Marker Of Therapeutic Response Research Articles

Serial monitoring of circulating tumor DNA in patients with metastatic colorectal cancer to predict the therapeutic response.

713 Background: Early biomarkers of therapeutic responses could help optimize the treatment of metastatic colorectal cancer (mCRC). This prospective study was designed to explore the serial changes in plasma-circulating tumor DNA (ctDNA) as an early marker of therapeutic response to systemic treatment in mCRC. Methods: Twenty-six mCRC patients receiving standard first-line therapy once every two weeks were enrolled. Plasma ctDNA, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were assessed serially before each of the first four cycles. Somatic mutations in plasma ctDNA were detected via next-generation sequencing using a panel of 50 cancer-related genes, and the mutation of maximal frequency in pretreatment ctDNA was selected as the candidate mutation for analysis. Radiologic responses were assessed after the fourth cycle. Results: Mutations in pretreatment ctDNA could be detected in 25 (96.2%) of the 26 initially enrolled patients. Among the 20 patients monitored serially, changes in ctDNA could differentiate patients with progressive disease two cycles (approximately four weeks) earlier than the changes in CEA and CA19-9 levels could, and changes in ctDNA levels as early as prior to cycle 2 predicted the radiologic responses after cycle 4. A log2 value of fold-change in ctDNA after cycle 1 (log2 (C1/C0)) > 0.044 predicted progressive disease, with a sensitivity and specificity of 100.0% (95%CI: 47.8-100.0%) and 86.7% (95%CI: 59.5-98.3%), respectively, and an accuracy of 90.0% (95%CI: 68.3-98.8%). Patients with log2 (C1/C0) > 0.044 showed worse progression-free survival than did those with log2 (C1/C0) ≤0.044 (median 2.0 versus 17.0 months; P = 0.092). Conclusions: Early changes in ctDNA that are detected via targeted sequencing could predict later radiologic responses in mCRC.

7 Genetic Variants in the Vascular Endothelial Growth Factor Pathway As Potential Markers of Ovarian Cancer Risk, Therapeutic Response, and Clinical Outcome

7 Genetic Variants in the Vascular Endothelial Growth Factor Pathway As Potential Markers of Ovarian Cancer Risk, Therapeutic Response, and Clinical Outcome

Genetics and Epigenetics of Glioblastoma: Therapeutic Challenges

Glioblastoma is a brain tumor that develops due to both genetic and epigenetic risk factors. Crosstalk between the genetic and the epigenetic offers new possibilities for therapy. Abnormal methylation of methylguanine-DNA methyltransferase (MGMT) promoter region and isocitrate dehydrogenase 1 (IDH1) mutations are prognostic and therapeutic response markers in glioblastoma. Mutations in genes such as epidermal growth factor receptor, TP53, and P16 have been reported in glioblastoma; therefore, they might associate with survival and worth to be used in estimating survival risks. MKI67 expression associates with posttreatment such as adjuvant radiotherapy results evaluation. On the other hand, monosomies, such as deletions of chromosome 10, especially q23 and q25–26, are good markers for estimating the progression and aggressiveness of glioblastoma. The profile of MGMT methylation is modified in glioblastoma and hence can be a good target for epigenetic drugs. Other useful strategies in the treatment of gliomas include several micro-RNAs (MiRs) which are alerted in glioblastoma and which affect the regulation of mRNAs are associated with gene expression profiles of the disease. Epigenetic drugs, such as azacitidine and decitabine, which belong to the DNA methyltransferases (DNMT) inhibitor 5-aza-2'deoxycytidine (5-aza-dC), can suppress DNMT1 and stimulate tumor suppressor genes expression. MGMT methylation status and IDH mutational status are two valuable prognosis and therapeutic response markers in glioblastoma. Regulation of glioblastoma through epigenetic drugs, such as not only inhibitors of EZH2, histone deacetylase, and DNMT, but also MiRs, are promising approaches in glioblastoma treatment. Improves in understanding cancer genetic and epigenetic disruptions is the key point in solving the puzzle of glioblastoma treatment.

