|Year : 2012 | Volume
| Issue : 3 | Page : 343-347
Personalized medicine of esophageal cancer
Lei Wang1, Hui-Yi Yang2, Yong-Qing Zheng2
1 Department of Cardiothoracic Surgery, Hebei Medical University Fourth Hospital, ShiJiaZhuang, Hebei, China
2 SurExam Bio Tech Co. Ltd., Guangzhou Technology Innovation Base, Science City, Guangzhou, China
|Date of Web Publication||17-Nov-2012|
SurExam Bio Tech Co. Ltd., Guangzhou Technology Innovation Base, Science City, Guangzhou
Source of Support: None, Conflict of Interest: None
The fatality rate of esophageal carcinomas is high in developing countries, making effective treatment desirable. Traditional treatment has now entered into the platform, and treatments based on the detection of biomarkers increasingly become a trend. This review presents several biomarkers of esophageal cancer, including chemotherapy-related biomarkers and targeted drug-related biomarkers, and the correlation of these biomarkers with drug response.
Keywords: Biomarker, drug response, esophageal carcinomas
|How to cite this article:|
Wang L, Yang HY, Zheng YQ. Personalized medicine of esophageal cancer. J Can Res Ther 2012;8:343-7
| > Introduction|| |
According to the 2008 Global Cancer Statistics, esophageal cancer ranks among the 10 most frequent cancers in the world, with most occurring in developing countries. Mortality rates are very similar to incidence rates (4,82,300 cases per year), due to the relatively late stage of diagnosis and the poor efficacy of treatment.  So, how to improve the therapeutic effect of advanced esophageal cancer is a pressing matter of the moment. As the present of new generation of chemotherapeutic agents, the patients received a certain survival benefits, but most patients' prognosis is still poor. In recent years, along with the development of pharmacogenetics and pharmacogenomics, relevant clinical studies also unceasingly thoroughly, personalized medicine based on detection of biological markers has gradually become the development direction of clinical treatment of cancer. The treatment of cancer can probably be improved by a better understanding of the molecular correlations of the disease. These have been facilitated by the development of molecular biomarkers for personalized treatment in lung cancer, breast cancer, colorectal cancer, and other cancers. This review will focus on important advances in biomarker research in esophageal carcinoma in recent years.
| > ERCC1|| |
Excision repair cross-complementing group 1 (ERCC1) is an important member of exonuclease repair family, which is encoded by ERCC1 gene. The function of the ERCC1 protein is predominantly in nucleotide excision repair (NER) of damaged DNA. Cisplatin was the first member of platinum-containing anticancer drugs, which now also includes carboplatin and oxaliplatin. These platinum complexes can bind to DNA and cause crosslinking of DNA, thereby inhibiting DNA replication, which ultimately triggers apoptosis. The relation between the ERCC1 expression and resistance to platinum compounds has been confirmed by many clinical studies in patients with advanced gastric, ovarian, colorectal, or non-small-cell lung cancer. ,,,, Measuring ERCC1 expression may have utility in clinical cancer medicine because one mechanism of resistance to platinum chemotherapy drugs correlates with high ERCC1 expression.
ERCC1 expression level has been associated with the outcome of cisplatin-based chemotherapy in esophageal cancer. Neoadjuvant treatment strategies have been developed to improve survival of patients with locally advanced esophageal cancer. It has been reported that ERCC1 expression level is a promising predictive marker in gastroesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy. , Fareed et al. validated the utility of ERCC1 as a predictive marker of clinicopathological outcomes in patients receiving platinum-based neoadjuvant chemotherapy.  ERCC1 level is also predictive for the survival. A study demonstrated that multivariate analysis identified an association with decreased survival for TS1, ERCC1, and GSTP1 high level (P = 0.007).  Another retrospective study confirmed the finding that patients with ERCC1-negative tumors showed tendencies toward prolonged overall survival (OS) (P = 0.10) and event free survival (P = 0.08).  Furthermore, ERCC1 polymorphism was significantly associated with formation of lymph node metastases.  It seems that the predictive value of ERCC1 has been well recognized. However, its test method has not formed a standard and still questionable.
| > BRCA1|| |
BRCA1 (breast cancer 1) is a caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. BRCA1 is expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired. If BRCA1 itself is damaged, damaged DNA is not repaired properly and this increases risks for cancers.  The protein encoded by the BRCA1 gene plays a role in transcription, DNA repair of double-stranded breaks, transcriptional regulation as well as other functions. Same as ERCC1, BRCA1 expression level is negatively correlated with the sensitivity to cisplatin in esophageal cancer.
