High CEA Research Articles

112P - A retrospective analysis of the association between perioperative, post adjuvant carcinoembryonic antigen level and prognosis in stage III colorectal cancer

BackgroundCarcinoembryonic antigen (CEA) is the most widespread tumour marker of colorectal cancer, however, it is not helpful to judge for recurrence of the disease because of low sensitivity and specificity. It is recommended for patients who were diagnosed with pStage III colorectal cancer to receive adjuvant chemotherapy after curative resection and to measure CEA every 3 months. Moreover, It is reported that postoperative CEA level is more informative than preoperative CEA level about the impact for prognosis but the association between postoperative, post adjuvant CEA level and the prognosis is still unclear. This study aimed to evaluate whether perioperative and post adjuvant CEA level was useful for estimation of the prognosis in stage III CRC. MethodsThis retrospective study was conducted at the Cancer Institute Hospital of JFCR. A total of 567 consecutive patients who underwent curative resection for stage III colon adenocarcinoma and adjuvant chemotherapy in our hospital from March 2005 to December 2013 were identified. The patients who received bevacizumab as adjuvant chemotherapy and didn’t measure CEA were excluded. ResultsThe 3-year DFS rate in patients with normal preoperative CEA is superior to patients with high preoperative CEA (HR:1.59;95%CI:1.10-2.31, p = 0.014). There was no significant difference in the 5-year OD between the two groups (HR1.17;95%CI:0.62–2.20, p = 0.63). The 3-year DFS rate and 5-year OS rate in patients with normal postoperative CEA were superior to patients with high postoperative CEA (HR:2.18;95%CI:1.23–3.88, p = 0.0079, and HR:2.40;95%CI:1.02–5.69, p = 0.046). The 3-year DFS in patients with normal postadjuvant CEA was superior to patients with high postadjuvant CEA(HR1.79;95%CI:1.23–3.88, p = 0.022), whereas regarding the 5-year OS there was no significant difference between the two groups (HR2.10;95%CI:0.98–4.53, p = 0.057).In the multivariate analysis, the histological type and N-stage were predictive factors of OS. ConclusionsHigh postoperative and post adjuvant CEA level may be negative prognosis factors for OS in patients who underwent curative resection for stage III CRC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Carcinoembryonic antigen (CEA) as a candidate prognostic marker of nonmucinous pneumonic adenocarcinoma (P-ADC) of the lung.

28 Background: Serum level of CEA as a prognostic marker in NSCLC is well known. In patients with non-mucinous P-ADC, there were some paradoxical cases with high CEA, in spite of improved symptom and chest X-ray after chemotherapy including first-generation EGFR-TKI. Methods: We retrospectively comfirmed serum level of CEA of five patients, including four patients with non-mucinous P-ADC and one patient with mucinous P-ADC, between 2001-2007, all Japanese female without smoking history, 66-78 years old (mean 73.6 y.o.). All of them revealed abnormal pneumonic shadow on chest X-ray, and were diagnosed by TBLB or cytology. These cases were all stage IIIB or IV, and were applied to chemotherapy including first-generation EGFR-TKI. We had measured serum CEA as possible from initial diagnosis and pre or post chemotherapy including first-generation EGFR-TKI to death. OS were between 25~66 months with four patients of non-mucinous P-ADC, and 9 month with one patient of mucinous P-ADC. Other tumor marker such as CYFRA and Pro GRP were all almost normal range. Results: CEA of three patients with non-mucinous P-ADC was elevated according to worsened symptom and X-ray, and were all highly maintained or increased in spite of improved symptom and X-ray after chemotherapy including first-generation EGFR-TKI. CEA of one patient with non-mucinous P-ADC was normal range in initial diagnosis, and no more measured. She has got symptom free and improved chest X-ray after chemotherapy. In one patient with mucinous P-ADC, serum CEA was normal range, so no longer measured. This patient was no effective for chemotherapy, and was dead 9 month after the initial diagnosis. Number of cases was quite few, so further examination is favorable. Furthermore, All cases were exaggerated finally, they might be resistant to first-generation EGFR-TKI. Conclusions: In three patients with non-mucinous P-ADC of the lung, serum CEA was paradoxically highly maintained or elevated in spite of improved symptom and chest X-ray after chemotherapy including first-generation EGFR-TKI. Therefore, serum CEA is a candidate for useful prognostic marker of non-mucimous P-ADC of the lung.

Prognostic value of preoperative carcinoembryonic antigen/tumor size in rectal cancer.

