Baseline Circulating Tumor Cells Count Research Articles

Prognostic significance of circulating tumor cells in non-small cell lung cancer patients undergoing chemotherapy.

The utility of circulating tumor cells (CTCs) as prognostic biomarkers in non-small cell lung cancer (NSCLC) is inconclusive due to the limitations of current CTC detection methods. Using a novel high-efficiency detection method, we determined the ability of CTCs to predict survival and chemotherapeutic responses in NSCLC. In 127 patients with advanced NSCLC, CTCs were counted and analyzed at baseline and during follow-up. Median overall survival (OS) and progression-free survival (PFS) were longer in patients with baseline CTC counts <8 CTCs/3.2 mL (20.0 vs. 10.4 months [P = 0.009] and 7.2 vs. 5.5 months [P < 0.001], respectively). Patients with post-treatment increases in the CTC count had poorer OS and PFS than those without increases (12.0 vs. 13.3 months [P = 0.028] and 5.2 vs. 6.4 months [P = 0.022], respectively). There was no association between the baseline CTC count and chemotherapeutic response (P = 0.734). However, the rate of progressive disease in patients with and without post-treatment increases in the CTC count were 15.6% and 2.4% (P = 0.042), respectively. The baseline CTC count and the change in the CTC count during treatment were both valuable prognostic indicators for NSCLC.

Prognostic value of circulating tumor cells in non-small cell lung cancer.

e20520 Background: Quantitative analysis of circulating tumor cells (CTCs) is increasingly investigated as a novel predictor of prognosis in non-small cell lung cancer (NSCLC). The primary aim of this study was to further investigate the prognostic value of CTCs enumeration in patients with advanced NSCLC. Methods: The medical records of patients with chemotherapy-naïve, advanced NSCLC and at least one available measurement of CTCs were retrospectively reviewed. The presence of CTCs was evaluated using the CellSearch system. A cut-off point of 2 CTCs ( &lt; 2 vs ≥2 ) was used to discriminate between negative and positive samples, respectively. The detection of CTCs was correlated with the clinicopathological features of patients and outcome. Results: Our study population comprised a total of 43 patients (mean age 67.1±9.9 years; male/female ratio: 39/4). Eight out of 43 patients (18.6%) harbored CTCs. No significant associations were found between treatment response and baseline count of circulating tumor cells (CTCs) (p = 0.067). Positive CTC count was associated with the presence of five or more metastatic sites (p = 0.018). Neither PFS nor OS were found to differ significantly between CTC-positive and CTC-negative cases (log-rank p = 0.079 and 0.549, respectively). The presence of five or more metastatic sites and worse PS were recognized as independent predictors of reduced PFS [HR = 2.9, p = 0.042 and HR = 2.7, p = 0.035, respectively], and reduced OS [HR = 7.8, p = 0.003 and HR = 16.9, p &lt; 0.001, respectively]. Conclusions:CTCs were detected in a relatively small percentage of our patient population and their presence was associated with increased metastatic burden. In contrast, we failed to observe any significant associations between baseline CTC count and the prognostic variables evaluated. Our results support the suggested role of CTCs in the metastatic dissemination of cancer and underline the need for more efficient methods of CTCs detection.

Efficacy and long-term safety with bevacizumab included in neoadjuvant and adjuvant therapies in patients with advanced ovarian cancer: Results of the ANTHALYA trial.

5538 Background: ANTHALYA showed that neoadjuvant Bevacizumab (B) added to Carboplatin and Paclitaxel (CP) was well tolerated and achieved encouraging complete resection rates at IDS (58.6%) in unresectable FIGO stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma (EJC 2017;70:133–42). We report response rates, PFS and long-term safety. Methods: Patients (pts) in ANTHALYA were randomized 2:1 to 4 cycles (c) of neoadjuvant CP ±3 c of B (15 mg/kg), IDS for eligible patients, then 1 c of CP + 3 c CPB + 21 c of B. Response and progression were evaluated by RECIST 1.1 using CT scan and CA-125. Circulating tumor cell counts (CTC) were evaluated at baseline, c2 and IDS. Results: 95 pts were treated in CP (n=37) or BCP (n=58) groups (mean study duration were 16.1 months [mo] and 16.9 mo, respectively). 80 pts (CP: 81% / BCP: 88%) had a CA-125 response (50% reduction in CA-125 level) before IDS. Objective response rates were 65% (62% CP / 67% BCP) before IDS (28 days after c4), 46% at c8 (46% CP/ 47% BCP) and 19% at c26 (19% CP/ 19% BCP). 24 (64.9%) CP pts and 26 (44.8%) BCP pts progressed during follow up (median PFS 21.2 mo [95%CI: 14.5, 26.7] and 23.5 mo [18.5, 30.6], respectively). Median PFS was respectively: 25.8 mo (21.0, 30.0) and 17.1 mo (13.5, 22.2) for pts with/without complete resection at IDS; 21.0 mo (15.0, 25.4) and 25.8 mo (18.5, 27.2) for pts with/without baseline CTCs (n=29 / 59); 21.8 mo (17.5, 27.1) and 22.2 mo (15.3, 38.0) for pts with FIGO IIIC and IV tumors. 36 pts did not receive adjuvant therapy within the study (21 were unresectable for IDS), 59 pts (57% CP / 66% BCP) received it. Of those, 34 pts (52% CP / 61% BCP) had Grade ≥3 adverse events including neutropenia (29% CP / 34% BCP), HBP (10% CP / 8% BCP), proteinuria (10% CP / 0% BCP), deep venous thrombosis (5% CP / 3% BCP), pulmonary embolism (0% CP / 8% BCP). Conclusions: Neoadjuvant BCP followed by IDS and adjuvant BCP achieves high response rates and extended PFS with an acceptable toxicity in this specific population of pts with FIGO stage IIIC/IV ovarian, tubal or peritoneal adenocarcinoma not eligible for primary debulking surgery. IDS outcome and CTC counts should be further explored as long term prognostic factors. Clinical trial information: NCT01739218.

