Molecular Biomarkers For The Evaluation Of Colorectal Cancer
Molecular Biomarkers for theEvaluation of Colorectal CancerGuideline From the American Society for Clinical Pathology,College of American Pathologists, Association for MolecularPathology, and American Society of Clinical Oncology
Webinar Host This series is sponsoredby the PersonalizedHealthcare (PHC)Committee Today’s webinar host isAllison M. CushmanVokoun, MD, PhD, FCAP 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Housekeeping This presentation will be recorded. The recordingand PDF will go out to all registrants in severalweeks All lines are muted during the presentation Please send in your questions as you think of themvia the “Question box” in your control panel 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Antonia R. Sepulveda, MD, PhD, FCAP Director, Division ofGastrointestinal Pathology, ViceChair for TranslationalResearch at Columbia University Professor, Departments ofPathology and Cell Biology atColumbia University AMP Co-chair, ASCP-CAP-AMPASCO Joint Guideline on theEvaluation of Molecular Markersfor Colorectal Cancer 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Disclaimer The CAP does not permit reproduction of any substantialportion of the material in this Webinar without its writtenauthorization. The CAP hereby authorizes attendees of theCAP Webinar to use the PDF presentation solely foreducational purposes within their own institutions. The CAPprohibits use of the material in the Webinar – and anyunauthorized use of the CAP’s name or logo – in connectionwith promotional efforts by marketers of laboratoryequipment, reagents, materials, or services. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Disclaimer, continued Opinions expressed by the speaker are the speaker’s ownand do not necessarily reflect an endorsement by the CAP ofany organizations, equipment, reagents, materials, orservices used by participating laboratories. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
DisclosuresDr. Sepulveda has no disclosures 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Objectives To establish an evidence-based guideline for themolecular biomarker testing for the evaluation ofcolorectal cancer.8 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
BackgroundThe CAP, ASCP, AMP, and ASCO convened an expertpanel to systematically review published documentsand develop an evidence-based guideline to: Establish evidence-based recommendations for themolecular testing of CRC tissues to guide targetedtherapies and conventional chemotherapy regimensSummarize emerging molecular testing approaches forCRC and provide insight on needed studies9 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Guideline Expert PanelAdvisory Panel MembersCharles David Blanke, MDCo-chairsJean-Francois Flejou, MD, PhDWayne Grody, MD – ASCPHeather Lynn Hampel, MSStanley Hamilton, MD – CAPJoel Randolph Hecht, MDKazunori Kanehira, MDAntonia R Sepulveda, MD, PhD – AMPFay Kastrinos, MD, MPHCarmen J Allegra, MD – ASCOCarla Beltran MacLeod, MDPamela McAllisterPeter J O'Dwyer, MDExpert Panel MembersAllison Marie Cushman-Vokoun, MD,PhDVeena M Singh, MD, ACMGJoseph Willis, MDBruce Minsky, MDJan Anthony Nowak, MD, PhDDaniel J. Sargent, PhDNoralane M Lindor, MDWilliam K. Funkhouser, MD, PhDFederico Alberto Monzon, MDChristopher Lieu, MDScott Kopetz, MDShuji Ogino, MD, PhDKim RyanWeijing Sun, MDJosep Tabernero, MD, PhDLaura H Tang, MD, PhDMary Kay Washington, MD, PhDStaffChristina Ventura, MLS(ASCP) – CAPLisa Fatheree, SCT(ASCP) – CAPCarol Colasacco, MLIS, SCT(ASCP) – CAPJennifer Clark, SCT(ASCP)cm MBcm – ASCPShiwen Song, MD, PhD – ASCPRobyn Temple-Smolkin, PhD – AMPRobert Bryan Rumble – ASCO Methodologist 2017 CAP, ASCP, AMP, ASCO. All rights reserved.10
Institute of Medicine Standards Establishing transparency Management of conflict ofinterest (COI) Guideline developmentgroup composition Articulation ofrecommendations External Review Updating Clinical practice guideline–systematic reviewintersection Establishing evidencefoundations for and ratingstrength ofrecommendationsClinical Practice Guidelines We Can Trust: IOM Report11 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Grades for Strength of mendationRecommendationRationaleRecommend for or against a particularSupported by convincing (high) or adequatemolecular testing practice for colorectal(intermediate) quality of evidence and clearcancer (Can include must or should)benefit that outweighs any harmsRecommend for or against a particularSome limitations in quality of evidencemolecular testing practice for colorectal(adequate [intermediate] or inadequate [low]),cancer (Can include should or may)balance of benefits and harms, values, or costsbut panel concludes that there is sufficientevidence and/or benefit to inform arecommendationExpert ConsensusOpinionRecommend for or against a particularSerious limitations in quality of evidencemolecular testing practice for colorectal(inadequate [low] or insufficient), balance ofcancer (Can include should or may)benefits and harms, values or costs, but panelconsensus is that a statement is necessaryNoRecommendationNo recommendation for or against aInsufficient evidence or agreement of theparticular molecular testing practice forbalance of benefits and harms, values, or costscolorectal cancerto provide a recommendation12 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Grades for Strength of EvidenceDesignationConvincingDescriptionQuality of EvidenceHigh confidence that available evidence reflectsHigh/Intermediate qualitytrue effect. Further research is very unlikely toevidencechange the confidence in the estimate of effect.AdequateModerate confidence that available evidenceIntermediate/Low quality ofreflects true effect. Further research is likely toevidencehave an important impact on the confidence inestimate of effect and may change the estimate.InadequateLittle confidence that available evidence reflectsLow/Insufficient evidence andtrue effect. Further research is very likely to haveexpert panel uses formalan important impact on the confidence in theconsensus process to reachestimate of effect and is likely to change therecommendationestimate.InsufficientEvidence is insufficient to discern net effect. AnyInsufficient evidence and expertestimate of effect is very uncertain.panel uses formal consensusprocess to reach recommendationAdapted by permission from BMJ Publishing Group Limited. GRADE: an emerging consensus on rating quality of evidence andstrength of recommendations. Guyatt GH, et al; GRADE Working Group. 2008;336(7650):924-926.913 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Systematic Evidence Review Identify Key Questions Literature search Data extraction Develop proposed recommendations Open comment period Considered judgment process14 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Molecular Testing Guidelines for ColorectalCancer: Overarching Key Questions What biomarkers are useful for colorectal cancer (CRC)management (selection of patients for targeted andconventional therapies)? How should tissue specimens be processed forbiomarker testing for CRC management? How should biomarker testing for CRC management beperformed? How should molecular testing of CRC be implementedand operationalized? Should other genes/biomarkers be routinely tested inCRC?15 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Systematic Review Systematic literature search: Initial dates from Jan 1,2008 through Aug 1, 2013 with a literature refresh withdates covering through February 12, 2015) Title-Abstract Screen: 4,197 abstracts Full-text Article Review: 866 articles Data Extraction: 123 articles for data extraction andqualitative analysis; Over 70 systematic reviews andmeta-analyses analyzed16 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Systematic Review, continued All expert panel members participated in the systematicreview of the literature. The expert panel convened to review the extracted dataand drafted recommendations. The draft recommendations were available for publiccommentary in April 2015. Draft recommendations were updated based on publiccommentary in July 2015.17 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Guideline Statements18
19Antonia R. Sepulveda, MD,PhD,1 Stanley R. Hamilton, MD,PhD,2 Carmen J.Allegra, MD,5 Wayne Grody, MD, PhD,6 Allison M. Cushman-Voukoun, MD,PhD,7 William K. Funkhouser, MD, PhD,8 Scott E. Kopetz, MD,PhD,3Christopher Lieu, MD,9 Noralane M. Lindor, MD,10 Bruce D. Minsky, MD,4Federico A. Monzon, MD,11 Daniel J. Sargent, PhD,12 Veena M. Singh,MD,13 Joseph, Willis MD,14 Jennifer Clark, SCT,MB (ASCP) CM,15 Carol,MLIS,16 R. Bryan Rumble,MSc,17 Robyn Temple-Smolkin, PhD,18 ChristinaB. Ventura, MT(ASCP),16 and Jan A. Nowak, MD,PhD19American Journal of Clinical Pathology (2017) 147 (3): 221-260Journal of Molecular Diagnostics (2017) 19 (2): 187–225Archives of Pathology and Laboratory Medicine doi: 10.5858/arpa.2016-0554-CPJournal of Clinical Oncology DOI: 10.1200/JCO.2016.71.9807 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
20Sepulveda AR et al. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Key Question: What biomarkers areuseful for colorectal cancer (CRC)management (selection of patientsfor targeted and conventionaltherapies)?21 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Targeting the EGFR Pathwayin CRCBardelli, A. et al. J Clin Oncol; 28:1254-1261 2010Copyright American Society of Clinical Oncology 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Guideline Statement 1Recommendation: Patients with CRC being consideredfor anti-EGFR therapy must receive RAS mutationaltesting. Mutational analysis should include KRAS andNRAS codons 12, 13 of exon 2, 59, 61 of exon 3, and 117and 146 of exon 4 ("expanded" or "extended" RAS). 2017 CAP, ASCP, AMP, ASCO. All rights reserved.23
