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Epidemiologia, anatomia patologica e storia naturale del tumore gastrico

Epidemiologia, anatomia patologica e storia naturale del tumore gastrico. Beppe Viale – IEO & UNIMI. HER2-positive gastric cancer. HER2-positive gastric cancer. HER2 status & clinico-pathological correlates. HER2 testing: gastric cancer versus breast cancer.

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Epidemiologia, anatomia patologica e storia naturale del tumore gastrico

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  1. Epidemiologia, anatomia patologica e storia naturale del tumore gastrico Beppe Viale – IEO & UNIMI

  2. HER2-positive gastric cancer

  3. HER2-positive gastric cancer

  4. HER2 status & clinico-pathological correlates

  5. HER2 testing:gastric cancer versus breast cancer

  6. Tumour heterogeneity is more common in gastric cancer Signet ring type Intestinal (gland forming) type High amplification No amplification

  7. Intra-tumoral & intra-glandular heterogeneity

  8. Heterogeneous gene amplification

  9. Tumore misto

  10. Tumore misto

  11. Heterogeneous gene amplification

  12. Heterogeneous gene amplification

  13. Gastric Biopsies (6 recommended)

  14. Tumour cells with incomplete (basolateral) membrane staining

  15. ToGA trial designPhase III, randomised, open-label, international, multicentre study Capecitabinecor 5-FU + cisplatin (n=290) 3807 patients screeneda 810 HER2 positive HER2-positiveadvanced GC (n=584b) R Capecitabinec or5-FU + cisplatin + trastuzumab (n=294) aScreening algorithm different from that used in breast cancer;b594 patients randomised, 10 patients never received treatment; cChosen at investigator’s discretion

  16. Overall survival by HER2 status Median OS (months) HR 95% CI N Subgroup All 584 11.1 vs 13.8 0.74 0.60, 0.91 Pre-planned analysis IHC 0 / FISH+ IHC 1+ / FISH+ IHC 2+ / FISH+ IHC 3+ / FISH+ IHC 3+ / FISH– 61 70 159 256 15 7.2 vs 10.6 10.2 vs 8.7 10.8 vs 12.3 12.3 vs 17.9 17.7 vs 17.5 0.92 1.24 0.75 0.58 0.83 0.48, 1.76 0.70, 2.20 0.51, 1.11 0.41, 0.81 0.20, 3.38 Exploratory analysis IHC 0 or 1+ / FISH+ IHC 2+ / FISH+ or IHC 3+ 131 446 8.7 vs 10.0 11.8 vs 16.0 1.07 0.65 0.70, 1.62 0.51, 0.83 0.2 0.4 0.6 1 2 3 4 5 Favours T Risk ratio Favours no T Interaction of treatment effect with HER2 result in exploratory analysis, p=0.0368 van Cutsem E, et al. J ClinOncol 2009; 27:Abstract 4509.

  17. Suggested HER2 testing algorithm in GC/GEJ cancer Patient tumour sample IHC 0 +1 +3 +2 retest FISH/SISH* – + Eligible for trastuzumab *cut off for FISH, SISH = HER2:CEP17 ratio ≥2

  18. Overall survival by HER2 status Median OS (months) HR 95% CI N Subgroup All 584 11.1 vs 13.8 0.74 0.60, 0.91 Pre-planned analysis IHC 0 / FISH+ IHC 1+ / FISH+ IHC 2+ / FISH+ IHC 3+ / FISH+ IHC 3+ / FISH– 61 70 159 256 15 7.2 vs 10.6 10.2 vs 8.7 10.8 vs 12.3 12.3 vs 17.9 17.7 vs 17.5 0.92 1.24 0.75 0.58 0.83 0.48, 1.76 0.70, 2.20 0.51, 1.11 0.41, 0.81 0.20, 3.38 Exploratory analysis IHC 0 or 1+ / FISH+ IHC 2+ / FISH+ or IHC 3+ 131 446 8.7 vs 10.0 11.8 vs 16.0 1.07 0.65 0.70, 1.62 0.51, 0.83 0.2 0.4 0.6 1 2 3 4 5 Favours T Risk ratio Favours no T Interaction of treatment effect with HER2 result in exploratory analysis, p=0.0368 van Cutsem E, et al. J ClinOncol 2009; 27:Abstract 4509.