Predictive and prognostic value of folate receptor-positive circulating tumor cells in small cell lung cancer patients treated with first-line chemotherapy.

To assess the predictive and prognostic significance of folate receptor (FR)-positive circulating tumor cells (CTCs) in patients with small cell lung cancer (SCLC) received first-line chemotherapy. Eligible patients with chemotherapy-naïve, unresectable SCLC were enrolled and blood samples were collected. CTCs were enumerated using ligand-targeted polymerase chain reaction (LT-PCR) at baseline, after two cycles of chemotherapy regimen and on disease progression. In total, 80 patients were enrolled and 67 (83.8%) had positive CTC count at baseline (CTCs ≥ 8.7 FU/3mL). The baseline CTC counts in patients with partial response (PR) were significantly higher than those with progression disease (PD) (P = 0.0365). An obvious reduction of CTC enumeration after two cycles of chemotherapy was significantly correlated with PR (P = 0.0380), instead of SD (P = 0.4934). Among positive CTC count group, patients with relative low CTC level had significantly longer progression-free survival (PFS) and overall survival (OS) than those with high CTC level (PFS: 9.1 vs 6.9 months, P = 0.0458; OS: 11.1 vs 8.6 months, P = 0.056). In multivariate analysis, distant metastases (HR = 1.466, P = 0.021) and relative low CTC level (HR = 0.656, P = 0.049) were the independent predictive factors for patients with SCLC received first-line chemotherapy. The present results demonstrated that baseline CTC counts could be the valuable predictive and prognostic biomarker for patients with SCLC received first-line chemotherapy. The reduction of CTC enumeration after two cycles of chemotherapy was a potential predictor of chemotherapeutic response in SCLC.

Circulating tumor cells as a prognostic marker for efficacy in the randomized phase III JO21095 trial in Japanese patients with HER2-negative metastatic breast cancer.

Prognostic effects of circulating tumor cells (CTCs) have been reported in metastatic breast cancer (MBC). However, few phase III trials have investigated the potential role of CTCs in treatment selection. We explored potential relationships between CTCs, efficacy, and differential treatment effects. Patients with HER2-negative MBC were randomized to receive either concurrent capecitabine plus docetaxel (XT) or sequential single-agent docetaxel followed by single-agent capecitabine at progression (T→X). Blood samples were collected at baseline, on day 1 of cycles 2 and 3, and at progression. CTCs were counted using the CellSearch® System. The relationship between baseline CTC count and outcomes was investigated using a pre-defined threshold of 2 CTCs/7.5mL. At screening, 44% of the 148 enrolled patients had positive CTC score. In multivariate analyses of pooled treatment arms, positive baseline CTC and triple-negative disease were strongly associated with worse progression-free survival (PFS) and overall survival (OS). Patients with positive CTC score at the baseline had worse OS, irrespective of change in CTC (decreased versus remaining positive) at cycle 2. The prognostic effect of baseline CTC count on OS appeared slightly less pronounced in XT-treated pts. compared with T→X. A baseline CTC count≥2 CTCs/7.5mL was associated with worse prognosis. However, some improvement in PFS and OS was shown with concurrent XT, thus baseline CTC could be a predictive marker. As the current trial was not designed to evaluate a change in chemotherapy according to on-treatment CTC changes, prospective investigation is required.

Prognostic value of circulating tumor cells in advanced gastric cancer patients receiving chemotherapy.

