1 / 73

Richard M Goldberg M.D. Klotz Family Chair in Cancer Research

Cancer of the Colon and Rectum: A Decade of Progress. Richard M Goldberg M.D. Klotz Family Chair in Cancer Research Professor and James Cancer Hospital Physician-in-Chief The Ohio State University. Seigel , Cancer S tatistics , 2012, CA Cancer J Clin .,62 : 10 - 29, 2012.

kay
Download Presentation

Richard M Goldberg M.D. Klotz Family Chair in Cancer Research

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012 Trends in Incidence Rates: 1975-2008

  3. Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012 US Death Rates in Men & Women:1975-200857,100 in 2003 & 51,690 in 2012

  4. The Genetics of Colorectal Cancer:Henry Lynch

  5. Colorectal Cancer: Genetics 85% 15% CIN (Chromosome Instability) MIN (MSI+) (Microsatellite Instability) 13% <1% 85% 2-3% Sporadic MSI(+) Lynch Sx FAP Sporadic Germline Mutation APC Acquired APC, p53, DCC, kras, LOH,... Germline Mutation MMR genes MLH1, MSH2, MSH6 & PMS2 • Epigenetic silencing of MLH1 by hypermethylation of its promoter region

  6. 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 adenomatouspolyposis should be excluded in the CRC case(s) if any • Tumors should be verified by pathological exam Vasen, Gastroenterology, 116: 1453-6, 1999

  7. Patient & Family Implications: Lynch Syndrome MLH1 MSH2 MSH6 PMS2

  8. 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. Albert de la Chapelle Heather Hampel N Engl J MedMed Volume 352:1851-1860, 2005

  9. 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 • 143,460new 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

  10. Genomics: Comprehensive Molecular Characterization of Human Colon and Rectal Cancer RajuKucherlapati The Cancer Genome Atlas NetworkNature 487: 330-337, 2012

  11. 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

  12. Genomics: Cancer Genome Atlas

  13. 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.

  14. Abstract 3511. Identification and validation of gene expression subtypes in a large set of colorectal cancer samples PETACC3 + public datasets J Clin Oncol 30, 2012 (suppl; abstr 3511) Sabine Tejpar

  15. NovelSubtypesareCharacterizedbyDistinct Biological Components thatPredict Patient Survival

  16. 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.

  17. 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

  18. Prevention Charles Fuchs Robert Sandler Jeff Mayerhardt John Baron

  19. Colorectal Cancer: Risk Factors Overview

  20. 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

  21. Physical Activity and Colorectal Cancer • Cohort study from Australia of 526 colorectal cancer patients with pre-diagnosis physical activity assessment Van Loon K, Wigler D, Niedzwiecki D, Venook AP, Fuchs C, Blanke C, Saltz L, Goldberg RM, MeyerhardtJA, Clin Colorectal Cancer.Epub ahead of print 1/11/ 2013 Colorectal cancer specific survival Haydon Gut. 2006 Jan;55(1):62-7

  22. 89803 and Exercise: Disease-Free Survivalin Stage III Colon Cancer Survivors Hazard Ratio Recurrence or Death Regular Physical Activity (met-hours per week) Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

  23. NSABP and Body Mass Index 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 Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654

  24. Glycemic Loadin Colon Cancer Patients Hazard Ratio for Cancer Recurrence or Death Quintiles of Glycemic Load MeyerhardtJA Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803.J NatlCancer Inst.104:1702-11, 2012. Meyerhardt, J. et al JNCI 2012

  25. 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.

  26. Screening

  27. ColonoscopicPolypectomy and Long-Term Prevention of Colorectal-Cancer Deaths Zauber A, Winawer SJ, O’Brien 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

  28. 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.

  29. DNA Stool Tests and CT Colonography Perry Pickhardt Ahlquist DA, Zou H, Domanico M, Mahoney DW, Yab TC, Taylor WR, Butz ML, ThibodeauSN, Rabeneck L, Paszat LF, Kinzler KW, Vogelstein B, Bjerregaard NC, Laurberg S, Sørensen HT, Berger BM, Lidgard GP. Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology. 142:248-56, 2012 PickhardtPJ, 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.

