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Richard M Goldberg M.D. Klotz Family Chair in Cancer Research Professor and James Cancer Hospital Physician-in-Chief The Ohio State University Cancer of the Colon and Rectum: A Decade of Progress

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2 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Trends in Incidence Rates: 1975-2008 Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012

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3 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute US Death Rates in Men & Women:1975-2008 57,100 in 2003 & 51,690 in 2012 Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012

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4 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute The Genetics of Colorectal Cancer: Henry Lynch

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5 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 13%

6 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Revised Lynch Syndrome Screening Criteria (Amsterdam criteria II) > 3 relatives with an HNPCC-associated cancer (CRC, cancer of the endometrium, small bowel, ureter, or renal pelvis) One should be a first-degree relative of the other 2 At least 2 successive generations should be affected At least 1 should be diagnosed before age 50 Familial adenomatous polyposis should be excluded in the CRC case(s) if any Tumors should be verified by pathological exam Vasen, Gastroenterology, 116: 1453-6, 1999

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7 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Patient & Family Implications: Lynch Syndrome MLH1 PMS2 MSH2 MSH6

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8 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Screening for the Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Hampel H, Frankel W, Martin E, Arnold M, Khanduja K, Kuebler P, Nakagawa H, Sotamaa K, Prior T, Westman J, Panescu J, Fix D, Lockman J, Comeras I, and de la Chapelle A. N Engl J MedMed Volume 352:1851-1860, 2005 Heather Hampel Albert de la Chapelle

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9 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Potential Impact Columbus Project: 44 of 1600 screened had Lynch Syndrome 50% diagnosed over age 50 25% met neither Amsterdam or Bethesda criteria Ohio Colorectal Cancer Prevention Initiative Nationally 143,460 new cases of CRC in the US in 2013 4,016 have Lynch syndrome (2.8%) 12,050 of their relatives have LS (~3 per proband) Total of 15,816 individuals who could be diagnosed with Lynch Syndrome with universal screening American Cancer Society Facts & Figures

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10 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute The Cancer Genome Atlas Network Nature 487: 330-337, 2012 Genomics: Comprehensive Molecular Characterization of Human Colon and Rectal Cancer Raju Kucherlapati

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11 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Methods and Key Findings Methods: Whole genome sequencing of 276 colorectal tumors Exome sequence, DNA copy number, promotor methylation, messenger and micro RNA expression Key Findings 16% hypermutated; 75% MSI-H Colon and rectal cancers share similar patterns of genomic alteration 24 genes significantly mutated: Expected: APC, TP53, SMAD4, PIK3CA, KRAS Unexpected: ARID1A, SOX9, FAM123B, ERBB2 Potential new targets: ERBB2, IGF2

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12 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Genomics: Cancer Genome Atlas

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13 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Significance While it may take years to translate this foundational genetic data on colorectal cancers into new therapeutic strategies and surveillance methods, this genetic information unquestionably will be the springboard for determining what will be useful clinically against colorectal cancers, said Harold Varmus, NCI director. Harold Varmus, NCI director.

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14 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Abstract 3511. Identification and validation of gene expression subtypes in a large set of colorectal cancer samples J Clin Oncol 30, 2012 (suppl; abstr 3511) PETACC3 + public datasets Sabine Tejpar

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15 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Novel Subtypes are Characterized by Distinct Biological Components that Predict Patient Survival

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16 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Subtypes are Validated in Independent Datasets Based on the set of gene modules derived, we performed subtype derivation in the validation set. While subtypes A, C, D and E appeared in the Larger datasets are needed to confirm and further study additional subtypes.

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17 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Subtype Summary A normal -like epithelial: KRAS, differentiated, no CSC markers, Wnt down, good OS and RFS B proliferative epithelial: differentiated, but lost secretory cells, proliferative, 20q genes up, Wnt active, MSS, nonBRAF, non-mucinous, good OS, RFS, SAR C CIMP-H like: undifferentiated carcinomas, MSI, BRAF, mucinous, right, less frequently p53 mutated, enriched in females, proliferative, immune, CIMP+, the shortest SAR, poor OS D mesenchymal: no proliferation, high CSC markers, Wnt inactive, active EMT, the shortest RFS, poor OS and SAR E intermediate: MSS, nonBRAF, non mucinous, left, CSC markers, EMT, proliferation, differentiation, p53 enriched

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18 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Prevention Charles Fuchs Jeff Mayerhardt Robert Sandler John Baron

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19 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Colorectal Cancer: Risk Factors Overview Decrease RiskIncrease RiskUncertain Impact ScreeningFamily historyStatins Exercise Aspirin / NSAIDs Ulcerative colitis/ Crohns Disease Fiber Glycemic load Vitamin DDiabetesFruits/Vegetables Post-menopausal estrogen Obesity Red meat Folic Acid CalciumWestern diet Alcohol Smoking

