Update on HER2 testing


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Update on HER 2 testing in Breast Cancer

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Update on HER2 testing

  1. 1. UPDATE ON HER-2 TESTING<br />Pathmanathan<br />Adjunct Professor <br />MonashMedical School<br />ManipalMedical School<br />Senior Consultant Pathologist, SDMC <br />
  2. 2. Introduction <br /><ul><li>For many years, breast cancer has been considered as a unique disease and treated as a unique disease based on clinical and pathological parameters
  3. 3. During the last 20 years, extended knowledge of breast cancer biology, has put some light in our understanding of breast cancer</li></li></ul><li><ul><li>High throughput technologies such as expression profiling recently introduce new classifications of IBC
  4. 4. Some cellular targets, such as HER2, have been identified and drugs have been designed to specifically fight them</li></li></ul><li>HER2 + breast cancer represents a heterogeneous disease targeted by specific drugs and is a hallmark of strategic treatment<br />
  5. 5. HER receptors<br />HER2<br />HER1<br />HER3<br />HER4<br />Cell membrane<br />5<br />
  6. 6. ErbB-2 <br />HER2/neu<br />Does not need ligands<br />activation occurs through heterodimerization with another ErbB family member or homidimerization when HER2 is overexpressed.<br />ErbB-2 is the preferred dimerization partner of the other 3 ErbB family members. <br />Heterodimers including ErbB-2 exhibit increased stability and prolonged activation <br />HER2 is a poor prognosis factor in breast cancer<br />
  7. 7. Trastuzumab: targeting HER2<br />Attacks HER2-positive tumours via 5 distinct mechanisms of action<br />Activation of antibody-dependent cellular cytotoxicity (ADCC)<br />Prevention of the formation of p95HER2, a truncated and very active form of HER2<br />Degradation of HER2 dimers<br />Inhibition of cell proliferation by preventing HER2-activated intracellular signalling<br />Inhibition of HER2-regulated angiogenesis<br />3<br />
  8. 8. Herceptinis an effective drug<br />For HER2 + positive patients (importance of the quality of testing<br />In the metastatic setting in combination with taxanes, other CT agents + / -antiaromatase (ER+)<br />Herceptin action<br />Potentialization of cytotoxic drugs and hormonal treatment<br />HER2 targeting <br />
  9. 9. HER-2 Positive state shortens survival<br />Median survival from first diagnosis:<br />HER2 positive  3 years<br />HER2 normal  6 - 7 years<br />Slamon DJ et al. Science 1987;235: 177-182<br />
  10. 10. HER2+ is a heterogeneous disease<br />Up to 50% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers are also oestrogen receptor (ER) positive<br />Evidence of crosstalk between HER2 and ER signalling pathways<br />Simultaneous targeting of both pathways may improve outcomes over monotherapy<br />Vogel et al 2001;Penault-Llorca et al 2002; Piccart-Gebhart et al 2005<br />
  11. 11. Herceptin® is indicated for HER2-positive breast cancer<br />HER2 positivity is the criterion to select patients for Herceptin® therapy<br />strong overexpression of the HER2 protein on the cell surface<br />HER2 gene amplification<br />
  13. 13. 0 ou 1+<br />FISH or CISH<br />IHC<br />+<br />2+<br />3+<br />–<br />FISH or CISH<br />+<br />–<br />Aneuploidy or ambiguous case<br />Tester by<br /> IHC<br />Anti her2 treatment<br />Anti her2 treatment<br />2+ or -<br />3+<br />Breast tumor<br />Anti her2 treatment<br />Anti her2 treatment<br />ASCO, CAP Guidelines 2006<br />
  14. 14. Importance of accurate testing<br />Accurate testing is essential to identify those patients who will benefit from Herceptin®<br />false-negative assessment:denies patients life-extending treatment <br />false-positive assessment: patients will not benefit from Herceptin®<br />Important requirements for the pathology laboratory<br />standardisation and regular validation of testing<br />quality control measures and quality assurance<br />minimum number of cases (&gt;150 per year)<br />detailed documentation<br />
  15. 15. Normal <br />Normal <br />Abnormal low<br />Abnormal high<br />amplification<br />amplification<br />Abnormal 2+<br />Abnormal 3+<br />Normal 0<br />Normal 1+<br />ErbB-2/HER2 in Breast Cancer<br />
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  18. 18. Published in 2007<br />Problem of tumour heterogeneity apparent at that time<br />Group consensus meeting in 2008 to discuss this problem<br />Vetted through CAP / American College of Medical Cytogenetics Resource Committee <br />ASCO / CAP guidelines<br />
  19. 19. Well documented<br />Represents subclonal diversity<br />Incidence varies from 5 – 30 %<br />Increases subjectivity of HER-2 interpretation by pathologist<br />Intratumoral heterogeneity<br />
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  24. 24. Definition<br />&gt; 5 % but &lt; 50 % of infiltrating tumour cells have ratio higher than 2.2<br />HER-2 genetic heterogeneity (GH)<br />
  25. 25. If 20 cells are counted and at least one cell is identified with a HER2/ CEP17 ratio of &gt; 2.2, the specimen has GH<br />If 60 cells are counted, &gt; 3 cells show a ratio of 2.2 , GH exists<br />These definitions based on published works, agreed by consensus<br />
  26. 26. Polyploidy 17<br />In about 19.5 % of cases tested with FISH which show an equivocal result by absolute copy number<br />About 1.3 % of patients showing equivocal result by HER2/ CEP17 ratio<br />Polysomy 17 in Breast Cancer<br />
  27. 27. Polysomy, PathVysion™ kit<br />The &gt;2 green signals (CEP17) and 2 orange signals (HER2 genes) per nucleus indicate polysomy<br />
  28. 28. Polysomy 17 on its own<br />Not associated with HER2 overexpression<br />Not associated with increased levels of HER2 mRNA on RT-PCR<br />Not associated with high grade tumours<br />Not associated with ER negativity<br />Not associated with reduced disease free survival<br />May not benefit from Herceptin therapy <br />MORE STUDIES NEEDED<br />Bempt et.al (2008) J ClinOncol 26: 30, pp 4869- 4874 <br />
  29. 29. Tubbs RR, Hicks DG, Cook J, et al. Diagn Mol Pathol. 2007;16:207– 210.<br /> Lewis JT, Ketterling RP, Halling KC, et al. Am J Clin Pathol. 2005;124:273–281. <br />Fujii H, Marsh C, Cairns P, Sidransky D, Gabrielson E. Cancer Res. 1996;56:1493–1497. <br /> Miller DV, Jenkins RB, Lingle WL, et al. 2004 ASCO Annual Meeting Proceedings. J Clin Oncol. 2004;22(14S):568. <br />Glockner S, Buurman H, Kleeberger W, Lehmann U, Kreipe H. Lab Invest. 2002;82:1419–1426<br />References<br />