proGRP Levels Research Articles

The importance of circulating tumor markers in lung cancer in clinical practice

We have reviewed the available publications about circulating tumor markers (CTM) — CYFRA 21‑1, CEА, SCC, NSE and proGRP, in patients with small‑cell (SCLC) and non‑small cell lung cancer (NSCLC). Elevated levels of at least one of them (CEA, CYFRA 21‑1 и SCC) were seen in 100 % of patients with stage III–IV NSCLC. CEA, CYFRA 21‑1 and SCC could have prognostic and predictive value. Their decrease during chemotherapy or immunotherapy correlates with better overall survival. For SCLC the main CTM are NSE and proGRP. Together with CTM for NSCLC these markers could predict correctly histological subtype of lung cancer in 79–97 % of patients. Levels of proGRP after 1, 2 and 3 cycles of chemotherapy in SCLC correlated with response to treatment and were associated with prognosis. Thus, it can be used as an additional response criterion, for example in patients with non‑measurable disease. CTM provide additional easy‑to‑use predictive and prognostic data for patients with lung cancer.

Selective application of neuroendocrine markers in the diagnosis and treatment of small cell lung cancer

AimsHere, we explored the potential application and selection of neuroendocrine biomarkers in the diagnosis and treatment of small cell lung cancer. MethodsWe retrospectively analyzed 118 patients with small cell lung cancer (SCLC), 166 patients with non-small cell lung cancer (NSCLC), 33 patients with benign lung disease (BLD), and 200 healthy individuals admitted to Zhejiang Provincial People’s Hospital between January 1, 2015 and May 31, 2019. All the patients were newly diagnosed with either SCLC, NSCLC, or BLD and previously untreated. Peripheral blood levels of ProGRP, NSE, CEA, and CYFRA21-1 were analyzed during the follow-up treatment, and 2-fold upper limit of reference intervals were defined as effective elevation. We used paired results to analyze the diagnostic efficiency of proGRP and NSE on SCLC. ResultsIn the 118 SCLC patients, proGRP levels were significantly higher compared with NSE levels. The diagnostic efficiencies of NSE and ProGRP for SCLC were 0.8554 and 0.9053, respectively. The combined diagnostic efficiency (0.9426) was higher relative to NSE, but there was no significant difference compared with proGRP. The effective elevation rate of proGRP was 45.3% higher than that of NSE in the limited stage of SCLC. In the extensive disease of SCLC patients, 70.7% cases had more than 10-fold increase in proGRP value, whereas 56.9% cases had less than 5-fold increase in NSE value. Compared with pre-treatment, the median concentrations of proGRP increased by 204.0% higher than that of NSE (71.3%) in the progressive group. Besides, the dynamic change in imaging characteristics and tumor size had a strong correlation with the levels of proGRP. SignificanceProGRP is a reliable neuroendocrine biomarker in SCLC. The effective elevation of proGRP has a potential diagnostic and efficacy value in the evaluation of SCLC. However, the combined detection of proGRP and NSE does not significantly improve the diagnosis of lung cancer.

Diagnostic Value and Clinical Significance of Combined Detection of Serum Markers CYFRA21-1, SCC Ag, NSE, CEA and ProGRP in Non-Small Cell Lung Carcinoma.

The aim of the study is to explore the diagnostic value and clinical significance of combined detection of serum markers CYFRA21-1, SCC Ag, NSE, CEA and ProGRP in non-small cell lung cancer. CYFRA21-1, SCC Ag, NSE, CEA, and ProGRP levels of 113 patients with lung cancer, 110 patients with benign lung diseases, and 90 healthy volunteers were detected by electrochemiluminescence assay. The correlations between positive expressions and clinical and pathological parameters were analyzed. The diagnostic values of CYFRA21-1, SCC, NSE, CEA, and ProGRP were evaluated by plotting ROC curves. The positive expression rates of CYFRA21-1, SCC Ag, NSE, CEA, and ProGRP in the lung cancer group significantly exceeded those of benign lung disease and healthy groups (p < 0.05). In the lung cancer group, CYFRA21-1, SCC Ag, NSE, CEA, and ProGRP levels significantly varied in patients with different degrees of invasion and clinical stages in the presence/absence of lymph node metastasis (p < 0.05). AUCs of diagnosis by CYFRA21-1, ProGRP, CEA, SCC Ag, and NSE were 0.737 [95% CI (0.582 - 0.893)], 0.829 [95% CI (0.742 - 0.915)], 0.848 [95% CI (0.739 - 0.956)], 0.758 [95% CI (0.642 - 0.874)], and 0.857 [95% CI (0.764 - 0.951)], respectively, with the optimal cutoff values of 11.38 µg/mL, 103.47 pg/mL, 5.78 ng/mL, 3.92 ng/mL, and 13.36 ng/mL, respectively. The combined diagnostic sensitivity and accuracy both exceeded those based on individual markers, but the combined diagnostic specificity was slightly lower than those using CYFRA21-1, SCC Ag, and ProGRP alone. CYFRA21-1, SCC Ag, NSE, CEA, and ProGRP levels of patients with lung cancer increased abnormally. The combined detection effectively improved diagnostic accuracy and sensitivity.

