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Study reveals discordance between HER-2 testing methodologies
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Clinicians should not rely on only one HER-2 testing methodology because each approach has limitations that make it difficult to rule out patients with breast cancer who might benefit from targeted therapy, study results suggest.
Peter A. Kaufman, MD, of Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center in New Hampshire, and colleagues evaluated tumor tissue samples from 522 women who participated in the VIRGO trial, a multicenter study of women with metastatic breast cancer.
During VIRGO, all samples were determined to be HER-2 negative after local testing with immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) assays.
In the current study, Kaufman and colleagues re-tested all samples centrally using IHC and FISH.
Results of central testing showed samples from 22 patients (4%; 95% CI, 2.4-5.7) actually were HER-2–positive.
Eighteen of those 22 samples had been identified as HER-2–negative during local testing with only one assay, and 15 were subsequently identified as HER-2 positive after central testing with the opposite assay.
IHC and FISH yielded discordant results for 11 of the 22 reclassified samples. Seven were identified as positive by IHC but negative by FISH, whereas four were identified as positive by FISH but negative by IHC.
The 22 patients with reclassified samples were younger (median age, 56.5 years vs. 60 years), more likely to have ER-/PR–negative tumors (27.3% vs. 22.3%) and more likely to have an advanced histologic grade compared with patients who had confirmed HER-2–negative disease.
The patients with misclassified HER-2 status also demonstrated shorter PFS (6.4 months vs. 9.1 months) and OS (25.9 months vs. 27.9 months) than those with confirmed HER-2–negative disease.
The results illustrate the limitations of employing only one HER-2 testing methodology, according to the researchers.
“The data from the VIRGO study highlight a cohort of patients who were denied potentially efficacious therapy due to possibly inaccurate HER-2 testing, which may impact a considerable number of patients with breast cancer,” Kaufman and colleagues concluded. “Given the magnitude of potential benefit provided by HER-2–directed therapy, it is essential to accurately and reliably test for HER-2 status so that patients may have the opportunity to receive the most efficacious treatment for their disease.”
Disclosure: The VIRGO study was funded by Genentech. The researchers report consulting fees, honoraria and research funding from, employment with and stock ownership in Genentech and Roche.
Perspective
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Adam M. Brufsky, MD, PhD, FACP
In an era in which there is highly efficacious targeted therapy, it is incumbent on all of us to get testing for the target right. In the case of trastuzumab (Herceptin, Genentech), where prediction of response to therapy is especially dependent on adequate HER-2 testing, this is even more important.After analyzing tumor blocks from the VIRGO registry, Kaufman and colleagues suggest that 4% or greater of tumors felt to be HER-2–negative on local IHC or FISH were found to be positive when both methodologies were used. The reasons for this discrepancy are not clear.
Lab error is certainly a possibility, but tumor heterogeneity — where part of the tumor is strongly HER-2–positive but the remainder is not — also is possible. Even more intriguing is the suggestion that downstream activation of the HER-2 pathway may not necessarily be predicted by IHC or FISH amplification in a minority of cases.
In any event, this report underscores the need to carefully examine cases in which the clinical picture may not necessarily match the pathologic stains in HER-2–positive breast cancer.
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