Prognostic Significance of Reduction in Ki67 Index After Neoadjuvant Chemotherapy in Patients With Breast Cancer in Kerman Between 2009 And 2014

Breast cancer is the most common malignancy among women. The Neoadjuvant chemotherapy is the treatment of choice for non-operable tumors. The Ki67 is a proliferation marker that can be used to predict the therapeutic response to chemotherapy and the patients' prognosis. This retrospective study was carried out on 55 consecutive patients with breast cancer referred to a Training Tertiary Healthcare Center in Kerman, Iran since 2009 to 2014. After diagnostic approval, the tissue samples of patients were examined for estrogen and progesterone receptors, ki67 and HER2-neu markers by using immunohistochemical staining. Then the patients were treated with 6 cycles of Neoadjuvant chemotherapy regimens by Doxorubicin and Taxans or 4 chemotherapy cycles, containing Anthracycline and Cyclophosphamide and 4 cycles of Paclitaxel. After mastectomy, their samples were reexamined for ki67 again and classified into three groups (low: ki67<15%), medium (Ki67 = 16-30%) and high (Ki67> 30%). Before chemotherapy, 54.5% of the patients had high expression of Ki67. But after chemotherapy, 52.7 of the patients had complete therapeutic response showing that the Ki67 level was reduced significantly (P=0.003). Before and after Neoadjuvant chemotherapy, Ki67 measurements may be used as a predictive marker of therapeutic response.

Clinical Utility of Serum Human Epidermal Growth Factor Receptor Type 2 Testing as a Marker of Therapeutic Response In Tissue HER2-Positive Breast Cancer Patients

Clinical Utility of Serum Human Epidermal Growth Factor Receptor Type 2 Testing as a Marker of Therapeutic Response In Tissue HER2-Positive Breast Cancer Patients

Disruption of DNA repair in cancer cells by ubiquitination of a destabilising dimerization domain of nucleotide excision repair protein ERCC1.

DNA repair pathways present in all cells serve to preserve genome stability, but in cancer cells they also act reduce the efficacy of chemotherapy. The endonuclease ERCC1-XPF has an important role in the repair of DNA damage caused by a variety of chemotherapeutic agents and there has been intense interest in the use of ERCC1 as a predictive marker of therapeutic response in non-small cell lung carcinoma, squamous cell carcinoma and ovarian cancer. We have previously validated ERCC1 as a therapeutic target in melanoma, but all small molecule ERCC1-XPF inhibitors reported to date have lacked sufficient potency and specificity for clinical use. In an alternative approach to prevent the repair activity of ERCC1-XPF, we investigated the mechanism of ERCC1 ubiquitination and found that the key region was the C-terminal (HhH)2 domain which heterodimerizes with XPF. This ERCC1 region was modified by non-conventional lysine-independent, but proteasome-dependent polyubiquitination, involving Lys33 of ubiquitin and a linear ubiquitin chain. XPF was not polyubiquitinated and its expression was dependent on presence of ERCC1, but not vice versa. To our surprise we found that ERCC1 can also homodimerize through its C-terminal (HhH)2 domain. We exploited the ability of a peptide containing this C-terminal domain to destabilise both endogenous ERCC1 and XPF in human melanoma cells and fibroblasts, resulting in reductions of up to 85% in nucleotide excision repair and near two-fold increased sensitivity to DNA damaging agents. We suggest that the ERCC1 (HhH)2 domain could be used in an alternative strategy to treat cancer.

Psoriasis pharmacogenetics: HLA-Cw*0602 as a marker of therapeutic response to ustekinumab

Psoriasis pharmacogenetics: HLA-Cw*0602 as a marker of therapeutic response to ustekinumab

Lymphocytes as Biomarkers of Therapeutic Response in Rheumatic Autoimmune Diseases, Is It a Realistic Goal?

