High Expression of Dihydropyrimidine Dehydrogenase in Lung Adenocarcinoma is Associated With Mutations in Epidermal Growth Factor Receptor: Implications for the Treatment of Non–Small-Cell Lung Cancer Using 5-Fluorouracil

Mochinaga, Koji; Tsuchiya, Tomoshi; Nagasaki, Toshiya; Arai, Junichi; Tominaga, Tetsuro; Yamasaki, Naoya; Matsumoto, Keitaro; Miyazaki, Takuro; Nanashima, Atsushi; Hayashi, Tomayoshi; Tsukamoto, Kazuhiro; Nagayasu, Takeshi

doi:10.1016/j.cllc.2013.09.002

Cited by 8 publications

(8 citation statements)

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“…The difference in PFS was not statistically significant [HR 0.78; 95 % confidence interval (CI) 0.57-1.06; p = 0.11]. In the First-SIGNAL trial, similar ORRs were reported in patients with and without EGFR mutations who were treated with cisplatin-gemcitabine (38 vs. 52 %, Tumors positive for EGFR mutations has a higher incidence of DPD immunopositivity (p = 0.003) Mochinaga et al (2014) respectively; p = 0.36). The PFS of the two subgroups was the same (6.3 vs. 6.4 months, respectively; HR 0.679; 95 % CI 0.34-1.35; p = 0.27).…”

Section: Predictive Roles Of Egfr Mutations In Response To Cytotoxic supporting

confidence: 78%

“…Although the findings of basic research also support this observation (Mochinaga et al 2014;Suehisa et al 2007), there is not enough evidence supporting the avoidance of adjuvant 5-FU-based agents in the treatment for lung cancers with EGFR mutations in clinical practices.…”

Section: Subset Analyses (Egfr-mutation-positive) Of Patients Selectementioning

confidence: 73%

“…(Ceppi et al 2006a; Chris- toph et al 2013;Filipits and Pirker 2011;Giovannetti et al 2005;Mizuuchi et al 2015;Mochinaga et al 2014; Olaus- sen et al 2006;Postel-Vinay et al 2012;Scagliotti et al 2008;Vilmar and Sorensen 2011).…”

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confidence: 95%

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Role of EGFR mutations in lung cancers: prognosis and tumor chemosensitivity

Suda

Mitsudomi

2015

Arch Toxicol

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Lung cancers with an epidermal growth factor receptor (EGFR) gene mutation account for ~40 % of adenocarcinomas in East Asians and ~15 % of those in Caucasians and African Americans, which makes them one of the most common molecularly defined lung cancer subsets. The discriminative clinical and pathological features of lung cancers with EGFR mutations have been intensively studied, and the predictive role of an EGFR mutation for treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) is well established. However, controversial issues remain regarding the clinical and therapeutic implications of EGFR mutations in lung cancers. These include the prognostic impact of the EGFR mutation, its predictive implication for successful treatment with anticancer agents other than EGFR-TKIs, appropriate cytotoxic agents for lung cancers with this mutation, and the chemosensitivity of EGFR-mutation-positive lung cancers after acquisition of resistance to EGFR-TKIs. In this review, we discuss these unanswered but important questions, referring to in vitro studies, basic research, retrospective analyses, and the results of phase III clinical trials.

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Section: Predictive Roles Of Egfr Mutations In Response To Cytotoxic supporting

confidence: 78%

Section: Subset Analyses (Egfr-mutation-positive) Of Patients Selectementioning

confidence: 73%

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Role of EGFR mutations in lung cancers: prognosis and tumor chemosensitivity

Suda

Mitsudomi

2015

Arch Toxicol

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“…The TS expression level was low in patients with well-differentiated NSCLC; DPD was downregulated in patients with squamous cell carcinoma, which was negatively correlated with maximum tumor diameter; TP was highly expressed in patients with vascular invasion; and the OPRT level was decreased in patients with adenocarcinoma. The reason for these findings is not known; however, it was reported that adenocarcinoma in situ, previously classified as bronchioloalveolar carcinoma (16), has a significantly higher epidermal growth factor receptor (EGFR) mutation frequency and DPD mRNA levels compared with other histological types (17), which may explain the high DPD mRNA levels observed in adenocarcinoma. On the other hand, OPRT activity is known to be increased in rapidly growing cells, including normal cells, such as those in the testis (18).…”

