Circulating Tumor Cells Status Research Articles

Prevalence of Circulating Tumor Cells After Adjuvant Chemotherapy With or Without Anthracyclines in Patients With HER2-negative, Hormone Receptor-positive Early Breast Cancer

BackgroundUse of anthracycline-based chemotherapy in patients with early breast cancer (EBC) has been well-established but is often associated with cardiotoxicity. Based on data suggesting a limited benefit of anthracyclines in human epidermal growth factor receptor 2 (HER2)-negative patients, the Simultaneous Study of Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as well as Life Style Intervention Strategies (SUCCESS) C study randomized patients to either anthracycline-containing or anthracycline-free chemotherapy. Given the proven prognostic value of circulating tumor cells (CTCs) in EBC, we compared the prevalence of CTCs after chemotherapy between both treatment arms for a preliminary efficacy assessment. MethodsThe SUCCESS C trial (NCT00847444) is an open-label, phase III study randomizing 3547 patients with HER2-negative EBC to either 3 cycles of epirubicin, 5-fluorouracil, and cyclophosphamide followed by 3 cycles of docetaxel (FEC-DOC) or 6 cycles of docetaxel and cyclophosphamide (DOC-C). CTC status was prospectively evaluated in hormone receptor-positive patients at the time of last chemotherapy cycle using the US Food and Drug Administration-approved CellSearch System (Janssen Diagnostics). ResultsData on CTC status were available for 1766 patients. Overall, CTCs were found in 221 (12.5%) patients. Univariate analyses revealed that presence of CTCs at time of last chemotherapy cycle was not significantly associated with tumor or patient characteristics (all P > .1). There was no significant difference with respect to presence of CTCs between patients randomized to FEC-DOC or DOC-C (11.5% vs. 13.6%; P = .18). ConclusionsThe comparable prevalence of CTCs at the time of last chemotherapy cycle may indicate that anthracycline-free chemotherapy is equally effective to anthracycline-containing chemotherapy in HER2-negative, hormone receptor-positive EBC. However, efficacy data from the final survival analysis of SUCCESS C have to be awaited to confirm these preliminary findings.

Clinical Significance of Early Changes inCirculating Tumor Cells from Patients Receiving First-Line Cisplatin-Based Chemotherapy for Metastatic Urothelial Carcinoma.

Background: The therapeutic paradigm of metastatic urothelial carcinoma (UC) is rapidly shifting and new biomarkers are needed to enhance patient selection.Objective: Early identification of dynamic predictors of outcome may be a key to optimize the sequence of effective therapies in metastatic UC patients.Methods: Blood samples from patients receiving first-line MVAC chemotherapy were collected at baseline (T0) and after 2 cycles (T2). Samples were processed by immunomagnetic beads (AdnaTest ProstateCancerSelect kit) and the expression of EPCAM, MUC1 and ERBB2 was studied using multiplex-PCR. Circulating tumor cell (CTC) positivity and cutoffs, obtained by receiver operator characteristic (ROC) curve analysis in healthy donors, were: ≥1 positive marker among EPCAM (≥0.40 ng/μl), MUC1 (≥0.10 ng/μl) and ERBB2 (≥0.20 ng/μl). CTC variation (T0/T2) was split in favorable (+/–, –/–, –/+) and unfavorable groups (+/+). Cox regression analyses evaluated associations with clinical factors.Results: In this pilot study to assess a new CTC detection method, among 31 evaluable patients, 17 (54.8%) were CTC-positive at T0. No association was found between CTC and objective response to MVAC. CTC dynamic changes better predicted 3-year progression-free (PFS) and overall survival (OS) compared to CTC status assessed at single time points. Unfavorable trend was univariably detrimental on 3-year PFS (10% vs. 49.2%, p = 0.006) and OS (20% vs. 63.5%, p = 0.017). Significance was maintained after controlling for liver metastases (p = 0.031 and p = 0.025 for PFS and OS) and MSKCC score (p = 0.014 and 0.025).Conclusions: Newly described early CTC changes during chemotherapy might be useful to improve our prognostic ability. Pending validation, these results could fulfill the promise to help accelerating therapeutic sequences.

