Dr. Nasir Ali Afsar MBBS, M.Phil Assistant Professor (Pharmacology)

1. Genotype Frequencies of Selected Drug Metabolizing Enzymes and ABC Transporters in Breast Cancer Patients Dr. Nasir Ali Afsar MBBS, M.Phil Assistant Professor (Pharmacology) & Ph.D Scholar in Clinical Pharmacology

2. Authors Nasir Ali Afsar, HR Ahmad, Kh Zafar Ahmed Ingolf Cascorbi, Sierk Haenisch, Mike Ufer Ahmed Mateen Ahmed Usman 19th MRSP Meeting, Lahore

3. Background • Breast cancer – most frequent malignancy among Pakistani females. • Hanif et al. 2009 Asian Pac J Cancer Prev • Bhurgri et al. 2006 J Pak Med Assoc 19th MRSP Meeting, Lahore

4. Clinical Stages at Presentation (%) Afsar et al: Unpublished data (n = 206). 19th MRSP Meeting, Lahore

5. Breast Cancer Chemotherapy (%) Afsar et al: Unpublished data (n = 206). 19th MRSP Meeting, Lahore

6. Response to Chemotherapy Afsar et al: Unpublished data (n = 206). 19th MRSP Meeting, Lahore

7. Drug Disposition andTherapeutic Resistance Drug X Transporter Transporter Drug X Phase-I Metabolism Phase-II Metabolism Metabolite Y (active) Metabolite Z (inactive) 19th MRSP Meeting, Lahore

8. Intravenous FAC Liver Target Tissue Phase-I (Non-synthetic) Metabolism: CycP CYP2C – activation ALDH – inactivation Phase-II (Synthetic) Metabolism: inactivation Efflux GST (CycP; Doxo) ABC Ts (Doxo; 5FU) 19th MRSP Meeting, Lahore

9. Drug disposition affects clinical outcome… Petros et al. (2005) J Clin Oncol: Overall survival following chemotherapy in relation to GSTM1 genotype. 19th MRSP Meeting, Lahore

10. Objective • To explore the “FAC pertinent” genotype in a local breast cancer cohort and their comparison with HapMap data. 19th MRSP Meeting, Lahore

11. Method • Institutional approval • Informed consent • Sixty eight IDC patients, all on FAC • Blood samples - DNA extraction • Technique • PCR amplification, followed by • RFLP detection on AGE, or • Pyrosequncing • New method development: GSTA1 -69 & -52, ALDH3A1 • Validation through Sanger’s chain termination method 19th MRSP Meeting, Lahore

12. Variant Allele Frequency Distribution *P < 0.05 * * * * * * 19th MRSP Meeting, Lahore

13. Variant Allele Frequency Distribution *P < 0.05 NA= not available * * * * 19th MRSP Meeting, Lahore

14. Variant Allele Frequency Distribution *P < 0.05 * * * NA= not available * * * 19th MRSP Meeting, Lahore

15. Variant Allele Frequency Distribution *P < 0.05 * * * 19th MRSP Meeting, Lahore

16. Possible Implications • Possible Effect: • Efficacy of CycP < Doxorubicin or 5FU • Treatment failure 19th MRSP Meeting, Lahore

17. Acknowledgement We are thankful to following for their support : • Ziauddin University, Karachi. • Higher Education Commission Pakistan: International Research Support Initiative Program. • Institut für Experimentelle und Klinische Pharmakolgie, Kiel, Germany. 19th MRSP Meeting, Lahore

18. Genotype Frequencies of Selected Drug Metabolizing Enzymes and ABC Drug Transporters among Breast Cancer Patients on FAC Thank You 19th MRSP Meeting, Lahore