BACKGROUNDCarcinoembryonic antigen (CEA) is a commonly used biomarker in colorectal cancer. However, controversy exists regarding the insufficient prognostic value of preoperative serum CEA alone in rectal cancer. Here, we combined preoperative serum CEA and the maximum tumor diameter to correct the CEA level, which may better reflect the malignancy of rectal cancer.AIMTo assess the prognostic impact of preoperative CEA/tumor size in rectal cancer.METHODSWe retrospectively reviewed 696 stage I to III rectal cancer patients who underwent curative tumor resection from 2007 to 2012. These patients were randomly divided into two cohorts for cross-validation: training cohort and validation cohort. The training cohort was used to generate an optimal cutoff point and the validation cohort was used to further validate the model. Maximally selected rank statistics were used to identify the optimum cutoff for CEA/tumor size. The Kaplan-Meier method and log-rank test were used to plot the survival curve and to compare the survival data. Univariate and multivariate Cox regression analyses were used to determine the prognostic value of CEA/tumor size. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively.RESULTSIn all, 556 patients who satisfied both the inclusion and exclusion criteria were included and randomly divided into the training cohort (2/3 of 556, n = 371) and the validation cohort (1/3 of 556, n = 185). The cutoff was 2.429 ng/mL per cm. Comparison of the baseline data showed that high CEA/tumor size was correlated with older age, high TNM stage, the presence of perineural invasion, high CEA, and high carbohydrate antigen 19-9 (CA 19-9). Kaplan-Meier curves showed a manifest reduction in 5-year OS (training cohort: 56.7% vs 81.1%, P < 0.001; validation cohort: 58.8% vs 85.6%, P < 0.001) and DFS (training cohort: 52.5% vs 71.9%, P = 0.02; validation cohort: 50.3% vs 79.3%, P = 0.002) in the high CEA/tumor size group compared with the low CEA/tumor size group. Univariate and multivariate analyses identified CEA/tumor size as an independent prognostic factor for OS (training cohort: hazard ratio (HR) = 2.18, 95% confidence interval (CI): 1.28-3.73, P = 0.004; validation cohort: HR = 4.83, 95%CI: 2.21-10.52, P < 0.001) as well as DFS (training cohort: HR = 1.47, 95%CI: 0.93-2.33, P = 0.096; validation cohort: HR = 2.61, 95%CI: 1.38-4.95, P = 0.003).CONCLUSIONPreoperative CEA/tumor size is an independent prognostic factor for patients with stage I-III rectal cancer. Higher CEA/tumor size is associated with worse OS and DFS.

Is Adjuvant Chemotherapy Worthwhile After Radical Resection for Single Lung Metastasis From Colorectal Cancer? A Multicentric Analysis Evaluating the Risk of Recurrence.

Background: Adjuvant chemotherapy after resection of colorectal cancer (CRC) lung metastases may reduce recurrences and improve survival. The choice of best candidates for adjuvant chemotherapy in this setting is controversial, especially when a single lung metastases (SLM) is resected. The aim of this study is to evaluate the risk of recurrence after radical resection for single lung metastasis from CRC.Patients and methods: Demographic, clinical, and pathological data were retrospectively collected for patients radically operated on for single pulmonary metastasis from CRC in 4 centers. Survival was computed by Kaplan-Meyer methods. Chi-square, log-rank test, and for multivariate analysis, Cox-regression and binary logistic regression were used when indicated.Results: The sample consisted of 344 patients, mean age 65 yrs. Overall 5 yrs survival was 61.9%. Recurrence occurred in 113 pts (32.8%). At univariate analysis, age > 70 (p = 0.046) and tumor size > 2 cm (p = 0.038) were predictive of the worst survival chance, while synchronous lung metastasis (p = 0.039), previous resection of extrathoracic metastasis (p = 0.017), uptake at FDG-PET scan (p = 0.006) and short (<12 months) disease-free interval (DFI) prior to lung metastasectomy (p = 0.048) were risk factors for recurrence. At multivariate analysis, only high CEA (>4 ng/mL) was associated with worst survival (HR: 4.3, p = 0.014), while prior abdominal surgery (HR: 3, p = 0.033), PET positivity (HR: 2.7, p = 0.041), and DFI > 12 months (HR: 0.14, p < 0.001) confirmed to predict recurrence of disease.Conclusions: Surgical resection of solitary lung metastases from CRC is associated with prolonged survival. High value of CEA, PET positivity, previous extrathoracic resected metastasis, and short (<12 months) DFI were found to be predictive of death or disease recurrence and might identify in this scenario patients at higher risk which could potential benefit of chemotherapy.

Abstract CT054: Clinical and pharmacokinetic study with a lipidic prodrug of mitomycin-c entrapped in liposomes in metastatic colorectal cancer patients

Abstract Background: A phase 1A/1B study was conducted to investigate the safety of Promitil, a liposomal formulation of a lipidic prodrug of mitomycin-c (MLP) within an open, dose-escalating, phase (1A, n=27) followed by an expanded phase (1B, n=61) restricted to metastatic colorectal cancer (mCRC) patients after failure to two or more lines of therapy. We report here on the correlation between pharmacokinetic (PK) parameters and clinical observations in patients with mCRC. Methods: PK analysis of plasma MLP levels was obtained in 53 mCRC patients (F=26, M=27), who received Promitil every 4 weeks either as single agent (n=28), in combination with capecitabine (Cap) (n=12), or in combination with Cap and bevacizumab (Bev) (n=13). The MLP dose range was 0.5-3.5 mg/kg with most patients (N=29) receiving 2.0-2.5 mg/kg. Out of 53 patients analyzed, 39 patients completed the 3rd cycle (study week 12) and were efficacy-evaluable by CT scan and Recist criteria. PK of plasma MLP levels was analyzed by noncompartmental methods. For statistical analysis and correlations of T½ and Clearance (CL) with age, sex, BMI, baseline neutrophil/lymphocyte ratio (NLR), CEA, and survival, we used t test and Pearson or Spearman coefficients. Results: The PK of MLP was stealth-like with long T½ (~1 day), slow CL, and small Volume of distribution. Stable Disease (SD) was reported in 14 patients (36%), and Progressive Disease (PD) in 25 patients. Median survival of all 39 patients (SD+PD) was 8.3 months. SD patients had significantly longer median survival than PD patients (14.3 vs 6.5 months, p=0.0002). SD patients had significantly longer T½ and slower CL than non-SD patients. A longer T½ and slower CL were significantly correlated with longer survival. A high NLR and high CEA were correlated with shorter T½ and/or faster CL. Dose of MLP, addition of Cap and/or Bev, age and BMI did not have any apparent effect on response or survival. Conclusions: SD was indicative of extended survival. The longer circulation time of the liposomal prodrug in SD patients and its correlation with longer survival are consistent with the well-known correlation between liposome circulation time and localization in tumors. A high NLR may signal inflammatory macrophage activation resulting in shorter liposomal circulation half-life and reducing the chances of disease control. Citation Format: Alberto A. Gabizon, Esther Tahover, Ruth Perets, Talia Golan, Ravit Geva, Yasmine Amitay, Hilary Shmeeda, Patricia Ohana. Clinical and pharmacokinetic study with a lipidic prodrug of mitomycin-c entrapped in liposomes in metastatic colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT054.

