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Two New HER2 Assays Poised to Challenge IHC, FISH Standard Tests in Breast Cancer

Breast cancer tests to gauge HER2 status based on immunohistochemistry and flourescent in situ hybridization techniques, which have thus far dominated the field, will now compete with two new types of assays whose makers last week claimed them to be an improvement over standard methods.
The first assay, Invitrogen’s SPOT-Light HER2 CISH kit, relies on a standard microscope and enables researchers to simultaneously assess HER2 gene amplification and examine tissue morphology. The US Food and Drug Administration cleared the test on July 8, and Invitrogen plans to launch it in mid-August.
The second test, debuted the same day, is the HERmark test made by Monogram, which the company claims can provide a more “precise and quantitative measurement of HER2 total protein and HER2 homodimer levels” than IHC and FISH tests. The HERmark test will be offered as a CLIA-validated assay through Monogram's CAP-certified clinical laboratory.
The two top players in the HER2 breast cancer diagnostics market are currently Dako, which sells the IHC-based HercepTest, and Abbott unit Vysis, which sells the FISH-based PathVysion HER-2 DNA probe kits. Both tests are approved by the FDA.
But various professional societies and expert scientific panels have recently determined that currently available IHC and FISH tests leave a lot of room for improvement when it comes to HER2 analysis.
For instance, guidelines released last February by the American Society of Clinical Oncology and the College of American Pathologists state that although certain FISH and IHC tests have received FDA approval, analyses of prospective, randomized, adjuvant trials of Genentech’s Herceptin show that testing algorithms to gauge HER2 expression have not been standardized and were developed “somewhat arbitrarily.”
Additionally, an expert panel formed by ASCO and CAP found “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.” [PGx Reporter 02-28-2007].
While Invitrogen and Monogram claim that their products improve on standard methods, and plan to use these claims to market their assays, neither Dako nor Abbott Molecular commented on how they would differentiate their products in the rapidly advancing HER2 testing market.
Abbott did not reply to questions regarding the differentiating qualities and price of its PathVysion kits.
Dako told Pharmacogenomics Reporter this week that the company “prefers not to debate [its] competitors’ products in the media.”
Invitrogen’s Innovation
According to the FDA, Invitrogen’s chromogenic in situ hybridization test is unique from other available HER2 tests because it is relatively easy to use and inexpensive.
The SPOT-Light test counts the number of HER2 genes in a tumor sample, which is stained with a chemical that colors the HER2 genes. “This color change can be visualized under a standard microscope, eliminating the need for the more expensive and complex fluorescent microscopes required to read assays already on the market,” the FDA said in a statement. Additionally, “unlike existing tests, the SPOT-Light allows labs to store the tissue for future reference.”
According to a recent review of CISH technology performed by Gong et al. at MD Anderson Cancer Center, and presented at the 2008 United States and Canadian Academy of Pathology Annual Meeting, CISH was slightly more concordant with FISH technology (99 percent) than with IHC assays (95.1 percent).
The researchers concluded there was “high agreement in HER2 status … between the three methods, and near-perfect agreement … between CISH and the corresponding FISH results.” They also concluded there was “excellent inter-site reproducibility … with FISH and CISH results.”

"Comparisons with local lab results by IHC or FISH suggest significantly larger numbers of discordant results.”