Prognostic Significance of Combined Biomarkers in Small Cell Lung Cancer.

Small cell lung cancer is an aggressive form of lung cancer with poor prognosis. Combined serum biomarkers may give us more information and predictive value. We retrospectively analyzed data and samples collected from 120 small cell lung cancer patients who had undergone surgery in Tianjin Medical University Cancer Institute and Hospital between June 2014 and November 2016. Correlations between serum biomarker levels and survival parameters were analyzed and prognostic factors were identified. By univariate analysis, limited disease (p < 0.001), more than 4 cycles of first line chemotherapy (p = 0.002), thoracic irradiation (p < 0.001), PCI (p = 0.013)), higher SCCA level (p = 0.058), and normal LDH level (p = 0.027) were significantly correlated with a good PFS. By multivariate analysis, clinical stage, number of chemotherapy cycles, thoracic irradiation, PCI, and SCCA level were independent prognostic factors for PFS. Higher ProGRP or NSE level with higher LDH, higher NSE with higher D-dimer had poor prognostic index. We observed that NSE, CEA, and CYFRA 21-1 were closely associated with tumor burden. The combination of NSE and ProGRP with LDH and D-dimer worked as prognostic factors for tumor progression in SCLC patients.

Diagnostic value of ProGRP for small cell lung cancer in different stages.

To investigate the roles of gastrin-releasing peptide (ProGRP) in the diagnosis of small cell lung cancer (SCLC). We retrospectively analyzed data from 11,206 patients with clinical suspicion of lung cancer from January 1, 2015 to May 31, 2018. ProGRP and neuron-specific enolase (NSE) were detected in peripheral blood, and receiver operating characteristic curve (ROC) was used for analysis. ROC indicated that the cutoff values of ProGRP and NSE were 66 ng/L and 18 µg/L respectively, and the diagnosis efficacy of ProGRP was greater than that of NSE (sensitivity: 86.5% vs. 78.8%; specificity: 96.5% vs. 86.3%, respectively) in the diagnosis of SCLC. Moreover, the median level of ProGRP in SCLC increased with the accompanying stages (P<0.001). Further analysis showed that diagnostic efficacy can be improved by using different cutoff values in different stages, but not stage I and II. The cut-off values of ProGRP in the diagnosis of SCLC in stage I-II, III and IV were 56, 71 and 99 ng/L respectively. In addition, the sensitivity (96.6% vs. 95.8% and 98.3% vs. 94.8%) and concordance rate (χ2 =1,526.9 and 988.7, both P<0.001) of detecting SCLC was improved by using different cutoff values compared with the only criteria of ProGRP being ≥66 ng/L in stage III and IV, but not stage I-II. Additionally in stage III and IV, the concordance rates of ProGRP ≥71 ng/L and ProGRP ≥99 ng/L were also higher than ProGRP ≥300 ng/L (both P<0.001), which was conventionally indicated for SCLC. ProGRP has significantly higher sensitivity and specificity than NSE in the diagnosis of SCLC. Furthermore, special thresholds for every stage may be more reasonable for the diagnosis of SCLC.

