Biomarker In Cancer Patients Research Articles

OC-14 - Baseline D-dimer levels are predictive of recurrent venous thromboembolism (VTE) at 6 months in cancer patients with VTE treated with tinzaparin

VTE is a major complication in cancer patients. Despite treatment with low molecular weight heparin (LMWH), 9% will have recurrent VTE within 6 months. Measurement of plasma biomarkers in cancer patients receiving LMWH may be predictive of recurrent VTE or overall survival (OS). We conducted a single arm phase 2 study to evaluate the efficacy and safety of once daily tinzaparin for the initial treatment and extended prophylaxis of VTE in cancer patients. The study included a prospective analysis of plasma biomarkers D-dimer and IL-6 to assess whether these were predictive of recurrent VTE or OS. Consecutive patients with active cancer diagnosed with a pulmonary embolism (PE) and/or proximal deep venous thrombosis (DVT) at the University of Southern California Norris Comprehensive Cancer Center, Los Angeles County Medical Center, or New York Presbyterian - Weill Cornell Medical Center were invited to participate in this study with a target enrollment of 100 patients. Key eligibility criteria included: age ≥18, ECOG score ≤2, adequate organ function, and ≥6 month estimated survival. Patients were treated with daily subcutaneously tinzaparin 175 U/kg for 6 months on study. Tinzaparin could be continued ≤1 year at the discretion of the treating physician. All patients who received ≥1 dose were evaluable for efficacy and safety. Primary study endpoints were recurrent VTE or major bleeding. Secondary outcome measures included OS and plasma biomarkers. Biomarkers were measured at baseline, 7 days, 1 month and 6 months after tinzaparin initiation. Patients who had baseline and 1 week or 1 month samples collected were included in the biomarker analysis. 97 patients were enrolled. 2 patients were ineligible. 8 patients did not have baseline or follow-up biomarkers completed. 87 patients were included in the analysis. 28 (32%) of patients completed≥6 months of tinzaparin. Major bleeding occurred in 2 patients. 11 patients had recurrent VTE at 6 months (3 PE, 7 DVT, 1 central venous thrombosis not associated with a catheter). Median baseline D-dimer level was 2759 ng/mL (range: 375-37,591). Median baseline IL-6 level was 9.4 pg/mL (range: 0.8-20.9). Baseline D-dimer>median was predictive of VTE recurrence at 6 months (p=.006). Baseline IL-6>median was not predictive of VTE recurrence at 6 months. Neither 1 month D-dimer or IL-6 levels were predictive of VTE recurrence at 6 months. D-dimer and IL-6 at baseline and at 1 month were not predictive of OS. In patients with active cancer and VTE treated with tinzaparin, baseline D-dimer levels above the median value were predictive of VTE recurrence at 6 months.

Longitudinal analysis of hemostasis biomarkers in cancer patients during antitumor treatment

ESSENTIALS: Hemostasis biomarkers impact thrombosis occurrence and survival in cancer patients. We performed a longitudinal analysis of hemostatic parameters in 112 cancer patients. Hemostatic parameters are associated with disease state, patients' prognosis, and the risk of VTE. The procoagulant state exists not only at diagnosis, but also during the course of disease. Hemostasis biomarkers are known to have an impact on venous thromboembolism (VTE) occurrence and survival in cancer patients. As there are almost no data on longitudinal changes, we aimed to evaluate those in the present prospective observational study during chemotherapy and the course of disease. Patients with cancer of the brain (n = 39), lung (n = 41), colon (n = 15) or pancreas (n = 17) were included before initiation of antitumor therapy. Blood samples for determination of factor VIII, thrombin peak height, D-dimer, F1 + 2 , fibrinogen and soluble P-selectin (sP-selectin) were drawn on a monthly basis. The study endpoints were death, VTE occurrence, or completion of the study period. Overall, 546 blood samples of 112 patients were analyzed. D-dimer and sP-selectin levels were significantly higher in patients with distant metastasis than in those without. Patients with complete remission had significantly lower levels of F1 + 2 , D-dimer and fibrinogen. Peak height thrombin levels showed a decrease over time in all tumor types. Levels of biomarkers behaved differently in the various tumor types. Patients who developed VTE (n = 14) showed increasing levels of FVIII, sP-selectin, and D-dimer. At the last blood sampling time-point before VTE occurrence, in 13 patients the D-dimer level was above the median, and in seven of these patients it was even above the 75th percentile; however, the individual course was highly variable. Regarding survival, steadily increased FVIII, sP-selectin and D-dimer levels were associated with higher mortality. Hemostatic parameters show an association with disease state, prognosis, and the risk of VTE, not only at diagnosis, but also during the course of antineoplastic treatment.