The identification of circulating tumor cells (CTCs) may provide important prognostic information in several types of solid tumors, including gastric cancer. The aim of this study was to investigate whether CTC count may be used to predict survival in patients with advanced gastric cancer treated with chemotherapy. The CELLection™ Epithelial Enrich kit was used to isolate and purify CTCs from samples of peripheral blood. Immunofluorescent staining was used for CTC counting. High CTC counts were associated with poor tumor differentiation and high serum CEA levels (P=0.021 and 0.005, respectively). After 3 months, 16 patients with decreasing CTC counts after the first cycle of chemotherapy obtained complete response, partial response or stable disease, while 13 patients with increasing CTC counts developed progressive disease. The patients with decreasing CTC counts also exhibited longer progression-free survival (PFS) (P≤0.001) and overall survival (OS) (P=0.002) compared with those with increasing CTC counts. Among all 59 patients, those with a CTC count of ≤2 cells/5 ml blood exhibited longer PFS (P≤0.001) and OS (P≤0.001) compared with those with a CTC count of >2 cells/5 ml blood. The multivariate analysis suggested that an increase of the CTC count after the first cycle of chemotherapy was only an independent prognostic marker of poor PFS (P=0.019). However, a baseline CTC count of >2 cells/5 ml blood was an independent poor prognostic marker for PFS (P=0.008) and OS (P=0.001) in all 59 patients. Our study suggested that patients with a low baseline CTC count or decrease of the CTC count after the first cycle of chemotherapy may benefit significantly from palliative chemotherapy. In conclusion, CTC count may be a good chemotherapy monitoring marker and an ideal prognostic marker for patients receiving palliative chemotherapy.

Interrogating Metastatic Prostate Cancer Treatment Switch Decisions: A Multi-institutional Survey

BackgroundEvaluation of responses to treatment for metastatic castration-resistant prostate cancer (mCRPC) remains challenging. Consensus criteria based on prostate-specific antigen (PSA) and clinical and radiologic biomarkers are inconsistently utilized. Circulating tumor cell (CTC) counts can inform prognosis and response, but are not routinely used. ObjectiveTo evaluate the use of biomarkers and trends in clinical decision-making in current mCRPC treatment. Design, setting, and participantsA 23-part online questionnaire was completed by physicians treating mCRPC. Outcome measures and statistical analysisResults are presented as the proportion (%) of physicians responding to each of the options. We used χ2 and Fisher's tests to compare differences. Results and limitationsA total of 118 physicians (22.1%) responded. Of these, 69.4% treated ≥50 mCRPC patients/year. More physicians administered four or fewer courses of cabazitaxel (27.9%) than for docetaxel (10.4%), with no significant difference in the number of courses between bone-only disease and Response Evaluation Criteria in Solid Tumours (RECIST)–evaluable disease. Some 74.5% of respondents considered current biomarkers useful for monitoring disease, but only 39.6% used the Prostate Cancer Working Group (PCWG2) criteria in clinical practice. PSA was considered an important biomarker by 55.7%, but only 41.4% discarded changes in PSA before 12 wk, and only 39.4% were able to identify bone-scan progression according to PCWG2. The vast majority of physicians (90.5%) considered clinical progression to be important for switching treatment. The proportion considering biomarkers important was 71.6% for RECIST, 47.4% for bone scans, 23.2% for CTCs, and 21.1% for PSA. Although 53.1% acknowledged that baseline CTC counts are prognostic, only 33.7% would use CTC changes alone to switch treatment in patients with bone-only disease. The main challenges in using CTC counts were access to CTC technology (84.7%), cost (74.5%), and uncertainty over utility as a response indicator (58.2%). ConclusionsA significant proportion of physicians discontinue treatment for mCRPC before 12 wk, raising concerns about inadequate response assessment. Many physicians find current biomarkers useful, but most rely on symptoms to drive treatment switch decisions, suggesting there is a need for more precise biomarkers. Patient summaryIn this report we analyse the results of a questionnaire evaluating tools for clinical decision-making completed by 118 prostate cancer specialists. We found that most physicians favour clinical progression over prostate-specific antigen or imaging, and that criteria established by the Prostate Cancer Working Group are not widely used.

The preliminary role of circulating tumor cells obtained from the hepatic or portal veins in patients with hepatobiliary–pancreatic cancer

Metastases, which result from circulating tumor cells (CTC) that have detached from the primary cancer and survived in distant organs, cause the majority of cancer deaths. The present study aimed to assess the prognostic relevance of CTC in patients with hepatobiliary–pancreatic cancer. A total of 30 consenting patients were enrolled. Pre-resection blood samples were obtained from the hepatic or portal veins of patients, respectively. CTCs were analyzed using the CellSearch system and isolated using antibodies against the epithelial cell adhesion molecule and cytokeratin. Patients were separated into 2 groups based on their CTC counts. The CTC-positive group included patients with baseline CTC counts >10/7.5 ml. Of the 30 patients, 12 (40 %) were considered CTC positive. CTC-positive patients had a shorter 1‑year progression-free survival (PFS) than CTC-negative patients (71.1 % vs. 36.4 %, p = 0.0324); however, no difference was observed in the 3‑year overall survival (47.1 % vs. 45.5 %, p = 0.7576). In particular, CTC-positive pancreatic carcinoma patients had a shorter 1‑year PFS (22.2 % vs. 0.0 % for CTC-negative, p = 0.0018). Elevated CTC from hepatic or portal veins might predict a shorter PFS in patients with hepatobiliary–pancreatic cancer, particularly those with pancreatic carcinoma.

