Search

Background Pancreatic neuroendocrine tumors are rare neoplasms for which few predictive and/or prognostic biomarkers have been validated. Our previous work suggested the potential of the combined expression of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) as prognostic factors for relapse and survival. Methods In this new multicenter study we evaluated immunohistochemistry expression in 76 patients with advanced PanNET who were treated with capecitabine-temozolomide or everolimus. Based on the immunohistochemistry panel, an immunohistochemistry prognostic score (IPS) was developed. Results In patients treated with capecitabine and temozolomide, low IPS was an independent prognostic factor for progression-free-survival and overall-survival. Similar findings were observed with highest IPS for overall-survival in patients treated with everolimus. Conclusion From our knowledge, it is the first time that a simple IPS could be useful to predict outcome for patients with metastatic pancreatic neuroendocrine tumors treated with everolimus or capecitabine and temozolomide.

Simple Summary Decision about treatment choice in early-stage colon cancer may be difficult for clinicians because of a lack of published data. Colon cancer is a very heterogeneous disease, but some previous efforts have helped us elucidate potential biomarkers for characterizing patients. Our goal is to create a panel of biomarkers capable of differentiating patients with a low, medium, and high risk of death or relapse. Our results suggest that, by combining PD-L1, GLUT-1, and mismatch repair proteins in a biomarker panel, patients could be significantly and evenly divided into one of these three groups. The resulting biomarker panel has the potential clinical value that, by being able to classify a patient with early colon cancer as being at high risk of death or tumor evolution, they could benefit from a more aggressive early treatment, while this approach might not be needed for low-risk patients. Abstract Molecular characterization of colorectal cancer has helped us understand better the biology of the disease. However, previous efforts have yet to provide significant clinical value in order to be integrated into clinical practice for patients with early-stage colon cancer (CC). The purpose of this study was to assess PD-L1, GLUT-1, e-cadherin, MUC2, CDX2, and microsatellite instability (dMMR) and to propose a risk-panel with prognostic capabilities. Biomarkers were immunohistochemically assessed through tissue microarrays in a cohort of 144 patients with stage II/III colon cancer. A biomarker panel consisting of PD-L1, GLUT-1, dMMR, and potentially CDX2 was constructed that divided patients into low, medium, and high risk of overall survival or disease-free survival (DFS) in equally sized groups. Compared with low-risk patients, medium-risk patients have almost twice the risk of death (HR = 2.10 (0.99–4.46), p = 0.054), while high-risk patients have almost four times the risk (HR = 3.79 (1.77–8.11), p = 0.001). The multivariate goodness of fit was 0.756 and was correlated with Kaplan–Meier curves (p = 0.002). Consistent results were found for DFS. This study provides a critical basis for the future development of an immunohistochemical assessment capable of discerning early-stage CC patients as a function of their prognosis. This tool may aid with treatment personalization in daily clinical practice and improve survival outcomes.

Background. There is a patent need to better characterize early-stage colorectal cancer (CRC) patients. PD-1 ligand (PD-L1) expression has been proposed as a prognostic factor but yields mixed results in different settings. The Consensus Molecular Subtype (CMS) classification has yet to be integrated into clinical practice. We sought to evaluate the prognostic value of PD-L1 expression overall and within CMS in early-stage colon cancer patients, in the hope of assisting treatment choice in this setting. Methods. Tissue-microarrays were constructed from tumor samples of 162 stage II/III CRC patients. They underwent automatic immunohistochemical staining for PD-L1 and the proposed CMS panel. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Results. PD-L1 expression was significantly and independently associated with better prognosis (HR = 0.46 (0.26–0.82), p = 0.009) and was mostly seen in immune cells of the tumor-related stroma. CMS4 five-folds the risk of mortalitycompared with CMS1 (HR = 5.58 (1.36, 22.0), p = 0.034). In the subgroup CMS2/CMS3 analysis, PD-L1 expression significantly differentiated individuals with better OS (p = 0.004) and DFS (p &lt, 0.001). Conclusions. Our study suggests that PD-L1 expression is an independent prognostic factor in patients with stage II/III colon cancer. Additionally, it successfully differentiates patients with better prognosis in the CMS2/CMS3 group and may prove significant for the clinical relevance of the CMS classification.