Abstract 4898: Clinical application of quantitative multiplex mass spectrometry-based proteomics in predicting clinical outcomes in locally advanced rectal cancer

Abstract Background: Neoadjuvant chemoradiotherapy (CRT) using 5-fluorouracil (5-FU) is a standard treatment for locally advanced rectal cancer (LARC) to improve clinical outcomes. The pathologic responses after neoadjuvant CRT is a major prognostic factor, thus identification of good or poor responder in advance is important. This study is to find candidate predictive biomarkers for CRT and prognosis in LARC patients using quantitative mass spectrometry (MS). Materials and methods: 86 patients with stage II/III LARC, received neoadjuvant CRT consisting of 5-FU/leucovorin followed by surgery were included. 14 proteins potentially associated with 5-FU activity or prognosis were evaluated in archived formalin-fixed, paraffin-embedded pre- and post-CRT tumor tissues using MS: DHFR, DPYD, EGFR, hENT1, Her2, MET, OPRT, p16, TK1, TYMP, TYMS, UCK1, UCK2, UPP1. Tumor regression grade (TRG) after CRT was assessed by Dworak criteria: 0, no regression; 1, dominant tumor mass with obvious fibrosis; 2, dominant fibrotic changes with few tumor cells; 3, very few tumor cells; 4, no tumor cells. Results: TGR was 0 in 2 (2.3%), 1 in 30 (34.9%), 2 in 23 (26.7%), 3 in 20 (23.3%), and 4 in 11(12.8%) patients. Major regression (TRG 2/3/4) was associated with high TK1 (P = 0.040), low TYMS (P = 0.037), p16 (P = 0.055), and UPP1 (P = 0.028) levels. Among the pre-CRT parameters, low CEA level (&amp;lt;5ng/mL, P = 0.013), clinical stage II (P&amp;lt;0.001), tumor differentiation (good, P = 0.052), low EGFR level (&amp;lt;200amol/ug, P=0.006), undetectable TYMS level (P = 0.070) were associated with longer recurrence-free survival (RFS). Among the post-CRT parameters, major pathologic response (P = 0.001), and the absence of lymphatic (P&amp;lt;0.001)/ vascular (P= 0.025)/ perineural invasion (P = 0.001) was associated with longer RFS. For 71 patients with available paired pre- and post-CRT tissues, the changes of protein expression were calculated. The pre-CRT/post-CRT ratio of DHFR (&amp;gt;1.1), Her2 (&amp;lt;1.25), MET (≥0.8), p16 (&amp;lt;2), TK1 (≥0.9) showed trend toward long RFS. Multivariate analysis showed that the presence of lymphatic invasion (HR=3.07; 95% CI, 1.35-7.01; P = 0.008) and pre-CRT high EGFR level (≥200amol/ug; HR=2.23; 95% CI, 1.03-4.83; P = 0.042) were significantly associated with shorter RFS. The presence of lymphatic invasion (P=0.005), positive pre-CRT TYMS level (P = 0.008), and high CEA level (P = 0.015) were significantly related to short survival. Conclusions: Quantitative MS-based proteomics can facilitate the identification of predictive biomarkers of CRT responses and prognosis in LARC patients. Citation Format: Ho Jung An, Ji-Han Jung, Byoung Yong Shim, Hyung Soon Park, Hyeon-Min Cho, Hyung-Jin Kim, Ri Na Yoo, Sung Hwan Kim, Jonghoon Lee, Kang-Moon Lee, Dae Bum Kim, Ji Min Lee. Clinical application of quantitative multiplex mass spectrometry-based proteomics in predicting clinical outcomes in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4898.