Tumor Exosomes: Cellular Postmen of Cancer Diagnosis and Personalized Therapy

Nanosized (30-150 nm) extracellular vesicles 'exosomes' are secreted by cells for intercellular communication during normal and pathological conditions. Exosomes carry biomacromolecules from cell-of-origin and, therefore, represent molecular bioprint of the cell. Tumor-derived exosomes or TDEx modulate tumor microenvironment by transfer of macromolecules locally as well as at distant metastatic sites. Due to their biological stability, TDEx are rich source of biomarkers in cancer patients. TDEx focused cancer diagnosis allows liquid biopsy-based tumor typing and may facilitate therapy response monitoring by developing novel exosomes diagnostics. Therefore, efficient and specific capturing of exosomes for subsequent amplification of the biomessages; for example, DNA, RNA, miRNA can reinvent cancer diagnosis. Here, in this review, we discuss advancements in exosomes isolation strategies, presence of exosomes biomarkers and importance of TDEx in gauging tumor heterogeneity for their potential use in cancer diagnosis, therapy.

Identification of circulatory biomarkers from clinical trial samples

Meeting abstracts Despite significant advances in genomics, proteomics and metabolomics, the identification and validation of circulatory immunological biomarkers in cancer patients, which could be useful to monitor disease progression and response to immunotherapeutic treatments, remains as

Nontoxic virus nanofibers improve the detection sensitivity for the anti-p53 antibody, a biomarker in cancer patients.

The presence of anti-p53 antibody in serum is a biomarker for cancer. However, its high sensitivity detection is still an issue in cancer diagnosis. To tackle this challenge, we used fd phage, a human-safe bacteria-specific virus nanofiber that can be mass-produced by infecting host bacteria in an error-free manner, and genetically engineered it to display a peptide capable of recognizing and capturing anti-p53 antibody on its side wall. We employed the resultant phage nanofibers as a capture probe to develop a modified version of the enzyme-linked immunosorbent assay (ELISA) method, termed phage-ELISA. We compared it to the traditional ELISA method for the detection of anti-p53 antibody, p53-ELISA, which uses recombinant wild-type p53 protein to capture anti-p53 antibody. We applied phage-ELISA to detect anti-p53 antibody in an experimental group of 316 patients with various types of malignant tumors. We found that a detection rate of 17.7% (56 positive cases) was achieved by phage-ELISA, which was comparable to the detection rate of 20.6% for p53-ELISA (65 positive cases). However, when both phage and p53 were combined to form antibody-capturing probes for phage/p53-ELISA, a detection rate of 30.4% (96 positive cases) was achieved. Our work showed that owing to the combined capture of the anti-p53 antibody by both phage nanofibers and p53, the phage/p53-ELISA achieved the highest diagnostic accuracy and detection efficiency for the anti-p53 antibody in patients with various types of cancers. Our work suggests that a combination of nanofibers and antigens, both of which capture antibody, could lead to increased detection sensitivity, which is useful for applications in the life sciences, clinical medicine, and environmental sciences.

The impact of mindfulness-based interventions on symptom burden, positive psychological outcomes, and biomarkers in cancer patients.

