1. Sex-Related Differences in Impact on Safety of Pharmacogenetic Profile for Colon Cancer Patients Treated with FOLFOX-4 or XELOX Adjuvant Chemotherapy.
- Author
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Ruzzo A, Graziano F, Galli F, Galli F, Rulli E, Lonardi S, Ronzoni M, Massidda B, Zagonel V, Pella N, Mucciarini C, Labianca R, Ionta MT, Bagaloni I, Veltri E, Sozzi P, Barni S, Ricci V, Foltran L, Nicolini M, Biondi E, Bramati A, Turci D, Lazzarelli S, Verusio C, Bergamo F, Sobrero A, Frontini L, and Magnani M
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Biomarkers, Pharmacological metabolism, Capecitabine administration & dosage, Chemotherapy, Adjuvant adverse effects, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Female, Fluorouracil administration & dosage, Fluorouracil adverse effects, Humans, Leucovorin administration & dosage, Leucovorin adverse effects, Male, Middle Aged, Multidrug Resistance-Associated Protein 2, Organoplatinum Compounds administration & dosage, Organoplatinum Compounds adverse effects, Oxaloacetates administration & dosage, Pharmacogenomic Testing methods, Polymorphism, Single Nucleotide genetics, Sex Characteristics, Antineoplastic Combined Chemotherapy Protocols adverse effects, Capecitabine adverse effects, Colonic Neoplasms drug therapy, Neoplasm Proteins genetics, Oxaloacetates adverse effects
- Abstract
Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.
- Published
- 2019
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