First comprehensive guideline released for the assessment of HER2 in patients with GEA

A new, evidence-based clinical practice guideline on human epidermal growth factor receptor 2 (HER2) testing for patients with gastroesophageal cancers has been released by the College of American Pathologists (CAP), the American Society for Clinical Pathology (ASCP), and the American Society of Clinical Oncology (ASCO).

Gastric and esophageal cancers are common malignancies worldwide, and they frequently present at advanced stages when therapies are limited. In 2010, results of an open-label, international, phase 3 randomized controlled trial (Trastuzumab for Gastric Cancer, ToGA), showed that the anti-HER2 humanized monoclonal antibody trastuzumab (Herceptin) statistically significantly prolonged overall survival compared with chemotherapy alone in patients with HER2–positive advanced gastroesophageal (GEA) adenocarcinomas.

This new guideline provides evidence-based recommendations specific for HER2 testing in GEA, to improve determination of patient eligibility for HER2-targeted therapy. The ASCO/CAP guidelines for breast cancer do not apply to HER2 IHC as performed on gastric cancer; accordingly, a guideline specific for GEA is needed.

Potential candidates

The guideline provides recommendations about appropriate HER2 testing for patients at key decision points throughout their cancer therapy to determine if they are eligible for targeted therapy. Potential candidates for HER2 testing are patients with advanced or metastatic GEA, who have a good performance status, low cardiac risk, and would otherwise be candidates for systemic therapy. If the patient would be unable to tolerate trastuzumab due to low performance status or comorbidities, then HER2 testing is not indicated.

With the establishment of HER2 testing as a standard of care for patients with advanced GEA, it is important to note that the treating clinician should not offer HER2-targeted therapy until HER2 positivity is confirmed. Since patients with advanced GEA can be symptomatic, it is recommended to start combination cytotoxic therapy as soon as feasible while waiting for the establishment of HER2 status. Once it is determined that GEA is HER2-positive, trastuzumab can be added to the chemotherapy combination. There is no documented benefit for starting HER2-directed treatment in the absence of confirmed HER2 positivity, and there is an added potential for the patient to incur unnecessary side effects or costs.

Why doesn’t the guideline recommend reflex testing for HER2 for all GEA cases? Available evidence does not support the determination of HER2 status in patients who have a surgically resectable GEA, and HER2 status is not useful to prognosticate survival or similar endpoints. However, for patients with locally advanced or metastatic GEA with a good performance status and low cardiac risk, and who would otherwise be candidates for systemic therapy including trastuzumab, HER2 testing should be performed and patients should be offered trastuzumab if their GEA is HER2-positive. Currently, there is no evidence of benefit of HER2-directed therapy in patients with GEA that is not at an advanced stage.

Selecting the tissue

Which tumor tissue should be used for HER2 testing? Given the issue of intratumoral heterogeneity in GEA specimens, a block containing multiple biopsy fragments (from a primary or metastatic site) or from the resected primary tumor is preferred to minimize sampling issues. If biopsies or surgical resection blocks are not available, testing a cytology specimen from an FNA cell block is acceptable. However, the specimens obtained in cytology specimens may not be truly representative, given the limited sampling of the tumor. In general, the pathologist should select the tissue block with the areas of lowest grade tumor morphology in biopsy and resection specimens. More than one tissue block may be selected if different morphologic patterns are present. HER2 overexpression is strongly associated with intestinal phenotype, and less frequently with diffuse (signet ring cell)
phenotype of GEA.

Although some institutions perform HER2 immunohistochemistry (IHC) and in situ hybridization (ISH) on all GEA specimens, the guideline does not recommend that. Available data indicate that HER2 amplification (ISH-positivity) alone does not correlate with response to trastuzumab therapy in GEA, but that the benefit from the addition of HER2-directed therapy correlates with HER2 protein expression as determined by IHC. Specifically, the ToGA trial demonstrated that the combination of trastuzumab plus chemotherapy significantly improved survival in patients with tumors showing high HER2 expression, defined as 3+ by IHC, or 2+ by IHC with HER2 amplification by fluorescent in situ hybridization (FISH). Accordingly, testing with IHC first, followed by ISH for cases showing 2+ HER2 expression, is a cost-effective method for determining eligibility for anti-HER2 therapy.

The guideline addresses the issue of tumor heterogeneity. For biopsy specimens, current recommendations state that, when possible, a minimum of five, and optimally six to eight, biopsies should be obtained to account for intratumoral heterogeneity and to provide sufficient tumor specimens for diagnosis and biomarker testing, and is also recommended by the National Comprehensive Cancer Network (NCCN) Guidelines.

Implementing the testing

Many laboratories implementing HER2 testing for GEA will already have a process for testing breast cancers in place, but pathologists may need to communicate with gastroenterology colleagues to ensure prompt fixation and documentation for biopsy specimens.

Full validation of the HER2 testing protocol should be performed for formalin-fixed, paraffin-embedded biopsy and resection specimens. For FDA-approved tests, use of 20 positive and 20 negative specimens is recommended, and for laboratory developed tests, 40 of each. While an HER2-expressing breast specimen may be initially used as the positive control, validation of actual GEA specimens is preferred, although breast carcinomas may be used if adequate numbers of GEA cases are not available. Because of potential differences in the handling and processing of cytologic preparations, appropriate evaluation of HER2 staining of cytologic specimens before testing and reporting patient sample is recommended.

Technical aspects of testing procedures for GEA and breast carcinoma are identical, but there are important differences in interpretation of IHC results between the two tumor types. The Ruschoff-Hofman scoring system used in the ToGA trial should be used for scoring HER2 IHC in GEA. Similar to breast cancer, only membranous staining, but not cytoplasmic staining, is considered for HER2 scoring; but unlike breast carcinoma, complete membranous staining is not required for positivity in GEA. Often the luminal surface of tumor cells fails to stain in HER2-amplified GEA. Only luminal surface staining in the absence of lateral and basal staining is considered negative. Assessment of IHC as weak, moderate, or strong for scoring is similar to that used for breast carcinoma. Assessment of gene amplification by ISH techniques is the same for both GEA and breast carcinoma.

Mary Kay Washington, MD, PhD, FASCP, is a pathologist at Vanderbilt University Medical Center, Nashville, TN. She represented the American Society for Clinical Pathology (ASCP) as one of the three organizational co-chairs of the international panel of pathology and oncology experts who developed the guideline.