• colorectal cancer
• glutathione S-transferases
• survival

• Humans
• Glutathione S-Transferase pi/genetics
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/drug therapy
• Glutathione Transferase/genetics
• Female
• Male
• Middle Aged
• Aged
• Prospective Studies
• Serbia
• Adenocarcinoma/genetics
• Adenocarcinoma/mortality
• Adenocarcinoma/drug therapy
• Polymorphism, Genetic
• Fluorouracil/therapeutic use
• Genotype
• Prognosis
• Kaplan-Meier Estimate
• Organoplatinum Compounds/therapeutic use
• Leucovorin/therapeutic use
• Oxaliplatin/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Proportional Hazards Models
• Adult

• Grant No. 200110 Ministry of Education, Science and Technological Development of the Republic of Serbia

• ADME
• biomarkers
• colorectal cancer
• germline variants
• immunity
• immunogenetics
• inflammation
• microenviroment
• pharmacogenetics

• FOLFIRINOX
• FOLFOX
• XELOX
• biomarker
• chemotherapy-induced peripheral neuropathy
• gastrointestinal cancer
• genomics
• neuropathy
• neurotoxicity
• oxaliplatin

• BRAF
• Biomarkers
• DPD deficiency
• EGFR
• HER2
• KRAS
• Lynch syndrome
• NRAS
• NTRK inhibitor
• UGT1A1
• colorectal cancers
• microsatellite instability
• mismatch repair

The introduction of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with either oxaliplatin or mitomycin C for patients with colorectal peritoneal metastasis (CPM) has resulted in a major increase in overall survival. Nonetheless, despite critical patient selection, the majority of patients will develop recurrent disease within one year following CRS + HIPEC. Therefore, improvement of patient and treatment selection is needed and may be achieved by the incorporation of genetic biomarkers. This systematic review aims to provide an overview of genetic biomarkers in the DNA repair pathway that are potentially predictive for treatment outcome of patients with colorectal peritoneal metastases treated with CRS + HIPEC with oxaliplatin or mitomycin C.

A systematic review was conducted according to the PRISMA guidelines. Given the limited number of genetic association studies of intraperitoneal mitomycin C and oxaliplatin in patients with CPM, we expanded the review and extrapolated the data from biomarker studies conducted in colorectal cancer patients treated with systemic mitomycin C– and oxaliplatin-based chemotherapy.

In total, 43 papers were included in this review. No study reported potential pharmacogenomic biomarkers in patients with colorectal cancer undergoing mitomycin C–based chemotherapy. For oxaliplatin-based chemotherapy, a total of 26 genetic biomarkers within 14 genes were identified that were significantly associated with treatment outcome. The most promising genetic biomarkers were ERCC1 rs11615, XPC rs1043953, XPD rs13181, XPG rs17655, MNAT rs3783819/rs973063/rs4151330, MMR status, ATM protein expression, HIC1 tandem repeat D17S5, and PIN1 rs2233678.

Several genetic biomarkers have proven predictive value for the treatment outcome of systemically administered oxaliplatin. By extrapolation, these genetic biomarkers may also be predictive for the efficacy of intraperitoneal oxaliplatin. This should be the subject of further investigation.

• DNA repair
• biomarker
• colorectal cancer
• hyperthermic intraperitoneal chemotherapy
• mitomycin C
• oxaliplatin
• treatment outcome

Single nucleotide polymorphisms (SNPs) are universally present in nucleotide excision repair (NER) pathway genes, which could make impacts on colorectal carcinogenesis and prognosis.

To explore the association of all tagSNPs in NER pathway genes with colorectal cancer (CRC) risk and prognosis in a northern Chinese population by a two-stage case-control design composed of a discovery and validation stage.

Genotyping for NER SNPs was performed using kompetitive allele specific PCR. In the discovery stage, 39 tagSNPs in eight genes were genotyped in 368 subjects, including 184 CRC cases and 184 individual-matched controls. In the validation stage, 13 SNPs in six genes were analyzed in a total of 1712 subjects, including 854 CRC cases and 858 CRC-free controls.

Two SNPs (XPA rs10817938 and XPC rs2607775) were associated with an increased CRC risk in overall and stratification analyses. Significant cumulative and interaction effects were also demonstrated in the studied SNPs on CRC risk. Another two SNPs (ERCC2 rs1052555 and ERCC5 rs2228959) were newly found to be associated with a poor overall survival of CRC patients.

Our findings suggest novel SNPs in NER pathway genes that can be predictive for CRC risk and prognosis in a large-scale Chinese population. The present study has referential values for the identification of all-round NER-based genetic biomarkers in predicting the susceptibility and clinical outcome of CRC.

