EGFR, K-RAS, BRAF Testing In The Elderly: Same As in ... · Emerging phenotype of CRC: Epigenetic...
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EGFR, KEGFR, K--RAS, BRAF Testing RAS, BRAF Testing In The Elderly: In The Elderly: Same As in Younger Patients?Same As in Younger Patients?
Nadine Jackson McCleary MD MPHNadine Jackson McCleary MD MPHGastrointestinal OncologyGastrointestinal OncologyDanaDana--Farber/Harvard Cancer CareFarber/Harvard Cancer CareBoston, MA, USABoston, MA, USA
OutlineOutline
Colorectal cancer (CRC) burden in older Colorectal cancer (CRC) burden in older individualsindividuals
Chemotherapy optionsChemotherapy options Biologic therapy optionsBiologic therapy options Molecular targetsMolecular targets Testing in older vs. younger individuals with Testing in older vs. younger individuals with
CRCCRC ConclusionsConclusions
DisclosuresDisclosures
NoneNone
CRC burden in older CRC burden in older individualsindividuals
Annual incidence 150k USA, 1 million Annual incidence 150k USA, 1 million worldwideworldwide
Majority of patients are elderlyMajority of patients are elderly–– Median age at diagnosis 72 yearsMedian age at diagnosis 72 years–– 12% older than 85 years12% older than 85 years
www.seer.gov
Emerging phenotype of CRC:Emerging phenotype of CRC:Genetic Genetic Genetic instabilityGenetic instability
–– Microsatellite instability (MSIMicrosatellite instability (MSI--H)H) Loss of DNA mismatch repair (e.g. hMLH1, hMSH2, hMSH6)Loss of DNA mismatch repair (e.g. hMLH1, hMSH2, hMSH6)
–– Chromosomal instability (CIN)Chromosomal instability (CIN) Loss of Loss of heterozygosityheterozygosity (LOH), (LOH), hypomethylationhypomethylation in tumor cellin tumor cell
Popat JCO 2006; Sargent JCO 2008; Ribic NEJM 2003; Samowitz Gastro 2005Ogino Gut 2006, JMD 2007, BMC Ca 2007; Cheng Clin Ca Res 2008
Emerging phenotype of CRC:Emerging phenotype of CRC:EpigeneticEpigenetic
Epigenetic instabilityEpigenetic instability
CpGCpG Island Methylator Phenotype (CIMP)Island Methylator Phenotype (CIMP)
HypermethylationHypermethylation of promoter regionsof promoter regions Leads to silencing of tumor suppressor genesLeads to silencing of tumor suppressor genes Associated with BRAF and KRAS mutationsAssociated with BRAF and KRAS mutations Independent of and inversely related to CINIndependent of and inversely related to CIN Variably related to MSIVariably related to MSI--HH
Popat JCO 2006; Sargent JCO 2008; Ribic NEJM 2003; Samowitz Gastro 2005Ogino Gut 2006, JMD 2007, BMC Ca 2007; Cheng Clin Ca Res 2008
Issa J Clin Cancer Res 2008;14:5939-5940
©2008 by American Association for Cancer Research
Tumor biology differs by Tumor biology differs by ageage
Increased CIMP with ageIncreased CIMP with age
Associated with poor prognostic factorsAssociated with poor prognostic factors BRAF mutationBRAF mutation Proximal tumor siteProximal tumor site Poor histologyPoor histology Advanced stageAdvanced stage
22--fold higher for age 70+ fold higher for age 70+ controlling for stage, histology, tumor site, controlling for stage, histology, tumor site,
KRAS/BRAF/p53 mutationKRAS/BRAF/p53 mutation
Samowitz Gastro 2008; NagasakaJCO 2005; Popat JCO 2006; Goel Gastro 2007
Differing response to Differing response to treatmenttreatment
Differing tumor biology potentially explainsDiffering tumor biology potentially explainsdiffering response to CRC treatment among differing response to CRC treatment among older and younger individualsolder and younger individuals
Metastatic vs. adjuvant settingMetastatic vs. adjuvant setting–– ChemotherapyChemotherapy–– BiologicsBiologics
Focus on EGFR antibodiesFocus on EGFR antibodies
Metastatic CRC, Chemotherapy Metastatic CRC, Chemotherapy -- BenefitBenefit
Metastatic settingMetastatic setting–– FolprechtFolprecht JCO 2008 JCO 2008 -- N=2,692 (22% N=2,692 (22% 70 yrs) 70 yrs)
4 trials of irinotecan4 trials of irinotecan--based therapy based therapy Improved PFS, trend to improved OS for elderly w/addition Improved PFS, trend to improved OS for elderly w/addition
of irinotecanof irinotecan
–– Goldberg JCO 2006 Goldberg JCO 2006 -- N=3,742 (16% N=3,742 (16% 70 yrs) 70 yrs) 4 trials of oxaliplatin4 trials of oxaliplatin--based therapybased therapy Similar survival benefit and toxicity in age subgroupsSimilar survival benefit and toxicity in age subgroups
