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Absent ‘Gold Standard’ for HER2 Testing, Researchers Question Role of Oncotype DX Beyond IHC/FISH

December 22, 2011

By Turna Ray

A recent study
challenging the accuracy of Genomic Health’s reporting of breast cancer patients’ HER2 status by an RT-PCR-based test has revived a longstanding debate about whether advanced diagnostic tools on the market today are truly an improvement over more established methods.

The study, published in the Journal of Clinical Oncology in October by researchers led by David Dabbs of the University of Pittsburgh Medical Center, tested the HER2 status of 843 patients across three labs by immunohistochemistry and fluorescence in situ hybridization and compared the results to HER2 status as assessed by Genomic Health’s RT-PCR-based Oncotype DX. The study authors reported that of the 36 cases deemed HER2-positive by standard FDA-cleared IHC/FISH testing, Oncotype DX determined only 10 patient samples as positive, 12 as “equivocal,” and 14 samples — or 39 percent of the patients who were previously thought to be HER2-positive by IHC/FISH — as HER2-negative.

Dabbs et al. concluded that HER2 reporting by Genomic Health’s assay had overall agreement of 98 percent with IHC/FISH testing, but deemed this number “meaningless” due to the large number of HER2-negative patients (93 percent) and the small number of HER2-positive patients in the study cohort. The researchers further found that positive agreement between Genomic Health’s test and IHC/FISH was less than 50 percent and concluded that Oncotype DX had an “unacceptable false-negative rate” when reporting HER2 status.

This is an assertion that Genomic Health contests. “We reviewed all the processes and the steps and the controls for these [14] cases,” Steve Shak, Genomic Health’s chief medical officer, told PGx Reporter. “We confirm that the HER2 cases in the report were reported accurately.” In its own validation studies for its HER2 assay, Genomic Health has shown 95 percent overall concordance between its test and IHC and 97 percent concordance between its test and FISH.

This discrepancy illustrates the challenge facing medical professionals as more personalized medicine products come to market. Industry observers estimate that molecular and genetic testing comprises a $7 billion market growing at between15 percent and 20 percent per year. However, the faster the molecular diagnostics industry grows, introducing new tools that promise to reduce the uncertainty about patients’ disease progression and drug response, the more the gap seems to widen between those advanced technologies and clinical practice.

Ongoing Controversy

In 1998, the US Food and Drug Administration approved Genentech’s Herceptin for HER2-positive metastatic breast cancer alongside Dako’s IHC-based HercepTest, making Herceptin the poster child for personalized medicine. Thirteen years later, however, many medical professionals still believe that when it comes to Herceptin there is no gold-standard diagnostic method for identifying best responders to the drug.

“It seems that controversy is ever present regarding the optimal approach to testing for HER2 status in breast cancer,” John Bartlett and Jane Starczynski of the Ontario Institute of Cancer Research wrote in an editorial accompanying Dabbs’ analysis in JCO. Clinicians and patients “need guidelines (provided by the American Society of Clinical Oncology-College of Molecular Pathology and other experts, for example) regarding the appropriate use of additional tests beyond conventional IHC and FISH.”

Bartlett and Starczynski believe that there is currently insufficient evidence to support qRT-PCR as a substitute for HER2 testing by IHC or FISH. However, with further research, the authors opine that there may be value in developing novel molecular diagnostic methods based on qRT-PCR or other multiplex technologies to provide more definitive results to patients who receive an equivocal result by IHC and FISH.

ASCO/CAP guidelines recommend that healthcare providers determine the HER2 status for all invasive breast cancer patients either by IHC or by FISH testing. The guidelines further state that labs performing HER2 testing show at least 95 percent concordance with another validated test for positive and negative assay values.

Genomic Health’s own studies show that HER2 reporting by Oncotype DX is robustly validated against IHC and FISH testing according to professional guidelines. Furthermore, the company maintains it has never marketed Oncotype DX’s independent HER2 readout as a substitute for IHC and FISH testing to determine who should receive HER2-targeted drugs.

In a validation study published in JCO last year, researchers at Genomic Health, the University of California, San Francisco, and PhenoPath Laboratories found a high degree of concordance between FISH and Oncotype DX for gauging HER2 status, but said that the assay needs to be studied further before it can be used to make treatment decisions with Herceptin.

“These data show that RT-PCR is highly concordant with high-quality, central laboratory-performed FISH and may be of use to clinicians and pathologists who are uncertain about select HER2 assay results obtained by FISH and IHC,” the authors wrote in the paper, but added that “assessment of HER2 status by IHC and/or FISH should continue as the approach for making [Herceptin] or [Tykerb] treatment decisions.”

Oncotype DX is a 21-gene expression test that assesses the recurrence risk for women with HER2-negative, estrogen receptor-positive, early-stage breast cancer that hasn’t spread to the lymph nodes. Studies have shown that post-menopausal women who have hormone receptor-positive breast cancer that has spread to the lymph nodes may also derive benefit from testing with Oncotype DX.

