Identification Of Predictive Markers Research Articles

Immune mechanisms and predictive biomarkers related to neoadjuvant immunotherapy response in stage III melanoma

The treatment for stage III melanoma has advanced significantly, nevertheless, a substantial proportion of patients experience relapse. Neoadjuvant immune checkpoint blockade has emerged as a promising approach, allowing early micrometastatic disease treatment, reduction of tumor burden before surgery, and enhanced tumor-specific T-cell responses. However, not all patients respond to treatment, highlighting the need for understanding immune mechanisms behind failure and identification of predictive markers. Here we performed a robust evaluation of systemic and tumoral immune profiles in a well-defined cohort of advanced melanoma patients treated with immune checkpoint inhibitors. Elevated CTACK and CXCL9 chemokines pre-treatment suggested their potential as predictive tools for treatment response. Furthermore, CD95 expression in CD8+ T lymphocytes surfaced as a favorable prognostic indicator, while PD-1, CD161, and PD-L2 exhibited correlations with worst outcomes. These findings shed light on the intricate interplay between immune markers and melanoma response to neoadjuvant immune checkpoint therapy, offering insights into personalized treatment strategies.

Abstract 639: Evaluation of individual drug response in tumor microenvironment to cisplatin treatment in precision-cut tumor slices of ovarian cancer

Abstract Ovarian cancer is a complex and heterogeneous disease and the major cause of death among women with gynecological cancers. While patients usually respond well to the platinum-based first-line chemotherapy, the disease often becomes increasingly resistant to the treatment. The tumor microenvironment (TME) plays an important role in tumor development and drug resistance. Characterizing the TME of ovarian cancer after drug treatment is essential to identify molecular mechanisms that allow residual tumor cells to survive chemotherapy in ovarian cancer. We have established a preclinical model using precision-cut tumor slices (PCTS) with 250 µm thickness which preserves the TME of solid tumors with their heterogeneous cell composition during cultivation. The tumor morphology, viability and heterogeneity in terms of tumor and stromal cells as well as the immune compartment are preserved within the system. Based on the PCTS model, we also established a method to perform single-cell RNA sequencing (scRNA-seq) of the PCTS after cultivation and drug treatment to characterize the cellular features and dynamic relationships of different cell populations in the TME after drug treatment. Over 20 cell subtypes including different clusters of epithelial cells, immune cells and fibroblasts can be identified in PCTS after cisplatin treatment through the scRNA-seq analysis. This enables further deeper analysis of each cell subgroup in the TME after drug treatment. In response to cisplatin treatment, patients PCTS showed an individual induction of PD-L1 in different cell types. Additionally, multiplex immunofluorescence (mIF) stainings of the PCTS were performed to spatially trace the response of the TME to drug treatment. The mIF staining allows the simultaneous detection of up to 6 different markers on one FFPE tissue section. Images were analyzed using a machine-learning based workflow, which allows the comparison of biomarker expression and immune cell spatial distribution in the PCTS stromal and tumor areas before and after treatment. Combining the PCTS as a preclinical model with scRNA-seq and mIF staining analysis allows us to bridge the cellular characteristics and cellular spatial distribution with treatment response in the TME of solid tumors. It enables the systematic analysis of residual cancer populations after cisplatin treatment within the complex TME and further identification of predictive markers and targets for an individualized combination of chemotherapy with compounds targeting these mechanisms. The individual drug response of patients can be deeply evaluated and efficacious therapies can be further developed. Citation Format: Julia Thiel, Adrian Kneer, Weimeng Yu, Bernd Winkler, Georg Sauer, German Ott, Walter E. Aulitzky, Thomas E. Mürdter, Matthias Schwab, Chunguang Liang, Meng Dong. Evaluation of individual drug response in tumor microenvironment to cisplatin treatment in precision-cut tumor slices of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 639.

