HER2 Testing in Breast Cancer: 2013 ASCO/CAP HER2 Guideline Update

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HER2 Testing in Breast Cancer: 2013 ASCO/CAP HER2 Guideline Update. Short Presentation in Emerging Concepts (SPEC). Why is accurate HER2 Testing Important?. - PowerPoint PPT Presentation

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  • About these slides SPEC Short Presentation in Emerging ConceptsProvided by the CAP as an aid to pathologists to facilitate discussion on the topic.Content has been reviewed by experts at the CAP, but does not necessarily reflect the official opinion of the College of American Pathologists.Non-CAP material with identified copyright source may only be copied or distributed under a license (permission) from the copyright holder, or under the doctrine offair use.Version 1.0, rev. 5/28/2014

  • HER2 Testing in Breast Cancer: 2013 ASCO/CAP HER2 Guideline Update

    Short Presentation in Emerging Concepts (SPEC)

  • Why is accurate HER2 Testing Important? Inaccurate HER2 testing by both IHC and ISH remains a clinical concern in routine practice given the significant demonstrated benefit from HER2-targeted therapy for HER2 positive breast tumors.Prospective sub-studies from two adjuvant trials demonstrate that up to 20% of HER2 results may be inaccurate. The ASCO/CAP HER2 Guideline provides standards for improving the accuracy and reliability of HER2 testing.

    To address ongoing testing needs and challenges in light of new published literature, the ASCO/CAP HER2 Guideline was updated in 2013.Wolff AC, et al., Arch pathol lab med. 2007;131:18-43.

  • 2013 HER2 Testing in BC Guideline Update What Changed? *Wolff AC et al. Arch pathol lab med. 2014;138:241-256.

    2013 UpdatesRecommendationsPerform HER2 testing on every primary invasive tumor and any subsequent reoccurrence including metastatic sites.Need for enhanced communication between pathologists and oncologistsGuidance for communicating with patientsOptimal tissue specimen handling proceduresMaximum time in fixative: 72 hoursNew algorithms for test interpretation and reportingLanguage on repeat testing (reflex and new tests)Revised test validation requirements to align with ER/PgR recommendations

  • 2013 HER2 Testing in BC Guideline Update What Remains the Same?*No Change from 2007RecommendationsWolff AC et al. Arch pathol lab med. 2014;138:241-256.

  • 2007 Guidelines1Resection specimens preferred sample for HER2 testingMore representative sample of the patients tumor, more tumor tissue for evaluation

    2013 Guideline Update2Increasing use of core for testingCore biopsies can be used for initial test (likely better pre-analytics)Repeat testing on the excision may be necessary if a HER2 result is negative on the core in certain circumstances2013 HER2 Testing in BC Guideline Update Tumor Specimens to be Tested1. Wolff AC, et al., Arch pathol lab med. 2007;131:18-43.2. Wolff AC, et al. Arch pathol lab med. 2014;138:241-256.

  • 2013 HER2 Testing in BC Guideline Update Tumor Specimen SelectionCore samples may not be optimal in some situationsCrushing and surface artifacts in cores may hamper interpretationTumor on resection may show morphologic heterogeneityTumor on resection may show intratumoral heterogeneityTissue is not fixed for adequate length of time*Intratumoral Heterogeneity(HER2 IHC)Crush(HER2 IHC)Edge Artifact (HER2 IHC)

  • 2013 HER2 Testing in BC Guideline Update Duration of Fixation*2007 GuidelinesTime in fixative6 48 hours

    Applies to both excision and core specimens

  • 2013 HER2 Testing in BC Guideline Update IHC HER2 Positive Interpretation Criteria, Redefined*HER2 (3+) in 10% of tumor(HER2 Positive)*Readily appreciated at low power.HER2 (3+) in >90% of tumor(HER2 Positive)

  • 2013 HER2 Testing in BC Guideline Update IHC HER2 Negative Interpretation Criteria, Redefined*HER2 IHC

  • 2007 Guidelines

    Positive for HER2 is FISH amplified (ratio ofHER2to CEP17 of > 2.2 or average HER2 gene copy number > six signals/nucleus for those test systems without an internal control probe).2013 Guideline update

    Positive for HER2 is ISH amplified ratio of HER2/CEP17 of 2.0 (with average HER2 signals >4) or if average HER2 signals are 6 signals/cell (regardless of ratio) in population of >10% of tumor cells.

    2013 HER2 Testing in BC Guideline Update ISH HER2 Positive Interpretation Criteria, RedefinedChromosome 17HER2CEP17

  • 2013 HER2 Testing in BC Guideline Update ISH HER2 Negative Interpretation Criteria, Redefined 2007 Guidelines

    Negative for HER2 is FISH HER2/CEP17 ratio of < 1.8 or averageHER2gene copy number of < 4 signals/nucleus for test systems without an internal control probe.

    2013 Guideline update

    Negative for HER2 ISH is HER2/CEP17 ratio < 2 or HER2 signals/nucleus < 4, regardless of ratio.

