Predictive value of ERCC2, ABCC2 and MMP2 of response and long-term survival in locally advanced head and neck cancer patients treated with chemoradiotherapy.

PURPOSE: Genetic variants in genes involved in the distribution, metabolism, accumulation or repair of lesions are likely to influence the response of drugs used in the treatment of Head and Neck Cancer (HNC). We examine the effect of 36 SNPs on clinical outcomes in patients with locally advanced HNC who were receiving platinum-based chemoradiotherapy (CRT). METHODS: These SNPs were genotyped in 110 patients using the iPLEX Gold assay on the MassARRAY method in blood DNA samples and used Kaplan-Meier and Cox regression analyses to compare genotype groups with the survival. RESULTS: Two SNPs, rs717620 (ABCC2) and rs12934241 (MMP2) were strongly associated with overall survival (OS) and disease-free survival (DFS). At a median follow-up of 64.4 months, the allele A of rs717620 (ABCC2) had an increased risk of disease progression {hazard ratio [HR] = 1.79, p = 0.0018} and death (HR = 2.0, p = 0.00027). ABCC2 was associated with OS after a Bonferroni adjustment for multiple testing. The MMP2 rs12934241-T allele was associated with an increased risk of worse OS and DFS (p = 0.0098 and p = 0.0015, respectively). One SNP of ABCB1 and three SNPs located in the ERCC2 gene showed an association with response in the subgroup of HNC patients treated with definitive CRT. CONCLUSIONS: Our findings highlight the potential usefulness of SNPs in different genes involved in drug metabolism and repair DNA to predict the response and survival to CRT. ABCC2 is a potential predictor of OS in patients with HNC.

Efficacy and toxicity of adjuvant chemotherapy on colorectal cancer patients: how much influence from the genetics?

We studied the predictive value for response and toxicity of functional polymorphisms in genes involved in the oxaliplatin/fluorouracil pathway in colorectal cancer patients. One hundred and twenty-seven (127) patients were treated with curative intended surgery followed by adjuvant chemotherapy with FOLFOX (fluorouracil, leucovorin and oxaliplatin) regimen. The median age was 65.53 (27-80) years (66.9% male, 59.1% rectum). The median follow-up was 8.5 years (IQR, 4.1-9.4). At the end of follow-up, 59 patients (46.5%) had relapsed or died in the whole study population. We did find that XRCC1GG genotype is associated with a higher risk of developing haematologic toxicity. Furthermore, we report a significant association of the TS 3'UTR 6 bp/6 bp polymorphism and the XRCC1 rs25487 with a higher risk of developing anaemia and diarrhoea, respectively. On the other hand, none of the studied polymorphisms showed clinically relevant association with disease-free survival and overall survival or early failure to adjuvant FOLFOX therapy.

Association of GSTP1 and ERCC1 polymorphisms with toxicity in locally advanced head and neck cancer platinum-based chemoradiotherapy treatment.

BACKGROUND: Platinum-based chemoradiotherapy (CRT) is the standard treatment for locally advanced head and neck squamous-cell carcinomas (HNSCC), and most patients experience serious toxicities. The aim of this study was to investigate the association between candidate genes involved in radiation/platinum pathways and acute toxicity of CRT to determine the predictive value of these polymorphisms for toxicity. METHODS: Thirty-six selected single nucleotide polymorphisms (SNPs) in 29 genes were genotyped in 110 patients treated with cisplatin-based CRT. DNA was obtained from blood samples, and SNP analysis was performed using a MassARRAY iPLEX Gold (Sequenom) method. RESULTS: Patients with ERCC1 rs11615-C allele (P = .0066), ERCC1 rs735482-C allele (P = .0204), and ERCC4 rs1799801-C allele (P = .0286) had lower risk of grade 2-3 hematologic toxicity. In addition, the presence of G allele of GSTP1 was associated with a significantly lower risk of severe dysphagia (P = .0004). CONCLUSION: Polymorphisms in ERCC1 and GSTP1 may act as prognostic factors of acute toxicity during treatment with CRT in HNSCC patients.