Revealing the role of SPP1+ macrophages in glioma prognosis and therapeutic targeting by investigating tumor-associated macrophage landscape in grade 2 and 3 gliomas

BackgroundGlioma is a highly heterogeneous brain tumor categorized into World Health Organization (WHO) grades 1–4 based on its malignancy. The suppressive immune microenvironment of glioma contributes significantly to unfavourable patient outcomes. However, the cellular composition and their complex interplays within the glioma environment remain poorly understood, and reliable prognostic markers remain elusive. Therefore, in-depth exploration of the tumor microenvironment (TME) and identification of predictive markers are crucial for improving the clinical management of glioma patients.ResultsOur analysis of single-cell RNA-sequencing data from glioma samples unveiled the immunosuppressive role of tumor-associated macrophages (TAMs), mediated through intricate interactions with tumor cells and lymphocytes. We also discovered the heterogeneity within TAMs, among which a group of suppressive TAMs named TAM-SPP1 demonstrated a significant association with Epidermal Growth Factor Receptor (EGFR) amplification, impaired T cell response and unfavourable patient survival outcomes. Furthermore, by leveraging genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) dataset, two distinct molecular subtypes with a different constitution of TAMs, EGFR status and clinical outcomes were identified. Exploiting the molecular differences between these two subtypes, we developed a four-gene-based prognostic model. This model displayed strong associations with an elevated level of suppressive TAMs and could be used to predict anti-tumor immune response and prognosis in glioma patients.ConclusionOur findings illuminated the molecular and cellular mechanisms that shape the immunosuppressive microenvironment in gliomas, providing novel insights into potential therapeutic targets. Furthermore, the developed prognostic model holds promise for predicting immunotherapy response and assisting in more precise risk stratification for glioma patients.Graphical abstract

Identification of predictive markers in the cerebrospinal fluid of patients with glioblastoma

Introduction. Glioblastoma (GB) is not yet curable despite recent advances in the treatment of other malignant solid tumors. The management of GB is based solely on histopathological features, imaging of the tumor and its genomic analysis (somatic mutations in the isocitrate dehydrogenase genes, methylation status of the O6-methylguanine-DNA methyltransferase gene promoter). To adapt the treatment to the most recent tumor evolution, molecular information should be received regularly throughout the course of therapy. However, tumor tissue is often not available for diagnosis as the disease progresses. In this regard, the development of less invasive methods, such as analysis of the proteome of biological fluids of patients, is of particular interest. Cerebrospinal fluid (CSF) is an important source disease biomarkers to monitor the presence and progression of the disease.Aim. To identify proteomic predictive biomarkers in the CSF of patients with GB.Materials and methods. During the study, samples of patients’ CSF samples, high-resolution proteomic mass spectrometry, modern biochemical methods and bioinformatic technologies were used.Results. For the first time, the analysis of proteomes of CSF samples of patients with GB obtained before and 7 days after the removal of the primary tumor was carried out. Potential biomarkers of GB have been identified. After their validation using open databases, 11 proteomic predictive markers of GB (S100A9, S100A8, PLA2G15, PPIB, LTBP2, VIM, LAMB1, STC1, NRP1, COL6A1, HSPA5) were selected and their role in the molecular mechanisms of gliomagenesis was assessed. Conclusion. The proposed panel of proteomic predictive CSF biomarkers in GB patients can be further used in the development of test systems for assessing the effectiveness of therapy and early detection of disease relapses.

Amoxicillin Plus Clavulanic Acid Versus Appendicectomy for Treatment of Acute Uncomplicated Appendicitis

