20 MT ~40% Adapted from multiple sources: 1- Wheeler DL, et al Nat Rev Clin Oncol 2010 7(9) : 493-507;2- De Roock et al . Lancet Oncology, 2010 11: 753-762; 3- Frattini M , BJC 2007 97; 1139-1145; 4- Di Nicolantonio F et al . Journal of Clin Oncol 2008 26(35); 5705-5712;5- Loupakis F et al. BJC 2009 101;715-721; 6- Tran B . Cancer 2011 ; 1-10. 10% 8%
  • • European Consortium: – Refractory CRC patients treated with irinotecan + cetuximab – 1022 tumour samples – 773 samples of quality De Roock, W et al. Lancet Oncol 2010;11:753-62 Beyond KRAS: BRAF, NRAS, PIK3CA mutations
  • Are All KRAS Mutations Created Equal? – p.G13D  Pooled analysis of OPUS and CRYSTAL Tejpar et al, 2011.
  • KRAS G13D: Treat Similar to 12 - Pooled analysis of panitumumab studies showed no difference between codon 13, and codon 12, KRAS mutations Peeters M, et al. J Clin Oncol. 2012; 30(Suppl 4). Abstract 838. Panitumumab Studies -’181 -’203 -’408 Cetuximab Studies - CRYSTAL - OPUS
  • Response Rate Overall Survival De Roock, W et al. Lancet Oncol 2010;11:753-62 Beyond KRAS: BRAF, NRAS, PIK3CA mutations
  • Updated Analysis of PRIME study KRAS exon 2 codon 12/13 40% KRAS exon 3 codon 61 4% KRAS exon 4 codon 117/146 6% NRAS exon 2 codon 12/13 3% NRAS exon 3 codon 61 4% BRAF exon 15 codon 600 8% 17% Oliner et al., ASCO 2013
  • Oliner et al., ASCO 2013 HR 0.83 (KRAS wt cod 12/13) HR 0.78 (all RAS wt) OS Detriment! Detriment!
  • Ir vs IrCs non-inferior efficacy primary endpoint PFS at 12 wks IrPan irinotecan + pan’mab IrCs irinotecan + c’sporin Ir irinotecan alone Ir vs IrPan superior efficacy primary endpoint OS Ir irinotecan alone KRAS mutated or unknown KRAS-wt (c.12/13 & 61) PICCOLO study target total n = 1200 (including 494 accrued under previous design) eligibility as before Seymour et al. Proc ASCO 2011:A3523 PICCOLO Study
  • IrPan better Ir better *Adjusted HRs, 95% CIs KRAS wt: 460 pts, 312 events HR=0.91 (0.73, 1.14), p=0.44 Double wt : 348 pts, 230 events; HR=0.87 (0.67, 1.13), p=0.30 BRAF mut: 63 pts, 53 events; HR=2.03 (1.13, 3.64) NRAS mut: 21 pts, 15 events HR=4.59 (1.19, 17.67) KRAS146 mut: 17 pts, 14 events HR=1.32 (0.30, 5.81) Any mut: 99 pts, 80 events HR=2.03 (1.26, 3.28) All wt: 264 pts, 171 events; HR=0.86 (0.63, 1.16), p=0.32 Seymour et al. Proc ASCO 2011:A3523 OS PICCOLO Study
  • BRAF Mutations in mCRC • BRAF is primary effector of KRAS signaling • BRAF mutations – Occur most frequently in exon 15 (V600E) – Found in 4%–14% of patients with CRC – Mutually exclusive with KRAS mutations Raf MEK Erk P Tumor cell proliferation and survival EGF Tumor cell Ras Di Nicolantonio et al, 2008; Yarden & Sliwkowski, 2001; Artale et al, 2008. P PP
  • CRYSTAL : Outcome in KRAS WT/BRAF MT mCRC KRAS WT (n = 566) KRAS WT/BRAF MT (n = 59) FOLFIRI (n = 289) FOLFIRI + Cetuximab (n = 277) FOLFIRI (n = 33) FOLFIRI + Cetuximab (n = 26) mOS (mos) 21.6 25.1 10.3 14.1 HR [95% CI] p Valuea 0.83 [0.687–1.004] .0549 0.91 [0.507–1.624] .7440 mPFS (mos) 8.8 10.9 5.6 8.0 HR [95% CI] p Valuea 0.68 [0.533–0.864] .0016 0.93 [0.425–2.056] .8656 RR (%) [95% CI] 42.6 [36.8–48.5] 61.0 [55.0–66.8] 15.2 [5.1–31.9] 19.2 [6.6–39.4] p Valueb < .0001 .9136 a Stratified log-rank test. b Cochran-Mantel-Haenszel test. Van Cutsem et al, 2011.
