NEW YORK (Reuters Health) – HER2 protein and gene expression predict the response of breast cancer patients to adjuvant trastuzumab therapy, but which test provides the best information?

Two articles in the August 9th Journal of Clinical Oncology online aim to address this question.

“Order protein analysis by IHC (immunohistochemistry), and if negative consider ordering FISH (fluorescent in situ hybridization) for gene analysis,” Dr. Edith A. Perez, the lead author of the first paper, told Reuters Health in an email.

“If protein is 3+, there is no indication for ordering a FISH test. If physicians decide to order FISH first, they should note that as many as 5-8% of the patients may have protein overexpression, so IHC should be strongly be considered to optimize patient selection for adjuvant trastuzumab (and avoid missing patients whose tumors are positive for HER2 and thus eligible to receive trastuzumab).”

Dr. Perez from the Mayo Clinic, Jacksonville, Florida, and colleagues used data from the North Central Cancer Treatment Group-led N9831 trial to examine associations between HER2 protein expression (using IHC), HER2 gene analysis (using FISH), and chromosome 17 copy number in tumors from breast cancer patients and disease-free survival.

Patients whose tumors had HER2 IHC scores of 3+ showed a 54% improvement in disease-free survival with the addition of trastuzumab, whereas patients whose tumors had lower HER2 IHC scores did not benefit significantly from trastuzumab (in terms of disease-free survival).

As for HER2 gene copy number, patients benefited from trastuzumab therapy whether their copy number was 4 or more or less than 4. Similarly, patients who had HER2 amplification with polysomic or normal chromosome 17 copy number both benefited from trastuzumab.

“The degree of gene amplification is not predictive of benefit; either protein or gene are predictive (gene no better than protein), and patients with protein positive by IHC but negative gene amplification by FISH benefit as much as those where both are positive,” Dr. Perez concluded.

In the second study, Dr. Frederick L. Baehner from University of California, San Francisco, compared central HER2 assessed by FISH and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using Oncotype DX by Genomic Health. (The study was funded by Genomic Health, which employed 3 of the 8 authors, including Dr. Baehner, and provided research funding to another).

There was 97% concordance between central FISH and RT-PCR, with 98% percent positive agreement and 97% percent negative agreement.

“In addition to being highly concordant,” Dr. Baehner told Reuters Health in an email, “RT-PCR minimizes the preanalytic variability associated with IHC and FISH, which may lead to differences in results and interpretation and, consequently, to potentially inappropriate treatment decisions.”

Dr. Baehner explained further, “Oncotype DX’s RT-PCR technology for HER2 gene expression employs reference genes, expression normalization, and a large number of controls and calibrators to enhance precision and reproducibility, all of which safeguard against any source of preanalytic variability, including degradation of samples that may occur prior to testing, in order to ensure a reproducible quantitative result.”

References:

HER2 and Chromosome 17 Effect on Patient Outcome in the N9831 Adjuvant Trastuzumab Trial

Human Epidermal Growth Factor Receptor 2 Assessment in a Case-Control Study: Comparison of Fluorescence In Situ Hybridization and Quantitative Reverse Transcription Polymerase Chain Reaction Performed by Central Laboratories

J Clin Oncol 2010.