- Email: [email protected]
Up-regulation of IBSP expression predicts poor prognosis of esophageal squamous cell carcinoma patients
abstracts Advisory / Consultancy: Amgen; Research grant / Funding (institution): Dainippon Sumitomo; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Janssen. All other authors have declared no conflicts of interest.
1858P
Transcriptomic difference of thymoma and thymic carcinoma
Background: Thymoma and thymic carcinoma (TC) are rare diseases of thymus with relatively good prognosis. Different pathological sub-types of thymoma and TC show clear differences on clinical characteristics, morphology, molecular markers, and prognosis. Methods: In this study, 26 thymoma and thymic carcinoma patients with most common thymic epithelial tumor subtypes were enrolled, including 2 type A, 6 type AB, 3 type B1, 1 type B1/B2, 5 type B2, 2 type B2/B3, 4 type B3, and 3 type TC patients in total. The frozen tissues of all patients were processed for RNA-seq sequencing. Results: We used unsupervised clustering to divide all samples into 5 clusters. Four clusters showed clear concordance with pathological subtypes, i.e. cluster AB (5 AB, 1 B1, and 2 B2), cluster B1/B2 (2 B1, 1 B1/B2, and 2B2), cluster B2/B3 (1 B2, 1 B2/B3, and 2B3), and cluster TC (3 TC and 1 A). Only one cluster (1 A, 1 AB, and 2 B3) was labeled as cluster A/AB according to the result of joint clustering analysis with TCGA THYM RNA-seq data. We performed gene function enrichment analysis on highly expressed genes in each cluster. Cluster A showed gene function enrichment on two development related pathways (nervous system development and epithelium development) and cell differentiation. Cluster AB had enriched function of cell proliferation and regulation of cell development. Cluster B1/B2 did not show any enriched functions. Cluster B2/B3 showed gene function enrichment of cell adhesion and regulation of developmental process. CD274 (PD-L1) was also highly expressed in this cluster. Cluster TC had enriched function of several pathways, including cell adhesion, cell migration, cell differentiation, immune system process, immune response, and nervous system development. Moreover, PI3K-Akt signaling pathway, pathway in cancer, and transcriptional misregulation in cancer were also enriched in cluster TC’s highly expressed genes. Conclusions: Thymic epithelial tumor subtypes show clearly different expression profiles. The highly expressed genes of each subtype relate to development, immune, and cancer related functions. PD-L1 is highly expressed in B2/B3 samples which suggests potential immunotherapy for the subtypes. Legal entity responsible for the study: Peking Union Medical College Hospital. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
1859P
A phase II trial of preoperative chemoradiotherapy and pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC)
S. Lee1, B.C. Ahn1, S.Y. Park2, D.J. Kim2, C.G. Lee3, J. Cho3, J.H. Kim4, H.R. Kim5, Y-H. Kim5, S.R. Park6, Y.J. Chun1, M.H. Hong1, H.R. Kim1, B. Cho1 1 Division of Medical Oncology, Yonsei Cancer Center Yonsei University, Seoul, Republic of Korea, 2Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea, 3Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea, 4 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 5Department of Thoracic and Cardiovasular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 6Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Background: Even though preoperative chemoradiotherapy (CRT) showed survival improvement in patients with resectable ESCC in a randomized trial over upfront surgery, ESCC still has a dismal prognosis. With the potential benefit of combining PD-1 blockade to CRT, we conducted a phase II trial which assessed the efficacy, feasibility, and safety of the combination of preoperative CRT and pembrolizumab (PEM) in ESCC (NCT02844075). Methods: Patients (pts) with histologically confirmed ESCC (clinical stage Ib to III according to the American Joint Committee on Cancer 7th staging system) were enrolled. Pts received concurrent neoadjuvant chemotherapy (weekly paclitaxel and carboplatin), radiotherapy (44.1 Gy in 21 fractions), and PEM (every 3 weeks, 200 mg) during 5 weeks followed by surgery. After surgery, pts were treated with PEM during 2 years or until progression, unacceptable toxicity, death, or pts’ refusal, which came first. The primary endpoint was pathologic complete response (pCR) rate in the primary
