Pharmacogenetics shows value in cancer treatment

Pharmacogenetics - which involves using a patient's genetic profile to examine whether they will respond to a particular drug or suffer serious side effects - has long been out forward as a way of improving therapy with medicines. This positive study provides some of the first evidence for a direct clinical benefit from the approach and should encourage drug developers to build pharmacogenetics into their drug development programmes from the outset.

The lead researcher in the project, Monika Hegi of the University Hospital of Lausanne in Switzerland, told the EORTC-NCI-AACR meeting in Geneva that pharmacogenetics would likely become routinely used in this form of brain cancer, called glioblastoma.

And the drug in question - Schering's Temodar (temozolomide) - would benefit by becoming the first-line therapy of choice in responder patients.

The test is based on detecting from biopsy material whether patients carry a gene called O-6-methylguanine-DNA methyltransferase (MGMT) - which is involved in DNA repair - and its respective methylation status in the patient's tumour.

Methylation is one of the ways that cells control which of their genes are active at a given time. If the MGMT promoter is methylated, the MGMT gene is silenced and this means that no MGMT repair enzyme will be produced, thus preventing correction of faults in the DNA.

The study, which includes a total of 573 glioblastoma patients, looked at a subset of 206 with biopsy material. 45 per cent of the samples indicated the patient had a methylated MGMT promoter, meaning that the MGMT gene was silent and their DNA repair system was impaired.

The researchers found that 46 per cent of those with the right genetic profile - a silenced MGMT promoter - were still alive after two years if they were treated with temozolomide alongside radiotherapy. In contrast, the chance of survival among patients with the wrong genetic signature was only 14 per cent - not much better than with radiotherapy alone.

Among the advantages of the approach are the ability to avoid raising the hopes of glioblastoma patients - especially as temozolomide became the first new drug for the disease in 30 years on its launch in 1999 - and allowing doctors to try alternative therapies straight away.

Radiation and surgery have been the first-line treatments for glioblastomas, but even with them the disease usually kills within a year or less. Intravenous chemotherapy first launched in the 1970s improves these odds only marginally and can have serious side effects.

Glioblastomas are the most aggressive of the 100 or so forms of cancer that originate in the brain and account for half or more of all cases. Around the world, 175,000 cases are diagnosed annually, with 125,000 deaths from the disease each year.

Cancer is the pathfinder indication for pharmacogenetics, with similar tests also being employed for two other recently launched therapeutics, Roche/Genentech's Herceptin (trastuzumab) for breast cancer and AstraZeneca's Iressa (gefitinib; ZD1839), used for tumours of the lung.

Meanwhile, Hegi and colleagues are also analysing the trial biopsies for molecular patterns that might indicate possible new drug targets.