Long Survival and Severe Toxicity Under 5-Fluorouracil-Based Therapy in a Patient With Colorectal Cancer Who Harbors a Germline Codon-Stop Mutation in TYMS.

We report the first clinical description of a patient with cancer with a heterozygous germline codon-stop mutation in the TYMS gene. The mutation g.657795_657826del, c.53_84del (NM_001071.2), p.Gln18Argfs*42 causes loss of function of one of the TYMS alleles, resulting in a truncated protein. This gene codifies for the target enzyme of 5-fluorouracil (5-FU), the basic treatment in colorectal cancer. The patient, diagnosed with metastatic colorectal cancer, had diarrhea and neutropenia grade 4 and mucositis and neurological toxicity grade 3 under 5-FU-based therapy and exceeded by more than 50% the average survival after metastasectomy. On the basis of the patient's characteristics and the key role of TYMS in 5-FU activity, we hypothesize that this mutation may contribute to the drug response and toxicities suffered by the patient.

X-ray cross-complementing group 1 and thymidylate synthase polymorphisms might predict response to chemoradiotherapy in rectal cancer patients.

PURPOSE: 5-Fluorouracil-based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients. We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series. METHODS AND MATERIALS: A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples. The genes analyzed were X-ray cross-complementing group 1 (XRCC1), ERCC1, MTHFR, EGFR, DPYD, and TYMS. The patients were treated with 225 mg/m(2)/d continuous infusion of 5-fluorouracil concomitantly with radiotherapy (50.4 Gy) followed by total mesorectal excision. The outcomes were measured by tumor regression grade (TRG) as a major response (TRG 1 and TRG 2) or as a poor response (TRG3, TRG4, and TRG5). RESULTS: The major histopathologic response rate was 47.3%. XRCC1 G/G carriers had a greater probability of response than G/A carriers (odds ratio, 4.18; 95% confidence interval, 1.62-10.74, p = .003) Patients with polymorphisms associated with high expression of thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) showed a greater pathologic response rate compared with carriers of low expression (odds ratio, 2.65; 95% confidence interval, 1.10-6.39, p = .02) No significant differences were seen in the response according to EGFR, ERCC1, MTHFR_C677 and MTHFR_A1298 expression. CONCLUSIONS: XRCC1 G/G and thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) are independent factors of a major response. Germline thymidylate synthase and XRCC1 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5-fluorouracil.

Anti-EGFR therapy in first-line colorectal cancer.

This Phase II clinical trial investigates the activity and safety of FOLFOX-cetuximab in the first-line treatment of colorectal cancer. This turns out to be an active regimen which allows a high rate of conversion and radical metastectomy. Overall response rate is concordant with those previously reported. The toxicity profile is also similar, and cutaneous toxicity severity seems to be a marker of activity. Retrospectively, the authors analyze the status of KRAS and BRAF in a subgroup of patients, only in 50%. KRAS appears mutated in 37%, and BRAF does not present as mutated in any of the remaining wild-type KRAS patients. KRAS mutation correlates with shorter overall survival and possibly time to progression. The sample is too small to find mutations in BRAF, or to convincingly establish the role of both biomarkers. These data demonstrate an active regimen that is first in line to be confirmed in larger Phase III trials.

Use of a comprehensive panel of biomarkers to predict response to a fluorouracil-oxaliplatin regimen in patients with metastatic colorectal cancer.