Font et al. analyzed BRCA1 mRNA expression by quantitative PCR in pretreatment endoscopic biopsies from 43 locally advanced esophageal cancer patient treated with cisplatin plus fluorouracil (FU) and concurrent with radiotherapy. Patients were divided into groups according to BRCA1 expression levels. Low BRCA1 expression is associated with a trend toward better pathologic remission (pR) in patient treated with preoperative chemoradiotherapy.  The predictive value of BRCA1 for platinum complexes have not been confirmed yet. Further studies to evaluate the application are wanted.
| > Tyms|| |
Thymidylate synthetase (TYMS) is the enzyme used to generate thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair. As an anticancer chemotherapy target, TYMS can be inhibited by the thymidylate synthase inhibitors such as fluorinated pyrimidine FU, or certain folate analogues.  Therefore, TYMS expression level is correlated with in vivo chemosensitivity to thymidylate synthase inhibitors.
Harpole et al. defined the prognostic value of a group of molecular tumor markers in a well-staged population of patients treated with trimodality therapy for esophageal cancer. One marker of possible 5-FU association (TYMS) was measured. High-level expression of TYMS was associated with a decreased survival. Multivariate analysis identified high-level expression of the 5-FU marker TYMS as independent predictors of early recurrence and death. Independent prognostic significance was observed, which suggests that it may be possible to predict which patients may benefit most from thymidylate synthase inhibitors.  Besides TYMS expression, TYMS 3'UTR polymorphisms can also predict outcomes in patients with esophageal adenocarcinoma treated with preoperative 5-fluorouracil-based chemoradiation. There was a trend of association between 6 bp/6 bp genotype and a decreased risk of local regional recurrence compared with other genotypes. 
| > Mthfr|| |
MTHFR gene encode methylenetetrahydrofolate reductase (MTHFR), an enzyme that can catalyze the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which participates in many important biochemical reaction. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer, and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.  MTHFR could play an important role in the action of 5-FU by converting 5,10-methylenetetrahydrofolate, a substrate of TYMS, to 5-methyltetrahydrofolate.
Previous study in advanced colorectal cancer showed a link between the MTHFR polymorphism and tumor response to fluoropyrimidine-based chemotherapy and suggests that MTHFR genotyping may be of predictive benefit in selecting treatment regimens.  Wu et al. applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients. In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival in patients treated with FU. The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively.  However, to our knowledge, this is the only study on association between MTHFR and the outcome of esophageal cancer patients treat with FU.
| > ABCB1/MDR1|| |
The protein encoded by ABCB1 gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by ABCB1 gene is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs.  It has been reported that patients with drug-resistant epilepsy were more likely to have the CC genotype at ABCB1 3435 than the TT genotype.  For patients with esophageal cancer receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk and improved survival. 
| > Bax|| |
The BAX gene encode Bcl-2 associated X protein, is the pro-apoptotic member of the Bcl-2 protein family. It promotes apoptosis by competing with Bcl-2 proper. Loss of Bax expression has been reported to be associated with poor response to chemotherapy in breast cancer.  Abnormal expression of Bax may play an important role in chemoradio-sensitivity in malignant tumors.
Ikeguchi et al. retrospectively investigated the prognostic significance of the expressions of Bax in patients with esophageal squamous cell carcinoma (ESCC). Immunoreactivities of Bax were evaluated in 141 surgically resected ESCC by using monoclonal antibodies. Prognoses of 141 patients with or without postoperative chemoradiotherapy were compared among groups with high and low expressions of Bax. High immunoreactivities of Bax were detected in 49 cases (33.1%). Bax expression correlated with favorable prognosis (P = 0.016) in 57 patients with postoperative chemoradiotherapy. However, in 84 patients without adjuvant therapy, the prognostic significance of Bax was minimal.  Kang et al. evaluated the prognostic significance of apoptosis-related proteins, p53, Bcl-2, Bax, and galectin-3 in patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy. High expression of Bax was observed in 67% of patients. The median OS of total patients was 14 months with 16% of 3-year OS. Low expression of Bax was significantly correlated with lack of clinical complete response (P = 0.023). Low expression of Bax was also associated with poor OS (P = 0.0008) in univariate analysis. In multivariate analysis, low expression of Bax was the most significant independent predictor of poor OS (P = 0.009), followed by low-dose intensity of cisplatin and lack of clinical complete response.  Therefore, Bax expression may be a good marker for chemoradio-sensitivity in patients with ESCC.
