Genetic Variability and Cancer Germline polymorphisms are frequent: 1 SNP every bp (> 1 per gene) Cancer has acquired mutations (some tumor “mutations” common: e.g. most CML has t(9;22); Rb has LOH relative to germline) The Intl SNP Map Working Group Nature 2001

Relling & Dervieux 2001;1: Host and tumor genomes affect variability in anticancer therapy

Given Similar Schedule and Regimen, Pharmacogenetics should Have Similar Implications for Children and Adults Host –developmental changes expressed in somatic tissues contribute to child vs adult PK, PD differences –germline poly- morphisms affect host similarly in children and adults Tumor –tumors different children vs adults – germline polymorphisms affect tumor response/invasive- ness similarly in children vs adults

Pharmacogenetics and Cancer Polymorphisms in: host metabolism host distribution & transport host receptors & targets tumor receptors & targets pathogens May affect: cancer risk host toxicity tumor response infectious complications

Glutathione S-Transferase Polymorphisms and Outcome of Chemotherapy in Childhood Acute Myeloid Leukemia By Stella M. Davies, Leslie L. Robison, Jonathan D. Buckley, Tom Tjoa, William G. Woods, Gretchen A. Radloff, Julie A. Ross, and John P. Perentesis J Clin Oncol 19: N = 306 Dex, VP, AraC, TG, dauno: standard vs intensive timing

GSTT1 genotype did not affect outcome with Standard timing, but did affect outcome with Intensive timing (P < 0.05) JCO 19:1279, 2001

Among women with breast cancer, GSTP1 mutation associated with improved survival

The effect of each polymorphism must be evaluated in the context of the disease and its therapy (e.g. intensifying therapy in GST wild-type pts may be correct in children with AML but not adults with breast cancer)

Gonzalez et al; Diasio et al

Relling & Dervieux Nature Ca Rev 2001;1:99-108

> 1 polymorphism affects drug efficacy Germline polymorphisms also affect tumor responsiveness

Polymorphisms in Gene Products for MTX Metabolism and Targets may Affect PK/PD

Greater oral mucositis index (OMI) after MTX among BMT patients with mutant MTHFR C677T genotypes than among patients with C677C genotypes Ulrich et al Blood 98:231-4, 2001

But MTHFR did not Affect Toxicity after HDMTX (with LV)

The effect of each polymorphism may be dependent upon dose and schedule of the anticancer agent

Relling & Dervieux 2001;1: UGT1A1 Polymorphism affects risk of Irinotecan Toxicity

Relling & Dervieux Nature Ca Rev 2001;1:99-108

Relling et al JNCI, 1999

XI X-RTSC X-High XII Antimetabolite Intensity (during irradiation) vs Cumulative Risk of Brain Tumor * Score = 1 for ITs during rads, -1 for LV during rads, 2 for systemic MTX during rads, 2 for full dose 6MP during rads Lancet 1999

Elucidating the clinical implications of each polymorphism may take a long time (AKA drugs have unintended consequences)

Incorporate Pharmacogenetics into all Clinical Trials Clinical trials are expensive freezing a tube of blood is cheap genotyping will get cheaper in the future obtain proper consent for future pharmacogenetic studies let’s not pretend we currently understand what to look at in the future

Polymorphisms Affecting Supportive Care Impact on Patient Outcome Antimicrobials (K+ channels) cardiovascular agents (ACE, beta receptors) antithrombotics (CYP2C9, MTHFR, Factor V Leiden, prothrombin)

“Emphasis should not be focused on population averages, but rather on providing prescribers with the tools to determine the most effective and safest drug dosage for individual patients with a minimum of trial and error.” –Gerhard Levy, Clin Pharmacokin 34: , 1998