Many therapies are available for patients with rheumatoid arthritis (RA) while biological therapies have limited effects in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). In both cases, biomarkers predicting drug response would be very useful to guide clinicians in their choice. We performed a systematic review to evaluate the value of lymphocyte phenotyping as a marker of therapeutic response. Of the 1063 articles retrieved, 39 fulfilled inclusion criteria and were included in the present review (25 for RA, 10 for SLE, and 4 for pSS). Lymphocyte phenotyping was described as a biomarker of therapeutic response in many studies, but most results could not be confirmed by independent teams using multivariate analysis. The most consistent result might be the association between rituximab response and the levels of memory B cells before therapy, although some studies were controversial. Thus, lymphocyte phenotyping cannot yet be proposed as a biomarker of response in rheumatic autoimmune diseases. The lack of reproducibility between studies may be explained by technical issues influencing lymphocyte phenotyping so standardization procedures should be developed for future studies. The patients' characteristics vary between studies, and large population studies, including a wide range of patients' characteristics and biomarkers, are required to provide predictive models for clinical outcomes. The use of new flow cytometry techniques such as single-cell mass cytometry technology might also help finder reliable biomarkers in the future.

Ventricular Diastolic Pressure Ratio as a Marker of Treatment Response in Pulmonary Hypertension

Pulmonary hypertension (PH) is diagnosed and classified through right-sided heart catheterization, with a number of hemodynamic markers used to help guide treatment decisions. These markers may not reflect the complex remodeling of the right ventricle or the interplay between ventricles and struggle to predict treatment response. This study investigates the use of a novel marker: the ratio of left ventricular end-diastolic pressure to right ventricular end-diastolic pressure (LVEDP/RVEDP) in predicting treatment outcomes in a cohort of patients with PH. We performed a retrospective analysis of patients with PH at INOVA Fairfax Hospital's advanced lung disease program with simultaneous left-sided and right-sided heart catheterization. The primary end point was the time to clinical improvement, defined by an improvement in distance walked on the 6-min walk test (6MWT) of > 35m in a year without interceding hospitalization for worsening PH or the need for additional PH therapy. A total of 51 patients were included in the final analysis, 21 of whom (41.2%) had a salutary treatment effect with a mean improvement in the 6MWT of 75 m. Treatment responders were more likely to have a lower LVEDP/RVEDP ratio (1.08 vs1.62; P= .051). This association persisted in the final multivariate regression model after adjustment for age and sex and controlling for severity of PH (OR, 0.17; 95%CI, 0.03-0.65; P= .024). The LVEDP/RVEDP ratio is a novel marker for therapeutic response in patients with PH treated with pulmonary vasodilator medications and may offer robust predictive value independent of existing markers of disease severity.

Current Update of Patient-Derived Xenograft Model for Translational Breast Cancer Research.

Despite recent advances in the treatment of patients with breast cancer (BrCa), BrCa remains the third leading cause of cancer death for women in the US due to intrinsic or acquired resistance to therapy. Continued understanding of gene expression profiling and genomic sequencing has clarified underlying intratumoral molecular heterogeneity. Recently, the patient-derived xenograft (PDX) models have emerged as a novel tool to address the issues of BrCa genomics and tumor heterogeneity, and to critically transform translational BrCa research in the preclinical setting. PDX models are generated by xenografting cancer tissue fragments obtained from patients to immune deficient mice, and can be passaged into next generations of mice. Generally, in contrast to conventional xenograft using cancer cell lines, PDXs are biologically more stable and recapitulate the individual tumor morphology, gene expression, and drug susceptibility of each patient. PDX may better model the original patient's tumor by retaining tumor heterogeneity, gene expression, and similar response to treatment. PDX models are thus thought to be more translationally relevant, especially as a drug development tool, because PDXs can capture the genetic character and heterogeneity that exists within a single patient's tumor and across a population of patients' tumors. PDX models also hold enormous potential for identifying predictive markers for therapeutic response. It has been repeatedly shown that PDX models demonstrate similar levels of activity as compared to the clinical response to therapeutic interventions. Therefore, this enables identification of therapeutic interventions that can most likely benefit a patient. This allows us to address the issues of BrCa genomics and tumor heterogeneity using PDXs in "pre-clinical" trials. Herein, we reviewed recent scientific development and future perspectives using PDX models in BrCa.

P.11.9: Mucosal and Transmural Healing During Anti-Tnf Therapy. Is Fecal Calprotectin a Marker of Therapeutic Response?

P.11.9: Mucosal and Transmural Healing During Anti-Tnf Therapy. Is Fecal Calprotectin a Marker of Therapeutic Response?