  19. HER2 testing in gastric cancer:best practice

  20. All stomach or GE junction tumour samples should be accurately tested for HER2 status HER2 status should be assessed routinely by primary IHC1 Patients whose tumours score IHC 3+ are eligible for trastuzumab Samples with an equivocal IHC 2+ score should be retested using ISH to confirm HER2 positivity Patients whose tumours score IHC 2+/FISH+ are eligible for trastuzumab HER2 testing should be performed by laboratories with demonstrated proficiency HER2 testing in gastric cancer 1. Hofmann M, et al. Histopathology 2008; 52:797–805.

  21. Unresectable gastric or GE junction cancer Surgical specimens or biopsy samples are acceptable for HER2 testing Initial tissue processing Transport tissue to laboratory promptly(within 20–30 min) Specimen is inked, cut and fixed in the laboratory Tissue collection

  22. Tissue fixation • Poor tissue fixation is the most common source of error in HER2 testing • Place tissue in fixative as soon as possible (within 20 min) • Duration of fixation • Surgically excised samples: 6–48 h (but at least 1 h/1 mm tissue) • Biopsy samples: no longer than 24 h (but at least 1 h/1 mm tissue) • Type of fixative • 10% neutral-buffered formalin is preferred • Fresh formalin (replace formalin regularly) • Other fixatives must be validated to obtain reliable results • IHC and ISH testing can be hampered by the use ofnon-formalin fixatives

  23. IHC/ISH testing Immunohistochemistry • HercepTest™ (Dako) • CONFIRM™ anti-HER2/neu (4B5, Ventana) In-situ hybridisation • HER2 FISH pharmDx™ (Dako) • INFORM™ HER2 SISH (Ventana) The following assays can be utilised, provided that the modified IHC scoring system according to Hofmann et al 20081 is strictly adhered to:

  24. Tissue samples are dehydrated in an ethanol/ xylene series and embedded in paraffin Prolonged incubation in molten paraffin should be avoided as high temperatures may degrade epitope Paraffin-embedded samples can be stored indefinitely prior to sectioning Use fresh paraffin Minimum size of paraffin block should be 1 cm2 to enable proper sectioning Paraffin embedding

  25. Sectioning Ideally, sections should be cut from the tissue block immediately prior to HER2 testing Sections must be cut from a representative area of the tumour Thickness of tissue sections can affect interpretation of results; ensure sections are cut to 2–4 μm Sections are mounted on slides and dried for 12–24 h at room temperature or 1 h at 60°C Dewaxing Ensure complete removal of paraffin; residual paraffin will cause false-negative assays and increase non-specific staining Sectioning and dewaxing

  26. IHC scoring criteria for gastric cancer IHC negative (0) No staining or membrane staining in <10% of cells IHC negative (1+) Faint/barely perceptible membrane staining in >10% of cells; cells only stained in part of membrane • IHC equivocal (2+) • Weak to moderate complete, basolateralor lateral • membrane staining in >10% of cells • Cohesive IHC2+ clones irrespective of size (>5 cells) • IHC positive (3+) • Strong complete, basolateral or lateralmembrane staining in >10% of cells in resection specimens or • Cohesive IHC 3+ clones irrespective of size in biopsy samples (>5 cells) Images courtesy of TARGOS

  27. Staining intensity & optical illusion

  28. Edge crushing artefacts Within tumour tissue Intestinal metaplasia, regenerative changes (near ulcerations) Within non-tumour tissue IHC: sample exclusion criteria HER2 IHC stained biopsy/surgical specimen Exclude poorly preserved tumour tissue Exclude non-specific staining Cytoplasmic, nuclear, only basal or luminal portion

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