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New ASCO/CAP HER2 Assay Guidelines May Mollify Critics Of Homebrew Tests

A new set of HER2 testing guidelines formulated by the American Society of Clinical Oncology and the College of American Pathologists may ease the concerns of those who feel that laboratory-developed tests are under-regulated.
In the guidelines, an expert panel convened by ASCO and CAP found that “as many as 15 percent to 20 percent of the HER2 assays performed in the field may be incorrect when the same specimen was reevaluated in a high-volume, central laboratory.”
To remedy this, the panel recommends that labs develop a testing algorithm to define numerical markers for a positive, negative, and equivocal HER2 result; validate assays using standardized procedures; and conduct HER2 testing in CAP-accredited labs.
Because the guidelines were crafted by medical organizations and are non-binding, they represent a way for the molecular diagnostics industry to regulate certain lab-made tests on its own.
The guidelines, published in the January issues of the Journal of Clinical Oncology and the Archives of Pathology and Laboratory and Medicine, come as the US Food and Drug Administration is considering strengthening its oversight over a complex subset of homebrew tests called in vitro diagnostic multivariate index assays, or IVDMIAs [see PGx Reporter 02-14-07].
During a recent FDA-sponsored public meeting on the regulation of IVDMIAs, presenters pointed to inconsistent results between labs performing HER2 testing to press for the FDA to regulate all laboratory-developed tests, not just IVDMIAs.
“Unfortunately recent studies indicate there are still problems … with accurate … HER2 assays,” Helen Schiff, a member of the Breast Cancer Advocate Group and a patient consultant for the FDA, said at the meeting. “For example, the cut point for ER positivity varies from lab to lab, from 1 percent to 25 percent of cells with estrogen receptor.”
A systematic review of the literature by the ASCO/CAP panel found that “when carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry or in situ hybridization as a predictor of benefit from anti-HER2 therapy.”
In the area of Her2 positive breast cancer, Dako’s HercepTest currently leads the market. Competitors include Oncor’s Inform HER-2/neu gene detection system, PathVision’s HER-2 DNA probe kits, and possibly Monogram’s dimerization assay [see PGx Reporter 12-06-06]. Oncor and PathVision’s products are based on fluorescence in situ hybridization detection of the HER-2/neu gene. Both tests, along with Dako’s product, have been approved by the FDA.
However, FDA approval doesn’t necessarily vouch for these tests’ performance, according to the panel. While both FDA-approved and homebrew HER2 tests are available on the market, “analysis of prospective randomized adjuvant trials of trastuzumab [Herceptin] illustrated that testing algorithms for HER2 had not been standardized and were developed somewhat arbitrarily,” the panel said.
In its guidelines, ASCO and CAP “strongly recommended” that laboratories validate assays, use standardized operating procedures, comply with new testing criteria to be “monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment.”

An analysis of prospective, randomized adjuvant trials of Herceptin showed that “testing algorithms for HER2 had not been standardized and were developed somewhat arbitrarily.”

The panel further recommends that HER2 testing be done in a CAP-accredited laboratory or that labs show 95-percent concordance with another validated test for positive and negative assay values, as well as participate in external proficiency testing.
The panel outlined algorithms defining positive, equivocal, and negative values. A positive HER2 result must have an IHC staining of 3+ and a FISH ratio of 2.2; a negative result should have an IHC staining of ‘0’ or 1+ and a FISH ratio of less than 1.8. “Equivocal results require additional action for final determination,” the panel states.
The ASCO/CAP guidelines were reviewed by experts in the field of clinical medicine, pathology, and health services research and approved by the board of directors of both ASCO and CAP. The expert panel searched databases for literature and reviewed abstracts presented at ASCO and CAP conferences between 2000 and 2005 and at the San Antonio Breast Cancer Symposium between 2003 and 2005.
The panel justified the need for accurate HER2 testing through a cost-benefit analysis of Herceptin therapy, which can range from $70,000 to $110,000 for 12 months of treatment. In clinical trials, treatment with Herceptin has been associated with cardiac dysfunction in 5 percent to 15 percent of patients, and with symptomatic congestive heart failure in 2 percent to 4 percent of patients.
“The ASCO/CAP Expert Panel found that HER2 testing inaccuracies, coupled with trastuzumab costs and associate cardiac toxicity, demand accurate HER2 testing.”
Following the release of the ASCO/CAP guidelines, Clarient, a company that performs molecular breast cancer tests, issued a statement on Feb. 15 saying that its HER-2 testing practices meet or exceed ASCO and CAP’s guidelines.
“The guidelines state that the assay equipment used for image analysis must be calibrated. Clarient’s [Automated Cellular Imaging System] is the only system currently on the market that provides a true calibration function,” the company said.
The “ACIS ensures that the digital image is obtained in a reproducible manner from day to day and instrument to instrument,” Clarient said. “In comparison, many other systems rely on the human eye.”
It was not immediately clear how these guidelines will impact diagnostics shops and if the cost of compliance will be steep for smaller companies.
At the FDA’s IVDMIA public meeting, many industry stakeholders complained that increased regulatory hurdles from FDA needed to be balanced with greater incentives to encourage innovation in the diagnostics industry [see PGx Reporter 02-14-07].

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