v754 | Thoracic Malignancies, Other
tumor and secondary endpoints were overall survival (OS), disease-free survival (DFS), the incidence of adverse events, and etc. Results: In a total of 28 enrolled pts (median age 60), 26 pts received esophagectomy. Two pts did not undergo surgery due to death (hematemesis) and consent withdrawal. There were two in-hospital mortality cases after surgery due to acute lung injury and four mortality cases due to disease progression. The pCR in primary tumor was achieved in 46.1% of pts who underwent resection (95% CI: 28.8 – 64.6). With a median follow-up of 12.4 months, median OS was not reached. Six, 12, and 18-month OS rates were 89.3%, 80.8%, and 73.1% respectively. There was a trend toward better DFS in the pCR group (n ¼ 12) compared with the non-pCR group (n ¼ 14) (HR ¼ 0.33, p ¼ 0.1). Most common treatment-related adverse events were neutropenia (50.0%) and liver enzyme elevation (30.8%) in the neoadjuvant and adjuvant period, respectively. Conclusions: The addition of PEM to preoperative CRT in ESCC demonstrated promising efficacy with acceptable toxicity. Based on the results, further investigation is warranted in a phase III clinical trial. The exploratory endpoints including biomarkers analyses are ongoing. Clinical trial identification: NCT02844075. Legal entity responsible for the study: The authors. Funding: MSD. Disclosure: All authors have declared no conflicts of interest.
1860P
The study of tumor associated exosomes in crosstalk between esophageal carcinoma and lymphatic endothelial cells
W. Mao1, A. Zhao2 Thoracic Surgery, Cancer Hospital of University of Chinese Academy of Sciences, Hangzhou, China, 2Cancer Hospital of University of Chinese Academy of Sciences, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Hangzhou, China
1
Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in china. Because the disease often has no symptoms in the early stages, it is usually detected at a more advanced stage that is more challenging to treat. The inter-communication between esophageal squamous cell carcinoma and its surrounding microenvironment is essential for tumor progression and metastasis. Exosome plays a key role in information delivery between primary lesion and pre-metastatic niche via its packed bioactive molecules. The aim of this study is to explore the effect of exosome from tumor plasma to angiogenesis in human lymphatic endothelial cells (HLEC) in vitro. Methods: Total circulation exosomes (CEs) were extracted and purified to selectively capture EpCAM positive exosomes by magnetic-bead technique. Proteins were separated by SDS-PAGE, and protein bands were analyzed by mass spectrometry. Tube formation assay and fluorescence imaging assay were performed in vitro. Results: The expression level of CEs in ESCC patients with lymph node metastasis were significantly higher than that in ESCC patients without metastasis and healthy control group (respectively; P < 0.001). The tumor associated exosomes could be taken by HLEC and its transferred into HLECs could to promote HLECs tube formation in vitro. In addition, the mass spectrometry was used to analysis the proteomic content in tumor associated exosomes, tumor-related proteins such as matrix-metalloproteinases, PP2A proteins and EIF proteins were identified in the exosome. Conclusions: Exosomes released by ESCC may play important roles in the microenvironment of ESCC and provide a potential application of therapy. Legal entity responsible for the study: Zhejiang Cancer Hospital. Funding: NSFC. Disclosure: All authors have declared no conflicts of interest.
