PreIMPAKT Training Course DNA

1
Pre-IMPAKT Training CourseDNA

• Romano Danesi, MD, PhD
• Division of Pharmacology Department of Internal
  Medicine
• Cancer Pharmacology Unit University Hospital
• University of Pisa, Italy

2
Disclosure slide

• I have no conflict of interest to declare
  concerning this presentation

3
SNPs may occur at any position in the gene
4
Genetic polymorphisms, pharmacokinetics and
pharmacodynamics of drugs
Yamayoshi Y et al. Int J Clin Oncol 2005
5
Pharmacogenetics as the science of candidate genes
6
Genes that may influence efficacy or safety of
breast cancer treatments
7
Genes that may influence efficacy or safety of
breast cancer treatments
8
CYP2D6-dependent metabolism of tamoxifen
Jin Y et al. J Natl Cancer Inst 97 30-9, 2005
9
CYP2D6 and SSRI interaction with tamoxifen
Jin Y, Desta Z, Stearns V, et al. CYP2D6
genotype, antidepressant use, and tamoxifen
metabolism during adjuvant breast cancer
treatment J Natl Cancer Inst 97 30-9, 2005

• CYP2D6 variants with null or reduced enzyme
  activity
• CYP2D63A (2549Agtdel) CYP2D64A (100CgtT 974CgtA
  984AgtG 997CgtG 1661GgtC 1846GgtA-splicing defect
  4180GgtC) CYP2D66A (1707Tgtdel) CYP2D67
  (2935AgtC) CYP2D68 (1661GgtC 1758GgtT-stop
  codon 2850CgtT 4180GgtC) CYP2D610 (100CgtT)
  CYP2D611 (883GgtC-splicing defect 1661GgtC
  2850CgtT 4180GgtC) CYP2D615 (138insT)

10
CYP2D6 phenotype in humans

• The CYP2D6 function in any particular subject may
  be described as one of the following
• poor metaboliser - these subjects have little or
  no CYP2D6 function
• intermediate metabolizers - these subjects
  metabolize drugs at a rate somewhere between the
  poor and extensive metabolizers
• extensive metaboliser - these subjects have
  normal CYP2D6 function
• ultrarapid metaboliser - these subjects have
  multiple copies of the CYP2D6 gene expressed, and
  therefore greater-than-normal CYP2D6 function

11
(No Transcript)
12
In tamoxifen-treated patients, women with the
CYP2D6 10 T/T genotype have a lower
4OH-tam/endoxifen levels in the serum and a worse
clinical outcome.
13
DFS of CYP2D6 10 breast cancer patients
receiving tamoxifen
152 patients
14
DFS of CYP2D6 10 breast cancer patients not
receiving tamoxifen
141 patients
15
CYP19 contributes to variation in the
pathophysiology of estrogen-dependence
16
Human CYP19 genetic polymorphisms
17
CYP19 recombinant allozyme activity, protein
levels and inhibitor kinetics
18
5-FU anabolic and catabolic pathways
19
Enzymatic activity of DPD and 5-FU toxicity
Normal
Deficiency
5-FU
5-FU
5-FdUMP
5-FdUMP
DPD
TS
TS
5-FDHU
5-FDHU
Tolerable toxicity
Tossicità grave
Danesi R et al. Trends Pharmacol Sci 2001 Di
Paolo A et al. Clin Pharmacol Ther 2002
20
Polymorphisms of DPYD
21
Polymorphisms of DPYD
22
TS polymorphisms
1 USF box TS
0 USF box TS
2 USF boxes TS
2 USF boxes TS
3
1 USF box TS
3
23
Pharmacogenetics of capecitabine in advanced
breast cancer patients
Purpose Germinal gene polymorphisms can explain
a part of the interpatient pharmacodynamic
variability of anticancer drugs, particularly
fluoropyrimidines. Experimental design Germinal
polymorphisms of TS (6 bp deletion in the 3'
region and 28 bp repeats, including GgtC mutation
in the 5' region), MTHFR (677CgtT and 1298AgtC),
and DPD (IVS14 1GgtA) were determined. Results
A higher toxicity grade 3 and 4 was observed in
patients TS 3RG homozygous compared with patients
TS 3RG heterozygous or 3RG null (50 versus 19
versus 13 respectively, P 0.064). A patient
bearing the DPD IVS14 1GgtA mutation
(heterozygous) deceased from hematologic
toxicity. Duration of response was significantly
shortened in patients homozygous for the 3RG
allele compared with others (P 0.037).
Conclusions The present data suggest that
3RG3RG breast cancer patients are not good
candidates for capecitabine therapy. In addition,
attention should be paid to DPD deficiency in
breast cancer patients receiving capecitabine.
24
What to do not to look to the wrong direction?
25
Major limitations of current studies on genetics
and drug activity

• Insufficiently powered to detect a difference
  among genetic variants
• Choice of genetic polymorphism often unclear
• Issue of germline vs. somatic variants not
  addressed
• Standard clinical endpoints may not be suitable
• Clinical trial design - retrospective vs.
  prospective data collection
• Ethnic issue often not taken into account
• Predictivity of drug effect confused with
  prognostic value

26
Conclusions

• The transfer of basic science concepts to cancer
  treatment greatly improved the collaboration
  between basic researchers and clinicians
• The relevance of genetic polymorphisms of drug
  targets, enzymes of drug metabolism and drug
  transporters in clinical decision making remains
  a matter of debate until full validation within
  clinical trials is obtained
• The selection of patients with highest
  probability of responding to treatment is
  mandatory to afford the cost of novel, highly
  expensive target-specific anticancer drugs