Prognostic value of Platelet-to-Lymphocyte Ratio (PLR) and IL-6 in patients with small cell lung cancer

Background: In order to identify patients with the most favourable prognosis, the effect of baseline level of interleukin-6 (IL-6) and platelet-to-lymphocyte ratio (PLR) on survival was analysed in patients with small cell lung cancer.&lt;br&gt;Material and Methods: 159 patients with small cell lung cancer were enrolled. Full blood count enabling computing the PLR, as well as NSE, ProGRP and IL-6 levels were done in all participants.&lt;br&gt;Results: We demonstrated significant effect of disease stage, performance status, sex, initial NSE, ProGRP and IL-6 levels as well as PLR on survival of patients with SCLC. In subgroups with normal initial levels of ProGRP (below 50.36 ng/L) and NSE (below 20.95 μg/L), the IL-6 level above 6.0 ng/L worsens the prognosis by 28% and 29%, respectively. In a subgroup with elevated initial ProGRP, the difference in survival between patients with normal vs elevated IL-6 level at baseline was 25%, whereas in a subgroup with elevated initial NSE it was 14%. The between-subgroup differences in PLR were less considerable. There was a significant effect of PLR on patient survival in a subgroup with normal initial NSE level and elevated initial ProGRP level.&lt;br&gt;Conclusion: In subgroups of SCLC patients identified based on initial tumour marker levels, IL-6 level can be a source of reliable prognostic information, whereas the effect of PLR is less marked. Patients with normal tumour marker levels and IL-6 below 6 ng/L at baseline have the most favourable prognosis.

Pro-gastrin-releasing peptide and outcome in patients with heart failure and anaemia: results from the RED-HF study.

AimsNeuroendocrine activation is associated with poor outcome in heart failure (HF). The neuropeptide gastrin‐releasing peptide (GRP), derived from the precursor proGRP1‐125 (proGRP), has recently been implicated in inflammation and wound repair. We investigated the predictive value of proGRP on clinical outcomes in HF patients with reduced ejection fraction.Methods and resultsThe association between plasma proGRP (time‐resolved immunofluorometric assay) and the primary endpoint of death from any cause or first hospitalization for worsening of HF was evaluated using multivariable Cox proportional hazard models in 1541 patients with systolic HF and mild to moderate anaemia, enrolled in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED‐HF) trial. Median proGRP levels in the RED‐HF cohort were markedly increased [95 ng/L (25th, 75th percentile, 69–129 ng/L)] with 64% patients above the 80 ng/L reference limit. Baseline proGRP correlated with estimated glomerular filtration rate (r = 0.52), N terminal pro brain natriuretic peptide (r = 0.33), troponin T (r = 0.34), and haemoglobin (r = 0.16) (all P < 0.001). The incidence outcome increased with increasing tertiles of baseline proGRP (primary endpoint third tertile vs. the lowest tertile; hazard ratio 1.91; 95% confidence interval 1.60–2.28, P < 0.001). However, these associations were markedly attenuated and non‐significant in adjusted models. No interaction between baseline proGRP and the effect of darbepoetin alfa treatment was detected. Moreover, no significant association between changes in proGRP during 6 month follow‐up and outcome was observed.ConclusionsPro‐gastrin‐releasing peptide is increased in patients with HF with reduced ejection fraction and anaemia, in particular in patients with poor renal function. However, proGRP adds little as a prognostic marker on top of conventional HF risk factors.

Serum ProGRP and NSE levels predicting small cell lung cancer transformation in a patient with ALK rearrangement-positive non-small cell lung cancer: A case report.

The resistance mechanisms to anaplastic lymphoma kinase (ALK) inhibitors comprise ALK gene variations, such as ALK point mutations and copy-number gains, the activation of bypass signaling through the activation of other oncogenes and small cell lung cancer (SCLC) transformation. To date, few studies have investigated whether tumor markers for SCLC correlate with the SCLC transformation in EGFR-mutant NSCLC and ALK-positive non-SCLC (NSCLC). The present case study reported a patient with SCLC transformation after alectinib treatment. The patient exhibited elevation of pro-gastrin-releasing peptide precursor and neuron-specific enolase levels, which may be predictive of SCLC transformation during the resistance to ALK-tyrosine kinase inhibitors.

Diagnostic and therapeutic value of progastrin-releasing peptide on small-cell lung cancer: A Single-Center Experience in China.