  • Potential Predictive Biomarkers MUTATIONS •KRAS mut •NRAS mut, BRAF mut •PIK3CA mut •TP53 mut, PTEN mut RECEPTOR EXPRESSION • EGFR (HER1), HER-2/neu, HER-3, HER-4, IGF1R LIGAND EXPRESSION • EGF, TGF-α, HB-EGF, amphiregulin (AREG), betacellulin, epiregulin (EREG) and epigen DOWNSTREAM EFECTORS EXPRESSION • MPK-1 (DUSP-1), DUSP-4, DUSP-6
  • Q: Do EGFR Antibodies Harm KRASMT ? A: Yes, especially combined with bevacizumab (VEGF antibody) Study Treatment Total Patients KRASMT PFS KRASWT PFS Tol NEJM 2009 CAPOX/Bev +/- C 755 8.1 mos (worst) 10.5 mos -- Hecht JCO 2009 5-FU/OX/Bev +/- P 823 10.4 mos HR=1.25 9.8 mos HR 1.36 Hecht JCO 2009 5-FU/IRI/Bev +/- P 230 8.3 mos HR 1.19 10.0 mos HR 1.50 Bokemeyer JCO 2009 FOLFOX +/- C 344 5.5 mos HR 1.83 7.7 mos HR 0.57 CAP = capecitabine; OX = oxaliplatin; IRI = irinotecan; Bev = bevacizumab; C = cetuximab; P = panitumumab Tol J, et al. N Engl J Med. 2009; 360(6):563-572; Hecht JR, et al. J Clin Oncol. 2009;27(5):672-680; Bokemeyer C, et al. J Clin Oncol. 2009;27(5) 663-671.
  • Q: Is Re-Biopsy Necessary? A: No > 96% concordance between primaries and metastases Only 2% clinically relevant Knijn N et al. Br J Cancer. 2011;104:1020-1026
  • Conclusions: EGFR mAbs • Efficacy in KRAS wt CRC well established • KRAS G13D and BRAF mutations likely have an adverse prognostic effect in mCRC • All-RAS wild-type mCRC > 45% of mCRC • Further molecular refinements in future (PTEN, EGFR ligands, PIK3CA…) could limit the patient population suitable for EGFR mAbs down to <35% – This refined patient population could sustain a marked benefit from use of first-line EGFR mAbs!
  • • In KRAS WT, bevacizumab or EGFR antibodies can be added to chemotherapy in first-line – Oxaliplatin-based regimens should not be used in combination with cetuximab (COIN and NORDIC studies negative) – EGFR antibodies maintain efficacy in later lines of therapy – Would favor bevacizumab for now ( FIRE 3 and Ras mutations?) in view of palliative setting and more favorable toxicity profile • Main toxicities of EGFR inhibitors include rash, diarrhea hypomagnesemia and hypersensitivity reactions • Main toxicities for bevacizumab include hypertension and less commonly arteriothromboembolic events ( in elderly patients with risk factors) and GI perforations. • Where to place aflibercept in the continuum? 44 Standard Therapy for Stage IV
  • 0 5 10 15 20 25 30 35 1980 1985 1990 1995 2000 2005 2010 2015 OS(months) median overall survival Advances in the Treatment of Stage IV CRC 1980 1985 1990 1995 2000 2005 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab BSC Panitumumab 20152010 Aflibercept Regorafenib BBP
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  • Fight Colorectal Cancer CONTACT US Fight Colorectal Cancer 1414 Prince Street, Suite 204 Alexandria, VA 22314 (703) 548-1225 Toll-Free Answer Line: 1-877-427-2111 www.FightColorectalCancer.org Email us: Info@FightColorectalCancer.org