Section: Discussionmentioning

confidence: 99%

Thymidine phosphorylase affects clinical outcome following surgery and mRNA expression levels of four key enzymes for 5‑fluorouracil metabolism in patients with stage�I and II non‑small cell lung cancer

et al. 2018

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The expression levels of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) may predict the clinical efficacy of 5-fluorouracil-based chemotherapy in patients with cancer. We herein investigated the differences in the mRNA levels of these enzymes in non-small-cell lung cancer (NSCLC) and evaluated their prognostic value for NSCLC treated by surgical resection. The intratumoral mRNA levels of TP, DPD, TS, and OPRT were quantified in 66 patients with pathological stage I and II NSCLC (adenocarcinoma or squamous cell carcinoma) following complete resection according to the Danenberg Tumor Profile method. The TP level was the only significant prognostic factor for disease-specific survival (DSS) following complete resection; the mean TP mRNA level differed significantly between the high and low mRNA expression groups. The DSS at 5 years was significantly higher in the low TP mRNA compared with that in the high TP mRNA expression group (83.4 vs. 58.6%, respectively; P=0.005). A Cox proportional hazards model revealed that pathological stage, sex, and TP expression were independent prognostic factors for DSS in patients with stage I and II NSCLC following complete resection. Thus, TP level may be used to monitor treatment efficacy and predict the outcome of NSCLC patients.

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“…This study showed that the rs2293347GA/AA genotype was associated with a lower risk of progressive disease compared with the rs2293347GG genotype (OR = 0.048, p = 6.32 × 10 −5 ). Recently, Mochinaga et al reported that high expression of DPD in lung adenocarcinoma is associated with mutations in EGFR [ 44 ]. Several studies have demonstrated that high DPD levels result in low sensitivity to fluoropyrimidine for various cancers, such as gastric cancer [ 45 , 46 ], colon cancer [ 47 ], bladder cancer [ 48 ], and breast cancer [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method

et al. 2015

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BackgroundVariability in drug response between individual patients is a serious concern in medicine. To identify single-nucleotide polymorphisms (SNPs) related to drug response variability, many genome-wide association studies have been conducted.MethodsWe previously applied a knowledge-based bioinformatic approach to a pharmacogenomics study in which 119 fluoropyrimidine-treated gastric cancer patients were genotyped at 109,365 SNPs using the Illumina Human-1 BeadChip. We identified the SNP rs2293347 in the human epidermal growth factor receptor (EGFR) gene as a novel genetic factor related to chemotherapeutic response. In the present study, we reanalyzed these hypothesis-free genomic data using extended knowledge.ResultsWe identified rs2867461 in annexin A3 (ANXA3) gene as another candidate. Using logistic regression, we confirmed that the performance of the rs2867461 + rs2293347 model was superior to those of the single factor models. Furthermore, we propose a novel integrated predictive index (iEA) based on these two polymorphisms in EGFR and ANXA3. The p value for iEA was 1.47 × 10−8 by Fisher’s exact test. Recent studies showed that the mutations in EGFR is associated with high expression of dihydropyrimidine dehydrogenase, which is an inactivating and rate-limiting enzyme for fluoropyrimidine, and suggested that the combination of chemotherapy with fluoropyrimidine and EGFR-targeting agents is effective against EGFR-overexpressing gastric tumors, while ANXA3 overexpression confers resistance to tyrosine kinase inhibitors targeting the EGFR pathway.ConclusionsThese results suggest that the iEA index or a combination of polymorphisms in EGFR and ANXA3 may serve as predictive factors of drug response, and therefore could be useful for optimal selection of chemotherapy regimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1721-z) contains supplementary material, which is available to authorized users.

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High Expression of Dihydropyrimidine Dehydrogenase in Lung Adenocarcinoma is Associated With Mutations in Epidermal Growth Factor Receptor: Implications for the Treatment of Non–Small-Cell Lung Cancer Using 5-Fluorouracil

Abstract: Running title: DPD and EGFR mutation in adenocarcinoma

Cited by 8 publications

References 30 publications

Role of EGFR mutations in lung cancers: prognosis and tumor chemosensitivity

Role of EGFR mutations in lung cancers: prognosis and tumor chemosensitivity

Thymidine phosphorylase affects clinical outcome following surgery and mRNA expression levels of four key enzymes for 5‑fluorouracil metabolism in patients with stage�I and II non‑small cell lung cancer

Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method

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