Adjuvant CRC, 5Adjuvant CRC, 5--FU FU -- BenefitBenefit
Adjuvant settingAdjuvant setting–– Sargent NEJM 2001 Sargent NEJM 2001 –– N=3351 (15% N=3351 (15% 70 yrs)70 yrs)
7 trials of 57 trials of 5--FU + levamisole/leucovorin v surgeryFU + levamisole/leucovorin v surgery No significant interaction observed between age and efficacy of No significant interaction observed between age and efficacy of
treatmenttreatment
Adjuvant CRC, Combination Chemotherapy Adjuvant CRC, Combination Chemotherapy ––Lack of added benefitLack of added benefit
ACCENTACCENT
Updated with 6 combination/oral Updated with 6 combination/oral fluoropyrimidinefluoropyrimidine trialstrials
12,669 pts accrued from 199712,669 pts accrued from 1997--2002 2002
17% 17% ≥≥70 years70 years
O'Connell MJ, et al. JCO 2008; Sargent DJ, et al. JCO 2007; Sargent DJ, et al. JCO 2005
Efficacy Efficacy –– oxaliplatinoxaliplatin--based therapybased therapy
2.57 v 1.37 2.57 v 1.37 (p=0.25)(p=0.25)
0.920.92(0.69,1.23)(0.69,1.23)
1.191.19(0.90,1.57)(0.90,1.57)
1.041.04(0.80,1.35)(0.80,1.35)
≥≥ 7070n = 703n = 703
0.21 0.21 0.037 0.037 0.016 0.016 InteractionInteractionof age byof age bytreatmenttreatmentpp--valuevalue
0.81 v 0.81 0.81 v 0.81 (p=1.0)(p=1.0)
0.760.76(0.67,0.86)(0.67,0.86)
0.810.81(0.71,0.93)(0.71,0.93)
0.770.77(0.68,0.86)(0.68,0.86)
<70<70n = 3,977n = 3,977
TTRTTR**OSOS**DFSDFS**
Deaths within Deaths within 6 mo 6 mo
Exp v Control Exp v Control % (p% (p--value)value)
EndpointEndpointHR (95% CI)HR (95% CI)
Experimental v Control IV 5Experimental v Control IV 5--FU/LVFU/LVAgeAge
* Values < 1 favor experimental arm
STEPP analysis STEPP analysis –– OxaliplatinOxaliplatin therapytherapy
0.0
20.0
40.0
60.0
80.0
100.0
37 42 47 52 57 62 67 72
Age
3 Ye
ar D
FS
ControlExperimental
P=value = 0.33
CRC treatment in older individuals CRC treatment in older individuals -- BiologicsBiologics
CetuximabCetuximab ((ErbituxErbitux))
PanitumumabPanitumumab ((VectibixVectibix))
Cunningham NEJM 2004; Chung JCO 2005; Benvenuti Ca Res 2007; De Roock Ann Oncol2008; Finocchiaro JCO 2007; Di Fiore Br J ca 2007; Khambata-Ford JCO 2007; Lievre JCO 2008; Di Nicolantonio EORTC/NCI/AACR symposium 2008
Expression of EGFR not Expression of EGFR not predictivepredictive
Effective in 10Effective in 10--20% of chemo20% of chemo--refractory casesrefractory cases
KRAS mutation accounts for 30KRAS mutation accounts for 30--40% of non40% of non--responsive casesresponsive cases
BRAF mutations may account for additional 12%BRAF mutations may account for additional 12%
Etiology for remaining failures is not yet knownEtiology for remaining failures is not yet known
KRAS/BRAF mutation is KRAS/BRAF mutation is predictivepredictive
KRASKRAS–– Test for activating mutation of KRAS Test for activating mutation of KRAS codoncodon 12 or 1312 or 13
BRAFBRAF–– Test for BRAFV600E mutationTest for BRAFV600E mutation
KRAS mutation KRAS mutation –– predictive predictive
0.01 vs. 0.110.01 vs. 0.115252333366
6161616188
NNRR, %RR, %mPFSmPFS, mo, mo
FOLFOX FOLFOX ±± CC(OPUS)(OPUS)
0.003 vs. 0.460.003 vs. 0.46105105363688
17217259591010
NNRR, %RR, %mPFSmPFS, mo, mo
FOLFIRI FOLFIRI ±± CC(CRYSTAL)(CRYSTAL)
0.10 vs. 0.040.10 vs. 0.049393--99
153153--1111
NNRR, %RR, %mPFSmPFS, mo, mo
XeloxXelox/A /A ±± CC(CAIRO2)(CAIRO2)
0.45 vs. 0.990.45 vs. 0.9984840077
12412417171212
NNRR, %RR, %mPFSmPFS, wks, wks
PanitumumabPanitumumab
0.40 vs. 0.990.40 vs. 0.9981811122
117117131344
NNRR, %RR, %mPFSmPFS, mo, mo
CetuximabCetuximab
HR HR (WT vs. M)(WT vs. M)KRAS KRAS MutMutKRAS WTKRAS WT
Reformatted from Allegra JCO 2009; Lievre JCO 2008; Bokemeyer JCO 2009; van Cutsem JCO 2007
KRAS mutation KRAS mutation --not clearly prognostic not clearly prognostic
Inconsistent data supporting activating Inconsistent data supporting activating mutation in KRAS affecting outcome, mutation in KRAS affecting outcome, independent of therapyindependent of therapy–– Similar survival for KRAS WT vs. Similar survival for KRAS WT vs. MutMut
mPFSmPFS 7.3 wks for both groups in best supportive 7.3 wks for both groups in best supportive care arm of care arm of panitumumabpanitumumab study study
