Rio Honma

Role of targeted therapy in metastatic colorectal cancer

Colorectal cancer (CRC) is a significant cause of cancer-related morbidity and mortality all over the world. Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC (mCRC), with a median overall survival of approximately 2 years and more in the past two decades. The biologic agents that have proven clinical benefits in mCRC mainly target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In particular, bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated significant survival benefits in combination with cytotoxic chemotherapy in the first-line, second-line, or salvage setting. Aflibercept, ramucirumab, and regorafenib are also used in second-line or salvage therapy. Recent retrospective analyses have shown that KRAS or NRAS mutations were negative predictive markers for anti-EGFR therapy. Based on the evidence from large randomized clinical trials, personalized therapy is necessary for patients with mCRC according to their tumor biology and characteristics. The aim of this paper was to summarize the results of the major randomized clinical trials and highlight the benefits of the molecular targeted agents in patients with mCRC.

Expression of fucosyltransferase 8 is associated with an unfavorable clinical outcome in non-small cell lung cancers.

Objecitive: Fucosyltransferase 8 (FUT8), the only enzyme responsible for the core α1,6-fucosylation of asparagine-linked oligosaccharides of glycoproteins, is a vital enzyme in cancer development and progression. We examined FUT8 expression in non-small cell lung cancers (NSCLCs) to analyze its clinical significance. We also examined the expression of guanosine diphosphate-mannose-4,6-dehydratase (GMD), which is imperative for the synthesis of fucosylated oligosaccharides. Methods: Using immunohistochemistry, we evaluated the expression of FUT8 and GMD in relation to patient survival and prognosis in potentially curatively resected NSCLCs. Results: High expression of FUT8 was found in 67 of 129 NSCLCs (51.9%) and was significantly found in non-squamous cell carcinomas (p = 0.008). High expression of FUT8 was associated with poor survival (p = 0.03) and was also a significant and independent unfavorable prognostic factor in patients with potentially curatively resected NSCLCs (p = 0.047). High expression of GMD was significantly associated with high FUT8 expression (p = 0.04). Conclusions: High expression of FUT8 is associated with an unfavorable clinical outcome in patients with potentially curatively resected NSCLCs, suggesting that FUT8 can be a prognostic factor. The analysis of FUT8 expression and its core fucosylated products may provide new insights for the therapeutic targets of NSCLCs.

A Case of High-Grade Neuroendocrine Carcinoma That Improved with Bevacizumab plus Modified FOLFOX6 as the Fourth-Line Chemotherapy

High-grade neuroendocrine carcinoma differs from usual neuroendocrine carcinoma, and its prognosis is dismal. In this case report, a case of high-grade neuroendocrine carcinoma that improved with bevacizumab plus modified FOLFOX6 as the fourth-line chemotherapy is presented. A 29-year-old male with a huge liver tumor was diagnosed with high-grade neuroendocrine carcinoma originating from the liver. Multiple liver and bone metastases were found one month after surgery. He was treated with three chemotherapy regimens used for the management of small-cell lung cancer with extensive disease. However, none of them could be maintained because of tumor progression. He was then treated with bevacizumab plus modified FOLFOX6 as the fourth-line regimen. Dramatic tumor shrinkage was obtained, and a partial response was achieved. This case suggests that high-grade neuroendocrine carcinoma can be treated with bevacizumab in combination with cytotoxic chemotherapy.

Late Onset of Non-islet Cell Tumor Hypoglycemia Managed via Multidisciplinary Treatment in a Patient with a Solitary Fibrous Tumor

Solitary fibrous tumor (SFT) is a rare subtype of soft tissue sarcoma (STS). We herein describe a case of late onset of non-islet cell tumor hypoglycemia (NICTH) that was managed via multidisciplinary treatment in a patient with SFT. A 67-year-old man previously diagnosed with SFT 4 years prior to this presentation and treated with several rounds of surgery, presented with massive tumors. Eighteen months following his prescribed chemotherapy, the patient developed hypoglycemia. He was diagnosed with NICTH, after confirming the presence of high molecular weight insulin-like growth factor-2. This case suggests that paraneoplastic syndrome can occur even in cases of rare cancers, such as STS.