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20 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Data from Observational Studies for Stage I-III Disease Decrease risk of recurrence Physical activity Avoidance of Western pattern diet Avoidance of class II/ III obesity (BMI > 35 kg/m2) Aspirin or COX-2 inhibitor Higher vitamin D levels No association with recurrence to date Weight change (gain or loss) Smoking status or history Multivitamin Credits: Charles Fuchs Jeffrey Meyerhardt Brian Wolpin Kimmie Ng Andrew Chan Nadine McCleary Donna Niedzwiecki Donna Hollis CALGB

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21 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Physical Activity and Colorectal Cancer Cohort study from Australia of 526 colorectal cancer patients with pre-diagnosis physical activity assessment Colorectal cancer specific survival Haydon Gut. 2006 Jan;55(1):62-7 Van Loon K, Wigler D, Niedzwiecki D, Venook AP, Fuchs C, Blanke C, Saltz L, Goldberg RM, Meyerhardt JA, Clin Colorectal Cancer. Epub ahead of print 1/11/ 2013

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22 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 89803 and Exercise: Disease-Free Survival in Stage III Colon Cancer Survivors Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006 Regular Physical Activity (met-hours per week) Hazard Ratio Recurrence or Death

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23 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute NSABP and Body Mass Index Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654 Disease-free and overall survival by body mass index (BMI) category in 4288 patients from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials for Dukes B and C colon cancer

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24 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Glycemic Load in Colon Cancer Patients Quintiles of Glycemic Load Hazard Ratio for Cancer Recurrence or Death Meyerhardt, J. et al JNCI 2012 Meyerhardt JA Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Natl Cancer Inst.104:1702-11, 2012..

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25 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Mortality among Patients with Colorectal Cancer, According to Regular Use or Nonuse of Aspirin after Diagnosis and PIK3CA Mutation Status. Liao X et al. N Engl J Med 367:1596-1606, 2012.

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26 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Screening

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27 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Colonoscopic Polypectomy and Long- Term Prevention of Colorectal-Cancer Deaths Zauber A, Winawer SJ, OBrien MJ, Lansdorp-Vogelaar I, van Ballegooijen M, Hankey BF, Shi W, Bond JH, Schapiro M, Panish JF, Stewart ET, and Waye JD. N Engl J Med 366:687-96, 2012. Ann Zauber

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28 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute National Polyp Study 2602 patients with adenomas removed between 1980-90. CRC deaths expected: 25.4 CRC deaths observed: 12 53% reduction in mortality These findings support the hypothesis that colonoscopic removal of adenomatous polyps prevents death from colorectal cancer.

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29 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute DNA Stool Tests and CT Colonography Perry Pickhardt Ahlquist DA, Zou H, Domanico M, Mahoney DW, Yab TC, Taylor WR, Butz ML, Thibodeau SN, Rabeneck L, Paszat LF, Kinzler KW, Vogelstein B, Bjerregaard NC, Laurberg S, Srensen HT, Berger BM, Lidgard GP. Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology. 142:248-56, 2012 Pickhardt PJ, Choi JR, Hwang I, Butler JA, Puckett ML, Hildebrandt HA, Wong RK, Nugent PA, Mysliwiec PA, Schindler WR. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med. 349:2191-200, 2003.

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30 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Stool DNA Testing Biologically rational Noninvasive No cathartic preparation No diet or med restriction Off-site collection Widely accessible Not affected by lesion site High sensitivity for both CRC & precancer Adenoma Normal Mucus at Cancer Surface

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31 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 31 Detection Rates at 90% Specificity Cutoffs Covariate analysis

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32 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute CT Colonography: Advanced Adenoma Polyp size 10 mm or >. Prevalence c.5 -7 %

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33 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute CT Colonography: Issues Sensitivity: Detection of patients with adenomas >9mm: SensitivitySpecificity Pickhardt94%96% Cotton55%96% Rockey59%96% NEJM 2003; 349: 2191; JAMA 2004; 291:1713-9; Rockey: Lancet 2005;365: 305-11

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34 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Surgical Techniques Laparoscopic Robotic

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35 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Laparoscopically Assisted Versus Open Colectomy For Colon Cancer Conventional Colectomy R Laparoscopic Colectomy (LAC) Conventional Colectomy R Laparoscopic Colectomy (LAC) 790 patients accrued Heidi Nelson N Engl J Med 351:933-934, 2004

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36 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute COST Outcomes Conversion rate Incision Cm Time Minutes LOS Days IV narcs Days PO narcs days LAC21%6150531 OpenNA1895642 P-value6 ">

53 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute MOSAIC OS with >6 Years Follow-up FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III Overall survival (months) Probability 1.0 0.8 0.6 0.4 0.2 0 0.9 0.7 0.5 0.3 0.1 06121824603036424854669672788490 0.1% 4.4% p=0.996 p=0.029

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54 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute NSABP C-07 Stage ll + lll FLOXFU/LV Randomize Stratify: # positive nodes

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55 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.