| > TP53|| |
TP53 gene encode a tumor suppressor protein, which is known as tumor protein 53 (Tp53). Tp53 is crucial in multicellular organisms, where it regulates the cell cycle and functions as a tumor suppressor.  The study by Valerie et al. analyzed 52 patients with stage IIIA NSCLC entered in a prospective clinical trial, and a significant association was observed between aberrant p53 expression and resistance to chemotherapy as assessed by pathological response. Furthermore, several studies in breast cancer showed a negative relationship between p53 expression and OS in patients undergoing chemotherapy. ,
Okumura et al. analyzed the expression of p53 protein and their responses to chemoradiation therapy (CRT) in cases of ESCC. CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. Statistically significant correlations were found between p53 expression and favorable response to CRT.  However, Heeren et al. analyzed the significance of p53 protein on tumor response and prognostic effect in a group of esophageal cancer patients treated with neoadjuvant chemotherapy. Expression of p53 in pretreatment specimens was 73% (22 / 30) and was not related to response to chemotherapy. While alteration in expression of p53 positivity in the pretreatment specimens to p53 negativity in the resection specimens was correlated with better response and survival.  The small sample size may explain the contradictory study results.
| > Egfr|| |
EGFR is a membrane-bound tyrosine kinase receptor that mediates growth and survival signals. It has been confirmed that somatic mutations within the EGFR kinase domain correlate with a dramatic clinical response to gefitinib in NSCLC patients. ,,,
Mir et al. have analyzed mutations in exons 19 to 21 of EGFR in 54 cases of ESCC from patients recruited in Kashmir, India. The detection of three mutations (6%) in the ATP-binding regulatory loops of the tyrosine kinase domain of EGFR (deletion 746-750, P753L, G719D) was reported. This is the first report of activating EGFR mutations in ESCC, which suggests that a small proportion of ESCC patients may benefit from treatment with EGFR tyrosine kinase inhibitors.  Furthermore, in a recent study in Chinese patients, EGFR mutations were found in 7 (14%) out of 50 patients, including G719X missense mutation (n = 1), in-frame deletion (n = 2), and L858R missense mutation (n = 5). The presence of EGFR mutations was not associated with gender, age, smoking history, cell differentiation, or cancer stage. In conclusion, the incidence of EGFR mutations in Chinese patients with ESCC was higher than that of previous reports, and the mutations were mainly located in exons 19 and 21. 
Several results suggest that the EGFR gene may be a clinically useful biomarker for predicting the prognosis of ESCC patients. ,, Moreover, gefitinib has a modest activity in second-line treatment of advanced esophageal cancer and the patient outcome was significantly better in patients demonstrating high EGFR expression.  In contrast, cetuximab, an EGFR-directed monoclonal antibody, had minimal clinical activity in patients with metastatic esophageal and gastric adenocarcinoma. Thirty-five patients with previously treated metastatic esophageal or gastric adenocarcinoma were treated with weekly cetuximab. Treatment with cetuximab was well tolerated, but only one (3%) partial treatment response was noted. Median progression-free survival and OS were 1.6 and 3.1 months, respectively.  The different outcome between gefitinib and cetuximab may partly because of the different patients involved gefitinib in patients with esophageal cancer and cetuximab in patients with esophageal, gastric, and GE junction adenocarcinomas. The prior treatments which the patients have received may also contribute to this.
This paper reviews the molecular markers involved in esophageal cancer [Table 1]. Despite extensive research, there remain no clear candidate biomarkers that predict pathological response, and there are only equivocal data for a limited number of markers that might predict survival for patients treated with multimodality therapy. The predictive value of these biomarkers in ESCC still needs further confirmation by prospective trials. The need for additional information about these biomarkers and the related mechanisms is becoming more pressing.
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