Validation Of Predictive Biomarkers Research Articles

A review of studies examining the association between genetic biomarkers (short tandem repeats and single-nucleotide polymorphisms) and risk of prostate cancer: the need for valid predictive biomarkers.

Prostate cancer (PCa) is a challenging polygenic disease because the genes that cause PCa remain largely elusive and are affected by several causal factors. Consequently, research continuously strives to identify a genetic marker which could be used as an indicator to predict the most vulnerable (i.e., predisposed) segments of the population to the disease or for the gene which may be directly responsible for PCa. To enhance the genetic etiology of PCa, this research sought to discover the key studies conducted in this field using data from the main journal publication search engines, as it was hoped that this could shed light on the main research findings from these studies, which in turn could assist in determining these genes or markers. From the research highlighted, the studies primarily used two kinds of markers: short tandem repeats or single-nucleotide polymorphisms. These markers were found to be quite prevalent in all the chromosomes within the research carried out. It also became apparent that the studies differed in both quantity and quality, as well as being conducted in a variety of societies. Links were also determined between the degree and strength of the relationship between these markers and the occurrence of the disease. From the studies identified, most recommended a larger and more diverse survey for the parameters which had not been studied before, as well as an increase in the size of the community (i.e., the population) being studied. This is an indication that work in this field is far from complete, and thus, current research remains committed toward finding genetic markers that can be used clinically for the diagnosis and screening of patients with PCa.

5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future.

5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for colorectal cancer (CRC) in the palliative and adjuvant settings. Over the past four decades, several modulation strategies including the implementation of 5-FU-based combination regimens and 5-FU pro-drugs have been developed and tested to increase the anti-tumor activity of 5-FU and to overcome the clinical resistance. Despite the encouraging progress in CRC therapy to date, the patients' response rates to therapy continue to remain low and the patients' benefit from 5-FU-based therapy is frequently compromised by the development of chemoresistance. Inter-individual differences in the treatment response in CRC patients may originate in the unique genetic and epigenetic make-up of each individual. The critical element in the current trend of personalized medicine is the proper comprehension of causes and mechanisms contributing to the low or lack of sensitivity of tumor tissue to 5-FU-based therapy. The identification and validation of predictive biomarkers for existing 5-FU-based and new targeted therapies for CRC treatment will likely improve patients' outcomes in the future. Herein we present a comprehensive review summarizing options of CRC treatment and the mechanisms of 5-FU action at the molecular level, including both anabolic and catabolic ways. The main part of this review comprises the currently known molecular mechanisms underlying the chemoresistance in CRC patients. We also focus on various 5-FU pro-drugs developed to increase the amount of circulating 5-FU and to limit toxicity. Finally, we propose future directions of personalized CRC therapy according to the latest published evidence.

Identification and Validation of Predictive Biomarkers to CD19- and BCMA-Specific CAR T-Cell Responses in CAR T-Cell Precursors

Identification and Validation of Predictive Biomarkers to CD19- and BCMA-Specific CAR T-Cell Responses in CAR T-Cell Precursors

YI04.02 Immuno-Oncology Trials: Other Endpoints Needed?

