Cancer Research UK scientists have developed a system to identify faulty or missing genes that could prevent specific chemotherapy regimes from working. This opens the doors for targeted breast cancer treatment, according to research published in the Lancet Oncology today (Monday).
An international team of scientists led by Cancer Research UK’s London Research Institute* together with the Technical University of Denmark developed a bespoke method to scan 829 genes involved in response to a breast cancer drug, in breast cancer tumour cells. They selected those which if missing or faulty would prevent a chemotherapy drug called paclitaxel, from working effectively in patients with breast cancer.
Taxanes** block the growth of cancer cells by stopping cell division. The group includes paclitaxel (Taxol) and docetaxel (Taxotere) which is given to patients with breast cancer before surgery.
The team used a technique called RNA interference*** to delete each of the 829 genes, one at time in cancer cells, to explore how well paclitaxel worked in tumour cells if one particular gene was not working normally.
They narrowed the search down to find six genes which if faulty prevent paclitaxel from working effectively in breast cancer cells in the laboratory. They then showed in patients that these same six genes in breast cancer cells could be used to predict which of them will derive the most benefit from paclitaxel before they are exposed to treatment.
Lead author Dr Charles Swanton, head of translational cancer therapeutics at Cancer Research UK’s London Research Institute, said: “A great challenge in cancer medicine is determining which patients will benefit from particular cancer drugs and it is hoped that this research is a step towards more rapid developments in this type of personalised medicine.”
“Since the whole human genome was sequenced, scientists have been trying to understand the role of each of the 21,000 genes contained within it. Our research shows it is now possible to rapidly pinpoint genes which prevent cancer cells from being destroyed by anti-cancer drugs and use these same genes to predict which patients will benefit from specific types of treatment.”
More than 45,500 women are diagnosed with breast cancer in the UK each year – and it is estimated that around 15 per cent of these women will be prescribed paclitaxel. The researchers estimate from this small study that they could spare the prescription of less effective treatment to half of patients currently receiving this drug.
This research paves the way for further studies to determine if the technique can be developed into a simple diagnostic test to be given to patients to help inform doctors about whether or not to prescribe paclitaxel.
Dr Swanton, added: “Now the challenge is to apply these methods to other drugs in cancer medicine and to help identify new drugs within clinical trials that might benefit patients who are predicted to be unresponsive to treatment. These could include treatments that are currently deemed too expensive to fund on the NHS – however, in the future, treating only the patients that will benefit from certain treatments will save the NHS money in the long term. By identifying which patients do not respond well to certain treatments, doctors are able to consider alternative therapies, within clinical trials, aimed at treating individual patients more effectively.”
Dr Lesley Walker, Cancer Research UK’s director of cancer information, said: “This important research shows the impact that discoveries in the lab can have in the development of better ways to treat patients”.
“New techniques such as these can enable drugs to be tailored to individual patients, and this could potentially improve cancer survival in the long term. Health professionals may in the future be able to use this information to direct treatment to patients most likely to benefit and avoid giving treatment that is less likely to be effective to patients with drug resistant cancers.
“Ultimately similar approaches could reduce the cost of delivering cancer care whilst enabling improved patient access to beneficial treatments.”
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- Juul, N., Szallasi, Z., Eklund, A., Li, Q., Burrell, R., Gerlinger, M., Valero, V., Andreopoulou, E., Esteva, F., & Symmans, W. (2010). Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials The Lancet Oncology DOI: 10.1016/S1470-2045(10)70018-8
* 1 Center for Biological Sequence Analysis, Technical University of Denmark, DK-2800 Lyngby, Denmark.
2 Children’s Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology Harvard Medical School, Boston, MA 02115, USA.
3 Translational Cancer Therapeutics Laboratory, Cancer Research UK London
4 Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
5 Department of Breast Medical Oncology and 6Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-1439, USA.
7 Medical Oncology Department, Jules Bordet Institute, Brussels, Belgium
8 Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium
9 Royal Marsden Hospital, Department of Medicine, Breast Unit, Downs Road, Sutton SM2 5PT, UK.
**Giving people with breast cancer taxanes before surgery increases the proportion of cases of the tumour completely disappearing – called complete pathological response (pCR). But a significant proportion of breast cancer patients do not respond – and the proportion of patients with oestrogen negative forms of breast cancer that do not achieve pCR is still poor. Identifying the patients which carry genes that will not respond to taxanes is the first step towards determining who might benefit from alternative drugs.
Small sections of RNA can be added to bind to specific sections of RNA produced by a gene
In order to turn up or turn off the activity of a particular gene – and can be used to prevent RNA producing a protein. This has the same effect as ‘deleting a gene’.
Breast cancer can be oestrogen positive – in which case it is driven by the hormone oestrogen attaching to oestrogen receptors on the breast cancer cells. If a breast cancer involves cells which do not have oestrogen receptors – it is ER negative – patients will usually be advised to have chemotherapy.