Scientists have found a genetic test that predicts whether bone marrow cancer treatments including thalidomide are likely to give patients a debilitating side-effect. The study led by The Institute of Cancer Research (ICR) is published today in the Journal of Clinical Oncology.
Around 4,000 British people are diagnosed each year with multiple myeloma, an aggressive cancer that affects a type of white blood cell in the bone marrow called plasma cells. Average survival after diagnosis is just three to five years, despite patients receiving intensive treatment with a combination of drugs.
All common treatment regimens for multiple myeloma also contain at least one drug with the side-effect of peripheral neuropathy – a disorder of the nervous system that can cause altered sensation, tingling, numbness and severe pain.
Almost one-third of patients of patients in this study who were treated with the immune stimulating therapy thalidomide developed neuropathy, along with around one-third of patients whose treatment regimen contained the chemotherapy drug vincristine. In contrast, only 6.4 per cent of patients whose treatment combination did not include thalidomide or vincristine developed neuropathy.
Symptoms sometimes clear when the patient stops the treatment or reduces their dose, but neuropathy can be permanent and crippling, and until now it has not been possible to predict which patients will be afflicted.
In this study*, the researchers analysed DNA from around 1,500 patients with multiple myeloma, searching through almost 1,000 genes that have previously been linked cancer growth and treatment response.
When they examined patients who had been treated with thalidomide, they found five regions of DNA were more common in patients who had suffered neuropathy than those who had not developed the condition. Interestingly, the regions are part of genes involved in repair, development and inflammation of the peripheral nervous system.
To determine whether the genes found were drug-specific, they ran the same scan on patients treated with vincristine and found a different set of genes – nine in total - were more common in patients who developed neuropathy. The finding indicates that each drug type causes neuropathy through a different biological pathway.
The study raises the possibility patients could have their blood screened for neuropathy risk genes.
“Doctors could use this simple and useful test to identify patients at high risk of neuropathy,” The ICR’s Professor Gareth Morgan, who is also Head of the Haematology Unit at The Royal Marsden Hospital NHS Foundation Trust, says. “At-risk patients could be closely monitored, and potentially given alternative treatments, lower doses or additional therapy to reduce side-effects. This knowledge may also help us develop treatments that could protect patients from neuropathy.”
This study also has implications for other cancer types as vincristine, for example, is commonly used to treat acute lymphoblastic leukaemia and lymphoma.
The study was funded by the Medical Research Council (MRC), International Myeloma Foundation, Myeloma UK and the National Institute for Health Research through its support of the Biomedical Research Centre at The Royal Marsden and the ICR.
* The study was a new arm of the MRC Myeloma-IX trial, which compared standard treatment with thalidomide-containing regiments. The trial included 970 patients treated with cyclophosphamide, thalidomide and dexamethasone (CTD) and 550 patients treated with cyclophosphamide, vincistine, doxorubicin and dexamethasone. The results were validated in a second comparable study, the HOVON-50/GMMG-HD3 trial.
“Genetic Factors Underlying the Risk of Thalidomide-Related Neuropathy in Patients With Multiple Myeloma” publishes in the Journal of Clinical Oncologyon March 1 2011, with an accompanying editorial “Genetic Predisposition for Chemotherapy-Induced Neuropathy in Multiple Myeloma” by Pamela S Becker, University of Washington.
The Institute of Cancer Research (ICR)