Prognostic Impact of HER2 and ER Status of Circulating Tumor Cells in Metastatic Breast Cancer Patients with a HER2-Negative Primary Tumor

BACKGROUND: Preclinical and clinical studies have reported that human epidermal growth factor receptor 2 (HER2) overexpression yields resistance to endocrine therapies. Here the prevalence and prognostic impact of HER2-positive circulating tumor cells (CTCs) were investigated retrospectively in metastatic breast cancer (MBC) patients with a HER2-negative primary tumor receiving endocrine therapy. Additionally, the prevalence and prognostic significance of HER2-positive CTCs were explored in a chemotherapy cohort, as well as the prognostic impact of the estrogen receptor (ER) CTC status in both cohorts. METHODS: Included were MBC patients with a HER2-negative primary tumor, with ≥1 detectable CTC, starting a new line of treatment. CTCs were enumerated using the CellSearch system, characterized for HER2 with the CellSearch anti-HER2 phenotyping reagent, and characterized for ER mRNA expression. Primary end point was progression-free rate after 6 months (PFR6months) of endocrine treatment in HER2-positive versus HER2-negative CTC patients. RESULTS: HER2-positive CTCs were present in 29% of all patients. In the endocrine cohort (n=72), the PFR6months was 53% for HER2-positive versus 68% for HER2-negative CTC patients (P=.23). In the chemotherapy cohort (n=82), no prognostic value of HER2-positive CTCs on PFR6months was observed either. Discordances in ER status between the primary tumor and CTCs occurred in 25% of all patients but had no prognostic value in exploratory survival analyses. CONCLUSION: Discordances regarding HER2 status and ER status between CTCs and the primary tumor occurred frequently but had no prognostic impact in our MBC patient cohorts.

A nonrandomized, prospective, clinical study on the impact of circulating tumor cells on outcomes of urothelial carcinoma of the bladder patients treated with radical cystectomy with or without adjuvant chemotherapy.

To investigate outcomes of urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC) according to the presence of circulating tumor cells (CTC) and the administration of adjuvant chemotherapy (AC). We prospectively enrolled 226 UCB patients treated with RC without neoadjuvant chemotherapy at our institution between 2007 and 2013. Blood samples were obtained from all patients preoperatively and analyzed for CTC using the CellSearch® system. Platinum-based AC was administered in 50 patients (27.0%). Cox regression models evaluated the association of CTC with disease recurrence, cancer-specific and overall mortality according to AC administration. 185 patients were available for analyses. CTC were present in 41 patients (22.2%). Patients with presence of CTC received AC more frequently, compared to patients without CTC (p = 0.027). At a median follow-up of 31months, the presence of CTC was associated with disease recurrence, cancer-specific and overall mortality (p-values < 0.001) in patients without AC administration. In patients who received AC, there was no difference in either endpoint between patients with or without presence of CTC. In multivariable analysis of patients without AC administration, the presence of CTC was an independent predictor for disease recurrence (HR: 4.9; p < 0.001), cancer-specific (HR: 4.2; p = 0.003) and overall mortality (HR: 4.2; p = 0.001). The CTC status may be implemented in decision-making regarding AC administration in UCB patients following RC. CTC measurement should be implemented in future UCB studies on systemic chemotherapy to validate our findings.

792P - Clinical significance of early circulating tumor cells (CTC) changes, analyzed by AdnaTest, in patients (pts) receiving first-line methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy (CT) for metastatic urothelial cancer (UC)

The therapeutic paradigm of metastatic UC is rapidly shifting due to the advent of new promising targeted therapies or immunotherapies. Liquid biopsies and the early identification of reliable predictive and prognostic factors in the treatment course may be a key to optimize the available standard therapies. 5 mL of whole blood from pts receiving first-line MVAC were collected at baseline (t0) and after 2 cycles (t2). Samples were processed by immunomagnetic beads (AdnaTest ProstateCancerSelect kit) and the expression of EPCAM, MUC1 and ERBB2 was studied using multiplex-PCR. CTC positivity and cutoffs, obtained by ROC curve analysis in healthy donors, were: ≥1 positive marker among EPCAM (≥0.40 ng/µl), MUC1 (≥0.10 ng/µl) and ERBB2 (≥0.20 ng/µl). CTC variation (t0/t2) was split in favorable (+/-, -/-, -/+) and unfavorable group (+/+) due to small numbers. Univariable analyses were undertaken for progression-free (PFS) and overall survival (OS). Multivariable analyses with bivariable associations with clinical factors were also done to improve understanding of effects. Among the 31 analyzed pts, 17 (54.8%) were CTC+ at t0 and no association was found with any baseline pt and tumor characteristic, as well as with CTC status and objective response to MVAC. Unfavorable CTC trend was observed in 10/26 (38.5%) cases. CTC dynamic changes better predicted for 3-year (3y) PFS and OS probability compared to CTC status assessed at single time points. Unfavorable trend was univariably detrimental on both 3y PFS probability (10% vs 49.2%, p = 0.006) and 3y OS probability (20% vs 63.5%, p = 0.017). Significance was maintained after adjusting for liver metastases (p = 0.031 and p = 0.025 for PFS and OS) and MSKCC risk score (p = 0.014 and 0.025). We proposed a novel technique to early assess CTC status in metastatic UC receiving MVAC CT. Early CTC changes may be useful to improve our prognostic ability. Pending validation, these results may lead to improved trial designs and to refine the sequence of conventional CT options in the clinical setting.