  • 2013 HER2 Testing in BC Guideline Update HER2 Equivocal Results Require a Reflex or Repeat Test2007 Guidelines

    Equivocal for HER2 IHC is 2+

    ISH: FISH HER2/CEP17 ratio of 1.8-2.2 or averageHER2gene copy number 4-6 HER2 signals/nucleus for test systems without an internal control probe

    2013 Guideline update

    Must report HER2 test result as Equivocal (HER2 tumor status Unknown) and order reflex test using the alternative test if:IHC: (2+) circumferential membrane staining, incomplete and/or weak/ moderate in >10% of the invasive tumor cells; or complete and circumferential membrane intense staining within 10% of the invasive tumor cells ISH: Dual Probe HER2/CEP17 ratio

  • Intratumoral heterogeneity for HER2 can be seen in breast cancer by IHC and ISH.With heterogeneity, the fields selected for evaluation will determine whether or not the tumor is reported as ISH amplified.Mean score/ratio depends on the number of amplified cells counted and gene copy # after dilution with non-amplified cells.Can lead to discordant results for HER2 analysisBetween IHC and ISH, cores vs excision, between blocksEasier to detect with IHC (can be used to target ISH analysis)Clinical significance of heterogeneity remains unclear however:Patients with HER2 IHC 3+ (10-30%) and ISH ratio (2-2.2) appear to benefit from treatment with HER2-targeted therapy.It is important to carefully review all the pathologic features (grade, proliferative index, ER/PR &HER2 results) for such cases.

    2013 HER2 Testing in BC Guideline Update Changes to Testing Algorithm Help Address HeterogeneityHanna, et al., Mod Pathol. 2014 Jan;27(1):4-18

  • In Situ Hybridization:HER2/CEP17 ratio of >2 observed in a homogenous or clustered contiguous population of at least 10% of the invasive tumor cells.HER2 copy# >6Immunohistochemistry:>10% of tumor cells with strong circumferential membrane staining observed in a homogenous or clustered contiguous population of at least 10% of invasive tumor cells.Strong membrane staining is readily appreciated at low power.

    ASCO/CAP 2013 HER2 Guideline Definition, HER2 Positive: HeterogeneityHER2/CEP17 = 7.1HER2/CEP17 = 1.5

  • 2013 HER2 Testing in BC Guideline Update Histopathologic Discordance and Repeat TestingWolff AC, et al. Arch pathol lab med. 2014;138:241-256.

    If the initial test result is HER2 NEGATIVE on Core:Order a New Test on the Excision if:DO NOT order a New Test if:Tumor is Histologic Grade-3

    Small amount of invasive tumor on core

    Resection contains high-grade component not present on core

    Core biopsy equivocal diagnosis by both IHC and ISH

    Questionable specimen handling of core or result is suspect to be negative due to testing errorTumor is histologic grade-1

    Infiltrating ductal or lobular carcinoma that is strongly ER/PR positive

    Tubular carcinoma (>90% pure)

    Mucinous carcinoma (>90% pure)

    Cribriform carcinoma (>90% pure)

    Adenoid cystic carcinoma (typically these tumors are triple negative)

  • Chromosomal Abnormalities involving CEP17 (Aneusomy)

    Polysomy 17 = increased copy number of HER2 & CEP17 signalsMost frequently defined as average CEP17# >3 by ISHHER2/CEP17 3.0 in ISH is frequently related to gain or amplification of the centromeric regionTypically high grade tumor and HER2 IHC is (2+) or (3+)HER2/CEP17 ratio < 2 may be misleading in such cases

    Chromosome 17HER2CEP17HER2 FISHHER2 IHCHanna, et al., Mod Pathol. 2014 Jan;27(1):4-18, Tse, et al., J Clin Oncol. 2011 Nov 1;29(31):4168-74

  • Co-amplification of CEP17 region is observed in many ISH assays with increased HER2 and CEP17 copy #May lead to a HER2/CEP17 ratio < 2.0 suggesting lack of HER2 amplification and discordant IHC/ISH resultsIf the HER2 copy number is >6, the HER2 test result must be reported as Positive regardless of the HER2/CEP17 ratioHER2 amplification defined by ratio criterion (>2), HER2 copy# criterion(>6) or bothSome labs may choose to repeat HER2 testing in the same specimen using an alternative chromosome 17 reference probe (another gene on chromosome 17 not expected to co-amplified with HER2) to help demonstrate an amplified ratio (>2)

    2013 HER2 Testing in BC Guideline Update Changes to Testing Algorithm Help Address Chromosomal Abnormalities involving CEP17 (Aneusomy)

  • Key MessagesGuidelines are living document which changeFrom user feedbackFrom new publications and dataIteration of guidelines leads to greater clarityAlgorithm changes in the HER2 testing guideline update will provide better safety for patientsPositive patients will be found and treatedEquivocal patients will have further work done to better define their HER2 statusNegative patients will be spared unnecessary treatmentScrutiny of cases by physicians will find patients with unusual situations and generate discussion between Pathologists and Medical Oncologists *

  • Selected Resources

    Wolff AC1, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch pathol lab med. 2007;131:18-43