A study published in this month's Journal of Clinical Oncology suggests that targeted therapy for women with HER-2 positive metastatic breast cancer is more effective and less costly when fluorescence in situ hybridization (FISH) technology is used to determine a patient's HER-2 gene status.
The study, a cost-effectiveness model developed by the Harvard University Center for Risk Analysis and School of Public Health, the Dana-Farber Cancer Institute, and Beth Israel Deaconess Medical Center, compared the use of FISH testing alone with its use in confirming the results of immunohistochemistry (IHC) testing to identify candidates for Herceptin (trastuzumab) therapy. The study states that the effectiveness of targeted therapeutic intervention depends on the identification of potentially responsive patients.
"Our analysis demonstrates the importance of considering both testing and treatment when estimating the cost-effectiveness of a biologically targeted intervention," wrote the authors of the study. "From a societal perspective, the diagnostic performance of the test used to identify trastuzumab candidates has considerable influence on cost-effectiveness, independent of test cost, due to the high cost of treating patients with false-positive test results and the missed opportunity for patients with false-negative test results to benefit from trastuzumab."
In clinical practice, HER-2 status is determined with IHC testing to detect protein overexpression and FISH is used to detect gene amplification. Currently, two IHC test kits (HercepTest and Pathway) and one FISH assay (Abbott's PathVysion) have U.S. Food and Drug Administration (FDA) approval for the selection of trastuzumab patients.
The study concludes that it is more cost-effective to use the FISH method alone or as confirmation of all positive IHC results, rather than using FISH to confirm only weak positive results or using IHC testing alone. "When multiple tests are available to identify treatment candidates, test characteristics may have a substantial impact on aggregate costs and effectiveness of treatment," the authors wrote.
Supported by a grant from the National Library of Medicine Research Training Program in Medical Informatics, the study was based on an analytical model designed to simulate clinical practice and estimate the incremental cost-effectiveness of different test methods currently used to identify and treat women with HER-2 positive metastatic breast cancer. The model simulated treatment outcomes in a hypothetical group of 65-year-old women newly diagnosed with metastatic breast cancer. To determine the cost of testing, average Medicare reimbursements were used as a proxy.
"This seminal study highlights the importance of pharmacogenomic testing of patients to identify those most likely to respond to a particular treatment and the clear need to consider all components of patient management before formulating conclusions about cost," said Steven Seelig, M.D., Ph.D., divisional vice president, molecular diagnostics research and development, Abbott Laboratories. "Personalized medicine, using therapies targeted to specific patient populations identified by molecular tests, are critical to the cost-effective practice of medicine. FISH plays an important role in the personalized medicine paradigm and specifically in the fight against breast cancer."
The presence of multiple copies of the HER-2 gene on a single chromosome, called "gene amplification," leads to overexpression of the HER-2 protein, which plays a pivotal role in the rapid growth of tumor cells. Accurate determination of HER-2 gene status is critical for determining therapeutic options. Women with HER-2 positive breast cancer experience resistance to certain therapies and decreased survival and are potential candidates for Herceptin, which is designed to block cell growth stimulated by the HER-2 protein. Herceptin is a monoclonal therapy that specifically targets tumor cells that overexpress the HER-2 protein. Among the 20 to 30 percent of metastatic patients who are HER-2 positive, trastuzumab combined with chemotherapy significantly improves overall response rate, time until disease progression, and overall survival, compared to chemotherapy alone.
PathVysion is the only FISH-based test the FDA has approved for inclusion in the Herceptin package insert for the selection of patients who may respond to treatment. Using FISH technology, Abbott's PathVysion test is designed to detect amplification of the HER-2 gene in breast cancer tissue. In addition to Herceptin therapy selection, PathVysion is also FDA approved for assessing patient prognosis and response to Adriamycin-based therapies.
PathVysion FISH measures the number of copies of the HER-2 gene at the DNA level. Using fluorescent colors and a microscope, physicians count the actual number of HER-2 genes present in the cell nucleus. The common alternate HER-2 testing method, IHC, measures the HER-2 protein overexpression on the surface of the cell, and is subjectively scored. In comparison, FISH technology offers objective, quantitative results.
In 2003, the National Comprehensive Cancer Network updated its Practice Guidelines in Oncology to indicate that FISH, the diagnostic technology used in Abbott's PathVysion test, may be more accurate than IHC. The organization's guidelines are widely recognized and used as the standard for clinical policy in cancer care, and are the only comprehensive set of guidelines updated annually by any national organization in any area of medicine.
The PathVysion HER-2 DNA Probe Kit is designed to detect amplification of the HER-2/neu gene via FISH in formalin-fixed, paraffin-embedded human breast cancer tissue specimens. Results from the PathVysion kit are intended for use as an adjunct to existing clinical and pathologic information currently used as prognostic factors in stage II, node-positive breast cancer patients. The PathVysion kit is further indicated as an aid to predict disease-free and overall survival in patients with stage II, node positive breast cancer treated with adjuvant cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) chemotherapy. The PathVysion kit is indicated as an aid in the assessment of patients for whom Herceptin treatment is being considered.
PathVysion is not intended for use to screen for or diagnose breast cancer. It is intended to be used as an adjunct to other prognostic factors currently used to predict disease-free and overall survival in stage II, node-positive breast cancer patients and no treatment decision for stage II, node-positive breast cancer patients should be based on HER-2/neu gene amplification status alone. Selected patients with breast cancers shown to lack amplification of HER-2/neu may still benefit from CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) adjuvant therapy on the basis of other prognostic factors that predict poor outcome (e.g. tumor size, number of involved lymph node and hormone receptor status). Conversely, selected patients with breast cancer shown to contain gene amplification may not be candidates for CAF therapy due to pre-existing or intercurrent medical illnesses.
All patients in the Herceptin clinical trials were selected using an investigational immunochemical assay (clinical trial assay). None of the patients in those trials were selected using the PathVysion assay. The PathVysion assay was compared to the clinical trial assay on a subset of clinical trial samples and found to provide acceptably concordant results. The actual correlation of the PathVysion assay to Herceptin clinical outcome in prospective clinical trials has not been established.
Abbott Laboratories' molecular diagnostics business focuses on genomic disease management and provides physicians with critical information based on the early detection of pathogens and subtle changes in patients' genes and chromosomes. These advanced diagnostic tests allow for earlier detection, selection of appropriate therapies and monitoring of disease progression.