Predictive Biomarker For Overall Survival Research Articles

494 Evaluating ERK1 2 Phosphorylation as a Predictive Biomarker for Survival in Recurrent Glioblastoma Patients: A REMARK Criteria-guided Analysis of a Clinical Trial Cohort Treated With Intracerebral PD-1 and CTLA-4 Blockade

INTRODUCTION: Glioblastoma patients exhibit variable clinical responses to anti-PD-1 immunotherapy. Our previous work identified ERK1/2 phosphorylation (p-ERK) in pre-treatment tumor samples as a predictive biomarker of overall survival in two independent cohorts of recurrent glioblastoma patients undergoing adjuvant anti-PD-1 therapy (Arrieta et al, Nat Cancer, 2021). This biomarker, however, has not yet been explored with alternative immune checkpoint blockade strategies nor assessed using REMARK criteria. METHODS: Adhering to REMARK criteria for biomarker validation, we investigated p-ERK as a predictor of survival in 24 evaluable recurrent glioblastoma patients from a clinical trial (NCT03233152; Duerinck J, et al, JITC, 2021). Patients underwent intracerebral administration of immune checkpoint inhibitors within a phase I clinical trial, receiving either ipilimumab (10 mg), or a combination of ipilimumab (5 mg) and nivolumab (10 mg), followed by postsurgical intravenous nivolumab (10 mg). We quantified p-ERK+ cell density in tumor regions and conducted a double-blinded statistical analysis of p-ERK’s association with survival outcomes, performed by an independent statistical team. RESULTS: Although analysis of the entire cohort revealed no statistically significant survival difference between patients with high and low p-ERK tumors (p = 0.29), a focused examination of wild-type IDH GBM patients demonstrated a significantly prolonged survival for those with high p-ERK tumors (median survival = 55.6 weeks, 95% CI 33.86-NA) compared to those with low p-ERK tumors (median OS of 30 weeks, 95% CI 16.14-NA; p = 0.036). CONCLUSIONS: Despite the limited sample size, this study highlights the promising predictive potential of p-ERK as a biomarker in a third independent prospective glioblastoma cohort treated with a novel immune checkpoint blockade administration approach, emphasizing the need for further investigation and validation in larger cohorts.

SLC11A1 predicts the overall survival of patients with colorectal cancer.

Colorectal cancer (CRC) remains a significant contributor to cancer-related mortality, emphasizing the critical need for identifying biomarkers that can improve clinical management and patient outcomes. In this retrospective study, we analyzed tumor samples from 25 patients with metastatic CRC, categorized based on long-term (> 50 months) or short-term (< 10 months) survival. Employing the PanCancer Immune Profile Panel, encompassing 770 genes, in the discovery dataset, we identified 54 differentially expressed genes (DEGs) within the tumor microenvironment of metastatic CRC. Validation of potential biomarkers was performed using two publicly available RNA-based sequencing datasets (TCGA 1 (n=371) and TCGA 2 (n=566)). Univariate COX regression unveiled that three significant biomarkers were associated with overall survival in CRC within the discovery dataset, which were SLC11A1 (hazard ratio (HR): 4.09, P=0.012), TNFSF11 (HR: 3.67, P=0.02), and MEF2C (HR: 0.34, P=0.037). Kaplan-Meier survival curve analyses confirmed the correlation between SLC11A1 expression and overall survival in CRC across the discovery set (P=0.0071) and the two independent datasets (TCGA 1 (P=0.0016) and TCGA 2 (P=0.025)). Receiver operating characteristic curve analysis demonstrated an area under the curve ranging from 0.64 to 0.76, with sensitivity of 59% to 87% and specificity of 60% to 73% for predicting CRC overall survival. Immunohistochemistry staining further validated the strong expression of SLC11A1 protein in CRC tumor cells, with high expression correlating with short-term survival. These findings suggest that SLC11A1 serves as a predictive biomarker for overall survival in CRC patients.

ERK1/2 Phosphorylation Predicts Survival in Recurrent Glioblastoma Following Intracerebral and Adjuvant PD-1/CTLA-4 Immunotherapy: A REMARK-guided Analysis.