• Nucleotide excision repair
• Polymorphism
• Colorectal cancer
• Susceptibility
• Prognosis

• Asian People/genetics
• Carcinogenesis/genetics
• Case-Control Studies
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/mortality
• DNA Repair/genetics
• DNA-Binding Proteins/genetics
• Endonucleases/genetics
• Female
• Genetic Markers/genetics
• Genetic Predisposition to Disease/genetics
• Genotype
• Humans
• Male
• Middle Aged
• Nuclear Proteins/genetics
• Polymorphism, Single Nucleotide
• Prognosis
• Risk Factors
• Signal Transduction/genetics
• Transcription Factors/genetics
• Xeroderma Pigmentosum Group D Protein/genetics

• CAPOX-toxicities
• DPYD*6
• DPYD*9A
• GSTP1 ile105va
• Predictive-markers

• chemotherapy
• efficacy
• gastrointestinal cancer
• glutathione S-transferases genes
• variants

Background

The nucleotide excision repair (NER) system is one of the most important deoxyribonucleic acid (DNA) repair mechanisms and is critical for chemotherapy resistance. We conducted the present study to investigate the association between two polymorphisms of excision of repair cross-complementing group 1 (ERCC1), the key component of the NER pathway, and the clinicopathological features of patients with non-small cell lung cancer (NSCLC).

Methods

A total of 38 patients with confirmed NSCLC were included in our study. DNA was extracted from peripheral blood. ERCC1 rs3212986 (8092) and rs11615 (118) were genotyped using molecular assays including polymerase chain reaction (PCR) with restriction fragment length polymorphism (by MboII and HpyCH4 enzymes) and sequencing.

Results

The PCR results indicated the correct performance of the genomics extraction and molecular protocols. The distribution of C/C, C/A and A/A genotypes at position 8092 was 42.10%, 47.36%, and 10.52% respectively (P=0.03). Multivariate regression analysis showed that there was a significant correlation between C8092A (rs3212986) polymorphism and metastasis, grade of the tumor, and response to treatment. Individuals carrying the rs3212986 CA genotype and A allele had a significantly worse response to the treatment. Also, the correlation between alteration at this genomics location and patients with NSCLC who used to smoke cigarettes was positive. However, no significant association was detected between rs11615 C118>T polymorphism and demographic characteristics of patients with NSCLC.

Conclusion

We concluded that in lung cancer patients there is a relationship between tumor stage and rs3212986C>A polymorphism.

• clinicopathological features
• ercc1
• nsclc
• sequencing

• Pan-Asian
• clinical practice guidelines
• colorectal cancer
• consensus

• Cancer survivors
• Cured
• Life-style
• late/long term side effects

• TYMS
• colorectal cancer
• fluoropyrimidines
• objective response rate
• toxicity
• variants

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme influencing the metabolism of fluoropyrimidines. The relevance of MTHFR polymorphisms with the clinical response to fluoropyrimidine-based chemotherapy has been explored, but the results remain controversial. Thus, a meta-analysis was performed to provide a comprehensive estimate in this account. Relevant studies were identified through PubMed, Embase and Web of Science databases from inception up to May 2017. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were applied to assess the strength of association. A total of 2118 colorectal cancer patients from 21 studies were included in the meta-analysis. Overall, there was no significant association between MTHFR C677T (rs1801133) or A1298C (rs1801131) polymorphisms and the clinical response to fluoropyrimidine-based chemotherapy under all of the three genetic models (allele model, dominant model, and recessive model) and stratification analysis, except for the retrospective study subgroup in the dominant model of MTHFR C677T and the “5-Fu + FA” treatment group in the allele contrast of MTHFR A1298C. No or moderate heterogeneity was observed in all genetic models. This meta-analysis suggested that MTHFR polymorphisms could not be considered as reliable factors for predicting the clinical response to fluoropyrimidine-based chemotherapy in colorectal cancer patients.

• MTHFR
• chemotherapy response
• fluoropyrimidine
• meta-analysis
• polymorphism

• Chemotherapy
• Neurotoxicity
• Oxaliplatin
• Pharmacogenetics
• Taxane
• Vincristine

• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Cohort Studies
• Genetic Predisposition to Disease
• Humans
• Neoplasms/drug therapy
• Neoplasms/genetics
• Peripheral Nervous System Diseases/chemically induced
• Peripheral Nervous System Diseases/genetics
• Polymorphism, Single Nucleotide

• MR/L006758/1 Medical Research Council

To investigate the impact of thymidylate synthase (TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer (mCRC) patients treated with chemotherapy.