We aimed to compare the diagnostic efficiency of proGRP and NSE on SCLC and to investigate whether the change of proGRP level would predict therapeutic response. Patients who were firstly diagnosed pathologically in Nanjing Chest Hospital and measured proGRP level consecutively were enrolled in the study. ProGRP level was detected using Elecsys ProGRP Assay. Totally 75 SCLC, 234 NSCLC and 264 benign lung diseases (BLD) were enrolled. Both proGRP and NSE levels in SCLC were significantly higher than those in NSCLC and BLD, and proGRP in extensive stage SCLC was higher than which in limited stage (P ≤ .001). The diagnostic efficiency of proGRP on SCLC was higher than that of NSE, but when the two biomarkers were bind together, the diagnostic efficiency was the best. When SCLC was differentiated from NSCLC and BLD, the cut‐off values were 114.35 pg/mL and 162.55 pg/mL respectively. For treatment responsive patients, proGRP level decreased markedly after the first cycle of therapy and kept a continued momentum of decline during treatment. But for unresponsive patients, no obvious decline was observed. ProGRP had higher diagnostic efficiency on SCLC when compared to NSE, and it could better predict therapeutic response of pulmonary target lesions on chemotherapy.

Establishment of the reference interval for serum pro-gastrin-releasing peptide in healthy adults of Chinese Han ethnicity.

The aim of this study is to establish the reference interval for serum pro-gastrin-releasing peptide (proGRP) determined by electrochemiluminescence immunoassay (ECLIA) in healthy Chinese Han ethnic adults. After screening, 9932 healthy Chinese Han adults (age range 18-95 years) were enrolled in this study, including 6220 men and 3712 women. Serum proGRP levels were measured by ECLIA. The reference interval was defined by non-parametric 95th percentile interval. Serum proGRP levels conformed to a non-Gussian distribution. The reference interval for healthy Chinese Han adults calculated by the non-parametric method was 0-73.90 ng/mL in this study. Since serum proGRP levels were significantly correlated with age (r=0.226, P<0.001), the participants were divided into six age groups: 18-39, 40-49, 50-59, 60-69, 70-79, and ⩾80 years. No significant difference for serum proGRP levels was found between the sexes at each of six age groups. The reference intervals were gradually increased with age (65.35 ng/mL, 68.65 ng/mL, 74.10 ng/mL, 77.65 ng/mL, 84.57 ng/mL, and 98.03 ng/mL in 18-39, 40-49, 50-59, 60-69, 70-79, and ⩾80 years, respectively). We established the reference interval for serum proGRP, which was determined by ECLIA in the healthy Chinese Han population. Furthermore, our study suggests that it is necessary to establish the age-specific reference intervals for serum proGRP.

Pro-Gastrin Releasing Peptide: A New Serum Marker for Endometrioid Adenocarcinoma

Background: Gastrin-releasing peptide (GRP) is thought to play a role in the metastatic process of various malignancies. The more stable precursor of GRP, pro-GRP (ProGRP), has been shown to be secreted by neuroendocrine tumors. This study was designed to assess the validity of ProGRP as a diagnostic marker in endometrioid adenocarcinomas (EAs) of the endometrium. Methods: Thirty-seven patients with a diagnosis of EA, 23 patients with endometrial hyperplasia, and 32 age-matched controls with normal endometrial histology were recruited for this study. Serum ProGRP and cancer antigen 125 (CA125) values were compared between groups. Results: Median serum ProGRP levels were significantly higher in the cancer group compared to corresponding levels in both the hyperplasia and control groups (p = 0.008 and p < 0.001 respectively; endometrial cancer: 27.5 pg/mL; hyperplasia: 16.1 pg/mL; controls: 12.9 pg/mL). Age and endometrial thickness were positively correlated with ProGRP levels (r = 0.322, p = 0.006 and r = 0.269, p = 0.023, respectively). Receiver Operating Characteristic curve analyses for EA revealed a threshold of 20.81 pg/mL, with a sensitivity of 60.7% and specificity of 81.4%, positive predictive value of 68% and negative predictive value of 76.1%. Conclusion: Significantly higher ProGRP levels were observed in patients with EA than in controls. Serum ProGRP has good diagnostic sensitivity and specificity for EA.

Clinical value of Pro-GRP and T lymphocyte subpopulation for the assessment of immune functions of lung cancer patients after DC-CIK biological therapy.