Research on the use of mindfulness-based stress reduction and related mindfulness-based interventions (MBIs) in cancer care has proliferated over the past decade. MBIs have aimed to facilitate physical and emotional adjustment to life with cancer through the cultivation and practice of mindfulness (ie, purposeful, nonjudgmental, moment-to-moment awareness). This descriptive review highlights three categories of outcomes that have been evaluated in MBI research with cancer patients – namely, symptom reduction, positive psychological growth, and biological outcomes. We also examine the clinical relevance of each targeted outcome, while describing recently published original studies to highlight novel applications of MBIs tailored to individuals with cancer. Accumulating evidence suggests that participation in a MBI contributes to reductions in psychological distress, sleep disturbance, and fatigue, and promotes personal growth in areas such as quality of life and spirituality. MBIs may also influence markers of immune function, hypothalamic–pituitary–adrenal axis regulation, and autonomic nervous system activity, though it remains unclear whether these biological changes translate to clinically important health benefits. We conclude by discussing methodological limitations of the extant literature, and implications of matching MBIs to the needs and preferences of cancer patients. Overall, the growing popularity of MBIs in cancer care must be balanced against scientific evidence for their impact on specific clinical outcomes.

Biological ageing and frailty markers in breast cancer patients.

Older cancer patients are a highly heterogeneous population in terms of global health and physiological reserves, and it is often difficult to determine the best treatment. Moreover, clinical tools currently used to assess global health require dedicated time and lack a standardized end score. Circulating markers of biological age and/or fitness could complement or partially substitute the existing screening tools. In this study we explored the relationship of potential ageing/frailty biomarkers with age and clinical frailty. On a population of 82 young and 162 older non-metastatic breast cancer patients, we measured mean leukocyte telomere length and plasma levels of interleukin-6 (IL-6), regulated upon activation, normal T cell expressed and secreted (RANTES), monocyte chemotactic protein 1 (MCP-1), insulin-like growth factor 1 (IGF-1). We also developed a new tool to summarize clinical frailty, designated Leuven Oncogeriatric Frailty Score (LOFS), by integrating GA results in a single, semi-continuous score. LOFS' median score was 8, on a scale from 0=frail to 10=fit. IL-6 levels were associated with chronological age in both groups and with clinical frailty in older breast cancer patients, whereas telomere length, IGF-1 and MCP-1 only correlated with age. Plasma IL-6 should be further explored as frailty biomarker in cancer patients.

ITOC2 – 038. Role of exosomes in immune suppression

Exosomes are endosome-derived nanovesicles involved in intercellular cross-talk through the transfer of proteins and genetic material. In cancer, exosomes can contribute to mould host micro- and macroenvironment, conditioning tumour immunity both at local and systemic level. We have been collecting evidence that these nanovesicles exert a broad array of detrimental effects on the immune system, ranging from apoptosis in activated antitumour T cells to impairment of monocyte differentiation into dendritic cells and induction of suppressive effectors. More recently, we observed that cells with phenotypic and functional properties overlapping with those displayed by myeloid-derived suppressor cells (MDSC) can be generated <i>in vitro</i> by culturing normal monocytes with exosomes released by melanoma cells (Exo-MDSC). Compared to untreated monocytes, Exo-MDSC show increased mRNA level and release of protumourigenic and immunosuppressive cyto/chemokines, down-modulate the expression of HLA-DR and TLRs, and acquire the ability to inhibit T cell proliferation. A defined gene-expression and miRNA signature, involving HIF1alfa, IL6 and several immune-related genes, has been identified in Exo-MDSC as triggered by exosomal TGFb, CCL2 and selected miRNA. Given their ability to efficiently recirculate in body fluids, tumour exosomes could spread systemically and directly condition myelopoiesis. This hypothesis is supported by the evidence that peripheral MDSC from melanoma patients share defined traits of Exo-MDSC gene-expression and miRNA signature, in addition with phenotypic and functional features of these cells. MDSC accumulate in peripheral blood of melanoma patients as an early event and in association with disease progression. High MDSC frequency is an acknowledged negative prognostic factor in several tumour histologies and predicts poor response to immunotherapy, including checkpoint blockade. The identification of exosomes as a potential pathway responsible for MDSC mobilisation and accrual paves the way to the development of novel immune-based therapeutic strategies and prognostic biomarkers in cancer patients. Supported by Italian Association For Cancer Research – AIRC Grant code 12162.