Clinical data were collected retrospectively from records of consecutive patients with mCRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. TYMS genotypes were identified with restriction fragment analysis PCR, while KRAS and BRAF mutation status was evaluated using real-time PCR assays. TYMS gene polymorphisms of each of the 3’ untranslated region (UTR) and 5’UTR were classified into three groups according to the probability they have for high, medium and low TYMS expression (and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed.

The analysis recovered 89 patients with mCRC (46.1% de novo metastatic disease and 53.9% relapsed). Of these, 46 patients (51.7%) had colon cancer and 43 (48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy (5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo (range 0-119.8), 85 patients (95.5%) experienced disease progression, and 63 deaths (70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of TYMS polymorphisms, KRAS and BRAF with clinicopathological parameters indicated that TYMS 3’UTR polymorphisms are associated with risk for disease progression and death (P < 0.05 and P < 0.03 respectively). When compared to tumors without any del allele (genotypes ins/ins and ins/loss of heterozygosity (LOH) linked with high TYMS expression) tumors with del/del genotype (low expression group) and tumors with ins/del or del/LOH (intermediate expression group) have lower risk for disease progression (HR = 0.432, 95%CI: 0.198-0.946, P < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, P < 0.03 respectively) and death (HR = 0.366, 95%CI: 0.162-0.827, P < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, P < 0.06 respectively). Additionally, KRAS mutation was associated independently with the risk of disease progression (HR = 1.600, 95%CI: 1.011-2.531, P < 0.05). The addition of irinotecan in 1^st line chemotherapy was associated independently with lower risk for disease progression and death (HR = 0.600, 95%CI: 0.372-0.969, P < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, P < 0.01 respectively).

The TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in mCRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.

• Thymidylate synthase
• Polymorphisms
• mCRC
• Loss of heterozygosity
• Survival
• Chemotherapy
• KRAS
• BRAF
• TYMS

• 3' Untranslated Regions/genetics
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor/genetics
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/pathology
• Disease Progression
• Disease-Free Survival
• Drug Resistance, Neoplasm/genetics
• Female
• Follow-Up Studies
• Genetic Testing/methods
• Humans
• Male
• Middle Aged
• Mutation
• Polymorphism, Single Nucleotide
• Prognosis
• Proto-Oncogene Proteins B-raf/genetics
• Proto-Oncogene Proteins p21(ras)/genetics
• Real-Time Polymerase Chain Reaction
• Retrospective Studies
• Survival Analysis
• Thymidylate Synthase/genetics
• Thymidylate Synthase/metabolism
• Treatment Outcome

Neurotoxic anticancer drugs, such as platinum-based anticancer drugs, taxanes, vinca alkaloids, and proteasome/angiogenesis inhibitors are responsible for chemotherapy-induced peripheral neuropathy (CIPN). The health consequences of CIPN remain worrying as it is associated with several comorbidities and affects a specific population of patients already impacted by cancer, a strong driver for declines in older adults. The purpose of this review is to present a comprehensive overview of the long-term effects of CIPN in cancer patients and survivors. Pathophysiological mechanisms and risk factors are also presented. Neurotoxic mechanisms leading to CIPNs are not yet fully understood but involve neuronopathy and/or axonopathy, mainly associated with DNA damage, oxidative stress, mitochondria toxicity, and ion channel remodeling in the neurons of the peripheral nervous system. Classical symptoms of CIPNs are peripheral neuropathy with a “stocking and glove” distribution characterized by sensory loss, paresthesia, dysesthesia and numbness, sometimes associated with neuropathic pain in the most serious cases. Several risk factors can promote CIPN as a function of the anticancer drug considered, such as cumulative dose, treatment duration, history of neuropathy, combination of therapies and genetic polymorphisms. CIPNs are frequent in cancer patients with an overall incidence of approximately 38% (possibly up to 90% of patients treated with oxaliplatin). Finally, the long-term reversibility of these CIPNs remain questionable, notably in the case of platinum-based anticancer drugs and taxanes, for which CIPN may last several years after the end of anticancer chemotherapies. These long-term effects are associated with comorbidities such as depression, insomnia, falls and decreases of health-related quality of life in cancer patients and survivors. However, it is noteworthy that these long-term effects remain poorly studied, and only limited data are available such as in the case of bortezomib and thalidomide-induced peripheral neuropathy.