The present study investigated the aptness of assessing the levels of progastrin-releasing peptide (Pro-GRP) in addition to the T lymphocyte subpopulation in lung cancer patients prior to and after therapy for determining immune function. A total of 45 patients with lung cancer were recruited and stratified in to a non-small cell lung cancer (NSCLC) and an SCLC group. Prior to and after treatment by combined biological therapy comprising chemotherapy or chemoradiotherapy followed by three cycles of retransformation of autologous dendritic cells-cytokine-induced killer cells (DC-CIK), the peripheral blood was assessed for populations of CD3+, CD4+, CD8+ and regulatory T cells (Treg) by flow cytometry, and for the levels of pro-GRP, carcinoembryonic antigen, neuron-specific enolase and Cyfra 21-1. The results revealed that in NSCLC patients, CD8+ T lymphocytes and Treg populations were decreased, and that CD3+ and CD4+ T lymphocytes as well as the CD4+/CD8+ ratio were increased after therapy; in SCLC patients, CD3+, CD4+ and CD8+ T lymphocytes were increased, while Treg cells were decreased after treatment compared with those at baseline. In each group, Pro-GRP was decreased compared with that prior to treatment, and in the SCLC group only, an obvious negative correlation was identified between Pro-GRP and the T lymphocyte subpopulation. Furthermore, a significant correlation between Pro-GRP and Tregs was identified in each group. In conclusion, the present study revealed that the immune function of the patients was improved after biological therapy. The results suggested a significant correlation between Pro-GRP and the T lymphocyte subpopulation in SCLC patients. Detection of Pro-GRP may assist the early clinical diagnosis of SCLC and may also be used to assess the immune regulatory function of patients along with the T lymphocyte subpopulation. Biological therapy with retransformed autologous DC-CIK was indicated to enhance the specific elimination of tumor cells and improve the immune surveillance function in cancer patients, and also restrained the immune evasion of the tumor, leading to decreased Pro-GRP levels.

P3.16-051 Implications of Preoperative Serum Tumor Levels on Pathological Characteristics in Patients with Lung Adenocarcinoma

Although preoperative serum tumor marker levels, such as carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC) are often evaluated in non-small cell lung cancer patients, the implication of these levels are still unknown. This study examined the predictive effect of preoperative tumor marker levels on pathological characteristics of lung adenocarcinoma. We retrospectively reviewed patients with lung adenocarcinoma who underwent macroscopic complete resection. The pathological metastasis and/or involvement was defined that positive pleural effusion or lavage cytology, pleural involvement, pulmonary metastasis, lymph node metastasis, and/or lymphovascular involvement were identified on pathological examination. To identify predictors for the pathological metastasis and/or involvement, tumor markers (CEA, SCC, Sialyl Lewisx-1 [SLX], cytokeratin-19 fragments [CYFRA], neuron-specific enolase [NSE], and pro-gastrin-releasing peptide [ProGRP]), and demographic and clinical factors were analyzed by a univariate analysis and multivariate logistic regression analysis. For the significant tumor markers, optimal cutoff points were determined with a receiver operating characteristic analysis. Of the 263 eligible patients, 138 were male and 125 were female. The median age was 70 years. The median preoperative CEA, SCC, SLX, CYFRA, NSE, and ProGRP levels were 3.7 ng/ml, 0.8 ng/ml, 28 U/ml, 1.8 ng/ml, 8.4 ng/ml, and 46.9 pg/ml, respectively. According to the 7th edition of the TNM classification, 186 patients (71%) had c-stage IA disease, 48 (18%) had c-stage IB disease, 26 (10%) had c-stage II disease, and 3 (1%) had c-stage III disease. Positive pleural effusion, positive pleural lavage cytology, pleural involvement, pulmonary metastasis, lymph node metastasis, lymphatic permeation, and vascular invasion were identified in 3 (1%), 4 (2%), 48 (18%), 9 (3%), 28 (11%), 20 (8%), and 35 patients (13%), respectively, and in total, 83 patients (32%) developed the pathological metastasis and/or involvement. The univariate analysis identified CEA, smoking index, size, solid size, and c-stage as significant predictors. A multivariate analysis revealed CEA (OR: 1.113, p=0.005) and solid size (OR: 1.052, p<0.001) as significant predictors. The optimal cutoff point was determined as 6.0 ng/ml for the preoperative CEA, and 35 of the 63 patients (56%) with ≥6.0 ng/ml of CEA developed the pathological metastasis and/or involvement whereas 48 of the 200 patients (24%) with <6.0 ng/ml of CEA developed pathological metastasis and/or involvement. Our results suggested the predictive effect of the high preoperative CEA level on pathological metastasis and involvement in patients with lung adenocarcinoma, and thus, we may consider preoperative CEA to decide surgical procedure for these patients, such as the extent of pulmonary resection and lymphadenectomy.

