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Central Laboratory HER2 Testing		  
Concordance Between Local and
          Central Laboratory HER2 Testing



Objectives
  • To assess the concordance between local community and central HER2 testing
  • To assess the concordance between central assays of HER2 protein overexpression (measured by the HercepTestTM) and central assays of HER2 gene amplification (measured by the PathVysionTM FISH assay)
Methods
  • A central review of the first 119 tumor specimens from patients entered into the North Central Cancer Treatment Group (NCCTG) trial N9831 was conducted.
  • Eligibility for NCCTG-N9831 required a score of 3+ with the HercepTestTM [immunohistochemistry (IHC) assay], strong membrane staining (>33 percent of the tumor cells) with other IHC assays, or gene amplification with fluorescence in situ hybridization (FISH).
  • A central laboratory assayed the tumor blocks for these cases with both the HercepTestTM and the PathVysionTM FISH assay.
Results

Concordance for Central Testing

The concordance between central testing for FISH and HercepTestTM was 92 percent. The discordance occurred among 9 (8%) specimens classified as HER2/neu not amplified by FISH but as 3+ by HercepTestTM.

Authors’ Conclusions

“Our results demonstrate that there is poor agreement between the results from local laboratory-based HER2 testing and those of central testing by experienced investigators.

“We have chosen to modify the HER2 testing requirement for our N9831 clinical trial… . Protocol eligibility was modified so that a woman can enroll in the trial if she has nodepositive breast cancer that is found to strongly overexpress HER2, or has HER2/neu gene amplification by central testing or by a local laboratory. … After central review, if the tumor specimen is found to strongly overexpress HER2 (3+ positivity by HercepTest™) or has HER2/neu amplification by FISH, then the patient will continue protocol treatment as randomly assigned.”

Research Leader Commentary

We were surprised when we found poor concordance between community and central laboratory testing, in terms of both HER2 protein expression and gene amplification. Perhaps more unexpected, we found poor concordance in terms of FISH testing in a central laboratory compared to the local laboratories. This last fact really came as a surprise, not only to us but also to many others, because the prevalent notion regarding FISH was that it was 100 percent accurate.

I’ve learned about these tests by spending time with our pathologists and looking at exactly what they see under the microscope with FISH. Although, theoretically, it is a matter of counting dots, it’s not as simple as that — many tumors are aneuploid, some tumors have deletions of the chromosomes, and some tumors have clumping of dots in one spot. In other specimens it may be difficult to obtain the appropriate hybridization. There are some technical difficulties involved in FISH analysis.

The data from these 119 cases was so important that we actually changed the eligibility criteria for this large cooperative group trial (NCCTG-N9831). We modified the protocol so that physicians can still conduct HER2 testing based on any technology in their local laboratories. The patient is then enrolled in the study and starts the doxorubicin/cyclophosphamide (AC) portion of the chemotherapy.

During that time, we test the tumor specimens again by the HercepTestTM and the PathVysionTM FISH assay. If we find that neither of those two tests demonstrates HER2 positivity, we send the tumor specimen to another central laboratory to double-check our laboratory at the Mayo Clinic. If the other central laboratory also finds that the tumor is HER2-negative by both assays, then we notify the physician that the patient really should not participate in the trial.

Edith A Perez, MD

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CME Information
Editor’s Note:
Getting It Right
Faculty

Concordance Between Local and Central Laboratory HER2 Testing
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Concordance of HER2 Status Between Primary and Metastatic Lesions
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HER2 Status and Response to Trastuzumab
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College of American Pathologists
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