Acute appendicitis is the most common indication for surgery in patients admitted to hospital for acute abdominal pain. In about 20% of cases, acute appendicitis is complicated, leading to local or diffuse peritonitis mostly. Although urgent appendicectomy is still the recommended treatment for acute uncomplicated appendicitis and also antibiotic treatment can cure acute appendicitis or can be the first line of treatment. In the Current study we assessed the efficacy of amoxicillin plus clavulanic acid by comparison with emergency appendicectomy for treatment of patients with uncomplicated acute appendicitis. In this Study open-label, non-inferiority, randomized trial, adult patients (aged 18–68 years) with uncomplicated acute appendicitis, as assessed by CT scan, were enrolled at Pakistan Instiute of Medical Sciences (PIMS) Hospital Islamabad Pakistan. A computer-generated randomization sequence was used to allocate patients randomly in a 1:1 ratio to receive amoxicillin plus clavulanic acid (3 g per day) for 8–15 days or emergency appendicectomy. The primary endpoint was occurrence of post intervention peritonitis within 30 days of treatment initiation. Non-inferiority was shown if the upper limit of the two-sided 95% CI for the difference in rates was lower than 10 percentage points. Both intention-to-treat and per-protocol analyses were done. The Current research Result show that Of 243 patients randomised, 123 were allocated to the antibiotic group and 120 to the appendicectomy group. Four were excluded from analysis because of early dropout before receiving the intervention, leaving 239 (antibiotic group, 120; appendicectomy group, 119) patients for intention-to-treat analysis. 30-day post intervention peritonitis was significantly more frequent in the antibiotic group (8%, n=9) than in the appendicectomy group (2%, n=2; treatment difference 5•8; 95% CI 0•3–12•1). In the appendicectomy group, despite CT-scan assessment, 21 (18%) of 119 patients were unexpectedly identified at surgery to have complicated appendicitis with peritonitis. In the antibiotic group, 14 (12% [7•1–18•6]) of 120 underwent an appendicectomy during the first 30 days and 30 (29% [21•4–38•9]) of 102 underwent appendicectomy between 1 month and 1 year, 26 of whom had acute appendicitis (recurrence rate 26%; 18•0–34•7).The Current result conclude that Amoxicillin plus clavulanic acid was not non-inferior to emergency appendicectomy for treatment of acute appendicitis. Identification of predictive markers on CT scans might enable improved targeting of antibiotic treatment. Keywords: Amoxicillin, clavulanic acid versus appendicectomy

Identification of proteomic markers for prediction of the response to 5-Fluorouracil based neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients

BackgroundNeoadjuvant chemoradiotherapy (nCRT) prior to surgery is the standard treatment for patients with locally advanced rectal cancer (LARC), while parts of them show poor therapeutic response accompanied by therapy adverse effects. Predictive biomarkers for nCRT response could facilitate the guidance on treatment decisions but are still insufficient until now, which limits the clinical applications of nCRT in LARC patients.MethodsIn our study, 37 formalin-fixed paraffin-embedded tumor biopsies were obtained from patients with LARC before receiving 5-fluorouracil based nCRT. Proteomics analyses were conducted to identify the differentially expressed proteins (DEPs) between total responders (TR) and poor responders (PR). The DEPs were validated via ROC plotter web tool and their predictive performance was evaluated by receiver operating characteristic analysis. Functional enrichment analyses were performed to further explore the potential mechanisms underlying nCRT response.ResultsAmong 3,998 total proteins, 91 DEPs between TR and PR were screened out. HSPA4, NIPSNAP1, and SPTB all with areas under the curve (AUC) ~ 0.8 in the internal discovery cohort were independently validated by the external mRNA datasets (AUC ~ 0.7), and their protein levels were linearly correlated with the graded responses to nCRT in the internal cohort. The combination of HSPA4 and SPTB could distinctly discriminate the TR and PR groups (AUC = 0.980, p < 0.0001). Moreover, multiple combinations of the three proteins realized increased specificity and/or sensitivity, while achieving favorable predictive value when moderate responders were introduced into the ROC analysis. Pathways including DNA damage repair, cell cycle, and epithelial mesenchymal transition were involved in nCRT response according to the enrichment analysis results.ConclusionsHSPA4, SPTB and NIPSNAP1 in tumor biopsies and/or their optional combinations might be potential predictive markers for nCRT response in patients with LARC. The DEPs and their related functions have implications for the potential mechanisms of treatment response to nCRT in patients with LARC.

Targeting Ribosome Biogenesis to Combat Tamoxifen Resistance in ER+ve Breast Cancer.

