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Genomic Health Continues to Explore Using PCR-based Oncotype Dx for HER2 Testing

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By Bernadette Toner

Since launching its RT-PCR-based Oncotype DX test in 2004, Genomic Health has run more than 120,000 assays to help assess breast cancer recurrence and chemotherapy benefit in tamoxifen-treated patients with early-stage, node-negative, estrogen receptor-positive breast cancer.

In that time, the company has sought to expand the test — which measures the expression of 21 genes to yield a "recurrence score" that categorizes patients into low-risk, intermediate-risk, or high-risk groups — into new indications, such as node-positive women, as well as new cancers, including colon cancer and kidney cancer.

Genomic Health has also been conducting a number of studies to examine how well its RT-PCR-based test compares to immunohistochemistry and fluorescence in situ hybridization for assessing the HER2 status of breast cancer patients, since the HER2 gene is one of the 21 genes that it includes in the test.

After Genomic Health presented data at the 2008 American Society of Clinical Oncology Breast Cancer Symposium showing that quantitative reporting of HER2 expression with Oncotype DX was 95 percent concordant with IHC testing and 97 percent concordant with FISH testing, the company began reporting HER2 status as a single-gene score in addition to the recurrence score in Oncotype DX results.

This past weekend, at the San Antonio Breast Cancer Symposium, the company presented the results of a study that further explored the use of quantitative RT-PCR by Oncotype DX for interpreting HER2 results.

The study, conducted in partnership with researchers at Kaiser Permanente Northern California and the University of California, San Francisco, aimed to explore the association between polysomy 17, HER2 status, and cancer death.

Polysomy 17 — extra copies of chromosome 17 — commonly occurs in breast cancer cells and can confound the interpretation of HER2 testing results because it can be difficult to determine whether an increased signal is due to amplification of the gene, or extra copies of the entire chromosome.

As a result, the PathVysion FISH HER2 assay made by Vysis, a unit of Abbott Molecular, looks at two probes — one specific for HER2, and the other that assesses chromosome 17 — in order to determine whether the gene is actually amplified or not.

However, Steve Shak, Genomic Health's chief medical officer, noted that "people have been interested in whether the increased number of chromosome 17 copies matter also, or is it just amplification?" The study that the company and its collaborators performed aimed to determine whether polysomy also plays a role in cancer prognosis.

In the study, which looked at 568 patients, polysomy 17 was found in HER2-amplified tumors in around one-third of the cases. According to an abstract of the presentation, HER2-positive patients with polysomy 17 tended to have a worse prognosis than other breast cancer patients, though it added that "the differences were not statistically significant."

The study also confirmed previous findings that quantitative RT-PCR by Oncotype DX for HER2 status "is highly concordant with HER2 status assessed by FISH and therefore is an alternative to FISH."

As far as the clinical implications for the polysomy 17 finding, "I think that deserves further study," Shak said. He added that the accurate interpretation of HER2 status is "critical for breast cancer care, so this emphasizes the importance of the continued investment in the development of diagnostic technologies."

A Replacement for IHC and FISH?

So far, Shak said, Genomic Health has provided quantitative HER2 assessment by RT-PCR to more than 50,000 patients. "Right now it's been very helpful in those many cases where the HER2 status is uncertain — where the existing assays sometimes don't agree, or give equivocal results," he said.

"The test is also playing a role in the quality assessment of HER2 assays that are being performed in hospital laboratories."

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As for whether clinicians might eventually turn to Oncotype DX instead of IHC and FISH testing for HER2, "we speculate about that," Shak said, but added that much work needs to be done before RT-PCR-based HER2 testing displaces current methods.

"The qualities of reproducibility and precision make it look very attractive, but that conclusion will depend on additional information that's accumulated over time," he said. "We are certainly doing more studies and gaining more insight on quantitative assessment using Oncotype DX."

IHC and FISH have their limits. The methods are both semiquantitative, require a tumor sample, and can be difficult to reproduce. Furthermore, the results of IHC, which measures over-expression of the HER2 protein, and FISH, which measures amplification of the HER2 gene, often don’t agree.

In guidelines for HER2 testing published in 2006 by the American Society of Clinical Oncology and the College of American Pathologists, ASCO and CAP noted that approximately 20 percent of HER2 assays performed at the primary treatment site "were incorrect when the same specimen was re-evaluated in a high-volume, central laboratory."

The ASCO/CAP guidelines recommend that labs use "a testing algorithm that defines positive, negative, and equivocal values for both the IHC and FISH tests," and add that equivocal results are a "new category" that requires "repeat testing or the use of a different test." The guidelines do not address RT-PCR HER2 testing specifically, however.

RT-PCR testing is still clearly in the minority when it comes to HER2 status assessment.

As reported by PCR Insider sister publication The Sample, at the most recent Association for Molecular Pathology meeting, an informal poll at one session indicated that only 8 percent of the pathologists in attendance use quantitative real-time PCR to measure HER2, while the vast majority use FISH.

In addition, ARUP Laboratories began offering a qPCR test several years ago to assess HER2 copy numbers, but it is "rarely ordered," according to Ronald Weiss, director of corporate communications.

"IHC and FISH generally remains the gold standard" for HER2 testing, Weiss noted.

Genomic Health is not the only group that has compared the utility of RT-PCR for HER2 testing to IHC and FISH.

In a study published last year in the American Journal of Clinical Pathology, a team led by Silvano Bosari at the University of Milan showed that quantitative real-time PCR-based HER2 testing provided results that were concordant with that of IHC and FISH, but at a lower cost.

The study found that IHC plus qRT-PCR cost €157.27 per case, while IHC plus FISH cost €525.68 per case, which "would favor the use of qRT-PCR instead of FISH for HER2 evaluation."

The authors propose that, given its cost advantages, "qRT-PCR could become the test of choice to evaluate HER2 status in breast cancer." They add, however, that in order to get to this point, "it will be necessary to validate qRT-PCR by multicenter trial, with the inclusion of several testing laboratories and the analysis of responses to inhibitory therapy."

Bosari told PCR Insider this week that while the costs cited in the study "might not be comparable" to costs in the US, the qRT-PCR-based test should prove to be "reasonably cost effective" in other settings.

He noted that "the cost effectiveness increases if the number of tests that you're doing in parallel increases. So the more tests you do, the more real-time is convenient."

Bosari added that despite the advantages of qRT-PCR for HER2 testing, broad acceptance by the medical community is "probably going to take time — particularly among pathologists, because pathologists tend to be, as a group, somewhat conservative."

Nevertheless, he said, "I think that future studies will validate in a pretty definitive way that this is appropriate to treat patients, and will become a very reasonable option."

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