Preoperative CA 19-9 and CEA as predictors of operative outcomes in resectable gastric cancer (GC).

e15581 Background: We sought to investigate whether preoperative serum CA 19-9 and CEA levels are predictive of resectability, postoperative outcomes, and survival in resectable GC. Methods: The National Cancer Database (NCDB) was interrogated to identify resectable GC patients between 2004-2015. Gastric adenocarcinoma cases without M1 disease and who did or did not undergo definitive surgery were included. Pretreatment CA 19-9 and CEA levels were classified as high (≥98 U/mL) or low ( &lt; 98 U/mL). Proportions of categorical variables were compared using the Chi-squared test (two-tailed). Hazard ratios (HRs) for overall survival (OS) were compared using multivariate Cox regression, adjusting for baseline demographic and clinical variables. Results: From 183,204 GC cases screened, a final 5,447 patients were available. Resection rates for patients with low (n = 1920) and high (n = 294) CA 19-9 were 69.2% and 40.8% (χ² 90.6, p &lt; 0.00001). 69.6% were resectable with low CEA (n = 5044) and 35.1% were resectable with high CEA (n = 97, χ² 53.0, p &lt; 0.00001). Mortality within 30 days of definitive surgery was 7.5% and 0% in those with high (n = 120) and low CA 19-9 (n = 1286, χ² 85.6, p &lt; 0.00001). There was no significant difference between 30-day mortality across high and low CEA and between 30-day readmission rates across high and low CA 19-9 and CEA levels. Age, median income, high school graduation rate, Charlson comorbidity index, and AJCC clinical N stage all significantly correlated with OS in this cohort. Compared to low preoperative CA 19-9, high CA 19-9 was significantly associated with worse OS (HR 1.24, 95% confidence interval (CI) 1.13-1.37, p &lt; 0.0001). Similarly, a high CEA correlated with worse OS compared to low CEA (HR 1.44, 95% CI 1.32-1.57, p &lt; 0.0001). Conclusions: High preoperative CA 19-9 and CEA are associated wither lower resection rates and worse OS in resectable GC. CA 19-9 but not CEA level predicts for 30-day mortality. Prospective validation is warranted.

Outcomes of metastatic colorectal cancer over fifteen years from an Indian tertiary care center: A retrospective analysis.

e15050 Background: Management of metastatic colorectal cancer (CRC) has revolutionised over the past 2 decades and a number of drugs are part of active disease management including biologicals. Published large database on metastatic CRC outcome has been lacking from India. Methods: A retrospective data analysis of metastatic CRC from prospectively based database was performed from the year, 2001-2015. All patients who have received at least 1 cycle of chemotherapy were enrolled. Kaplan Meier analysis was done for overall survival (OS). Cox-regression model was done to determine prognostic factors of OS. Results: A total of 288 patients including upfront metastatic (n = 197, 68%) and relapsed (n = 91, 32%) with male to female ratio of 1.4:1 and median age of 46 years were studied. CEA was high in 78% with median level of 20 ng/ml. Most common site of primary tumor location was rectum (47%). Proportions of left side, right side and transverse colon was 75%, 20% and 4.2%. Mucinous and signet histologies were seen in 24% and 9.2% of patients. Most common sites of metastases being liver (43%), peritoneum (31%) and lung (18%). Oxaliplatin based therapy was used 71% of patients as 1st line. Median chemotherapy cycles for both 1st and 2nd line regimen was 6. Biologicals were part of 1st line regimen in only 12.5% of patients. Median OS of our cohort was 18.5 months. Predictors of poor OS were ECOG PS &gt; 1 (HR 2, CI: 1.3-3.3, p value = 0.003), high CEA ( &gt; 5ng/ml, HR 2.5, CI: 1.3-4.6, p value = 0.004), low albumin (&lt; 3.5 g/dl, HR 1.7, CI: 1.03-2.9, p value = 0.045), &lt; 2 lines of chemotherapy received (HR 2, CI: 1.3-3.3, p value = 0.001). Conclusions: Outcomes of metastatic CRC in our cohort with use of doublet chemotherapy (small proportion with biologicals) is comparable to published literature worldwide. We have higher proportion of younger population, rectum cancer, signet and mucinous histology and higher incidence of peritoneal involvement.

The “effect” of T classification on colorectal liver metastasis.

e15049 Background: T classification is considered as a detail and credible category of the depth of tumor invasion. Generally, with the increasing T category, the risk of metastases should be continuously rising. However, there is a group of metastatic patients with early T classification, who were supposed to have a low metastatic probability. Our study aims to present the T classification on metastatic liver colorectal cancer (CRLM) in both clinical and biological aspects, and explore preoperative predictions to develop a convenient individual assessment model for clinicians to speculate whether these patients, whose prognosis is extremely poor. Methods: Tissue samples of primary colorectal cancer were obtained at our center. Patients with CRLM during 2010 to 2014 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier and Cox models were used to analyze the survival differences. We identified preoperative prognostic factors based on the Cox analysis and constructed a nomogram model. The predictive accuracy and discriminative ability were measured by concordance index (C-index) and calibration curve. Results: The mRNA array from our hospital showed that there is an obvious difference between the T1/2N0M1 subgroup and the T3/4N0M1 subgroup. Patients with early T classification (T1) were more often have tumors located in rectum, with well differentiation, with no lymph node metastasis and a higher CEA level. Further survival analysis indicated that early T classification (T1) was an independent prognostic factor with poorer survival. When the lymph node (N) status was taken into consideration, patients with T1 N+ had an obvious better survival than T1 N0 patients. A clinical nomogram was constructed based on preoperative factors. The calibration curves for probability of 1-, 2-, and 5-year overall survival showed a good agreement between nomogram prediction and actual observation. Conclusions: The prognosis of T1M1 is extremely poorer than T3/4M1. The prognosis of T1N+ is better than T1N0. It is time to pay more attention to the high-risk monitoring and screening of T1 in early colon cancer.

Prognostic impact of telomeric repeat-containing RNA expression on long-term oncologic outcomes in colorectal cancer.