Circulating tumor cells: A promising marker of predicting tumor response in rectal cancer patients receiving neoadjuvant chemo-radiation therapy.

PurposeThe aim of this study was to investigate the role of circulating tumor cells (CTCs) in assessing and predicting tumor response to neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC).MethodsA total of 115 patients with T3-4 and/or N+ rectal cancer were enrolled. All patients received neoadjuvant CRT followed by radical surgery after 6-8 weeks. The pathological results after surgery were evaluated according to tumor regression grade (TRG) classification.ResultsBased on TRG score, patients were classified as responders (TRG3-4) and non-responders (TRG0-2). The baseline CTC counts of responders were significantly higher than those of non-responders (44.50±11.94 vs. 37.67±15.45, P=0.012). By contrast, the post-CRT CTC counts of responders were significantly lower than those of non-responders (3.61±2.90 vs. 12.08±7.40, P<0.001). According to ROC analysis, Δ%CTC (percentage difference in CTC counts between baseline and post-CRT) was identified as the stronger predictor to discriminate responders from non-responders (AUC: 0.860). The results of multivariate analysis also indicated that post-CRT CTC counts and Δ%CTC were significantly and independently associated with tumor response to CRT.ConclusionsThe detection of CTCs is a powerful and promising tool for evaluating and predicting responses to neoadjuvant CRT in LARC patients.

Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer

BackgroundTreatment response biomarkers are urgently needed for castration-resistant prostate cancer (CRPC). Baseline and post-treatment circulating tumor cell (CTC) counts of ≥5 cells/7.5ml are associated with poor CRPC outcome. ObjectiveTo determine the value of a ≥30% CTC decline as a treatment response indicator. Design, setting, and participantsWe identified patients with a baseline CTC count ≥5 cells/7.5ml and evaluable post-treatment CTC counts in two prospective trials. InterventionPatients were treated in the COU-AA-301 (abiraterone after chemotherapy) and IMMC-38 (chemotherapy) trials. Outcome measures and statistical analysisThe association between a ≥30% CTC decline after treatment and survival was evaluated using univariable and multivariable Cox regression models at three landmark time points (4, 8, and 12 wk). Model performance was evaluated by calculating the area under the receiver operating characteristic curve (AUC) and c-indices. ResultsOverall 486 patients (122 in IMMC-38 and 364 in COU-AA-301) had a CTC count ≥5 cells/7.5ml at baseline, with 440, 380, and 351 patients evaluable at 4, 8, and 12 wk, respectively. A 30% CTC decline was associated with increased survival at 4 wk (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.36–0.56; p<0.001), 8 wk (HR 0.41, 95% CI 0.33–0.53; p<0.001), and 12 wk (HR 0.39, 95% CI 0.3–0.5; p<0.001) in univariable and multivariable analyses. Stable CTC count (<30% fall or <30% increase) was not associated with a survival benefit when compared with increased CTC count. The association between a 30% CTC decline after treatment and survival was independent of baseline CTC count. CTC declines significantly improved the AUC at all time-points. Finally, in the COU-AA-301 trial, patients with CTC ≥5 cells/7.5ml and a 30% CTC decline had similar overall survival in both arms. ConclusionsA 30% CTC decline after treatment from an initial count ≥5 cells/7.5ml is independently associated with CRPC overall survival following abiraterone and chemotherapy, improving the performance of a multivariable model as early as 4 wk after treatment. This potential surrogate must now be prospectively evaluated. Patient summaryCirculating tumor cells (CTCs) are cancer cells that can be detected in the blood of prostate cancer patients. We analyzed changes in CTCs after treatment with abiraterone and chemotherapy in two large clinical trials, and found that patients who have a decline in CTC count have a better survival outcome.

Circulating tumor cell (CTC) rise and outcome in patients with metastatic castration-resistant prostate cancer (mCRPC) with low baseline CTC counts.

5042Background: CTCs are prognostic in CRPC. Baseline (BL) CTC < 5 CTCs/7.5mL are associated with improved prognosis. We have previously shown that a post-treatment 30% decline in CTC is associated...