Guideline Statements 4, 5, 6No Recommendation: There is insufficient evidence torecommend BRAF V600, PIK3CA, mutational status andPTEN IHC as predictive molecular biomarkers forresponse to anti-EGFR inhibitors 2017 CAP, ASCP, AMP, ASCO. All rights reserved.24
Guideline Statement 1, continuedRationale: 311 primary studies with 74,546 patients that reportedtreatment outcomes in metastatic CRCcomparing RAS mutation vs. RAS nonmutated(nm)/wild type(wt) inearlier studies of mostly KRAS exon 2 mutations Survival advantage for patients treated with anti-EGFR MoAb with KRASnm/wt vs. KRAS mutation tumors Studies reported an overall response rate (ORR) & progression free survival(PFS) advantage for adding anti-EGFR MoAb to chemotherapy for patientswith KRAS nm/wt 2017 CAP, ASCP, AMP, ASCO. All rights reserved.25
Guideline Statement 1, continuedRationale: There is also conclusive evidence that other RAS mutations in KRAS andNRAS are associated to nonresponse of metastatic CRC to anti-EGFRmonoclonal antibody therapy (Sorich MJ et al. 2015) Patients with colorectal cancers that are KRAS exon 2 nm/wt but harborRAS mutations in KRAS exons 3 and 4 or NRAS exons 2, 3, and 4 alsohave significantly inferior anti-EGFR treatment outcomes benefitcompared with those without any RAS mutations (Sorich MJ et al. 2015) No progression free survival (PFS) or overall survival (OS) benefit with useof anti-EGFR mAbs for tumors harboring any RAS mutationSepulveda AR et al. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Prevalence of new RASmutations across studiesa: proportion of the KRAS exon 2 wild-type groupSorich MJ, et al. Ann Oncol. 2015;26:13–21. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
All RAS MutantCRC:KRAS exon 2 c12 &c13 mutationsand extended RASmutationsSorich MJ, et al. Ann Oncol. 2015;26:13–21. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Guideline Statement 4No Recommendation: There is insufficient evidence to recommendBRAF c.1799 p.V600 mutational status as a predictive molecularmarker for response to anti‐EGFR inhibitors.Rationale: Studies used nonrandomized cohorts which makes the evaluation of thepotential predictive value of the BRAF p.V600 mutation difficult to determine With the low mutation prevalence , the evaluation of the relative benefit of antiEGFR inhibitors is also difficult to determine A meta-analysis of 463 patients with KRAS wt and BRAF p.600 mutation did notprovide sufficient evidence to determine the magnitude of benefits seen inKRAS/BRAF wt tumors Another M-A showed that EGFR monoclonal antibody therapy in BRAF p.600mutation patients was not associated with significant OS (p .43), although itshowed a better PFS (p .07) 2017 CAP, ASCP, AMP, ASCO. All rights reserved.29
Guideline Statement 5No Recommendation: There is insufficient evidence to recommendPIK3CA mutational analysis of colorectal carcinoma tissue fortherapy selection outside of a clinical trial.Note: Retrospective studies have suggested improved survival withpost‐operative aspirin use in patients whose colorectal carcinomaharbors a PIK3CA mutation.Rationale: Comprehensive PIK3CA testing would increase response rate in the firstline setting by only 1% The prognostic impact of PIK3CA in stage I to III disease has beeninconsistent Multiple prospective observational studies have demonstrated anassociation between aspirin use and decreased CRC mortality 2017 CAP, ASCP, AMP, ASCO. All rights reserved.30
Guideline Statement 6No Recommendation: There is insufficient evidence to recommendPTEN analysis [expression by immunohistochemistry (IHC) ordeletion by fluorescence in situ hybridization (FISH)] in colorectalcarcinoma tissue for patients who are being considered for therapyselection outside of a clinical trial.Rationale: There is evidence suggesting that PTEN is a critical factor in cancerdevelopment, but the association between PTEN expression andpredictive/prognostic value remains controversial Several studies suggesting an association with poorer prognosis andothers finding no association at all Due to the discordant studies, the prognostic or predictive role of PTEN inCRC is still unknown. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.31
Guideline Statement 2ARecommendation: BRAF V600 (BRAF c.1799 [p.V600]) positionmutational analysis should be performed in CRC tissue in selectedpatients with colorectal carcinoma for prognostic stratification.Rationale: CRC patients with BRAF mutation have worse outcome relative to nmpatients Studies show that patients with advanced CRC with a BRAF mutationshow poorer progression free survival (PFS), overall survival (OS), and adecreased response rate to anti-EGFR therapy Patients with BRAF mutation showed modest beneficial impact from theuse of anti-EGFR agents relative to those patients with RAS mutation 2017 CAP, ASCP, AMP, ASCO. All rights reserved.32
