DNA Repair Polymorphisms and Treatment Outcomes of Patients with Malignant Mesothelioma Treated with Gemcitabine-Platinum Combination Chemotherapy

Erčulj, Nina; Kovač, Viljem; Hmeljak, Julija; Franko, Alenka; Dodic-Fikfak, Metoda; Dolžan, Vita

doi:10.1097/jto.0b013e3182653d31

Cited by 14 publications

(20 citation statements)

References 46 publications

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“…In previous studies, we have identified some polymorphisms that influence MPM treatment with gemcitabine and cisplatin 26,43,44. Our present results show for the first time that MTHFD1 , ABCC2 , and SLCO1B1 polymorphisms may play an important role in PMX treatment response in patients with MPM.…”

Section: Discussionsupporting

confidence: 63%

Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma

Goričar

Kovač

Dolžan

2014

Radiology and Oncology

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IntroductionA combination of pemetrexed and cisplatin has been shown to improve the outcome in patients with malignant pleural mesothelioma (MPM), however, there is a great heterogeneity in treatment response among patients. The aim of our study was to evaluate the influence of polymorphisms in folate pathway and transporter genes on pemetrexed treatment outcome in Slovenian patients with MPM.MethodsMPM patients treated with pemetrexed in the course of a prospective randomized clinical trial were genotyped for nineteen polymorphisms in five genes of folate pathway and six transporter genes. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity, while Cox regression was used to determine their influence on progression-free and overall survival.ResultsPatients with at least one polymorphic MTHFD1 rs2236225 allele had a significantly lower response rate (p = 0.005; odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.03−0.54) and shorter progression-free survival (p = 0.032; hazard ratio [HR] = 3.10; 95% CI = 1.10−8.74) than non-carriers. Polymorphisms in transporter genes did not influence survival; however, several were associated with toxicity. Liver toxicity was significantly lower in carriers of polymorphic ABCC2 rs2273697 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85), SLCO1B1 rs4149056 (p = 0.028; OR = 0.23; 95% CI = 0.06−0.85) and rs11045879 (p = 0.014; OR = 0.18; 95% CI = 0.05−0.71) alleles compared to non-carriers, as well as in patients with SLCO1B1 GCAC haplotype (p = 0.048; OR = 0.17; 95% CI = 0.03−0.98). Gastrointestinal toxicity was much more common in patients with polymorphic ABCC2 rs717620 allele (p = 0.004; OR = 10.67; 95% CI = 2.15−52.85) and ABCC2 CAG haplotype (p = 0.006; OR = 5.67; 95% CI = 1.64−19.66).ConclusionsMTHFD1 polymorphism affected treatment response and survival, while polymorphisms in ABCC2 and SLCO1B1 transporter genes influenced the risk for toxicity. These polymorphisms could serve as potential markers of pemetrexed treatment outcome in patients with MPM.

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Section: Discussionsupporting

confidence: 63%

Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma

Goričar

Kovač

Dolžan

2014

Radiology and Oncology

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“…The selection of genetic and clinical variables was based on results of our previous studies where pathway-based approach was used to identify factors influencing tumor response, PFS or OS in Slovenian MM patients11121314. In this study genotyping for all polymorphisms in gemcitabine, pemetrexed and cisplatin metabolism, transport and drug target genes and DNA repair pathways significantly associated with treatment outcome in previous studies was extended to all patients.…”

Section: Methodsmentioning

confidence: 99%

“…So far, no target mutations were identified in MM that could guide targeted treatment. MM treatment outcome was associated with clinical characteristics10 and genetic variability in drug transport, metabolism and target genes and DNA repair pathways11121314.…”

mentioning

confidence: 99%

“…In our previous studies, single nucleotide polymorphisms (SNPs) in the target RRM1 gene, and in DNA repair genes ERCC1, ERCC2 , and XRCC1 were associated with survival in MM patients111213.…”

mentioning

confidence: 99%

“…Although we have previously identified pharmacogenetic markers that may influence MM treatment outcome, these results have not been used yet for treatment guidance11121314. Translation of pharmacogenetic results into clinical practice can be challenging, especially as they are seldom incorporated in actionable forms such as scores or dosing guidelines.…”

