molecular testing and tumor testing: why is this important?
DESCRIPTION
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.TRANSCRIPT
Welcome!
Molecular and Genetic
Tumor Testing: Why is it Important?
Part of Fight Colorectal Cancer’s Monthly Patient Webinar Series
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Dr. Tanios Bekaii-Saab, MDSection 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; AFAPMixed Polyposis SyndromeAshkenazi I1307KCHEK2 (HBCC)MYHTGFBR1
PJSFJPCDBRRS
= as yet undiscovered hereditary cancer variants
HamartomatousPolyposis
Syndromes
AC-1 without MMR(Familial CRC of
syndrome “X”)
Colorectal Stage Distribution at Diagnosis (%)
19 % patients have Stage IV disease on diagnosis5 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 bychemotherapy
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
expo
sed to
toxicity
Surgery alone
Surgery plus Chemotherapy
20%
%
Dis
ease
Fre
e S
urv
ival
60%
20%
20%
20%
Moertel CG, N Engl J Med 1990 IMPACT investigators, Lancet 1995
André T, J Clin Oncol. 2009Yothers G, J Clin Oncol 2011Haller D, J Clin Oncol 2011
Moertel CG, N Engl J Med 1990 IMPACT investigators, Lancet 1995
André T, J Clin Oncol. 2009Yothers G, J Clin Oncol 2011Haller 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: 5FUDashed: 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 + irinotecanIrinotecan
+ oxaliplatinBolus 5-FU/LV
LV5-FU2
FOLFOXIRI
CAIRO
22
21
20
19
18
17
16
15
14
13
12
Med
ian
OS
(m
os)
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”
ChimericMouse-Human Ab
“ximab”
Humanized Ab“zumab”
Fc
Fab
Human Ab“mumab”
Biologic Agents in CRC =MoAbs
(17-1A) Cetuximab Bevacizumab
PanitumumabEGFR
VEGFMoAbs = monoclonal antibodies.McRee & Goldberg, 2011; Eng, 2010.
Extracellular
Intracellular
Ligand
EGFR
PI3K
Akt
Raf
MEK
MAPK
Cell Motility
MetastasisAngiogenesisProliferation
Cell SurvivalDNA
PTEN
Ras
Fakih & Wong, 2010; Williams & Lockhart, 2009.
KRAS WT = Wild TypeKRAS MT = Mutant ( codons 12 and 13)
VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangiogenesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGFVEGF-B
VEGF-C, VEGF-D
Fu
nc
tio
ns
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-βFGFR
VEGFR1-3TIE2
Regorafenib
Inhibition of neoangiogenes
is
Inhibition of neoangiogenes
is
Inhibition of tumor
microenvironment signaling
Inhibition of tumor
microenvironment signaling
Inhibition of proliferation Inhibition of proliferation
Biochemicalactivity
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 init ial dose250 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 + BevacizumabBevacizumab: 5 mg/kg i.v. 30-90min q 2w
mCRC1st-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.
PanitumumabStudies-’181-’203-’408
CetuximabStudies- 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 2codon 12/13
40%
KRAS exon 3codon 61
4%
KRAS exon 4codon 117/146
6%
NRAS exon 2codon 12/13
3%
NRAS exon 3codon 61
4%
BRAF exon 15codon 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 IrCsnon-inferior efficacy
primary endpoint PFS at 12 wks
IrPanirinotecan + pan’mab
IrCsirinotecan + c’sporin
Iririnotecan alone
Ir vs IrPansuperior efficacy
primary endpoint OS
Iririnotecan alone
KRAS mutated or unknown KRAS-wt (c.12/13 & 61)
PICCOLO studytarget 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 eventsHR=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 eventsHR=4.59 (1.19, 17.67)
KRAS146 mut: 17 pts, 14 eventsHR=1.32 (0.30, 5.81)
Any mut: 99 pts, 80 eventsHR=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 cellproliferationand 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 14.1HR [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 8.0HR [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
aStratified log-rank test.bCochran-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 TreatmentTotal
Patients
KRASMT
PFS
KRASWT
PFS
Tol
NEJM 2009
CAPOX/Bev
+/- C755
8.1 mos
(worst)
10.5 mos
--
Hecht
JCO 2009
5-FU/OX/Bev
+/- P823
10.4 mos
HR=1.25
9.8 mos
HR 1.36
Hecht
JCO 2009
5-FU/IRI/Bev
+/- P230
8.3 mos
HR 1.19
10.0 mos
HR 1.50
Bokemeyer
JCO 2009
FOLFOX
+/- C344
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% concordancebetween primariesand metastases
Only 2% clinicallyrelevant
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
median overall survival
Advances in the Treatment of Stage IV CRC
1980 1985 1990 1995 2000 2005
5-FUIrinotecan
CapecitabineOxaliplatin
CetuximabBevacizumab
BSC
Panitumumab
20152010
Aflibercept
Regorafenib
BBP
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