Wednesday February 24 2010
Around 10% of people do not respond to tamoxifen
The Daily Express said today that “thousands of breast cancer sufferers have been given fresh hope” by research into why so many fail to respond to a life-saving drug treatment.
The research looked at the action of a gene called FGFR1, linking it to the process that prevents the long-term chemotherapy tablet tamoxifen from working in an estimated 10% of patients. The presence of the gene could partially explain why some women see their cancer return years after treatment. It also potentially means that new drugs could potentially block the gene’s action, a possibility currently being examined through ongoing research.
As early research, this study has tested a new theory, and although new treatments for breast cancer recurrence would be welcome, it is not possible to say yet if treatments based on this finding will be effective.
Where did the story come from?
This research was carried out by Dr Nicholas Turner and colleagues from a number of research centres, including the Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research at the Royal Marsden Hospital. The study received grants from Cancer Research UK and Breakthrough Breast Cancer, plus National Health Service funding through the National Institute for Health Research Biomedical Research Centre. The study was published in the peer-reviewed journal, Cancer Research.
While the Daily Express has suggested the research ‘gives hope’ to women with breast cancer, BBC News concentrated on the scientific implications of the study, saying that it had identified a gene error that scientists believe they can fix.
What kind of research was this?
This was research looking at how a particular chemical receptor, the fibroblast growth factor receptor 1 (FGFR1), affects prognosis in breast cancer.
Fibroblast growth factor receptors are a group of receptors that occur on the surface of cells and attach to the family of proteins known as fibroblast growth factors (FGR). These proteins regulate many developmental pathways in the body, including controlling events in the early embryo and the development of multiple organ systems. Their signalling action also extends to many physiological roles in adults, including the regulation of blood vessel growth and wound repair.
While FGF signalling has a number of important roles in the body, it can encourage growth of tumours. The researchers say the widespread actions of FGF signalling in the body makes the pathway particularly susceptible to subversion by cancer cells.
The researchers conducted a laboratory experiment with tumour cell samples, looking for whether the cells that ‘overexpressed FGFR1’ (i.e. had large numbers of this receptor) would grow faster and develop more resistance to the endocrine therapies currently used in breast cancer treatment.
Endocrine therapies, such as the use of tamoxifen, are based on blocking the body’s hormones from encouraging tumour growth.
What did the research involve?
The researchers explain that despite improvements in treatment for breast cancer, cancers can become resistant to therapy. A number of distinct subtypes of breast cancer have been identified, such as those that have oestrogen receptors on their surface (known as ER-positive) that make them grow faster in the presence of the female sex hormone.
The oestrogen receptor status of tumours is described in two broad categories (A or B receptor types) depending on whether the cancer cells have a low or high number of receptors. In general, cancers that are ER-positive have a good prognosis. However, B–type tumours, that tend to grow rapidly, have a poor prognosis in patients treated with hormone therapies such as tamoxifen. Tamoxifen blocks the female sex hormone oestrogen, that fuels the growth of ER-positive breast cancers.
The researchers looked at two independent lines of cancer cells that were ER-positive. They looked at how the protein FGFR1 was expressed, identifying the cells in which this expression was amplified. They also looked at how these cells grew when exposed to different concentrations of the drug, 4-hydroxytamoxifen. They then chemically blocked the actions of the growth factor and retested the growth rates of the tumours.
The researchers also looked at the genes that produce the FGFR proteins, looking for mutations associated with the expression of these proteins.
What were the basic results?
The researchers say that the cell lines showing increased activity of the FGFR1 receptor were resistant to 4-hydroxytamoxifen and that this resistance was reversed by chemically blocking the actions of FGFR1. They say this suggests that FGFR1 overexpression promotes resistance to endocrine therapy.
How did the researchers interpret the results?
The researchers say their data suggests that “amplification and overexpression of FGFR1” may be a major contributor to poor prognosis in B type, ER-positive breast cancers. They say that this is because of the increased resistance to endocrine therapy that comes with overexpression of FGFR1.
This interesting science is based on molecular cell biology and points the way to future research.
The researchers note that, in addition to FGFR1, other genes are also likely to contribute to the development of cancer and that these genes may act in collaboration with FGFR1.
The researchers have also said that it is possible that their finding might help in diagnosis or treatment. It seems plausible that a test could be devised to measure FGFR1 activity in some cancers and identify those women who would benefit from more intensive therapy. However, there is a need for much further research before any such theoretical test could potentially be used.
The researchers also mention the possibility of developing drugs to block the activity of FGFR1, highlighting the continuing development of drugs known as FGFR tyrosine kinase inhibitors. While the research into these drugs is of interest, it should also be remembered that not all breast cancers are the same. Even if proven to work for this type of breast cancer, FGFR inhibitors may not be suitable for everyone with the disease.