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A novel nomogram and risk classification system predicting radiation pneumonitis in patients with esophageal cancer receiving radiotherapy
abstracts 763P
Comprehensive genomic profiling of early-stage esophageal squamous cell carcinoma
J. Zuo1, Z. Fan1, Y. Jia1, Y. Wang1, L. Wang1, A. Lizaso2, B. Li3 Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China, 2 Medicine, Burning Rock Biotech, Guangzhou, China, 3Bioinformatics, Burning Rock Biotech, Guangzhou, China
1
764P
A novel nomogram and risk classification system predicting radiation pneumonitis in patients with esophageal cancer receiving radiotherapy
L. Wang, X. Meng, J. Yu Radiation Oncology, Shandong Cancer Hosptial, Jinan, China Background: We initially ascertained the value of inflammatory indexes in predicting severe acute radiation pneumonitis (SARP). Furthermore, we firstly built a novel nomogram and risk classification system integrating clinicopathological, dosimetric and biological parameters to individually and precisely identify SARP in patients with esophageal cancer (EC) who received radiotherapy (RT). Methods: All data were collected from 312 EC patients. Logistic regression was used to choose predictors of SARP and then build nomogram. The validation of nomogram was performed by area under the ROC curve (AUC), calibration curves and decision curve analyses (DCA). A risk classification system was generated by recursive partitioning analysis (RPA). Results: The Subjective Global Assessment (SGA) score, pulmonary fibrosis score (PFS), planning target volume/total lungs volume (PTV/LV), mean lung dose (MLD) and systemic immuneinflammation index (SII) were independent predictors of SARP and finally incorporated into the nomogram. The AUC of nomogram for SARP prediction was 0.852, which was much higher than any other factor (range, 0.604-0.712). Calibration curves indicated favorable consistency between the nomogram prediction and the actual outcomes. DCA exhibited satisfactory clinical utility. A risk classification system was built to perfectly divide patients into three risk groups which were low-risk group (7.1%, score 0–158), intermediate-risk group (38%, score 159–280), and highrisk group (71.4%, score>280). Conclusions: SGA score, PFS, PTV/LV, MLD and SII were potential valuable markers in predicting SARP. The constructed nomogram and corresponding risk classification system with superior prediction ability for SARP could assist in patients counseling and guide treatment decision making. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
v296 | Gastrointestinal Tumours, Non-Colorectal
765P
Drinking alcohol, smoking, multiple dysplastic lesions and the risk of field cancerization of squamous cell carcinoma in the esophagus and head and neck region
C. Katada1, T. Yokoyama2, T. Yano3, I. Oda4, Y. Shimizu5, H. Doyama6, T. Koike7, K. Takizawa8, M. Hirao9, H. Okada10, H. Ishikawa11, A. Yokoyama12, M. Muto13 1 Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan, 2Department of Health Promotion, National Institute of Public Health, Wako, Japan, 3Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan, 4Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan, 5Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan, 6Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Ishikawa, Japan, 7Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan, 8Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan, 9Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan, 10Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Okayama, Japan, 11 Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan, 12Clinical Research Unit, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan, 13Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan Background: Multiple development of squamous cell carcinoma (SCC) in the upper aero-digestive tract is known as the field cancerization phenomenon. We examined the association of this phenomenon with dysplastic squamous epithelium in the background mucosa, drinking alcohol, and smoking. Methods: 331 patients with early esophageal SCC were enrolled. Using Lugol chromoendoscopy, we evaluated the dysplastic squamous epithelium in the esophagus. Lugol voiding lesions (LVL) were graded into 3 categories (A ¼ no lesion; B ¼ 1 to 9 lesions; C 10 lesions). The endpoint of this cohort study was the cumulative incidence of metachronous multiple SCC in the esophagus or head and neck after endoscopic resection of esophageal SCC according to the grade of LVL. At study entry, all patients were instructed to abstain from drinking alcohol and smoking. Data collected from a different cross-sectional cohort (n ¼ 1042) were used as an historical control. ALDH2 status was determined by questionnaire facial flushing after drinking alcohol (present and past flushing¼inactive ALDH2, never