The implementation of immunotherapies has completely changed and improved management of patients with non-small-cell lung cancer (NSCLC). In contrast to cytotoxic agents and targeted therapies immunotherapies do not directly affect the tumor but lead to an indirect reactivation of T-cell mediated immune reaction. Therefore different endpoints may be required for an appropriate assessment of efficacy of these novel compounds. In various trials it could be demonstrated that in contrast to conventional anti tumor therapies, which show an impact on early overall survival (OS), immunotherapies seem to impact the long term survival rates, leading to a phenomenon, which is characterized as “plateau of long term survival“. In contrast other conventional markers of efficacy like response rate (RR) or progression free survival (PFS) do not appear as the best endpoints to reflect the complete efficacy of immunotherapies at least not in biomarker unselected populations. In a number of randomized phase 3 trials in untreated as well as pretreated patients no significant differences in PFS were shown despite the fact that these trials demonstrated a clear survival benefit in favour of the immunotherapies or immunotherapy combinations. In addition exploratory analyses revealed a survival benefit even in patients, who received immunotherapies beyond progression suggesting that indeed response and PFS may be suboptimal endpoints. Reflecting these experiences clearly new statistical approaches are needed to focus on OS as probably the most relevant endpoint and to provide the opportunity to capture the late impact of immunotherapies on OS with the prolongation of long-term survival in an adequate way. Currently the first modifications of conventional statistical models are in development evaluating for example the model of disproportional hazard ratios and others in upcoming trials. Another significant problem is the appearance of “crossing” Kaplan Meier curves, which has frequently been observed in trials with immunotherapy combinations. These curves suggest, that there are different subpopulations with different sensitivities toward the novel treatments represented. Reflecting the lack of valid predictive biomarkers, which are able to separate the different subgroups, innovative statistical models are needed to define and to describe the benefitting populations. Lastly the “explosion” of numerous clinical trials investigating novel immunotherapy combinations will require a modification of our traditional endpoints. Given the number of novel agents and the speed of development it won't be feasible to conduct individual signal generating phase II trials for each of these agents. New models of platform trials with a new model of statistical assessment are required to provide the opportunity to investigate multiple combinations in one trial and to provide the flexibility to add novel combinations, which just may have been developed to ongoing protocols. In summary immunotherapies have substantially contributed to therapeutic improvements in NSCLC, but they are requesting a change of our conventional consideration of efficacy. Besides all endpoints of objective efficacy it will be of paramount importance that future endpoints also cover patient relevant endpoints like tolerability, improvement of quality of life or duration of symptom control.

A Consensus Molecular Classification of Muscle-invasive Bladder Cancer.

Background:Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application.Objective:To achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes.Design, setting, and participants:We used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts.Outcome measurements and statistical analysis:We performed a network-based analysis of six independent MIBC classification systems to identify a consensus set of molecular classes. Association with survival was assessed using multivariable Cox models.Results and limitations:We report the results of an international effort to reach a consensus on MIBC molecular subtypes. We identified a consensus set of six molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes. We provide a single-sample classifier that assigns a consensus class label to a tumor sample’s transcriptome. Limitations of the work are retrospective clinical data collection and a lack of complete information regarding patient treatment.Conclusions:This consensus system offers a robust framework that will enable testing and validation of predictive biomarkers in future prospective clinical trials.Patient summary:Bladder cancers are heterogeneous at the molecular level, and scientists have proposed several classifications into sets of molecular classes. While these classifications may be useful to stratify patients for prognosis or response to treatment, a consensus classification would facilitate the clinical use of molecular classes. Conducted by multidisciplinary expert teams in the field, this study proposes such a consensus and provides a tool for applying the consensus classification in the clinical setting.

Immunotherapy of Melanoma: Facts and Hopes.

Melanoma is among the most sensitive of malignancies to immune modulation. Although multiple trials conducted over decades with vaccines, cytokines, and cell therapies demonstrated meaningful responses in a small subset of patients with metastatic disease, a true increase in overall survival (OS) within a randomized phase III trial was not observed until the development of anti-CTLA-4 (ipilimumab). Further improvements in OS for metastatic disease were observed with the anti-PD-1-based therapies (nivolumab, pembrolizumab) as single agents or combined with ipilimumab. A lower bound for expected 5-year survival for metastatic melanoma is currently approximately 35% and could be as high as 50% for the nivolumab/ipilimumab combination among patients who would meet criteria for clinical trials. Moreover, a substantial fraction of long-term survivors will likely remain progression-free without continued treatment. The hope and major challenge for the future is to understand the immunobiology of tumors with primary or acquired resistance to anti-PD-1 or anti-PD-1/anti-CTLA-4 and to develop effective immune therapies tailored to individual patient subsets not achieving long-term clinical benefit. Additional goals include optimal integration of immune therapy with nonimmune therapies, the development and validation of predictive biomarkers in the metastatic setting, improved prognostic and predictive biomarkers for the adjuvant setting, understanding mechanisms of and decreasing toxicity, and optimizing the duration of therapy.