Telomeres are transcribed into long, noncoding telomeric repeat-containing RNAs (TERRA) that have been implicated in the regulation of telomerase, the enzyme that lengthens telomeres, in heterochromatin formation at telomeres, and in telomere stability. This study aimed to evaluate the correlation between TERRA expression and long-term oncologic outcomes in colorectal cancer (CRC).We evaluated 18p TERRA expression and telomere length using quantitative real-time PCR in 60 patients who underwent surgical resection for CRC between June 2008 and November 2010.Patients were grouped according to 18p TERRA expression, with 29 (48.3%) and 31 (51.7%) patients in the low and high TERRA expression groups, respectively. The median follow-up period was 80 months (range 2–103). The 18p TERRA expression was marginally significantly associated with preoperative carcinoembryonic antigen (CEA; P = .082) and was significantly associated with telomere length (P < .05). Multivariate analysis revealed that preoperative CEA (hazard ratio [HR], 2.728; 95% confidence interval [CI], 0.832–8.944, P = .098) and 18p TERRA expression (HR, 0.113; 95% CI, 0.011–1.126, P = .071) were marginally significant independent prognostic factors for overall survival (OS), whereas preoperative CEA (HR, 4.254; 95% CI, 1.394–12.985, P = .011) and 18p TERRA expression (HR, 0.108; 95% CI, 0.011–1.037, P = .054) were significant independent prognostic factors for disease-free survival (DFS). According to our prognostic model with 2 prognostic factors, the OS and DFS rate increased to 76.2% and 80.63%, respectively, in patients with high 18p TERRA expression and CEA levels ≤5 (P = .178, P = .057, respectively).18p TERRA expression was marginally significantly associated with preoperative CEA and significantly associated with telomere length, rendering it a potential prognostic factor for long-term oncologic outcomes in CRC.

The role of preoperative CEA in the management of colorectal cancer: A cohort study from two cancer centres

BackgroundThe primary aim of this study was to investigate whether a preoperative elevation in serum CEA is an independent prognostic factor for both 5-year overall and disease-free survival within an Australian patient cohort. Materials and methodsA retrospective study of a prospectively maintained colorectal neoplasia database for patients between January 2010 and June 2016 was performed. Patients were categorized into two groups according to the preoperative serum CEA level: low (<2.5), high CEA (≥2.5), and elevated (≥5 ng/ml); and further stratified by disease stage. Inclusion criteria were patients having had a resection for either a colonic or upper third rectal adenocarcinoma and with a preoperative CEA value. Data on patient demographics, mortality, and morbidity and survival were compiled. Five-year estimates of overall (OS) and disease-free survival (DFS) were assessed. Results623 patients met the inclusion criteria. The median patient age was 73 (range 22–97) and 55% female (n = 340). There were 572 colonic cancers and 51 rectal cancers. The median follow-up time was 25 months (range 1–71). Eight patients (1%) had a local recurrence and 62 patients (10%) had evidence of metastatic disease after the initial curative resection. The 5-year OS and DFS rates for patients with CEA level <2.5 ng/ml were 85% and 86% respectively, which were higher than those with CEA level ≥2.5 ng/ml (73% and 79% respectively). Independent predictors of recurrence were a CEA ≥5 ng/ml (HR 1.8; 95% CI 1.09–3.00; p = 0.002) and stage II (HR 5.33; 95% CI 1.59–17.90; p = 0.007) and stage III (HR 10.91; 95% CI 3.34–35.60; p=<0.001). A CEA ≥5 ng/ml was associated with a higher risk of death (HR 1.79; 95% CI 1.00–3.19; p = 0.046). ConclusionPreoperative CEA levels were associated with age, BMI, ASA and tumour stage. Overall, CEA remains a reliable predictor of recurrence and survival after curative surgery in patients with colorectal cancer.

Prognostic models based on postoperative circulating tumor cells can predict poor tumor recurrence-free survival in patients with stage II-III colorectal cancer

Background: It is urgent to develop robust prognostic biomarkers for non-metastatic colorectal cancer (CRC) patients undergoing surgery. The current study aimed to explore and compare the clinical significance of preoperative and postoperative blood tumor biomarkers including circulating tumor cells (CTCs), and develop prognostic models based on tumor biomarkers in patients with stage II-III CRC receiving surgery.Methods: A prospective study was performed to enroll 130 patients with stage II-III CRC receiving surgery between January 2015 and December 2017. Preoperative and postoperative blood tumor biomarkers including CTCs were detected and their prognostic value in predicting tumor recurrence-free survival (RFS) in stage II-III CRC were identified by Kaplan-Meier curves and Cox proportional hazard regression models.Results: CTCs counts within three postoperative days were significantly higher than preoperative CTCs (pre-CTCs). No significant association of pre-CTCs with clinical characteristics and tumor biomarkers was observed while positive postoperative CTCs (post-CTCs) were associated with female, older onset age, high TNM stage, tumor recurrence, and preoperative CEA. Kaplan-Meier curve with log-rank test and univariate Cox proportional hazard regression analysis suggested high N stage, TNM stage, positive pre-carbohydrate antigen (CA) 125, pre-CA19-9, post-CA125, post-CA19-9, post-CA72-4, post-carcinoembryonic antigen (CEA), and post-CTCs were correlated with poor RFS. In multivariate analysis, only TNM stage (adjusted HR=3.786, 95% CI=1.330-10.780; P=0.013), post-CA72-4 (adjusted HR=5.675, 95% CI=2.064-15.604; P=0.001), and post-CTCs (adjusted HR=2.739, 95% CI=1.042-7.200; P=0.041) were significantly correlated with poor RFS. We then developed prognostic models combining post-CTCs and post-CA72-4 with TNM stage or not to stratify the patients into different risk groups. These prognostic models exert a similar good performance in predicting tumor RFS in stage II-III CRC patients.Conclusions: Postoperative CTCs were prior to preoperative CTCs in predicting tumor recurrence survival in non-metastatic CRC patients undergoing surgery. We also developed CTCs-based prognostic models to predict tumor recurrence in stage II-III CRC, which might be used to identify the patients with high risk of recurrence and guide aggressive treatment to improve the clinical outcomes of those patients.