Treatment of different phenotypes of chronic obstructive pulmonary disease

The aim of the study was to investigate COPD phenotypes in order to improve treatment efficacy of occupational COPD and comorbidity of COPD and hypertension.Methods. This singlecenter observational study involved 97 patients with occupational COPD (according to GOLD 2011 criteria) exposed to chemicals (n = 42) or dusts (n = 55) and 103 patients with of COPD and hypertension (according to ESH/ESC 2013 criteria). Comparison groups included patients with 73 smokers with COPD and 99 patients with COPD without hypertension. Phenotypic features of occupational COPD caused by different workrelated factors and comorbidity of COPD and hypertension were described. The obtained results underlie the treatment programs for each group. A singlecenter openlabel comparative study was conducted to evaluate the efficacy of this approach.Results. Beclometasone/formoterol combination and tiotropium were used for therapy of COPD related to chemical exposure; indacaterol, glycopyrronium and budesonide were used for therapy of dustrelated COPD. Patients with comorbidity of COPD and hypertension were treated with budesonide/formoterol combination and aclidinium. Coprimary endpoints were exacerbation rate and change of FEV1pred. Treatment with beclometasone/formoterol and tiotropium decreased the exacerbation rate, increased FEV1, improved symptoms, and decreased pulmonary hypertension in patients with COPD related to chemical exposure. Treatment with indacaterol, glycopyrronium and budesonide decreased the exacerbation rate, increased FEV1, improved symptoms, and decreased pulmonary hypertension in patients with dustrelated COPD. Treatment with budesonide/formoterol and aclidinium improved lung function, decreased pulmonary hypertension and improved symptoms in patients with comorbidity of COPD and hypertension.Conclusion. Different risk factors of COPD could be considered as markers of therapeutic response.

P598 Mucosal and transmural healing during anti-TNF therapy. Is fecal calprotectin a marker of therapeutic response?

P598 Mucosal and transmural healing during anti-TNF therapy. Is fecal calprotectin a marker of therapeutic response?

Actualités sur l’immunothérapie en pathologie des voies aérodigestives supérieures

Head and neck (HN) carcinomas (mostly represented by squamous cell carcinomas [SCC]) still have a poor prognosis, which could be dramatically improved with immunotherapy. Tumor's microenvironment changes, caused by many endogenous or exogenous events, can correlate with prognosis and therapeutic response. Here, we review recent data regarding HNSCC, nasopharyngeal carcinomas (NPC) and salivary gland malignant tumors, all three being potential target of immunotherapies. About half of HNSCC exhibit PD-L1expression, this expression being upregulated in HPV-positive tumors. In recent clinical trials, a better therapeutic response to anti-PD-1has been obtained in patients with higher PD-L1expression. Food and Drug Administration (FDA) approved the use of these therapeutics without the screening of patients regarding PD-L1status. Activation status, density and localisation of TIL as well as PD-L2, γ-interferon, inflammatory cytokines, epithelial-mesenchymal transition phenotype and mutational burden may all be potential therapeutic response markers. In Epstein-Barr Virus (EBV)-induced nasopharyngeal non-keratinizing cancer, PD-L1is over-expressed compared to EBV negative-tumors. A 22% response rate has been observed under anti-PD-1treatment, among PD-L1-positive HNSCC patients. There is little data regarding microenvironment of salivary gland cancer. PD-L1shows great heterogeneity in localisation, when expressed. A 11% response rate has been obtained under anti-PD-1treatment among PD-L1-positive NPC patients. A better understanding of immune checkpoint regulation processes needs to be achieved to allow patients with HN carcinomas to benefit from these promising immunotherapies.