Abstract 3128: miR-9 expression regulates and predicts the response to EGFR inhibitors in head & neck squamous cell carcinoma

Abstract Introduction. Most Head & Neck Squamous Cell Carcinoma (HNSCC) patients are diagnosed with a locally advanced disease. Radiotherapy (RT) plus anti-EGFR monoclonal antibodies (Cetuximab - CTX) represents an effective combination therapy for locally advanced HNSCC patients. However, the 5-year overall survival is still 45%, mainly due to the appearance of loco-regional recurrences, suggesting that the identification and validation of predictive biomarkers of CTX activity is urgently needed to identify patients at high-risk of recurrence, who will benefit more from this therapeutic strategy. We recently validated a 4-microRNAs (miRs) signature, related to Epithelial to Mesenchymal Transition (EMT) and able to stratify HNSCC patients at high-risk of recurrence development. Among these 4 miRs, miR-9 was the only up-regulated in primary tumors from patients who developed recurrence within 2-year follow-up. Here we evaluated whether miR-9 expression had a functional role in HNSCC onset, progression and response to therapies. Methods. miR-9 modified (overexpressing and silenced) HNSCC cells were generated, characterized for their growth and response to radio-, chemo- and targeted-therapies (i.e.Cisplatin, Paclitaxel, 5-Fluorouracil and CTX) in vitro and in vivo. Preclinical evidences were confirmed in a cohort of primary HNSCC samples by intercrossing the expression of miR-9 and selected target genes with patients’ clinical variables and response to therapy. Results. Biochemical and biological in vitro and in vivo experiments showed that high miR-9 expression triggers EMT and increases tumor initiating properties in HNSCC cells. Interestingly, miR-9 silenced HNSCC cells displayed a higher sensitivity to RT and CTX, but not to chemotherapy, when compared to controls. Using an in vivo model of HNSCC, we observed that intra-tumor injection of anti-miR-9 improves the efficacy of RT alone and remarkably in combination with CTX. Mechanistically, we demonstrated that in HNSCC cells, EGFR activation triggers miR-9 expression that promotes the transcription of SP1, establishing a positive forward loop between EGFR activation and SP1 transcription. Accordingly, in primary HNSCC miR-9 expression strongly correlates with the one of SP1 and EGFR. More importantly, in a cohort of HNSCC patients treated with RT plus CTX, high miR-9 expression acts as an efficient predictive biomarker of intrinsic resistance. Conclusion. Altogether by integrating wet-lab and clinical data, we provide strong evidences indicating that in HNSCC a subpopulation of miR-9 expressing cells is intrinsically resistant to RT plus CTX therapy, confirming its potential prognostic value. Since we set up an assay to easily and quantitatively evaluate miR-9 expression in diagnostic tumor biopsies, we propose that it could be used to personalize the treatments for this group of patients, avoiding unfaithful toxic therapies. Citation Format: Francesca Citron, Gian Luca Rampioni Vinciguerra, Giuseppe Fanetti, Ilenia Segatto, Barbara Belletti, Andrea Vecchione, Giovanni Franchin, Gustavo Baldassarre. miR-9 expression regulates and predicts the response to EGFR inhibitors in head & neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3128.

Personalised medicine in renal cell tumours

The extensive use of abdominal imaging reveals an increasing number of small and asymptomatic kidney tumours, for which primary treatment versus observation strategies need to be discussed. Elaborate surgical techniques and a variety of systemic treatment options are available for patients with localised and advanced tumours. This necessitates a demanding and complex individualised decision-making process. A better understanding of tumour biology including validated biomarkers is therefore essential in order to improve diagnostics, prognostic evaluation and therapeutic strategies.Renal cell tumours are currently subdivided into 16 histological subtypes, each characterised by specific genetic changes. As tumour aggressiveness differs significantly, knowledge of these distinct subtypes is important for adequate treatment choice and follow-up. Molecular markers may facilitate an exact diagnosis and will further differentiate the individual prognosis within each subtype, which is already possible for clear cell renal cell carcinoma (RCC). This will lead to individualised follow-up protocols and a better selection of patients benefitting from observational or adjuvant strategies after surgery.For metastatic tumours, the number of systemic treatment options targeting specific cellular signal or communication pathways has increased tremendously. Valid predictive biomarkers for differential treatment are not available to date. However, there is promising evidence of correlations between molecular signatures and treatment response to tyrosine kinase inhibitors or checkpoint inhibitors. Biomarkers will most likely supersede clinical scores for individual treatment selection in the near future.Prospective multicentre studies are needed so that promising biomarkers can be implemented in daily clinical practice in due consideration of existing insights from the tumour biology of the distinct RCC subtypes. This is essential for further improvement of diagnosis and treatment.