Serum HER2 extracellular domain levels and HER2 circulating tumor cell status in patients with metastatic breast cancer.

To shed light on the clinical role of HER2 status in serum as extracellular domain (ECD) and corresponding circulating tumor cells (CTCs) in metastatic breast cancer patients. 68 patients were analyzed. Serum HER2 was determined by ADVIA Centaur(®) Serum HER2 test. CellSearch System was performed for CTC quantification. HER2 was overexpressed in 21 primary tumors. In total, 19 patients had ECD >15 ng/ml (the cut-off used), 48 patients had at least one CTC. ECD positivity was associated with CTC number (p = 0.01), HER2-positive CTC (p = 0.01) and the ratio HER2-positive CTC/total CTC (p = 0.02). ECD was not associated with survival. ECD in combination with HER2 CTC status would deserve further investigation in larger series for addressing its putative prognostic relevance.

Detection of Circulating Tumor Cells by Fluorescent Immunohistochemistry in Patients with Esophageal Squamous Cell Carcinoma: Potential Clinical Applications.

BackgroundCirculating tumor cells (CTCs) are tumor cells that leave the primary tumor site and enter the bloodstream, where they can spread to other organs; they are very important in the diagnosis, treatment, and prognosis of malignant tumors. However, few studies have investigated CTCs in esophageal squamous cell carcinoma (ESCC). The aim of this study was to investigate the CTCs in blood of ESCC patients and its potential relevance to clinicopathological features and prognosis.Material/MethodsCTCs were acquired by a negative enrichment method that used magnetic activated cell sorting (MACSTM). Fluorescent immunohistochemistry (IHC) was used to identify the CTCs. Then, the positive CTC patients with ESCC were analyzed, after which the relationship between CTCs and clinicopathologic features was evaluated.ResultsIn the present study, 62 out of 140 (44.3%) patients with ESCC were positive for CTCs. The positive rate of CTCs was significantly related with stage of ESCC patients (P=0.013). However, there was no relationship between CTC status and age, sex, smoking tumor history, tumor location, differentiation of tumor, lymphatic invasion, or lymph venous invasion (P>0.05). Kaplan-Meier analysis showed that patients positive for CTCs had significantly shorter survival time than patients negative for CTCs. Multivariate analysis demonstrated that stage and CTC status were significant prognostic factors for patients with ESCC.ConclusionsCTCs positivity is an independent prognostic biomarker that indicates a worse prognosis for patients with ESCC.

MP49-07 THE RISK OF POSTOPERATIVE VENOUS THROMBOEMBOLISM ACCORDING TO THE CIRCULATING TUMOR CELL STATUS IN PATIENTS WITH UROTHELIAL CARCINOMA OF THE BLADDER TREATED WITH RADICAL CYSTECTOMY

You have accessJournal of UrologyBladder Cancer: Invasive III1 Apr 2016MP49-07 THE RISK OF POSTOPERATIVE VENOUS THROMBOEMBOLISM ACCORDING TO THE CIRCULATING TUMOR CELL STATUS IN PATIENTS WITH UROTHELIAL CARCINOMA OF THE BLADDER TREATED WITH RADICAL CYSTECTOMY Armin Soave, Sabine Riethdorf, Roland Dahlem, Lars Weisbach, Valentin Maurer, Oliver Engel, Sarah Minner, Klaus Pantel, Margit Fisch, and Michael Rink Armin SoaveArmin Soave More articles by this author , Sabine RiethdorfSabine Riethdorf More articles by this author , Roland DahlemRoland Dahlem More articles by this author , Lars WeisbachLars Weisbach More articles by this author , Valentin MaurerValentin Maurer More articles by this author , Oliver EngelOliver Engel More articles by this author , Sarah MinnerSarah Minner More articles by this author , Klaus PantelKlaus Pantel More articles by this author , Margit FischMargit Fisch More articles by this author , and Michael RinkMichael Rink More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.420AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Urothelial carcinoma of the bladder (UCB) patients are at a relevant risk for venous thromboembolism (VTE) following radical cystectomy (RC). In other cancer entities, circulating tumor cells (CTC) are associated with an increased risk of VTE. To evaluate whether the presence of CTC is associated with an increased postoperative risk of VTE and surgical complications in UCB patients treated with RC. METHODS We included 201 UCB patients treated with RC with bilateral pelvic lymphadenectomy without neoadjuvant chemotherapy at an academic center between 2007 and 2014. Preoperatively collected blood samples (7.5 ml) were analyzed for CTC using the CellSearch® system (Janssen, USA). Postoperative VTE was defined as clinically apparent venous thrombosis and/or pulmonary embolism following RC, and was confirmed by diagnostic imaging studies. Data on postoperative VTE and complications were collected retrospectively by patients' chart review. Postoperative complications were classified according to the Clavien-Dindo classification of surgical complications. Clinico-pathologic features were correlated with the VTE status and the CTC status. RESULTS Prior to RC, 54 patients (26.9%) had presence of CTC (mean CTC number: 4.9±31.3 (standard deviation (SD); median: 0; range: 0-372). Within 30 days postoperatively, 6 patients (3.0%) had VTE, and 136 patients (67.7%) had any surgical complication. The most frequent complications were Clavien-Dindo grade 1 and 2 complications in 95 patients (47.3%), followed by grade 3 complications in 25 patients (12.4%) and grade 4 complications in 15 patients (7.5%), respectively. The presence of VTE was not associated with the CTC status or any other clinico-pathologic characteristics. There was no difference in the number of CTC in patients with VTE (mean CTC number: 1.0±1.5 SD) and without VTE (mean CTC number: 5.0±31.7 SD), respectively. The VTE status and the CTC status were not associated with surgical complications. The presence of CTC was associated with a positive soft tissue surgical margin, the presence of lymphovascular and micro-vessel invasion, and the administration of adjuvant chemotherapy (all p-values≤0.045). CONCLUSIONS While complications occur frequently within 30 days after RC, VTE are relatively rare events. Following RC, UCB patients with presence of CTC do not seem to be at an increased risk of VTE. In addition, the presence of CTC is not associated with surgical complications. However, a longer follow-up is urgently warranted. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e666-e667 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Armin Soave More articles by this author Sabine Riethdorf More articles by this author Roland Dahlem More articles by this author Lars Weisbach More articles by this author Valentin Maurer More articles by this author Oliver Engel More articles by this author Sarah Minner More articles by this author Klaus Pantel More articles by this author Margit Fisch More articles by this author Michael Rink More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Perioperative circulating tumor cells in surgical patients with non-small cell lung cancer: does surgical manipulation dislodge cancer cells thus allowing them to pass into the peripheral blood?

