Toward molecularly selected chemotherapy for advanced gastric cancer: State of the art and future perspectives

ArticleinCancer Treatment Reviews 35(5):451-62 · June 2009with14 Reads
DOI: 10.1016/j.ctrv.2009.04.008 · Source: PubMed
In the last few years therapeutic options for gastric cancer patients have slowly, but constantly expanded following the introduction of both new chemotherapy agents and innovative indications for treatment. Along with the medical therapy also our knowledge of the molecular mechanisms underlying this disease has progressively improved. However although the available treatment options have undoubtedly increased no clear definitive indications can be made for a standard chemotherapy regimen and we are still unable to accurately select the appropriate treatment for the appropriate patient. Many molecular determinants of response/toxicity to chemotherapy agents have been identified, but only few of them seem to possess the necessary potential for a subsequent application in the clinical practice. Some of these factors have also been indicated as a therapeutic target for a novel class of anti-cancer compounds. This systematic review will analyse available data about these factors with the aim to constitute a starting point for future research.
    • "Although the incidence of gastric cancer has been substantially declining for several decades, it is still the fourth most common cancer and the second most frequent cause of cancer death [1,2]. A multiple of genes seem to contribute to the malignant biological behaviour of gastric cancer [3,4]. It is very important to identify the prognostic factors in order to maximize the therapeutic effect and to minimize the adverse effects in the treatment of cancer patients. "
    [Show abstract] [Hide abstract] ABSTRACT: Background and objective: miR-132 plays a role in regulating neuronal morphology and cellular excitability. Little is known about the effects of miR-132 in cancer. The aim of this study is to evaluate the expression of miR-132 and its clinical significance in gastric cancer. Cancerous tissues and corresponding normal tissues from 79 patients with gastric cancer were examined for the expression of miR-132 using quantitative PCR and the association between miR-132 expression levels and clinicopathological factors and prognosis was analyzed. In 79 clinical samples of gastric cancer patients, miR-132 expression levels in cancer tissues were significantly higher than those in the corresponding normal tissues (P =0.001). Higher expression levels of miR-132 were associated with more frequent lymph node metastasis (P =0.033), more lymphatic tumor emboli (P =0.007), and more advanced stage (P =0.016). Additionally, expression of miR-132 was an independent prognostic factor for overall survival (P =0.020). miR-132 could serve as an efficient prognostic factor for gastric cancer patients.Virtual slides: The virtual slide(s) for this article can be found here:
    Full-text · Article · Mar 2014
    • "Actually, preliminary evidences have shown that the three distinct GC subtypes identified on histopathologic and anatomic criteria, present different gene expression profiles [7]. In the last few years, several studies have demonstrated that molecular markers may correlate to either response or toxicity to specific antineoplastic drugs in GC [18]. Differential expression of biological factors involved in chemotherapy activity, including targets of chemotherapeutic agents, such as thymidylate synthase (TS) for 5-FU, but also genes involved in drug metabolism, may explain the different response to treatment observed in our study. "
    [Show abstract] [Hide abstract] ABSTRACT: Recently, a new classification for gastric cancer (GC) has been proposed, based on Lauren's histology and on anatomic tumour location, identifying three subtypes of disease: type 1 (proximal non diffuse GC), type 2 (diffuse GC) and type 3 (distal non diffuse GC). Aim of our analysis was to compare clinical outcome according to different GC subtypes (1,2,3) in metastatic GC patients receiving first-line chemotherapy. Advanced GC pts treated with a first-line combination chemotherapy were included in our analysis. Pts were divided in three subgroups (type 1, type 2 and type 3) as previously defined. A total of 248 advanced GC pts were included: 45.2% belonged to type 2, 43.6% to type 3 and 11.2% to type 1. Patients received a fluoropyrimidine-based chemotherapy doublet or three drugs regimens including a platinum derivate and a fluoropyrimidine with the addition of an anthracycline, a taxane or mytomicin C. RR was higher in type 1 pts (RR = 46.1%) and type 3 (34,3%) compared to type 2 (20,4%), (p = 0.015). Type 2 presented a shorter PFS, median PFS = 4.2 months, compared to type 1, mPFS = 7.2 months, and type 3, mPFS = 5.9 months (p = 0.011) and also a shorter OS (p = 0.022). Our analysis suggests that GC subtypes may be important predictors of benefit from chemotherapy in advanced GC patients. Future clinical trials should take in account these differences for a better stratification of patients.
    Full-text · Article · Nov 2013
    • "While the therapeutic potential of available cytotoxic compounds remains rather limited, there are some ways to improve the efficacy of GC treatment by customized selection of drug cocktails. Studies on predictive molecular markers have offered some promising opportunities [6]. Earlier reports revealed that tumors with low level of thymidylate synthase (TS) respond better to the treatment by fluoropyrimidines, probably because of more efficient intratumoral inhibition of this enzyme by therapeutically relevant doses of this drug789 . "
    [Show abstract] [Hide abstract] ABSTRACT: Sensitivity of gastric cancer (GC) to conventional cytotoxic therapy may be at least in part attributed to molecular features of the tumor cells. We analyzed all patients with metastatic GC treated in the N.N. Petrov Institute of Oncology (St. Petersburg) within years 1999–2010 and identified 65 cases with evaluable treatment response and available biological material. Two of 65 patients (3 %) carried germ-line BRCA1 5382insC mutation and demonstrated particularly pronounced response to the treatment; both of their tumors showed loss of the remaining BRCA1 allele, thus confirming the causative role of BRCA1 heterozygosity in GC predisposition. RNA expression of TS, DPD, BRCA1, ERCC, TOP2A and bTUBIII was analyzed in the remaining 63 tumors. Low BRCA1 expression was associated with increased response rate [6/9 (67 %) vs. 17/54 (32 %), p = 0.04]. Low bTUBIII level correlated with the improved probability of tumor response [21/49 (43 %) vs. 1/13 (8 %), p = 0.02] and prolonged overall survival (10.5 vs. 7.1 months, p = 0.02); this trend was maintained both for taxane-containing and for taxane-free drug combinations. We conclude that GC should be considered as a part of BRCA1-related hereditary cancer syndrome. Tumors with BRCA1 inactivation and low bTUBIII expression demonstrate improved response to cytotoxic therapy.
    Full-text · Article · Jun 2013
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