Abstract 379: Circulating tumor cells (CTCs) in clinically localized prostate cancer (PCa): searching a prognostic tool

Abstract Background If PCa screening has reduced advanced disease and disease-specific mortality, the tradeoff is an over-diagnosis of cases that would not have caused clinical consequences during a man's lifetime if left untreated. Conversely, a vast numbers of men, which harbor occult extra-prostatic extension, develop recurrence after surgery. Despite it looks like an addressable question by quantifying Circulating Tumor Cells (CTCs), unlike breast cancer, in which prognostic and predictive impact of tumor cells in peripheral blood or bone marrow (Disseminated Tumor Cells, DTCs) was largely provided, their role in localized PCa is far from clear. Methods From July 2011 to August 2013, we quantify the tumor burden at diagnosis in peripheral blood of 153 PCa patients stage T2a-T3b, enrolled at three clinical sites (Roma, Orbassano and Padova). All the patients were candidate to undergo radical prostatectomy because of positive biopsy for cancer. Two labs (Orbassano and Padova) performed the CellSearch assay. In patients enrolled in Roma (Janus trial, a phase II study for the use of zoledronic acid as neoadjuvant treatment of invasive PCa), we evaluated in parallel the DTCs. Results We used data obtained in patients enrolled in Orbassano (n = 50) and Roma (n = 15) as training set, meanwhile we used patients of Padova (n = 88) as validation set. Consistently with previous reports (Kraan, Sleijfer et al. 2011) reporting low inter-test and inter-lab variability, the baseline CTC count in the two sets did not significantly differ (Mann-Whitney Rank Sum Test, p = 0.170), so that they were further analyzed altogether. Overall, we found that 74 out of 153 PC patients (48,4%) had at least 1 CTC per 7.5 ml of peripheral blood; 45 PC (29,4%) patients had &amp;gt; 2 cells and 21 PC patients (13,7%) had &amp;gt; 3 cells. Interestingly, 8 out of 153 PC patients (5,2%) had &amp;gt; 5 cells at the first blood draw, before surgery. When we synchronously detected CTCs and DTCs, we found consistent results in 64% of patients (Wilcoxon signed Rank Test, p = 0.339). Conclusions Even when the PCa is pathologically organ confined at surgery, it was reported 5% to 20% of these patients harbor foci of micro-metastatic disease that will later manifest itself as recurrent disease. Here we show CTCs by CellSearch assay in close to 50% of biopsy-confirmed PCa patients, obtaining evidence of a systemic disease. Prospective studies will be required to investigate whether CTC-status is associated with worst outcome in the M0 setting of PCa, as already provided in early breast cancer patients (Lucci, Hall et al. 2012). Citation Format: Elisabetta Rossi, Antonella Facchinetti, Vittorio Aneloni, Emanuel Zilio, Massimo Dal Bianco, Alice Zoccoli, Daniele Santini, Diletta Garrou, Francesco Porpiglia, Rita Zamarchi. Circulating tumor cells (CTCs) in clinically localized prostate cancer (PCa): searching a prognostic tool. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 379. doi:10.1158/1538-7445.AM2015-379

Early CTC decline as a biomarker of response to treatment in castration-resistant prostate cancer (CRPC): Analysis of the COU-AA-301 and IMMC38 trials.

5014 Background: Circulating tumor cell counts (CTC) are prognostic in CRPC. Baseline (BL) CTC ≥ 5 CTCs/7.5mL are associated with worse prognosis. A post-treatment 30% decline in CTC has been assoc...

Effect of prostate-specific membrane antigen (PSMA) radioimmunotherapy on circulating tumor cell (CTC) count.

199 Background: CTC counts with CellSearch methodology are prognostic; changes following therapy may be associated with improved outcomes. Since FDA clearance, baseline and follow up CTC counts were included in studies of radiolabeled J591. The effect of J591 alone (without an effector molecule) is unknown. Methods: Our phase II single-dose 177Lu-J591 (Cohort 3), phase I fractionated dose 177Lu-J591 (expansion cohorts), and phase I fractionated 177Lu-J591 + docetaxel (all pts) trials were analyzed. Any pt with baseline and at least 1 follow-up CTC count (CellSearch) was included in the analysis. A retrospective subset of patients undergoing J591-based imaging without an effector molecule attached was also analyzed. Results: 48 pts received 177Lu-J591 with prospectively measured CTC counts with median age of 73.7 years. 26 of 48 (54.2%) had unfavorable (≥5 CTCs/7.5 mL blood) baseline CTCs (median 29, range 5-449 CTCs/7.5 mL). Of the 23 with ≥5 baseline CTCs and available 4-6 wk post-treatment counts, 22 (95.6%) had declines of 15-100%, with 12 (52.2%) converting to favorable counts. Of the 18 with ≥5 baseline CTCs and available 12-14 wk post-treatment counts, 10 (55.5%) had declines of 8-100%, with 7 (38.9%) converting to favorable counts. Of the 22 of 48 (45.8%) with baseline CTC counts &lt;5, 1 became unfavorable at 4-6 wks, later re-converting to favorable (early control rate of 95.5%) and 1 became unfavorable at 12-14 wks (sustained control rate of 95.5%). 7 men with unfavorable counts underwent imaging with 20 mg of J591 without an attached effector molecule; 4 (57%) demonstrated decline in CTCs following the imaging dose, with 1 stable and 2 continued to increase prior to subsequent therapy. Conclusions: In addition to the favorable PSA declines previously reported, radiolabeled J591 results in frequent favorable changes in CTC counts, with &gt;90% of men with baseline unfavorable counts receiving 177Lu-J591 demonstrating CTC count decline or control in pts with baseline favorable counts. A small retrospective subset suggests that CTC counts may also be controlled with naked (unlabeled) anti-PSMA monoclonal antibody and a prospective study investigating this phenomenon will begin enrollment. Clinical trial information: NCT00195039 , NCT00538668 , NCT00916123 .