We herein evaluated the status of circulating tumor cells (CTC) dislodged from the tumor during surgery in patients who underwent pulmonary resection for non-small cell lung cancer (NSCLC) to assess the clinical implications. Tumor cells in the peripheral arterial blood before surgery (Before) and immediately after lung resection (After) and in the blood from the pulmonary vein of the resected lung were detected using a size selective method. The clinicopathological characteristics and the prognosis were then analyzed according to the CTC status: no tumor cells detected (N), single tumor cell or total number less than 4 cells (S), and existence of clustered cells (C). According to the CTC status, the patients were classified into the following three groups: Before-C and After-C, Group I (n=6); Before-S or N and After-C, Group II (n=9); and Before-S or N and After-S or N, Group III (n=8). Group III showed a high rate of p-stage IA, smaller tumor size, lower CEA level, lower SUVmax level, and a higher relapse-free survival rate than the other groups. CTCs were detected in patients after undergoing lung resection, some of which may have been dislodged by the surgical procedure. The presence of clustered CTCs after the operation indicated an unfavorable outcome.

Abstract S2-03: Persistence of circulating tumor cells in high risk early breast cancer patients during follow-up care suggests poor prognosis – Results from the adjuvant SUCCESS A trial

Abstract Background: Recent data suggest that circulating tumor cells (CTCs) are of prognostic relevance in early as well as metastatic breast cancer (BC). While persisting CTCs immediately after chemotherapy are known to indicate poor prognosis, there is a lack of data regarding the prognostic role of CTCs assessed during long-term follow-up care. Hence the prognostic value of CTCs two years after chemotherapy was analyzed. Methods: The SUCCESS A trial is a randomized, open-label, 2x2 factorial design Phase III study in high-risk breast cancer patients (≥N0 or T2–T4 or grade 3 or age ≤ 35 or hormone-receptor negative). Patients were first randomized to adjuvant chemotherapy treatment with 3 cycles of epirubicin-fluorouracil-cyclophosphamide followed by either 3 cycles of docetaxel or 3 cycles of gemcitabine-docetaxel. In addition, patients were randomized to 2 vs. 5 years of zoledronate treatment. Presence of CTCs was assessed using the FDA-approved CellSearch System (Janssen Diagnostics, LLC). CTC positivity was defined as ≥ 1 CTC in 7.5 ml whole blood. To investigate if CTC status 2 years after chemotherapy is of prognostic relevance independent from CTC status before chemotherapy and to evaluate the prognostic relevance of changed CTC status, only patients with data on CTC status before and 2 years after chemotherapy were included. Patient outcomes in terms of overall survival (OS) and disease-free survival (DFS) were analyzed by univariate log-rank tests and multivariate Cox regressions adjusted for age, menopausal status, tumor stage, nodal stage, grading, histological type, hormone receptor status and HER2 status. Survival time was measured beginning with the date of follow-up CTC assessment two years after chemotherapy. Results: Data on CTC status before and 2 years after chemotherapy were available for 1103 (29.4 %) of 3754 randomized patients. The CTC status 2 years after chemotherapy was positive in 204 (18.5%) patients. The median follow-up time was 37 months. Multivariate Cox regressions including CTC status before chemotherapy showed significant independent prognostic role for CTC status 2 years after chemotherapy on OS (hazard ratio (HR) 3.95, 95% confidence interval (CI) 2.13 – 7.32, p &amp;lt; 0.001) and DFS (HR 2.28, 95% CI 1.48 – 3.50, p &amp;lt; 0.001). The prognostic value of CTC status 2 years after chemotherapy was independent from hormone- and HER2-receptor status. Overall, 719 (65.2%) patients were CTC negative before and 2 years after chemotherapy, while 157 (14.2%) had a negative CTC status before and a positive CTC status 2 years after chemotherapy. 