Another study, by Di Palma et al., published last year in the Journal of Clinical Pathology, analyzed 161 breast cancer tissue samples by IHC, FISH, and CISH. The researchers, who worked in the histopathology lab at Royal Surrey County Hospital in the UK, conducted the study to decide whether or not to set up a HER2 testing service using CISH.
The researchers found seven (4.4 percent) IHC 3+ cases that were found by CISH to be not amplified. Results of these seven cases were re-confirmed by dual-color FISH analysis.
One case (0.6 percent), originally scored IHC 1+, showed amplification by CISH, again re-confirmed by dual-color FISH. There was 100 percent agreement between the two examining pathologists, the study authors reported.
“CISH, like FISH, directly visualizes the number of gene copies present in the nucleus, it is cheaper and it produces a permanent record of the slide that can be interpreted with a light microscope in the context of the tumor histopathology,” the researchers said.
They concluded, “CISH can reliably be used to assess breast tumor samples for patient eligibility for [Herceptin] therapy.”
Based on numerous published studies confirming that CISH is at least as good as or better than existing IHC and FISH tests, Invitrogen is confident that doctors will be eager to adopt its technology.
“Our market research showed that clinicians would be open to CISH as an alternative to FISH and IHC because it provided the same patient guidance with greater efficiency and lower costs,” David Phan, Invitrogen’s product manager for the SPOT-Light test, told Pharmacogenomics Reporter.
Invitrogen held that while the turnaround time for IHC tests is shorter than FISH- and CISH-based tests, the SPOT-Light test still “represents a more efficient solution,” Phan said.
“A typical pathology lab will screen their metastatic breast cancer cases using IHC, and then send out any unclear or weakly positive IHC results for confirmation by FISH at an outside reference lab,” he said. “This whole process, using both IHC and FISH, can take anywhere from five to seven business days, while CISH will provide the same information as FISH in two days.”
IHC and FISH tests are an indirect measure of gene amplification. If there is an inconclusive test, the samples must be sent to another reference laboratory for confirmation.
However, because the SPOT-Light test works with a standard microscope, the test can simultaneously assess HER2 gene amplification and tissue morphology at any histology lab, the company claims. Thus, Invitrogen will be marketing its test broadly to all hospitals and medical centers with histology labs that analyze breast cancer tissue.
“We are currently working out an arrangement with a distributor to help provide maximum coverage for the clinical customer base,” Phan said. He did not name the distributor.
According to Invitrogen, the CISH test falls under the same reimbursement category as FISH testing, "Morphometric analysis, in situ hybridization (quantitative or semi-quantitative) [of] each probe; manual,” and has the same CPT code, 88368.
Based on Invitrogen’s numbers, with insurance, the cost of getting HER2 testing with the CISH test falls between the price of leading FISH and IHC tests. At $145 per test, Abbott's PathVysion Kit is the most expensive, followed by Invitrogen’s FISH-light test with a $70 price tag, and Dako’s HercepTest at $43 a pop.
Abbott and Dako did not respond to questions regarding the price of their tests.
Monogram’s Mark
The same day that the FDA approved Invitrogen’s SPOT-Light CISH test, Monogram announced the availability of its HERmark Breast Cancer Assay in the US, starting July 15 through its CAP-certified clinical laboratory.
Monogram is claiming that its test is more accurate than IHC and FISH technologies in gauging which breast cancer patients will benefit from treatment with Herceptin.
"Comparisons with local lab results by IHC or FISH suggest significantly larger numbers of discordant results,” Michael Bates, Monogram’s VP of clinical research, said in a statement. “We believe the HERmark Assay … will help physicians to make treatment decisions with high confidence."
HERmark is the first commercialized product based on Monogram’s VeraTag technology. The proprietary technology provides a quantitative measurement of HER2 total protein and HER2 homodimer levels, while conventional methods are an indirect measure of the HER2 gene, Monogram claims.
“By measuring these protein targets, VeraTag assays are making quantitative measurements of the actual targets of drugs, not gene-based aspects that are far removed from the actual drug target,” Monogram’s Chief Financial Officer Alfred Merriweather told Pharmacogenomics Reporter this week.
The company highlights that HERmark can detect HER2 at levels from 2,500 to over 1 million receptors per cell, which is seven to 10 times more sensitive than IHC.
Furthermore, Monogram estimates that its HERmark assay can correctly reclassify the 20 percent of false determinations that ASCO and CAP have determined IHC and FISH tests make.
In clinical trials, Monogram has found HER2 expression and HER2 homodimer levels to be “independent correlates of both time-to-progression and overall survival.”
Results from the HERmark assay are reported to physicians within seven days. The report the physician receives will indicate patients’ HERmark status as "positive," "negative," or "equivocal."
“The boundaries for the equivocal zone represent an upper level above which 95 percent are positive and a lower level below which 95 percent are negative patients,” the company said.
According to Merriweather, patients who currently want to be tested with HERmark without insurance will pay $3,350. “We will be working with patients' insurance companies to obtain coverage,” Merriweather added.
In marketing the HERmark test, Monogram has a narrower focus than Invitrogen.
“Our initial target will be medical oncologists in large community practices,” Merriweather said. “We will start with a very focused sales force in six metropolitan areas.”
Merriweather noted that the company’s first two sales representatives are trained and in the field, and that the company plans to recruit additional reps in the coming weeks.
Although inclusion of the HERmark in treatment guidelines will be a long-term goal for Monogram, its main focus “for this year is to educate the medical and payor communities and to gain initial adoption of HERmark,” Merriweather said.

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