ABSTRACT
Genetic polymorphisms in the early onset of oxaliplatin neuropathy after adjuvant FOLFOX
1CRO, Experimental and Clinical Pharmacology, Aviano, 33081, Italy, 2S. Filippo Neri, Oncology, Rome, 00135, Italy, 3S.Maria Della Misericordia, Oncology, Udine, 33100, Italy, 4 Conegliano Hospital, Oncology, Conegliano, 31015, Italy, 5Latisana Hospital, Oncology, Latisana, 33053, Italy, 6Pierfortunato Calvi, Oncology, Noale, 30033 , Italy, 7Umberto I, Oncology, Mestre, 30174, Italy, 8CRO, Oncology, Aviano, 33081, Italy
Oxaliplatin is used in the adjuvant treatment of colorectal cancer (CRC). Its dose limiting side effect is a cumulative peripheral neuropathy usually observed after 4 to 6 months of treatment. The molecular basis of this toxicity has not been elucidated yet. Different cellular pathways have been hypothesized to play a role in the neurotoxicity development and specific genetic variants seem to describe the phenotypic trait heritability.
Aim of this prospective study is to define the role in the neurotoxicity development of a panel of genetic polymorphisms in different cellular pathways as the DNA repair; phase I and II metabolism; apoptosis; folate cycle; and cellular transport pathways. Secondary aim is to highlight the role of the same genetic variants on hematological and non-hematological toxicity development. We analyzed 78 polymorphisms in 34 genes (XPD, XRCC1, XRCC3, APE1, hOGG1, hMSH6, hMSH2, hMLH1, PARP1, MGMT, hEXO1, ERCC1, RAD51, XPG, ATM, MDM2, GSTP1, GSTA1, GSTT1, GSTM1, GSTM3, UGT1A1, SOD2, AGXT, PMP2, TLR4, TYMS, MTHFR, TP53, SLCN2A, ABCC1, ABCB1, ABCC2, ABCG2), in 154 CRC patients homogeneously treated with adjuvant FOLFOX regimen (oxaliplatin, 100 mg/m2 every 2 wks+ 5-fluorouracil/leucovorin). Neuropathy was graded according to the oxaliplatin-specific scale (by Caussanel). Hematological and non hematological toxicities were graded by NCI-CTC criteria. The highest grade of neurological, hematological and non-hematological toxicities developed during the entire course of chemotherapy (12 bi-weekly administrations) were considered for the statistical analyses. Stepwise logistic regression analysis was employed for the calculation of toxicity relationships to the polymorphisms. The molecular analyses, based on Pyrosequencing®, TaqMan allelic discrimination, and automated fragment analysis technologies, were carried out on genomic DNA extracted from peripheral blood lymphocytes. Multivariate analysis highlighted a significant association between severe grade 3 neuropathy and two polymorphisms: UGT1A1-rs4124874 and XRCC1-rs1799782. The presence of at least one variant allele resulted protective towards G3 neurotoxicity development (OR=0.23, 95%CI 0.06- 0.91; P=0.037) for the UGT1A1 polymorphism, otherwise it resulted a risk factor for the XRCC1 polymorphism (OR=6.94, 95%CI 1.60- 30.15; P=0.007).
Severe hematological toxicity (G0-2 vs G3-4) was associated to ABCG2-rs3219191 and ABCC1-rs35587 polymorphisms by multivariate analysis. Both the polymorphisms in the transport proteins appeared to be protective against severe hematological toxicity development with an OR of 0.22 for the homozygous ABCG2-rs3219191 patients (95% CI 0.08- 0.65; P=0.006), and 0.46 for patients carrying at least one ABCC1-rs35587 variant allele (95% CI 0.23-0.94; P=0.033). G3-4 non-hematological toxicity resulted associated to XRCC1-rs3213239 and XRCC3-rs1799794 by multivariate analysis. The homozygous variant genotype for the XRCC1 polymorphism appeared to be protective for toxicity development (OR=0.24, 95%CI 0.09- 0.65; P=0.005). On the contrary the carriage of at least one XRCC3-rs1799794 variant allele represented a risk factor for severe toxicity (OR=9.60, 95%CI 2.41- 38.13; P=0.001).
In conclusion, two genetic polymorphisms in the DNA repair pathway (XRCC1-rs1799782) and in the glucuronidation pathway (UGT1A1-rs4124874) could be useful in selecting patients at risk for G3 neuropathy development from the FOLFOX regimen used as adjuvant chemotherapy in CRC. Moreover two polymorphisms in transporter genes (ABCG2-rs3219191 and ABCC1-rs35587) and two in the DNA repair pathway (XRCC1-rs3213239 and XRCC3-rs1799794) have been associated to severe hematological and non-hematological toxicities, respectively.