Clinical implications for pro-GRP in small cell lung cancer. A single center experience.

Recently, pro-gastrin-releasing peptide (pro-GRP) became available as an alternative sensitive, specific and reliable tumor marker for patients with small cell lung cancer (SCLC), both in limited (LD) and diffuse disease (DD). We retrospectively analyzed pro-GRP, neuron-specific enolase (NSE) and CEA in patients with SCLC and non-small cell lung cancer (NSCLC). Serum pro-GRP level was measured with electrochemiluminescence at our laboratory (cutoff 77.8 pg/mL). Continuous variables were analyzed with the Mann-Whitney test, contingency data with Fisher's exact test. Receiver operator characteristic (ROC) curve analysis was performed to identify threshold values to set the highest sensitivity (Sn) and specificity (Sp) values. A total of 65 patients were studied (49 men, median age 67 years, range 27-79). Thirty-seven patients had SCLC (29 DD, 8 LD) and 28 advanced NSCLC. Median pro-GRP level was 919 pg/mL (range 22-147,350) in SCLC and 32 pg/mL (range 10-119.2) in NSCLC (p<0.0001). NSE was 4.38-fold higher in SCLC patients (p = 0.0005); CEA did not reveal significant differences between groups. Pro-GRP Sn and Sp were 86.4% and 96.4%, respectively. With ROC curve analysis, a cutoff value of 329.3 pg/mL showed a Sn of 75.8% and Sp of 87.5% in discriminating DD from LD. Pro-GRP was not influenced by either liver metastases or renal impairment. Pro-GRP is sensitive for SCLC diagnosis. Since high marker levels are related to high disease burden, pro-GRP may have a negative prognostic significance. Follow-up studies are required to define its role in clinical practice in monitoring responses to treatment and early relapses.

The Combination of the Tumor Markers Suggests the Histological Diagnosis of Lung Cancer

Tumor markers are beneficial for the diagnosis and therapy monitoring of lung cancer. However, the value of tumor markers in lung cancer histological diagnosis is unknown. In this study, we analyzed the serum levels of six tumor markers (CEA, CYFRA21-1, SCC, NSE, ProGRP, and CA125) in 2097 suspected patients with lung cancer and determined whether the combination of the tumor markers was useful for histological diagnosis of lung cancer. We found that CYFRA21-1 was the most sensitive marker in NSCLC. ProGRP showed a better clinical performance than that of NSE in discriminating between SCLC and NSCLC. The serum level of CYFRA21-1 or SCC was significantly higher in squamous carcinoma (p < 0.05), and the levels of ProGRP and NSE were significantly higher in SCLC (p < 0.05). According to the criteria established, SCLC and NSCLC were discriminated with sensitivity of 87.12 and 62.63% and specificity of 64.61 and 99.5%, respectively. The sensitivity and specificity in the differentiation of adenocarcinoma and squamous carcinoma were 68.1 and 81.63% and 70.73 and 65.93%, with NPV of 46.03 and 68.97% and PPV of 85.82 and 79.47%, respectively. Our results suggested the combination of six tumor markers could discriminate the histological types of lung cancer.

P1.07-011 Extensive-Stage Small Cell Lung Cancer in a 13-Year-Old Male Patient Treated with Bevacizumab Followed by High-Dose Chemotherapy

