Moving Toward Personalized Treatment for Gastric Cancer:
Role of HER2 Testing
Frédérique Penault-Llorca, MD, PhDProfessor of Pathology
Centre Jean Perrin Université d'Auvergne Clermont
Clermont-Ferrand, France
HER2 Testing in Gastric Cancer: Common Characteristics and Unique Features
HER2 testing algorithm
Tissue collection Tissue morphology
Turn-around time Scoring criteria
• Multiple biopsies (6–8) recommended
• Representative samples of surgical specimens
HER2 = human epidermal growth factor receptor 2
The Need for Multiple Biopsies
Images property of Frédérique Penault-Llorca, MD, PhD.
HER2 testing algorithm
Tissue collection Tissue morphology
Turn-around time Scoring criteria
• Multiple biopsies (6–8) recommended
• Representative samples of surgical specimens
• High level of tumor heterogeneity (small HER2-positive foci)
• Screening of the entire specimen required for FISH
FISH = fluorescence in situ hybridization
HER2 Testing in Gastric Cancer: Common Characteristics and Unique Features
Tumor Heterogeneity
Images property of Frédérique Penault-Llorca, MD, PhD.
Complete, Basolateral or Lateral Membranous Staining• HER2-positive gastric and
gastroesophageal junction tumors may show complete, basolateral, or lateral membranous staining
• Basolateral/lateral staining occurs due to the structure of low-grade gastric adenocarcinoma cells
Hofmann M et al. Histopathology. 2008;52:797-805.
Image property of Frédérique Penault-Llorca, MD, PhD.
HER2 testing algorithm
Tissue collection Tissue morphology
Turn-around time Scoring criteria
• Multiple biopsies (6–8) recommended
• Representative samples of surgical specimens
• High level of tumor heterogeneity (small HER2-positive foci)
• Screening of the entire specimen required for FISH
• Similar to breast cancer• Primary IHC testing• HER2-positive: IHC 3+ or
IHC 2+/FISH+ • Bright-field methodologies
preferred
HER2 Testing in Gastric Cancer: Common Characteristics and Unique Features
IHC = immunohistochemistry
0
FISH
+– Eligible for trastuzumab
1+ 2+ 3+
IHC
Patient tumor sample
Recommended HER2 Testing Algorithm in Metastatic Gastric and Gastroesophageal Junction Cancer
Trastuzumab EU SmPC: http://www.ema.europa.eu/humandocs/PDFs/EPAR/Herceptin/emea-combined-h278en.pdf.
HER2-Positivity Rate in Advanced Gastric Cancer
EMA licensed population
(IHC 2+/FISH+ or IHC 3+)
Exploratory analysisToGA population
Eligiblefor ToGA
(IHC 3+ and/orFISH+)
78%
22%
78%
16%
Not eligiblefor ToGA
Not eligiblefor ToGA
IHC 0/FISH+ orIHC 1+/FISH+
6%
Chung H et al. Eur J Cancer Suppl. 2 009; 7:364.
HER2 Testing in Gastric Cancer: Common Characteristics and Unique Features
HER2 testing algorithm
Tissue collection Tissue morphology
Turn-around time Scoring criteria
• Multiple biopsies (6–8) recommended
• Representative samples of surgical specimens
• High level of tumor heterogeneity (small HER2-positive foci)
• Screening of the entire specimen required for FISH • Similar to breast cancer
• Primary IHC testing• HER2-positive: IHC 3+
or IHC 2+/FISH+ • Bright-field methodologies
preferred
• Strong basolateral, lateral or complete membrane staining in ≥10% of tumor cells is considered positive (IHC)
• No percentage cut-off for biopsies
HER2 Scoring Criteria in Gastric Cancer
Surgical specimenstaining pattern
Biopsy specimenstaining pattern Score Assessment
No reactivity ormembranous reactivity in
< 10% of tumor cells
No reactivity or no membranous reactivity
in any tumor cell0 Negative
Faint ⁄ barely perceptiblemembranous reactivityin ≥ 10% of tumor cells;cells are reactive only inpart of their membrane
Tumor cell cluster with a faint ⁄ barely perceptible membranous reactivity
irrespective of percentage of tumor cells stained
1+ Negative
Weak to moderatecomplete basolateral or
lateral membranousreactivity in ≥ 10% of tumor
cells
Tumor cell cluster with a weak to moderate complete basolateral or lateral
membranous reactivity irrespective of percentage of tumor cells stained
2+ Equivocal
Strong, completebasolateral or lateral
membranous reactivity in≥ 10% of tumor cells
Tumor cell cluster with a strong, complete basolateral or
lateral membranous reactivity irrespective of percentage of
tumor cells stained
3+ Positive
Trastuzumab EU SmPC: http://www.ema.europa.eu/humandocs/PDFs/EPAR/Herceptin/emea-combined-h278en.pdf.
HER2 Testing in Gastric Cancer: Common Characteristics and Unique Features
HER2 testing algorithm
Tissue collection Tissue morphology
Turn-around time Scoring criteria
• Multiple biopsies (6–8) recommended
• Representative samples of surgical specimens
• High level of tumor heterogeneity (small HER2-positive foci)
• Screening of the entire specimen required for FISH • Similar to breast cancer
• Primary IHC testing• HER2-positive: IHC 3+
or IHC 2+/FISH+ • Bright-field methodologies
preferred
• Strong basolateral, lateral or complete membrane staining in ≥10% of tumor cells is considered positive (IHC)
• No percentage cut-off for biopsies
• Turn-around times should not exceed 5 working days (metastatic gastric cancer progresses very quickly)
• Need for a multidisciplinary approach
Patient
Medical technician
Oncologist/Gastroenterologist
Pathologist Surgeon/Endoscopist
Tissue removal, orientation & storage
until collection
Sample processingTest methodology
Test interpretation and reporting
Request appropriate tests & arrange sample
collection
Successful HER2 Testing Requires a Multidisciplinary Approach
HER2 Testing in Gastric Cancer: Conclusions• All patients with gastric cancer should be tested for
HER2
• Patients with HER2-positive metastatic gastric cancer are eligible to receive trastuzumab
• Testing should be performed by experienced pathologists
• Quality assurance/control procedures should be followed to ensure quality of HER2 testing