College of American Pathologists
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Science, strategy pair off at HER2 conference

June 2001
Jacquelyn Lloyd

Dako’s HercepTest, used to predict response to Herceptin in breast cancer patients, may be the first such FDA-approved predictor of therapeutic efficacy, but it is unlikely to be the last, say Noel Weidner, MD, and Richard Zarbo, MD, DMD. How it’s used is going to set the stage for future similar tests.

"This is the paradigm," says Dr. Weidner. "It is the prototype for predictive testing. What happens with HER2/neu testing is likely to repeat itself."

Dr. Zarbo agrees. "We are seeing the proverbial tip of the iceberg," he declares. "This is just the start. We’re going to see many more ’smart’ immunotherapies directed toward specific aspects of cancer cells. The way we handle this one will almost certainly set a precedent for future tests that are tied to therapeutics."

HER2/neu testing may be today’s standard of care for metastatic breast cancer, but pathologists remain far from consensus on what test methods are most appropriate, effective, and reliably predictive. Controversies continue and questions abound.

Drs. Zarbo and Weidner and others will help pathologists sort through the HER2/neu maze at the CAP’s first Strategic Science program, "HER2/neu Testing of Breast Cancer Patients in Clinical Practice," to be held Sept. 15-16 in Chicago. Dr. Zarbo, interim chair of pathology at Henry Ford Hospital, Detroit, and professor of pathology at Case Western Reserve University, Cleveland, is program director of this Strategic Science program. Dr. Weidner, professor and director of anatomic pathology at the University of California San Diego, is the program’s scientific director.

For years, pathologists have been providing HER2/neu test results for prognostic and research purposes, and in recent years to help clinical oncologists qualify patients for Herceptin therapy. Why a conference now?

"HER2/neu testing is a natural because it’s an area that many of us in practice get questions about and have yet to resolve," says Dr. Zarbo. "This program is focused on answering many of the questions that are on people’s minds. When is HER2/neu testing clinically indicated? What is the most useful assay, and the most useful scoring method? What quality monitoring measures are needed? Is it necessary to use an FDA-approved test? What does it mean in terms of liability if you do your own in-house analyte-specific reagent test? What does it cost to do the various assays? What is the reimbursement? This is information you can’t glean from the literature."

With unanswered questions like these about HER2/neu methods, cost, liability, and quality monitoring, there is more than science for pathologists to contend with here. The CAP Strategic Science program promises to cover all the bases.

"There is no standard, no consensus out there on how we should or should not accomplish this testing," Dr. Weidner says. "Many laboratories-including my own-are using IHC assays they’ve developed in-house. The HercepTest was in agreement with the HER2/neu clinical trials assay in 79 percent, and the FDA decided that was enough. Thus, if another assay performs as well or better, when compared with the HER2/neu clinical trials assay, then that alternative test would be as good or better than the HercepTest."

Unfortunately, he adds, it is unlikely laboratories will be able to compare their own IHC assays for HER2/neu with the clinical trials assay. "We are left comparing to the HercepTest or to molecular assays-for example, FISH-for HER2/neu gene amplification, that is, if determinations of HER2/neu gene amplification correlate as well or better with patient outcomes, and recent data suggest this may be the case," he says.

The underlying question is, What does FDA approval mean for a predictive assay? Will FDA approved be interpreted legally as de facto required? What risks are associated with using more cost-effective home-brew tests? How can the pathologist balance concerns about cost and liability?

The September program will explore FDA’s involvement and pathologist liability from a number of practical perspectives. The FDA’s Steven Gutman, MD, of the Office of Device Evaluation, will talk about the agency’s approval of the Dako test. "Dr. Gutman also will address the issue of analyte-specific reagents and what is required to be able to use that ASR," Dr. Zarbo says. Attorney Jack Bierig of Sidley and Austin will discuss malpractice and the liability issues related to FDA regulation.

"This test is used in a different manner than the usual IHC test," Dr. Zarbo notes. "This test is one that will determine therapy, that will qualify patients for treatment. It’s novel, and there may be risks associated with not using FDA-approved tests. Pathologists need to know what those risks are."

The Strategic Science program will offer balanced views, too, on the hierarchy of testing. "The current non-consensus wisdom is that if you have a 1+ or 2+ result, you should confirm it with a FISH test," Dr. Weidner says. "But our goal is to treat patients. You want to use the test that’s going to predict the utility of the treatment in the patients. Some data suggest the FISH test is better at predicting which patients will respond to the drug. Should FISH testing be primary? What is the most efficient way to use it for confirmation? FISH is costly and difficult. People all over the country are going in their own directions."

The goal of the CAP HER2/neu program is to gather input on those various directions, Dr. Zarbo says. Kenneth Bloom, MD, associate attending pathologist at Rush-Presbyterian-St. Luke’s Medical Center in Chicago, will cover the controversies surrounding the two techniques, Dr. Zarbo says, "including recent advances, the major differences, the advantages and disadvantages of using FISH and IHC." Raymond Tubbs, DO, of the Cleveland Clinic, will talk about proficiency testing and quality assurance.

"This is not a scientific consensus conference," Dr. Zarbo cautions. "We are presenting the facts as they currently exist to help practicing pathologists decide whether they are sufficiently confident in the state of this art to do this procedure on their own-or whether they want to wash their hands of HER2/neu testing and send it out to a reference laboratory."

The program is broad-based, and the science is "only the starting point," Dr. Zarbo says. "We’ve wrapped this topic in everything that is germane to the practice of pathology—quality, cost, risk management, advocacy, policy—presented by 10 noted speakers." A leading oncologist will present the clinical perspective, and Genentech and Dako scientists will present industry’s view.

"The Strategic Science series is designed to get at the truth," Dr. Weidner says. "We expect a lot of discussion about the pros and cons of various approaches. We’re going to get all sides of this issue. This is a program that is designed to be very even-handed, to present a balanced view so that pathologists can learn what the risks are and how they can minimize those risks and make an informed decision about how they want to proceed with HER2/neu testing."

Jacquelyn Lloyd is a freelance writer in Park Ridge, Ill.