Small cell lung cancer (SCLC) is exceedingly rare in children. We herein report a pediatric case of extensive-stage SCLC in a patient who was treated with intensive chemotherapy and high-dose chemotherapy (HDC). A 13-year-old male patient was admitted to our department with a three-month history of cough. Thoracic CT and MRI showed two large masses, one was a 5.8 × 4.3 × 3.9 cm primary tumor that was located close to the right middle lobe bronchus; the other was a subcarinal lymph node. Systemic PET-CT revealed multiple bone metastases. A serological analysis revealed high levels of pro-GRP (4,075 pg/mL [normal, ≤ 81 pg/mL]) and NSE (52.3 ng/mL [normal, ≤ 16.3 ng/mL]). The patient’s plasma level of VEGF was 259 pg/mL (normal, ≤ 115 pg/mL). We diagnosed the patient with SCLC based on the results of the histopathological examination of endoscopically-obtained biopsy specimens that were obtained from part of the tumor that was partially exposed on the bronchial wall. Treatment was initiated with cisplatin and irinotecan (PI). After four courses of PI therapy followed by two courses of PI plus etoposide (PIE) therapy, there was a reduction in the tumor volume and a remarkable decrease in the patient’s biomarker levels. Thereafter, we administered three courses of chemotherapy consisting of bevacizumab, cisplatin and etoposide. Furthermore, HDC with autologous peripheral blood stem cell rescue and prophylactic cranial irradiation were performed. Early recurrence appeared one month after the completion of the series of initial treatments. He died ten months after the relapse. The long-term prognosis of adult SCLC patients is generally poor, even if desirable initial treatment responses are obtained. In order to improve their prognosis, new trials with other anti-cancer agents should be performed. Bevacizumab, an anti-VEGF monoclonal antibody that is effective against non-SCLC, is an intriguing candidate molecular target drug that should be evaluated for SCLC. Because the value of VEGF in the present patient’s plasma was high, we were of the opinion that the administration of bevacizumab after effective chemotherapy with PI and PIE might have represented an intensive treatment that had the potential to improve his prognosis. Because intensive chemotherapy has been observed to be highly tolerable in adolescence and young adults, we expected HDC to have a greater effect on the patient’s disease. However, the intensified therapy strategy had no impact on the patient’s disease and the results were similar to those observed in elderly patients with extensive-stage SCLC.

PUB030 Use NSE and ProGRP to Judge Therapeutic

Small cell lung cancer (small cell lung cancer, SCLC) accounts for about 13% of lung cancer patients. Compared with non-small cell lung cancer. It has a early metastatic potential and sensitive to first-line cytotoxic chemotherapy. NSE and ProGRP in SCLC sometimes can be high. Collect 205 cases of untreated small cell lung cancer (SCLC) 2013-2016 in Peking Union Medical College Hospital, analysis their clinical data.Compare before and after the treatment course, peripheral blood tumor index of neuron specific enolase (NSE) and gastrin release peptide precursor (GRP) level and follow-up, through the comparison of the TTP, Cr rate data of NSE and ProGRP level on the treatment and prognosis of guiding significance. ORR, TTP, and 2 year survival rates were higher in abnormal NSE and ProGRP than in patients with normal NSE and ProGRP in patients with SCLC, but not statistically significant. NSE and ProGRP decreased to normal compared with the normal subjects after 4 chemotherapy, and had statistical significance. ORR, TTP, and 2 year survival rates of patients with normal SCLC and ProGRP were higher than those in patients with elevated NSE and ProGRP, and the elevation of and NSE showed poor prognosis. NSE and ProGRP decreased after chemotherapy, which indicated that the prognosis was good, especially the NSE decline was more significant. Therefore, ProGRP and NSE have a certain significance in predicting the prognosis and treatment effect of SCLC, and the significance of NSE is more prominent.

Instability of Plasma and Serum Progastrin-Releasing Peptide During Repeated Freezing and Thawing

ObjectivesProgastrin-releasing peptide (proGRP) is a promising biomarker for small cell lung cancer. However, not much is known about how sample processing and storage conditions affect the stability of proGRP. Here, we examined the effects of repeated freeze–thaw cycles on the stability of proGRP in plasma and serum. MethodsConcentrations of proGRP were measured in plasma and serum samples exposed to two, three, or four freeze–thaw cycles and these were compared with values of corresponding samples exposed to one cycle (baseline). We also performed the area under the receiver-operating-characteristic curve (AUC) analysis to determine whether the differences of proGRP concentrations between each paired plasma and serum sample (ΔproGRP) can be used for identifying the samples that have been exposed to multiple freeze–thaw cycles. ResultsConcentrations of proGRP gradually decreased in both plasma and serum samples with increasing numbers of freeze–thaw cycles. Reduction rates of proGRP concentrations were greater in serum than in plasma samples and serum proGRP levels declined with statistical significance (p < 0.001) up to 10.1% after four freeze–thaw cycles. The ΔproGRP measurement showed fair accuracy (AUC = 0.741) for identifying samples that had been through four freeze–thaw cycles. The sensitivity was 82.8% and specificity was 62.1% at an optimal cut-off point of > 4.9. ConclusionOur study shows that the stability of circulating proGRP is affected in both plasma and serum samples by repeated freezing and thawing. We also show that ΔproGRP could be used for identifying paired plasma and serum samples subjected to multiple freeze–thaw cycles.