1861P
Up-regulation of IBSP expression predicts poor prognosis of esophageal squamous cell carcinoma patients
M. Wang Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China Background: Esophageal squamous cell carcinoma (ESCC), a common gastrointestinal tumor, is listed as the sixth leading cause of cancer-related death worldwide, with high morbidity and mortality as its important characteristics. In recent years, despite advances in diagnosis and treatment of ESCC, the mortality rate of ESCC is still very high, with an average overall 5-year survival rate of about 10% 41%.As with many other solid tumors, development and progression of ESCC are also considered gene regulatory disorders caused by oncogene activation and inactivation accumulation and disorders of tumor suppressor genes (TSG). Therefore, screening and exploring the key gene proteins for the occurrence, development, treatment and clinical prognosis of ESCC is an important topic in the field of ESCC research at present.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz266.020/5578186 by guest on 26 October 2019
N. Liang1, L. Liu1, H. Liu1, W. Wang1, Y. Bi2, Z. Liang2, N. Li3, R. Lin3, T. Wang3, S. Li1 Department of Thoracic Surgery, Peking Union Medical College Hospital, Beijing, China, 2Department of Pathology, Peking Union Medical College Hospital, Beijing, China, 3Department of Clinical Research, Hangzhou Repugene Technology Inc., Beijing, China
1
Annals of Oncology
Annals of Oncology
Volume 30 | Supplement 5 | October 2019
Conclusions: the results of this study showed that IBSP up-regulation was often found in ESCC tumor specimens, indicating poor prognosis of ESCC patients. Moreover, it also demonstrated that IBSP could improve the ability of ESCC cell proliferation and tumor metastasis, which may be a valuable prognostic indicator in ESCC patients. Yet, the mechanism by which IBSP promotes tumorigenesis and development needs more researches. Legal entity responsible for the study: The author. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz266.020/5578186 by guest on 26 October 2019
Methods: Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical (IHC) staining were employed to determine IBSP expression at the mRNA and protein levels in clinical ESCC samples. Moreover, functional studies were adopted to study the tumor-promoter function of IBSP. Results: IBSP up-regulation was found in 21 of 45 (46.7%) primary ESCC cells at mRNA level by transcription-polymerase chain reaction (RT-PCR). In addition, IHC staining further demonstrated that IBSP was up-regulated in ESCC cases and up-regulation of IBSP protein was significantly relevant to lymph node metastasis (P ¼ 0.017), clinicopathologic stage (P ¼ 0.001) and poor disease survival (P ¼ 0.000) of ESCC patients. Moreover, functional studies illustrated that IBSP gene can promote the ability of proliferation and metastasis of ESCC cells. Furthermore, it was found that IBSP can regulate the EMT process by regulating MMP2 gene and N-cadherin, which promotes the metastasis of tumor cells.
abstracts
doi:10.1093/annonc/mdz266 | v755
1858P
Transcriptomic difference of thymoma and thymic carcinoma
Background: Thymoma and thymic carcinoma (TC) are rare diseases of thymus with relatively good prognosis. Different pathological sub-types of thymoma and TC show clear differences on clinical characteristics, morphology, molecular markers, and prognosis. Methods: In this study, 26 thymoma and thymic carcinoma patients with most common thymic epithelial tumor subtypes were enrolled, including 2 type A, 6 type AB, 3 type B1, 1 type B1/B2, 5 type B2, 2 type B2/B3, 4 type B3, and 3 type TC patients in total. The frozen tissues of all patients were processed for RNA-seq sequencing. Results: We used unsupervised clustering to divide all samples into 5 clusters. Four clusters showed clear concordance with pathological subtypes, i.e. cluster AB (5 AB, 1 B1, and 2 B2), cluster B1/B2 (2 B1, 1 B1/B2, and 2B2), cluster B2/B3 (1 B2, 1 B2/B3, and 2B3), and cluster TC (3 TC and 1 A). Only one cluster (1 A, 1 AB, and 2 B3) was labeled as cluster A/AB according to the result of joint clustering analysis with TCGA THYM RNA-seq data. We performed gene function enrichment analysis on highly expressed genes in each cluster. Cluster A showed gene function enrichment on two