Her2 in gastric cancer


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Her2 in gastric cancer

  1. 2. <ul><li>About 95% of gastric cancers are adenocarcinomas </li></ul><ul><li>The WHO Classification recognizes four main categories: </li></ul><ul><li>Tubular </li></ul><ul><li>Papillary </li></ul><ul><li>Mucinous </li></ul><ul><li>Poorly cohesive (including signet ring cell type) </li></ul>
  2. 5. <ul><li>Treatment of gastric cancer is </li></ul><ul><li>Surgery </li></ul><ul><li>Chemotherapy </li></ul><ul><li>Radiation therapy. </li></ul>
  3. 6. <ul><li>There are benefits of palliative chemotherapy. However the prognosis of advanced GC is still poor (median survival 7-10 months). </li></ul><ul><li>Targeted therapies are now being considered in advanced GC. </li></ul>
  4. 7. <ul><li>Recently, trastuzumab (Herceptin®Genentech/Roche¶), </li></ul><ul><li>A monoclonal antibody </li></ul><ul><li>Interferes with HER2/neu receptor function. </li></ul><ul><li>Has shown to improve the survival of patients with advanced gastric cancer. </li></ul>
  5. 10. <ul><li>Imatinib </li></ul><ul><ul><li>CML </li></ul></ul><ul><ul><li>GISTs </li></ul></ul><ul><li>Gefitinib </li></ul><ul><ul><li>Non small cell ca </li></ul></ul><ul><li>Bortezomib </li></ul><ul><ul><li>multiple myeloma </li></ul></ul><ul><li>Rituximab </li></ul><ul><ul><li>non Hodgkin lymphoma </li></ul></ul><ul><li>Transtuzumab </li></ul><ul><ul><li>breast cancer </li></ul></ul><ul><li>Cetuximab </li></ul><ul><ul><li>colon cancer and non-small cell lung cancer </li></ul></ul><ul><li>Bevacizumab </li></ul><ul><ul><li>colon cancer, breast cancer, non-small cell lung cancer </li></ul></ul>
  6. 11. <ul><li>Targeted therapies for GC has emerged and several molecular targeting agents are being tested; </li></ul><ul><li>Anti-angiogenic agents </li></ul><ul><li>(EGFR) antagonists </li></ul><ul><li>Tyrosine kinase inhibitors (TKI) </li></ul><ul><li>Matrixmetalloproteinase (MMP) </li></ul>
  7. 12. <ul><li>Insulin-like growth factor-1 receptor </li></ul><ul><li>Fibroblast growth factor </li></ul><ul><li>c-Met and downstream signaling inhibitors </li></ul><ul><li>Cell cycle associated drugs </li></ul><ul><li>All these are under evaluation in phase I and II studies with advanced GC patients </li></ul>
  8. 13. <ul><li>So far, trastuzumab is the only targeted therapy that has a proven survival benefit in GC </li></ul><ul><li>The addition of trastuzumab to standard chemotherapy has helped patients with advanced gastric cancer to live longer (about 2.7 months) vs. patients who received chemotherapy alone. </li></ul>
  9. 14. <ul><li>This talk is an effort to inform you all about </li></ul><ul><li>The ToGA trial. </li></ul><ul><li>The emerging use of trastuzumab in gastric cancer. </li></ul><ul><li>Status of Her2 staining in gastric carcinoma. </li></ul><ul><li>The salient differences between breast and gastric cancer HER2 testing. </li></ul>
  10. 15. <ul><li>The first randomized, controlled phase III trial, (ToGA) evaluated trastuzumab efficacy and safety in HER2-positive advanced GC. </li></ul><ul><li>The largest data set of 3,883 advanced GC samples, found HER2-positivity rates of 22.9%; immunohistochemical (IHC) and </li></ul><ul><li>fluorescence in situ hybridization (FISH) concordance was 87.3%. </li></ul>
  11. 16. <ul><li>HER2-positivity was higher in intestinal than diffuse/mixed cancer </li></ul><ul><li>32.2(intestinal) vs. 6.1%(diffuse);20.4%(mixed); </li></ul><ul><li>p<0.001 </li></ul><ul><li>Positivity in gastro-esophageal junction </li></ul><ul><li>cancers was higher than GC </li></ul><ul><li>33.2(gastro-esophageal) vs. </li></ul><ul><li>20.9%(GC); </li></ul><ul><li>p<0.001 </li></ul>
  12. 17. <ul><li>Preliminary results showed better median survival with the addition of trastuzamab vs. chemotherapy alone </li></ul><ul><li>13.8 vs. 11.1 month </li></ul><ul><li>p=0.0048; </li></ul><ul><li>26% reduction in risk of death. </li></ul><ul><li>PFS was 6.7 vs. 5.5 months </li></ul><ul><li>(p=0.002) </li></ul><ul><li>Disease control (DC) </li></ul><ul><li>47.3% vs. 34.5% </li></ul><ul><li>(p=0.0017) </li></ul>
  13. 18. <ul><li>The advantage of IHC is that the method is inexpensive in terms of reagents and equipment. </li></ul><ul><li>Discussions about the accuracy of the test results are still ongoing due to the fact that IHC produces inconsistent results in breast cancer. </li></ul>