Simple SummaryResistance to tamoxifen treatment is an obstacle for ER+ve breast cancer therapy. The overexpression of c-MYC is a known driver of cancer progression and is associated with tamoxifen resistance. Through mediating the up-regulation of ribosome biogenesis and alteration of the transcriptome, c-MYC modulates the translation profile to facilitate the development of tamoxifen resistance. c-MYC is, however, undruggable. Thus, targeting downstream mechanisms mediated by c-MYC might be a more feasible approach. Studies have demonstrated that inhibition of ribosome biogenesis can achieve tumour suppression. Targeting ribosome biogenesis may thus be a feasible strategy to reverse tamoxifen resistance. This article reviews the current evidence to support the feasibility of suppressing ribosome biogenesis to reverse tamoxifen resistance in ER+ve breast cancer.Breast cancer is a heterogeneous disease. Around 70% of breast cancers are estrogen receptor-positive (ER+ve), with tamoxifen being most commonly used as an adjuvant treatment to prevent recurrence and metastasis. However, half of the patients will eventually develop tamoxifen resistance. The overexpression of c-MYC can drive the development of ER+ve breast cancer and confer tamoxifen resistance through multiple pathways. One key mechanism is to enhance ribosome biogenesis, synthesising mature ribosomes. The over-production of ribosomes sustains the demand for proteins necessary to maintain a high cell proliferation rate and combat apoptosis induced by therapeutic agents. c-MYC overexpression can induce the expression of eIF4E that favours the translation of structured mRNA to produce oncogenic factors that promote cell proliferation and confer tamoxifen resistance. Either non-phosphorylated or phosphorylated eIF4E can mediate such an effect. Since ribosomes play an essential role in c-MYC-mediated cancer development, suppressing ribosome biogenesis may help reduce aggressiveness and reverse tamoxifen resistance in breast cancer. CX-5461, CX-3543 and haemanthamine have been shown to repress ribosome biogenesis. Using these chemicals might help reverse tamoxifen resistance in ER+ve breast cancer, provided that c-MYC-mediated ribosome biogenesis is the crucial factor for tamoxifen resistance. To employ these ribosome biogenesis inhibitors to combat tamoxifen resistance in the future, identification of predictive markers will be necessary.

The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumor mainly associated with asbestos exposure and is characterized by a very difficult pharmacological approach. One of the molecular mechanisms associated with cancer onset and invasiveness is the epithelial-to-mesenchymal transition (EMT), an event induced by different types of inducers, such as transforming growth factor β (TGFβ), the main inducer of EMT, and oxidative stress. MPM development and metastasis have been correlated to EMT; On one hand, EMT mediates the effects exerted by asbestos fibers in the mesothelium, particularly via increased oxidative stress and TGFβ levels evoked by asbestos exposure, thus promoting a malignant phenotype, and on the other hand, MPM acquires invasiveness via the EMT event, as shown by an upregulation of mesenchymal markers or, although indirectly, some miRNAs or non-coding RNAs, all demonstrated to be involved in cancer onset and metastasis. This review aims to better describe how EMT is involved in driving the development and invasiveness of MPM, in an attempt to open new scenarios that are useful in the identification of predictive markers and to improve the pharmacological approach against this aggressive cancer.

Identification of Predictive Markers for the Generation of Well-Differentiated Human Induced Pluripotent Stem Cell-Derived Kidney Organoids.

Human-induced pluripotent stem cell (iPSC)-derived kidney organoids have the potential to advance studies to kidney development and disease. However, reproducible generation of kidney organoids is a challenge. A large variability in the percentage of nephron structures and the expression of kidney-specific genes was observed among organoids, showing no association with iPSC lines. To associate the quality of kidney organoid differentiation with predictive markers, a ranking system was developed based on the ratio of nephron structure determined by histological examination. Well-differentiated organoids were defined as organoids with >30% nephron structure and vice versa. Subsequently, correlations were made with expression profiles of iPSC markers, early kidney development markers, and fibrosis markers. Higher expression of sex-determining region Y-box 2 (SOX2) during differentiation was associated with poorly differentiated kidney organoid. Furthermore, early secretion of basic fibroblast growth factor (FGF2) predicted poorly differentiated kidney organoid. Of interest, whereas cadherin-1 (CDH1) expression in kidney organoids indicates distal tubules formation, onefold higher CDH1 expression in iPSC predicted poor differentiation. High expression of the stromal progenitor marker Forkhead Box D1 (FOXD1) and significantly increased TGFβ levels were found in well-differentiated kidney organoids. These early expression profiles could predict the outcome of kidney organoid formation. This study helps to improve the robustness of kidney organoid protocols.

Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy.

BackgroundImmune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy.MethodsAge-adapted delta telomere length (ΔTL) of 84 patients treated with ICIs for solid malignancies was measured via quantitative real-time PCR. ΔTL was correlated with outcome and clinical data.ResultsΔTL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, ΔTLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter ΔTL was 5.7 months compared to 18.0 months in patients showing longer ΔTL. The prognostic role of age-adapted ΔTL was further confirmed by uni- and multivariate Cox-regression analyses.ConclusionIn the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.

Identification of Predictive Markers and Outcomes of Late-onsetPneumocystis jiroveciiPneumonia in Kidney Transplant Recipients

AbstractBackgroundIn the era of prophylaxis, Pneumocystis pneumonia (PCP) has become a late-onset opportunistic infection requiring indications for prolonged prophylaxis to be defined. The primary objective of our study was therefore to evaluate risk factors associated with late-onset PCP. The secondary objective was to assess the impact of this infection on graft and patient survival.MethodsWe conducted a French case-control study in Bordeaux and Toulouse center by matching 1 case to 1–2 controls from the same center based on the transplant date and the type of induction treatment.ResultsSeventy cases and 134 controls were included. PCP occurred at a median of 3 years after transplantation. The total lymphocyte count and CD4+ and CD8+ T-lymphocyte values were lower in the cases than in their matched controls on the day of infection and annually up to 4 years earlier. The covariables independently associated with PCP were the total lymphocyte count 1 year before Pneumocystis, mTOR inhibitors used as maintenance immunosuppressive drugs, and the administration of corticosteroid boluses used in acute rejection. A total lymphocyte count threshold &amp;lt;1000/µL offered the best predictive value for infection occurrence. PCP was associated with high incidence of graft loss and patient death (30% and 17% respectively, 3 years after PCP).ConclusionsPneumocystis pneumonia has dramatic consequences in kidney transplant recipients; a targeted prophylaxis based on simple criteria, such as chronic lymphopenia and/or history of corticosteroid boluses, could be useful to avoid life-threatening complications.

CDK4/6 Inhibitor Biomarker Research: Are We Barking Up the Wrong Tree?

CDK4/6 inhibitors have emerged as a significant advance for the treatment of patients with advanced estrogen receptor-positive breast cancer. However, the identification of predictive markers that optimize their use is proving harder than expected. In this commentary we advocate for unbiased discovery and a collaborative approach across trials.See related article by Finn et al., p. 110.

Immunothérapie en urologie : principes et résultats

The purpose of this article is to update current data on immunotherapy in uro-oncology. Synthesis of data from recent literature and data presented at national and international conferences on immunotherapy in urological cancers. Current immunotherapies restore the anti-tumor immunity, by blocking immunity-negative feedback checkpoints. In metastatic renal cell carcinoma and bladder carcinoma, immunotherapy has first shown a significant survival benefit in second-line, and more recently in first-line for kidney cancer. Trials are currently ongoing in adjuvant and neoadjuvant settings. In prostate cancer, there is little data and immunotherapy seems to benefit a limited subgroup of patients. Immunotherapy is a key treatment in kidney and bladder cancer. In the future, the identification of predictive markers should allow us to better select patients responding to immunotherapy.

Molecular markers and prediction of response to immunotherapy in non-small cell lung cancer, an update.