180 (16.3%) patients converted from positive to negative CTC status and 47 (4.3%) patients were persistently positive for CTCs. There were significant differences in OS and DFS among the four patient groups (log rank tests, both p &amp;lt; 0.001) and persistently CTC positive patients had the worst outcome in terms of OS and DFS. Conclusion: The presence of CTCs two years after chemotherapy analyzed during routine breast cancer follow-up care was associated with decreased survival. According to these results, persisting CTCs during long term follow-up independently predict patients' outcome and may serve as surveillance marker. Citation Format: Janni W, Rack B, Fasching P, Haeberle L, Friedl T, Tesch H, Lorenz R, Neugebauer J, Koch J, Jaeger B, Fehm T, Mueller V, Schneeweiß A, Lichtenegger W, Beckmann M, Scholz C, Pantel K, Trapp E. Persistence of circulating tumor cells in high risk early breast cancer patients during follow-up care suggests poor prognosis – Results from the adjuvant SUCCESS A trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-03.

Limited prognostic value of preoperative circulating tumor cells for early biochemical recurrence in patients with localized prostate cancer

IntroductionThe presence of circulating tumor cells (CTCs) is an established marker for prognosis in men with castration-resistant prostate cancer. A cutoff of ≥5 CTCs/7.5ml blood in the CellSearch Epithelial Cell Test has been shown to stratify prognostic groups and predict outcome of abiraterone treatment. In contrast, the value of CTC detection in men with localized prostrate cancer before radical prostatectomy (RP) is unknown. Materials and methodsA total of 152 patients treated with RP between 06/2009 and 09/2009 were included. Peripheral venous blood drawn the day before RP was evaluated for CTCs by the CellSearch system. The detection of CTCs was correlated with prostate-specific antigen (PSA) and the histopathological outcome of the RP specimen. A cutoff of 0 vs. ≥1 CTC/7.5ml blood was defined as the threshold for positive vs. negative CTC status. ResultsMedian age was 62 years and median PSA was 6.7ng/dl. Staging revealed 62.5% pT2, 26.3% pT3a, and 11.2% pT3b tumors, and high-grade disease (≥Gleason 4+3) was determined in 25.6% of patients. CTCs were detected in 17 patients (11%) with a median CTC count/7.5ml of 1 (range: 1–clusters with>100 epithelial cells) without significant correlations to PSA levels, pT stage, or Gleason scores. Postoperative pT stage was a significant predictor of biochemical recurrence (BCR) in univariable logistic regression models and as a composite measure together with positive CTC counts (P<0.0001). CTC positivity alone tended to have a higher hazard ratio for BCR, but this was not statistically significant (P = 0.1). After a median follow-up of 48 months, there was no significant difference in BCR-free survival between patients with or without CTCs (P = 0.7). ConclusionUsing the CellSearch system, we infrequently detected CTCs in patients with localized tumors before RP. The detection of CTCs did not correlate significantly with PSA, disease characteristics, or the development of BCR. However, larger cohorts with extended follow-up are needed to validate our findings.

F34 - Circulating tumor cells status in metastatic renal cell carcinoma (mRCC) after metastasectomy (RESORT trial)

F34 - Circulating tumor cells status in metastatic renal cell carcinoma (mRCC) after metastasectomy (RESORT trial)

Prognostic Value of Circulating Tumor Cells in Ovarian Cancer: A Meta-Analysis.