Estrogen receptor, progesterone receptor, and HER2 are part of the 21-gene RT-PCR panel that underlies Oncotype DX’s recurrence assessment. In 2008, upon the request of its customers, the company began reporting ER, PR, and HER2 gene expression status separately with every Oncotype DX test performed.

A pathologist involved with the recent JCO study and an independent oncologist both told PGx Reporter that doctors don’t normally send samples deemed HER2 positive by IHC or FISH for reanalysis by Oncotype DX. However, when patients receive discordant results by IHC and FISH and require a third test, or if oncologists are trying to figure out whether to treat patients with chemotherapy, they might send patients’ samples to Genomic Health for analysis.

“In truth I do not know any oncologist who does not get HER2 and ER testing by standard means,” ASCO president George Sledge told PGx Reporter. “To do so would be outside the standard of care, and … most hospital standard operating procedures require ER and HER2 testing on invasive cancers.

“I suspect that this implies that a few oncologists obtain [HER2 testing through Oncotype DX] as a tie-breaker when there is an indeterminate FISH result or [there is] heterogeneity in the HER2 testing, though this would just be speculation on my part,” continued Sledge. “If this is the case, then the argument, such as it is, is over those cases that were tough calls to begin with, rather than the standard run-of-the-mill determinations.”

Sledge said he holds no financial ties to Genomic Health. However, he was one of the authors of a 2008 study published in JCO comparing HER2 reporting by Genomic Health’s Oncotype DX to IHC.

In Sledge’s view, the discrepancy between Dabbs et al. and Genomic Health with regard to the accuracy of the RT-PCR-based test only highlights the difficulty of identifying a best-in-class HER2 test for healthcare providers.

“I don’t think there is a true ‘gold standard’ for these tests. Every study ever done shows divergent results and lack of concordance between expert pathologists performing HER2 and ER testing,” Sledge reflected. “Pathologist A disagreeing with Lab B or vice versa doesn’t mean that A was right and B was wrong, merely that they disagree.”

Over-reliance on Oncotype DX?

Researchers collected more than 800 patient samples analyzed by Dabbs et al. from patients at Magee-Women’s Hospital, Cleveland Clinic, and Riverside Methodist Hospital in Columbus, Ohio. According to Rohit Bhargava, co-director of surgical pathology at Magee-Womens Hospital and a co-author of the JCO paper, only two out 19 labs invited to participate in the study did so, because the other centers did not have enough ER-positive, HER2-positive patient samples that they had submitted to Genomic Health for analysis.

Still, Dabbs and colleagues found that among the population who were HER2-positive by IHC/FISH but HER2-negative by Oncotype DX, three patients at Magee-Women’s Hospital and two patients at Cleveland Clinic were not given Herceptin based on their Oncotype DX results. The fact that some patients were denied Herceptin based on Oncoytpe DX, even though the test is not indicated for such use, suggests that there may be some variability in the way oncologists are using the assay.

“If you speak with oncologists in the field, there is a sense in the community that there is an over-reliance on the Oncotype DX assay,” Bhargava told PGx Reporter. “These are new tests that are [indicated] for something else. Initially Genomic Health wasn’t reporting ER/PR/HER2. But when they started reporting these, then oncologists started getting confused about the information they had and the information [Genomic Health] reported.”

In their study, Dabbs and colleagues raise concern that cases determined to be HER2-positive by FDA-approved IHC and FISH tests were found to be equivocal or negative by Oncotype DX, which has not been FDA cleared but is analyzed in a CLIA-certified lab. “That was the highlight of our paper: Not to over-rely on just one test, especially where the HER2 component is not reliably assigning the patients who are clearly HER2-positive by the currently used assays that have been shown to predict response with Herceptin-based chemotherapy,” Bhargava said.

Bhargava believes that Genomic Health’s marketing of its separate ER/PR/HER2 reporting may have had a hand in prodding some oncologists to use the assay to perform diagnoses for which it is not validated. Although Genomic Health does not claim that Oncotype DX should be used to make treatment decisions with HER2-targeted drugs, the company does state in its marketing materials that its test is highly concordant with IHC and FISH-based tests in gauging patients’ HER2 status, which, according to Bhargava, may be enough to drive use of the test in this setting.

Bartlett and Starczynski in their editorial concede that some oncologists may be using Oncotype DX in settings not supported by treatment guidelines. “Dabbs et al. express concern that clinicians may be using the quantitative HER2 score supplied by Genomic Health to substitute for in situ analyses and indeed suggest that this may have occurred for at least one patient during their study,” they wrote. “A careful review of the data provided in several independent reports (including that cited on the Genomic Health Web site) shows that this concern may be valid.”

Article source: http://www.genomeweb.com/mdx/absent-gold-standard-her2-testing-researchers-question-role-oncotype-dx-beyond-i


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