AIM: Polymorphisms in the metabolism, detoxification or DNA repair pathways have been proposed as potential predictors of response to 5-fluorouracil and oxaliplatin. We have studied the predictive value of a set of germline genetic polymorphisms in metastatic colorectal cancer patients treated with mFolfox-6. MATERIALS & METHODS: A total of 72 patients, comprising 50 men (69.4%) and 22 women (30.6%), were included after the signing of an informed consent form. Median age was 65.5 years (range: 32-80). All participants received mFolfox-6. DNA was extracted from peripheral blood samples and genotyped by direct sequencing, SnapShot(®) and multiplex PCR techniques. Eight polymorphisms within six genes were investigated: TS 5´-UTR (variable number tandem repeat + G/C), TS 3´-UTR (TS1494del6); MTHFR C677T and A1298C; GSTP1 I105V; ERCC1 C118T; XPD Lys751Gln and XRCC1 Arg399Gln. Association was evaluated by univariate analysis, and Cox regression and Kaplan-Meier assessed survival. The local ethics committee approved the pharmacogenetic study protocol and all subjects signed an informed consent before participating in the study. RESULTS: The sample was in Hardy-Weinberg equilibrium. Only XPD Lys751Gln was found to be significantly associated with a favorable progression-free survival (PFS). Median PFS for XPD Lys751Gln patients (n = 33) was 16 months (95% CI: 9.2-22.7), 10 months (95% CI: 6.1-13.9) for Gln/Gln (n = 11) and 8 months (95% CI: 5.8-10.2) for Lys/Lys (n = 28), p = 0.019. The increased risk of progression was: 1.93 (95% CI: 1.13-13.30; p = 0.017) for Lys/Lys and 2.1 (95% CI: 1.01-4.22; p = 0.047) for Gln/Gln. Patients with one or two Val alleles of GSTP1 tended to a lower risk of progression compared with Ile/Ile homozygotes, p = 0.067. When XPD Lys751Gln and GSTP1 were analyzed jointly, patients who carried one or two favorable genotypes, XPD Lys751Gln and Val, had a longer median PFS: 11 months (95% CI: 7.4-14.6) compared with six (95% CI: 4.6-7.4) with unfavorable genotypes, p < 0.001. CONCLUSION: In metastatic colorectal cancer patients treated with mFolfox-6, the combination of haplotype XPD Lys751Gln-GSTP1 105Val seems to predict the risk of progression.

Pharmacogenetic analysis in neoadjuvant chemoradiation for rectal cancer: high incidence of somatic mutations and their relation with response.

AIMS: The identification of predictive markers of response to chemoradiotherapy treatment remains a promising approach for patient management in order to obtain the best response with minor side effects. Initially, we investigated whether the analysis of several markers previously studied and others not yet evaluated could predict response to 5-fluorouracil- and capecitabine-based neoadjuvant treatment in locally advanced rectal cancer. METHODS & MATERIALS: We studied germline and tumoral samples of 65 stage II/III rectal patients. A panel of pharmacogenetic markers was genotyped in paired peripheral blood samples and rectal cancer tumors. RESULTS: Our results seem to confirm the previously described association of thymidylate synthase and the prediction of chemoradiotherapy response in rectal cancer. However, it failed to confirm the clinical utility proposed for XRCC1, ERCC1, ERCC2, MTHFR and EGFR polymorphisms in blood/germline samples. Subsequently, with the aim of improving prediction of individual response and assessing the role of studied polymorphisms in response to treatment, we determined if changes in tumor response to these markers could predict clinical outcome. We found a high degree of changes between germline and tumor samples, mainly somatic mutations without microsatellite instability, and a minor frequency of loss-of-heterozygosity events. In tumoral samples, XRCC1 appeared to be significantly associated (p = 0.006) with downstaging of the tumor (odds ratio: 7.93; 95% CI: 1.03-60.83), but the increasing of TYMS low-expression alleles contradict the previous results observed in germline samples. CONCLUSION: The detection of somatic mutations in rectal cancer tumors led us to re-evaluate the utility of the tests performed in blood samples for these polymorphisms in rectal cancer. Furthermore, studies aimed at assessing the influence of pharmacogenetic markers in treatment response performed in blood samples should take into account the particular pattern of hypermutability present in each tumor type. We hypothesize that different patterns of hypermutability present in each tumor type would be related to the different results in association studies related to response to the treatment.