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confidence: 99%

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Clinical-pharmacogenetic models for personalized cancer treatment: application to malignant mesothelioma

Goričar

Kovač

Dolžan

2017

Sci Rep

Self Cite

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Large interindividual differences in treatment outcome are observed in cancer patients undergoing chemotherapy. Our aim was to develop and validate clinical-pharmacogenetic prediction models of gemcitabine/cisplatin or pemetrexed/cisplatin treatment outcome and develop an algorithm for genotype-based treatment recommendations in malignant mesothelioma (MM). We genotyped 189 MM patients for polymorphisms in gemcitabine, pemetrexed and cisplatin metabolism, transport and drug target genes and DNA repair pathways. To build respective clinical-pharmacogenetic models, pharmacogenetic scores were assigned by rounding regression coefficients. Gemcitabine/cisplatin model was based on training group of 71 patients and included CRP, histological type, performance status, RRM1 rs1042927, ERCC2 rs13181, ERCC1 rs3212986, and XRCC1 rs25487. Patients with higher score had shorter progression-free (PFS) and overall survival (P < 0.001). This model’s sensitivity was 0.615 and specificity 0.812. In independent validation group of 66 patients the sensitivity and specificity were 0.667 and 0.641, respectively. Pemetrexed/cisplatin model was based on 57 patients and included CRP, MTHFD1 rs2236225, and ABCC2 rs2273697. Patients with higher score had worse response and shorter PFS (P < 0.001). This model’s sensitivity was 0.750 and specificity 0.607. In independent validation group of 20 patients the sensitivity and specificity were 0.889 and 0.500, respectively. The proposed algorithm based on these models could enable the choice of the most effective chemotherapy for 85.5% of patients and lead to improved treatment outcome in MM.

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The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

Zheng

Deng

Yin

et al. 2017

Intl Journal of Cancer

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Genetic variations in genes involved in repairing platinum-induced DNA lesions may contribute to the toxicity of platinum-based chemotherapy. The role of single-nucleotide polymorphisms (SNPs) within DNA repair pathways in the occurrence of severe toxicity is not yet understood. Current studies prefer to do original works rather than analyze previously published data. Our study aimed to replicate associations between previously investigated SNPs and toxicities and to identify new genetic makers. We systematically examined the relevance of 97 SNPs in 54 candidate genes responsible for repairing DNA interstrand and intrastrand cross-links to severe toxicity in a discovery cohort of 437 NSCLC patients receiving platinum-based chemotherapy. Statistically significant SNPs were then assessed for replication in an independent validation cohort of 781 NSCLC patients. We found that 7 SNPs were significant at p < 0.01 (RRM1 rs12806698, XPC rs2228000, XPF rs1799801, hMLH1 rs1800734, PMS2 rs1062372, REV3L rs462779 and FANCC rs4647554) in the discovery cohort. Among them, two SNPs (RRM1 rs12806698 and hMLH1 rs1800734) remained significant after Bonferroni correction. XPC rs2228000 showed a significant relationship with severe gastrointestinal toxicity in the validation cohort. When the two cohorts were combined, XPC rs2228000 presented better tolerance of severe hematologic toxicity, gastrointestinal toxicity and leukopenia (OR = 0.677, 95% CI: 0.510-0.899, p = 0.007; OR = 0.565, 95% CI: 0.368-0.869, p = 0.009; OR = 0.628, 95% CI: 0.439-0.899, p = 0.011, respectively). Our findings can offer comprehensive pharmacogenetic information for platinum-induced toxicities.

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DNA Repair Polymorphisms and Treatment Outcomes of Patients with Malignant Mesothelioma Treated with Gemcitabine-Platinum Combination Chemotherapy

Abstract: Our results support the hypothesis that DNA repair gene polymorphisms, particularly XRCC1 Arg399Gln, may modify the response to gemcitabine-platinum combination chemotherapy and, for the first time, show this effect in patients with MM.

Cited by 14 publications

References 46 publications

Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma

Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesothelioma

Clinical-pharmacogenetic models for personalized cancer treatment: application to malignant mesothelioma

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

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