Inaccurate lab reports put breast cancer patients at risk

Studies show that thousands of women may be receiving the wrong breast cancer treatment because of faulty laboratory reports. More disturbing, this trend was identified years ago. A 2006 study led by Genentech found 14% to 16% of HER2 tests were false positive and 18% to 23% were false negative.

"We all make the assumption that every test is done well. It turns out it's not a correct assumption," commented Lee Newcomer, MD, senior vice president of UnitedHealthcare (UHC).

Large payer tackles problem

A pilot study conducted by UHC found that 12% of their breast cancer patients receiving trastuzumab (Herceptin) did not overexpress HER2. The researchers examined the actual pathology reports and found that many were inaccurate and lacked quantitative results.

"We found that simple human error accounted for this problem; physicians don't willfully disregard the results of tests," Dr. Newcomer said.

He added that UHC now prevents inappropriate therapy by reviewing HER2 test results "as a requirement for coverage beyond the first dose." He added that UHC covers repeat tests.

Dr. Newcomer noted that the quality of pathology interpretation is determined largely by the technical components and experience of the facility.

"Low-volume laboratories seem to have more inaccuracies. This is documented in the references to the ASCO/CAP guideline," he said. [The guideline was published in the Journal of Clinical Oncology (25:118-145, 2007) and is discussed below.]

The first step

The first step to address this problem, Dr. Newcomer said, is to require public reporting of labs that pass quality proficiency standards for these specific tests.

"I would prefer to reimburse only those facilities that meet quality standards. We also need more awareness by clinicians; they should demand that the labs meet the highest level of quality testing, and only refer their specimens to labs that have established quality standards," Dr. Newcomer said.

ASCO recommendations

In response to reports of false test results, ASCO and the College of American Pathologists (CAP) convened a panel of experts to conduct a systematic review of the literature and develop recommendations for optimal HER2 testing.

The board of directors from both organizations reviewed the findings, concluding that approximately 20% of current HER2 tests may be inaccurate.

The panel recommended that HER2 testing be conducted in laboratories that have been accredited by CAP, meeting the proficiency standards set out by the ASCO/CAP guideline (www.asco.org/guidelines/her2).

Faulty test results have caught the attention of lawmakers on Capitol Hill before. In the wake of reports of inaccurate Pap smears, Congress enacted the Clinical Laboratory Improvement Amendments (CLIA) of 1988 to ensure accuracy of laboratory testing. One problem, however, is that our regulatory system doesn't keep pace with scientific innovations such as HER2 testing.

Under current CLIA law, laboratories must pass outside proficiency checks on 83 types of tests from a list devised back in 1992 that does not include hormone-receptor or HER2 tests for breast cancer patients.

In a public statement, Barry M. Straube, MD, chief medical officer, Centers for Medicare & Medicaid Services (CMS), said the agency was considering adding additional tests to its proficiency-standard list and the breast cancer tests in question were likely candidates.

A recent report from the Institute of Medicine, entitled Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment—strongly recommended that CMS develop a specialty area for molecular diagnostics under CLIA.

Federal lawmakers are contemplating increasing oversight for laboratory-developed tests.

Senators Edward Kennedy (D-Mass) and Barack Obama (D-Ill) have introduced bipartisan legislation that renews a call for CMS to establish a molecular testing specialty area, similar to that outlined in the IOM report.

Slide-based assays

In a recent article in Clinical Cancer Research (13:2831-2835, 2007), Jeffrey S. Ross, MD, chair of pathology and laboratory medicine, Albany Medical College, and his associates analyzed the problems associated with slide-based assays that contribute to the unacceptably high false-negative and false-positive rates in HER2 testing. Dr. Ross told ONI that in order for these slide-based breast cancer tests to achieve higher reliability, the tissue removed from the patient must be treated in a specific standardized manner before the actual laboratory procedure is performed.

"This is how we currently treat blood samples: They are placed in tubes preloaded with preservatives specifically selected for the tests that will be done," Dr. Ross said.

An important approach to prevent false-negative immunohistochemical staining for ER/PR and HER2, he said, is to place the positive control tissue on the same slide as the section of the tumor from the new patient. If the control tissue does not stain as expected, the slide should be discarded and the staining repeated.

"Absence of the positive control tissue on the same slide as the patient's tissue is a major cause for false-negative results," Dr. Ross said.

A patient's story

The human side of this issue was recently captured in a Wall Street Journal article (January 4, 2008) that highlighted the case history of a woman who was first diagnosed with breast cancer in 2002. At that time, she was tested for HER2 expression and ER/PR status. The local laboratory reported both tests as negative and she was treated accordingly.

In 2007, she was diagnosed with recurrent breast cancer, which had metastasized to the bone. The sample of her original tumor was retested and found to be ER positive; the first pathology report had been inaccurate.

Her current physician, Charles L. Vogel, MD, of Aptium Oncology, Lynn Cancer Institute West, Boca Raton, Florida, said that prescribing tamoxifen after her original diagnosis might have prevented her cancer from recurring.

More oversight

Speaking to Oncology News International, Dr. Vogel emphasized that the central problem is that every laboratory uses a different method and different criteria to call a case positive.

He pointed out that the laboratory tests in themselves are fine, "but we need more oversight and much stricter guidelines."

When asked if this issue is a concern in his daily management of women with breast cancer, he replied, "Of course, how couldn't it be?"