Integrative In Vivo Drug Testing Using Gene Expression Signature and Patient-Derived Xenografts from Treatment-Refractory HER2 Positive and Triple-Negative Subtypes of Breast Cancer.

Patient-derived xenografts (PDXs) are powerful tools for translational cancer research. Here, we established PDX models from different molecular subtypes of breast cancer for in vivo drug tests and compared the histopathologic features of PDX model tumors with those of patient tumors. Predictive biomarkers were identified by gene expression analysis of PDX samples using Nanostring nCount cancer panels. Validation of predictive biomarkers for treatment response was conducted in established PDX models by in vivo drug testing. Twenty breast cancer PDX models were generated from different molecular subtypes (overall success rate, 17.5%; 3.6% for HR+/HER2−, 21.4% for HR+/HER2+, 21.9% for HR−/HER2+ and 22.5% for triple-negative breast cancer (TNBC)). The histopathologic features of original tumors were retained in the PDX models. We detected upregulated HIF1A, RAF1, AKT2 and VEGFA in TNBC cases and demonstrated the efficacy of combined treatment with sorafenib and everolimus or docetaxel and bevacizumab in each TNBC model. Additionally, we identified upregulated HIF1A in two cases of trastuzumab-exposed HR−/HER2+ PDX models and validated the efficacy of the HIF1A inhibitor, PX-478, alone or in combination with neratinib. Our results demonstrate that PDX models can be used as effective tools for predicting therapeutic markers and evaluating personalized treatment strategies in breast cancer patients with resistance to standard chemotherapy regimens.

(Not Giving Up) The Marathon Race of MET Targeting Therapy: Are We There Yet?

Among the various MET aberrations, MET amplification and METex14 have emerged as valid predictive biomarkers for MET inhibition. Despite challenges that have limited the development of MET inhibitors, we can learn from the latest efforts in biomarker-based therapy to better identify the patients who will benefit from treatment with these agents.See related articles by Hong et al., p. 2403 and Van Cutsem et al., p. 2414.

Protein array profiling of circulating angiogenesis-related factors during bevacizumab containing treatment in metastatic colorectal cancer.

BackgroundProlonged angiogenesis inhibition may improve treatment outcome in metastatic colorectal cancer (mCRC) patients. However, due to the complexity of the angiogenic pathways there is a lack of valid predictive biomarkers for anti-angiogenic agents. Here, we describe and optimize a procedure for simultaneous dynamic profiling of multiple angiogenesis related proteins in patient serum to explore associations with the response and acquired resistance to anti-angiogenic therapy.Materials and methodsPatients (n=22) were selected from a clinical trial investigating maintenance treatment with bevacizumab alone after response to induction chemotherapy + bevacizumab in mCRC. Serum samples were analysed for 55 unique angiogenesis related proteins using a commercial proteome profiler array and a publicly available image analysis program for quantification. Samples were collected at baseline before induction treatment start, at start of maintenance treatment, and at end of treatment after tumour progression.Main results and conclusionFor eight proteins, the antibody array signals were below detection range in all patient samples. None of the proteins showed levels at baseline or at start of maintenance with strong evidence for correlation to time to progression (lowest nominal p-value 0.03). The dynamic ranges of protein levels measured during the induction treatment period and during the maintenance period were analysed separately for time trends. Evidence for changing trends (up/down) in the levels of MMP-8, TIMP-4 and EGF was observed both during response to induction treatment and at progressive disease, respectively. For three of the proteins (IL-8, Activin A and IGFBP-2), weak evidence for correlation between increasing protein levels during induction with chemotherapy and bevacizumab and time to progression was observed.In conclusion, semi-quantitative profiling of angiogenesis related proteins in patient serum may be a versatile tool to screen for protein patterns aiming at identifying resistance mechanisms of anti-angiogenic treatment in patients with mCRC.

