HER2 levels may aid in treatment selection for metastatic breast cancer

Dec 02, 2008

Findings published in the December 1, 2008, issue of Clinical Cancer Research, a journal of the American Association for Cancer Research, show lapatinib benefits women with HER2-positive breast cancer, while women with HER2-negative breast cancer or those who express EGRF alone derive no incremental benefit. In addition, a misclassification of metastatic breast cancer patients by as much as 10 percent prevents some people from receiving optimal therapy.

Lapatinib, an oral chemotherapy agent, inhibits both HER2 and EGRF receptors, leaving unanswered questions about which patients are more likely to benefit. Researchers at the Norris Comprehensive Cancer Center found that HER2 amplification ("HER2-positive"), but not EGRF expression, is correlated with responsiveness to lapatinib. Women with both high and low levels of HER2 amplification respond to lapatinib. However, women with HER2-negative metastatic breast cancers do not respond.

Women with HER2-postitive metastatic breast cancer who receive lapatinib and chemotherapy have shown an improvement of approximately 50 percent in progression-free survival when compared to chemotherapy alone. Unfortunately, high volume laboratories using laboratory technicians instead of pathologists to score gene amplification misclassify approximately 10 percent of HER2 amplified breast cancers as not amplified, preventing these patients from being candidates for lapatinib.

"I would like to see all women with breast cancer tested appropriately, using the best method and certified personnel, to assess the HER2 status of their breast cancer so the appropriate treatment can be selected," said Michael Press, M.D., Ph.D., Norris Comprehensive Cancer Center Harold E. Lee Chair in Cancer Research and lead author of the study.

Currently lapatinib is approved by the FDA for use only in women who have HER2-positive metastatic breast cancer who were previously treated with anthracyclines, trastuzumab and taxane.

Source: American Association for Cancer Research

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gdpawel
5 / 5 (1) Dec 03, 2008
Dr. Michael Press states that he "would like to see all women with breast cancer tested appropriately, using the best method and certified personnel, to assess the Her2 status of their breast cancer so the appropriate treatment can be selected."

However, all the gene amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don%u2019t tell you if one drug or combination is better or worse than some other drug or combination which may target this. There are differences.

The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems%u2019 response to drug treatments, not just one target or pathway.

No gene-based test can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can an available gene-based test identify situations in which it is advantageous to combine a targeted drug with other types of conventional cancer drugs.

Previous studies demonstrated that there is poor agreement between the results from local laboratory-based Her2/neu testing and those of central testing by experienced investigators. There has been poor concordance between community and central laboratory testing, in terms of both Her2 protein expression and gene amplification.

Even still, there has been poor concordance in terms of FISH testing in a central laboratory compared to local laboratories, which the prevalent notion regarding FISH is that it is 100% accurate.

It doesn't matter if there is a target molecule in the cell that the targeted drug is going after, if the drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, drug resistance is multifactorial.

Over the past few years, researchers have put enormous efforts into genetic profiling as a way of predicting patient response to targeted therapies. However, no gene-based test can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can gene-based testing identify situations in which it is advantageous to combine a targeted drug with other types of conventional cancer drugs.

So far, only a functional profiling has demonstrated this critical ability. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, functional profiling is measuring them through the surrogate of measuring if the cell is alive or dead. It can show this in the "population" of cells.

Literature Citation:

Weisenthal, L.M. Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007

Nagourney, R.A. Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)
E_L_Earnhardt
not rated yet Dec 03, 2008
cyroablation works on both types!

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