mPFSmPFS 1.8 mo for both groups in best supportive 1.8 mo for both groups in best supportive care arm of care arm of cetuximabcetuximab study study
Andreyev Br J Ca 2001; Esteller JCO 2001; Ince JNCI 2005; Amado JCO 2008; Karapetis NEJM 2008
KRAS Mutation TestingKRAS Mutation Testing
Acceptable samplesAcceptable samples–– Freshly extractedFreshly extracted–– Rapidly frozenRapidly frozen–– Formalin fixed, paraffin embeddedFormalin fixed, paraffin embedded
Acceptable assaysAcceptable assays–– RealReal--time polymerase chain reactiontime polymerase chain reaction–– Direct sequencing analysisDirect sequencing analysis
Jimeno JCO 2009
Testing RecommendedTesting Recommended
ASCO Provisional clinical opinion (JCO 2009)ASCO Provisional clinical opinion (JCO 2009)–– All pts with All pts with mCRCmCRC should have testing for KRAS should have testing for KRAS
mutations in CLIAmutations in CLIA--accredited labaccredited lab–– Pts should not receive antiPts should not receive anti--EGFR EGFR AbAb therapy if mutation therapy if mutation
in in codoncodon 12/1312/13
LimitationsLimitations–– Does not reflect data regarding activating KRAS Does not reflect data regarding activating KRAS
mutations at mutations at codonscodons 61, 14661, 146–– Does not reflect contribution of other genetic alterations Does not reflect contribution of other genetic alterations
affecting response to antiaffecting response to anti--EGFR EGFR MoAbsMoAbs–– No FDANo FDA--approved assay; Institution lab choiceapproved assay; Institution lab choice
Allegra JCO 2009; http://www.cap.org/POETwww.bcbs.com/blue resources.tec.press.KRAS-mutations-epidermal.html
Need for standardization Need for standardization ––sample selection sample selection
Process of fixation affects DNA stabilityProcess of fixation affects DNA stability
Mutation rate in formalinMutation rate in formalin--fixed paraffinfixed paraffin--embedded tissue less than in frozen tissueembedded tissue less than in frozen tissue
Allegra JCO 2009; Jimeno JCO 2009; gallegos Cell Oncol 2007
Need for standardization Need for standardization ––assay selectionassay selection
Sensitivity, Specificity of KRAS mutation testing Sensitivity, Specificity of KRAS mutation testing assays varyassays vary
PCR requires higher mutantPCR requires higher mutant--toto--wild type copies wild type copies for amplificationfor amplification
Alternate optionsAlternate options
Need for standardization Need for standardization ––patient selectionpatient selection
No age correlationNo age correlation
Age 70+ excluded from CRYSTAL (FOLFIRI Age 70+ excluded from CRYSTAL (FOLFIRI ±± C C in in mCRCmCRC)) given DSMB concerns at interim given DSMB concerns at interim analysisanalysis
NCIC CO.17: NCIC CO.17: –– N=572, 41% 65+, 25% with comorbid condition N=572, 41% 65+, 25% with comorbid condition –– Similar overall survival benefit by ageSimilar overall survival benefit by age for C vs. BSCfor C vs. BSC–– Neither age nor Neither age nor comorbiditycomorbidity prognosticprognostic
Jimeno JCO 2009; Goldberg ASCO 2009; Powell ASCO 2009
Is age a factor in mutation Is age a factor in mutation testing?testing?
Genetic/epigenetic alterations predict Genetic/epigenetic alterations predict response to antiresponse to anti--EGFR EGFR MoAbMoAb therapytherapy
Age is poor prognostic factor in CRCAge is poor prognostic factor in CRC Unclear if age is prognostic in context of Unclear if age is prognostic in context of
EGFR/KRAS/BRAF mutations OR predictive EGFR/KRAS/BRAF mutations OR predictive in context of antiin context of anti--EGFR EGFR MoAbMoAb
Standardization of testing imperative, Standardization of testing imperative, particularly in this prevalent populationparticularly in this prevalent population
AcknowledgementsAcknowledgements
International Society of Geriatric OncologyInternational Society of Geriatric Oncology Cancer and Research Aging GroupCancer and Research Aging Group Hartford Foundation, American Society of Hartford Foundation, American Society of
Clinical OncologyClinical Oncology DanaDana--Farber Cancer Institute, Farber Cancer Institute,
Gastrointestinal OncologyGastrointestinal Oncology–– Jeffrey Jeffrey MeyerhardtMeyerhardt, MD MPH, MD MPH
Questions/CommentsQuestions/Comments