Abstract 3573: Comprehensive non-invasive tumor sequencing: High fidelity sequencing of tumor-derived circulating cell-free DNA across 300 cancer patients

Abstract Background: Analysis of circulating tumor nucleic acids by massively parallel DNA sequencing has created an exciting new tool for capturing an accurate, more complete and real-time picture of a patient's tumor profile throughout the body and the course of disease. However, the widespread use of this biomarker has been limited by the high-quality false positives and non-systematic distortion present in current NGS assays, especially where the tumor-derived fraction is low (&amp;lt;1%). These limitations have heretofore impeded routine clinical use of circulating DNA in oncology. Methods: Our differentiated sequencing assay, Digital Sequencing Technology, has enabled robust, ultra-sensitive and ultra-specific detection of rare genomic abnormalities in cell-free circulating DNA. Digital Sequencing relies on enabling single-molecule sequencing using current next-gen sequencers. Our assay is able to eliminate most of the errors and distortion introduced by these sequencers and produce near-perfect representations of all rare variants. Results: We have shown that in sequencing 0.1% cancer cell line titrated samples across a broad 80kbp cancer panel, standard Illumina sequencing generates several high-quality false positives with allele frequencies of 0.05-5%, while our novel Digital Sequencing Technology results in high sensitivity and completely error-free detection of rare variants. Furthermore, we have applied our technology to analyze rare tumor-derived cell-free DNA from more than 300 cancer patient plasma samples collected at multiple sites (various US and international locations) and across different cancer types. We investigated the concordance of tumor mutation profiles derived from circulating cell-free DNA with those derived from matched tumor biopsy samples in colorectal, breast, NSCLC, prostate and melanoma cancers across patients (Stage II-IV). We also studied the presence of de novo mutations (SNV and CNV) in these cancer patient plasma samples. In general, the range of tumor DNA in plasma was determined to be between 0.03%-85.9% in these studies. This comprehensive dataset illustrates the broad power of cell-free DNA analysis as a diagnostic biomarker in cancer patients. Conclusion: The present work shows the strong potential clinical impact of Digital Sequencing in analysis of circulating cell-free tumor-derived nucleic acids, thereby allowing researchers and clinicians to comprehensively and non-invasively monitor the genetic dimension of cancer throughout the body. Citation Format: Stefanie A. Mortimer, Dragan Sebisanovic, Gangwu Mei, Benjamin Schiller, Lai Mun Siew, Aubrey Zapanta, Helmy Eltoukhy, AmirAli Talasaz. Comprehensive non-invasive tumor sequencing: High fidelity sequencing of tumor-derived circulating cell-free DNA across 300 cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3573. doi:10.1158/1538-7445.AM2014-3573

MicroRNAs: a novel non-invasive biomarker for patients with urological malignancies.

MicroRNAs are small non-coding RNA molecules which do not code for proteins, but control the expression of a significant proportion of the genome. The microRNA expression differences of normal and malignant tissue, as well as the differences in various tumor entities qualify this RNA species as biomarker for cancer patients. The detection of microRNAs in various bodily fluids stimulated research, and it was demonstrated for most human malignancies that tumorassociated microRNAs are detectable in patients circulation, thereby providing diagnostic and/or prognostic information.