Evidence suggests that MAPK pathway activation, as measured by ERK1/2 phosphorylation (p-ERK), predicts overall survival (OS) in patients with recurrent glioblastoma receiving anti-PD-1 therapy. We aimed to validate these findings in independent cohorts. In a 24-patient clinical trial on recurrent glioblastoma and high-grade gliomas, we examined the link between p-ERK levels and OS. Patients received intravenous nivolumab, followed by maximal safe resection and an intracerebral injection of either ipilimumab alone or combined with nivolumab. Biweekly adjuvant nivolumab was then administered up to five times (NCT03233152). Using REporting recommendations for tumor MARKER prognostic studies (REMARK) criteria, we conducted independent analyses for p-ERK quantification and statistical evaluations. Additional comparative analysis included prior cohorts, totaling 65 patients. Cox proportional hazards models and meta-analysis were employed to assess p-ERK as a predictive biomarker after immunotherapy. Lower median p-ERK+ cell density was observed compared with prior studies, likely due to variable tissue processing across cohorts. Nonetheless, high p-ERK was associated with prolonged OS, particularly in isocitrate dehydrogenase wild-type glioblastomas (P = 0.036). Median OS for high and low p-ERK patients were 55.6 and 30 weeks, respectively. Multivariable analysis reinforced p-ERK's significance in survival prediction (P = 0.011). Upon p-ERK normalization across cohorts (n = 65), meta-analysis supported the survival benefit of elevated tumor p-ERK levels (P = 0.0424). This study strengthens the role of p-ERK as a predictive biomarker for OS in patients with glioblastoma on immune checkpoint blockade. Future research should focus on further validation in prospective trials and the standardization of preanalytical variables influencing p-ERK quantification.

Clinical, molecular, and immune correlates of the Immunotherapy Response Score in patients with advanced urothelial carcinoma under atezolizumab monotherapy: analysis of the phase II IMvigor210 trial

In the advanced urothelial carcinoma (aUC) scenario there are no consistent immune checkpoint blockade predictive biomarkers. Recently a novel pan-tumor molecular tissue-based biomarker, the Immunotherapy Response Score (IRS), has been proposed. We conducted a retrospective study to validate the prognostic/predictive utility of the IRS in patients with aUC under atezolizumab monotherapy and to characterize its underlying molecular/immune features in the context of the IMvigor210 phase II trial. This is a post hoc pooled analysis of 261 patients with available clinical, molecular, and immune tumor data treated with atezolizumab monotherapy in the IMvigor210 phase II clinical trial. Efficacy endpoints were overall survival (OS), disease control rate (DCR), and overall response rate (ORR). Survival estimates were calculated by the Kaplan-Meier method, and groups were compared with the log-rank test. The Cox proportional hazards regression model was used to evaluate factors independently associated with OS. Factors associated with disease control (DC) and response were tested with logistic regression in univariable and multivariable analyses. Comparisons between patient and disease characteristics were carried out using chi-square or Fisher's exact tests. All P values were two-sided, and those <0.05 were considered statistically significant. High IRS was significantly associated with a better OS in univariable [hazard ratio (HR)= 0.49, P < 0.001] and multivariable (HR= 0.60, P= 0.018) analyses. DCR and ORR were significantly higher among high IRS patients (DCR for high IRS versus low IRS patients: 57% versus 32%, P < 0.001; ORR: 42% versus 10%, P < 0.001). High IRS patients presented a higher probability of DC and response in univariable [DC: odds ratio (OR)= 2.72, P < 0.001; response: OR= 3.92, P < 0.001] and multivariable (DC: OR= 2.72, P < 0.001; response: OR= 3.92, P < 0.001) analyses. This study validates IRS as a strong independent prognostic and predictive biomarker for OS and DC/response in patients with aUC treated with atezolizumab monotherapy in the IMvigor210 phase II clinical trial.

Computed Tomography-Based Texture Analysis as a Predictor of Survival in Patients with T-Cell Lymphomas

