richard m goldberg m.d. klotz family chair in cancer research

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

Professor and James Cancer Hospital Physician-in-ChiefThe Ohio State University

Cancer of the Colon and Rectum: A Decade of Progress

2

The Ohio State University Comprehensive Cancer Center –

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

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

3



US Death Rates in Men & Women:1975-200857,100 in 2003 & 51,690 in 2012

Seigel, Cancer Statistics, 2012, CA Cancer J Clin.,62:10-29, 2012

4



The Genetics of Colorectal Cancer:Henry Lynch

5



13% <1% 85%FAP Sporadic

MIN (MSI+)(Microsatellite Instability)

CIN (Chromosome Instability)

Lynch Sx Sporadic MSI(+)

Germline Mutation MMR genesMLH1, MSH2, MSH6 & PMS2

15%

2-3%

•Epigenetic silencing of MLH1 by hypermethylation of its promoter region

85%

Colorectal Cancer: Genetics

Acquired APC, p53, DCC, kras, LOH,...

Germline Mutation APC

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 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

7



Patient & Family Implications: Lynch Syndrome

MLH1

PMS2

MSH2 MSH6

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.

N Engl J MedMedVolume 352:1851-1860, 2005

Heather Hampel Albert de la Chapelle

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

143,460 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

10



The Cancer Genome Atlas NetworkNature 487: 330-337, 2012

Genomics:Comprehensive Molecular

Characterization of Human Colon and Rectal Cancer

Raju Kucherlapati

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.

http://www.cancer.gov/aboutnci/director

14



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

15



Novel Subtypes are Characterized by Distinct Biological Components that Predict 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 theLarger datasets are needed to confirm and further study additional subtypes.

17



Subtype SummaryA – 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

Jeff Mayerhardt

Robert Sandler

John Baron

19



Colorectal Cancer: Risk Factors Overview

Decrease Risk Increase Risk Uncertain ImpactScreening Family history StatinsExercise Aspirin / NSAIDs

Ulcerative colitis/ Crohn’s Disease

Fiber Glycemic load

Vitamin D Diabetes Fruits/VegetablesPost-menopausal estrogen

Obesity Red meat

Folic Acid

Calcium Western dietAlcoholSmoking

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 FuchsJeffrey MeyerhardtBrian WolpinKimmie NgAndrew ChanNadine McClearyDonna NiedzwieckiDonna HollisCALGB

21



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

22



89803 and Exercise: Disease-Free Survivalin Stage III Colon Cancer Survivors

Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

Regular Physical Activity (met-hours per week)

Haz

ard

Rat

io R

ecur

renc

e or

Dea

th

<3 3-8.9 9-17.9 18.0-26.9 >270

0.2

0.4

0.6

0.8

1

1.2

Chart Title

23



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

24



Glycemic Loadin Colon Cancer Patients

Quintiles of Glycemic Load

Haz

ard

Rat

io fo

r Can

cer R

ecur

renc

e or

Dea

th

Meyerhardt, J. et al JNCI 2012

1 2 3 4 50

0.5

1

1.5

2

2.5

1

0.650.81

1 0.91

1 0.99 1.07

1.7

2.26

BMI < 25

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.

http://www.ncbi.nlm.nih.gov/pubmed/23136358

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



Colonoscopic Polypectomy and Long-Term Prevention of Colorectal-Cancer

DeathsZauber 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, Thibodeau SN, Rabeneck L, Paszat LF, Kinzler KW, Vogelstein B, BjerregaardNC, 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

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.

30



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

31


Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 31

Detection Rates at 90% Specificity Cutoffs

Training Set Test Set Combined Set0

10

20

30

40

50

60

70

80

90

100

88.8

78.1

85.3

63.9 63.6 63.8

CRCAdenoma >1cm

Covariateanalysis

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 SpecificityPickhardt 94% 96%Cotton 55% 96%Rockey 59% 96%

NEJM 2003; 349: 2191; JAMA 2004; 291:1713-9; Rockey: Lancet 2005;365: 305-11

34



Surgical Techniques

Laparoscopic Robotic

35



Laparoscopically Assisted Versus Open Colectomy For

Colon Cancer

Conventional ColectomyR Laparoscopic Colectomy (LAC)