Immunotherapy represents one of the most promising therapeutic approaches in lung cancer, however 50% of lung cancer patients will not respond to this treatment, while others will have transitory or durable responses. Because side effects may be life threatening and treatment costs remain very high, the identification of predictive markers is mandatory and actually extensively studied. Factors that determine response to immune checkpoint inhibitors (ICI) are numerous including tumor microenvironment, immune tumor infiltrates, expression of immune checkpoint proteins (PD-1/PD-L1), gene expression signatures and molecular tumor profiles. Based on high impact factor publications and recent literature this review focuses on the potential predictive value of tumor molecular alterations and tumor mutation burden as predictive markers of response or resistance to ICI. We also discuss the role of circulating tumor DNA (ctDNA) to monitor ICI responses and propose an algorithm that integrates molecular markers upcoming recommendations for first line treatment.

Stem-Like Signature Predicting Disease Progression in Early Stage Bladder Cancer. The Role of E2F3 and SOX4.

The rapid development of the cancer stem cells (CSC) field, together with powerful genome-wide screening techniques, have provided the basis for the development of future alternative and reliable therapies aimed at targeting tumor-initiating cell populations. Urothelial bladder cancer stem cells (BCSCs) that were identified for the first time in 2009 are heterogenous and originate from multiple cell types; including urothelial stem cells and differentiated cell types—basal, intermediate stratum and umbrella cells Some studies hypothesize that BCSCs do not necessarily arise from normal stem cells but might derive from differentiated progenies following mutational insults and acquisition of tumorigenic properties. Conversely, there is data that normal bladder tissues can generate CSCs through mutations. Prognostic risk stratification by identification of predictive markers is of major importance in the management of urothelial cell carcinoma (UCC) patients. Several stem cell markers have been linked to recurrence or progression. The CD44v8-10 to standard CD44-ratio (total ratio of all CD44 alternative splicing isoforms) in urothelial cancer has been shown to be closely associated with tumor progression and aggressiveness. ALDH1, has also been reported to be associated with BCSCs and a worse prognosis in a large number of studies. UCC include low-grade and high-grade non-muscle invasive bladder cancer (NMIBC) and high-grade muscle invasive bladder cancer (MIBC). Important genetic defects characterize the distinct pathways in each one of the stages and probably grades. As an example, amplification of chromosome 6p22 is one of the most frequent changes seen in MIBC and might act as an early event in tumor progression. Interestingly, among NMIBC there is a much higher rate of amplification in high-grade NMIBC compared to low grade NMIBC. CDKAL1, E2F3 and SOX4 are highly expressed in patients with the chromosomal 6p22 amplification aside from other six well known genes (ID4, MBOAT1, LINC00340, PRL, and HDGFL1). Based on that, SOX4, E2F3 or 6q22.3 amplifications might represent potential targets in this tumor type. Focusing more in SOX4, it seems to exert its critical regulatory functions upstream of the Snail, Zeb, and Twist family of transcriptional inducers of EMT (epithelial–mesenchymal transition), but without directly affecting their expression as seen in several cell lines of the Cancer Cell Line Encyclopedia (CCLE) project. SOX4 gene expression correlates with advanced cancer stages and poor survival rate in bladder cancer, supporting a potential role as a regulator of the bladder CSC properties. SOX4 might serve as a biomarker of the aggressive phenotype, also underlying progression from NMIBC to MIBC. The amplicon in chromosome 6 contains SOX4 and E2F3 and is frequently found amplified in bladder cancer. These genes/amplicons might be a potential target for therapy. As an existing hypothesis is that chromatin deregulation through enhancers or super-enhancers might be the underlying mechanism responsible of this deregulation, a potential way to target these transcription factors could be through epigenetic modifiers.

