Fortune telling – the role of gene signatures in predicting response and toxicities

Doctors at the Australia and New Zealand joint scientific meeting for the Medical Oncology Group of Australia and the Faculty of Radiation Oncology, were treated to an insight into genetic testing that can identify which patients are likely to benefit most from cancer treatments and also to identify those patients who are most at risk of side effects.

Professor David Kerr, Rhodes Professor of Clinical Pharmacology and Cancer Therapeutics at the University of Oxford, talked about the identification of gene markers which predicted which stage 2 colon cancer patients were likely to benefit from adjuvant chemotherapy. He pointed out that for every 100 patients with stage 2 (Dukes B) colon cancer given adjuvant chemotherapy, 80% were already cured by surgery, 16% died despite chemotherapy and 4% were cured by the addition of chemotherapy to surgery. Is it possible to identify those patients who would benefit?

Prof Kerr proposed stratifying patients into high, low and intermediate risk using prognostic genes and predictive genes to identify those who would best benefit from treatment. He discussed the role of Affymetrix U133a which was studied in 74 patients with Dukes B disease (Wary et al JCO 2004). There were 31 relapses within 3 years and gene profiling identified 3 genes whose signature was predictive for recurrence with accuracy of 78%.

The ColoPrint project identified 140 samples from two Dutch cancer institutions with stage 2 and 3 disease. This was validated with a further 200 samples from 4 European cancer centres with stage 2 disease. Further validation tests were then performed on samples from patients with rectal cancer and stage 3 colon cancer in a US setting.

The gene profiling was able to stratify patients into high risk and low risk population which showed the time taken for first metastasis to appear. The high risk population showed a 40% metastasis rate in 2 years compared to a 5% metastasis rate in the low risk group.

The Illumina Hap 550SNP Array identifies single nucleotide polymorphisms on chromosome 15q which were associated with risk of colorectal cancer. This was used to assess samples form 850 patients from VICTOR adjuvant colon study and 1000 patients from the QUASAR II study. The germ line SNP was studied in 250 patients with recurrence vs. 250 matched controls without recurrence. It enabled stratification of toxicity seen from capecitabine and bevacizumab into high risk and low risk groups.

It is hoped that this information will subsequently become more validated as enrolment in QUASAR II progresses. Patients at high risk of toxicity due to SNP could then in theory be offered different chemotherapy or be dose-adjusted to ensure that they avoid toxicity from standard therapies.