790 patients accrued

Heidi NelsonN Engl J Med 351:933-934, 2004

36



COST Outcomes

Conversion rate

IncisionCm

TimeMinutes

LOSDays

IV narcsDays

PO narcsdays

LAC 21% 6 150 5 3 1

Open NA 18 95 6 4 2

P-value <.001 <.001 <.001 <.001 <.02

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 2002Nelson, NEJM 2004

38



Other Effects

s

39



Eligible pt with stage II-IIIprimary rectal adenocarcinoma

by ERUS or MRI staging

Laparoscopicrectal resection

Openrectal resection

Randomization

Z6051: Lap Rectal Cancer TrialRectal Cancer

40



TME: a comparison of oncological and functional outcomes between robotic and

laparoscopic surgery for rectal cancer.

# Pts Time min

Med # nodes

Margin < 2 mm

Efficacy

Robotic 50 270 16.5 0 ?

Laparoscopic 50 275 13.8 6 ?

D'Annibale A, Pernazza G, Monsellato I, Pende V, Lucandri G, Mazzocchi P, Alfano G. Surg Endosc. Epub ahead of print, Jan 5, 2013

41



Liver ResectionGross Anatomy Eight Segments

Rene Adam

42



Survival After Liver Resection In Metastatic Colorectal Cancer: Review And Meta-analysis Of Prognostic Factors

3-yr survival (%)

5-yr survival (%)

Median survival

yearsAll 58% 40% 3.6 years

Solitary 61 47 3.6

Extrahepatic 40 24 3.6

Isolated 54 39 3.2

Periop chemo 55 37 3.3

Resectable at Dx 55 41 3.3

Synchronous 46 37 3.2

Metachronous 58 43 3.3

Kanas GP, Taylor A, Primrose JN, Langeberg W, Kelsh MA, Mowat FS,Alexander DD, Choti MA, and Poston G. Clin Epidemiol. 4: 283–301, 2012.

43



SteatosisSinusoidal Dilatation

Steatohepatitis(NASH)

Types of Chemotherapy-Induced Hepatic Injury

44



Stereotactic body radiotherapy for colorectal liver metastases

Chang AT, Swaminath A, Kozak M, Weintraub J,Koong AC, John Kim J, Dinniwell R, 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 Cancer

Sauer 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

Raab R 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 Clin Oncol. 30:1926-33, 2012

47



Cumulative Incidence of Local RelapseMedian Follow-up: 40 months

6050403020100

.14

.12

.10

.08

.06

.04

.02

0.00

Months

Loco

regi

onal

Rec

urre

nces

p = 0.006

Post-op CRT

Pre-op CRT

12%

6%

48



German Rectal Cancer Trial

Preop Post op P-valuePelvic recur 6% 12% 0.006

Distant recur 29.8% 29.6% 0.90Survival 59.6% 59.9% 0.9Gr 3-4 tox 29% 32% N.S.Anastomotic stenosis 2.7% 8.5% 0.001

APR 39% 19% 0.004

49



Advances in the Drug Treatment of CRC

1980 1985 1990 1995 2000 2005

Therapeutic conceptsPalliative chemotherapy

Adjuvant chemotherapy

Neoadjuvant chemotherapy

CapecitabineOxaliplatin

CetuximabBevacizumab

Irinotecan5-FU

Updated from Kelly and Goldberg. J Clin Oncol. 2005;23:4553

2013

AfliberceptRegorafinib

Hanna Kelly Sanoff

50



Oxaliplatin Vs 5-FU/LV In Adjuvant Therapy

MOSAIC & NSABP C-07

Aimery de Gramont Thierry Andre Greg Yothers Norman Wolmark

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.

Yothers G, 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 Clin Oncol 29:3768–74, 2011.

