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Prospective Comparison of Oncotype DX and Central Pathology Assessment Shows HER2 Discordance

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A group of researchers led by Oleg Gluz of the West German Study Group, and including employees of Genomic Health, has shared data from the phase III WSG-Plan B trial showing that high-risk recurrence scores obtained by Genomic Health's Oncotype DX test predict high risk as measured by some other risk-assessment measures, but not vice-versa.

In addition, the findings revealed some discordance between the risk-assessment tools in measuring HER2 status, the researchers reported in a poster presented at the annual meeting of the American Society for Clinical Oncology, held last month in Chicago.

Though there were few cases with discordant RT-PCR recurrence score results in samples deemed HER2-negative by central pathology methods, the authors wrote in their abstract that these discrepancies could "potentially have a substantial impact on clinical patient management."

The group notes in its abstract that the use of multi-gene real-time PCR-based assays like Oncotype DX — as well as assessments of single markers like tumor grade, uPA/PAI-1, ER/PR, HER2, and KI-67 — is "currently controversially discussed" in early breast cancer as ways to gauge the likelihood that patients' disease will recur.

The team, which included Genomic Health's chief medical officer Steve Shak and several researchers who have served as consultants to the company, reported that it found correlations between the Oncotype DX recurrence score and other risk-assessment parameters like luminal B subtype by Ki-67 status in the 2,448 patients randomized in the WSG-Plan B trial, but these other risk parameters did not, in turn, predict high-risk status as measured by Oncotype DX.

Shak told PGx Reporter that the data boil down to a conclusion that you can't predict Oncotype DX's recurrence score with any one or any combination of other traditional risk factors.

"It means there are a lot of people with high risk by those other factors that have low recurrence scores," Shak said. "So that would be misleading if you acted on the basis of [those other measures as a surrogate for recurrence score]."

Oncotype DX is featured in treatment guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network as a tool to gauge breast cancer recurrence in patients with early-stage, hormone receptor-positive, HER2-negative disease that hasn't spread to the lymph nodes. "In newly diagnosed patients with node-negative, estrogen receptor–positive breast cancer, the Oncotype DX assay can be used to predict the risk of recurrence in patients treated with tamoxifen," ASCO states in its guidelines. "Oncotype DX may be used to identify patients who are predicted to obtain the most therapeutic benefit from adjuvant tamoxifen and may not require adjuvant chemotherapy."

These guidelines do not recommend Oncotype DX as the sole determinant of breast cancer recurrence risk, but state that the multi-gene test should be used by oncologists in concert with other information, such as patients' clinical factors, as well as ER, PR, and HER2 status. Although Genomic Health reports patients' ER, PR, and HER2 scores separately from the Oncotype DX recurrence score, the test is not specifically recommended in treatment guidelines as a tool to assess these markers.

"Some NCCN institutions consider performing RT-PCR analysis (e.g., Oncotype DX assay) to further refine risk stratification for adjuvant chemotherapy for patients with node-negative, ER-positive, HER2-negative breast cancers greater than 0.5 cm, whereas others do not," NCCN states in its latest guidelines.

In the study reported at the ASCO annual meeting, when researchers compared assessment of hormone receptor and HER2 status by Oncotype DX's RT-PCR and by local and central IHC assessment, they found that there was an "overall high concordance." Agreement between IHC by central lab and RT-PCR on HR status (ER or PR) was almost 99 percent. However, a small number of patients — 23, or 2 percent — were HER2 positive by central lab assessment and HER2 negative by RT-PCR or vice versa, the group reported.

A study published in the Journal of Clinical Oncology last October by pathologists at the University of Pittsburgh Medical Center found that of 36 cases deemed HER2-positive by standard FDA-cleared IHC/FISH testing, Oncotype DX reported 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. Based on these findings, the authors of this study concluded that the data suggested Oncotype DX had an "unacceptable false-negative rate" when reporting HER2 status (PGx Reporter 12/21/2011).

Genomic Health contended that the discordance should not be viewed as an example of false-negatives considering the fact that the IHC/FISH is not itself viewed as a gold standard for measurement of HER2 status.

The German group's ASCO presentation demonstrated a HER2 discordance rate similar to the JCO results. The researchers reported that 2,364 patients had data available for analysis, representing local and central IHC measurements as well as RT-PCR results from Oncotype DX. Among these, 28 tumors were marked HER2-positive by central IHC. Oncotype DX found 17 of these to be negative.

Overall, Oncotype's RT-PCR analysis marked 11 tumors as HER2-positive. Of these, 6 were negative by IHC.

"A small number — 23 — went in both directions," Shak confirmed. "[But] in the vast majority of cases that were called negative locally, they were also negative by Oncotype DX. That's quite encouraging," he said.

Shak reiterated that the discordant results don't reveal which method is correct and which incorrect — since there is no agreement that IHC should be considered the gold standard in measuring HER2 status. However, IHC/FISH testing is recommended in current guidelines from organizations like ASCO for HER2 analysis.

Respecting these current guidelines, Shak said, "[We are] continuing to try to study, can we better define who benefits or not from [HER2-targeted] therapies? Further investigation is needed. That's why we're reporting our results."

Shak noted that the most accurate method of characterizing HER2 status for personalizing breast cancer treatment is "a very active topic" for investigation. "Ultimately [what] clinicians and patients care about is the assessment that predicts whether they would benefit from HER2 targeted therapy or not," he said.

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