The CD4+/CD14+HLA-DRlo/neg ratio as a prognostic biomarker in cancer patients

Meeting abstracts The immune status of an individual is made up of the absolute number (cells/μl) and relative ratios of each category of immune cells. To determine the extent of similarity of the immune status between individuals across malignancies, we described the immune status using

Method validation of circulating tumour cell enumeration at low cell counts

BackgroundCirculating tumour cells (CTC) are receiving increasing attention as prognostic, predictive and pharmacodynamic biomarkers in cancer patients. However, their clinical significance can be dependent on an accurate determination of CTC around cut-off values at low cell counts (<10 cells/7.5 ml). Consequently, we have conducted method validation of the CellSearch™ system focusing on clinical samples containing CTC in the cut-off region.MethodsAnalytical accuracy was first assessed employing quality controls (QC) and spiked healthy volunteer blood specimens. Results were analysed by β-expectation tolerance intervals (BETI). Inter-operator error (6 different readers) was then characterised in 38 different patient samples, 68% of which had ≤5 CTC and data were analysed by β-content γ-confidence tolerance intervals (BCTI).ResultsResults from QCs and spiked blood confirmed a 3-4-fold higher degree of imprecision at the low (48 cells, BETI = + 0.288/-0.345, β = 95%) compared to the high QC (987 cells, BETI = +0.065/-0.140, β = 95%). However, when data for individual analysts were interrogated characteristic systematic errors were detected. In the analysis of patient samples again individual analysts introduced a highly specific error into the interpretation of CTC images, which correlated to the level of training and experience. When readers were selected based on BETI and BCTI results, the high level of between-operator error (up to 170%) observed at CTC of ≤ 5 was reduced to < 30%.ConclusionsInter-operator variability in enumeration of CTC at low cell counts can be considerable, but is also potentially avoidable by following simple guidance steps.

Analyses of anticancer drugs by capillary electrophoresis: a review

Capillary electrophoresis is a fast, inexpensive and low detection limit technique for the analysis of anticancer drugs. It has been used to analyze various anticancer drugs in biological samples, pharmaceutical preparations and environmental matrices. It has also been used to detect various cancer biomarkers in cancer patients. The present article describes the state-of-the art of capillary electrophoresis for the analyses of anticancer drugs. Various drugs discussed belong to several groups such as antimitotic agents, nucleoside analogs, antibiotics, topoisomerase inhibitors and DNA intercalating agents. In addition, efforts have also been made to discuss sample preparation, applications of capillary electrophoresis in genomic research, optimization and future perspectives.

Shedding of Soluble Epidermal Growth Factor Receptor (sEGFR) Is Mediated by a Metalloprotease/Fibronectin/Integrin Axis and Inhibited by Cetuximab

Soluble epidermal growth factor receptor (sEGFR) is a circulating serum biomarker in cancer patients. Recent studies suggest that baseline serum sEGFR concentrations may predict responsiveness to EGFR-targeted therapy. Here, we demonstrate that sEGFR is generated through proteolytic cleavage of a cell surface precursor of an alternately spliced EGF receptor isoform and that sEGFR binds to EGF with high affinity. Proteolytic cleavage is stimulated by an anti-α5/β1 integrin antibody and 4-aminophenylmercuric acetate, and inhibited by fibronectin. Two FDA-approved therapeutic anti-EGFR antibodies also inhibit shedding of sEGFR, thus implicating the cell surface precursor of sEGFR as a competing target for anti-EGFR antibodies in human tissues. These observations parallel trastuzumab regulation of HER2 shedding and have implications for patient stratification in future clinical trials of EGFR-targeted antibodies.

Abstract 54: Marked reduction of sequence artifacts in massively parallel sequencing of formalin-fixed paraffin-embedded DNA by depletion of uracil containing templates.