BackgroundThe prognostic value of circulating tumor cells (CTCs) in ovarian cancer has been investigated in previous studies, but the results are controversial. Therefore we performed a meta-analysis to systematically review these data and evaluate the value of CTCs in ovarian cancer.Materials and MethodsA literary search for relevant studies was performed on Embase, Medline and Web of Science databases. Then pooled hazard ratios (HRs) for survival with 95% confidence intervals (CIs), subgroup analyses, sensitivity analyses, meta-regression analyses and publication bias were conducted.ResultsThis meta-analysis is based on 11 publications and comprises a total of 1129 patients. The prognostic value of the CTC status was significant in overall survival (OS) (HR, 1.61;95% CI,1.22–2.13) and progression-free survival (PFS)/disease-free survival (DFS) (HR, 1.44; 95%CI, 1.18–1.75). Furthermore, subgroup analysis revealed that the value of CTC status in OS was significant in "RT-PCR" subgroup (HR, 2.02; 95% CI, 1.34–3.03), whereas it was not significant in "CellSearch" subgroup (HR, 1.15; 95% CI 0.45–2.92) and "other ICC" subgroup (HR, 1.09; 95% CI 0.62–1.90). The presence of CTC was also associated with an increased CA-125 (OR, 4.07; 95%CI, 1.87–8.85).ConclusionOur study demonstrates that CTC status is associated with OS and PFS/DFS in ovarian cancer.

Abstract P4-11-21: Prevalence of circulating tumor cells (CTCs) after five years of zoledronate treatment in the adjuvant SUCCESS-A study

Abstract Aim: The prognostic value of CTCs at primary diagnosis has recently been confirmed by the SUCCESS A Study (Rack et al. JNCI 2014). Key questions on the role of adjuvant bisphosphonate treatment, including patient populations deriving benefit and optimal timing/scheduling of therapy are still controversial. Aim of this study was therefore to evaluate CTCs in the context of two different zoledronate regimens. Methods: The SUCCESS A trial is a large, randomized, open-label, 2x2 factorial design Phase III study in patients with high risk breast cancer (stage N1 or T2–T4 or grade 3 or age ≤ 35 or hormone-receptor negative). Patients were first randomized to adjuvant chemotherapy treatment with 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide (FEC) followed by either 3 cycles of Docetaxel or 3 cycles of Gemcitabine-Docetaxel. In addition, patients were randomized to 2 years vs. 5 years of zoledronate treatment. CTC status 5 years after primary diagnosis was assessed using the FDA-approved CellSearch System (Veridex, USA), and CTC positivity was defined as ≥ 1 CTC. We studied the influence of zoledronate treatment duration on CTC prevalence at 5 years in addition to well-known patient and tumour characteristics using a multiple logistic regression analysis on the ITT population. Results: Data on CTC status at 5 years after primary diagnosis were available for 728 (19.4%) out of 3754 randomized patients. 310 patients had been randomized to 2 years of zoledronate treatment and 418 patients had been randomized to 5 years of zoledronate treatment. In these patients a difference in CTC positivity after 5 years could not be shown between patients randomized to 2 or 5 years of zoledronate (p = 0.13, Wald test). The adjusted odds ratio for 2 years vs 5 years was 0.65 (95%CI: 0.37 to 1.13). Conclusions: The final survival analysis of the SUCCESS A trial will give further insight, whether CTCs can be used as early predictive marker for the efficacy of adjuvant zoledronate treatment. Citation Format: Brigitte Rack, Peter A Fasching, Lothar Häberle, Thomas Friedl, Mahdi Rezai, Jörn Hilfrich, Hans Tesch, Georg Heinrich, Helmut Forstbauer, Julia Neugebauer, Elisabeth Trapp, Susanne Albrecht, Bernadette Jäger, Tanja Fehm, Volkmar Müller, Andreas Schneeweiss, Klaus Friese, Werner Lichtenegger, Matthias W Beckmann, Wolfgang Janni. Prevalence of circulating tumor cells (CTCs) after five years of zoledronate treatment in the adjuvant SUCCESS-A study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-21.

Abstract P4-01-03: Prognostic relevance of circulating tumor cells across different molecular subgroups in the adjuvant SUCCESS-A study