development related pathways (nervous system development and epithelium development) and cell differentiation. Cluster AB had enriched function of cell proliferation and regulation of cell development. Cluster B1/B2 did not show any enriched functions. Cluster B2/B3 showed gene function enrichment of cell adhesion and regulation of developmental process. CD274 (PD-L1) was also highly expressed in this cluster. Cluster TC had enriched function of several pathways, including cell adhesion, cell migration, cell differentiation, immune system process, immune response, and nervous system development. Moreover, PI3K-Akt signaling pathway, pathway in cancer, and transcriptional misregulation in cancer were also enriched in cluster TC’s highly expressed genes. Conclusions: Thymic epithelial tumor subtypes show clearly different expression profiles. The highly expressed genes of each subtype relate to development, immune, and cancer related functions. PD-L1 is highly expressed in B2/B3 samples which suggests potential immunotherapy for the subtypes. Legal entity responsible for the study: Peking Union Medical College Hospital. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
1859P
A phase II trial of preoperative chemoradiotherapy and pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC)
S. Lee1, B.C. Ahn1, S.Y. Park2, D.J. Kim2, C.G. Lee3, J. Cho3, J.H. Kim4, H.R. Kim5, Y-H. Kim5, S.R. Park6, Y.J. Chun1, M.H. Hong1, H.R. Kim1, B. Cho1 1 Division of Medical Oncology, Yonsei Cancer Center Yonsei University, Seoul, Republic of Korea, 2Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea, 3Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea, 4 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 5Department of Thoracic and Cardiovasular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, 6Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Background: Even though preoperative chemoradiotherapy (CRT) showed survival improvement in patients with resectable ESCC in a randomized trial over upfront surgery, ESCC still has a dismal prognosis. With the potential benefit of combining PD-1 blockade to CRT, we conducted a phase II trial which assessed the efficacy, feasibility, and safety of the combination of preoperative CRT and pembrolizumab (PEM) in ESCC (NCT02844075). Methods: Patients (pts) with histologically confirmed ESCC (clinical stage Ib to III according to the American Joint Committee on Cancer 7th staging system) were enrolled. Pts received concurrent neoadjuvant chemotherapy (weekly paclitaxel and carboplatin), radiotherapy (44.1 Gy in 21 fractions), and PEM (every 3 weeks, 200 mg) during 5 weeks followed by surgery. After surgery, pts were treated with PEM during 2 years or until progression, unacceptable toxicity, death, or pts’ refusal, which came first. The primary endpoint was pathologic complete response (pCR) rate in the primary
v754 | Thoracic Malignancies, Other
tumor and secondary endpoints were overall survival (OS), disease-free survival (DFS), the incidence of adverse events, and etc. Results: In a total of 28 enrolled pts (median age 60), 26 pts received esophagectomy. Two pts did not undergo surgery due to death (hematemesis) and consent withdrawal. There were two in-hospital mortality cases after surgery due to acute lung injury and four mortality cases due to disease progression. The pCR in primary tumor was achieved in 46.1% of pts who underwent resection (95% CI: 28.8 – 64.6). With a median follow-up of 12.4 months, median OS was not reached. Six, 12, and 18-month OS rates were 89.3%, 80.8%, and 73.1% respectively. There was a trend toward better DFS in the pCR group (n ¼ 12) compared with the non-pCR group (n ¼ 14) (HR ¼ 0.33, p ¼ 0.1). Most common treatment-related adverse events were neutropenia (50.0%) and liver enzyme elevation (30.8%) in the neoadjuvant and adjuvant period, respectively. Conclusions: The addition of PEM to preoperative CRT in ESCC demonstrated promising efficacy with acceptable toxicity. Based on the results, further investigation is warranted in a phase III clinical trial. The exploratory endpoints including biomarkers analyses are ongoing. Clinical trial identification: NCT02844075. Legal entity responsible for the study: The authors. Funding: MSD. Disclosure: All authors have declared no conflicts of interest.