flushing¼active ALDH2). Results: In the median follow-up period of 69.6 months, LVL grade (A to B to C) was associated with progressive increases in the 5-year cumulative incidence of metachronous multiple SCC (esophagus ¼ 6.0%, 17.8% and 47.1%, respectively, p ¼ 0.022 for A vs. B and p < 0.0001 for A vs. C; head and neck ¼ 0.0%, 4.3% and 13.3%, respectively, p ¼ 0.12 for A vs. B and p ¼ 0.0007 for A vs. C; esophagus or head and neck ¼ 6.0%, 19.8% and 52.6%, respectively, p ¼ 0.012 for A vs. B and p < 0.0001 for A vs. C). Alcohol and smoking abstinence decreased the risk of multiple SCC of the esophagus (adjusted hazard ratio¼0.47 and 0.49, respectively) (p ¼ 0.013 for alcohol and p ¼ 0.024 for smoking). Adjusted odds ratio (OR) of LVL grade B and C associated with heavy drinking was significantly stronger in inactive ALDH2 (OR ¼ 47.5 and 358, respectively) than active ALDH2 (OR ¼ 12.8 and 138, respectively) (p < 0.05 for B and p < 0.05 for C). Conclusions: Multiple dysplastic lesions in the esophagus are a useful predictor of the risk of multiple SCC associated with field cancerization. Alcohol and smoking abstinence is required to prevent a second primary SCC. Clinical trial identification: UMIN000001676. Legal entity responsible for the study: JEC study group. Funding: National Cancer Center Research and Development Fund 36 by the Ministry of Health, Labour and Welfare of Japan. Disclosure: All authors have declared no conflicts of interest.
766P
Neoadjuvant chemotherapy can eliminate the negative impact of postoperative infectious complications on recurrence in patients with esophageal cancer
K. Kano, T. Ogata, K. Komori, H. Watanabe, Y. Shimoda, Y. Kumazu, H. Fujikawa, T. Yamada, T. Oshima Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan Background: Some authors have suggested that the immunological response to postoperative infectious complications (ICs) enhances the viability of undetectable residual tumor cells after surgery, thereby inducing disease recurrence. We hypothesize that recurrence might not occur if neoadjuvant chemotherapy (NAC) treatment of micrometastases can prevent residual cancer cell growth. We evaluated whether or not NAC exerted prophylactic effects against the negative prognostic impact induced by postoperative ICs and assessed its interaction among subgroups of histological response. Methods: We retrospectively examined 111 patients who received NAC followed by radical esophagectomy between January 2011 and September 2015. Risk factors for the recurrence-free survival (RFS) were examined by Cox proportional hazard analyses. Pathological responders to NAC were defined as those with a tumor disappearance of
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz247.090/5576941 by guest on 18 October 2019
Background: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers without effective therapy. To explore therapeutic options, the mutational profile of ESCC tumors has to be elucidated to understand the molecular mechanism of its development and explore targetable mutations. In this study, we aim to elucidate the mutational profile of ESCC patients. Methods: Capture-based targeted sequencing was performed on tissue samples surgically-removed from 29 early-stage ESCC patients using a 520-gene panel to comprehensively profile the genomic alterations in ESCC. Tumor mutation burden was also estimated for all the samples. Results: A total of 421 mutations in 39 genes were detected in all the patients, revealing a mutation detection rate of 100%. The mutation types detected in the cohort included 55% single nucleotide variations, 35% copy number amplification and the remaining 10% were small insertion-deletions and large deletions. Except for 1 patient, all of the patients were TP53 mutant. Copy number amplifications (CNA) in CCND1, FGF3, FGF4 and FGF19 were found in 41% (12/29) of the patients, respectively, with all CNA in 4 genes occurring concurrently in all patients. Interestingly, mutations in NFjB1A, previously unreported in ESCC, were detected in 21% (6/29) of the patients. Further analysis reveals mutations in genes involved in pathways including cell cycle, chromatin modification, Notch and JAK-STAT signaling, suggesting that these may be the most critical pathways involved in the development and progression of ESCC. No actionable mutations in receptor tyrosine kinases were detected in our cohort. Instead, potential therapeutic target analysis identified CDKN2A and PIK3CA, with mutation detection rate of 20.7% and 13.8%, respectively, as candidates for targeted therapy. In addition, the median TMB of the cohort was 5.6 mutations/Mb, ranging from 0.8 to 42.9 mutations/Mb. Conclusions: Our study reveals the comprehensive mutation profile of ESCC tumors, shedding light on potential molecular mechanisms associated with its development and possible therapeutic options for ESCC patients. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