• anticancer drugs
• chemotherapy-induced peripheral neuropathy
• long-term effects
• pathophysiological mechanisms
• risk factors

Oxaliplatin is a chemotherapy agent active against digestive tumors. Peripheral neuropathy is one of the most important dose-limiting toxicity of this drug. It occurs in around 60–80% of the patients, and 15% of them develop severe neuropathy. The pathophysiology of oxaliplatin neurotoxicity remains unclear. SCN9A is a gene codifying for a subtype sodium channel (type IX, subunit α) and mutations in this gene are involved in neuropathic perception. In this study we investigated whether SCN9A genetic variants were associated with risk of neurotoxicity in patients diagnosed of cancer on treatment with oxaliplatin.

Blood samples from 94 patients diagnosed of digestive cancer that had received oxaliplatin in adjuvant or metastatic setting were obtained from three hospitals in Madrid. These patients were classified into two groups: “cases” developed oxaliplatin-induced grade 3–4 neuropathy (n = 48), and “controls” (n = 46) had no neuropathy or grade 1. The neuropathy was evaluated by an expert neurologist and included a clinical examination and classification according to validated neurological scales: National Cancer Institute Common Toxicity Criteria (NCI-CTC), Oxaliplatin-Specific Neurotoxicity Scale (OSNS) and Total Neuropathy score (TNS). Genotyping was performed for 3 SCN9A missense polymorphisms: rs6746030 (R1150W), rs74401238 (R1110Q) and rs41268673 (P610T), and associations between genotypes and neuropathy were evaluated.

We found that SCN9A rs6746030 was associated with protection for severe neuropathy (OR = 0.39, 95% CI = 0.16–0.96; p = 0.041). Multivariate analysis adjusting for diabetes provided similar results (p = 0.036). No significant differences in neuropathy risk were detected for rs74401238 and rs41268673.

SCN9A rs6746030 was associated with protection for severe oxaliplatin-induced peripheral neuropathy. The validation of this exploratory study is ongoing in an independent series.

• Calcium channel
• Oxaliplatin neuropathy
• SCN9A

5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC). Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR) and genetic polymorphisms (MTHFR, TSER, DPYD) on survival.

Genetic polymorphisms of MTHFR, TSER and DPYD, and the 5-FUDR of homogenous patients with mCRC were retrospectively studied. Genetic markers and the 5-FUDR were correlated with clinical outcome.

133 patients affected by mCRC, treated with fluoropyrimidine-based chemotherapy from 2009 to 2014, were evaluated. Patients were classified into three metabolic classes, according to normal distribution of 5-FUDR in more than 1000 patients, as previously published: poor-metabolizer (PM) with 5-FU-DR ≤ 0,85 ng/ml/10⁶ cells/min (8 pts); normal metabolizer with 0,85 < 5-FU-DR < 2,2 ng/ml/10⁶ cells/min (119 pts); ultra-rapid metabolizer (UM) with 5-FU-DR ≥ 2,2 ng/ml/10⁶ cells/min (6 pts). PM and UM groups showed a longer PFS respect to normal metabolizer group (14.5 and 11 months respectively vs 8 months; p = 0.029). A higher G3-4 toxicity rate was observed in PM and UM, respect to normal metabolizer (50% in both PM and UM vs 18%; p = 0.019). No significant associations between genes polymorphisms and outcomes or toxicities were observed.

5-FUDR seems to be significantly involved in predicting survival of patients who underwent 5-FU based CHT for mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes.

Gastric and colorectal cancers remain the major causes of cancer-related death. Although chemotherapy improves the prognosis of the patients with gastrointestinal cancers, some patients do not benefit from therapy and are exposed to the adverse effects. The polymorphisms in genes including GSTM1 and GSTT1 have been explored to predict therapeutic efficacy; however, the results were inconsistent and inconclusive.

A systematic review and meta-analysis was performed by searching relevant studies about the association between the GSTM1 and GSTT1 polymorphisms and chemotherapy efficacy in gastrointestinal cancers in databases such as PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure, and Wanfang database up to January 10, 2016. Subgroup analyses were also performed according to ethnicity, cancer type, evaluation criteria, study type, chemotherapy type, and age.

A total of 19 articles containing 3,217 cases were finally included. Overall analysis suggested that no significance was found between overall toxicity, neurotoxicity, neutropenia, gastrointestinal toxicity, tumor response, and progression-free survival, and the polymorphisms in GSTM1 and GSTT1, while GSTM1 polymorphism associated with overall survival (OS; hazard ratio =1.213, 95% confidence interval =1.060–1.388, P=0.005). Subgroup analyses suggested that neurotoxicity was associated with GSTM1 polymorphism in the Asian population, neutropenia was associated with GSTM1 polymorphism in palliative chemotherapy and older patients (mean age >60 years), and tumor response was associated with GSTT1 polymorphism in gastric cancer and responders defined by complete and partial responses. Meanwhile, GSTM1 was associated with OS in Caucasians, Asians, those with colorectal cancer, and patients with mean age <60 years. GSTT1 polymorphism was also associated with OS in Caucasians and patients with mean age >60 years.