Multiple sclerosis: Association of gelatinase B/matrix metalloproteinase-9 with risk and clinical course the disease

BackgroundMultiple sclerosis (MS) is an autoimmune disease characterized by inflammation and axonal degeneration of the central nervous system and a leading cause of disability in young adults. The matrix metalloproteinases in general and specially gelatinase B/metalloproteinase-9 (MMP-9) plays a role in the pathogenesis of multiple sclerosis. ObjectiveTo investigate the presence of the MMP-9 −1562C/T polymorphism in a Portuguese population of MS patients and assess its impact in susceptibility and course of the disease. The relation of MMP-9 serum levels with the polymorphism and with clinical and therapeutic factors will also be assessed. MethodsOur study included 355 Caucasian individuals distributed as MS patients (n=169) and controls (n=186). Samples were genotyped for −1562C/T polymorphism by PCR-RFLP analysis. MMP-9 concentration in serum was analyzed using a commercially available enzyme-linked immunosorbent assay. ResultsA significant increase in T-allele frequency was found in female MS patients, but not in the total patient population. No association between the presence of the polymorphism and disease progression was found. MMP-9 serum concentrations were increased in patients, and although not influenced by the −1562C/T polymorphism, were modified by INF-beta therapy. ConclusionAlthough we did not find an association of this polymorphism with disease susceptibility or prognosis, MMP-9 appears to be a good therapeutic response marker for multiple sclerosis.

72. Corticospinal reserve and disability predict efficacy of repetitive transcranial stimulation on walking abilities in people with progressive multiple sclerosis undergoing rehabilitation

Walking impairment has a strong impact on quality of life of multiple sclerosis (MS) patients. Excitatory Transcranial-Repetitive-Magnetic-Stimulation (rTMS) enhances corticospinal excitability and plasticity, potentially favouring the effects of neurorehabilitation. The aim of this study is to explore the impact of neurophysiological and clinical features on rTMS efficacy on walking in progressive MS patients undergoing neurorehabilitation. 42 progressive MS patients, randomized into real and sham-placebo rTMS, underwent 11 rTMS sessions during neurorehabilitation. Motor-threshold (RMT), duration of disease progression, walking speed (10mt-walking-test) and endurance (2 and 6 mwt) were assessed at baseline and at the end of treatment, as well as Modified-Ashworth-Scale (MAS), pain and spasticity VAS, Fatigue-Severity-Scale, EDSS, MS-walking-scale-12, PASAT and nine-hole-peg-test. Real rTMS patients showed greater improvement both in 10mt (p = 0.007) and 6mwt (p = 0.04). Greater disability was associated with greater 6mwt improvement in all patients (p = 0.01) and in the real-rTMS subgroup (p = 0.04), not in sham. In real-rTMS group, RMT negatively correlated with 6mwt improvement (p = 0.003). The potential for improvement, greater in more disabled patients after rTMS, can be exploited using this treatment associated with neurorehabilitation. RMT, resulting from combination of corticospinal excitability and of corticomotor fibres available for conduction, could be considered a predictive marker of therapeutic response to rTMS neuromodulation.

Frequent detection of PIK3CA mutations in single circulating tumor cells of patients suffering from HER2-negative metastatic breast cancer

Modern technologies enable detection and characterization of circulating tumor cells (CTC) in peripheral blood samples. Thus, CTC have attracted interest as markers for therapeutic response in breast cancer. First studies have incorporated CTC analyses to guide therapeutic interventions and stratification of breast cancer patients. Aim of this study was to analyze characteristic features of CTC as biomarker for predicting resistance to HER2-targeted therapies. Therefore, CTC from metastatic breast cancer patients with HER2-negative primary tumors screened for the prospective randomized phase III trial DETECT III were explored for their HER2 status and the presence of PIK3CA mutations. Detection and characterization of HER2 expression of CTC were conducted with the CellSearch® system. Fifteen of 179 CTC-positive patients (8.4%) contained ≥1 CTC with strong HER2 expression. Genomic DNA from individual CTC isolated by micromanipulation was propagated by whole genome amplification and analyzed for PIK3CA mutations in exons 9 and 20 by Sanger sequencing. One or more CTC/7.5 mL were detected in 179/290 patients (61.7%). In 109 patients (34.8%), ≥5 CTC/7.5 mL were found. We detected at least one CTC with the mutation p.E542K, p.E545K, p.H1047R, p.H1047L or p.M1043V in 12/33 patients (36.4%). Thirty six of 114 CTC (31.6%) harbored one of these mutations. CTC in individual patients exhibited heterogeneity concerning PIK3CA mutations and HER2 expression. In conclusion, clinically relevant genomic aberrations such as mutations in the hotspot regions of exon 9 and 20 of the PIK3CA gene can be detected in single CTC and might provide insights into mechanisms of resistance to HER2-targeted therapies.