51



MOSAIC Phase III Trial

RANDOMI

Z ATION

LV5FU2

FOLFOX4N=1100

N=1100

• 40% Stage II• 60% Stage III

52



Disease-free Survival: Stage II and III Patients

FOLFOX4 stage IILV5FU2 stage IIFOLFOX4 stage IIILV5FU2 stage III

Months

Prob

abili

ty

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 72

3.8%

7.5%

p=0.258

p=0.005

53



MOSAIC OS with >6 Years Follow-up

FOLFOX4 stage IILV5FU2 stage IIFOLFOX4 stage IIILV5FU2 stage III

Overall survival (months)

Prob

abili

ty1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 6 12 18 24 6030 36 42 48 54 66 9672 78 84 90

0.1%

4.4%

p=0.996

p=0.029

54



NSABP C-07

Stage ll + lll

FLOXFU/LV

Randomize

Stratify: # positive nodes

55



Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.

56



3-year DFS (stage III)Study treatment 3-year

DFSMoertel Observation 52%IMPACT Observation 44%IMPACT 5FU/LV 62%Punt 5FU/LV 65%Fields 5FU/LV 67%André 5FU/LV 61%MOSAIC 5FU/LV 65%X-Act Capecitabine 64%MOSAICC-07

FOLFOX4FLOX

73%76%

no RX

mon

othe

rapy

2 drugs

57



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.

58



FOLFOX4: oxaliplatin + infusional 5-FU/LV

IFL: irinotecan + bolus

5-FU/LV

IROX: oxaliplatin + irinotecan

Intergroup Study N9741: A Combination Chemotherapy Comparison

RANDOMIZATION

n=267

n=264

n=264

Years

% o

f pat

ient

s

IFL (median 15.0 mo)FOLFOX4 (median 19.5 mo)IROX (median 17.4 mo)

0 1 2

FOLFOX4 vs IFL P=0.0001; HR=0.66IROX vs IFL P=0.04; HR=0.81FOLFOX4 vs IROX P=0.09; HR=0.830

102030405060708090

100

59



Phase III Trial of Bevacizumab in First Line MCRC

IFL + placebo (n=411)

5-FU/LV + bevacizumab*(5 mg/kg, q2w) (n=110)

IFL + bevacizumab (5 mg/kg, q2w) (n=402)

RANDOMIZATION

Median Survival (mo)IFL + placebo = 15.1IFL + bevacizumab = 20.55-FU/LV + bevacizumab =

18.3

Months

Prop

ortio

n su

rviv

ing

0.2

250 10 30 400

0.8

1.0

0.4

0.6

Treatment GroupIFL + placebo (n=101)*IFL + bevacizumab (n=103)*5-FU/LV + bevacizumab (n=110)

60



Cetuximab and Panitumumab

Cetuximab for the Treatment of Colorectal CancerJonker 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 ComparedWith Best Supportive Care Alone in Patients With Chemotherapy-RefractoryMetastatic 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.

61



Single Agent Cetuximab

RANDOMI ZE

Cetuximab* + BSC

BSC alone

62



Kaplan–Meier 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 aloneCorrelated with K-ras Status

63



Single Agent Panitumumab

RANDOMI ZE

Panitumumab + BSC

BSC alone

http://jco.ascopubs.org/content/vol26/issue10/images/large/zlj0100869810002.jpeg

64



Single Agent Panitumumab: N=208

K-Ras Mutation Wild-Type K-Ras

Panitumumab registration trial



65



Aflibercept and Regorafinib

Grothey A, Cutsem EV, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché 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, Prausová 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.

66



R

600 ptsAflibercept 4 mg/kg IV+ FOLFIRI

600 ptsPlacebo + FOLFIRI

FOLFIRI +/- Aflibercept

67



Regorafinib

R

505 pts Regorafinib po+ BSC

255 pts Placebo + BSC

68



Regorafenib Cetuximab Panitumumab

Progression-Free Survival


69



median overall survival

Advances in the Treatment of Stage IV CRC

1980 1985 1990 1995 2000 2005

5-FUIrinotecan

CapecitabineOxaliplatin

CetuximabBevacizumab

BSC

Panitumumab

20152010

AfliberceptRegorafenibBBP



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

71



Guidelines

72



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%

73



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

richard m goldberg m.d. klotz family chair in cancer research

Documents

cancer statistics

cancer researchprofessor

ca cancer j clin

hnpccassociated cancer

solove research institute13

henry lynch

panescu j

westman j