The polymorphisms in GSTM1 and GSTT1 did not associate with the chemotherapy-related toxicity in gastrointestinal cancers, while GSTT1 polymorphism associated with OS, and further well-designed, larger-scale epidemiological studies are needed to validate our results.

• GSTM1
• GSTT1
• chemotherapy
• gastrointestinal cancer
• meta-analysis
• polymorphism

• Chemotherapy
• Colorectal cancer
• GSTP1
• Gastric cancer
• Meta-analysis
• Polymorphism

• GSTM1
• GSTP1
• GSTT1
• NSCLC
• polymorphism

• R01 CA131324 NCI NIH HHS
• R03 CA192197 NCI NIH HHS
• R25 DA026120 NIDA NIH HHS
• R01 DE022891 NIDCR NIH HHS
• P30 CA016672 NCI NIH HHS

• Models
• Neurotoxicity
• Pathogenesis
• Platinum
• Polymorphism
• Prevention

• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Humans
• Neuroprotective Agents/pharmacology
• Neurotoxicity Syndromes/diagnosis
• Neurotoxicity Syndromes/etiology
• Pharmacogenetics
• Platinum Compounds/adverse effects
• Platinum Compounds/therapeutic use
• Polymorphism, Genetic

The relationship between the excision repair cross-complementing 1 (ERCC1) rs11615 polymorphism (C/T) and responses to oxaliplatin-based chemotherapy for gastric cancer (GC) and colorectal cancer (CRC) patients is controversial. Therefore, we performed a meta-analysis to assess this relationship.

Relevant studies were retrieved by searching the PubMed database. A systematic review and meta-analysis was performed to evaluate the predictive value of the ERCC1 rs11615 polymorphism for the clinical outcomes of GC and CRC patients receiving oxaliplatin-based chemotherapy. Therapeutic response to chemotherapy, progression-free survival (PFS), and overall survival (OS) were analyzed.

A total of 22 studies were included in this meta-analysis, including 1,242 cases of GC and 1,772 cases of CRC. For the ERCC1 rs11615 polymorphism, the T allele was associated with a reduced response to chemotherapy in Asians and GC patients (P<0.05). On the other hand, the T allele was associated with a significant increase in the risk for shorter PFS and OS in all patients (PFS: hazard ratio [HR] =1.22, P<0.001, 95% confidence interval [CI] =0.93–1.51 and OS: HR =1.12, P<0.001, 95% CI =0.85–1.40).

The ERCC1 rs11615 polymorphism was closely associated with the clinical outcomes of GC and CRC patients treated with oxaliplatin-based chemotherapy.

• ERCC1 rs11615
• colorectal cancer
• gastric cancer
• meta-analysis
• oxaliplatin-based chemotherapy
• polymorphism

Anticancer chemotherapy (CT) produces non-desirable effects on normal healthy cells and tissues. Oxaliplatin is widely used in the treatment of colorectal cancer and responsible for the development of sensory neuropathy in varying degrees, from complete tolerance to chronic neuropathic symptoms. We studied the differential gene expression of peripheral leukocytes in patients receiving oxaliplatin-based chemotherapy to find genes and pathways involved in oxaliplatin-induced peripheral neuropathy. Circulating white cells were obtained prior and after three cycles of FOLFOX or CAPOX chemotherapy from two groups of patients: with or without neuropathy. RNA was purified, and transcriptomes were analyzed. Differential transcriptomics revealed a total of 502 genes, which were significantly up- or down-regulated as a result of chemotherapy treatment. Nine of those genes were expressed in only one of two situations: CSHL1, GH1, KCMF1, IL36G and EFCAB8 turned off after CT, and CSRP2, IQGAP1, GNRH2, SMIM1 and C5orf17 turned on after CT. These genes are likely to be associated with the onset of oxaliplatin-induced peripheral neuropathy. The quantification of their expression in peripheral white cells may help to predict non-desirable side effects and, consequently, allow a better, more personalized chemotherapy.

• Antineoplastic Agents/therapeutic use
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Humans
• Organoplatinum Compounds/therapeutic use
• Oxaliplatin
• Polymorphism, Genetic/genetics
• Prognosis
• Risk Factors
• Xeroderma Pigmentosum Group D Protein/genetics