Genes and Breast Cancer

March 2009 - A study led by Washington University School of Medicine in St. Louis and published online in the Journal of Clinical Oncology has found that a set of 50 genes can reliably identify all four types of breast cancer, potentially enabling personalized therapy for individual patients. Researchers explain that this represents an advance on OncotypeDX, an alternative test in common use.

Dr Matthew Ellis, professor of medicine in the Division of Medical Oncology said:

"Unlike a widely used genomic test that applies only to lymph-node negative, estrogen-receptor positive breast cancer, this new genomic test is broadly applicable for all women diagnosed with breast cancer."

Co-authors include Dr Charles Perou, associate professor of genetics and pathology at the University of North Carolina at Chapel Hill School of Medicine, Dr Philip S. Bernard, assistant professor of pathology and medical director of the molecular pathology laboratory at the University of Utah Huntsman Cancer Institute, and Dr Torsten Nielsen, assistant professor of pathology and laboratory medicine at the University of British Columbia.

Researchers explain that breast cancers result from a variety of genetic abnormalities. The study analysed gene activity in more than 1000 tumors to identify their genetic signature and found that among thousands of genetic differences a set of 50 genes was uniquely associated with each type of tumor. Of the four forms of breast cancer (known as luminal A, luminal B, HER2-enriched and basal-like) the latter three tend to be associated with a poor prognosis.

Matthew Ellis explained:

"Our test is the first to incorporate a molecular profile for the basal-like type breast cancers. That's important because these breast cancers are arguably the most aggressive yet the most sensitive to chemotherapy. By identifying them we can ensure they are treated adequately."

The test also recognises a type typically known as 'normal-like' but researchers conclude that rather than being a fifth form of breast cancer, this classification tends to be associated with a sample containing insufficient tumor cells to make a molecular diagnosis.

Researchers compared the activity of the 50-gene set with the responses of 133 breast cancer patients to standard chemotherapy and found that the test was highly sensitive and more predictive than other clinical molecular markers (such as estrogen receptor status, progesterone receptor status or HER2 gene expression status).

The study found that the good-prognosis luminal A type was not sensitive to chemotherapy, suggesting that patients could be prescribed hormone-based therapy. Among the poor-prognosis tumor types, basal-like breast cancer was most sensitive to chemotherapy and luminal B the least.

Matthew Ellis added:

"Luminal B tumors are a very poor prognosis group, and none of the current conventional therapies are particularly effective against it. The ability to identify luminal B tumors accurately makes it possible to develop better therapies for this type."

Researchers are currently investigating how each tumor type responds to over 20 available drugs to help determine the best treatment. The 50-gene set can be assayed in preserved tumor samples, enabling retrospective study of post-treatment outcomes.

Braking Genes and Cancer Cell Division

February 2007 - A study by a team of physicists, mathematicians, computer scientists, and biologists from the Weizmann Institute of Science in Israel, the Sheba Medical Center and the M.D. Anderson Cancer Center in Houston, Texas, published in the online edition of Nature Genetics, has identified a number of genes involved in the mechanism that prevents uncontrolled cell division and found that aberrations are linked to certain types of cancer as well as to the relative aggressiveness of the disease.

Researchers explain that cell division is one way in which cancer cells differ from normal cells. Normal cell division is prompted by an external chemical signal from a growth factor initiating a sequence of events within the cell. Researchers mapped the network of genes activated as a result and found that some of the proteins produced caused cell division while others put brakes on the process. Researchers hope that the current study may lead to development of mechanisms to "restore the brakes" in cancer cells and halt disease progression.

The study found that after receipt of the growth factor signal, cell activity occurs in separate waves in which genes are turned on and off for different periods of time. First the activity of a few genes increases for about 20 to 40 minutes, causing cell division. However, the next four waves, from 40 to 240 minutes after the signal, primarily involve gene activity associated with the breaking mechanism, halting cell division. Researchers identified 50 genes that interfere with the first wave, producing proteins that directly attach to the cell-division genes or dismantle messenger RNA carrying instructions for cell division.

Tissues from ovarian cancer patients revealed a correlation between levels of activity in the "braking" genes, survival rates, and the aggressiveness of the disease. Researchers suggest that these findings may contribute to development of a personal genetic profile, identifying genetic defects responsible for each cancer, tailoring individual treatment plans, and helping to predict prognosis.

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