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Update on HER2 testing

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Update on HER 2 testing in Breast Cancer

Update on HER 2 testing in Breast Cancer

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    Update on HER2 testing Update on HER2 testing Presentation Transcript

    • UPDATE ON HER-2 TESTING
      Pathmanathan
      Adjunct Professor
      MonashMedical School
      ManipalMedical School
      Senior Consultant Pathologist, SDMC
    • Introduction
      • For many years, breast cancer has been considered as a unique disease and treated as a unique disease based on clinical and pathological parameters
      • During the last 20 years, extended knowledge of breast cancer biology, has put some light in our understanding of breast cancer
      • High throughput technologies such as expression profiling recently introduce new classifications of IBC
      • Some cellular targets, such as HER2, have been identified and drugs have been designed to specifically fight them
    • HER2 + breast cancer represents a heterogeneous disease targeted by specific drugs and is a hallmark of strategic treatment
    • HER receptors
      HER2
      HER1
      HER3
      HER4
      Cell membrane
      5
    • ErbB-2
      HER2/neu
      Does not need ligands
      activation occurs through heterodimerization with another ErbB family member or homidimerization when HER2 is overexpressed.
      ErbB-2 is the preferred dimerization partner of the other 3 ErbB family members.
      Heterodimers including ErbB-2 exhibit increased stability and prolonged activation
      HER2 is a poor prognosis factor in breast cancer
    • Trastuzumab: targeting HER2
      Attacks HER2-positive tumours via 5 distinct mechanisms of action
      Activation of antibody-dependent cellular cytotoxicity (ADCC)
      Prevention of the formation of p95HER2, a truncated and very active form of HER2
      Degradation of HER2 dimers
      Inhibition of cell proliferation by preventing HER2-activated intracellular signalling
      Inhibition of HER2-regulated angiogenesis
      3
    • Herceptinis an effective drug
      For HER2 + positive patients (importance of the quality of testing
      In the metastatic setting in combination with taxanes, other CT agents + / -antiaromatase (ER+)
      Herceptin action
      Potentialization of cytotoxic drugs and hormonal treatment
      HER2 targeting
    • HER-2 Positive state shortens survival
      Median survival from first diagnosis:
      HER2 positive  3 years
      HER2 normal  6 - 7 years
      Slamon DJ et al. Science 1987;235: 177-182
    • HER2+ is a heterogeneous disease
      Up to 50% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers are also oestrogen receptor (ER) positive
      Evidence of crosstalk between HER2 and ER signalling pathways
      Simultaneous targeting of both pathways may improve outcomes over monotherapy
      Vogel et al 2001;Penault-Llorca et al 2002; Piccart-Gebhart et al 2005
    • Herceptin® is indicated for HER2-positive breast cancer
      HER2 positivity is the criterion to select patients for Herceptin® therapy
      strong overexpression of the HER2 protein on the cell surface
      HER2 gene amplification
    • HER2
      TESTING
      HER2 PROTEIN OVEREXPRESSION
      IHC
      FISH OR CISH
      HER2 GENE AMPLIFICATION
    • 0 ou 1+
      FISH or CISH
      IHC
      +
      2+
      3+

      FISH or CISH
      +

      Aneuploidy or ambiguous case
      Tester by
      IHC
      Anti her2 treatment
      Anti her2 treatment
      2+ or -
      3+
      Breast tumor
      Anti her2 treatment
      Anti her2 treatment
      ASCO, CAP Guidelines 2006
    • Importance of accurate testing
      Accurate testing is essential to identify those patients who will benefit from Herceptin®
      false-negative assessment:denies patients life-extending treatment
      false-positive assessment: patients will not benefit from Herceptin®
      Important requirements for the pathology laboratory
      standardisation and regular validation of testing
      quality control measures and quality assurance
      minimum number of cases (>150 per year)
      detailed documentation
    • Normal
      Normal
      Abnormal low
      Abnormal high
      amplification
      amplification
      Abnormal 2+
      Abnormal 3+
      Normal 0
      Normal 1+
      ErbB-2/HER2 in Breast Cancer
    • Published in 2007
      Problem of tumour heterogeneity apparent at that time
      Group consensus meeting in 2008 to discuss this problem
      Vetted through CAP / American College of Medical Cytogenetics Resource Committee
      ASCO / CAP guidelines
    • Well documented
      Represents subclonal diversity
      Incidence varies from 5 – 30 %
      Increases subjectivity of HER-2 interpretation by pathologist
      Intratumoral heterogeneity
    • Definition
      > 5 % but < 50 % of infiltrating tumour cells have ratio higher than 2.2
      HER-2 genetic heterogeneity (GH)
    • If 20 cells are counted and at least one cell is identified with a HER2/ CEP17 ratio of > 2.2, the specimen has GH
      If 60 cells are counted, > 3 cells show a ratio of 2.2 , GH exists
      These definitions based on published works, agreed by consensus
    • Polyploidy 17
      In about 19.5 % of cases tested with FISH which show an equivocal result by absolute copy number
      About 1.3 % of patients showing equivocal result by HER2/ CEP17 ratio
      Polysomy 17 in Breast Cancer
    • Polysomy, PathVysion™ kit
      The >2 green signals (CEP17) and 2 orange signals (HER2 genes) per nucleus indicate polysomy
    • Polysomy 17 on its own
      Not associated with HER2 overexpression
      Not associated with increased levels of HER2 mRNA on RT-PCR
      Not associated with high grade tumours
      Not associated with ER negativity
      Not associated with reduced disease free survival
      May not benefit from Herceptin therapy
      MORE STUDIES NEEDED
      Bempt et.al (2008) J ClinOncol 26: 30, pp 4869- 4874
    • Tubbs RR, Hicks DG, Cook J, et al. Diagn Mol Pathol. 2007;16:207– 210.
      Lewis JT, Ketterling RP, Halling KC, et al. Am J Clin Pathol. 2005;124:273–281.
      Fujii H, Marsh C, Cairns P, Sidransky D, Gabrielson E. Cancer Res. 1996;56:1493–1497.
      Miller DV, Jenkins RB, Lingle WL, et al. 2004 ASCO Annual Meeting Proceedings. J Clin Oncol. 2004;22(14S):568.
      Glockner S, Buurman H, Kleeberger W, Lehmann U, Kreipe H. Lab Invest. 2002;82:1419–1426
      References