Pretherapeutic Levels Research Articles

Low Pretherapeutic Serum Albumin as a Risk Factor for Poor Outcome in Esophageal Squamous Cell Carcinomas

The number of esophageal cancer patients is increasing worldwide and lots of patients suffer from malnutrition and hypoalbuminemic. Serum albumin is a widely acceptable method of assessing nutritional and inflammation status in cancer patients. But whether serum albumin has prognostic value with regard to short-term and long-term outcomes in patients who undergo esophagectomy for cancer is still unclear. We therefore investigated the prognostic role of serum albumin in patients with esophageal cancer. We retrospectively reviewed 208 patients who underwent esophagectomy from September 1, 2003 to December 31, 2008. Clinico-pathological characteristics and postoperative outcomes were compared between different pretherapeutic serum albumin classes: low (hypoalbuminemic), <35 g/l; middle, 35–40 g/l and high, >40 g/l. Older, female, and higher T-stages were more likely to be associated with hypoalbuminemic. Meanwhile, hypoalbuminemic patients had a higher rate of postoperative mortality and complications including sepsis, respiratory insufficiency, arrhythmia, and cardiac insufficiency. But for preoperative comorbidities, no significant difference was found between different pretherapeutic serum albumin classes. The overall 5-year survival rate was 28.6%, 43.9%, and 50.8% for patients with low, middle, and high pretherapeutic serum albumin levels, respectively. Hypoalbuminemic was associated with poor survival (P = 0.016). In a multivariate analysis, the pretherapeutic albumin level was proved to be an independent predictor of survival (hazard ratio = 0.731; 95% confidence interval: 0.544–0.982, P = 0.037). Pretherapeutic serum albumin level is a significant prognostic factor for short-term and long-term outcomes in patients who undergo esophagectomy for cancer, which therefore should be taken into consideration along with other well-defined prognostic factors for better preoperative assessment and prognostic evaluation.

Efficacy and safety of transarterial chemoembolization combined to conformal radiotherapy for uninodular hepatocellular carcinoma

Purpose: A proportion of patients with uninodular hepatocellular carcinoma (HCC) cannot benefit from potential curative therapies such as liver transplantation, surgical resection or radiofrequency ablation. Thus, they are prone to receive transarterial chemoembolization (TACE) that is a palliative option with low probability of both complete response and prolonged local control. Herein, we assessed the combination of TACE and 3D-high dose conformal radiotherapy (3D-HDCRT) for efficacy and safety in HCC. Methods: We retrospectively analyzed the outcome of 35 consecutive patients with uninodular HCC ≤ 100 mm, treated by one course of TACE combined to 3D-HDCRT. The follow-up consisted on clinics, biology, hepatic CT-scan or MRI at month-1 and -3, and thereafter every 3 months. Results: Complete response was obtained in 80% of patients following mRECIST criteria (95% in HCC ≤ 50 mm, and 60% in HCC > 50 mm) with uncommon local recurrence (11%), overall survival rates of 79%, 59% and 44% at respectively 1, 2 and 3 years (median, 37.3 months), and 11.4% grade-3/4 toxicities. Pre-therapeutic α-fetoprotein level ≥ 200 ng/mL was found as a strong predictor of poorer outcome. Conclusion: We showed that TACE combined to 3D-HDCRT can be highly efficient to reach local control and interesting overall survival rates for uninodular HCC, with limited severe toxicities for Child-Pugh A patients. Subsequent prospective controlled trials are warranted for comparison with therapeutic standards.

Pretherapeutic gamma-glutamyltransferase is an independent prognostic factor for patients with renal cell carcinoma.

Background:Gamma-glutamyltransferase (GGT) regulates apoptotic balance and promotes cancer progression and invasion. Higher pretherapeutic GGT serum levels have been associated with worse outcomes in various malignancies, but there are no data for renal cell carcinoma (RCC).Methods:Pretherapeutic GGT serum levels and clinicopathological parameters were retrospectively evaluated in 921 consecutive RCC patients treated with nephrectomy at a single institution between 1998 and 2013. Gamma-glutamyltransferase was analysed as continuous and categorical variable. Associations with RCC-specific survival were assessed with Cox proportional hazards models. Discrimination was measured with the C-index. Decision-curve analysis was used to evaluate the clinical net benefit. The median postoperative follow-up was 45 months.Results:Median pretherapeutic serum GGT level was 25 U l−1. Gamma-glutamyltransferase levels increased with advancing T (P<0.001), N (P=0.006) and M stages (P<0.001), higher grades (P<0.001), and presence of tumour necrosis (P<0.001). An increase of GGT by 10 U l−1 was associated with an increase in the risk of death from RCC by 4% (HR 1.04, P<0.001). Based on recursive partitioning-based survival tree analysis, we defined four prognostic categories of GGT: normal low (<17.5 U l−1), normal high (17.5 to <34.5 U l−1), elevated (34.5 to <181.5 U l−1), and highly elevated (⩾181.5 U l−1). In multivariable analyses that adjusted for the effect of standard features, both continuously and categorically coded GGT were independent prognostic factors. Adding GGT to a model that included standard features increased the discrimination by 0.9% to 1.8% and improved the clinical net benefit.Conclusions:Pretherapeutic serum GGT is a novel and independent prognostic factor for patients with RCC. Stratifying patients into prognostic subgroups according to GGT may be used for patient counselling, tailoring surveillance, individualised treatment planning, and clinical trial design.

The clinical value of serum hepatocyte growth factor levels in patients undergoing primary radiotherapy for glioma: effect on progression-free survival.

Hepatocyte growth factor (HGF) has been shown to be overexpressed in gliomas, and high-grade gliomas (glioblastoma multiforme) express more HGF than lower-grade astrocytoma, and HGF enhances their resistance to radiotherapy. To examine the effect of serum HGF levels on the likelihood of response to radiotherapy and the disease-free survival in patients with glioma, the blood samples of the patients were collected before commencing treatment and serum HGF was measured by quantitative ELISA in 48 patients with glioma grade I-IV, and all patients underwent primary conventionally fractionated radiotherapy. For statistical analysis, SPSS Version 13.0 software was used. Thirty-eight of the 48 patients had a response to treatment, and ten patients had persistent disease at 3 months. Overall, the median serum HGF level was 1,219.5 pg/ml (range 650.4-2,264.7 pg/ml). Eight patients with local failure had HGF levels >1,219.5 pg/ml, and 28 patients with response had serum HGF level of ≤ 1,219.5 pg/ml (P = 0.01). The median time to progression was 6 months in patients with HGF level of >1,219.5 pg/ml compared with 17 months in patients with HGF level of ≤ 1,219.5 pg/ml (log-rank, P = 0.041). In multivariate analysis, serum HGF, the KPS, tumour size and pathological grade, but not the patient's age, gender and oligodendroglial component influenced the progression-free survival. Elevated pre-therapeutic serum HGF levels are associated with poor response and a shorter time to progression in patients with glioma undergoing primary radiotherapy.

Interleukin 4, interleukin 6 and osteopontin-serological markers of head and neck malignancy in primary diagnostics: A pilot study.

The progression of head and neck squamous cell carcinoma (HNSCC) is stimulated by various angiogenic peptides and growth factors. A correlation between tumor progression and the secretion of various serological mediators in patients with malignant tumors of the head and neck is of major interest for tumor diagnostics, evaluation of the therapy response and it may predict prognosis by specifying the individual tumor biology. Established chemotherapeutic regimes for head and neck tumors usually consist of platinum-based chemotherapeutic drugs and 5-fluorouracil (5-FU). The present pilot study sought to assess the eligibility of seven serological factors as biomarkers for malignant tumors of the head and neck: Platelet-derived growth factor, vascular endothelial growth factor, epidermal growth factor receptor, osteopontin, granulocyte-colony stimulating factor, interleukin-4 (IL-4) and IL-6. The serum levels of each factor in 20 patients receiving concomitant radiochemotherapy with cisplatin or carboplatin and 5-FU with curative intent were determined prior and subsequent to chemotherapy and were compared with 40 healthy controls. Another aim of the pilot study was to investigate whether the serum of patients showed significant differences in the concentrations of the analyzed factors at the start of concomitant radiochemotherapy compared with the controls, whether those markers indicated a neoplastic process and whether concomitant radiochemotherapy with cisplatin or carboplatin and 5-FU induced significant alterations of concentration compared with pre-therapeutic levels. The included patients were histopathologically diagnosed with HNSCC and the average age was 62.3 years. The serum samples of the patients were obtained during the course of regular pre- and post-chemotherapeutic blood draws one week prior to the start of radiochemotherapy and one week following the completion of chemotherapy. The healthy controls were collected from patients of the Sleep Laboratory of the Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital (Mannheim, Germany) without clinical evidence or laboratory signs of inflammation or history of a malignant disease. The average age was 50.3 years. The serological level of each factor was ascertained by enzyme-linked immunosorbent assay in duplicate. Serum levels of IL-4, IL-6 and osteopontin were significantly increased in patients with HNSCC compared with those in chemotherapy-naive healthy controls. IL-4 and osteopontin showed no significant therapy-associated alterations. Notably, IL-6 levels significantly increased post-therapeutically. Using logistic regression with osteopontin and IL-4, an individual risk-profile for random samples was calculated. IL-4, IL-6 and osteopontin appear to be suitable indicators of the neoplastic process as they are significantly increased in HNSCC patients compared with the control group. With the exception of IL-6, whose levels were in fact increased following therapy, a significant therapy-associated alteration of these factors was missing. Therefore, these serological markers failed to predict the therapy response, but they may be valuable as a screening instrument in primary diagnostics.

Prognostic significance of gamma-glutamyltransferase in patients with resectable esophageal squamous cell carcinoma.

Gamma-glutamyltransferase (GGT) is a membrane-bound enzyme involved in the glutathione metabolism. Studies suggested that GGT was a marker of apoptotic balance and modulated tumor progression, invasion and drug resistance. Recently, GGT was shown to be associated with the progression of high-grade esophageal epithelial dysplasia to invasive carcinoma. This study was conducted to investigate the value of pre-therapeutic serum GGT levels as prognostic parameter in esophageal squamous cell carcinoma. Six hundred thirty-nine resectable esophageal squamous cell carcinoma patients were recruited in this study and were stratified into two GGT risk groups. The association of pre-therapeutic serum GGT levels and clinical-pathological parameters was examined. Univariate and multivariate survival analyses were performed. GGT serum levels were associated with gender, smoking status, TNM stage and lymph node involvement. Higher pre-therapeutic serum GGT was found in males, smoker, advanced TNM stage and lymph node positive patients. Patients assigned to the low-risk group had higher 5-year overall survival rate (53.1% vs. 33.0%, P < 0.01) and disease-free survival rate (45.2% vs. 23.4%, P < 0.01) than the high-risk group. Patients with high-risk group of GGT had 1.568 (95% confidence interval [CI], 1.259 ∼ 1.952) times the risk of death and 1.582 (95% CI, 1.286 ∼ 1.946) times the risk of disease recurrence contrast with those with low-risk group of GGT. The pre-therapeutic serum GGT is a novel independent prognostic parameter for disease-free survival and overall survival in resectable esophageal squamous cell carcinoma.

Hemoglobin Level Influences Tumor Response and Survival After Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma

Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy confers a survival benefit on patients with esophageal cancer. However, nCRT might be less meaningful for poor responders. Thus, being able to predict responses would help ensure the selection of optimal therapy. We reviewed data from 123 patients with esophageal squamous cell carcinoma (ESCC) who underwent nCRT that comprised concurrent radiation (40 Gy) and chemotherapy followed by esophagectomy. We assessed associations between clinical and blood data obtained before starting nCRT and the pathologic response. We compared good (Japan Esophageal Society response evaluation criteria grades 3/2; n = 89, 72.4%) and poor (grades 1/0; n = 34, 27.6%) responders. Performance status (p = 0.02), hemoglobin level (p = 0.005), and platelet counts (p = 0.03) were statistically significant pretherapeutic factors for a response to nCRT. Multivariable analysis subsequently selected the hemoglobin level (odds ratio 1.52; 95% confidence interval 1.08-2.15; p = 0.02) as the sole independent predictor. Receiver operating characteristic curves showed that the optimal cutoff for pretherapeutic hemoglobin was 13 g/dl for predicting a response. We found that 48.8 and 17.1% of patients with hemoglobin level ≤13 and >13 g/dl, respectively, were poor responders (p = 0.0002), with 5-year overall survival rates of 40.9 and 58.9%, respectively (p = 0.048). Pretherapeutic hemoglobin levels can influence responses and survival after nCRT for ESCC. Thus, hemoglobin levels can serve as a useful marker for tailoring optimal therapies for individual patients with advanced ESCC.

Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial

BackgroundThe proliferation marker Ki67 has been suggested as a promising cancer biomarker. As Ki67 needs an exact quantification, this marker is a prototype of a new generation of tissue-based biomarkers. In this study, we have systematically evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort. Patients and methodsWe have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial. We used the standardized cutoff-finder algorithm for three end points [response to neoadjuvant chemotherapy (pCR), disease-free (DFS) and overall-survival (OS)]. The analyses were stratified for hormone receptor (HR) and HER2 status by molecular subtype radar diagrams (MSRDs). ResultsA wide range of Ki67 cut points between 3%–94% (for pCR), 6%–46% (for DFS) and 4%–58% (for OS) were significant. The three groups of Ki67 ≤ 15% versus 15.1%–35% versus >35% had pCR-rates of 4.2%, 12.8%, and 29.0% (P < 0.0005), this effect was also present in six of eight molecular subtypes. In MSRD, Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive, but not triple-negative tumors. ConclusionsKi67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data-derived cut point optimization might not be possible. Ki67 could be used as a continuous marker; in addition, the scientific community could define standardized cut points for Ki67. Our analysis explains the variability observed for Ki67 cut points in previous studies; however, this should not be seen as weakness, but as strength of this marker. MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer. The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers.

Association of gamma-glutamyltransferase with severity of disease at diagnosis and prognosis of ovarian cancer

Background:Gamma-glutamyltransferase (GGT) – a membrane-bound enzyme crucially involved in the cell's detoxification pathway and apoptotic balance – is involved in tumour development, progression and chemotherapy resistance. Elevated GGT serum levels are associated with increased cancer risk in women and worse prognosis in gynaecologic cancers. The present study investigated the prognostic role of GGT in ovarian cancer patients.Methods:In this multicenter study, pre-therapeutic GGT levels were ascertained in 634 consecutive patients with epithelial ovarian cancer (EOC, n=567) and borderline tumour of the ovary (BTO, n=67). Gamma-glutamyltransferase serum levels were associated with clinicopathological parameters and uni- and multivariate survival analyses were performed. Immunohistochemistry of GGT was performed in ovarian cancer tissue and correlated with GGT serum levels.Results:Pre-therapeutic GGT serum levels were higher in patients with EOC (28.56 (38.24) U l−1) than in patients with BTO (20.01 (12.78) U l−1, P=0.01). High GGT serum levels were associated with advanced FIGO stage (P<0.001) and with worse overall survival in univariate (P<0.001) and multivariable analysis (P=0.02, HR 1.2 (1.1–1.5)). We further investigated the association between systemic GGT serum levels and local GGT expression in EOC tumour tissue and observed an association between these two parameters (P=0.03).Conclusion:High pre-therapeutic GGT serum levels are associated with advanced tumour stage and serve as an independent prognostic marker for worse overall survival in patients with EOC. Gamma-glutamyltransferase expression in ovarian cancer tissue is reflected in GGT serum levels.

P-0204 - Cytokeratins in Predicting Therapy Response and Prognosis of Colorectal Cancer Patients

Methods:We analyzed the courses of CYFRA 21-1, TPA, TPS, M30, CEA and CA 19-9 in prospectively collected sera of 30 patients with colorectal cancer during adjuvant (N = 15) and primary (N = 15) chemotherapy and correlated the marker levels with therapy response after two months and overall survival (OS). In addition we investigated pretherapeutic serum levels of CYFRA 21-1, M30, CEA and CA 19-9 in 42 CRC patients, 45 with benign colorectal diseases and 51 healthy controls.

Circulating nucleosomes and immunogenic cell death markers HMGB1, sRAGE and DNAse in patients with advanced pancreatic cancer undergoing chemotherapy

Serum biomarkers are urgently needed for patient stratification and efficient treatment monitoring in pancreatic cancer (PC). Within a prospective diagnostic observation study, blood samples were obtained from 78 patients with advanced PC before and weekly during the course of palliative chemotherapy. Circulating nucleosomes and immunogenic cell death markers, high-mobility group box 1 (HMGB1), soluble receptors of advanced glycation end products (sRAGE) and DNAse activity, were measured by enzyme-linked immunosorbent assay and correlated with results of radiological staging after 2 months of treatment, with time to progression (TTP) and overall survival (OS). Median TTP and OS of PC patients were 3.9 and 7.7 months, respectively. Pretherapeutic baseline biomarker levels did not correlate with objective response; however, nucleosome levels on day (d) 28 were higher (p = 0.048) and sRAGE levels at time of staging (d56) were lower in progressive patients (p = 0.046). Concerning estimation of prognosis, high nucleosome levels (d7, d14, d21 and d56), low sRAGE levels (d56) and DNAse activity courses (d0-d7) correlated with TTP, whereas high nucleosomes (d7, d14 and d56), high HMGB1 (d21 and d56) and DNAse (d0-d7) were associated with OS. After adjustment to Karnofsky performance score, nucleosomes and HMGB1 (both d56) and DNAse (d0-d7) remained independent prognostic factors. Thus, courses of circulating nucleosomes and immunogenic cell death markers HMGB1 and sRAGE show prognostic relevance in PC patients undergoing chemotherapy.

Pretherapeutic Plasma Pro- and Anti- Inflammatory Mediators Are Related to High Risk of Oral Mucositis in Pediatric Patients with Acute Leukemia: A Prospective Cohort Study

ObjectiveThis prospective study evaluated clinical risk indicators as well as pro- and anti- inflammatory mediators at the time of malignancy diagnosis in relation to chemotherapy-related oral mucositis in pediatric population.MethodsPatients (n = 104) under 18 years of age with primary malignancies and undergoing chemotherapy were included. Potential risk indicators were analyzed using binary logistic regression with oral mucositis as the outcome. In a subgroup (n = 35), plasma samples at the time of malignancy diagnosis were analyzed for inflammatory cytokines and an antimicrobial protein pro-LL-37 (hCAP18).ResultsIn the multivariable model, type of malignancy diagnosis was significantly associated with oral mucositis, with highest risk of oral mucositis in patients with acute leukemia compared to those with lymphoma or solid tumors. At the time of malignancy diagnosis, plasma from patients with acute leukemia displayed higher concentrations (P<0.05) of IL-6, IL-8, IL-10, and TNF-α and lower levels of pro-LL-37 (P<0.001).ConclusionsThe results imply that pretherapeutic high levels of inflammatory cytokines and low levels of pro-LL-37 in plasma might contribute to the high incidence of oral mucositis in patients with acute leukemia. These findings may add to our understanding of the predispositions to oral mucositis in children with malignancies.

The role of gamma-glutamyltransferase in malignant transformation and prognosis of ovarian cancer.

e16524 Background: Gamma-glutamyltransferase (GGT) – a membrane bound enzyme crucially involved in the cell’s detoxification pathway and apoptotic balance – is involved in tumor development, progression and chemotherapy resistance. Elevated GGT serum levels are associated with increased cancer risk in women and worse prognosis in gynecologic cancers. The present study investigated the prognostic role of GGT in ovarian cancer patients. Methods: In this multi-center study, pre-therapeutic GGT levels were ascertained in 634 consecutive patients with epithelial ovarian cancer (EOC, n = 567) and borderline tumor of the ovary (BTO, n = 67). GGT serum levels were associated with clinico-pathological parameters and uni- and multivariate survival analyses were performed.Immunohistochemistry of GGT was performed in ovarian cancer tissue and correlated with GGT serum levels. Results: Pre-therapeutic GGT serum levels were higher in patients with EOC (28.56 [38.24] U/L) than in patients with BTO (20.01 [12.78] U/L, p = 0.01). High GGT serum levels were associated with advanced FIGO stage (p&lt;0.001) and with worse overall survival in univariate (p &lt; 0.001) and multivariable analysis (p=0.02, HR 1.2 [1.1-1.5]). We further investigated the association between systemic GGT serum levels and local GGT expression in EOC tumor tissue and observed an association between these two parameters (p = 0.03). Conclusions: High pre-therapeutic GGT serum levels are associated with advanced tumor stage and serve as an independent prognostic marker for worse overall survival in patients with EOC. GGT expression in ovarian cancer tissue is reflected in GGT serum levels.

Prediction of response to neoadjuvant chemotherapy in breast cancer patients by circulating apoptotic biomarkers nucleosomes, DNAse, cytokeratin-18 fragments and survivin

Biomarkers predicting response to neoadjuvant chemotherapy in locally confined breast cancer (LBC) are highly needed. We prospectively assessed serial blood levels of apoptotic biomarkers nucleosomes, DNAse activity, cytokeratin-18 fragments (M30) and survivin in 51 LBC patients and correlated them with response to neoadjuvant treatment and established tumor markers. As controls, we used 31 healthy subjects, 13 patients with benign diseases and 28 with metastatic breast cancer (MBC). Levels of nucleosomes and survivin were elevated in LBC and MBC while M30, CEA and CA 15-3 levels were only elevated in MBC. During neoadjuvant chemotherapy, LBC patients with no change of disease (N=13) had significantly higher pretherapeutic levels of nucleosomes than patients with remission (N=38). We conclude that apoptotic biomarkers bear valuable information for diagnosis and therapy response prediction in LBC patients.

Abstract 166: Elevated levels of serum fatty acid synthase (FAS) in patients with gastric carcinoma.

Abstract Aim: Gastric cancer is the second leading cause of cancer mortality in the world. In East Asia especially, in countries such as China, Japan, and Korea, more than one million new cases are diagnosed each year. The need remains for biomarkers to detect early stage gastric cancer. Fatty acid synthase (FAS) is highly expressed in many human cancers, but the potential utility of measuring FAS for detection of gastric cancer has not been previously investigated. The aim of this study was to provide a preliminary assessment of serum FAS as a marker of gastric carcinoma. Materials and methods: Our study included 47 patients with gastric cancer (37 men and 10 women, aged 33-89 years) and 150 healthy subjects (113 men and 37 women, aged 33-83 years). Serum FAS levels were measured by ELISA and compared across the two groups of patients. Blood samples were collected from each cancer patient before treatment, and additionally, post-therapeutic samples were obtained from eleven of the patients with gastric cancer. Measurement data were analyzed using the Mann-Whitney test. P&amp;lt;0.05 was considered statistically significant. The receiver operator characteristic (ROC) curve was used to determine sensitivity and specificity values. Results: We found significantly higher levels of serum FAS in gastric cancer patients (95% confidence interval, 95% CI=30.37-52.46) than in healthy controls (95% CI=1.331-2.131), with elevated levels even in patients with early stage tumors. Using 5.5 ng/ml as the cut-off value, the sum of sensitivity (95.74%) and specificity (91.33%) was the highest, and the positive predictive values and negative predictive values were 77.59% and 98.56%, respectively (Area Under the Curve=0.9845, Standard Error=0.0084, 95% CI=0.9681-1.001). The pre-therapeutic FAS levels were greater than 5.5 ng/ml, and in 8 of 11 patients, the post- therapeutic serum FAS levels decreased to less than 5.5 ng/ml. Conclusion: Our results suggest that measuring serum FAS levels has strong potential to provide a biomarker for detection of gastric cancer with high sensitivity and high specificity. Citation Format: Tomoaki Ito, Koichi Sato, Hiroshi Maekawa, Takashi Tada, Mutsumi Sakurada, Hajime Orita, Kazunori Shimada, Ryo Wada, Masaaki Abe, Okio Hino, Yoshiaki Kajiyama. Elevated levels of serum fatty acid synthase (FAS) in patients with gastric carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 166. doi:10.1158/1538-7445.AM2013-166

Systemic therapy with bevacizumab in patients with hereditary hemorrhagic telangiectasia (HHT)

Frequent epistaxis, the hallmark of hereditary hemorrhagic telangiectasia (HHT) significantly affects quality of life. Hepatic involvement may be associated with capsular pain, abdominal angina, high-output cardiac failure and portal hypertension with ascites and variceal bleeding. Liver transplantation as well as hepatic artery embolization as invasive treatment options for hepatic involvement are both associated with a certain morbidity and mortality. Three patients with HHT and symptomatic hepatic involvement prospectively underwent off-label systemic treatment with the vascular endothelial growth factor (VEGF)-inhibitor bevacizumab in 6 cycles. Clinical symptoms and cardiac output were assessed before as well as 3 months after therapy. At 3 months follow-up, capsular pain and abdominal angina were significantly reduced in two of the three patients (Numerical Rating Scale (NRS) grade 4 and 5 changed to grade 2). Cardiac output, which was initially raised in both patients, normalized and was associated with an improvement in the signs and symptoms of cardiac insufficiency by one stage according to the NYHA classification in both patients. Symptoms however returned back gradually to pre-therapeutic levels after 9 months in one of these two patients. In the third patient with a normal cardiac status prior to therapy, a marked subjective improvement in the performance status, fatigability and quality of life was noted. Grade 2 nasal bleeding reduced to grade 0 - 1 in all three patients; this clinical improvement was persistent at 3, 7 and 9 months follow-up. No significant lasting complications were observed. Sytemic bevacizumab therapy could become an important therapy option in the non-invasive medical treatment of patients with HHT. Further studies to document long-term results, to determine the appropriate drug dosage as well as to evaluate the necessity of a maintenance drug regime are warranted.