Background: T-cell lymphomas constitute a heterogeneous group of hematological malignancies with global poor outcomes. Computed tomography (CT)-based texture analysis (CTTA) is a promising technique to predict the survival of these patients. Objectives: The present study aimed to investigate whether CTTA features on the pretreatment unenhanced CT scans of 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) examination can predict the survival of patients with T-cell lymphomas. Patients and Methods: In this retrospective cohort study, patients with T-cell lymphomas, undergoing pretreatment 18F-FDG PET/CT scan during 2008 - 2019, were included, and their clinical and biological characteristics were collected. The mean gray value, entropy, kurtosis, skewness, and standard deviation were derived from the pixel distribution histogram before and after spatial filtration at different anatomic scales in up to five lesions per patient, indicating a high focal uptake on 18F-FDG PET scan. A Lasso-penalized Cox regression analysis was performed to identify independent predictors of overall survival (OS), progression-free survival at 24 months (PFS24), and PFS. Results: A total of 23 patients (7 females and 16 males; median age, 69 years; age range, 33 - 86 years) were included in this study. The CTTA was performed for 60 lesions. The median OS and PFS were 391 days (range, 10 - 3,463 days) and 268 days (range, 10 - 2,321 days), respectively. No CT texture parameter was associated with PFS or PFS24. The standard deviation at a coarse filter scale was independently associated with a poor OS (hazard ratio [HR] = 1.009, confidence interval [CI]: 1.0012 - 1.016, P = 0.02). A value above 143 was associated with a poor prognosis with a specificity of 81%. Conclusion: The pretreatment CTTA-derived tumor standard deviation at a coarse filter scale may be a predictive biomarker of OS in patients with T-cell lymphomas.

Predicting sulforaphane-induced adverse effects in colon cancer patients via in silico investigation

Colorectal cancer (CRC) is a significant global health burden that ranks as the third most diagnosed and second most common cause of cancer related deaths worldwide. New therapeutic strategies include chemoprevention and use of molecules which could prevent, suppress or reverse CRC progression such as sulforaphane (SFN). However, evidences about its safety in CRC patients are still lacking. The aim of this in silico investigation was to predict SFN-induced adverse effects in CRC patients by computational analysis. The study showed that 334 genes were consistently dysregulated in CRC (223 downregulated and 111 upregulated), while 38 were recognized as significant and might be used as predictive biomarkers for overall survival and metastasis (TCGA, GEO, R studio). Among them, SFN interacted with 86 genes, out of which 11 were marked as significant (correlate with overall prognosis and metastasis). Sulforaphane potentiates the overexpression of TIMP1, AURKA, and CEP55, and promotes inhibition of CRYAB, PLCE1, and MMP28, that might lead to the progression of CRC (CTD). Pathway enrichment analysis revealed that SFN stimulated Transcriptional activation of RUNX2, AURKA activation by TPX2, IL-10 signaling, while inhibited Differentiation of White and Brown Adipocyte process, an underlying pathway which inactivation led to obesity (Cytoscape ClueGo + CluePedia, DAVID). Thus, genome signature of CRC patients could serve as important factor when addressing the risk-to-benefit profile of SFN. Patients with colon cancer and increased expression of TIMP1, CCL20, SPP1, AURKA, CEP55, NEK2, SOX9 and CDK1, or downregulation of CRYAB, PLCE1, MMP28, BMP2 and PLAC8 may not be ideal candidates for SFN chemoprevention.

CTIM-04. BIOMARKER IMMUNE CORRELATES IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) TREATED WITH ATEZOLIZUMAB IN COMBINATION WITH TEMOZOLOMIDE (TMZ) AND RADIATION

Abstract BACKGROUND Checkpoint inhibitor therapy has demonstrated overall limited efficacy in the treatment of GBM. Mechanisms of resistance to checkpoint blockade need to be better elucidated. Analysis of the tumor microenvironment is critical to identify correlates of response to immune checkpoint blockade. 60 newly diagnosed GBM patients unselected for MGMT status underwent treatment with concurrent atezolizumab with radiation therapy and TMZ followed by adjuvant atezolizumab and TMZ (NCT03174197). Clinical data has been reported previously. METHODS Tissue image immunoprofiling was conducted using 2 multiplex immunofluorescence (mIF) panels against; CD3, CD8, PD-1, PD-L1, Granzyme B, FOXP3, CD45RO, CD68, and GFAP antibodies. PDL-1 (Clone SP263) malignant cells expression was assessed by immunohistochemistry. Correlations between mIF biomarkers co-expressions, IHC PD-L1, and clinical outcome including OS, radiographic response, and PFS were evaluated. RESULTS Of 60 patients enrolled, image immunoprofiling was performed successfully on pre-treatment tissue in 48 patients. 20 of 60 patients underwent re-resection for suspected recurrent disease of which 10 patients had immunoprofiling performed successfully on pre and post treatment samples. An analysis of CD3CD8+ cytotoxic T lymphocytes was consistent with prior work, showing no or relatively low levels at baseline, and no association with clinical outcome. PDL-1 expression by IHC, at thresholds of &amp;gt;1% or &amp;gt;5%, was not associated with clinical outcome. Tumors with a higher number of GFAP-expressing cancer cells had a significantly lower tumor response (p&amp;lt; 0.05) and median OS (430 vs. 799 days, p&amp;lt; 0.01). CONCLUSIONS For newly diagnosed GBM patients treated with standard of care radiation and temozolomide in combination with atezolizumab, T-cell levels and PDL-1 expression were not predictive of outcome. GFAP may represent a novel predictive biomarker of overall survival. Ongoing studies to evaluate the gut microbiome and tumor genomic (WES, CNA) and transcriptomic (RNAseq) features of these and matched tumors are underway.