The Clinical and Cost-Effectiveness of 4 Enzyme-Linked Immunosorbent Assay Kits for Monitoring Infliximab in Crohn Disease Patients: Protocol for a Validation Study.

BackgroundCurrently, treatment decisions for people with Crohn disease are based on clinical judgment and trial and error. Consequently, people may continue to receive high drug dosages and experience unnecessary toxicity when it is possible to reduce or discontinue without a detrimental effect on clinical outcomes. Therapeutic drug monitoring (TDM) involves regularly testing blood samples for drug and antibody levels that could help clinicians identify the optimal treatment strategy and pre-empt treatment failure. However, heterogeneity in the assays can lead to a discrepancy in results and difficulties in decision-making. Standardization of the kits, and therefore results, would allow clinicians to optimize the use of biologics. Currently, there is also a lack of evidence for the cost-effectiveness of TDM using commercial test kits.ObjectiveThis study aims to analyze the clinical and cost-effectiveness of 4 commercial enzyme-linked immunosorbent assay (ELISA) kits (LISA TRACKER, IDKmonitor, Promonitor, and RIDASCREEN) to generate evidence which could support a recommendation for wider adoption in the National Health Service.MethodsWe propose to carry out a prospective-retrospective predictive biomarker validation study using the blood samples and clinical/utilization data collected during the ongoing SPARE trial (NCT02177071). A total of 200 stored samples from people with Crohn's disease who respond to treatment with infliximab will be used along with clinical and cost data from the trial. We will investigate the relationship between the drug and antidrug antibody levels with the main clinical outcomes (relapse rate at 2 years and time spent in remission), as well as resource utilization and quality of life.ResultsFunding is being sought to conduct this research.ConclusionsThis is the first study to compare the 4 ELISA kits for monitoring infliximab in patients with Crohn disease. It aims to address the uncertainties in the potential benefits of using the technologies for TDM.International Registered Report Identifier (IRRID)PRR1-10.2196/11218

Dicentric Dose Estimates for Patients Undergoing Radiotherapy in the RTGene Study to Assess Blood Dosimetric Models and the New Bayesian Method for Gradient Exposure.

The RTGene study was focused on the development and validation of new transcriptional biomarkers for prediction of individual radiotherapy patient responses to ionizing radiation. In parallel, for validation purposes, this study incorporated conventional biomarkers of radiation exposure, including the dicentric assay. Peripheral blood samples were taken with ethical approval and informed consent from a total of 20 patients undergoing external beam radiotherapy for breast, lung, gastrointestinal or genitourinary tumors. For the dicentric assay, two samples were taken from each patient: prior to radiotherapy and before the final fraction. Blood samples were set up using standard methods for the dicentric assay. All the baseline samples had dicentric frequencies consistent with the expected background for the normal population. For blood taken before the final fraction, all the samples displayed distributions of aberrations, which are indicative of partial-body exposures. Whole-body and partial-body cytogenetic doses were calculated with reference to a 250-kVp X-ray calibration curve and then compared to the dose to blood derived using two newly developed blood dosimetric models. Initial comparisons indicated that the relationship between these measures of dose appear very promising, with a correlation of 0.88 (P = 0.001). A new Bayesian zero-inflated Poisson finite mixture method was applied to the dicentric data, and partial-body dose estimates showed no significant difference (P > 0.999) from those calculated by the contaminated Poisson technique. The next step will be further development and validation in a larger patient group.

Apalutamide for the treatment of prostate cancer

ABSTRACTIntroduction: Five new agents have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer, including two targeting androgen receptor signaling (abiraterone acetate plus prednisone; enzalutamide). Recognition that these tumors remain driven by androgen receptor signaling has prompted clinical evaluation of these agents at earlier states in the prostate cancer disease continuum, along with the continued development of new agents targeting this pathway.Areas covered: This article focuses on apalutamide, a next-generation nonsteroidal antiandrogen, with current literature queried in PubMed/Medline. A narrative review strategy describes studies from engineering of the compound through to a 5-year outlook.Expert commentary: In the phase III SPARTAN study, apalutamide significantly improved metastasis-free survival in patients with nonmetastatic castration-resistant prostate cancer – the first treatment approved by the US Food and Drug Administration for this indication. Phase III studies are under way to determine the clinical benefit of apalutamide in other disease states. Given the multiplicity of prostate cancer treatment options now available, there is a need to maximize individual patient benefit through the development and validation of predictive biomarkers of sensitivity to drugs that can be used in real time to determine the optimal sequence and combinations of treatments for patients in need.