Progastrin-releasing peptide as a diagnostic and therapeutic biomarker of small cell lung cancer.

Progastrin-releasing peptide (proGRP) is a recently identified biomarker of small cell lung cancer (SCLC). We evaluated the usefulness of plasma proGRP level as a tumor marker for diagnosis and treatment monitoring in patients with SCLC. Plasma samples were collected prospectively from 452 [212 non-small cell lung cancer (NSCLC), 105 SCLC, and 135 other diseases] patients who visited the hospital for tissue diagnosis. Plasma proGRP levels were measured using a two-step automated immunoassay. The median proGRP level was significantly higher in patients with SCLC (892.7 pg/mL) than those with NSCLC (32.6 pg/mL, P<0.001) and other diseases (26.6 pg/mL, P<0.001). At cutoff level of 63 pg/mL, proGRP shows 85.7% sensitivity, 90.2% specificity, 72.5% positive predictive value and 95.4% negative predictive value in patients with SCLC. The area under the curve values were 0.93 for distinguishing SCLC from NSCLC, and 0.943 for distinguishing SCLC from the other conditions. Median proGRP level was higher in extensive disease (1,055.2 pg/mL) than limited disease (253.8 pg/mL, P=0.005). Median OS was significantly shorter in patients with extensive disease (6.0±0.7 months) than limited disease (12.7±4.5 months, P<0.01). Among the 39 patients with SCLC who were followed, the median proGRP levels of the 23 responders decreased after chemotherapy (P<0.001). Plasma proGRP level could be a useful diagnostic and therapeutic monitoring biomarker for patients with SCLC and the initial level may help with SCLC tumor staging.

Abstract 4704: The evaluation of INCB059872, an FAD-directed inhibitor of LSD1, in preclinical models of human small cell lung cancer

Abstract Methylated histone marks on H3K4 and H3K9 are generally coupled with transcriptional activation and repression, respectively. Altered levels of these histone methylation marks lead to abnormal gene expression and are associated with oncogenesis. Lysine specific demethylase 1 (LSD1) catalyzes demethylation of mono and di-methylated lysine 4 and 9 of histone H3 via an FAD-dependent redox-process. Deregulated LSD1 activity perturbs normal gene expression and can lead to cellular transformation. In particular, the function of LSD1 has been reported to maintain stem cell-like gene expression patterns in various cancers, most notably small cell lung cancer (SCLC), a cancer type that is characterized by a highly undifferentiated state and with high unmet medical need. INCB059872 is a potent, selective and orally bioavailable inhibitor of LSD1 that achieves inhibitory activity through the formation of covalent FAD-adducts. The effect of INCB059872 in SCLC cell lines was assessed in vitro and in vivo. In these studies, the proliferation of a panel of SCLC cell lines was inhibited by INCB059872, with EC50 values ranging from 47 to 377 nM. Non-tumorigenic cells, such as IL-2 stimulated T cells from normal donors, by contrast, were significantly less sensitive with IC50 values &amp;gt; 10 μM. Oral administration of INCB059872 on once daily (QD) and alternative day (QoD) dosing regimens inhibited tumor growth in the NCI-H526 and NCI-H1417 human SCLC xenograft models. Consistent with previous reports, INCB059872 treatment in these models led to the induction of the FEZ1 and UMODL1 genes relative to vehicle-treated animals, as part of a gene signature in SCLC cell lines that is predictive of LSD1 responsiveness. Moreover, serum levels of the neuroendocrine marker pro-GRP were markedly reduced at all efficacious dosing regimens in the NCI-H1417 human SCLC xenograft model, suggesting that serum pro-GRP levels could be used as a surrogate pharmacodynamic marker of LSD1 inhibition. Currently, the efficacy of INCB059872 in combination with standard of care therapies for SCLC is under evaluation in these preclinical models. These data support the clinical evaluation of INCB059872 in patients with SCLC. Citation Format: Sang Hyun Lee, Xuesong Mike Liu, Melody Diamond, Valerie Dostalik, Margaret Favata, Chunhong He, Liangxing Wu, Richard Wynn, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle, Bruce Ruggeri. The evaluation of INCB059872, an FAD-directed inhibitor of LSD1, in preclinical models of human small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4704.