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Molecular Profiling of Peripheral Blood Is Associated with Circulating Tumor Cells Content and Poor Survival in Metastatic Castration-Resistant Prostate Cancer

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Molecular Profiling of Peripheral Blood Is Associated with Circulating Tumor Cells Content and Poor Survival in Metastatic Castration-Resistant Prostate Cancer www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No. 12 Molecular profiling of peripheral blood is associated with circulating tumor cells content and poor survival in metastatic castration-resistant prostate cancer Mercedes Marín-Aguilera1, Òscar Reig1,2, Juan José Lozano3, Natalia Jiménez1, Susana García-Recio1,4, Nadina Erill5, Lydia Gaba2, Andrea Tagliapietra2, Vanesa Ortega2, Gemma Carrera6, Anna Colomer5, Pedro Gascón4 and Begoña Mellado1,2 1 Translational Genomics Group and Targeted Therapeutics in Solid Tumors Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain 2 Medical Oncology Department, Hospital Clínic, Barcelona, Spain 3 Bioinformatics Platform Department, Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Barcelona, Spain 4 Laboratory of Translational Oncology, Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain 5 Althia, Barcelona, Spain 6 Medical Oncology Department, Hospital Plató, Barcelona, Spain Correspondence to: Begoña Mellado, email: [email protected] Keywords: circulating tumor cells, peripheral blood, microarrays, cell search system Received: January 22, 2015 Accepted: February 14, 2015 Published: March 12, 2015 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The enumeration of circulating tumor cells (CTCs) in peripheral blood correlates with clinical outcome in castration-resistant prostate cancer (CRPC). We analyzed the molecular profiling of peripheral blood from 43 metastatic CRPC patients with known CTC content in order to identify genes that may be related to prostate cancer progression. Global gene expression analysis identified the differential expression of 282 genes between samples with ≥5 CTCs vs <5 CTCs, 58.6% of which were previously described as over-expressed in prostate cancer (18.9% in primary tumors and 56.1% in metastasis). Those genes were involved in survival functions such as metabolism, signal transduction, gene expression, cell growth, death, and movement. The expression of selected genes was evaluated by quantitative RT-PCR. This analysis revealed a two-gene model (SELENBP1 and MMP9) with a high significant prognostic ability (HR 6; 95% CI 2.61 - 13.79; P<0.0001). The combination of the two-gene signature plus the CTCs count showed a higher prognostic ability than CTCs enumeration or gene expression alone (P<0.05). This study shows a gene expression profile in PBMNC associated with CTCs count and clinical outcome in metastatic CRPC, describing genes and pathways potentially associated with CRPC progression. INTRODUCTION profile of peripheral blood is of interest for determining molecular alterations that may justify a more aggressive Prostate cancer (PC) is the second leading cause of clinical behavior in patients with higher CTCs count. death from cancer in men [1]. During the progression of Studies mostly have focused on the capability of CTCs the disease, subgroups of cancer cells reach the circulation as biomarkers but also their potential utility in diagnosis, and are able to proliferate in distant tissues [2]. prognosis, and as a marker of treatment effectiveness [3]. Interest has been growing in recent years about These studies are supported by technologies that allow the circulating tumor cells (CTCs) as leaders in the metastatic reproducible detection and quantification of CTCs. These process. Because of its great accessibility, the expression cells can be separated from other hematopoietic cells by physical characteristics such as size and shape, or by www.impactjournals.com/oncotarget 10604 Oncotarget biological characteristics such as expression of epithelial count in the PBMNC of patients with metastatic CRPC or cancer-specific markers. The CellSearch System and molecular pathways that may be associated with (Veridex, LLC) is the most widely used CTC-isolation CRPC progression. Notably, most of the detected genes technology in clinical testing. This semi-automated in patients with ≥5 CTCs were previously described as method received U.S. Food and Drug Administration over expressed in PC, and specifically 56.1% were over- approval for the enumeration of CTCs in whole blood [4, expressed in PC metastasis. RT-PCR expression of two 5]. In castration-resistant PC (CRPC), the quantification genes, SELENBP1 and MMP9, together with the CTC of CTCs by CellSearch system has been proved to be count showed a significant prognostic ability in CRPC clinically relevant. Studies have used this technology to patients. Overall, our findings support that expression define groups with unfavorable and favorable prognosis studies