Programmed Death-Ligand 1 Tumor Proportion Score and Overall Survival From First-Line Pembrolizumab in Patients With Nonsquamous Versus Squamous NSCLC

IntroductionFor patients with NSCLC receiving immune checkpoint inhibitors, programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) has been validated as a predictive biomarker for improved overall survival (OS). Nevertheless, its histology-specific predictive value in patients with advanced squamous versus nonsquamous cancers remains unclear. To evaluate the differential value of PD-L1 TPS as a predictive biomarker for OS after first-line pembrolizumab in patients with squamous versus nonsquamous NSCLC. MethodsRetrospective, observational study of patients diagnosed with having advanced NSCLC who were treated between October 2015 and April 2019 at community oncology clinics and academic medical centers in a deidentified electronic health record–derived database. Included patients were diagnosed with having advanced or metastatic NSCLC, received treatment with first-line, single-agent pembrolizumab, and had documentation of PD-L1 testing with a numeric result. Exclusion criteria included alterations in EGFR, ALK, and ROS1. The primary end point was OS from start of first-line pembrolizumab therapy by squamous or nonsquamous histology and PD-1 expression level measured by TPS (low, <50% or high, ≥50%). ResultsThe cohort of 1460 patients with NSCLC who received pembrolizumab as a first-line therapy had a mean age of 72 years. Histology was 28% squamous and 72% nonsquamous. PD-L1 expression was low in 13% and high in 87%. No meaningful differences in age, sex, or smoking history were observed by PD-L1 TPS or histology type. A generalized gamma model adjusting for sex and stage at diagnosis found that for patients with nonsquamous histology, high PD-L1 TPS was significantly associated with improved OS by a median OS difference of 8.4 months (p < 0.001). In contrast, for patients with squamous histology, there was no evidence of association between PD-L1 expression level and OS (p = 0.283). PD-L1–related incremental differences in median OS between the patients with squamous and nonsquamous tumors were significantly different (p = 0.034). ConclusionsAmong patients with NSCLC treated with first-line pembrolizumab, high PD-L1 TPS is associated with OS among patients with nonsquamous NSCLC, but not among patients with squamous NSCLC.

Neutrophil extracellular traps (NETs) and thrombosis (Thr) in pancreaticobiliary cancer (PBC).

e16230 Background: NETs are linked to tissue damage, Thr and cancer progression. Detection of NETs in pancreatic cancer (PC) tissue and NET products in plasma, such as citrullinated Histone 3 (cit-H3) and myeloperoxidase (MPO), can predict survival. A robust biomarker to identify PC patients that may benefit from prophylactic antithrombotic interventions is still lacking. We hypothesized that NET products can predict PC patients at risk of poor outcomes. Methods: Frozen plasma collected on diagnosis from a cohort of 117 patients with HPBC (69% with PC) with known tissue factor (TF) levels was analyzed for MPO and cit-H3 by ELISA. Plasma MPO is a marker of neutrophil degranulation while cit-H3 is a more specific marker of NETosis. Univariate association of clinical variables, TF, cit-H3, MPO with overall survival (OS) was performed. For multivariable analysis, Cox proportional hazards regression model and backward stepwise selection based on the Bayesian information criterion (BIC) were used. Results: We observed a strong correlation between MPO and cit-H3. MPO also correlated with TF. Only TF showed a trend with association with the risk of Thr (p=0.053). Results of the multivariable model for OS are presented in the table (all patients and stratified by Thr status). High absolute neutrophil count (ANC) predicted worse OS only in patients without Thr. Increased cit-H3 was associated with worse OS. Higher MPO predicted worse OS in stage IV patients, which is in contrast to their relationship in stage I-III patients, where increased MPO was associated with improved OS. This interaction effect is stronger in patients with thrombosis. Conclusions: Plasma cit-H3, a systemic marker of NETosis, was associated with worse OS in PBC. Significant MPO by stage interaction implies a differential association of MPO with the OS among patients in different cancer stages. The activation status of neutrophils, including degranulation and NETosis, may be an important predictive biomarker for OS in patients with HPBC with interactions with both stage and Thr. Prospective studies to confirm and extend our findings are ongoing.[Table: see text]

Diffusion Magnetic Resonance Imaging Phenotypes Predict Overall Survival Benefit From Bevacizumab or Surgery in Recurrent Glioblastoma With Large Tumor Burden.

