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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