Guideline Statement 2BRecommendation: BRAF p.V600 mutational analysis should beperformed in dMMR tumors with loss of MLH1 to evaluate for LynchSyndrome risk. Presence of a BRAF mutation strongly favors asporadic pathogenesis. The absence of BRAF mutation does notexclude risk of Lynch syndrome.Rationale: Testing for BRAF mutations may help distinguish between germline fromepigenetic dMMR, especially in the cases where the dMMR is the result ofepigenetic silencing of MLH1 Testing may help to further refine the risk of Lynch syndrome for patientswith germline-based dMMR. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.33
Guideline Statement 3Recommendation: Clinicians should order mismatch repair statustesting in patients with colorectal cancers for the identification ofpatients at high risk for Lynch syndrome and/or prognosticstratification.Rationale: Diagnosis of Lynch Syndrome is important to allow patients to activelymanage cancer risks to benefit gene mutation carriers Emerging data indicate that MMR status may have predictive value insome settings, specifically in patients with advanced disease beingconsidered for anti-programmed cell death protein-1 (PD-1)/ programmedcell death ligand protein-1 (PD-L1) immune checkpoint inhibitor therapy 2017 CAP, ASCP, AMP, ASCO. All rights reserved.34
BRAF and dMMR/MSI: Prognostic andPredictive Markers for Stage II/III CRCdMMR BRAFwtdMMRBRAFmutpMMRBRAFwtPrognostic: BRAFmut shorter survivaltime at recurrencepMMRBRAFmutPrognostic: dMMR/MSI betterOS survival (BRAF wt)Gavin PG, et al. Clin Cancer Res. 2012;18:6531– 6541. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
ABCD Poorly differentiatedadenocarcinoma withmedullary features &prominent TILs Immunohistochemistry forMLH1: Loss of expression intumor cell nuclei Mucinous adenocarcinoma Immunohistochemistry forMLH1: loss of expression intumorMolecular Pathology of GastrointestinalNeoplasia Springer, LLC, New York, NY.AR Sepulveda and JP Lynch (eds.). 2013. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
CRC emerging molecular biomarkers MSI/MMR status may have predictive value inpatients with advanced CRC being considered foranti-PD-1/PD-L1 immune checkpoint inhibitortherapy DNA MMR statustested by MSI DNAtest Pembrolizumab IV 82% had HNPCCgermline detectedLe DT et al. N Eng J Med 2015; 372:2509-20 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Key Question: How should tissuespecimens be processed for biomarkertesting for CRC management?38 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Guideline Statement 7Expert Consensus Opinion: Metastatic or recurrent colorectalcarcinoma tissues are the preferred specimens for treatmentpredictive biomarker testing and should be used if such specimensare available and adequate. In their absence, primary tumor tissue isan acceptable alternative, and should be used.Rationale: Despite high concordance between the primary and metastatic orrecurrent, discordant mutational status may still happen in some cases,therefore metastatic or recurrent tissue is preferred If the metastatic or recurrent tissue is unavailable, the primary tissue maybe used for testing 2017 CAP, ASCP, AMP, ASCO. All rights reserved.39
Concordance between primary andmetastasesGenes TestedConcordance Rate (%)KRAS (n 117)91.0KRAS, NRAS, BRAF (n 84)98.8PIK3CA (n 117)94.0PIK3CA (n 84)92.8PTEN IHC (n 117)66.0Sepulveda AR et al. 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Guideline Statement 8Expert Consensus Opinion: Formalin fixed paraffin embedded (FFPE)tissue is an acceptable specimen for molecular marker mutationaltesting in colorectal carcinoma. Use of other specimens (e.g.cytology specimens) will require additional adequate validation, aswould any changes in tissue processing protocols.Rationale: The use of FFPE tissue or cell blocks allows for the evaluation of tumorcell content and viability Cytology specimens may be adequate for testing but will require propervalidation Note: Laboratories need to establish the minimum tumor cell content forspecimens based on the performance characteristics of their validatedassay 2017 CAP, ASCP, AMP, ASCO. All rights reserved.41
Sepulveda AR et al.42 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Key Questions How should biomarker testing for CRCmanagement be performed? How should molecular testing of CRC beimplemented and operationalized?43 2017 CAP, ASCP, AMP, ASCO. All rights reserved.
Guideline Statement 9Strong Recommendation: Laboratories must use validated colorectalcarcinoma molecular marker testing methods with sufficientperformance characteristics for the intended clinical use. Colorectalcarcinoma molecular biomarker testing validation should followaccepted standards for clinical molecular diagnostics tests.Rationale: Validation should be performed to ensure all molecular marker testingmethods, such as those used for colorectal carcinoma, are ready forimplementation in the clinical laboratory 2017 CAP, ASCP, AMP, ASCO. All rights reserved.44
Table 13 (continuation)Sepul
Molecular Biomarkers for the Evaluation of Colorectal Cancer Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology
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