Circulating tumor cell thresholds and survival scores in advanced metastatic breast cancer: The observational step of the CirCe01 phase III trial

The clinical validity of circulating tumor cell (CTC) count changes during chemotherapy in metastatic breast cancer patients has been validated, but its clinical utility remains to be demonstrated. We report here the non-randomized run-in phase of the CirCe01 trial which was designed to evaluate CTC changes and thresholds to other palliative prognostic scores and establish CTC thresholds to be used in the randomized part of the study. CTC count (CellSearch®) and other prognostic parameters (serum albumin level, lymphocyte level, LDH level, prognostic inflammatory and nutritional index (PINI) and Barbot's score) were assessed in 56 metastatic breast cancer patients before the first cycle of third line chemotherapy. Early changes of CTC count were correlated with treatment outcome. Independent prognostic markers in multivariate analysis were: low serum albumin (HR = 11.1), poor performance status (HR = 3.8), ≥5 CTC/7.5 ml (HR = 3.8) and triple negative subtype (HER2+ and hormone positive vs triple negative: both HR = 0.2). Among patients with ≥5 CTC/7.5 ml at baseline, a composite criteria (<5 CTC/7.5 ml or relative decrease ≥−70% of the baseline CTC count) showed better prognostication for PFS (p = 0.002).

Circulating tumor cells in newly diagnosed inflammatory breast cancer.

IntroductionCirculating tumor cells (CTCs) are an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer. Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. The prognostic value of a CTC count in newly diagnosed IBC has not been established. The aim of this study was to assess the prognostic value of a baseline CTC count in patients with newly diagnosed IBC.MethodsThis retrospective study included 147 patients with newly diagnosed IBC (77 with locally advanced and 70 with metastatic IBC) treated with neoadjuvant therapy or first-line chemotherapy during the period from January 2004 through December 2012 at The University of Texas MD Anderson Cancer Center. CTCs were detected and enumerated by using the CellSearch system before patients were started with chemotherapy.ResultsThe proportion of patients with ≥1 CTC was lower among patients with stage III than among patients with metastatic IBC (54.5% versus 84.3%; P = 0.0002); the proportion of patients with ≥5 CTCs was also lower for stage III than for metastatic IBC (19.5% versus 47.1%; P = 0.0004). Patients with fewer than five CTCs had significantly better progression-free survival (PFS) (hazard ratio (HR) = 0.60; P = 0.02) and overall survival (HR = 0.59; P = 0.03) than patients with five or more CTCs. Among patients with stage III IBC, there was a nonsignificant difference in PFS (HR = 0.66; 95% confidence interval (CI), 0.31 to 1.39; P = 0.29) and OS (HR = 0.54; 95% CI, 0.24 to 1.26; P = 0.48) in patients with no CTCs compared with patients with one or more CTCs. In multivariate analysis, CTC was prognostic for PFS and OS independent of clinical stage.ConclusionsCTCs can be detected in a large proportion of patients with newly diagnosed IBC and are a strong predictor of worse prognosis in patients with newly diagnosed IBC.

Effect of circulating tumor cells combined with negative enrichment and CD45-FISH identification in diagnosis, therapy monitoring and prognosis of primary lung cancer.