EPMA World Congress: Traditional Forum in Predictive, Preventive and Personalised Medicine for Multi-Professional Consideration and Consolidation

A multilevel integrated approach for the identification of predictive markers of metabolic syndrome. Open Multiscale Systems Medicine (OpenMultiMed), E-COST CA15120

Abstract 3803: Characterization of fluid biopsy using the HD-SCA platform to re-stratify intermediate-risk organ-confined prostate cancer patients

Abstract Recent studies have demonstrated that even with current risk stratification of intermediate-risk organ-confined prostate cancer patients, 30-50% of patients are incorrectly categorized and overtreated. As the second leading cause of cancer in men, 90% of prostate cancer patients are diagnosed at organ-confined stages, where radical prostatectomy (RP) is the “golden standard” of treatment. However, deferring intervention is becoming a more popular option for low-risk patients, with a 15-year progression-free survival of 95%. High-risk patients greatly benefit from RP, with a 5-year progression-free survival of 85%, while the decision to proceed with RP is not so candid for intermediate-risk patients. Using the high-definition single cell assay (HD-SCA) platform, circulating tumor cells (CTCs) from peripheral blood (PB) and disseminating tumor cells (DTCs) from bone marrow aspirate (BMA) will be analyzed for morphological, genomic, and proteomic profiling. We hypothesize that by using morpho-proteo-genomic parameters we may develop predictive markers for a more accurate stratification of intermediate-risk patients, offering a more personalized treatment for each individual. Preliminary data shows 86% (n=43) of PB samples and 5% (n=40) of BMA are positive for Cytokeratin (CK) expressing rare circulating cells, as defined by ≥5 cells/mL. The incidence of CK+ cells in PB did not correlate with PSA, Gleason score, or clinical parameters. However, incidence of CK+ cells in PB was higher in high-risk group, though not statistically significant (p=0.784) when compared to intermediate-risk groups. Additionally, higher levels of CK expression (p&amp;lt;0.0001), as measured by relative intensity of fluorescent staining, were detected in cells detected in PB of high-risk patients relative to intermediate- and low-risk groups as measured by an analysis of variance (ANOVA) statistical model. Low levels of genomic aberrations are observed in all CK+ rare circulating cells (5%, n=118), which may speak to the fact that these patients are in early stages of their disease. The use of the HD-SCA platform to characterize the fluid biopsy may result in the identification of predictive markers of treatment response for intermediate-risk patients, resulting in reduction of overtreatment. Citation Format: Paymaneh D. Malihi, Kenneth Pienta, James Hicks, Michael Gorin, Carmen Ruiz Velasco, Anders Carlsson, Anand Kolatkar, Mariam Rodriguez Lee, Michael Morikado, Peter Kuhn. Characterization of fluid biopsy using the HD-SCA platform to re-stratify intermediate-risk organ-confined prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3803. doi:10.1158/1538-7445.AM2017-3803

Early rebiopsy to identify mechanisms and biomarkers of tumor cell survival following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy.

TPS9100 Background: Significant advances in the clinical outcomes of lung cancer patients have been achieved in part due to the identification of targetable driver mutations. The success of targeting oncogenic drivers with TKIs has allowed for improvements in response rates, progression free survival and overall survival. Despite these improvements, patients ultimately relapse. Acquired resistance has been evaluated in post-progression tumor samples and is caused by a variety of mechanisms including secondary resistance mutations, gene copy number gains, gene amplification, or bypass pathway activation. Residual tumor burden with surviving cancer cells are the origin of the ultimate tumor progression. Studies analyzing signaling pathways and other markers of these tumor cells or microenvironmental cells in tumor samples before clinical resistance develops are needed to determine how best to target this compartment. Methods: Eligible patients will have a new diagnosis of advanced NSCLC with an EGFR TKI sensitizing mutation. Additional inclusion criteria include ECOG 0-2, a tumor measurable by RECIST 1.1 and at least 2cm in one dimension, and tumor site that is accessible and safe to biopsy. Patients will undergo a pretreatment target lesion biopsy, begin treatment with an EGFR TKI then receive a second biopsy of the same target lesion after two weeks of therapy. Our primary objective is to identify differences between pretreatment and early treatment tumor samples. To do this we will be using a combination of RNA seq, multiplex protein expression analysis and proximity ligation assays. Secondary objectives include identification of predictive markers that can be used to determine which tumors will undergo epithelial to mesenchymal transition or activate other survival pathways and determination of the success rate and adverse event rate of repeat biopsy. Patients are currently being enrolled at a single academic institution however, additional clinical site openings are pending. Our goal enrollment for this study is 47 patients to achieve 20 paired biopsy samples. We will present updated enrollment and demographic information. Clinical trial information: NCT03042221.