Comprehensive genomic profiling of early-stage esophageal squamous cell carcinoma
J. Zuo1, Z. Fan1, Y. Jia1, Y. Wang1, L. Wang1, A. Lizaso2, B. Li3 Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China, 2 Medicine, Burning Rock Biotech, Guangzhou, China, 3Bioinformatics, Burning Rock Biotech, Guangzhou, China
1
764P
A novel nomogram and risk classification system predicting radiation pneumonitis in patients with esophageal cancer receiving radiotherapy
L. Wang, X. Meng, J. Yu Radiation Oncology, Shandong Cancer Hosptial, Jinan, China Background: We initially ascertained the value of inflammatory indexes in predicting severe acute radiation pneumonitis (SARP). Furthermore, we firstly built a novel nomogram and risk classification system integrating clinicopathological, dosimetric and biological parameters to individually and precisely identify SARP in patients with esophageal cancer (EC) who received radiotherapy (RT). Methods: All data were collected from 312 EC patients. Logistic regression was used to choose predictors of SARP and then build nomogram. The validation of nomogram was performed by area under the ROC curve (AUC), calibration curves and decision curve analyses (DCA). A risk classification system was generated by recursive partitioning analysis (RPA). Results: The Subjective Global Assessment (SGA) score, pulmonary fibrosis score (PFS), planning target volume/total lungs volume (PTV/LV), mean lung dose (MLD) and systemic immuneinflammation index (SII) were independent predictors of SARP and finally incorporated into the nomogram. The AUC of nomogram for SARP prediction was 0.852, which was much higher than any other factor (range, 0.604-0.712). Calibration curves indicated favorable consistency between the nomogram prediction and the actual outcomes. DCA exhibited satisfactory clinical utility. A risk classification system was built to perfectly divide patients into three risk groups which were low-risk group (7.1%, score 0–158), intermediate-risk group (38%, score 159–280), and highrisk group (71.4%, score>280). Conclusions: SGA score, PFS, PTV/LV, MLD and SII were potential valuable markers in predicting SARP. The constructed nomogram and corresponding risk classification system with superior prediction ability for SARP could assist in patients counseling and guide treatment decision making. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
v296 | Gastrointestinal Tumours, Non-Colorectal
765P
Drinking alcohol, smoking, multiple dysplastic lesions and the risk of field cancerization of squamous cell carcinoma in the esophagus and head and neck region
C. Katada1, T. Yokoyama2, T. Yano3, I. Oda4, Y. Shimizu5, H. Doyama6, T. Koike7, K. Takizawa8, M. Hirao9, H. Okada10, H. Ishikawa11, A. Yokoyama12, M. Muto13 1 Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan, 2Department of Health Promotion, National Institute of Public Health, Wako, Japan, 3Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan, 4Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan, 5Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan, 6Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Ishikawa, Japan, 7Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan, 8Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan, 9Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan, 10Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Okayama, Japan, 11 Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan, 12Clinical Research Unit, National Hospital Organization Kurihama Medical and Addiction Center, Yokosuka, Japan, 13Department of Clinical Oncology, Kyoto University Hospital, Kyoto, Japan Background: Multiple development of squamous cell carcinoma (SCC) in the upper aero-digestive tract is known as the field cancerization phenomenon. We examined the association of this phenomenon with dysplastic squamous epithelium in the background mucosa, drinking alcohol, and smoking. Methods: 331 patients with early esophageal SCC were enrolled. Using Lugol chromoendoscopy, we evaluated the dysplastic squamous epithelium in the esophagus. Lugol voiding lesions (LVL) were graded into 3 categories (A ¼ no lesion; B ¼ 1 to 9 lesions; C 10 lesions). The endpoint of this cohort study was the cumulative incidence of metachronous multiple SCC in the esophagus or head and neck after endoscopic resection of esophageal SCC according to the grade of LVL. At study entry, all patients were instructed to abstain from drinking alcohol and smoking. Data collected from a different cross-sectional cohort (n ¼ 1042) were used as an historical control. ALDH2 status was determined by questionnaire facial flushing after drinking alcohol (present and past flushing¼inactive ALDH2, never flushing¼active ALDH2). Results: In the median follow-up period of 69.6 