An observational study has found that 1 in 25 patients with invasive breast cancer who were diagnosed with HER2-negative disease were actually HER2 positive.

HER2-positive breast cancers, which account for approximately 15% to 20% of breast cancer cases, are more aggressive and have poorer prognosis than HER2-negative cancers. Targeted therapy with trastuzumab is highly effective against HER2-positive tumors, but its benefits would not be available to women whose cancer was misdiagnosed.

“We, and other groups, have previously shown that a certain percentage of cases found to be HER2-positive in local laboratories are in fact HER2-negative when tested in more experienced central labs,” said lead author Peter Kaufman, MD, of the Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center. “There has, however, been almost no research evaluating the accuracy of a negative HER2 result. This is the first large study to look at this.”

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The research was conducted using tissue samples from VIRGO, a large observational study of women with HER2-negative metastatic breast cancer, which was designed to characterize the clinical outcomes of various subgroups of patients. Most of the tumors had been evaluated at local laboratories with either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH).

The investigators retested 552 tumor samples at a central laboratory using both IHC and FISH. Although 530 samples were confirmed as HER2 negative, 22 samples (4.0%) were determined to be HER2 positive.

The new testing results were not always straightforward or easy to interpret: when tested in the central laboratory, 11 of the 22 tumors were HER2 positive on one test and HER2 negative on another. Many tumors showed heterogeneous IHC testing, with a mixture of strongly, moderately, and weakly stained cells.

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Patients who had been misdiagnosed were younger than those who had not been (56.5 vs. 60.0 years) and more likely to have hormone receptor–negative tumors (27.3% vs. 22.3%). They were also more likely to have tumors of advanced histologic grade.

The misdiagnosed patients had worse outcomes than the other patients, including shorter progression-free survival (6.4 vs. 9.1 months) and overall survival (25.9 vs. 27.9 months).

More Testing Recommended

Based on these results, the authors recommend that, when either IHC or FISH yields a HER2-negative result, testing with the other method or on a second tumor specimen be considered so that all women who could benefit from trastuzumab therapy will receive it.

Numerous studies have demonstrated that treatment of HER2-positive metastatic disease with targeted agents improves clinical outcomes. One estimate is that, in the adjuvant setting, use of trastuzumab will prevent as many as 55,000 breast cancer recurrences over 25 years in the United States alone.

Despite evidence of misdiagnosis, the authors were encouraged by the relatively low rate of errors. “What is comforting is that we found that retesting in experienced, larger labs confirmed the original local lab results in the majority of cases,” Dr. Kaufman said.


  1. Kaufman PA, Bloom KJ, Burris H, et al. Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2-negative breast cancer. Cancer. 2014 Jun 13. doi: 10.1002/cncr.28710. [Epub ahead of print]