  30. Stool DNA Testing Mucus at Cancer Surface • 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 Normal Adenoma

  31. Detection Rates at 90% Specificity Cutoffs Covariate analysis

  32. CT Colonography:Advanced Adenoma Polyp size 10 mm or >. Prevalence c.5 -7 %

  33. CT Colonography: Issues • Sensitivity: Detection of patients withadenomas >9mm: Sensitivity Specificity Pickhardt94% 96% Cotton 55% 96% Rockey59% 96% NEJM 2003; 349: 2191; JAMA 2004; 291:1713-9; Rockey: Lancet 2005;365: 305-11

  34. Surgical Techniques Robotic Laparoscopic

  35. 790 patients accrued Conventional Colectomy R Laparoscopic Colectomy (LAC) Laparoscopically Assisted Versus Open Colectomy For Colon Cancer Heidi Nelson N Engl J Med 351:933-934, 2004

  36. COST Outcomes

  37. LAC vs Open Colectomy • No difference in • Complication rate • Wound recurrences • 30 day mortality (4 open, 2 LAC) • Disease free survival • Overall survival • Equivalent cancer procedures Weeks, JAMA 2002 Nelson, NEJM 2004

  38. Other Effects s

  39. Randomization Openrectal resection Laparoscopicrectal resection Rectal Cancer Z6051: Lap Rectal Cancer Trial Eligible pt with stage II-IIIprimary rectal adenocarcinomaby ERUS or MRI staging

  40. TME: a comparison of oncological and functional outcomes between robotic and laparoscopic surgery for rectal cancer. D'AnnibaleA, Pernazza G, Monsellato I, Pende V, LucandriG, Mazzocchi P, Alfano G. SurgEndosc. Epubahead of print, Jan 5, 2013

  41. Liver Resection Gross Anatomy Eight Segments Rene Adam

  42. Survival After Liver Resection In Metastatic Colorectal Cancer: Review And Meta-analysis Of Prognostic Factors Kanas GP, Taylor A, Primrose JN, Langeberg W, Kelsh MA,Mowat FS, Alexander DD, Choti MA, and Poston G. ClinEpidemiol. 4: 283–301, 2012.

  43. Types of Chemotherapy-Induced Hepatic Injury Sinusoidal Dilatation Steatosis Steatohepatitis (NASH)

  44. Stereotactic body radiotherapy for colorectal liver metastases Chang AT, Swaminath A, KozakM, WeintraubJ,Koong AC, John Kim J, DinniwellR, Brierley J, Kavanagh BD, Dawson LA, Schefter TE. Cancer 117:4060–4069, 2011

  45. Steriotactic Radiosurgery • 47 patients • Median dose: 42 Gray • 3 fraction model • 1 year local control 92% Daniel Chang

  46. Preoperative versus PostoperativeChemoradiotherapy for Rectal CancerSauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens J-H, Liersch T, Schmidberger H, and RaabR for the German Rectal Cancer Study Group • Locally advanced rectal cancer • Radiation pre vs post operatively • 5-FU chemotherapy • TME • 823 pts randomized • Median follow up now 10 years N Engl J Med 351:1731-174, 2004. J ClinOncol. 30:1926-33, 2012

  47. .14 .12 .10 .08 .06 .04 .02 0.00 0 30 60 20 10 40 50 Months Cumulative Incidence of Local Relapse Median Follow-up: 40 months 12% Post-op CRT Locoregional Recurrences 6% p = 0.006 Pre-op CRT

  48. German Rectal Cancer Trial

  49. Irinotecan Capecitabine Oxaliplatin Advances in the Drug Treatment of CRC 1980 1985 1990 1995 2000 2005 2013 5-FU Hanna Kelly Sanoff Cetuximab Bevacizumab Aflibercept Regorafinib Therapeutic concepts Palliative chemotherapy Adjuvant chemotherapy Updated from Kelly and Goldberg. J ClinOncol. 2005;23:4553 Neoadjuvant chemotherapy

  50. MOSAIC & NSABP C-07 Aimery de Gramont Thierry Andre Greg Yothers Norman Wolmark Oxaliplatin Vs 5-FU/LV In Adjuvant Therapy André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer: MOSAIC Investigators. N Engl J Med 350: 2343–51, 2004. YothersG, O'Connell MJ, Allegra CJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: Updated results of NSABP C-07, including survival and subset analyses. J ClinOncol29:3768–74, 2011.

More Related