Diffusion magnetic resonance (MR) characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-vascular endothelial growth factor (VEGF) therapy; however, its use in large volume recurrence has not been evaluated. To determine if diffusion MR characteristics can predict survival outcomes in patients with large volume recurrent glioblastoma treated with bevacizumab or repeat resection. A total of 32 patients with large volume (>20 cc or > 3.4 cm diameter) recurrent glioblastoma treated with bevacizumab and 35 patients treated with repeat surgery were included. Pretreatment tumor volume and apparent diffusion coefficient (ADC) histogram analysis were used to phenotype patients as having high (>1.24 μm2/ms) or low (<1.24 μm2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor. In bevacizumab and surgical cohorts, volume was correlated with overall survival (Bevacizumab: P=.009, HR=1.02; Surgical: P=.006, HR=0.96). ADCL was an independent predictor of survival in the bevacizumab cohort (P=.049, HR=0.44), but not the surgical cohort (P=.273, HR=0.67). There was a survival advantage of surgery over bevacizumab in patients with low ADCL (P=.036, HR=0.43) but not in patients with high ADCL (P=.284, HR=0.69). Pretreatment diffusion MR imaging is an independent predictive biomarker for overall survival in recurrent glioblastoma with a large tumor burden. Large tumors with low ADCL have a survival benefit when treated with surgical resection, whereas large tumors with high ADCL may be best managed with bevacizumab.

Prognostic impact of cytoplasmatic EGFR upregulation in patients with oral squamous cell carcinoma: A pilot study.

In various tumors, epidermal growth factor-receptor (EGFR) serves a role in tumorigenesis and has an impact on survival. Usually the EGF-receptor is located on the surface of the cell membrane and is involved in various signaling pathways. The dimerization of EGFR with other ErbB family proteins, such as HER2, is important for the tumor progression. Nevertheless, a second EGFR-associated signaling pathway appears to be important for tumor cells, which is cytoplasmic/nuclear EGFR. The present study examined the influence of membranous or cytoplasmic localized EGFR on the prognosis of patients with oral squamous cell carcinoma (OSCC). Slides from 45 OSCC tumor samples were stained against EGFR using immunohistochemistry and analysed by the Remmele score system. The association with histopathological parameters and survival data was analyzed. Cytoplasmatic EGFR localization was identified as an independent predictive biomarker for overall survival in the examined OSCC cohort according to multivariate Cox regression analysis. Positive cytoplasmatic EGFR staining was correlated with a higher risk of early death (RR=3.0; P=0.035), while membranous EGFR localization did not affect patient survival. To the best of our knowledge, the present study is the first study to demonstrate that cytoplasmatic-localized EGFR is an independent prognostic biomarker for the overall survival of patients with OSCC.

8P STC1, a baseline predictive biomarker for overall survival in metastatic colorectal cancer (mCRC)

8P STC1, a baseline predictive biomarker for overall survival in metastatic colorectal cancer (mCRC)

Cell cycle progression score as a predictive biomarker for overall survival in patients with adrenocortical carcinoma

Cell cycle progression score as a predictive biomarker for overall survival in patients with adrenocortical carcinoma

PD-L1 tumor proportion score and clinical benefit from first-line pembrolizumab in patients with advanced nonsquamous versus squamous non-small cell lung cancer (NSCLC).