Feasibility of event-related potential (ERP) biomarker use to study effects of mother’s voice exposure on speech sound differentiation of preterm infants

ABSTRACTAtypical maturation of auditory neural processing contributes to preterm-born infants’ language delays. Event-related potential (ERP) measurement of speech–sound differentiation might fill a gap in treatment-response biomarkers to auditory interventions. We evaluated whether these markers could measure treatment effects in a quasi-randomized prospective study. Hospitalized preterm infants in passive or active, suck-contingent mother’s voice exposure groups were not different at baseline. Post-intervention, the active group had greater increases in/du/-/gu/differentiation in left frontal and temporal regions. Infants with brain injury had lower baseline/ba/-/ga/and/du/-/gu/differentiation than those without. ERP provides valid discriminative, responsive, and predictive biomarkers of infant speech–sound differentiation.

Single nucleotide polymorphisms as prognostic and predictive biomarkers in renal cell carcinoma.

Despite major advances in the knowledge of the molecular basis of renal cell carcinoma, prognosis is still defined using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. With these premises, we aimed to analyse the expression and to determine the prognostic and predictive value of 64 key single nucleotide polymorphisms in 18 genes related with angiogenesis or metabolism of antiangiogenics in two cohorts of patients with localized and advanced renal cell cancer treated at our institution. The presence of the selected single nucleotide polymorphisms was correlated with clinical features, disease free survival, overall survival and response rate. In patients with localized renal cell cancer, 5 of these polymorphisms in 3 genes involved in angiogenesis predicted for worse disease free survival (VEGFR2: rs10013228; PDGFRA: rs2228230) or shorter overall survival (VEGFR2: rs10013228; VEGFR3: rs6877011, rs307826) (p < 0.05). Rs2071559 in VEGFR2 showed a protective effect (p = 0.01). In the advanced setting, 5 SNPs determined inferior overall survival (IL8: rs2227543, PRKAR1B: rs9800958, PDGFRB: rs2302273; p = 0.05) or worse response rate (VEGFA: rs699947, rs3025010 p ≤ 0.01)). Additionally 1 single nucleotide polymorphism in VEGFB predicted for better response rate rs594942 (p = 0.03). Genetic analysis of renal cell carcinoma patients might provide valuable prognostic/predictive information. A set of SNPs in genes critical to angiogenesis and metabolism of antiangiogenics drugs seem to determine post-surgical outcomes and treatment response in our series.

Role of the adverse outcome pathway (AOP) framework in the validation of predictive biomarkers

Role of the adverse outcome pathway (AOP) framework in the validation of predictive biomarkers

Predicting outcomes in renal cell cancer: The role of single nucleotide polymorphisms (SNPs).

e16074 Background: Despite major advances in the knowledge of the molecular basis of RCC, prognosis is still defined mostly using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. The aim of this work is analyzing the expression and determining the prognostic and predictive value of 64 key SNPs in 18 genes related with angiogenesis or metabolism of antiangiogenics in two cohorts of RCC patients (pts) [localized and advanced] RCC treated at our institution. Methods: DNA from formalin fixed paraffin embedded tumor and non-tumor samples from 99 pts with RCC (26 advanced/ 73 localized) was extracted with QiAGEN Kit and amplified with a specific primers pool for every SNP as determined by the manufacturer (Lifetech). Sixty-four SNPs were chosen based on their Minor Allele Frequency by HapMap, linkage disequilibrium by Haploview and information from SNP data base (dSNP) and were studied by TaqMan OpenArray (Lifetech). Statistically significant SNPs were validated in an external cohort by individual assays. The presence of the selected SNPs was correlated with clinical features, disease free survival (DFS), overall survival (OS) and response to treatment (RR). SPSS v20 was utilized for statistical analyses. Results: In pts with localized RCC, 2 SNPs in 2 genes involved in angiogenesis showed a protective effect (VEGFR2: rs2071559, PDGFRA: rs4358459) and others SNPs predicted for worse DFS (VEGFR2: rs10013228, rs1870377, PDGFRA: rs2228230) and shorter OS (VEGFR2: rs2305948, rs10013228; VEGFR3: rs6877011, rs307826) (p &lt; 0.05). In the advanced setting, 6 SNPs in genes related to both angiogenesis and metabolism of antiangiogenics were statistically implicated in OS (IL8: rs2227543, PDGFA: rs9800958, PDGFRB: rs2302273 (p≤0.05)) and RR (VEGFA: rs699947, rs3025010, VEGFB: rs594942 (p &lt; 0.03)). These 14 SNPs are currently being validated in an external cohort of 80 patients with RCC and this data will be presented. Conclusions: These SNPs in genes critical to angiogenesis and metabolism of antiangiogenics might be used as potential prognostic/predictive biomarkers. Prospective validation is ongoing.