Circulating CEA-dNLR score predicts clinical outcome of metastatic gallbladder cancer patient.

Cancer-related inflammation promotes gallbladder tumorigenesis and metastasis of gallbladder cancer (mGBC). The levels of circulating inflammatory-related cell and protein as well as the ratios of them may imply the severity of chronic inflammation in GBC patients, and all of them are candidate prognostic biomarkers for mGBC. In our study, pre-treatment circulating immune cell, fibrinogen (Fib), albumin (Alb), and pre-albumin (pAlb) were detected in 220 mGBC patients, and we calculated neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), Alb-to-Fib ratio (AFR), and Fib-to-pAlb ratio (FPR) replying on the detection. Three years' follow-up was carried out in those patients, and we investigated the possible associations between those biomarkers and three years' overall survival (OS) of these patients using X-tile software, Kaplan-Meier curve, Cox regression, and time-dependent receiver operating characteristics (ROC). Our results showed that OS of the patients with high pAlb and LMR was significantly superior to the cases with the low biomarkers, respectively. However, survival of the cases with high CEA, dNLR, and FPR was significantly inferior to the patients with low levels of those biomarkers. Area under the curve (AUC) of time-dependent ROC of CEA and dNLR was higher than pAlb, LMR, and FPR, respectively. Additionally, higher CEA-dNLR score (adjusted HR=3.09, 95% CI=1.01-4.51 for the score one; adjusted HR=4.99, 95% CI=2.32-7.21 for the score two) was significantly associated with reduced survival of the patients, and AUC of the score for predicting clinical outcome of mGBC patients was 0.756, and it was significantly higher than the single CEA and dNLR, respectively. Our findings implied that pretreatment CEA-dNLR score was superior to the other biomarkers to predict OS of mGBC patients, and it was an independent prognostic factor for the disease.

Impact of Global DNA Methylation in Treatment Outcome of Colorectal Cancer Patients.

Background: Global DNA methylation has an impact in cancer pathogenesis and progression. This study aimed at investigating the impact of global DNA methylation in treatment outcome of Colorectal Cancer (CRC).Patients and Methods: Global DNA methylation was measured by LC/MS/MS in peripheral blood leucocytes of 102, 48, and 32 Egyptian CRC patients at baseline and after 3 and 6 months of Fluoropyrimidine (FP) therapy respectively, in addition to 32 normal healthy matched in age and sex. The genetic expressions of DNA methyl transferases (DNMTs) were determined and correlated with patients‘ survival using univariate and multivariate methods of analyses.Results: Egyptian CRC patients had significant global hypomethylation of 5mC level and 5mC % with overexpression of DNMT3A and DNMT3B. Significant higher 5mC levels were shown in patients > 45 years, male gender, T2 tumors, stage II, negative lymph nodes, and absence of metastasis. FP therapy significantly reduced DNA methylation particularly in the subgroups of patients with high DNA methylation level at baseline and good prognostic features. After 3 years of follow up, patients with 5mC % > 8.02% had significant poor overall survival (OS) while, significant better event-free survival (EFS) was found in patients with 5mC level > 0.55. High initial CEA level and presence of metastasis were significantly associated with hazards of disease progression and death.Conclusion: Global DNA methylation has a significant impact on the treatment outcome and survival of Egyptian CRC patients treated with FP- based therapy.

P2.16-34 Visceral Pleural Invasion is Closely Associated with Nodal Spread in cStage IA Lung Adenocarcinoma

Survival outcomes of patients with clinical Stage IA (cIA) lung adenocarcinoma (LAD) are favorable after resections. In this decade, limited resection without lymphnodes dissections have been indicated for selected cases based on the radiological findings and intraoperative hilar explorations, while we sometimes experience occult lymphnodes metastases among them. These facts refer that limited resections could potentially induce underestimation of the disease, local failure and worsened patients’ prognoses. In the present study, we retrospectively investigate the clinicopathological and oncogenic factors in association with the occult nodal spread and skip metastases, and aim to identify population for standard resection in cIA LAD. We retrospectively investigated 287 patients with cIA LAD who underwent standard pulmonary resections with mediastinal dissections from January 2013 through December 2017. Clinicopathological factors including location of the tumor, radiological pleural invasion and oncogenic status (EGFR/KRAS/ALK/Triple Negative) were reviewed for outcomes of occult nodal spread and skip metastasis. According to the ROC curves analyses, cutoff values of total diameter (TD), solid diameter (SD), mediastinal window diameter (MD) in CT image and pathological invasive size (IS) were settled to diagnose nodal metastases and skip pN2, respectively. Among 287 patients with cIA LAD, 34 (11.8%) with lymph node metastases and 8 (2.8%) with pN2 without hilar metastases (skip pN2) were identified. Univariate analyses revealed that high serum CEA level, TD, MD, SUVmax, IS and pathological pleural invasion (pl) were predictive for nodal metastases. And multivariate analysis showed that pl was closely associated with nodal metastases (Odds Ratio: 3.3, p=0.007). Furthermore, multivariate analysis following the univariate analyses also showed that presence of pl was the factor closely associated with skip N2 metastases (Odds Ratio: 5.7, p=0.029), whereas radiological findings nor oncogenic status were not so. In the clinical valuables, serum CEA level, SD, MD, SUVmax were significantly associated with pl. In resected cIA LAD, pathological pleural invasion was closely associated with both occult nodal spread and skip pN2, while any other preoperative factors and oncogenic status were not. New diagnostic modalities for pl may provide the candidates for standard resections in cIA LAD.