in PBMNC in metastatic CRPC patients may among patients with metastatic prostate cancer [6] and translate the biology of the CTCs and may be used to for molecular studies of CTCs [6-10]. Furthermore, identify patients with a more aggressive clinical behavior. the decline in the number of CTCs under treatment is a stronger prognostic factor for post-treatment survival RESULTS than a 50% decline in prostate-specific antigen (PSA) [11]. However, the detection of CTCs by the expression of epithelial specific markers, may have as a consequence Patients and CTCs count that CTCs with different molecular characteristics cannot be detected. In addition to CTCs, non-tumoral epithelial and Seventy-four patients were included in the study. circulating hematopoietic cells may also be involved in Four of them were excluded from the analysis: one patient tumor progression [12]. Indeed, two recently published that did not accomplish the inclusion criteria and three studies described transcriptional profiles in peripheral samples that failed the quality control were discarded for blood associated with prognosis in patients with CRPC being analyzed. The clinical characteristics of the 70 final [13, 14]. patients are shown in Table 1. Patients were prospectively The detection of tumor or epithelial markers by followed from the time of inclusion in the study. reverse-transcriptase polymerase chain reaction (RT- PBMNC from 43 patients were tested for CTC count PCR) in the mononuclear cell fraction of peripheral blood and microarrays analysis. All the 70 samples were studied (PBMNC) have been widely use as a strategy to detect by qRT-PCR. Clinical characteristics between patients CTCs in patients with cancer [15]. In the present work with ≥5 CTCs and <5CTCs were well balanced (Table 1). we describe a transcriptional profile associated with CTCs The median number of CTCs per patient sample was 59 (range 1-899). Specifically, 23 patients (53.4%) Figure 1: Survival analysis according to CTC count. A) Kaplan-Meier curves that estimate the probabilities of overall survival (OS) of CRPC patients with <5 and ≥5 CTCs. The log-rank test was used to assess the statistical difference between the two groups (P<0.001); B) Receiver operating characteristic (ROC) curve for prediction accuracy of ≥5 CTCs content in OS of CRPC. www.impactjournals.com/oncotarget 10605 Oncotarget Table 1: Clinical characteristics of patients and CTC count; 1CTCs: circulating tumor cells; 2PSA: prostatic specific antigen; 3AP: Alkaline phosphatase; 4LDH: Lactate dehydrogenase; 5“events” refer to number of deaths. Patients' characteristics CTC1 load <5 CTCs ≥5 CTCs CTCs non-eval Total Number of patients 23 20 27 70 Age (years) Median (range) 72 (40.1-78.3) 73.5 (49-83) 67.5 (51-79.8) 66.5 (40.1-83.1) Gleason N (%) ≤ 7 9 (39.1) 7 (35) 13 (48.3) 29 (41.5) 8-10 12 (52.2) 10 (50) 12 (44.4) 34 (48.6) Unknown 2 (9) 3 (15) 2 (7.4) 7 (10) PSA2 (ng/mL) Median (range) 24.3 (1.3-1,375) 40.4 (1.8-1,002) 47.5 (1.8-445.6) 57.9 (1.3-1,375) AP3 (U/L) Median (range) 180.5 (71-679) 401 (121-5797) 265 (91-1143) 253 (71-5797) LDH4 (U/L) Median (range) 408 (253-628) 588 (336-1569) 351 (232-604) 408 (232-1569) Hemoglobin (g/dL) Median (range) 127 (86-153) 112.5 (74-144) 129 (96-156) 127 (74-156) Previous chemotherapy (%) Yes 9 (39.1) 7 (35) 6 (22.2) 22 (31.4) No 14 (60.9) 13 (65) 21 (77.8) 48 (68.6) Metastasis Bone 18 (46.1) 20 (64.5) 22 (51.2) 60 (53.1) Visceral 5 (12.8) 1 (3.2) 7 (16.3) 13 (11.5) Lymph nodes 15 (38.5) 10 (32.3) 12 (27.9) 37 (32.7) Local relapse 1 (2.6) 0 2 (4.7) 3 (2.7) CTC number (%) 0-2 20 (46.5) - - - 3-4 3 (6.9) - - - 5-20 - 6 (13.9) - - 21-50 - 9 (20.9) - - >51 - 5 (11.6) - - Follow-up (months) Median (range) 12 (1.9-36.8) 12.23 (1.2-35.3) 12 (3.3-26.2) 12 (1.2-36.8) Number of events5 (%) 14 (60.9) 18 (90) 4 (14.8) 36 (51.4) presented <5 CTCs (average 1 cell) and 20 patients assessed by the ROC curve (area under curve=0.790) (Fig. (46.5%) had ≥5 CTCs (average 126 cells). During a 1B). median follow-up period of 12 months, 32 of the 43 patients (74.4%) died. Univariate Cox proportional Gene expression profiling in peripheral blood hazards regression analysis assessed the number of CTCs mononuclear cells is associated with CTC count as a risk factor for overall survival (OS). Patients with <5 CTCs had longer survival relative to patients with ≥5 CTCs by log-rank analysis (Cox HR 5.5; 95%CI, 2-15.3; Hierarchical clustering and principal component log-rank P<0.001) (Fig. 1A). The predictive accuracy of analysis algorithms were used to examine the sample the number of CTCs (≥5 CTCs vs <5 CTCs) for OS was groupings in the expression data. Expression profiles www.impactjournals.com/oncotarget 10606 Oncotarget Table 2: Genes differentially expressed between ≥5 CTCs and <5 CTCs and also between primary tumor/metastasis and normal prostate tissue according to previous data in the literature [16];*qRT-PCR validated genes.
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