Advancing Immune and Cell-Based Therapies Through Imaging

Immunotherapies include various approaches, ranging from stimulating effector mechanisms to counteracting inhibitory and suppressive mechanisms, and creating a forum for discussing the most effective means of advancing these therapies through imaging is the focus of the newly formed Imaging in Cellular and Immune Therapies (ICIT) interest group within the World Molecular Imaging Society. Efforts are being made in the identification and validation of predictive biomarkers for a number of immunotherapies. Without predictive biomarkers, a considerable number of patients may receive treatments that have no chance of offering a benefit. This will reflect poorly on the field of immunotherapy and will yield false hopes in patients while at the same time contributing to significant cost to the healthcare system. This review summarizes the main strategies in cancer immune and cell-based therapies and discusses recent advances in imaging strategies aimed to improve cancer immunotherapy outcomes.

Single-nucleotide polymorphisms (SNPs) associated with outcomes in patients with localized and metastatic renal cell carcinoma (RCC).

437 Background: Despite major advances in the knowledge of the molecular basis of RCC, prognosis is still defined using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. The aim of this work is analyzing the expression and determining the prognostic and predictive value of 64 key SNPs in 18 genes related with angiogenesis or metabolism of antiangiogenics in patients (pts) with both localized and advanced RCC treated at Hospital Universitario Virgen del Rocío. Methods: DNA from formalin fixed paraffin embedded tumor and non-tumor samples from 99 pts with RCC (26 advanced/ 73 localized) was extracted with QiAGEN Kit and amplified with a specific primers pool for every SNP as determined by the manufacturer (Lifetech). 64 SNPs were chosen based on their Minor Allele Frequency by HapMap, linkage disequilibrium by Haploview, and information from SNP data base (dSNP) and were studied by TaqMan OpenArray (Lifetech). The presence of the selected SNPs was correlated with clinical features, disease free survival (DFS), overall survival (OS), and response to treatment (RR). SPSS v16 was utilized for statistical analyses. Results: In pts with localized RCC, 6 SNPs in 3 genes involved in angiogenesis predicted for worse DFS (VEGFR2: rs10013228, rs2071559; PDGFRA: rs2228230) and shorter OS (VEGFR2: rs10013228; VEGFR3: rs6877011, rs307826) (p&lt;0.05). In the advanced setting, 7 SNPs in genes related to both angiogenesis and metabolism of antiangiogenics determined inferior OS (IL8: rs2227543, NR1l2: rs3814055, NR1l3: rs2307424, PDGFA: rs9800958, PDGFRB: rs2302273) and worse RR (VEGFA: rs699947, rs3025010 p&lt;0.01)). Additionally 3 SNPs in PDGFR-B and VEGF isoforms predicted for better RR (PDGFRB: rs17708574 (p=0.08), VEGFB: rs594942 (p=0.03), VEGFC: rs2016110 (p=0.07). Conclusions: Genetic analysis of RCC patients might provide valuable prognostic/predictive information. A set of SNPs in genes critical to angiogenesis and metabolism of antiangiogenics seem to determine post-surgical outcomes and treatment response in our series. These results are promising. Validation of the results is ongoing.