9539 Background: The predictive value of PD-L1 tumor proportion score (TPS) on NSCLC tumor cells as a biomarker for response to PD-(L)1 inhibitors is well established. However, its histology specific value in advanced (a) squamous (Sq) versus nonsquamous (NS) cancers remains unclear. Here, we used real world data to assess the differential value of PD-L1 TPS as a predictive biomarker for overall survival (OS) after first-line pembrolizumab (P) in patients (pts) with Sq versus NS NSCLC. Methods: Inclusion criteria for this analysis of the Flatiron Health EHR-derived de-identified database required that pts were diagnosed with aNSCLC, tested for PD-L1 TPS and received a numerical result, had no alteration in EGFR, ALK, or ROS, and received first-line, single agent P. The primary endpoint was overall survival (OS) from the first dose of P in patients with TPS ≥ 50% (H) compared to patients with TPS &lt; 50% (L). Due to the violation of the proportional hazards assumption, a generalized gamma model of OS was used, adjusting for demographic variables and estimated median OS and their confidence intervals with the bootstrap method. The PD-L1-histology interaction was examined by comparing the differences in median OS (H vs. L) between Sq and NS patients. Results: Of 1560 pts with NSCLC treated from 1/2011 – 5/2019, 1055 had NS and 405 Sq. No meaningful differences in age, gender, or smoking history were seen between PD-L1 H and L pts with either histology. Among NS pts, H had significantly longer OS than L, with unadjusted hazard ratio (HR) of 0.71 (95% CI: 0.53 - 0.94; p = 0.018). Among Sq pts, H was not associated with longer OS than L, with unadjusted HR 0.89 (95% CI: 0.64 - 1.25; p = 0.514). Based on the generalized gamma model, PD-L1 H in Sq patients was associated with a 0.19 year improvement in median OS (95% CI: -0.22-0.49, P = 0.283), whereas PD-L1 H in the NS group was associated with a 0.70 year improvement in OS (95% CI: 0.34-1.05, P &lt; 0.001). The median improvements between the Sq and NS patients were significantly different (P = 0.034), after adjusting for demographic variables. Conclusions: PD-L1 TPS of ≥ 50% predicted longer OS in pts with NS NSCLC treated with first-line P compared to pts whose tumors had a TPS of &lt; 50%. However, no relationship between PD-L1 TPS and OS after first-line P was seen in patients with Sq NSCLC. These data suggest that PD-L1 may not be an appropriate predictive biomarker for checkpoint inhibitor use in NSCLC with squamous histology.

Metastatic melanoma: pretreatment contrast-enhanced CT texture parameters as predictive biomarkers of survival in patients treated with pembrolizumab.

To determine whether texture analysis features on pretreatment contrast-enhanced computed tomography (CT) images can predict overall survival (OS) and progression-free survival (PFS) in patients with metastatic malignant melanoma (MM) treated with an anti-PD-1 monoclonal antibody, pembrolizumab. This institutional-approved retrospective study included 31 patients with metastatic MM treated with pembrolizumab. Texture analysis of 74 metastatic lesions was performed on CT scanners obtained within 1month before treatment. Mean gray-level, entropy, kurtosis, skewness, and standard deviation values were derived from the pixel distribution histogram before and after spatial filtration at different anatomic scales, ranging from fine to coarse. Lasso penalized Cox regression analyses were performed to identify independent predictors of OS and PFS. Median OS and PFS were 357days (range 42-1355) and 99days (range 35-1185), respectively. Skewness at coarse texture scale (SSF = 6; HR (CI 95%) = 6.017 (1.39, 26.056), p = 0.016), Response evaluation criteria in solid tumors (RECIST) conclusion (HR (CI 95%) = 3.41 (1.17, 9.89), p = 0.024), and body weight (HR (CI 95%) = 0.96 (0.92, 0.995), p = 0.026) were independent predictors of OS. Skewness at coarse texture scale (SSF = 6; HR (CI 95%) = 4.55 (1.46, 14.13), p = 0.0089) and RECIST conclusion (HR (CI 95%) = 10.63 (3.11, 36.29), p = 0.00016) were independent predictors of PFS. Skewness values above - 0.55 at coarse texture scale were significantly associated with both lower OS and lower PFS after administration of pembrolizumab. Pretreatment CT texture analysis-derived tumor skewness may act as predictive biomarker of OS and PFS in patients with metastatic MM treated with pembrolizumab. • Pretreatment skewness at coarse texture scale in metastases from malignant melanoma was an independent predictor of overall survival and progression-free survival. • Skewness values above -0.55 at coarse texture scale were significantly associated with both lower OS and lower PFS after administration of pembrolizumab. • In patients with metastatic MM, texture analysis performed on pretreatment CT may act as a useful tool to select the best candidates for pembrolizumab therapy.