Abstract Formalin-fixed and paraffin-embedded (FFPE) tissues are commonly used for the detection of mutational biomarkers in cancer patients. One of the challenges associated with FFPE DNA in genetic testing is its high number of sequence artefacts, thus increasing the risk of false positive results particularly for low level mutations. We have previously shown that uracil lesions in FFPE DNA due to deamination of cytosines are the major cause of C:G&amp;gt;T:A sequence artefacts and pretreatment of damaged FFPE DNA with uracil-DNA glycosylase (UDG) prior to PCR amplification markedly reduces the C:G&amp;gt;T:A sequence artefacts using methodologies suitable for the testing of limited numbers of genomic loci. As the number of cancer associated mutations increases, massively parallel sequencing (MPS) approaches are increasingly necessary. In particular, the use of targeted amplicon based strategies is being implemented in many laboratories. We set out to test whether sequence artifacts were a serious problem and whether the UDG pretreatment strategy is also applicable to a amplicon based targeted MPS approach (Truseq Cancer Panel). Samples not treated with UDG showed multiple sequence artefacts with a significant portion of changes greater than background sequencing error, with C:G&amp;gt;T:A changes forming the vast majority of artefacts. Treatment of the samples with UDG prior to sequencing dramatically reduced the majority of C:G&amp;gt;T:A changes without affecting the detection of known SNPs and somatic mutations. Elimination of artefactual changes by UDG treatment also improved the accurate detection of low-level sequence variants. Interestingly, most C:G&amp;gt;T:A changes that occurred in the context of CpG dinucleotides were resistant to the UDG treatment as a likely consequence of 5-methyl cytosine being deaminated to thymine. This approach will greatly facilitate accurate detection of mutations in FFPE samples using amplicon-based approaches which is imperative for personalised cancer medicine, especially when working with samples of low tumour purity. This work also has implications for choice of tissue and protocols for the assessment of heterogeneity in tumours. Citation Format: Hongdo Do, Stephen Q. Wong, Jason Li, Alexander Dobrovic. Marked reduction of sequence artifacts in massively parallel sequencing of formalin-fixed paraffin-embedded DNA by depletion of uracil containing templates. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 54. doi:10.1158/1538-7445.AM2013-54 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Circulating tumor cells as therapy-related biomarkers in cancer patients.

Carcinomas (tumors of epithelial origin) are responsible for most of all new cancers in the industrialized countries. Due to the high mortality rate caused by the metastatic spread of aggressive cancer cells, there is an urgent demand in finding new biomarkers, which should detect early formation of metastases and monitor efficacy of systemic adjuvant therapy in a timely manner. It has been considered that the molecular analysis of cells which are shed from tumors into the blood system (circulating tumor cells (CTCs)) might provide new insights for the clinical management of cancer, probably far earlier than using traditional high-resolution imaging technologies. Clinical trials indicated that CTCs can be deployed for diagnostic, monitoring, and prognostic purposes. Furthermore, these cells are discussed to be suitable as predictive markers. In any case, identification of CTCs requires innovative and challenging technologies as detection methods should be specific, sensitive, standardized, and highly reproducible. Although many different approaches have been developed until now, only the CellSearch™ method has been cleared by the American Food and Drug Administration. Although the detection of CTCs has already shown to have a prognostic impact in many tumor entities including breast, prostate, lung and colon cancer, ongoing and future studies are aimed to explore whether CTCs can be used for an individual therapy decision making including novel immunotherapeutic approaches. This review discusses (1) different detection strategies for CTCs, (2) their clinical impact, and (3) the potential use of CTCs guiding the treatment of individual cancer patients.

Cell-free microRNA expression profiles in malignant effusion associated with patient survival in non-small cell lung cancer.

13 Background: MicroRNAs (miRNAs) expression is altered in cancer cells, and miRNAs could serve as diagnostic and prognostic biomarker for cancer patients. This study was designed to analyze circulating miRNAs expression in the malignant pleural effusion (MPE) and their association with patient survival in non-small cell lung cancer (NSCLC). Methods: Pleural effusion from 184 patients with NSCLC and MPE were collected. MiRNA microarray and bioinformatics interpretation were used to evaluate miRNA expression profiles in 10 NSCLC patients with different survival prognosis. Associations were validated in 184 patients (randomly classified into training and validation set with equal number in each group) using quantitative RT-PCR. Risk scores were formulated based on the expression signature of miRNAs. Clinical data, such as patient survival, were collected for correlation analysis. Results: Thirty-three miRNAs were found to be altered more than two-fold by microarray in malignant effusions between longer-survival and shorter-survival groups, and levels of five miRNAs (miRNA-93, miRNA-100, miRNA-134, miRNA-151, and miRNA-345) were significantly associated with overall survival. High expression of miR-100 and low expression of miRNA-93, miRNA-134, miRNA-151, and miRNA-345 were associated with poor survival in both the training and validation cohort. Patients with high risk scores had overall poor survival compared to the patients with low risk scores. Risk score was an independent predictor of patient survival. Conclusions: Expression patterns of miRNAs are systematically altered in MPE of patient with NSCLC. The five miRNA signature from the effusion may serve as a predictor for the overall survival of patients with lung cancers.

