Herceptin Targets Breast Cancer Stem Cells

[News]

A gene that is overexpressed in 20 percent of breast cancers increases the number of cancer stem cells, the cells that fuel a tumor's growth and spread, according to a new study from the University of Michigan Comprehensive Cancer Center. The gene, HER2, causes cancer stem cells to multiply and spread, explaining why HER2 has been linked to a more aggressive type of breast cancer and to metastatic disease, in which the cancer has spread beyond the breast, the researchers say.

More... (http://www.medicalnewstoday.com/articles/114466.php)

[gdpawel]

Some patients' tumors respond to chemotherapy and some do not. A pathway/mechanism - cancer stem cells - may be the cause. To prevent cancer's return may require one therapy to shrink a tumor and another therapy to kill the abnormal seeds that sprouted it. Conventional cancer therapies have been good at shrinking tumors, but the ability to shrink tumors has little or no correlation to survival times. Newer treatments need to decrease the number of cancer stem cells.

There is a communication between stem cells and a tumor. It sends out a signal that make the different cells of the tumor and the cancer cells then (send chemical messages) that cycle back to the cancer stem cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific pathways that involve various genes and proteins in a cell.

Finding the protein that prevents cancer from metastasizing, isolating factors within the stem cell microenvironment, can influence tumor cell fate and reverse the cancerous properties of metastatic tumor cells. However, it is not the only tumor suppressive factor within the stem cell microenvironment. Not all genes and proteins have a critical role in the survival and growth of cancer cells.

In some cases, targeted drugs may kill tumor cells without killing microvascular cells in the same time frame. In other cases, they may kill microvascular cells without killing tumor cells. Yet in other cases, they could kill both types of cells or neither type of cells. The ability to these targeted agents to kill tumor and/or microvascular cells in the same tumor is highly variable among the different agents.

You still need to measure the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific cancer drugs, not just the individual molecular targets. Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease.

Sources:
Cell Function Analysis
European Science Foundation
American Association for Cancer Research

[gdpawel]

The Wall Street Journal Health Blog reported that Aetna put out an announcement that says if there's uncertainty about the accuracy of a genetic test that breast cancer patients get, the insurer will cover a do-over.

The test determines whether a patient's tumor expresses an excess amount of the protein HER2. If the test comes back positive, the patient may be a candidate for Herceptin, which targets HER2.

But the tests have sometimes proved unreliable. Some problems have to do with the labs' technique, others have to do with how the results are interpreted by doctors.

Aetna is not alone. United Health Care's Lee Newcomer, SVP of oncology services, says that there's been a lack of consistency in how the test results are reported to doctors, which leads them to have trouble interpreting them.

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Her-2/neu testing is not available in every laboratory. Both IHC and FISH require experience and special training to perform and interpret. Your doctor will probably send your sample to a reference laboratory and the results may take several weeks to return.

The FISH test, which can be done on new or old tumor tissue samples, is considered the most accurate test for HER2/neu gene malfunction. It's the preferred method for testing older tissue samples (if new biopsy material is unavailable).

Most hospitals still use the older IHC technique to measure the amount of HER2/protein in the cells. Most testing laboratories are more familiar with IHC, and it's much less expensive than FISH ($100 vs. $400). Results demonstrate that there is poor agreement between the results from local laboratory-based HER2 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. Perhaps more unexpected, there has been poor concordance in terms of FISH testing in a central laboratory compared to the local laboratories. The latter is surprising because the prevalent notion regarding FISH was that it was 100 percent accurate. It's not.

What pathologists see under the microscope with FISH is a matter of counting dots, although 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.

It costs well in excess of $1,000 to do EGFR mutation and FISH for amplification. All of which tells you whether or not to give one drug (Herceptin). Cell-based function analysis more often find breast cancer patient sensitive to other compounds and combinations and can recommend these all from one assay. It costs a lot more to give a single cycle of chemotherapy than it does to test all of the possible options.

All the gene amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one drug (Herceptin) is better or wrose than another drug (Tykerb) which may target this.

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.

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’ response to drug treatments, not just one target or pathway.

About the AngioRx Assay in breast cancer:

ER and PR tests in breast cancer, which detect only VEGF expression, or even overexpression, are valuable not because they measure expression of estrogen and progesterone but rather because they detect (and supposedly measure) the ER and PR receptors in the nucleus. The presence of positive IHC staining of such receptors in at least 10% of nuclei implies that the tumor is hormonally dependent and that, therefore, depriving the cells of the hormone will kill them or retards their growth.

Unlike a test for the presence of receptors to a specific antigen, which only "implies" dependence upon that antigen, an AngioRx assay is functional in that it actually assesses the direct or indirect effect of the drug upon the cell, whether it is a tumor cell or an endothelial cell. VEGF just happens to be one molecule which has been implicated in the process but there may be more.

If it were the only protein involved, then one would expect that VEGF expression would correlate with Avastin activity 100% of the time but it actually does so only about 20% of the time. The AngioRx assay doesn't just focus on VEGF or any one protein or mechanism. Whether it's VEGF alone (unlikely) or in combination with other proteins and other mechanical factors, the assay works by assessing the net effect of all those factors.