Abstract Aim: The prognostic value of circulating tumor cells (CTCs) in the adjuvant setting has recently been demonstrated in the SUCCESS A Study (Rack et al. JNCI 2014). As breast carcinomas depend on partly different pathways for progression, the relevance of CTCs could differ between molecular intrinsic subtypes of breast cancer. Aim of this study was therefore to analyze the prognostic impact of CTCs in molecular subtypes of a large patient cohort. Methods: Within the adjuvant SUCCESS A Study, patients were treated either with 5-Flourouracil, Epirubicin and Cyclophosphamid (FEC) followed by Docetaxel (D) or with FEC followed by D and Gemcitabine (DG). There was no restriction with regard to molecular subtype, however a high recurrence risk was required for study entry. In addition patients were assessed prospectively for the presence of CTCs before chemotherapy. Molecular subtypes were defined as: triple negative (TN), hormone receptor positive and grading 1/2 (LUM A like), hormone receptor positive and grading 3 (LUM B like), HER2 positive (HER2 like). We studied whether the addition of CTC status (0 CTC vs &amp;gt; 0 CTCs) to well-known predictors such as age, BMI, tumor size, lymph node status improved the prediction of overall survival (OS) and disease free survival (DFS) across all patients and especially within molecular subtypes using likelihood ratio tests, which compared multivariable Cox regression models with and without CTC and the interaction between CTC and molecular subtype. Results: Information about molecular subtype and CTCs was available in a total of 1994 patients. At least one CTC was seen in 422 (21.2%) of patients. 383 (19.2%) were TN, 798 were LUM A like (40.0%), 328 (16.4%) were LUM B like (16.4%) and 485 (24.3%) were HER2 like. The effect of CTC on overall survival had a HR of 2.50 (95%: 1.75 to 3.58) for the entire cohort. However as the effect was different across subtypes (p=0.04, likelihood ratio test), subtype specific HR were calculated. The effects on OS were most prominent in LUM B like patients (HR=3.96; 95%CI: 1.93 to 8.14) and LUM A like patients (HR=3.57; 95%CI: 1.81 to 7.03), less strong in HER2 like (HR=2.35; 95%CI: 1.04 to 5.32) and not present in TN patients (HR=1.18; 95%CI: 0.62 to 2.24). CTC status had a clear effect on DFS as well (HR=1.93, 95%CI: 1.48 to 2.52). It could not be shown that this effect was different across subtypes (p=0.07, likelihood ratio test). However, the effect size was similarly distributed like the ones for OS. Conclusion: With regard to OS the prognostic effect of CTCs in this study cohort seems most prominent in patients with hormone receptor positive disease. It is still significant in HER2 positive, but not in TN breast cancer patients. Results with regard to DFS trended into the same direction, differences within subgroups could however not be shown, possibly due to power reasons. Citation Format: Wolfgang Janni, Andreas Schneeweiss, Lothar Häberle, Peter A Fasching, Lukas Schwentner, Mahdi Rezai, Jörn Hilfrich, Hans Tesch, Georg Heinrich, Helmut Forstbauer, Thomas Friedl, Fabienne Schochter, Susanne Albrecht, Bernadette Jäger, Julia Jückstöck, Tanja Fehm, Volkmar Müller, Klaus Friese, Werner Lichtenegger, Matthias B Beckmann, Brigitte Rack. Prognostic relevance of circulating tumor cells across different molecular subgroups in the adjuvant SUCCESS-A study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-03.

Prognostic value of circulating tumor cells in patients with squamous cell carcinoma of the head and neck: a systematic review and meta-analysis.

The prognostic value of circulating tumor cells (CTCs) in patients with squamous cell carcinoma of the head and neck (SCCHN) is controversial. The objective of this study was to evaluate the prognostic value of CTCs in patients with SCCHN by conducting a meta-analysis. We systematically searched scientific literature published before June 10, 2014, using the PubMed, ScienceDirect, Cochrane Library, and EMBASE databases. Studies evaluating the correlation of CTC status with tumor-node-metastasis (TNM) disease stage, nodal involvement, and disease progression (recurrence or metastasis) in patients with SCCHN were selected for the analysis. Pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated using the fixed-effects model or the random-effects model in the presence of heterogeneity. Our analysis consisted of eight studies, enrolling a total of 433 patients. The disease progression (recurrence/metastasis) rate in the CTC-positive patients was significantly higher (OR 3.44; 95 % CI 1.87-6.33; p < 0.01) compared with the patients without disease progression. However, there was no significant difference between TNM disease stage III-IV and stage I-II in the presence of CTCs (OR 1.54; 95 % CI 0.87-2.72; p > 0.05). CTC status did not correlate with nodal involvement (OR 1.20; 95 % CI 0.67-1.90; p > 0.05). This meta-analysis indicates that detection of CTCs has a predictive value in patients with SCCHN, particularly those with tumor progression. The presence of CTCs in patients with SCCHN has a poor prognosis compared with the patients without CTCs. Detection of CTCs might be served as a prognosticator in patients with SCCHN. Further studies based on homogeneous populations are warranted to confirm these findings.

Detection of Circulating Tumor Cells at Surgery and at Follow-Up Assessment to Predict Survival After Two-Stage Liver Resection of Colorectal Liver Metastases.

The presence of circulating tumor cells (CTCs) is negatively associated with survival after resection of colorectal liver metastases (CLM). The current study aimed to determine the prognostic value of CTCs and disseminated tumor cells (DTCs) at the time of surgery and the prognostic value of CTCs at follow-up assessment, for patients scheduled to undergo two-stage hepatectomy with portal vein embolization (PVE) for CLM. Samples were collected at surgery (blood and bone marrow) and at follow-up assessment (blood) for the period 2008 through 2011. In this study, CTCs were detected with the CellSearch system, and DTCs were detected using standard immunocytochemical analysis. Of 24 patients, 18 completed both stages, and no patients were lost to follow-up. The median overall survival (OS) was 37 months, and the median recurrence-free survival (RFS) was 7 months. At surgery, CTCs were found in nine patients (38 %), and their presence was associated with reduced OS (p < 0.001) and RFS (p = 0.006). Follow-up CTC status was available for 11 patients. All eight patients with positive CTC status experienced recurrence. Two of three patients with negative CTC status remained recurrence free. In seven patients (32 %), DTCs were detected but were not associated with OS or RFS. The presence of CTCs at surgery is associated with worse OS and RFS for patients undergoing two-stage hepatectomy with PVE for CLM. Analysis of CTCs should be explored further for their potential to assist in treatment decisions and monitoring for CLM patients.