Abstract 2625: Clinicopathological features of programmed cell death ligand 1 (PD-L1) expression in resected non-small cell lung cancers

Background: Antibodies against programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) have recently demonstrated a survival benefit in several types of cancer, including melanoma and non-small cell lung cancer (NSCLC). PD-L1 expression has provided a predictive biomarker for anti-PD-1/PD-L1 therapy. However, the relationship between PD-L1 expression and clinical and clinicopathological characteristics remains unclear in NSCLCs. The aim of this study was to investigate the relevance of PD-L1 expression to clinical and clinicopathological factors in resected NSCLCs. Materials and Methods: PD-L1 expression was evaluated in 154 surgically resected NSCLC specimens by immunohistochemistry (IHC) using the SP142 antibody. Before the IHC of clinical samples, we performed a concordance study of Western blot analysis and IHC in 17 lung cancer cell lines. We evaluated the relationship between PD-L1 expression and clinical and clinicopathological factors by univariate and multivariate analyses. Survival curves were estimated by the Kaplan-Meier methods, and differences in survival distributions were evaluated by the log-rank test. Results: PD-L1 expression was well concordantly observed in Western blot analysis and IHC in the lung cancer cell lines analyzed. PD-L1 expression was observed in 51 of 154 (33%) surgically resected NSCLCs. PD-L1 expression was significantly correlated with male, heavy smoking history, squamous cell carcinoma, and moderate/poor differentiation of tumors by univariate analysis. In multivariate analysis, tumor differentiation had a strong relationship with PD-L1 expression (odds ratio: 6.32, 95% CI: 1.70-23.49, P = 0.006). The survival was not statistically different between patients with high and low PD-L1 expression (5-year survival rate: 44.1% versus 58.1%, P = 0.22). PD-L1 expression was not an independent prognostic factor in univariate and multivariate analyses. Conclusion: PD-L1 expression was strongly associated with tumor differentiation in resected NSCLCs. PD-L1 expression was not a prognostic factor in this cohort of resected NSCLCs. Citation Format: Yoshihito Ohhara, Ichiro Kinoshita, Utano Tomaru, Kanako C. Hatanaka, Yutaka Hatanaka, Rio Honma, Satoshi Takeuchi, Yasushi Shimizu, Kichizo Kaga, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita. Clinicopathological features of programmed cell death ligand 1 (PD-L1) expression in resected non-small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2625. doi:10.1158/1538-7445.AM2017-2625

Abstract 3164: Decreased expression of GDP-mannose-4,6-dehydratase (GMD) and GDP-fucose transporter is associated with squamous histology in non-small cell lung cancers (NSCLCs)

We have previously reported that low expression of α1,6-fucosyltransferase (FT), an enzyme for the core fucosylation of N-glycans, is significantly more prevalent in squamous cell carcinomas compared with non-squamous cell carcinomas of the lung. GMD generates GDP-fucose from GDP-mannose, and is imperative for the synthesis of all fucosylated oligosaccharides. GDP-fucose is transported into the Golgi apparatus by GDP-fucose transporter to serve as a substrate of FTs. In the present study, we examined expression of GMD and GDP-fucose transporter by immunohistochemistry in 156 surgically resected NSCLCs. High, moderate and low expression of GMD was found in 32 (20.5%), 32 (20.5%) and 92 (59.0%) NSCLCs, respectively. High/moderate, low and no expression of GDP-fucose transporter was found in 7 (4.5%), 23 (14.7%) and 126 (80.8%) NSCLCs, respectively. Low GMD expression was significantly more prevalent in tumors from men than in those from women (p = 0.02), in tumors from smokers compared with nonsmokers (p = 0.047), and in squamous cell carcinomas compared with non-squamous cell carcinomas (p = 0.0003) by the χ2 test. Multivariate logistic regression analysis for the correlation between GMD expression and various characteristics revealed a significant association between low GMD expression and squamous cell carcinomas, as compared with non-squamous cell carcinomas (low vs. moderate, p = 0.005; low vs. high, p = 0.02). Among biological characteristics of tumors studied previously in this cohort of NSCLCs, Ki-67 labeling index was significantly higher in tumors with low GMD expression than in those with high GMD expression (low vs. high, p = 0.003). Low expression of α1,6-FT was more prevalent in tumors with low GMD expression than in those with moderate or high GMD expression (p = 0.002). Low GDP-fucose transporter expression was significantly more prevalent in squamous cell carcinomas compared with non-squamous cell carcinomas (p = 0.003) by the χ2 test. GMD and GDP-fucose transporter expressions were not associated with survival. These results indicate that GMD and GDP-fucose transporter may be new markers of NSCLCs with specificity for histology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3164. doi:10.1158/1538-7445.AM2011-3164