836P - Use of nuclear-localized androgen receptor splice variant 7 protein in CTCs after 1st androgen receptor signaling inhibitor (ARSi) as a predictive biomarker for overall survival on a second ARSi or taxane chemotherapy in metastatic castration-resistant prostate cancer (mCRPC)

836P - Use of nuclear-localized androgen receptor splice variant 7 protein in CTCs after 1st androgen receptor signaling inhibitor (ARSi) as a predictive biomarker for overall survival on a second ARSi or taxane chemotherapy in metastatic castration-resistant prostate cancer (mCRPC)

Differential MicroRNA Expression Levels in Cutaneous Acute Graft-Versus-Host Disease.

Allogeneic hematopoietic stem cell transplantation is a curative treatment for numerous hematological malignancies. However, acute graft-versus-host disease (aGvHD) is a major complication affecting 40–70% of all transplant patients, whereby the earliest and most frequent presentation is in the skin. MicroRNAs play a role in varied biological process and have been reported as potential biomarkers for aGvHD. More recently, microRNAs have received added attention as circulatory biomarkers that can be detected in biofluids. In this study, we performed global microRNA expression profiling using a discovery cohort of diagnostic cutaneous aGvHD biopsies (n = 5, stages 1–3) and healthy volunteers (n = 4), in order to identify a signature list of microRNAs that could be used as diagnostic biomarkers for cutaneous aGvHD. Candidate microRNAs (n = 8) were then further investigated in a validation cohort of post-HSCT skin biopsies (n = 17), pre-HSCT skin biopsies (n = 6) and normal controls (n = 6) for their association with aGvHD. Expression of let-7c (p = 0.014), miR-503-5p (p = 0.003), miR-365a-3p (p = 0.02), miR-34a-5p (p < 0.001) and miR-34a-3p (p = 0.006) were significantly differentially expressed between groups and significantly associated with survival outcome in post-HSCT patients (miR-503-5p ROC AUC = 0.83 p = 0.021, Log Rank p = 0.003; miR-34a-3p ROC AUC = 0.93, p = 0.003, Log Rank p = 0.004). There was no association with relapse. A statistical interaction between miR-34a-3p and miR-503-5p (p = 0.016) was diagnostic for aGvHD. Expression levels of the miR-34a-5p protein target p53 were assessed in the epidermis of the skin, and an inverse correlation was identified (r2 = 0.44, p = 0.039). Expression of the validated candidate microRNAs was also assessed at day 28 post-HSCT in the sera of transplant recipients, in order to investigate their potential as circulatory microRNA biomarkers. Expression of miR-503-5p (p = 0.001), miR-34a-5p (p = 0.005), and miR-34a-3p (p = 0.004) was significantly elevated in the sera of patients who developed aGvHD versus no-aGvHD (n = 30) and miR-503-5p was associated with overall survival (OS) (ROC AUC = 0.80, p = 0.04, Log Rank p = 0.041). In conclusion, this investigation reports that microRNA expression levels in clinical skin biopsies, obtained at the time of cutaneous aGvHD onset, show potential as diagnostic biomarkers for aGvHD and as predictive biomarkers for OS. In addition, the same microRNAs can be detected in the circulation and show predictive association with post-HSCT outcomes.

Abstract 2620: Aquaporin 11 as a new predictive biomarker of overall survival and platinum-based chemotherapy response in lung adenocarcinoma patients

