Role of depth of response and MTHFR genotype as predictors of fluorouracil rechallenge therapy for refractory metastatic colorectal cancer

Kim, Ka‐Rham; Yoon, Jung‐Hwan; Shim, Hyungbo; Hwang, Jun‐Eul; Bae, Woo-Kyun; Chung, Ik‐Joo; Kim, Hee-Nam; Shin, Min‐Ho; Cho, Sang‐Hee

doi:10.3892/ol.2017.6414

Cited by 4 publications

(3 citation statements)

References 45 publications

(52 reference statements)

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“…It indicated that patients whose DpR ≥45% was correlated with longer PFS (median 16.4 vs. 8.1 months for DpR <45%, P=0.006) and OS (median 58.6 vs. 30.9 months for DpR <45%, P=0.041). Similar results were also obtained in Kim et al ’s ( 28 ) retrospective study of patients receiving chemotherapy alone. PFS, OS, and PPS of patients with DpR ≥60% were significantly improved.…”

Section: Methodssupporting

confidence: 88%

A narrative review: depth of response as a predictor of the long-term outcomes for solid tumors

Xie¹,

Li²,

Yao³

2021

Transl Cancer Res TCR

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Response Evaluation Criteria in Solid Tumors (RECIST 1.1) is classical and popular for public. However, there are some problems recently. For example, partial response ranges from 30% to 99%, objective response is dichotomous, so there may be some heterogeneity. New metrics for evaluating the efficacy have been investigating, such as early tumor shrinkage, time to response and depth of response (DpR). DpR has been used in hematologic malignancies and is considered as a predictor of efficiency. In solid tumors, DpR was firstly proposed by Mansmann et al. in metastatic colorectal cancer (mCRC) and defined as the percentage of tumor shrinkage, which is a continuous metric, and could avoid the information loss due to dichotomization of responses that has been widely applied to several kinds of solid tumors. Some authors have found associations between DpR and OS, DpR is a valuable surrogate endpoint for mCRC, metastatic breast cancer, metastatic melanoma and advanced pancreatic cancer. However, the predictive value of DpR is still uncertain in the research of lung cancer and gastric cancer. Which indicating that a mature and unified application standard has not yet been formed for DpR. This article summarizes researches on the DpR as a predictor of the long-term outcomes for solid tumors, it also discusses the challenges and limitations in the applications of DpR.

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Section: Methodssupporting

confidence: 88%

A narrative review: depth of response as a predictor of the long-term outcomes for solid tumors

Xie¹,

Li²,

Yao³

2021

Transl Cancer Res TCR

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“…Two common polymorphism variants with the outcome of MTHFR enzymatic deficiency have been identified, namely, the rs1801133 (C677T) and rs1801131 (A1298C) [ 269 ]. Positive correlation between MTHFR polymorphisms and colon cancer patient’s response to 5-FU treatment is often reported involving variant A1298C with C677T seeing 5-FU benefits only exclusively in refractory cases [ 239 , 270 , 271 ]. Interestingly, in vitro studies have implicated both polymorphisms in the development of 5-FU resistance in colon cancer cells [ 240 ].…”

Section: Mechanism Of Resistance By Key 5-fluorouracil Enzymesmentioning

confidence: 99%

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

Azwar

Seow

Abdullah

et al. 2021

Biology

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5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient’s overall survival.

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“…In a recent study conducted in two cohorts of stage II/III of CRC patients treated with adjuvant fluoropyrimidine chemotherapy, the MTHFR 1298CC genotype carriers underwent worsened disease free survival and overall survival in both cohorts [ 51 ]. Similarly, an even more recent study of 242 Korean patients with mCRC showed that the presence of a C677CC genotype was associated with a good prognosis in multivariate analysis [ 52 ]. On the basis also of the significant ethnic differences in the C677T and A1298C genotypes frequency, larger studies including different populations are needed to determine the role of these polymorphisms in response to fluoropyrimidines [ 53 ].…”

Section: Fluoropyrimidinesmentioning

confidence: 99%

SNPs in predicting clinical efficacy and toxicity of chemotherapy: walking through the quicksand

et al. 2018

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In the “precision medicine” era, chemotherapy still remains the backbone for the treatment of many cancers, but no affordable predictors of response to the chemodrugs are available in clinical practice. Single nucleotide polymorphisms (SNPs) are gene sequence variations occurring in more than 1% of the full population, and account for approximately 80% of inter-individual genomic heterogeneity. A number of studies have investigated the predictive role of SNPs of genes enrolled in both pharmacodynamics and pharmacokinetics of chemotherapeutics, but the clinical implementation of related results has been modest so far. Among the examined germline polymorphic variants, several SNPs of dihydropyrimidine dehydrogenase (DPYD) and uridine diphosphate glucuronosyltransferases (UGT) have shown a robust role as predictors of toxicity following fluoropyrimidine- and/or irinotecan-based treatments respectively, and a few guidelines are mandatory in their detection before therapy initiation. Contrasting results, however, have been reported on the capability of variants of other genes as MTHFR, TYMS, ERCC1, XRCC1, GSTP1, CYP3A4/3A5 and ABCB1, in predicting either therapy efficacy or toxicity in patients undergoing treatment with pyrimidine antimetabolites, platinum derivatives, irinotecan and taxanes. While formal recommendations for routine testing of these SNPs cannot be drawn at this moment, therapeutic decisions may indeed benefit of germline genomic information, when available. Here, we summarize the clinical impact of germline genomic variants on the efficacy and toxicity of major chemodrugs, with the aim to facilitate the therapeutic expectance of clinicians in the odiern quicksand field of complex molecular biology concepts and controversial trial data interpretation.

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Role of depth of response and MTHFR genotype as predictors of fluorouracil rechallenge therapy for refractory metastatic colorectal cancer

Cited by 4 publications

References 45 publications

A narrative review: depth of response as a predictor of the long-term outcomes for solid tumors

A narrative review: depth of response as a predictor of the long-term outcomes for solid tumors

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

SNPs in predicting clinical efficacy and toxicity of chemotherapy: walking through the quicksand

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