Circulating tumor cells (CTCs) are valuable for diagnosis, monitoring therapy and prognosis in primary lung cancer. Herein, we evaluated the clinical significance of lung cancer CTCs in this study. Detection of CTCs was performed using epithelial cell adhesion molecule-independent enrichment and CD45 fluorescence in situ hybridization detection. CTCs ≥ 2/3.2 mL were considered as positive. The positive rates in primary lung cancer, benign lung disease and healthy control groups were 84, 0 and 4.2 %. CTCs count was significantly higher in lung cancer patients than healthy controls and benign lung disease, with an area under ROC curve of 0.917 (95 % confidence interval 0.855-0.979; p = 0.000) between lung cancer and nonmalignant diseases. CTCs count significantly increased with an increase in pathological stage with mean count of 2.3 ± 2.6 (stage I-II), 3.5 ± 3.3 (stage III) and 4.5 ± 4.3 (stage IV), respectively. The positive detection rate of CTCs for primary lung cancer diagnosis was higher than serum tumor markers. In total, 25 metastasis lung cancer patients participated in the follow-up. Changes in CTCs count after two cycles of chemotherapy were consistent with radiographic appearance. Moreover, CTCs count was better than serum tumor markers for monitoring chemotherapy response. Median progression-free survival (PFS) was 2.05, 3.25 and 8.348 months (p < 0.05) in group in which post-treatment CTCs count was increased, unchanged and decreased, respectively. Furthermore, PFS in patients whose post-treatment CTCs count increased or were unchanged accompanied by a baseline CTCs count ≥3 was significantly shorter than those whose post-treatment CTCs count decreased or was unchanged accompanied with baseline value C < 3 (1.85 vs. 8.22 months, p = 0.000) [Corrected]. Therefore, CTCs are a reproducible indicator of disease status that may be superior to imaging.

Circulating tumor cells as early predictors of metastatic spread in breast cancer patients with limited metastatic dissemination.

IntroductionTraditional factors currently used for prognostic stratification do not always adequately predict treatment response and disease evolution in advanced breast cancer patients. Therefore, the use of blood-based markers, such as circulating tumor cells (CTCs), represents a promising complementary strategy for disease monitoring. In this retrospective study, we explored the role of CTC counts as predictors of disease evolution in breast cancer patients with limited metastatic dissemination.MethodsA total of 492 advanced breast cancer patients who had a CTC count assessed by CellSearch prior to starting a new line of systemic therapy were eligible for this analysis. Using the threshold of 5 CTCs/7.5 ml of blood, pretreatment CTC counts were correlated in the overall population with metastatic site distribution, evaluated at baseline and at the time of treatment failure, using Fisher’s exact test. Time to visceral progression and time to the development of new metastatic lesions and sites were estimated in patients with nonvisceral metastases and with single-site metastatic disease, respectively, by the Kaplan-Meier method. Survival times were compared between groups according to pretreatment CTC count by logrank test.ResultsIn the overall population, a pretreatment level ≥5 CTCs/7.5 ml was associated with an increased baseline number of metastatic sites compared with <5 CTCs/7.5 ml (P = 0.0077). At the time of treatment failure, patients with ≥5 CTCs/7.5 ml more frequently developed new metastatic lesions and sites compared with those with <5 CTCs/7.5 ml (development of new lesions: P = 0.0002; development of new sites: P = 0.0031). Among patients with disease originally confined to nonvisceral sites, ≥5 CTCs/7.5 ml was associated with remarkably shorter time to visceral metastases (P = 0.0021) and overall survival (P = 0.0006) compared with <5 CTCs/7.5 ml. In patients with single-site metastatic disease, ≥5 CTCs/7.5 ml was associated with a significant reduction of the time to development of new metastatic sites (P = 0.0051) and new lesions (P = 0.0002) and with worse overall survival (P = 0.0101).ConclusionOur results suggest that baseline CTC counts can be used as an early predictor of metastatic potential in breast cancer patients with limited metastatic dissemination.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0440-8) contains supplementary material, which is available to authorized users.

Circulating Tumor Cell Counts Are Prognostic of Overall Survival in SWOG S0421: A Phase III Trial of Docetaxel With or Without Atrasentan for Metastatic Castration-Resistant Prostate Cancer

Circulating tumor cell (CTC) enumeration has not been prospectively validated in standard first-line docetaxel treatment for metastatic castration-resistant prostate cancer. We assessed the prognostic value of CTCs for overall survival (OS) and disease response in S0421, a phase III trial of docetaxel plus prednisone with or without atrasentan. CTCs were enumerated at baseline (day 0) and before cycle two (day 21) using CellSearch. Baseline counts and changes in counts from day 0 to 21 were evaluated for association with OS, prostate-specific antigen (PSA), and RECIST response using Cox regression as well as receiver operator characteristic (ROC) curves, integrated discrimination improvement (IDI) analysis, and regression trees. Median day-0 CTC count was five cells per 7.5 mL, and CTCs < versus ≥ five per 7.5 mL were significantly associated with baseline PSA, bone pain, liver disease, hemoglobin, alkaline phosphatase, and subsequent PSA and RECIST response. Median OS was 26 months for < five versus 13 months for ≥ five CTCs per 7.5 mL at day 0 (hazard ratio [HR], 2.74 [adjusting for covariates]). ROC curves had higher areas under the curve for day-0 CTCs than for PSA, and IDI analysis showed that adding day-0 CTCs to baseline PSA and other covariates increased predictive accuracy for survival by 8% to 10%. Regression trees yielded new prognostic subgroups, and rising CTC count from day 0 to 21 was associated with shorter OS (HR, 2.55). These data validate the prognostic utility of CTC enumeration in a large docetaxel-based prospective cohort. Baseline CTC counts were prognostic, and rising CTCs at 3 weeks heralded significantly worse OS, potentially serving as an early metric to help redirect and optimize therapy in this clinical setting.