Abstract Background: Biomarkers predictive of response to chemotherapy are critically needed for the precise selection of treatment protocols in lung adenocarcinoma (LUAD). Aquaporins (AQPs), transmembrane water channels, are emerging targets in cancer. Recently discovered, non-ubiquitous family member aquaporin 11 (AQP11), a tissue-specific endoplasmic reticulum (ER) resident, was identified as a cellular pro-survival factor implicated in the maintenance of ER homeostasis. AQP11 is mapped to 11q13-q14 amplicon harboring oncogenic drivers and associated with poor prognosis in cancer patients. We recently showed that high AQP11 expression is an in-vitro therapeutic biomarker of cisplatin therapy, which directly interferes with AQP11 functional structure. In addition, silencing of AQP11 expression in human lung cancer cell lines significantly increased response to cisplatin treatment. We hypothesized that LUAD tumors expressing high levels of AQP11 depend on AQP11-mediated cytoprotection and would be more responsive to platinum-based chemotherapy targeting AQP11. Method: We downloaded and curated matched mRNA expression, survival, and drug response data from The Cancer Genome Atlas (TCGA) LUAD dataset (N=369). Results: Analysis of PRECOG and TCGA databases showed that high AQP11 mRNA expression is negatively prognostic in patients with LUAD. TCGA LUAD cases were categorized by AQP11 mRNA levels into high and low expression (high = AQP11 mRNA expression mean + 1 standard deviation). Patients with high tumor AQP11 mRNA expression (10.3%) had significantly worse overall survival (OS) compared to patients with low AQP11 expression (p=0.0015). An analysis of patients treated with platinum-based chemotherapy (N=74) showed that patients with high AQP11 mRNA expression (7%) had significantly higher OS then patients with LUAD expressing low levels of AQP11 (p=0.0263). Conclusions: This study identifies AQP11 as a new biomarker of OS and chemotherapy in LUAD patients. It is conceivable that lung tumors expressing high levels of AQP11 are dependent on its function and elevated AQP11 expression renders tumor resistance to microenvironment and therapy-induced stress and associates with lower OS of patients. At the same time, as cisplatin efficiently targets AQP11 functional multimeric structure, these AQP11-depending tumors are more prone to platinum based chemotherapy. This study provides a rationale for combination anti-AQP11 and chemotherapy in LUAD tumors with high AQP11 expression. Citation Format: Michael Sharpnack, David P. Carbone, Mikhail M. Dikov, Elena E. Tchekneva. Aquaporin 11 as a new predictive biomarker of overall survival and platinum-based chemotherapy response in lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2620.

Multivariate analysis of preoperative and postoperative neutrophil-to-lymphocyte ratio as an indicator of head and neck squamous cell carcinoma outcome

Recent publications have highlighted a greater utility of routine blood tests in patients with various cancers than previously assumed. It appears that the neutrophil-to-lymphocyte ratio (NLR) may be a good predictive biomarker for overall survival (OS) and disease-free survival (DFS). Preoperative and postoperative NLR data for patients with head and neck cancers have yet to be established. The aim of this study was to evaluate the preoperative and postoperative NLR in 182 patients with head and neck squamous cell carcinoma and to determine the association of NLR with OS and DFS. The statistical analysis of OS and DFS and their predictors was performed using Kaplan–Meier survival analysis and multivariate Cox proportional hazards regression analysis, with factors including age, sex, alcohol and tobacco use, tumour location, treatment after surgery, and lymphocyte and neutrophil counts. Longer OS was significantly associated with not consuming alcohol, preoperative neutrophil and lymphocyte counts, preoperative NLR, and the difference between the preoperative and postoperative NLR (P=0.016). Longer DFS was significantly associated with not consuming alcohol, preoperative neutrophil and lymphocyte counts, postoperative NLR, and the difference between preoperative and postoperative NLR (P=0.028).

Circulating metabolite profiles to predict overall survival in advanced non-small cell lung cancer patients receiving first-line chemotherapy

ObjectivesThe prognosis for advanced-stage non-small cell lung cancer (NSCLC) is usually poor. However, survival may be variable and difficult to predict. In the current study, we aimed to identify circulating metabolites as potential predictive biomarkers for overall survival of advanced-stage (III/IV) NSCLC patients treated with first-line platinum-based chemotherapy. Materials and methodsUsing two-stage study design, we performed global metabolomic profiling in blood of 220 advanced-stage NSCLC patients, including 110 with poor survival and 110 with good survival. Metabolomic profiling was conducted using Metabolon platform. The association of each metabolite with survival was assessed by Cox proportional hazard regression model with adjustment for covariates. Results and conclusionWe found levels of 4 metabolites, caffeine, paraxanthine, stachydrine, and methyl glucopyranoside (alpha+beta), differed significantly between NSCLC patients with poor and good survival in both discovery and validation phases (P<0.05). Interestingly, majority of the identified metabolites are involved in caffeine metabolism, and 2 metabolites are related to coffee intake. In fact, caffeine metabolism pathway was the only significant pathway identified which significantly differed between NSCLC patients with poor and good survival (P=1.48E-07) in the pathway analysis. We also found 4 metabolites whose levels were significantly associated with good survival in both discovery and validation phases. Strong cumulative effects on overall survival were observed for these 4 metabolites. In conclusion, we identified a panel of metabolites including metabolites in caffeine metabolism pathway that may predict survival outcome in advanced-stage NSCLC patients. The identified small metabolites may be useful biomarker candidates to help identify patients who may benefit from platinum-based chemotherapy.