Project title ： The Association of Pharmacogenetics and Chemotherapy-Induced Toxicities in Breast Cancer Patients Receiving Chemotherapy
Principal investigator ： Prof Tang, Leung Sang Nelson, Department of Chemical Pathology, The Chinese University of Hong Kong
Co-investigator ： Prof Winnie Yeo, Associate Professor, Department of Chemical Pathology, The Chinese University of Hong Kong

“Summary of the project”
 
Chemotherapy is a main stage treatment in many breast cancer patients. However, such treatment is associated with toxicity leading to side effects including symptoms of vomiting. Anemia (low haemoglobin), and pancytopenia (low white blood cells) are important side effects due to toxicity of chemotherapy to the bone marrow. Presently, it is not able to predict which patient will have more severe toxic effect and therefore, all patients receive the same empirical dosage of cytotoxic drugs. These cytotoxic drugs are cleared or metabolised by the body by groups of enzymes. It is recognised that genetic variations in single base of the genes of these enzymes could affect the ability of the body to metabolize the cytotoxic drugs. Therefore, the purpose of this study is to analysis the genetic variations in these enzymes and their inducer genes in Hong Kong Chinese and their association with clinical toxicity after chemotherapy in breast cancer patients. In the long term, the goal of this and future studies of this kind is to enable prediction of body response to drug and therefore, patients will be given personalised medicine, that is dosage or regimen of drug tailormade to persons’ body/genetic makeup.
 
Report of Progress (up to June 2008)
 
The project has been commenced since 1 June 2006.
 
Up to June 2008, we have completed follow up of 80 patients during their chemotherapy course which is consists of 4 cycles of treatment. In our recent study, we investigated the association of a functional SNP in PTGS-2 (encoding for the COX-2, cyclooxygenase-2) and clinically significant neutropenia after chemotherapy among breast cancer patients because COX-2 regulate the expression of MDR-1 (P-glycoprotein) which affect cellular transport of many cytotoxic drugs and thus, their cytotoxicity. COX-2 is the inducible isoenzyme for which we have previously identified a putative functional SNP in the coding gene for COX-2, PTGS-2. Eighty Chinese female breast cancer patients were studied and monitor throughout the cycles of treatment by a standard doxorubicin-cyclophosphamide regimen. A 3-UTR SNP (rs5275, Ex10+837 T>C) in the PTGS-2 gene was genotyped by PCR-RFLP as described previously. In the study cohort, 16% of patients developed clinically significant neutropenia requiring a change of treatment cycle/regimen, 12 of them were homozygote TT genotype while 43 out of 60 of those not affected were homozygote. The genotype of patients with clinically significant neutropenia were compared to a sample of 244 population controls and the allelic frequencies of T allele showed a borderline significant difference (0.96 in neutropenia group and 0.81 in population, p=0.06).
 
Preliminary findings
 
This 3-UTR SNP was a potential functional SNP located within a region which had been shown to influence mRNA stability. The T allele had been implicated for regulation of COX-2 activity. It is postulated that prostaglandin metabolism may contribute to the growing dimension in pharmacogenetics of chemotherapy toxicity.

These results have been presented in an abstract in the XX International Congress of Genetics in Berlin, Germany (July 12 – 17, 2008).