P3.01-66 Clinicopathological Characteristics and Mutation Status of Pulmonary Invasive Mucinous Adenocarcinoma

In the 2015 classification, invasive mucinous adenocarcinoma (IMA) is categorized as one but an uncommon subtype of lung adenocarcinoma. This study attempted to clarify the clinicopathological characteristics and mutation status of IMA. A total of 37 patients with IMA from among 1376 surgically resected patients with lung adenocarcinoma were enrolled. We analyzed them from the standpoints of clinicopathological characteristics, mutation status and the prognosis. KRAS mutations were observed in 9 patients and all of them were Codon 12 mutations. A total of 10 cases exhibited EGFR mutations. ALK rearrangement was detected in only 1 case. The DFS at 5 years were 68.0%. On univariate analysis for DFS, high CEA level (p =0.024), lymphatic permeation and vascular invasion (p =0.015), pleural invasion (p =0.031), tumor size (p=0.023) and N staging(p=0.027) were poor prognostic predictors for DFS. The results revealed that different mutation statuses were observed in IMA. So, we believe that IMA would be subclassified into distinct subtypes with mutation status. And CEA level, lymphatic permeation and vascular invasion, pleural invasion, tumor size and N staging may be the factors related to mitigating DFS in IMA.

Clinical Significance and Radiation Response of miR-302a, miR-105 and miR-888 Expression in Rectal Cancer

Differential expressions of micoRNA (miRNA or miR) were intensively evaluated in colorectal cancer. However, the value of certain miRNAs on radiation response and clinical outcome in rectal cancer patients remains to be elucidated. Here, the expression of miR-302a, miR-105 and miR-888 was determined using Real-time PCR in normal mucosa and rectal cancer from 39 patients with and 41 patients without radiotherapy (RT) before surgery. The relationship of miR-302a, miR-105 and miR-888 expression with biological factors and prognosis was analyzed and identified by The Cancer Genome Atlas (TCGA) database. miR-105 expression in rectal cancer was higher than that in normal mucosa in RT (P=0.042) and non-RT cases (P=0.003), which was associated with mucinous histological type (P=0.004), Cox-2 (P=0.042) and p73 expression (P=0.030). miR-302a expression was more frequently in tumors with necrosis (P=0.033) and cytoplasmic Wrap53 expression (P=0.030), and miR-888 expression occurred more frequently in tumors with Survivin (P=0.015), AEG-1 (also known as MTDH, P=0.003) and SATB1 expression (P=0.036). TargetScan also predicted AEG-1 and SATB1 as putative targets for miR-888. TCGA database demonstrated that miR-105 expression was associated with high CEA level (P=0.048). RT reduced miR-302a, miR-105 and miR-888 expression. miR-888 expression was independently related to worse survival of rectal cancer patients without RT (OS, P=0.001; DFS, P=0.009). Thus, our findings suggest the involvement of miR-105 in pathogenesis and of miR-888 in prognosis, and imply potential value of miR-302a, miR-105, and miR-888 on radiation response in rectal cancer. Funding: This work was supported by the grants from the Swedish Cancer Foundation, Swedish Research Council and the Health Research Council in the South-East of Sweden. Declaration of Interest: The authors have no conflicts of interest. Ethical Approval: Informed consent was obtained from all patients, and the study protocol was approved by the Institutional Review Board of Linkoping University, Sweden. All experiments were performed in accordance with relevant guidelines and regulations.

