Pharmacogenomic Assessment of Patients with Colorectal Cancer and Potential Treatments.

Abstract

Evolving intensiveness of colorectal cancer (CRC) treatment, including chemotherapeutics and targeted agents associations, in adjuvant and metastatic CRC (MCRC) settings, increased overall survival (OS) with individual variability of toxicity. Pharmacogenomic guidelines recommended pre-treatment identification of at-risk patients suggesting dose adjustment of fluoropyrimidines based on dihydropyrimidine dehydrogenase (DPYD), and irinotecan on UDP glucuronosyl-transferase 1 family polypeptide A1 (UGT1A1) genetic variants, but they are poorly applied in clinical practice. This review highlighted clinically validated pharmacogenetic markers, to underline the need of their implementation in the multidisciplinary molecular board for individual CRC patients in clinical practice. Five clinically relevant DPYD variants with different prevalence impair enzymatic effectiveness and significantly increase toxicity: c.1236 G>A (c.1129–5923 C>G, HapB3), 4.1–4.8%; c.1679 T>G (DPYD*13), c.1905+1G>A (DPYD*2A), c.2846 A>T, c.2194 A>T (DPYD*6) 1% each. c.1679T>G and c.1905+1G>A are most deleterious on DPD effectiveness, moderately reduced in c.1236/HapB3 and c.2846A>T. Cumulatively, these variants explain approximately half of the estimated 10–15% fluoropyrimidine-related gastrointestinal and hematological toxicities due to DPD. Prevalent UGT1A1 gene [TA]7TAA promoter allelic variant UGT1A1*28, characterized by an extra TA repeat, is associated with low transcriptional and reduced enzymatic effectiveness, decreased SN38 active irinotecan metabolite glucuronidation, vs wild-type UGT1A1*1 [A(TA)6TAA]. Homozygote UGT1A1*28 alleles patients are exposed to higher hematological and gastrointestinal toxicities, even more than heterozygote, at >150 mg/m2 dose. Dose reduction is recommended for homozygote variant. Wild-type UGT1A1*28 alleles patients could tolerate increased doses, potentially affecting favorable outcomes. Implementation of up-front evaluation of the five validated DPYD variants and UGT1A1*28 in the multidisciplinary molecular tumor board, also including CRC genetic characterization, addresses potential treatments with fluoropyrimidines and irinotecan associations at proper doses and schedules, particularly for early CRC, MCRC patients fit for intensive regimens or unfit for conventional regimens, requiring treatment modulations, and also for patients who experience severe, unexpected toxicities. Integration of individual evaluation of toxicity syndromes (TS), specifically limiting TS (LTS), an innovative indicator of toxicity burden in individual patients, may be useful to better evaluate relationships between pharmacogenomic analyses with safety profiles and clinical outcomes.