e16707 Background: Previously our group showed the potential use of a score based (SPI) on MGMT, NDRG-1 and PHLDA-3 immunohistochemistry (IHC) expression as predictor of outcome in operated PanNET (Viúdez et al. Oncotarget 2016). The present retrospective multicenter project is analyzing the predictive/prognosis role of MGMT, NDRG-1 and PHLDA-3 in patients treated with advanced PanNET treated CAPTEM or everolimus. Methods: IHC nuclear staining for MGMT and PHLDA-3 is being scored as 0, 1-5%, 6-50% and ≥ 51%. For NDRG-1, we are using a cytoplasmic score from 0 to 2 based on distribution pattern (null, patched or diffuse). Results: 60 of 105 pts have been fully analyzed., most of then women (53%) and median age of 63 (27-79). 30 pts were treated with CAPTEM and 30 pts with everolimus. Median previous lines were 1 (21,7% received chemotherapy previously), and 91,7% pf pts had ki67 < 20%. 65,5%, 10,2% and 29,1% were null for MGMT, NDRG-1 and PHLDA-3 IHC analysis. In the entire cohort K-M analysis showed significant differences for PFS or OS based on best response observed (p = 0,0001) and number previous lines received (p = 0,05), respectively. In pts treated with CAPTEM, log rank analysis showed significant differences for PFS (p = 0,047 HR:4,63 CI95%: 1,023-20,990) and OS (p = 0,040 HR:5,433 CI95%: 1,082-27,266) based on our SPI. Similar, although not significant, results were observed in everolimus-treated cohort for PFS (p = 0,529) and OS (p = 0,592) according to SPI. Conclusions: As it was described previously in operated PanNET, our SPI also seems to own predictive role in pts with advanced PanNET treated with CAPTEM or everolimus. More mature results of our work are needed and will be presented during 2020 ASCO Annual Meeting.

[Introduction] There are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients., [Methods] KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test., [Results] Hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014)., [Conclusions] We identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors., The project was funded by the Instituto de Salud Carlos III (ISCIII) - Fondo Europeo de Desarrollo Regional (FEDER), through a public competitive call (project reference PI15/01254; principal Investigator Javier Martín Broto), and the Spanish Group for Research on Sarcoma (GEIS).

Background Previously our group showed the potential use of a score based on MGMT, NDRG-1 and PHLDA-3 immunohistochemistry (IHC) expression as predictor of outcome in operated PanNET. The present multicenter project is retrospectively analyzing the predictive/prognosis role of MGMT, NDRG-1 and PHLDA-3 in patients with advanced PanNET treated CAPTEM or everolimus. Methods IHC nuclear staining for MGMT and PHLDA-3 is being scored as 0, 1-5%, 6-50% and ≥ 51%. For NDRG-1, we are using a cytoplasmic score from 0 to 3 based on staining intensity and distribution pattern (patched or diffuse). Results Until now, clinical and samples data from 96 patients (110 samples) has been collected ad are currently being analyzed. Based on our previous results, we will develop an imunohistochemistry prognostic score (IPS, score from 0 to 4) and try to correlate it with clinical variables collected in our database. Conclusions As we described previously in operated PanNET, we will try to describe the potential role of IPS as predictive/ prognostic factor in advanced PanNET. More mature results of this work will be presented during 2019 ESMO Congress. Legal entity responsible for the study Navarrabiomed Biomedical Research Center, Pamplona, Navarra, Spain. Funding GETNE. Disclosure All authors have declared no conflicts of interest.

e14656 Background: The RECIST criteria may be limited in assessing response to biologic agents such as bevacizumab (BVZ). Retrospective studies of patients (pts) with colorectal liver metastases (C...