RA09.08: EVALUATION OF THE EIGHTH YPTNM CLASSIFICATION SYSTEM IN ESOPHAGEAL CANCER PATIENTS

Abstract Background The 7th edition of the Union for International Cancer Control (UICC) TNM staging system is based on pathologic data from esophageal cancers treated by surgery alone. In the 8th edition of UICC-TNM staging system, there is no information available for treatment modality (surgery alone or neoadjuvant therapy [NAC] followed by surgery [NAC-S]), although clinical stage, neoadjuvant pathologic stage, and pathologic stage were analyzed and identified. The objective of this study was to evaluate the prognostic impact of the new staging system on esophageal squamous cell cancer (ESCC) patients treated by NAC-S. Methods Database of 140 consecutive ESCC patients in our hospital was retrospectively restaged in 7th and 8th UICC-TNM system. The prognostic impacts of pathologic stage after NAC according to the both staging systems were compared. Results The median follow-up period was 4.8 years (range 0.2–9.7), with 49 patients dead at the time of analysis. In 7th edition, the 3-year overall survival rates (3y-OS) of ypStages 0, I, II, III, and IV were 100%, 93.5%, 93.5%, 43.9%, and 0.0%, respectively. In 8th edition, the 3y-OS of ypStages 0, I, II, III, and IV were 100%, 96.5%, 90.2%, 51.7%, and 29.6%, respectively. There were no marked differences between 7th and 8th edition in the prognoses. The both editions poorly distinguish the prognoses of ypStages 0, I, and II. For pathological prognostic group in 7th edition, the 3y-OS of Groups 0, I, II, III, and IV were 100%, 97.0%, 90.6%, 43.9%, and 0.0%, respectively. For pathological prognostic group in 8th edition, the 3y-OS of Groups 0, I, II, III, and IV were 100%, 96.7%, 89.8%, 51.7%, and 29.6%, respectively. For patients with ypStages 0-II, pretreatment higher CEA was poor prognostic factor (HR 7.1, 95% confidence interval 1.9–25.9). Conclusion Our study indicates the problem that the ypStage in the 8th TNM staging system poorly distinguish the prognoses of ypStages 0, I, and II in patients undergoing NAC-S. Additional study is needed to evaluate the role of ypStage 0-II incorporation of new prognostic factors. Disclosure All authors have declared no conflicts of interest.

The clinical application value of human serum exosomal CEA in the diagnosis of colorectal cancer

Objective To isolate and identify exosomes from human serum, explore the feasibility of exosomal CEA for the diagnosis of colorectal cancer. Methods Retrospective study.64 cases with colorectal cancer patients(41 cases with normal CEA results and 23cases with high CEA results), 20 cases with benign colorectal diseases patients and 40 cases with healthy people of department of physical examination from October 2015 to December 2016 in Tongji Hospital of Tongji University. Exosomes were isolated from these serum using ExoQuick, and then identified by using transmission electron microscopy, and Western Blot for morphology and molecular phenotype.The serum level of CEA and exosomal CEA was measureed by enzyme linked immunosorbent assay (ELISA). The diagnostic efficacy of serum Exosomal CEA concentration in the colorectal cancer by using U test and the subject work characteristic curve (ROC). Results Exosomes in human serum was successfully extracted with ExoQuick kit.Exosomal CEA concentration in 64 cases with colorectal cancer patients (1 056.36-28 637.78)pg/ml was significantly higher than in cases with benign colorectal diseases patients (394.61-2 437.83)pg/ml and healthy controls(610.89-2 076.70)pg/ml(U=124.000, U=119.000, P<0.01). Exosomal CEA concentration in 41 colorectal cancer patients with normal serum CEA concentration(1 056.36-5 832.07)pg/ml was significantly higher than in benign colorectal diseases patients and healthy controls(U=113.000, U=119.000; P<0.01). ROC analysis of exosomal CEA yielded an AUC(area under the ROC curve)of 0.954(95% CI=0.919-0.988), which was higher than the serum CEA.The area under the ROC curve of serum Exosomal CEA concentration for colorectal cancer diagnosis is 0.954(95% CI=0.919-0.988), which is superior to the serum CEA concentration[0.636 (95% CI=0.531-0.742)]. Conclusions Isolation and detection of serum Exosomal CEA concentrations have a good diagnostic efficacy in colorectal cancer. It′s possible to be a marker for early diagnosis of colorectal cancer.(Chin J Lab Med, 2018, 41: 503-508) Key words: Colorectal neoplasms; Exosomes; Carcinoembryonic antigen; Biomarkers, Tumor

Predictors of Survival after Yttrium-90 Radioembolization for Colorectal Cancer Liver Metastases

PurposeTo identify clinical parameters that are prognostic for improved overall survival (OS) after yttrium-90 radioembolization (RE) in patients with liver metastases from colorectal cancer (CRC). Materials and MethodsA total of 131 patients who underwent RE for liver metastases from CRC, treated at 2 academic centers, were reviewed. Twenty-one baseline pretreatment clinical factors were analyzed in relation to OS by the Kaplan-Meier method along with log-rank tests and univariate and multivariate Cox regression analyses. ResultsThe median OS from first RE procedure was 10.7 months (95% confidence interval [CI], 9.4–12.7 months). Several pretreatment factors, including lower carcinoembryonic antigen (CEA; ≤20 ng/mL), lower aspartate transaminase (AST; ≤40 IU/L), neutrophil-lymphocyte ratio (NLR) <5, and absence of extrahepatic disease at baseline were associated with significantly improved OS after RE, compared with high CEA (>20 ng/mL), high AST (>40 IU/L), NLR ≥5, and extrahepatic metastases (P values of <.001, <.001, .0001, and .04, respectively). On multivariate analysis, higher CEA, higher AST, NLR ≥5, extrahepatic disease, and larger volume of liver metastases remained independently associated with risk of death (hazard ratios of 1.63, 2.06, 2.22, 1.48, and 1.02, respectively). ConclusionsThe prognosis of patients with metastases from CRC is impacted by a complex set of clinical parameters. This analysis of pretreatment factors identified lower AST, lower CEA, lower NLR, and lower tumor burden (intra- or extrahepatic) to be independently associated with higher survival after hepatic RE. Optimal selection of patients with CRC liver metastases may improve survival rates after administration of yttrium-90.