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