The End of the Beginning: Circulating Tumor Cells As a Biomarker in Castration-Resistant Prostate Cancer

Although circulating tumor cells (CTCs) were first observed from patients with metastatic malignancies more than 100 years ago, only recently has the clinical and research potential of CTCs become widely recognized. Because CTCs are thought to represent cells that are shed by primary or metastatic tumors, significant interest has focused on examining CTCs as prognostic or predictive biomarkers in several malignancies, including breast and prostate cancer. One could hypothesize that the number of CTCs could be prognostically important by potentially estimating the total-body burden of disease and/or a tumor’s invasiveness. Alternatively, changes in CTC counts might indicate sensitivity or resistance to an anticancer therapy. CTCs could also represent research tools to personalize treatment by serving as a so-called liquid biopsy of an individual’s disease. Quantitation and characterization of CTCs may therefore represent a means to directly inform clinical care but also serve as an investigational platform to elucidate basic mechanisms of tumor biology. The most extensively studied clinical role for CTCs is as a prognostic biomarker; that is, counts at a specific time point are associated with a later discrete clinical end point. In this capacity, CTC counts that are enumerated using the CellSearch platform (Veridex, Raritan, NJ) are the most studied. CellSearch enriches for CTCs with antibodies directed against the epithelial cell adhesion molecule (EpCAM), which is expressed on epithelially derived cells. CTCs are then identified and quantitated on the basis of nuclear staining with 4,6diamidino-2-phenylindole (DAPI), and anticytokeratin and antiCD45 antibodies, which distinguishes CD45 epithelial cells from CD45 leukocytes. In clinical trials, CellSearch CTC counts are prognostic for overall survival (OS) in metastatic breast, colon, and prostate cancers. In prostate cancer, specifically, the Circulating Tumor Cells and the Prediction of Overall Survival in Patients With Androgen Independent Prostate Cancer Entering Onto Chemotherapy (IMMC38) study demonstrated the prognostic value of CellSearch CTCs in 238 men with metastatic castration-resistant disease (mCRPC) starting a new first, second, or third line of chemotherapy. In this study, a pretreatment CTC threshold of 5 CTCs/7.5 mL of blood distinguished patients into favorable and unfavorable groups, the latter having shorter median OS (11.5 v 21.7 months; hazard ratio, 3.3; P .001). In their modeling, the best predictor of survival incorporated baseline high-serum lactate dehydrogenase (LDH) levels with baseline CTC counts; the addition of prostate-specific antigen (PSA) did not improve prediction of survival. In patients with unfavorable baseline counts, conversion to a favorable count after the initiation of treatment was also associated with improved survival. Conversely, conversion to unfavorable counts after treatment initiation was associated with worse survival. Perhaps most importantly, CTC counts outperformed PSA in predicting survival at all time points. More recently, the prognostic value of 5 CTCs/7.5 mL of blood (with the CellSearch assay) was confirmed in a randomized phase III study of abiraterone acetate, a novel hormonal therapy, in men with mCRPC who were previously treated with docetaxel. In this study, CTCs were enumerated at baseline and during the first three cycles. CTC conversion from 5 CTCs to 5 CTCs, along with changes in serum LDH, was strongly predictive of OS. Similar results were recently observed in a phase III study of docetaxel with or without lenalidomide. Building on these findings, in the article that accompanies this editorial, Goldkorn et al present an analysis of the impact of baseline and post-treatment CTC counts on OS and disease response in a subset of men with mCRPC who were treated as part of the Southwest Oncology Group (SWOG) trial 0421, a phase III study comparing the effectiveness of docetaxel plus atrasentan, an endothelin receptor antagonist, versus docetaxel alone. The study itself failed to meet its coprimary end points of improved OS and progression-free survival with the addition of atrasentan and was halted early for futility. Nevertheless, as part of the study, CTCs were enumerated at baseline and 21 days after the first dose of the study treatment. In contrast to the IMMC-38 study, this study had a uniform cohort of men with chemotherapy-naive CRPC and a longer duration of median follow-up (24 v 16 months). In their analysis, the authors showed that baseline CTC counts were correlated with recognized prognostic markers, including PSA, alkaline phosphatase, bone pain, liver disease, and hemoglobin, although relationship with LDH, a widely recognized prognostic marker, was not assessed. Baseline CTC count was associated with subsequent PSA declines and with objective responses. Importantly, median survival for patients with 5 CTCs/7.5 mL of blood at baseline was far better than for those with 5 CTCs (26 v 13 months), and after adjustment for known prognostic factors, the baseline CTC JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 11 APRIL 1