The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma

Erčulj, Nina; Kovač, Viljem; Hmeljak, Julija; Dolžan, Vita

doi:10.1093/annonc/mdr324

Cited by 30 publications

(35 citation statements)

References 40 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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“…GSTT1 has been found to be a probable factor for therapy-related adverse events in medulloblastoma (Barahmani et al, 2009). However, in a study on malignant mesothelioma patients treated with either cisplatin or carboplatin combined regimen, GSTT1 null was found to have no influence on treatment-related leucopenia or thrombocytopenia (Erculj et al, 2012). In this study no role for GSTT1 in producing hematologic toxicity or other carboplatin-related toxicity was observed.…”

Section: Discussioncontrasting

confidence: 62%

GSTT1 null and MPO -463G>A Polymorphisms and Carboplatin Toxicity in an Indian Population

Bag

Pant²,

Jeena³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Carboplatin, a second generation platinum drug, is widely used to treat different types of cancers. However, myelosuppression remains a major consideration in its use. Genetic polymorphisms of enzymes involved in drug disposition can influence therapeutic outcome. The homozygous null deletion of phase II metabolic gene GSTT1 that abolishes its xenobiotic-detoxifying ability may be associated with carboplatin toxicity. Further, since carboplatin generates oxidative stress, polymorphisms of oxidative stress genes that regulate the cellular level of free radicals may have important roles in generating drug-related adverse effects. We here investigated the null polymorphism of GSTT1, and the -463G>A promoter polymorphism of oxidative stress gene myeloperoxidase (MPO) for carboplatin toxicity in a population of northern India. Cancer patients who were treated with carboplatin, and developed toxicity was considered. The study group comprised of 10 patients who developed therapy-related adverse effects. Peripheral blood was taken from patients for DNA isolation. GSTT1 null genotype was determined by conducting duplex PCR and MPO-463 G>A was determined by PCR followed by RFLP. Hematologic toxicity was experienced by 5 patients, 2 of them had grade 3 and 4 toxicity and 3 others had grade 2 toxicity. They also had gastrointestinal (GI) toxicity. Remaining 5 individuals developed GI toxicity but no hematological toxicity. While GG homozygous of MPO was present in majority of patients having hematologic toxicity (in 4 out of 5 individuals), one A allele (AG genotype) was present in 4 patients who did not have any hematological toxicity. Thus variant A allele of MPO -463G>A may be related to lower hematological toxicity. These preliminary data, however, are required to be confirmed in larger studies along with other relevant polymorphisms.

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“…In studies of non small-cell lung cancer, the the variant allele (Cys→Ala) tends to predict worse outcomes [13], [14], [15]. In other tumors treated with platinum-based chemotherapy, such as ovarian cancer, malignant mesothelioma, or advanced squamous cell carcinoma of the head and neck, association of the ERCC1 8092Ala allele with poor survival has been consistently reported [16], [17], [18]. Other investigators [19], [20] have demonstrated that the presence of at least one 8092Ala allele is associated with improved outcomes in patients with advanced non-small cell lung cancer.…”

Section: Discussionmentioning

confidence: 97%

ERCC1 Cys8092Ala and XRCC1 Arg399Gln Polymorphisms Predict Progression-Free Survival after Curative Radiotherapy for Nasopharyngeal Carcinoma

et al. 2014

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BackgroundSingle nucleotide polymorphisms (SNPs) in DNA repair genes can alter gene expression and activity and affect response to cancer treatment and, correspondingly, survival. The present study was designed to evaluate the utility of the XRCC1 Arg399Gln and ERCC1 Cys8092Ala SNPs, measured in pretreatment biopsy samples, as predictors of response to radiotherapy in patients with non-metastatic nasopharyngeal carcinoma (NPC).Materials and methodsThe study included 75 consecutive patients with stage II-IVA-B NPC. XRCC1 Arg399Glu and ERCC1 Cys8092Ala SNPs were identified from paraffin-embedded biopsy specimens via Sanger sequencing. Expression of p53 and pAkt protein was analyzed by immunohistochemical staining. Potential relationships between genetic polymorphisms and progression-free survival (PFS) were analyzed by using a Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test.ResultsMultivariate analysis showed that carriers of the ERCC1 8092 Ala/Ala genotype [hazard ratio (HR) 1.882; 95% confidence interval (CI) 1.031–3.438; P = 0.039] and heavy smokers (≥20 pack-years) carrying the XRCC1 Arg/Arg genotype (HR 2.019; 95% CI 1.010–4.036; P = 0.047) had significantly lower PFS rates. Moreover, combined positive expression of p53 and pAkt led to significantly increased PFS in subgroups carrying the XRCC1 Gln allele (HR 7.057; 95% CI 2.073–24.021; P = 0.002) or the ERCC1 Cys allele (HR 2.568; 95% CI 1.056–6.248; P = 0.038).ConclusionsThe ERCC1 Cys8092Ala polymorphism is an independent predictor of response to radiotherapy for NPC, and the XRCC1 Arg399Glu mutation combined with smoking status seems to predict PFS as well. Our results further suggest a possible correlation between these genetic polymorphisms and p53 protein status on survival.

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The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma

Cited by 30 publications

References 40 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

GSTT1 null and MPO -463G>A Polymorphisms and Carboplatin Toxicity in an Indian Population

ERCC1 Cys8092Ala and XRCC1 Arg399Gln Polymorphisms Predict Progression-Free Survival after Curative Radiotherapy for Nasopharyngeal Carcinoma

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