e14589 Background: Tejpar et al (JCO2012; 30(29):3570-7) showed that patients with aCRC and Gly13D kras mutation experienced worse response rate with chemotherapy alone compared to those with other kras mutations. This retrospective study analyzes differences in clinical and radiological response between patients with the two main kras mutations: Gly12Val or Gly13D. Methods: In this retrospective-observational trial, patients with aCRC and Gly12Val and Gly13D kras mutation tumours participated. Clinical and radiological responses of patients with each of the two kras mutation, detected by Therascreen technique and treated with conventional first-line chemotherapy schemes, were recorded. SPSSv17 was employed. ORR (Overall Response Rate: CR+PR) and OCR (Overall Control Rate: CR+PR+SD) were calculated. Results: From November 2005 to October 2012, 51 patients with aCRC and Gly12Val or Gly13D kras mutations were included. Median age was 66 (41-80); 52.7 % men and 49.1% with synchronous disease. Kras mutation status was: 47.3% Gly13D and 52.7% Gly12Val. The chemotherapy schedules were based on Oxaliplatin, Irinotecan and others (61.5%, 25% and 13.5% respectively). While ORR was observed in 39.22 % (38.46 % Gly12Val and 40% Gly13D; p: 0.57), OCR was 76.5% (76.9% Gly12Val and 76% Gly13D; p: 0.60). In the Kaplan-Meier analysis, OS showed no difference between both kras mutation groups (Gly12Val: 29 months; Gly13D: 28 months; p: 0.28). Conclusions: According to our results, and in contrast to other studies outcomes, there is no difference regarding ORR, OCR or OS in patients with both different kras mutation: Gly12Val or Gly13D; however, the hypothetical role of Gly13D mutation as a biomarker of chemotherapy resistance, should be evaluated in prospective studies.

e14057 Background: MicroRNAs (miRNA), small non-coding RNA molecules act as post-transcriptional regulators of gene expression and have shown diagnostic and prognostic potential in cancer. We profiled miRNA expression in LARC patients treated with neoadjuvant CRT to assess whether a miRNA signature correlated with the degree of pathological response. Methods: FFPE-derived tumour samples from 85 LARC patients treated with preoperative CRT (45 Gy plus 5.4 Gy boost, 180-cGy daily fractions and concurrent capecitabine) were analyzed for miRNA signature generation and IHQ-EGFR protein expression. Pathological response was scored according to the Mandard’s TRG scale. Expression profile of 667 mature miRNAs obtained by TLDA Human MicroRNA Panel or individual TaqMan MicroRNA Assays were normalized using RNU48, selected as the best normalizer by Normfinder program. The correlation between miRNA expression profile and pathologic response was assessed by class-comparison, unsupervised hierarchical cluster analysis and U-Mann Whitney test. Results: A pathological complete response was achieved in 12 patients (14%), whereas no response (TRG 3-4) was observed in 49 patients (58%). As expected, TRG correlated with both relapse and disease-free survival (p

674 Background: Recent reports have shown that pathological response predicts for better outcome (overall survival) following preoperative chemotherapy and surgical resection of colorectal cancer (CRC) liver-only metastases. The aim of this retrospective analysis was to evaluate the effect of adding bevacizumab to standard chemotherapy on pathological response in patients with CRC liver only metastases. Methods: Patients with stage IV CRC with liver metastases who received neoadjuvant chemotherapy (oxaliplatin-or irinotecan-based) at two Spanish centres were analysed retrospectively. Pathological response was evaluated as follows: complete pathological response (cPR), PR1 (25% of residual tumour), PR2 (25–50% of residual tumour), PR3 (>50% of residual tumour). cPR or PR1 was considered to be a good response, and PR2 or PR3 a poor response. Results: A total of 81 patients were evaluated. Of these, 43 received chemotherapy alone and 38 received chemotherapy plus bevacizumab. Baseline characteristics were as follows: median age 61.0 years (range 43.0–80.0 years); male/female (67%/33%); tumour location – colon (69%) / rectum (31%); hepatic metastases – synchronous (74%) / metachronous (26%); In terms of pathological response, 58% of patients receiving bevacizumab had a good response (cPR + PR1) compared with 28% of those receiving chemotherapy alone. At the end of the analysis, 68% of patients were still alive. Conclusions: Adding bevacizumab to oxaliplatin-based chemotherapy in the neoadjuvant setting improves the pathological response of liver metastases in patients with stage IV CRC. These findings indicate that pathological response might be a good indicator of outcome for patients receiving bevacizumab in the neoadjuvant setting.