Abstract A25: microRNAs associated with chemoresistance in gastric cancer patients tumors treated with neoadjuvant chemoterapy
Authors: Barcelos-Baldoni Michelle Maccarini , Coutinho-Camillo Claudia Malheiros , Puga Renato David , Ferreira-Begnami Maria Dirlei 
Published: May 2016

Abstract: Results of randomized controlled studies conducted to verify the effectiveness of neoadjuvant chemotherapy (NC) for gastric carcinoma (GC) have suggested that this treatment is therapeutically useful for the patients instead of surgery alone. However, in some patients with apparently the same molecular and histological tumor characteristics, the objective clinical response with NC is not achieved, and this lack of response may delay curative surgery and the toxicity induced by chemotherapy may increase surgical complications. Therefore, the main challenge for improving clinical outcomes is to understand the molecular mechanisms that may play essential roles in patients' responses of GC treatments. So, predictive novel molecules identification may be crucial for correct patients' selection. Emerging evidence suggested that some microRNAs (miRNAs) can have prognostic and diagnostic value in many types of cancer. Expression levels of several miRNAs have been found to be correlated with GC prognosis and could determine the clinical response for neoadjuvant chemotherapy. Objective: Our goal was to analyze the association between tumor miRNA expression and the pathological response grade of gastric carcinoma patients treated with neoadjuvant chemotherapy. Methods: A total of 52 paraffined samples were selected from a retrospective database of A.C. Camargo Cancer Center: From these samples, 34 were biopsy tumor samples (collected before chemotherapy) of GC patients treated with NC and 18 were normal gastric tissue (controls). The chemotherapy schemes used in NC were epirubicin, cisplatin and fluoracil, with adaptations using docetaxel, xeloda and oxaliplatin. All patients treated with NC received chemotherapy prior the surgery, and subsequently they were submitted to a complete resection (R0). To determine the tumor response of patients treated of neoadjuvant chemotherapy, we analyzed representative tumor slides stained with hematoxilin and eosine, and evaluated the percentage of viable tumor cells present in the gastric resection after NC. For trial analyses we used TLDA (Taqman® Low Density Array) qRT-PCR to determine the expression of 377 miRNAs. After that, validation of differentially expressed miRNAs was done by qRT-PCR using individual assays. Results: According to the percentage of viable tumor cells seen in microscopic analysis we established a graduation from 0% to 100% of viable tumor cells, being this relationship proportional inversely to treatment response. After evaluating the percentage of viable tumor cells present in gastric resection after NC, we categorized the samples in quartiles. After statistical analysis, the samples with a 100% of viable tumor cells after neoadjuvant treatment, showed us nine downregulated miRNAs. We performed qRT-PCR using individual assays, and confirmed downregulated expression of 3 miRNAs in biopsy tumor samples of patients treated with NC with 100% of viable tumor cells in gastric resection tumor. Conclusion: We found proteomic and expression profiles reports about the relationship of these 3 downregulated miRNAs with some genomic alterations involved in gastric cancer pathways and with some mechanisms of drugs resistance. These miRNA signature may be useful as potential biomarkers to predict response of gastric cancer patients to NC.

Citation Format: Michelle Maccarini Barcelos-Baldoni, Claudia Malheiros Coutinho-Camillo, Renato David Puga, Maria Dirlei Ferreira-Begnami. microRNAs associated with chemoresistance in gastric cancer patients tumors treated with neoadjuvant chemoterapy. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A25.