This document provides an introduction and overview for a webinar on molecular and genetic tumor testing for colorectal cancer. It discusses the importance of tumor testing to help determine treatment for stages II-IV colorectal cancer and highlights several key biomarkers such as KRAS, NRAS, BRAF and MSI status that can help predict response to targeted therapies like EGFR inhibitors and determine optimal treatment strategies. The webinar aims to explain how molecular profiling of tumors can personalized treatment decisions and improve outcomes for colorectal cancer patients.
Using Data Visualization in Public Health Communications
Molecular Testing and Tumor Testing: Why is this important?
1. 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
2. Fight Colorectal Cancer
1. Tonight’s speaker: Dr. Tanios Bekaii-Saab, MD
2. Archived webinars: Link.FightCRC.org/Webinars
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4. Fight Colorectal Cancer
Up coming webinars
Wednesday, September 18th
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How do these affect my treatment decisions?
Wednesday, October 16th
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Peripheral Neuropathy: Will it ever go away?
Problems, Causes, Solutions
6. 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
7. 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
8. 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”)
9. 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. 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
11. 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)
12. 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
14. Oncotype DX: Primary Analysis: Recurrence Score Predicts
Recurrence Risk in Stage II Colon Cancer Patients in QUASAR
15. 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
16. 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
18. A high number of agents is currently available
for the treatment of mCRC
5-FU Capecitabine Irinotecan
Oxaliplatin Bevacizumab
Panitumumab
Cetuximab
AfliberceptRegorafenib
20. 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.
23. 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)
24. 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.
27. 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)
28. 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
29. 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%
30. • 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
31. Are All KRAS Mutations Created Equal? – p.G13D
Pooled analysis of OPUS and CRYSTAL
Tejpar et al, 2011.
32. 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
35. Oliner et al., ASCO 2013
HR 0.83
(KRAS wt cod 12/13)
HR 0.78
(all RAS wt)
OS
Detriment!
Detriment!
36. 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
38. 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
41. 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.
42. 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
43. 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!
44. • 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
45. 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
47. Fight Colorectal Cancer
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Email us: Info@FightColorectalCancer.org
Hinweis der Redaktion
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.