Monday January 25 2010
Higher activity in certain genes affected chemotherapy response
“A genetic breakthrough could help tailor treatments for breast cancer to individual patients,” The Daily Telegraph reported. It said that doctors are a step closer to personalised cancer care, after researchers discovered the reason why cancer in some patients responds to chemotherapy while it is resistant in others.
This story is based on research that found that tumours from patients whose cancer spread after surgery were more likely to have an increased expression of two genes. These genes were found to reduce the sensitivity of tumours to one type of chemotherapy but not to others.
Personalised chemotherapy regimens based on the genetic profile of tumours are feasible, and this valuable research contributes towards that goal. However, this is a laboratory study, and much more research would be needed before this were possible.
Where did the story come from?
The study was carried out by Dr Yang Li and colleagues from the Harvard Medical School in Boston, Massachusetts, US; the Technical University of Denmark, Lyngby, Denmark; and the Jules Bordet Institute and Université Libre de Bruxelles in Brussels, Belgium. The research was funded by the Breast Cancer Research Foundation in New York. The paper was published in the peer-reviewed medical journal Nature Medicine.
Both the Daily Mail and The Daily Telegraph generally reported the research in a balanced manner, although both placed slightly undue emphasis on the implications for personalised cancer treatment. The improved classification of cancers could potentially lead to more tailor-made chemotherapy regimens. Although these genes were found to still be susceptible to platinum-based and other chemotherapy drugs, further work is needed to assess the best treatment options for patients with a higher expression of LAPTM4B and YWHAZ.
What kind of research was this?
This laboratory study involved screening the genetic profiles of breast cancer tumours and assessing whether these genes are linked to how the tumours respond to adjuvant chemotherapy. Adjuvant chemotherapy is typically combined with surgical removal of a tumour to target any remaining small amounts of cancer, which could potentially spread or have already spread to other areas.
Some women with breast cancer do not respond to adjuvant therapy, and go on to develop cancer in other parts of the body. The researchers wanted to see whether there are certain genes that influence how well women respond to adjuvant therapy.
What did the research involve?
The researchers measured the gene expression profiles of 115 breast cancers from women diagnosed between 2000 and 2003. These women had been treated according to current guidelines, with additional (adjuvant) chemotherapy if necessary.
The researchers looked for genetic differences between tumours that had subsequently spread and tumours that had not. This analysis identified 12 genes that were in the same region of chromosome 8 that were overexpressed (more active) in tumours that spread.
To establish whether the genes in this region affected response to chemotherapy, the researchers grew breast cancer cells in the laboratory with a higher expression of chromosome 8. They then selectively turned off certain genes in this region to assess whether the cancer cells were more or less likely to respond when exposed to three different classes of chemotherapy treatments: anthracycline-based and platinum-based drugs, and chemotherapy drugs called taxanes, which stop cell division.
This technique showed which genes changed the cancer cells’ sensitivity to chemotherapy drugs. The researchers then looked at the levels of these genes in other breast cancer cells to see if there was a link between the expression of these genes and how much those cells responded to the chemotherapy.
Finally, they looked at the expression of the genes in tumour biopsies in trials of either anthracycline-based or platinum-based drugs when they were given before surgery as a single therapy.
What were the basic results?
There were 75 genes that had different expression in tumours that had spread compared to those that had not.
Of the genes associated with recurrent breast cancer, 12 were found on chromosome 8. Breast cancer cells where two of these genes, YWHAZ and LAPTM4B, were switched off, had more sensitivity to anthracycline-based chemotherapy. Other breast cancer cells with higher activity of YWHAZ or LAPTM4B were less responsive to anthracycline-based chemotherapy.
Platinum-based chemotherapy and taxanes appeared to have no such association with these genes. Adding these genes to cancer cells decreased their sensitivity to anthracycline-based chemotherapy, but did not affect their response to platinum-based chemotherapy or taxanes.
The genes appeared to affect the sensitivity of anthracycline-based chemotherapy in different ways. Higher levels of LAPTM4B appeared to prevent anthracycline drugs from reaching their target in the cell (the nucleus), while YWHAZ protected the cells from dying when treated.
In trials where a type of anthracycline chemotherapy was given before surgery, high expression levels of LAPTM4B and YWHAZ were again associated with a poorer response. However, when a type of platinum-based chemotherapy or a type of taxane was given, these genes did not affect the outcome.
How did the researchers interpret the results?
The researchers concluded that LAPTM4B and YWHAZ prevent the activity of anthracycline chemotherapy. Because these genes are located close together on a region of chromosome 8, tumours that have increased activity in this region may have a higher resistance to anthracycline chemotherapy.
They say that although anthracyclines seem to be a reasonable treatment in tumours without these increases, patients with this change may need alternative treatment.
This study found that two genes - LAPTM4B and YWHAZ - may inhibit the response of anthracycline-based adjuvant chemotherapy for breast cancer. Further work is now needed to determine how these genes affect the action of the drug and how many patients with breast cancer tumours express higher levels of these genes.
The improved classification of cancers could potentially lead to tailor-made chemotherapy regimens. Although these genes were found to still be susceptible to platinum-based chemotherapy and other drugs, further work is needed to assess the best treatment options for patients exhibiting a higher expression of LAPTM4B and YWHAZ.
Personalised chemotherapy regimes based on the genetic profile of tumours are feasible, and this valuable research contributes towards that goal. However, this is a laboratory study, and much more research would be needed before this were possible.