EGFR mutations in circulating tumour DNA

EGFR-mutated non-small-cell lung cancer (NSCLC) responds well to EGFR tyrosine-kinase inhibitors such as erlotinib. Median progression-free survival (PFS) reported in the erlotinib group of the European Tarceva versus Chemotherapy (EURTAC) trial 1 Rosell R Carcereny E Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13: 239-246 Summary Full Text Full Text PDF PubMed Scopus (4347) Google Scholar was 9·7 months compared with 5·2 months in the standard chemotherapy group (hazard ratio [HR] 0·37, 95% CI 0·25–0·54; p<0·0001). The HR for progression in EURTAC was much the same as the pooled HR for progression of 0·23 (95% CI 0·19–0·27) reported in four randomised studies in Asian patients. 1 Rosell R Carcereny E Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13: 239-246 Summary Full Text Full Text PDF PubMed Scopus (4347) Google Scholar However, the disease-free time to progression was still less than 1 year in EURTAC, 1 Rosell R Carcereny E Gervais R et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13: 239-246 Summary Full Text Full Text PDF PubMed Scopus (4347) Google Scholar and thus identification of mechanisms of acquired resistance, including to the EGFR T790M resistance mutation, is crucial. To this end, a second biopsy at the time of progression is becoming increasingly accepted. However, often only a small amount of tumour is obtained and, to circumvent the problem of access to tissue samples, studies have focused on circulating tumour DNA (ctDNA) in plasma or serum. ctDNA can be used as a liquid biopsy, allowing repeated blood samples to be taken and changes in mutation status to be tracked throughout a cancer treatment, paving the way for a potential use in following up of treatment response, gauging prognosis, or monitoring of recurrence. 2 Schwarzenbach H Hoon DS Pantel K Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011; 11: 426-437 Crossref PubMed Scopus (1971) Google Scholar

Circulating nucleic acids as biomarkers in cancer patients

Circulating nucleic acids as biomarkers in cancer patients

Serum NT‐proBNP in the early detection of doxorubicin‐induced cardiac dysfunction

Cardiac dysfunction is a major limitation of anthracycline treatment in cancer patients. There are several useful serum markers in other types of cardiomyopathy, including N-terminal pro-brain-natriuretic peptide (NT-proBNP), troponin-T and creatine kinase MB isoform. We investigated the potential application of these serum biomarkers in cancer patients receiving treatment with anthracycline. We collected data from 52 female breast cancer patients receiving doxorubicin and cyclophosphamide every 3 weeks for four cycles. Cardiac function evaluations by echocardiography were done at baseline and at the end of the fourth cycle of chemotherapy. Patients' blood samples were serially measured for cardiac biomarkers. The mean cumulative dose of doxorubicin in this study was 237 mg/m(2) . No symptomatic heart failure was detected during the study period. However, there were significant asymptomatic reductions of left ventricular ejection fraction (LVEF) from mean ± SD 70.7 ± 6% at baseline to 67.0 ± 5% (P < 0.001). By clinical toxicity criteria the LVEF decline was grade I in 18% and grade II in 4%. After one dose of chemotherapy, a significant rise of serum NT-proBNP occurred in patients who subsequently developed an LVEF reduction compared with patients with normal LVEF (P = 0.04). A correlation analysis demonstrated that the reduction of fractional shortening was significantly associated with elevated NT-proBNP (r = -0.016, P = 0.014). Asymptomatic reductions in cardiac function are common in breast cancer patients treated with doxorubicin. NT-proBNP may serve as a convenient serum biomarker for the early detection of cardiotoxicity induced by anthracycline.