months, LVL grade (A to B to C) was associated with progressive increases in the 5-year cumulative incidence of metachronous multiple SCC (esophagus ¼ 6.0%, 17.8% and 47.1%, respectively, p ¼ 0.022 for A vs. B and p < 0.0001 for A vs. C; head and neck ¼ 0.0%, 4.3% and 13.3%, respectively, p ¼ 0.12 for A vs. B and p ¼ 0.0007 for A vs. C; esophagus or head and neck ¼ 6.0%, 19.8% and 52.6%, respectively, p ¼ 0.012 for A vs. B and p < 0.0001 for A vs. C). Alcohol and smoking abstinence decreased the risk of multiple SCC of the esophagus (adjusted hazard ratio¼0.47 and 0.49, respectively) (p ¼ 0.013 for alcohol and p ¼ 0.024 for smoking). Adjusted odds ratio (OR) of LVL grade B and C associated with heavy drinking was significantly stronger in inactive ALDH2 (OR ¼ 47.5 and 358, respectively) than active ALDH2 (OR ¼ 12.8 and 138, respectively) (p < 0.05 for B and p < 0.05 for C). Conclusions: Multiple dysplastic lesions in the esophagus are a useful predictor of the risk of multiple SCC associated with field cancerization. Alcohol and smoking abstinence is required to prevent a second primary SCC. Clinical trial identification: UMIN000001676. Legal entity responsible for the study: JEC study group. Funding: National Cancer Center Research and Development Fund 36 by the Ministry of Health, Labour and Welfare of Japan. Disclosure: All authors have declared no conflicts of interest.
766P
Neoadjuvant chemotherapy can eliminate the negative impact of postoperative infectious complications on recurrence in patients with esophageal cancer
K. Kano, T. Ogata, K. Komori, H. Watanabe, Y. Shimoda, Y. Kumazu, H. Fujikawa, T. Yamada, T. Oshima Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan Background: Some authors have suggested that the immunological response to postoperative infectious complications (ICs) enhances the viability of undetectable residual tumor cells after surgery, thereby inducing disease recurrence. We hypothesize that recurrence might not occur if neoadjuvant chemotherapy (NAC) treatment of micrometastases can prevent residual cancer cell growth. We evaluated whether or not NAC exerted prophylactic effects against the negative prognostic impact induced by postoperative ICs and assessed its interaction among subgroups of histological response. Methods: We retrospectively examined 111 patients who received NAC followed by radical esophagectomy between January 2011 and September 2015. Risk factors for the recurrence-free survival (RFS) were examined by Cox proportional hazard analyses. Pathological responders to NAC were defined as those with a tumor disappearance of
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz247.090/5576941 by guest on 18 October 2019
Background: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers without effective therapy. To explore therapeutic options, the mutational profile of ESCC tumors has to be elucidated to understand the molecular mechanism of its development and explore targetable mutations. In this study, we aim to elucidate the mutational profile of ESCC patients. Methods: Capture-based targeted sequencing was performed on tissue samples surgically-removed from 29 early-stage ESCC patients using a 520-gene panel to comprehensively profile the genomic alterations in ESCC. Tumor mutation burden was also estimated for all the samples. Results: A total of 421 mutations in 39 genes were detected in all the patients, revealing a mutation detection rate of 100%. The mutation types detected in the cohort included 55% single nucleotide variations, 35% copy number amplification and the remaining 10% were small insertion-deletions and large deletions. Except for 1 patient, all of the patients were TP53 mutant. Copy number amplifications (CNA) in CCND1, FGF3, FGF4 and FGF19 were found in 41% (12/29) of the patients, respectively, with all CNA in 4 genes occurring concurrently in all patients. Interestingly, mutations in NFjB1A, previously unreported in ESCC, were detected in 21% (6/29) of the patients. Further analysis reveals mutations in genes involved in pathways including cell cycle, chromatin modification, Notch and JAK-STAT signaling, suggesting that these may be the most critical pathways involved in the development and progression of ESCC. No actionable mutations in receptor tyrosine kinases were detected in our cohort. Instead, potential therapeutic target analysis identified CDKN2A and PIK3CA, with mutation detection rate of 20.7% and 13.8%, respectively, as candidates for targeted therapy. In addition, the median TMB of the cohort was 5.6 mutations/Mb, ranging from 0.8 to 42.9 mutations/Mb. Conclusions: Our study reveals the comprehensive mutation profile of ESCC tumors, shedding light on potential molecular mechanisms associated with its development and possible therapeutic options for ESCC patients. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology