Biomarkers For Prediction Of Outcomes Research Articles

Immune-related gene expression signatures as predictive biomarkers for outcome after concurrent chemoradiation in patients with locally advanced oropharyngeal carcinomas.

6056Background: Immune-related gene expression signatures as candidate predictive biomarkers for cisplatin (CDDP)- and mitomycin C (MMC)-based chemoradiation (CRTX) were established in oropharyngea...

Role of signal peptide-Cub-Egf domain-containing protein-1 in serum as a predictive biomarker of outcome after severe traumatic brain injury

BackgroundSignal peptide-Cub-Epidermal growth factor domain-containing protein 1 (SCUBE1), a marker for coagulation, is secreted under hypoxia and inflammatory conditions from platelet α granules. This study was designed to determine the associations of serum SCUBE1 concentrations with trauma severity and prognosis after severe traumatic brain injury. MethodsSerum SCUBE1 concentrations of 113 patients and 113 controls were measured. An unfavorable outcome was defined as Glasgow Outcome Scale score of 1–3. ResultsSerum SCUBE1 concentrations were significantly higher in patients than in controls (15.5±6.0 vs. 1.1±0.3ng/ml, P<0.001) and were associated with Glasgow coma scale scores (r=−0.439, P<0.001) and blood platelet count (r=0.420, P<0.001). SCUBE1 was identified as an independent prognostic marker of 6-month unfavorable outcome (odds ratio, 1.357; 95% confidence interval, 1.159–1.589; P<0.001), and had high predictive value according to receiver operating characteristic curve (area under curve, 0.830; 95% confidence interval, 0.748–0.890; P<0.001). ConclusionsIncreased serum SCUBE1 concentrations are associated highly with trauma severity, platelet activation and poor outcome, suggesting that SCUBE1 might be a novel prognostic biomarker after traumatic brain injury.

Association of Nuclear PIM1 Expression with Lymph Node Metastasis and Poor Prognosis in Patients with Lung Adenocarcinoma and Squamous Cell Carcinoma.

Increasing evidence indicates that aberrant expression of PIM1, p-STAT3 and c-MYC is involved in the pathogenesis of various solid tumors, but its prognostic value is still unclear in non-small cell lung cancer (NSCLC). Here, we sought to evaluate the expression and prognostic role of these markers in patients with lung adenocarcinoma (AD) and squamous cell carcinoma (SCC). Real time RT-PCR and Western blotting was used to analyze the mRNA and protein expression of PIM1 in NSCLC cell lines, respectively. The expression of PIM1, p-STAT3, and c-MYC was immunohistochemically tested in archival tumor samples from 194 lung AD and SCC patients. High nuclear PIM1 expression was detected in 43.3% of ADs and SCCs, and was significantly correlated with lymph node (LN) metastasis (P = 0.028) and histology (P = 0.003). High nuclear PIM1 expression (P = 0.034), locally advanced stage (P < 0.001), AD (P = 0.007) and poor pathologic differentiation (P = 0.002) were correlated with worse disease-free survival (DFS). High nuclear PIM1 expression (P = 0.009), advanced clinical stage (P < 0.001) and poor pathologic differentiation (P = 0.004) were independent unfavorable prognostic factors for overall survival (OS). High p-STAT3 expression was not associated with OS but significantly correlated with LN metastasis, while c-MYC was not significantly correlated with any clinicopathological parameter or survival. Therefore, in AD and SCC patients, nuclear PIM1 expression level is an independent factor for DFS and OS and it might serve as a predictive biomarker for outcome.

Urine marker to the rescue

Renal and urinary EGF are biomarkers for prediction of outcomes in chronic kidney disease.

Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker.

Chronic kidney disease (CKD) affects 8 to 16% people worldwide, with an increasing incidence and prevalence of end-stage kidney disease (ESKD). The effective management of CKD is confounded by the inability to identify patients at high risk of progression while in early stages of CKD. To address this challenge, a renal biopsy transcriptome-driven approach was applied to develop noninvasive prognostic biomarkers for CKD progression. Expression of intrarenal transcripts was correlated with the baseline estimated glomerular filtration rate (eGFR) in 261 patients. Proteins encoded by eGFR-associated transcripts were tested in urine for association with renal tissue injury and baseline eGFR. The ability to predict CKD progression, defined as the composite of ESKD or 40% reduction of baseline eGFR, was then determined in three independent CKD cohorts. A panel of intrarenal transcripts, including epidermal growth factor (EGF), a tubule-specific protein critical for cell differentiation and regeneration, predicted eGFR. The amount of EGF protein in urine (uEGF) showed significant correlation (P < 0.001) with intrarenal EGF mRNA, interstitial fibrosis/tubular atrophy, eGFR, and rate of eGFR loss. Prediction of the composite renal end point by age, gender, eGFR, and albuminuria was significantly (P < 0.001) improved by addition of uEGF, with an increase of the C-statistic from 0.75 to 0.87. Outcome predictions were replicated in two independent CKD cohorts. Our approach identified uEGF as an independent risk predictor of CKD progression. Addition of uEGF to standard clinical parameters improved the prediction of disease events in diverse CKD populations with a wide spectrum of causes and stages.

Androgen receptor profiling predicts prostate cancer outcome.

Prostate cancer is the second most prevalent malignancy in men. Biomarkers for outcome prediction are urgently needed, so that high-risk patients could be monitored more closely postoperatively. To identify prognostic markers and to determine causal players in prostate cancer progression, we assessed changes in chromatin state during tumor development and progression. Based on this, we assessed genomewide androgen receptor/chromatin binding and identified a distinct androgen receptor/chromatin binding profile between primary prostate cancers and tumors with an acquired resistance to therapy. These differential androgen receptor/chromatin interactions dictated expression of a distinct gene signature with strong prognostic potential. Further refinement of the signature provided us with a concise list of nine genes that hallmark prostate cancer outcome in multiple independent validation series. In this report, we identified a novel gene expression signature for prostate cancer outcome through generation of multilevel genomic data on chromatin accessibility and transcriptional regulation and integration with publically available transcriptomic and clinical datastreams. By combining existing technologies, we propose a novel pipeline for biomarker discovery that is easily implementable in other fields of oncology.

Abstract 3994: Herpes virus microRNA expression and significance in serous ovarian cancer

Abstract Serous ovarian cancer (SEOC) is the deadliest gynecologic malignancy. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate gene expression and protein translation. MiRNAs are also encoded by viruses with the intent of regulating their own genes and those of the infected cells. This is the first study assessing viral miRNAs in SEOC. MiRNAs sequencing data from 487 SEOC patients were downloaded from the TCGA website and analyzed through in-house sequencing pipeline. To cross-validate TCGA analysis, we measured the expression of miR-H25 by quantitative immunofluorescence in an additional cohort of 161 SEOC patients. Gene, miRNA expression, and cytotoxicity assay were performed on multiple ovarian cancer cell lines transfected with miR-H25 and miR-BART7. Outcome analysis was performed using multivariate Cox and Kaplan-Meier method. Viral miRNAs are more expressed in SEOC than in normal tissues. Moreover, Herpetic viral miRNAs (miR-BART7 from EBV and miR-H25 from HSV-2) are significant and predictive biomarkers of outcome in multivariate Cox analysis. MiR-BART7 correlates with resistance to first line chemotherapy and early death, whereas miR-H25 appears to impart a protective effect and long term survival. Integrated analysis of gene and viral miRNAs expression suggests that miR-BART7 induces directly cisplatin-resistance, while miR-H25 alters RNA processing and affects the expression of noxious human miRNAs such as miR-143. This is the first investigation linking viral miRNA expression to ovarian cancer outcome. Viral miRNAs can be useful to develop biomarkers for early diagnosis and as a potential therapeutic tool to reduce SEOC lethality. Citation Format: Deep Pandya, Marisa Mariani, Mark McHugh, Mirko Andreoli, Steven Sieber, Shiquan He, Candice Dowell-Martino, Paul Fiedler, Giovanni Scambia, Cristiano Ferlini. Herpes virus microRNA expression and significance in serous ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3994. doi:10.1158/1538-7445.AM2015-3994

Herpes virus microRNA expression and significance in serous ovarian cancer.

Serous ovarian cancer (SEOC) is the deadliest gynecologic malignancy. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate gene expression and protein translation. MiRNAs are also encoded by viruses with the intent of regulating their own genes and those of the infected cells. This is the first study assessing viral miRNAs in SEOC. MiRNAs sequencing data from 487 SEOC patients were downloaded from the TCGA website and analyzed through in-house sequencing pipeline. To cross-validate TCGA analysis, we measured the expression of miR-H25 by quantitative immunofluorescence in an additional cohort of 161 SEOC patients. Gene, miRNA expression, and cytotoxicity assay were performed on multiple ovarian cancer cell lines transfected with miR-H25 and miR-BART7. Outcome analysis was performed using multivariate Cox and Kaplan-Meier method. Viral miRNAs are more expressed in SEOC than in normal tissues. Moreover, Herpetic viral miRNAs (miR-BART7 from EBV and miR-H25 from HSV-2) are significant and predictive biomarkers of outcome in multivariate Cox analysis. MiR-BART7 correlates with resistance to first line chemotherapy and early death, whereas miR-H25 appears to impart a protective effect and long term survival. Integrated analysis of gene and viral miRNAs expression suggests that miR-BART7 induces directly cisplatin-resistance, while miR-H25 alters RNA processing and affects the expression of noxious human miRNAs such as miR-143. This is the first investigation linking viral miRNA expression to ovarian cancer outcome. Viral miRNAs can be useful to develop biomarkers for early diagnosis and as a potential therapeutic tool to reduce SEOC lethality.

Serum uric acid as a biomarker for prediction of outcomes of patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease

Serum uric acid, the final product of purine degradation, has been shown to be increased in the hypoxic state as well as in systemic inflammation including patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the possible role of serum uric acid as a biomarker for the prediction of outcome of patients hospitalized for acute exacerbation of COPD (AECOPD). Serum uric acid levels were measured in 115 eligible AECOPD patients on admission. The primary end-point was all-cause mortality at 30 days. The secondary outcomes included the length of hospital stay, need for noninvasive ventilation, or ICU admission within 30 days. Serum uric acid presented an area under the receiver operating characteristic curve of 0.721 (95% confidence interval: 0.63–0.80) for the prediction of 30-day mortality in patients with AECOPD, with a sensitivity of 0.82 and a specificity of 0.61 for the cutoff point greater than 6.9 mg/dl (P = 0.021). Also, patients with higher serum uric acid levels required longer hospitalization and more often required the use of noninvasive ventilation and ICU admission at 30 days. In addition, serum uric acid levels were higher in patients with more severe airflow limitation, patients with cardiovascular comorbidity, and among frequent exacerbators. High serum uric acid levels on admission were associated with increased 30-day mortality in patients with AECOPD. The results of this work suggest a possible role for serum uric acid in the identification of COPD patients at an increased risk of adverse outcomes who may need early intensive management. Egypt J Broncho 2014 8:115–120

Abstract 19792: Prediction of Right Ventricular Failure After Cardiac Transplantation : A Recipient Transcriptomic Study

Introduction: Right ventricle failure (RVF) is a frequent and severe complication after cardiac transplantation. However, risk stratification for RVF is poorly achieved. Development of transcriptomic biomarkers for outcome prediction in cardio-vascular diseases is promising. Hypothesis: Our aim was to identify right ventricular gene expression signature associated to RVF and to define a transcriptomic biomarker that could predict post-transplantation RVF. Methods: Recipient RV myocardial samples of 44 patients transplanted from February 1998 to November 2002 in our center were collected. We retrospectively identified patients with (RVF group) and without (CTL group) post-transplantation RVF. A 4035-gene expression profile was obtained for all patients. Differentially expressed genes between RVF and CTL groups were identified and a molecular RVF predictor was used to determine for each patient a RVF prediction score (RVFs). Results: 9 (20%) and 18 (41%) patients were classified in RVF and CTL groups respectively. As compared to CTL group, RVF patients showed higher pre-operative bilirubin level and higher post-operative death rate. Molecular RVF predictor included 75 differentially expressed genes. Using this predictor, risk for post-transplantation RVF was 2.8-fold greater if RVFs was &gt;0.5 (CI 95%: 1.243-6.305). Sensitivity and specificity of RVFs were 0.778 and 0.889, respectively. Using receiver operating characteristic analysis, RVFs area under curve (AUC) was significantly greater than AUC of commonly used RVF predictors (pulmonary vascular resistance, trans-pulmonary gradient). Conclusions: Gene expression profiling of recipient right ventricle could be used to predict post-transplantation RVF. Transcriptomic biomarkers should be further investigated as a new tool for selection of cardiac transplant candidates.

Abstract 329: Six at Six: Interleukin-6 Measured at 6 Hours After Cardiac Arrest Is a Good Predictive Biomarker of Outcome of Post--Cardiac Arrest Syndrome in Humans

Introduction: As early as 3h after cardiac arrest (CA), the blood level of various cytokines increases and may be associated with outcome of post cardiac arrest syndrome (PCAS). However, it remains uncertain whether blood levels of these cytokines including IL-6 have significance as predictors of outcome following cardiac arrest. Objective: To demonstrate any association between circulating IL-6 level, one of major pro-inflammatory cytokines, and mortality in PCAS of humans. Methods: This was a multicenter observational study conducted between 2006-09 in Chiba, Japan, involving non-trauma CA adult patients. All patients admitted to acute care units were included. Patient characteristics were extracted following an Utstein template. The primary outcome was mortality through the end of the study. IL-6 blood levels were measured on admission, at 6hr, and 24hr after CA. Patients were classified into three groups (high, middle, and low) according to IL-6 levels at each time point. We evaluated the association of IL-6 levels with survival using the Kaplan-Meier method. A Cox proportional hazard model with a step-wise selection procedure was used to identify independent variables associated with overall survival. Results: A total of 227 patients were included in this study. Survival time in “High IL-6” group was shorter than “Low” group. There were significant differences in blood level of IL-6 in the three groups, high (&gt;811pg/mL), mid (811-93pg/mL), and low (&lt;93pg/mL), only at 6hr (long rank; high vs. low p&lt;0.001, high vs. mid p=0.07, and mid vs. low p=0.001 on admission; p&lt;0.001, p&lt;0.001, and p&lt;0.001 at 6hr, respectively; p&lt;0.001, p&lt;0.001, and p=0.936 at 24hr, respectively). Three factors were identified as independent predictors of early death; no bystander CPR (hazard ratio [95% confidential interval], 2.59 [1.10-6.10], p=0.03), a lack of therapeutic hypothermia (2.68 [1.70-4.22], p&lt;0.001), and IL-6 levels at 6hr (high, reference; mid, 0.41 [0.25-0.66], p&lt;0.001; low, 0.11 [0.06-0.20], p&lt;0.001). Conclusions: IL-6 measured at 6hr can predict mortality. It should be studied further to see if it can help direct therapeutic decision-making and whether it can define optimal populations for study in clinical trials.

Prognostic value of C-reactive protein in esophageal cancer: a meta-analysis.

The classical inflammatory biomarker, C-reactive protein (CRP), has been identified to be related to progression of esophageal cancer. Some research showed that elevated pretreatment serum CRP indicated a poor prognosis, but results have been inconsistent. We searched the Medline, Embase and the Cochrane Central Search Library for suitable studies and a meta-analysis of eleven (1,886 patients) was conducted to examine the relationship between elevated serum CRP level and overall survival (OS) in esophageal cancer cases. Moreover, correlation analyses were conducted to assess links between pretreatment serum CRP level and tumor node metastasis (TNM) stage as well as T, N, M grade, respectively. The pooled analysis showed that elevated pretreatment serum CRP level was significantly associated with poorer overall survival (HR 2.09, 95%CI 1.52-2.87, p<0.01). Subgroup analyses were conducted by "country", "cut-off value", "treatment" and "number of patients", and no single factor could alter the result. Elevated pretreatment serum CRP was significantly correlated with more advanced TNM stage and T, N, M grade respectively. Elevated pretreatment serum CRP levels are associated with poorer prognosis in esophageal cancer patients, and could serve as a useful biomarker for outcome prediction.

Blood- and tissue-based biomarkers for prediction of outcomes in urothelial carcinoma of the bladder

ObjectivesUrothelial carcinoma of the bladder (UCB) is a highly heterogeneous malignancy that causes significant morbidity and mortality. Standard pathologic features (stage, grade, and nodal status) are insufficient to predict accurately a patient's outcome. Biomarkers could help clinicians provide individualized prognostications and allow risk-stratified clinical decision making regarding surgical and medical treatment. This review summarizes the existing tissue- and blood-based biomarkers in UCB. Material and methodsA PubMed/Medline search was conducted to identify original articles regarding molecular biomarkers and UCB. Searches were limited to papers published in English. Keywords included urothelial carcinoma, bladder cancer, transitional cell, biomarker, marker, staining, cystectomy, recurrence or progression, survival, prediction, and prognosis. ResultsThe articles with the highest level of evidence were selected and reviewed, with the consensus of all the authors of this paper. ConclusionsThere is no doubt that a panel of biomarkers would eventually improve our clinical decision making regarding treatment and follow-up. However, to date, no biomarker panel is yet validated for daily clinical practice.

Serial Plasma Choline Measurements after Cardiac Arrest in Patients Undergoing Mild Therapeutic Hypothermia: A Prospective Observational Pilot Trial

ObjectiveCholine is related to phospholipid metabolism and is a marker for global ischaemia with a small reference range in healthy volunteers. The aim of our study was to characterize the early kinetics of plasma free choline in patients after cardiac arrest. Additionally, we investigated the potential of plasma free choline to predict neurological outcome.MethodsTwenty patients admitted to our medical intensive care unit were included in this prospective, observational trial. All patients were enrolled between May 2010 and May 2011. They received post cardiac arrest treatment including mild therapeutic hypothermia which was initiated with a combination of cold fluid and a feedback surface cooling device according to current guidelines. Sixteen blood samples per patient were analysed for plasma free choline levels within the first week after resuscitation. Choline was detected by liquid chromatography-tandem mass spectrometry.ResultsMost patients showed elevated choline levels on admission (median 14.8 µmol/L; interquartile range; IQR 9.9-20.1) which subsequently decreased. 48 hours after cardiac arrest choline levels in all patients reached subnormal levels at a median of 4.0 µmol/L (IQR 3-4.9; p = 0.001). Subsequently, choline levels normalized within seven days. There was no significant difference in choline levels when groups were analyzed in relation to neurological outcome.ConclusionsOur data indicate a choline deficiency in the early postresucitation phase. This could potentially result in impaired cell membrane recovery. The detailed characterization of the early choline time course may aid in planning of choline supplementation trials. In a limited number of patients, choline was not promising as a biomarker for outcome prediction.

Interferon-gamma in ascites could be a predictive biomarker of outcome in ovarian carcinoma

ObjectiveThe ovarian cancer-associated ascites is an ideal material for evaluating the interaction between the host immune system and cancer cells in the tumor micro-environment. The aim of this study was to investigate whether the selected target cytokine expression levels in ascites could serve as an immune biomarker for predicting outcomes in ovarian cancer. MethodsEighty-eight specimens of ovarian cancer-associated ascites were evaluated to select the target cytokine by a cytokine profiling kit. The 144 total samples were subsequently analyzed for this target cytokine. The correlation between the target cytokine and clinical characteristics was analyzed. ResultsInterferon-gamma (IFN-γ) was identified as the target cytokine. Higher levels of IFN-γ in the ascites of the tumor micro-environment were associated with advanced disease (p=0.012), higher tumor histological grading (p=0.004), and sub-optimal surgical status (p=0.040). By multivariate analysis, the adjusted hazard ratios (HRs) were 2.74 (95% confidence interval (CI) 1.85–4.05, p<0.001) for disease-free survival (DFS) and 1.72 (95% CI 1.01–2.93, p=0.048) for overall survival (OS) for a 10-fold increase in IFN-γ concentration in the ascites. An inverse dose–response relationship between IFN-γ level and survival was also noted (Ptrend<0.001 for DFS and Ptrend<0.042 for OS). ConclusionsPatients with ovarian cancer and higher IFN-γ expression levels in cancer-associated ascites will have shorter DFS and OS. IFN-γ levels in the ascites may be a prognostic marker and a potential reference for immunotherapy targeting IFN-γ.

Abstract 4782: Two-dimensional gel analysis of protein expression profile in patients with invasive squamous cell carcinoma of the uterine cervix for identification of differentially expressed proteins in relation to response to radiation therapy

Abstract Background: Cancer of uterine cervix is the second most common cancer and an important cause of cancer related mortality among women worldwide. These patients are treated by chemoradiation, response to which is a major factor affecting their outcome. Objective: To identify differentially expressed proteins in the tissue biopsies of patients with invasive cervical cancer by two-dimensional gel electrophoresis [2-DE] and correlate it with their clinical outcome. Methods: After an informed consent, 10 patients of invasive squamous cervical cancer, stage IIB, between 40-50 years treated with chemoradiation as per standard protocol were recruited. Based on the 24 month-outcome, there were two groups (N=5): i) Evidence of disease (ED) and ii) No evidence of disease (NED). Pooled protein from the tissue biopsies were subjected to 2-DE using pH 3-10 IPG strips of 7cm length, silver stained and expression profile compared using Image Master 7.0 software (GE Healthsciences). The differentially expressed protein spots were identified and isoelectric point (pI) &amp; Molecular Weight (MW) was determined from the plot of relative electrophoretic mobility (Rf) values of the marker against their respective molecular weight and the plot of pI marker against their respective distance from the anode respectively. The TagIdent software was used for their identification. Results: Out of a total of 327 spots identified, 89 spots showed differential expression, of which 40 were highly significant (ANOVA p &amp;lt;0.03) between ED vs NED groups. Conclusion: 2-DE has provided preliminaryinformation regarding differentially expressed proteins which may help identify biomarkers for prediction of outcome in patients with invasive cervical cancer which needs further confirmation. Differentially expressed proteins in NED vs ED groups in invasive cervical cancer Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4782. doi:1538-7445.AM2012-4782

The usefulness of S100B, NSE, GFAP, NF-H, secretagogin and Hsp70 as a predictive biomarker of outcome in children with traumatic brain injury

Predicting the long-term outcome after traumatic brain injury (TBI) is an important component of treatment strategy. Despite dramatically improved emergency management of TBI and apparent clinical recovery, most patients with TBI still may have long-term central nervous system (CNS) impairment. Sixty-three patients with TBI were enrolled into the prospective study. Venous blood samples were taken at admission and every 24 h for a maximum of 6 consecutive days. Serum concentrations of the biomarkers S100B, neuron-specific enolase (NSE), GFAP, NF-H, secretagogin and Hsp70 were quantified immuno-luminometrically or by enzyme-linked immunosorbent assay. The outcome was evaluated 6 months after TBI using the Glasgow Outcome Scale (GOS) in all patients. The S100B levels in patients with worse outcome (GOS 4 or death) were already significantly higher at D0 (p < 0.001; p = 0.002). NSE levels were significantly higher in patients who died or had worse outcomes (p < 0.001; p = 0.003). Patients who had worse outcomes (GOS) or died had higher GFAP values (p < 0.001; p < 0.001), but their dynamics were similar over the same period. NF-H grew significantly faster in patients who had a worse GOS or died (p < 0.001; p = 0.001). Although further prospective study is warranted, these findings suggest that levels of biomarkers correlate with mortality and may be useful as predictors of outcome in children with TBI.

Use of 18F-FDG PET/CT as a Predictive Biomarker of Outcome in Patients With Head-and-Neck Non–Squamous Cell Carcinoma

The purpose of this article is to establish whether pretreatment (18)F-FDG uptake predicts disease-free survival (DFS) and overall survival in patients with head-and-neck non-squamous cell carcinoma (SCC). Eighteen patients (six women and 12 men; mean [± SD] age at diagnosis, 57.89 ± 13.54 years) with head-and-neck non-SCC were included. Tumor FDG uptake was measured by the maximum standardized uptake value (SUV(max)) and was corrected for background liver FDG uptake to derive the corrected SUV(max). Receiver operating characteristic analyses were used to predict the optimal corrected SUV(max) cutoffs for respective outcomes of DFS (i.e., absence of recurrence) and death. The mean corrected SUV(max) of the 18 head-and-neck tumors was 5.63 ± 3.94 (range, 1.14-14.29). The optimal corrected SUV(max) cutoff for predicting DFS and overall survival was 5.79. DFS and overall survival were significantly higher among patients with corrected SUV(max) < 6 than among patients with corrected SUV(max) ≥ 6. The mean DFS for patients with corrected SUV(max) < 6 was 25.7 ± 11.14 months, and the mean DFS for patients with corrected SUV(max) ≥ 6 was 7.88 ± 7.1 months (p < 0.018). Among patients with corrected SUV(max) < 6, none died, and the mean length of follow-up for this group was 35.2 ± 9.96 months. All of the patients who died had corrected SUV(max) ≥ 6, and the overall survival for this group was 13.28 ± 12.89 months (p < 0.001). FDG uptake, as measured by corrected SUV(max), may be a predictive imaging biomarker for DFS and overall survival in patients with head-and-neck non-SCC.

Measurement of baseline serum SDF-1 levels as a predictive biomarker for outcomes in the NCIC CTG MA.14 trial of octreotide, a somatostatin analogue in postmenopausal breast cancer.

577 Background: Stromal cell derived-factor 1 (SDF-1) is a chemokine implicated in breast tumor growth and metastasis. Blood SDF-1 levels have a significant prognostic value in primary breast cancers. We have reported that 4 month serum SDF-1 levels had a significant EFS predictive value in the adjuvant breast cancer population of MA.14 (ASCO 2010). Here, we sought to confirm the association with baseline assessments of SDF-1. Methods: NCIC CTG MA.14 is a randomized phase III trial in postmenopausal women of tam 20 mg daily for 5 yr +/- octreotide LAR for 2 yr. Stratification factors were adjuvant chemo, axillary nodal status, and ER status. The primary endpoint was event-free survival (EFS) defined as time from randomization to recurrence, second malignancy, or death due to any cause. Serum was collected at various timepoints throughout the trial. Baseline SDF-1 serum levels were measured with an ELISA kit (R&D). To assess the effect of SDF-1 on EFS in the context of factors considered in the main trial, we used step-wise forward multivariate adjusted Cox modeling, adjusting by the stratification factors, and adding a factor if the likelihood ratio criterion was significant, p ≤ 0.05. Events for the analysis were those reported at ASCO 2008. Results: 667 women were accrued (333 to tam, 334 to tam + oct), and followed for a median 7.9 years. We successfully measured the baseline levels of SDF-1 in 469 (70%) patients, 241 on tamoxifen arm, of whom 80 (33%) experienced an EFS event; and for 228 on tamoxifen and octreotide LAR arm, of whom 70 (31%) had an EFS event.Consistent with our previous findings, we found that in a step-wise multivariate analysis, higher log (SDF-1) (p < 0.0001) was significantly associated with worse EFS. Also, the interaction of treatment and SDF-1 split at median was significantly (p < 0.0001) associated with EFS with inclusion of the significant main trial factors. Conclusions: We have confirmed that baseline SDF-1 levels have a predictive value in the breast cancer population of MA.14 treated with octreotide LAR. Further validation of SDF-1 and investigation of a possible pharmacogenetic effect with octreotide therapy is warranted.

Potential markers predicting bevacizumab efficacy for metastatic colorectal cancer patients.

e14107 Background: Fluoropyrimidine-based chemotherapy plus bevacizumab (BV) is standard first-line treatment for metastatic colorectal cancer (mCRC). However, useful markers predicting BV efficacy have not been cleared. The aim of this study was to investigate potential markers of efficacy of BV combined with FOLFOX in mCRC retrospectively. Methods: Eighty-five consecutive patients with previously untreated mCRC were included in this study. All patients received FOLFOX4 plus BV 5mg/kg until progression or unmanageable toxicity occurred. Biomarkers including testing the KRAS gene by DNA direct sequencing as well as clinical factors were evaluated as predictors of outcome. Hazard ratios (HR) and 95% confidence intervals (CI) for survival were estimated using the Cox proportional hazards analysis. Results: The overall response and disease control rate was 61.2% and 95.3% respectively. The median progression-free survival (PFS) and time to treatment failure (TTF) were 18.4 and 13.1 months respectively. Two-year survival rate was 65.9%. In univariate analysis, small number of metastatic site (N-meta), good tumor response (TR), temporary interruption of oxaliplatin (L-OHP) and continuance of BV as clinical factors and normal CA125, ALP and LDH levels as biomarkers were associated with better PFS and overall survival (OS). Normal D-dimer level significantly prolonged PFS and TTF. KRAS gene status (72.7% wild-type, 27.3% mutant) did not impact on TR, PFS, TTF or OS. According to multivariate analysis results, TR (HR 0.24; 95%CI 0.12-0.48, p < 0.001) and normal LDH level (HR 0.13; 95%CI 0.06-0.29, p < 0.001) were associated with better PFS. TR (HR 0.11; 95%CI 0.03-0.43, p = 0.002), N-meta (HR 0.38; 95%CI 0.12-0.74, p = 0.004) and dose reduction of 20% for L-OHP (HR 0.07; 95%CI 0.02-0.29, p < 0.001) were significantly associated with better OS. Conclusions: This study suggests that continuing L-OHP and BV accepting appropriate interruption due to adverse events were considered to improve survival for mCRC patients receiving L-OHP-based chemotherapy plus BV. Moreover, CA125, ALP, LDH and D-dimer may have the possibility to be predictive biomarkers of outcome, but KRAS gene status could not be a predictor. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chugai Pharma, Yakult Honsha Co.