Evaluating HER2 in Gastroesophageal Cancer

For physicians, questions about when to deploy HER2-targeted therapy for patients with advanced gastroesophageal adenocarcinoma (GEA) are getting answered with the publication of the first evidence-based guideline for HER2 testing in this cancer.

In patients with HER2-positive advanced GEA, trastuzumab (Herceptin; Roche) has been shown to modestly improve overall survival when added to standard combination chemotherapy. Currently, HER2 is the only validated biomarker for selecting patients with GEA who may benefit from targeted therapy.

Until now, however, pathologists have had no generally accepted standards for testing HER2 in these tumors. Benchmarks developed for breast cancer over the last decade do not translate to GEA, where HER2 expression is much more variable and it is rare to find complete membrane staining, a criterion for HER2 positivity in breast cancer.

To create the new guideline, a panel convened by the College of American Pathologists, the American Society for Clinical Pathology, and the American Society of Clinical Oncology systematically reviewed more than 900 publications related to GEA treatment. The panel also relied on consensus and expert opinion to craft the guideline's 11 recommendations.

One key recommendation: Physicians should evaluate HER2 status in all newly diagnosed patients with advanced GEA who are healthy enough for targeted therapy, and offer combination chemotherapy plus a HER2-targeted agent to those with positive results. Testing should be done in a timely manner—preferably within 10 days—and in the meantime patients should start chemotherapy.

The guideline also includes detailed HER2 testing procedures, covering everything from tissue collection and processing to scoring, reporting, and assay validation. Immunohistochemistry (IHC) is the recommended first step, followed by in situ hybridization if IHC results are equivocal. Although many antibodies and probes are available, the panel did not recommend a specific reagent, but called for proper validation of any test. The panel found insufficient evidence to recommend for or against any type of genomic testing.

Panel co-chair Jaffer Ajani, MD, a medical oncologist at The University of Texas MD Anderson Cancer Center in Houston, notes that although the guideline calls for testing just one tumor specimen, GEA is notoriously heterogeneous. If that specimen is negative, should additional samples be assessed, and how many are needed for HER2 status clarity? “There are no data” addressing this issue, says Ajani, “so we need good prospective studies.”

Overall, the recommendations “are in keeping with current clinical practice and will certainly help pathologists understand the differences between breast cancer and GEA” with respect to HER2, says Ronan Kelly, MD, MBA, director of the Johns Hopkins Gastroesophageal Cancer Therapeutics program in Baltimore, MD.

Charles Fuchs, MD, MPH, of Dana-Farber Cancer Institute in Boston, MA, says that the guideline is “right on,” and “its greater value is that HER2 testing is described in detail, so we can proceed in a common fashion to advance this science into the clinic.”

Ajani would like to see the guideline go global. “This is not just for members of the three societies. We want everyone to start using these recommendations—they're comprehensive and thoughtfully generated, and are a plus for patients.” –Pat McCaffrey