97 Evaluation of predictive markers of therapeutic response to oral supplementation with l -arginine in patients with preeclampsia

Introduction Dysfunction of l -arginine/NO endothelial system is one of the factors that contribute to preeclampsia development. The supplementation with l -arginine could be used as treatment and/or prevention for this disorder. Objective To supplement pregnant women with preeclampsia and determine whether endogenous biomarkers can indicate which pregnant women will respond or not supplementation with l -arginine. Patients and methods We analyzed 56 pregnant women diagnosed with preeclampsia, divided into two groups 39 without supplementation and 17 who underwent supplementation with 3 g l -arginine orally for 10 days. Results The concentrations of the inflammation markers IL-6 and CRP were lower at the beginning of the supplementation when compared with the end of supplementation IL-6 (4.08 ± 3.74 vs. 10.67 ± 9.03, P = 0,03); PCR (5.52 ± 2.72 vs. 7.00 ± 3.37, P = 0.04). For other biomarkers analyzed we did not observe significant changes or the comparison between groups (sVCAM: P = 0.74; ADMA: P = 0.76; endoglin: P = 0 28; CD40: P = 0.22 and sFlt-1: P = .35) or between the beginning and the end of supplementation (sVCAM: P = 0.53; ADMA: P = 0.89; endoglin: P = 0.15; CD40: P = 0.53 and sFlt-1: P = 0.55). Conclusion The quantification of biomarkers showed that the participants were not responsive to supplementation with l -arginine since there was no change in the concentration thereof, or in the clinical and laboratory findings.

Circulating Bone Marrow-Derived CD45-/CD34+/CD133+/VEGF+ Endothelial Progenitor Cells in Adults with Crohn's Disease.

Circulating endothelial progenitor cells (EPCs) are bone marrow-derived stem cells able to migrate to sites of damaged endothelium and differentiate into endothelial cells. Altered EPC level and function have been described in various inflammatory diseases and have been shown to augment vasculogenesis in murine models. Previous studies of EPC in the context of Crohn's disease (CD) have yielded conflicting results. To determine whether the circulating levels of EPCs are changed in the context of CD. CD patients and healthy controls were recruited. Disease activity was assessed by CDAI. Peripheral blood mononuclear cells were isolated and EPC numbers evaluated by FACS analysis using anti-CD34, anti-VEGF receptor-2, anti-CD133, and anti-CD45 markers. Eighty-three subjects, including 32 CD patients and 51 controls were recruited, including 19 (59.4%) and 23 (45%) males (p=0.26), aged 34.8±14.9 and 43.3±18.5years (p=0.64), in cases and controls, respectively. Mean CDAI was 147±97, disease duration was 12.7±11.1years, and 28 (87.5%) were receiving biologics for a mean duration of 21.7±16.8months. The mean level of peripheral EPCs in CD patients was 0.050±0.086 percent and 0.007±0.013% in controls (p<0.01). There was no significant correlation between EPC levels and age (r=-0.13, p=0.47), CDAI (r=-0.26, p=0.15), disease duration (r=-0.04, p=0.84), or duration of treatment with biologics (r=0.004, p=0.99). EPCs are elevated in patients with CD. Further studies are needed to examine the function of EPCs and their possible role as a marker of disease severity or therapeutic response.

The Role of microRNAs in the Diagnosis and Treatment of Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a very challenging malignancy. Disease is diagnosed in an advanced stage in the vast majority of patients, and PDAC cells are often resistant to conventional cytotoxic drugs. Targeted therapies have made no progress in the management of this disease, unlike other cancers. microRNAs (miRs) are small non-coding RNAs that regulate the expression of multitude number of genes by targeting their 3′-UTR mRNA region. Aberrant expression of miRNAs has been linked to the development of various malignancies, including PDAC. In PDAC, a series of miRs have been defined as holding promise for early diagnostics, as indicators of therapy resistance, and even as markers for therapeutic response in patients. In this mini-review, we present an update on the various different miRs that have been defined in PDAC biology.