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