Abstract S4-5: Ki67 levels in pretherapeutic core biopsies as predictive and prognostic parameters in the neoadjuvant GeparTrio trial

Abstract Background: Ki67 has been suggested as a marker for definition of luminal A and luminal B tumors by the 2011 St. Gallen consensus panel. However, the cutoffs for Ki67 are still under debate. In particular, it is not clear if one single cutoff is useful for prognostic and predictive information in the different molecular subtypes. It is an advantage of the neoadjuvant approach that predictive and prognostic outcome measurements can be separated in the same cohort. In this study, we evaluated a large cohort of core biopsies from the neoadjuvant GeparTrio trial to investigate the impact of pretherapeutic Ki67 levels as a predictive marker for response to neoadjuvant chemotherapy as well as a prognostic marker for progression-free and overall survival. The analysis was stratified for hormone-receptor positive and negative tumors as well as HER2 status. Methods: A total of 1166 pretherapeutic core biopsies from the neoadjuvant Gepartrio trial were evaluated for Ki67 by immunohistochemistry, a total of 200 cells were counted in each sample. Ki67 cutoffs were evaluated using web-based software Cutoff Finder (http://molpath.charite.de/cutoff/). The details of the GeparTrio study design have been described before (von Minckwitz, JNCI 2008). We compared pCR rate as well as the overall and disease free survival in the complete cohort as well as subgroups of patients based on hormone receptor and HER2 expression. Results: Using Ki67 as a continuous parameter, a wide range of cutoffs between 10% and 80% for Ki67 were predictive for pCR. For DFS and OS, a wide range of cutoffs between 10% and 45% was significant. For further analysis, the three groups of Ki67 0–15% vs. Ki67 15.1%–35% vs. Ki67 &amp;gt;35 were defined and were compared for different outcome parameters. The pCR rates in these three groups of Ki67 expression were 4.2%, 12.9% and 29.0% (p &amp;lt; 0.0005). For DFS and OS, the groups were significantly linked to prognosis in univariate and multivariate analysis. A detailed subgroup analysis was performed showing that Ki67 was significantly predictive for pCR in all molecular subgroups. However, in subgroup survival analysis, Ki67 was prognostic in luminal, but not in triple-negative tumors. Conclusion: Ki67 is a valid predictive and prognostic marker in breast cancer. This marker is significant over a wide range of different cutoffs, which explains the different results of Ki67 cutoffs in different previous studies. Therefore, the variability observed in different studies evaluating Ki67 might reflect A) the wide range of valid cutoffs B) the different clinical endpoints of the studies and C) the different contribution of the molecular subtypes in the study cohorts. Based on our results we suggest three subgroups for Ki67 (0–15% vs. 15.1–35 vs. &amp;gt;35%) as a reasonable approach for further standardization of this marker. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S4-5.

Pretherapeutic laboratory findings, extent of metastasis and choice of treatment as prognostic markers in ocular melanoma– a single centre experience

Uveal melanoma is the most common intraocular neoplasm with a high tendency to metastasize predominantly to the liver. Prognostic parameters for progression and overall survival are not well defined. The aim of this study was to assess the value of pretherapeutic serum levels of C-reactive protein (CRP), lactate dehydrogenase, albumin and fibrinogen in patients with uveal melanoma and to evaluate their significance as prognostic parameters for survival. Forty-nine patients with metastatic uveal melanoma treated between 2000 and 2010 were retrospectively analysed. The potential influence of levels of CRP, lactate dehydrogenase, fibrinogen and albumin as well as other commonly known prognostic variables on progression-free and overall survival were investigated. Patients' age and treatment with systemic chemotherapy were the only variables to show significant influences on progression-free and overall survival in a univariate analysis. Multivariate analysis confirmed the influence of these variables on progression-free survival, presence of metastasis, pretherapeutic CRP levels and treatment with systemic chemotherapy were associated with overall survival. In this patient cohort elevated pretherapeutic CRP and extent of metastasis are independent prognostic factors for decreased overall survival, whereas treatment with systemic chemotherapy showed a significant association with improved overall survival.

Circulating immunogenic cell death biomarkers HMGB1 and RAGE in breast cancer patients during neoadjuvant chemotherapy

Neoadjuvant chemotherapy in breast cancer patients aims at preoperative reduction of tumor volume for better resection results and prognosis. As not all patients respond to neoadjuvant therapy, predictive biomarkers are needed for more efficient individual management. In prospectively collected sera of 51 consecutive locally confined breast cancer (LBC) patients receiving preoperative, neoadjuvant chemotherapy, value level kinetics of soluble high mobility group box 1 (HMGB1), soluble receptor for advanced glycation end products (sRAGE) as well as the established breast cancer biomarkers CA 15-3 and carcinoembryonic antigen (CEA) were investigated and correlated with therapy response objectified by pathological staging at surgery. In addition, biomarkers were measured in sera of 30 healthy controls (HC), 13 patients with benign breast diseases, and 28 metastatic breast cancer (MBC) patients. Pretherapeutic levels of soluble HMGB1 were decreased in MBC, while sRAGE was already decreased in LBC. In contrast, CA 15-3 and CEA were strongly elevated in MBC, but not in LBC. Combination of sRAGE and CA 15-3 enabled best discrimination of LBC from HC (AUC 78.2%; sens 58% at 95% spec), while CA15-3 and CEA discriminated best between MBC and all controls (AUC 90.9%; sens 70% at 95% spec). In LBC patients undergoing neoadjuvant chemotherapy, nine patients achieved complete remission (CR), 29 achieved partial remission (PR), while 13 had no change of disease (NC). NC patients tended to have higher HMGB1 and lower sRAGE levels before therapy onset (p = 0.056 and p = 0.054), while CA 15-3 and CEA did not predict therapeutic outcome. Furthermore, kinetics of HMGB1 during therapy correlated with efficacy of the treatment (p = 0.053). Markers of immunogenic cell death are valuable for the diagnosis of MBC and early estimation of response to neoadjuvant therapy in LBC patients.

600P - Bifractionated CPT-11 with LV5FU2 Infusion (FOLFIRI-3) In Combination with Bevacizumab Followed by a Capecitabine and Bevacizumab Maintenance Therapy: A Phase II Study in First-Line Metastatic Colorectal Cancers

ABSTRACT Background Bevacizumab (Bev) with FOLFIRI or FOLFOX regimen is a standard of care in first-line metastatic colorectal cancers (mCRC). As second-line regimen after FOLFOX, FOLFIRI-3 has shown a significantly better PFS in comparison with other irinotecan-based regimen. We therefore evaluated the safety, efficacy and possible predictive factors for FOLFIRI-3 in combination with Bev as initial treatment for mCRC. Since fully validated biomarkers in mCRC are still lacking, we decided to assess the prognostic value of Angiopoietin-2 (Ang-2). Patients and methods We conducted a three-institution phase II trial of FOLFIRI-3 regimen (irinotecan 100mg/m2 before and after a 46-hour continuous infusion of fluorouracil (2400 mg/m2) with Bev (5mg/kg day 1) repeated every 2 weeks, as first-line treatment in mCRC. Induction treatment (FOLFIRI-3 and Bev) was administrated for 6 months, followed by a maintenance treatment including Bev (7.5 mg/kg day 1) and capecitabine (1000 mg/m2 day 1 to 14), repeated every 3 weeks. Plasma VEGF and serum Ang-2 were measured at baseline. The primary endpoint was ORR. Secondary endpoints were PFS, OS, and biologic analysis of potential predictive factors of response to treatment. Results 61 patients were enrolled for treatment. The ORR was 66.7% (95% CI, 55-79). SD in 25% of patients (DCR of 91.7%). PFS was 12 months (95% CI, 9-16) and OS was 33 months (95% CI, 19-44). A total of 41 patients entered the maintenance phase of the study. Bev/capecitabine maintenance therapy appeared as an appropriate and well-tolerated option. High pre-therapeutic serum Ang-2 level was identified as a potential biomarker correlated to worse outcomes in this cohort (median progression free survival of 14.7 months vs. 7.3 months, p Conclusions As front-line regimen in mCRC, FOLFIRI-3/Bev regimen, followed by a capecitabine-based maintenance therapy, is effective and might be considered for future development particularly in patients treated by oxaliplatin in the adjuvant setting. Serum angiopoietin 2 is a promising biomarker to predict PFS and OS in mCRC patients treated with chemotherapy and bevacizumab. External validation is in course. Disclosure All authors have declared no conflicts of interest.