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56 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 3-year DFS (stage III) Studytreatment 3-year DFS MoertelObservation52% IMPACTObservation44% IMPACT5FU/LV62% Punt5FU/LV65% Fields5FU/LV67% Andr5FU/LV61% MOSAIC5FU/LV65% X-ActCapecitabine64% MOSAICC-07FOLFOX4FLOX73%76% no RX monotherapy 2 drugs

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57 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Advances In Treatment Of Advanced Disease Since 2013 Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S., Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer, N Engl J Med 350:2335-2342, 2004. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanthan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SA. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22: 23-30, 2004.

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58 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute FOLFOX4: oxaliplatin + infusional 5-FU/LV IFL: irinotecan + bolus 5-FU/LV IROX: oxaliplatin + irinotecan Intergroup Study N9741: A Combination Chemotherapy Comparison RANDOMIZATIONRANDOMIZATION n=267 n=264 Years % of patients IFL (median 15.0 mo) FOLFOX4 (median 19.5 mo) IROX (median 17.4 mo)

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59 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Phase III Trial of Bevacizumab in FirstLine MCRC IFL + placebo (n=411) 5-FU/LV + bevacizumab* (5 mg/kg, q2w) (n=110) IFL + bevacizumab (5 mg/kg, q2w) (n=402) RANDOMIZATIONRANDOMIZATION Median Survival (mo) IFL + placebo = 15.1 IFL + bevacizumab = 20.5 5-FU/LV + bevacizumab = 18.3 Months Proportion surviving 0.2 250103040 0 0.8 1.0 0.4 0.6 Treatment Group IFL + placebo (n=101)* IFL + bevacizumab (n=103)* 5-FU/LV + bevacizumab (n=110)

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60 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Cetuximab and Panitumumab Cetuximab for the Treatment of Colorectal Cancer Jonker DJ, O'Callaghan CJ, Karapetis C, Zalcberg JR, Tu D, Au H-J, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, and Moore MJ. N Engl J Med 2007; 357:2040-2048 Van Cutsem E, Peeters M, Salvatore Siena S, Humble Y, Hendlisz A, Neyns B, Canon J-L, Van Laethem J-L, Maurel J, Richardson G, Wolf M, and Amado RG. Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer, J Clin Oncol. 25:1658-1664, 2007. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634.

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61 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Single Agent Cetuximab RANDOMIZERANDOMIZERANDOMIZERANDOMIZE Cetuximab* + BSC BSC alone

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62 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute KaplanMeier Curves for Progression-free Survival According to Treatment. Karapetis CS et al. N Engl J Med 2008;359:1757- 1765. Progression Free Survival with Cetuximab alone Correlated with K-ras Status

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63 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Single Agent Panitumumab RANDOMIZERANDOMIZERANDOMIZERANDOMIZE Panitumumab + BSC BSC alone

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64 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Single Agent Panitumumab: N=208 K-Ras Mutation Wild-Type K-Ras Panitumumab registration trial

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65 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Aflibercept and Regorafinib Grothey A, Cutsem EV, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouch O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; for the CORRECT Study Group. Regorafenib monotherapy for previously treatedmetastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. Epub Nov 21 2012. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausov J, Macarulla T, Ruff P, van Hazel GA, Moiseyenko V, Ferry, McKendrick J, Polikoff J, Tellier A, Castan R, Allegra C. Addition Of Aflibercept To Fluorouracil, Leucovorin, And Irinotecan Improves Survival In A Phase III Randomized Trial In Patients With Metastatic Colorectal Cancer Previously Treated With An Oxaliplatin-based Regimen. J Clin Oncol. 30:3499-506, 2012.

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66 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute R 600 pts Aflibercept 4 mg/kg IV + FOLFIRI 600 pts Placebo + FOLFIRI FOLFIRI +/- Aflibercept

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67 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Regorafinib R 505 pts Regorafinib po + BSC 255 pts Placebo + BSC

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68 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Regorafenib Cetuximab Panitumumab Progression-Free Survival

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69 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute median overall survival Advances in the Treatment of Stage IV CRC 198019851990199520002005 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab BSC Panitumumab 20152010 Aflibercept Regorafenib BBP

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The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Guidelines: Association Between Adherence To National Comprehensive Cancer Network Treatment Guidelines And Improved Survival In Patients With Colon Cancer. Boland GM, Chang GJ, Haynes AB, Chiang YJ, Chagpar R, Xing Y, Hu CY, Feig BW, You YN, Cormier JN. Cancer. Epub ahead of print Dec 21, 2012 Janice Cormier

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71 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Guidelines

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72 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Adjuvant Therapy of Colon Cancer National Cancer Database 1998-2002 High risk Stage II and Stage III 167,434 patients Rates of guideline adherence 36% for high-risk stage II 74% Stage III 5-year survival versus adherence to guidelines Yes: 67.7% No: 54.5%

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73 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute A Decade of Progress Declining mortality by > 10% Potential for universal Lynch Syndrome screening Unraveling the mysteries of the genome Prevention & prevention of recurrence New screening tools: fecal DNA, CT colonograpy Laparoscopic, robotic and hepatic surgery Preoperative rectal radiation and Cyberknife Oxaliplatin, bevacizumab, cetuximab, panitumumab, aflibercept, regorafinib