HER2 status determination is an important component in the diagnostic evaluation of a patient with breast cancer. The various methods for determining HER2 status measure gene amplification, RNA overexpression, or protein overexpression. HER2 protein overexpression is frequently measured by immunohistochemistry (IHC), while fluorescence in situ hybridization (FISH) detects HER2 gene amplification. Results obtained with IHC and FISH are not always concordant. The clinical outcomes associated with trastuzumab are dependent upon the HER2 status of the patient. Retrospective analyses demonstrate that patients with HER2 gene amplification are more likely to benefit from trastuzumab compared to patients with HER2 protein overexpression with respect to overall response and survival. Since the scientific literature on the subject of HER2 is still evolving, clinicians are advised to follow this topic closely as it continues to develop.

ASSESSING HER2 STATUS

The NCCN guidelines call for HER2 testing of all breast cancers; however, this year we were much more specific than in the past. We call for HER2 testing by IHC, and if the IHC result is 2+ by the HercepTest., we call for FISH analysis. This is primarily because in the metastatic setting, when you're looking for the benefit or lack thereof from trastuzumab, FISH-positivity is by far the best predictor of responsiveness.

Women whose breast cancers are IHC 3+ by the HercepTest. are almost all FISH-positive, while those that are IHC 0 or 1+ are almost always FISH-negative. This approach is based upon the study reported by Chuck Vogel, which looked at trastuzumab as a single agent and found very good rates and long duration of response in those women who were either IHC 3+ or IHC 2+ and FISH-positive.

Robert W Carlson, MD

DISCORDANCE IN THE ASSESSMENT OF HER2 STATUS

There is a significant problem with HER2 testing in the community. When we designed our adjuvant study - evaluating trastuzumab in combination with chemotherapy - we included a plan for central analysis of HER2 status. Unfortunately, when we looked at the initial 119 patients, we found a high level of discordance in HER2 testing by IHC, and even by FISH, when comparing measurements in the community versus central testing.

We found discordant results in six of the nine FISH test assays. These were FISH-positive in the community, but FISH-negative in the central lab. The number of patients is very, very small to date, so we cannot conclude that FISH is a bad test to be performed in the community, but we need to look into why this discordance occurs. IHC concordance between the community and central laboratories was about 75 percent.

We've done another study of HER2 testing, based on 1,500 specimens sent to Mayo Medical Laboratories over a five-month period. We took 213 specimens labeled as HER2 2+ and evaluated them for protein overexpression and gene amplification, and we found that only 12 percent of the tumors scored as 2+ by the HercepTest. actually were FISH-positive.

Edith A Perez, MD

Molecular targets for determining HER2 status and the tests used to detect these molecules.   mRNA = messenger RNA ECD = extracellular domain ELISA = enzyme-linked immunosorbent assay IHC = immunohistochemistry CISH = chromogenic in situ hybridization PCR = polymerase chain reaction FISH = fluorescence in situ hybridization Adapted from Schaller et al. Ann Oncol 2001;12:(Suppl 1):S97-S100   Overall response rates for trastuzumab trials in breast cancer according to IHC score. (t=trastuzumab, A=anthracycline, C=cyclophosphamide) 1. Cobleigh MA et al. J Clin Oncol 1999;17:2639-2648. Abstract 2. Herceptin® [Package Insert], 2000. 3. Uber KA et al. , Pro ASCO 2001; Abstract 1949. 4. Burstein HJ et al. J Clin Oncol 2001;19:2722-2730. Abstract Frequency of IHC scores according to level of HER2 gene amplification. (Pauletti G et al. J Clin Oncol 2000 ; 18:3651-3664) Level of HER-2 Gene Amplification (HER2/neu signals per cell) 1. Cobleigh MA et al. J Clin Oncol 1999;17:2639-2648. Abstract 2. Herceptin® [Package Insert], 2000. 3. Uber KA et al. , Pro ASCO 2001; Abstract 1949. 4. Burstein HJ et al. J Clin Oncol 2001;19:2722-2730. Abstract O N C O LO G I S T S In approximately what percentage of your patients with primary breast cancer do you assess HER2 status? 100% In the last year, approximately how many women have you evaluated and/or treated with metastatic breast cancer? Median = 53 In approximately what percentage of your patients with metastatic breast cancer do you attempt to assess HER2 status? 100% About how many patients were HER2-positive? Median = 10 How often do you obtain FISH results on a patient you are treating? O N C O LO G I S T S Occasionally 50% Commonly 35% Rarely 10% Have not done it 5% In approximately how many patients have you asked a lab to do FISH testing? O N C O LO G I S T S Mean 19

Jacobs TW et al. Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol 1999;17:1974-1982. Abstract

Kakar S et al. Comparison of PathVysion and INFORM fluorescence in situ hybridization kits for assessment of HER-2/neu status in breast carcinoma. Molecular Diagnosis 2000;5:193-197. Abstract

Mass RD et al. The concordance between the clinical trials assay (CTA) and fluorescence in situ hybridization (FISH) in the Herceptin pivotal trials. Proc ASCO 2000;19: Abstract 291.

Schaller G et al. Current use of HER2 tests. Ann Oncol 2001;12 (suppl 1):S97-S100. Abstract

Thor A. HER2 - a discussion of testing approaches in the USA. Ann Oncol 2001;12(suppl 1):S101-S107. Abstract

Tubbs RR et al. Discrepancies in clinical laboratory testing of eligibility for trastuzumab therapy: Apparent immunohistochemical false-positives do not get the message. J Clin Oncol 2001;19:2714-2721. Abstract

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