Cisplatin in the modern era: The backbone of first-line chemotherapy for non-small cell lung cancer.

The treatment of advanced non-small cell lung cancer (NSCLC) may be changing, but the cisplatin-based doublet remains the foundation of treatment for the majority of patients with advanced NSCLC. In this respect, changes in practice to various aspects of cisplatin use, such as administration schedules and the choice of methods and frequency of monitoring for toxicities, have contributed to an incremental improvement in patient management and experience. Chemoresistance, however, limits the clinical utility of this drug in patients with advanced NSCLC. Better understanding of the molecular mechanisms of cisplatin resistance, identification of predictive markers and the development of newer, more effective and less toxic platinum agents is required. In addition to maximising potential benefits from advances in molecular biology and associated therapeutics, modification of existing cisplatin-based treatments can still lead to improvements in patient outcomes and experiences.

Abstract 3225: Identification of predictive drug resistance markers in preclinical xenograft models (PDX) of soft tissue sarcomas

Abstract Soft tissue sarcomas are a rare and heterogeneous type of cancer. Although targeted therapies have extended and improved treatment options for many cancers, treatment of sarcomas is still mainly based on standard chemotherapy with marginal improvements over the last years. As cell cultures can hardly model the complex environment of the disease we established a large panel of patient derived sarcoma xenografts (PDX). A set of 11 new sarcoma PDX models was established from samples of 29 primary human soft tissue sarcomas patients which were obtained directly from the clinic. The tumour samples were taken from representative peripheral areas of the original tumour. Fragments from each tumour were transplanted subcutaneously into immunodeficient mice. These models were together with another panel of sarcoma PDX models (Hoffmann et al. 1999) screened for sensitivity to a set of standard of care drugs (e.g. ifosfamide, docetaxel, gemcitabine, doxorubicin, dacarbazin) and some new investigational compounds (everolimus, imatinib). The main objective of the study was to establish and characterise the soft tissue sarcomas PDX, the evaluation of therapeutic options and the identification of predictive markers. Conservation of the typical sarcoma morphology of the PDX (pleomorphic-, ewing-, clear cell-, myxofibrosarcoma) was compared with the original tumour by histological and immunohistochemical staining. Heterogeneity of tumour cells in size and shape and nuclear irregularities were observed. The models were further analyzed for common oncogenic mutations using the Illumina TrueSeq Cancer Panel. Frequent mutations were detected in KDR, MET, RB1 and TP53. However no typical mutational profile was found within the panel as many of the sarcomas showed individual profiles. Most of the PDX responded to docetaxel and gemcitabine followed by doxorubicin and ifosfamide whereas only some were sensitive to dacarbazine. Sensitivity to some targeted drug has been evaluated in a subset of the PDX models. All PDX tested so fare did not respond to everolimus or imatinib. Comparison of the chemosensitivity profile of the PDX and the patient outcome was possible for 9 patients. Analysis revealed that the prediction for a therapy resistance was correct in 10 out of 13 cases. Further analysis for correlations between mutation and gene expression profiles and drug response will be performed. We have shown, that our set of established sarcoma PDX models closely resemble the patient malignancy and particularly predict treatment response in the clinic. Available pharmacological data on drug response together with the molecular characterization will allow comprehensive investigations of therapy-related response markers any may help to introduce new targeted drugs in sarcoma therapy. Citation Format: Jana Rolff, Frank Traub, Per-Ulf Tunn, Jens Hoffmann, Iduna Fichtner. Identification of predictive drug resistance markers in preclinical xenograft models (PDX) of soft tissue sarcomas. [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 3225. doi:10.1158/1538-7445.AM2015-3225