1860P
The study of tumor associated exosomes in crosstalk between esophageal carcinoma and lymphatic endothelial cells
W. Mao1, A. Zhao2 Thoracic Surgery, Cancer Hospital of University of Chinese Academy of Sciences, Hangzhou, China, 2Cancer Hospital of University of Chinese Academy of Sciences, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Hangzhou, China
1
Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in china. Because the disease often has no symptoms in the early stages, it is usually detected at a more advanced stage that is more challenging to treat. The inter-communication between esophageal squamous cell carcinoma and its surrounding microenvironment is essential for tumor progression and metastasis. Exosome plays a key role in information delivery between primary lesion and pre-metastatic niche via its packed bioactive molecules. The aim of this study is to explore the effect of exosome from tumor plasma to angiogenesis in human lymphatic endothelial cells (HLEC) in vitro. Methods: Total circulation exosomes (CEs) were extracted and purified to selectively capture EpCAM positive exosomes by magnetic-bead technique. Proteins were separated by SDS-PAGE, and protein bands were analyzed by mass spectrometry. Tube formation assay and fluorescence imaging assay were performed in vitro. Results: The expression level of CEs in ESCC patients with lymph node metastasis were significantly higher than that in ESCC patients without metastasis and healthy control group (respectively; P < 0.001). The tumor associated exosomes could be taken by HLEC and its transferred into HLECs could to promote HLECs tube formation in vitro. In addition, the mass spectrometry was used to analysis the proteomic content in tumor associated exosomes, tumor-related proteins such as matrix-metalloproteinases, PP2A proteins and EIF proteins were identified in the exosome. Conclusions: Exosomes released by ESCC may play important roles in the microenvironment of ESCC and provide a potential application of therapy. Legal entity responsible for the study: Zhejiang Cancer Hospital. Funding: NSFC. Disclosure: All authors have declared no conflicts of interest.
1861P
Up-regulation of IBSP expression predicts poor prognosis of esophageal squamous cell carcinoma patients
M. Wang Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China Background: Esophageal squamous cell carcinoma (ESCC), a common gastrointestinal tumor, is listed as the sixth leading cause of cancer-related death worldwide, with high morbidity and mortality as its important characteristics. In recent years, despite advances in diagnosis and treatment of ESCC, the mortality rate of ESCC is still very high, with an average overall 5-year survival rate of about 10% 41%.As with many other solid tumors, development and progression of ESCC are also considered gene regulatory disorders caused by oncogene activation and inactivation accumulation and disorders of tumor suppressor genes (TSG). Therefore, screening and exploring the key gene proteins for the occurrence, development, treatment and clinical prognosis of ESCC is an important topic in the field of ESCC research at present.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz266.020/5578186 by guest on 26 October 2019
N. Liang1, L. Liu1, H. Liu1, W. Wang1, Y. Bi2, Z. Liang2, N. Li3, R. Lin3, T. Wang3, S. Li1 Department of Thoracic Surgery, Peking Union Medical College Hospital, Beijing, China, 2Department of Pathology, Peking Union Medical College Hospital, Beijing, China, 3Department of Clinical Research, Hangzhou Repugene Technology Inc., Beijing, China
1
Annals of Oncology
Annals of Oncology
Volume 30 | Supplement 5 | October 2019
Conclusions: the results of this study showed that IBSP up-regulation was often found in ESCC tumor specimens, indicating poor prognosis of ESCC patients. Moreover, it also demonstrated that IBSP could improve the ability of ESCC cell proliferation and tumor metastasis, which may be a valuable prognostic indicator in ESCC patients. Yet, the mechanism by which IBSP promotes tumorigenesis and development needs more researches. Legal entity responsible for the study: The author. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz266.020/5578186 by guest on 26 October 2019
Methods: Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical (IHC) staining were employed to determine IBSP expression at the mRNA and protein levels in clinical ESCC samples. Moreover, functional studies were adopted to study the tumor-promoter function of IBSP. Results: IBSP up-regulation was found in 21 of 45 (46.7%) primary ESCC cells at mRNA level by transcription-polymerase chain reaction (RT-PCR). In addition, IHC staining further demonstrated that IBSP was up-regulated in ESCC cases and up-regulation of IBSP protein was significantly relevant to lymph node metastasis (P ¼ 0.017), clinicopathologic stage (P ¼ 0.001) and poor disease survival (P ¼ 0.000) of ESCC patients. Moreover, functional studies illustrated that IBSP gene can promote the ability of proliferation and metastasis of ESCC cells. Furthermore, it was found that IBSP can regulate the EMT process by regulating MMP2 gene and N-cadherin, which promotes the metastasis of tumor cells.
abstracts
doi:10.1093/annonc/mdz266 | v755