  14. 19. <ul><li>Predominant External Factors Influencing HER2 IHC Results: </li></ul><ul><li>1. Fixative </li></ul><ul><li>2. Fixation duration </li></ul><ul><li>3. Tissue slide thickness </li></ul><ul><li>4. Time between section preparation </li></ul><ul><li>and staining </li></ul><ul><li>5. Antibody retrieval method </li></ul><ul><li>6. Antibody type </li></ul><ul><li>7. Antibody dilution </li></ul><ul><li>8. Incubation temperature </li></ul><ul><li>9. Incubation time </li></ul><ul><li>10. Antibody detection system </li></ul><ul><li>11. Use of autostainer </li></ul><ul><li>12. Scoring system </li></ul><ul><li>13. Training of pathologist </li></ul><ul><li>14. Use of HER2 IHC analysis software </li></ul>
  15. 21. <ul><li>Pattern Score/Classification </li></ul><ul><li>RESECTION SPECIMENS </li></ul><ul><li>-No reactivity or membranous reactivity in <10% of cells 0/negative (No drug) </li></ul><ul><li>-Faint/barely perceptible membranous reactivity in >10% 1+/ negative ( No drug) </li></ul><ul><li>of cells; cells are reactive only in part of their membrane </li></ul><ul><li>-Weak to moderate complete or basolateral 2+/equivocal (ISH) </li></ul><ul><li>reactivity in >10% of cells </li></ul><ul><li>-Moderate to strong complete or basolateral membranous 3+/ positive (Drug) </li></ul><ul><li>reactivity in >10% of cells </li></ul>
  16. 22. <ul><li>Pattern Score/Classification </li></ul><ul><li>SMALL BIOPSIES. </li></ul><ul><li>-Biopsy samples with cohesive IHC3+ or FISH+ clones 3+/ positive (Drug) </li></ul><ul><li>irrespective of size (even if <10%) </li></ul>
  17. 23. <ul><li>If the specimen shows IHC 0 or IHC 1+ results, a patient will not receive trastuzumab. </li></ul><ul><li>If the specimen is scored 3+, the patient is eligible for trastuzumab therapy. </li></ul><ul><li>A score of 2+ is considered as equivocal and should be subject to ISH analysis. </li></ul>
  18. 24. <ul><li>HER2 testing in gastric cancer is generally similar to HER2 analysis in breast cancer, with some slight interpretative differences. </li></ul><ul><li>There are a no of pathologists worldwide who are familiar with Her2 testing in breast ca, but not in gastric Ca. </li></ul><ul><li>There is a danger that pathologists may use breast cancer scoring criteria on gastric samples that may lead to underestimation of positive cases. </li></ul><ul><li>Basolateral or lateral (GC) as compared to complete membranous (breast) staining. </li></ul><ul><li>>10% cells (GC) vs. >30% cells (breast Ca) </li></ul><ul><li>In Situ cases. </li></ul><ul><li>Small biopsies Vs resection specimen. </li></ul>
  19. 30. <ul><li>Carcinomas of the stomach are heterogeneous group of lesions in terms of architecture, pattern of growth, cell </li></ul><ul><li>differentiation, and histogenesis... </li></ul>
  20. 33. <ul><li>The FISH cut-off ratio (HER2/CEP17) was kept at ≥2.0 (also standard for breast cancer in 2005) for the definition of HER2 gene amplification (assessed on 20 cells). Re-assessment of FISH results with 40 cells in the range of 1.8 to 2.2 is recommended. </li></ul>
  21. 34. <ul><li>Predominant External Factors Influencing HER2 FISH Results: </li></ul><ul><li>1. Fixative </li></ul><ul><li>2. Fixation duration </li></ul><ul><li>3. Tissue slide thickness </li></ul><ul><li>4. Time between probe hybridization and analysis (due to signal bleaching) </li></ul><ul><li>5. Scoring system (including the amount of counted cells) </li></ul><ul><li>6. Training of pathologist / use of technician for counting </li></ul><ul><li>7. Use of HER2 FISH analysis software </li></ul>
  22. 37. <ul><li>“ Since trastuzumab in combination with chemotherapy is becoming the standard of care in gastric cancer, appropriate patient selection by HER2 IHC and ISH testing will now be part of routine pathology.” </li></ul><ul><li>The application of HER2 testing methods and guidelines in gastric cancer will benefit the patients. </li></ul>
  23. 38. <ul><li>The aim of future HER2 testing in gastric </li></ul><ul><li>cancer will be the standardization of IHC and </li></ul><ul><li>FISH testing. </li></ul><ul><li>Further investigation are required to evaluate trastuzumab’s efficacy for advanced GC as monotherapy </li></ul>
  24. 39. <ul><li>Maintenance treatment after doublet or </li></ul><ul><li>triplet regimens </li></ul><ul><li>In combination with second line therapy </li></ul><ul><li>In curative treatment trials for GC </li></ul><ul><li>patients, such as peri-operative or post operative therapy. </li></ul>