Circulating tumor cells as a longitudinal biomarker in patients with advanced chemorefractory, RAS-BRAF wild-type colorectal cancer receiving cetuximab or panitumumab.

A still relevant number of patients with RAS-BRAF wild-type colorectal cancer (CRC) do not respond to treatment with antiepidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab, suggesting that additional biomarkers to guide patient selection are urgently needed. Circulating tumor cells (CTCs) may represent such a biomarker. In this prospective study, 38 patients with advanced RAS-BRAF-wild-type CRC received third-line therapy with cetuximab-irinotecan or panitumumab. Peripheral blood samples for CTC status determination were collected at baseline, during treatment at early (2-4 weeks) and at later (8-10 weeks) times. CTC enrichment was done with the AdnaTest ColonCancerSelect kit, whereas CTC detection was done with the AdnaTest ColonCancerDetect kit. CTC status positivity was defined according to the kit manufacturer's thresholds. Fifty percent of patients were defined as CTC positive at baseline and the overall RECIST response rate was 26%. CTC baseline status was not associated with treatment response, whereas early CTC status and CTC status changes during treatment were significantly associated with tumor response. Kaplan-Meier analysis showed a significantly shorter progression-free survival (median, 2.0 versus 4.0 months, p = 0.004) and overall survival (4.7 versus11.4, p = 0.039) in patients with early CTC + status compared with CTC - ones. In multivariable analysis including classical prognostic factors, the CTC status changes profile during treatment was an independent predictor of both progression-free survival (p < 0.001) and overall-survival (p = 0.001). CTC status assessed early during treatment with anti-EGFR monoclonal antibodies may predict treatment failure in advance compared to imaging-based tools.

Clinical implications of circulating tumor cells of breast cancer patients: role of epithelial-mesenchymal plasticity.

There is increasing interest in circulating tumor cells (CTCs) due to their purported role in breast cancer metastasis, and their potential as a “liquid biopsy” tool in breast cancer diagnosis and management. There are, however, questions with regards to the reliability and consistency of CTC detection and to the relationship between CTCs and prognosis, which is limiting their clinical utility. There is increasing acceptance that the ability of CTCs to alter from an epithelial to mesenchymal phenotype plays an important role in determining the metastatic potential of these cells. This review examines the phenotypic and genetic variation, which has been reported within CTC populations. Importantly, we discuss how the detection and characterization of CTCs provides additional and often differing information from that obtained from the primary tumor, and how this may be utilized in determining prognosis and treatment options. It has been shown for example that hormone receptor status often differs between the primary tumor and CTCs, which may help to explain failure of endocrine treatment. We examine how CTC status may introduce alternative treatment options and also how they may be used to monitor treatment. Finally, we discuss the most interesting current clinical trials involving CTC analysis and note further research that is required before the breast cancer “liquid biopsy” can be realized.

Clinical Significance of Circulating Tumor Cells in Peripheral Blood of Patients with Esophageal Squamous Cell Carcinoma.

BackgroundEsophageal squamous cell carcinoma is an aggressive gastrointestinal tract cancer. To date, the presence of circulating tumor cells (CTC) has been reported as a prognostic factor in peripheral blood from patients with gastrointestinal cancers.MethodsThe CellSearch system was used to isolate and enumerate CTCs. A total of 90 patients with esophageal squamous cell carcinoma who received chemotherapy or chemoradiotherapy were enrolled. Peripheral blood specimens were collected before and after treatments.ResultsAt baseline analysis, CTCs were detected in 25 patients (27.8 %). Overall survival was significantly shorter in patients with than without CTCs. Follow-up blood specimens were obtained from 71 patients. Partial response, stable disease, and progressive disease after treatment were seen in 32, 12, and 27 patients, respectively. CTC positivity after treatment in the progressive disease group (40.7 %) was significantly higher than that of the partial response group (6.3 %). Patients with a change in CTC status from positive to negative had a good prognosis as well as patients without baseline CTCs.ConclusionsEvaluation of CTCs may be a promising indicator for predicting tumor prognosis and the clinical efficacy of chemotherapy or chemoradiation therapy in patients with esophageal squamous cell carcinoma.Electronic supplementary materialThe online version of this article (doi:10.1245/s10434-015-4392-8) contains supplementary material, which is available to authorized users.