Beverly C. Handy

Multicenter analytical evaluation of a high-sensitivity troponin T assay.

BACKGROUND High-sensitivity cardiac troponin assays are being introduced clinically for earlier diagnosis of acute myocardial infarction (AMI). We evaluated the analytical performance of a high-sensitivity cardiac troponin T assay (hscTnT, Roche Diagnostics) in a multicenter, international trial. METHODS Three US and 5 European sites evaluated hscTnT on the Modular® Analytics E170, cobas® 6000, Elecsys 2010, and cobas® e 411. Precision, accuracy, reportable range, an inter-laboratory comparison trial, and the 99th percentile of a reference population were assessed. RESULTS Total imprecision (CVs) were 4.6-36.8% between 3.4 and 10.3 ng/L hscTnT. Assay linearity was up to 10,000 ng/L and the limit of blank and detection were 3 and 5 ng/L, respectively. The 99th percentile reference limit was 14.2 ng/L (n=533). No significant differences between specimen types, assay incubation time, or reagent lots existed. A substantial positive bias (76%) exists between the 4th generation and hscTnT assays at the low end of the measuring range (<50 ng/L). hscTnT serum pool concentrations were within 2SD limits of the mean of means in the comparison trial, indicating comparable results across multiple platforms and laboratories. CONCLUSION The Roche hscTnT assay conforms to guideline precision requirements and will likely identify additional patients with myocardial injury suspicious for AMI.

Circulating Tumor Cells and [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Outcome Prediction in Metastatic Breast Cancer

PURPOSE Circulating tumor cells (CTCs) and [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) are two new promising tools for therapeutic monitoring. In this study, we compared the prognostic value of CTC and FDG-PET/CT monitoring during systemic therapy for metastatic breast cancer (MBC). PATIENTS AND METHODS A retrospective analyses of 115 MBC patients who started a new line of therapy and who had CTC counts and FDG-PET/CT scans performed at baseline and at 9 to 12 weeks during therapy (midtherapy) was performed. Patients were categorized according to midtherapy CTC counts as favorable (ie, < five CTCs/7.5 mL blood) or unfavorable (> or = five CTCs/7.5 mL blood) outcomes. CTC counts and FDG-PET/CT response at midtherapy were compared, and univariate and multivariate analyses were performed to identify factors associated with survival. RESULTS In 102 evaluable patients, the median overall survival time was 14 months (range, 1 to > 41 months). Midtherapy CTC levels correlated with FDG-PET/CT response in 68 (67%) of 102 evaluable patients. In univariate analysis, midtherapy CTC counts and FDG-PET/CT response predicted overall survival (P < .001 and P = .001, respectively). FDG-PET/CT predicted overall survival (P = .0086) in 31 (91%) of 34 discordant patients who had fewer than five CTCs at midtherapy. Only midtherapy CTC levels remained significant in a multivariate analysis (P = .004). CONCLUSION Detection of five or more CTCs during therapeutic monitoring can accurately predict prognosis in MBC beyond metabolic response. FDG-PET/CT deserves a role in patients who have fewer than five CTCs at midtherapy. Prospective trials should evaluate the most sensitive and cost-effective modality for therapeutic monitoring in MBC.

Circulating tumor cells in metastatic breast cancer: From prognostic stratification to modification of the staging system?

The aim of the current study was to assess the prognostic value of baseline circulating tumor cells (CTCs) in a large cohort of patients with newly diagnosed metastatic breast cancer (MBC).

Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment

IntroductionCirculating tumor cells (CTCs) represent an independent predictor of outcome in patients with metastatic breast cancer (MBC). We assessed the prognostic impact of CTCs according to different first-line systemic treatments, and explored their potential predictive value in MBC patients.MethodsWe retrospectively evaluated 235 newly diagnosed MBC patients, treated at the University of Texas MD Anderson Cancer Center. All patients had a baseline CTC assessment performed with CellSearch®. Progression-free survival and overall survival were compared with the log-rank test between groups, according to CTC count (< 5 vs. ≥ 5) and type of systemic therapy. We further explored the predictive value of baseline CTCs in patients receiving different treatments.ResultsAt a median follow-up of 18 months, the CTC count was confirmed to be a robust prognostic marker in the overall population (median progression-free survival 12.0 and 7.0 months for patients with CTC < 5 and ≥ 5, respectively; P < 0.001). Conversely, in patients with human epidermal growth factor receptor-2-overexpressed/amplified tumors receiving trastuzumab or lapatinib, the baseline CTC count was not prognostic (median progression-free survival 14.5 months for patients with CTC < 5 and 16.1 months for those with CTC ≥ 5; P = 0.947). Furthermore, in patients with human epidermal growth factor receptor-2 normal tumors, a baseline CTC count ≥ 5 identified subjects who derived benefit from more aggressive treatments, including combination chemotherapy and chemotherapy plus bevacizumab.ConclusionsThis analysis suggests that the prognostic information provided by CTC count may be useful in patient stratifications and therapeutic selection, particularly in the group with positive CTCs, in which various therapeutic choices may procure differential palliative benefit.

Circulating Tumor Cells in Peripheral Blood Samples From Patients With Increased Serum Prostate Specific Antigen: Initial Results in Early Prostate Cancer

PURPOSE We evaluated the hypothesis that circulating tumor cells as determined using the CellSearch System would correlate with tumor volume, pathological stage and Gleason score in men with localized prostate cancer. MATERIALS AND METHODS Samples of blood (30 ml) were drawn from 97 men with localized prostate cancer before radical prostatectomy, on postoperative days 2 to 3 and at 6 weeks. A control group consisted of 25 men with an increased prostate specific antigen and no tumor detected on extended prostate biopsy. Samples were analyzed for circulating tumor cells using the CellSearch System. RESULTS Circulating tumor cells were detected in 21% of patients with cancer and 20% of controls (p = 0.946). At 6 weeks after prostatectomy circulating tumor cells were detected in 16% and 11% (p = 0.51) of the men positive and negative for circulating tumor cells at baseline, respectively. Of the 20 patients with cancer who had circulating tumor cells at baseline 18 showed no circulating tumor cells after surgery. Circulating tumor cell values did not correlate with tumor volume, pathological stage or Gleason score. Only 3.1% of the men with cancer and 8% of the control group had 3 or more circulating tumor cells per 22.5 ml blood at baseline. CONCLUSIONS In metastatic breast, prostate and other cancers more than 5 circulating tumor cells are often detected using the CellSearch System, and may correlate with prognosis. However, in the setting of localized prostate cancer the number of detectable circulating tumor cells was low, with findings comparable to those in men who were biopsy negative for cancer. We found no correlation between the number of circulating tumor cells and known prognostic factors in this population.

Characterization of metastatic breast cancer patients with nondetectable circulating tumor cells

Circulating tumor cells (CTC) are an independent prognostic factor in metastatic breast cancer patients (MBC). However, CTC are undetectable in one third of patients. The aim of this study was to assess the prognostic factors in MBC patients without detectable CTC. This retrospective study included 292 MBC patients evaluated between January 2004 and December 2007. CTC were enumerated before patients started a new line of treatment using the CellSearch™. Overall survival (OS) was calculated from the date of CTC measurement and estimated by the Kaplan‐Meier product limit method. CTC were not detected in 35.96% patients, whereas 40.75% patients had CTC ≥ 5. Undetectable CTC status was positively correlated with presence of brain metastasis (OR: 6.17, 95%CI = 2.14–17.79; p = 0.001), and inversely correlated with bone metastasis (OR: 0.47; 95%CI = 0.27–0.80; p = 0.01). In multivariate analysis, hormone receptors, number of metastatic sites and lines of therapy were independent prognostic factors for OS in patients without detectable CTC. Patients without detectable CTC before starting of a new line of therapy comprise a heterogeneous group with substantially different prognosis. We showed that some important metastatic disease characteristics are predictive of undetectable CTC status in MBC.

Circulating tumor cells in immunohistochemical subtypes of metastatic breast cancer: lack of prediction in HER2-positive disease treated with targeted therapy

BACKGROUND Circulating tumor cells (CTCs) are associated with inferior prognosis in metastatic breast cancer (MBC). We hypothesized that the relationship between CTCs and disease subtype would provide a better understanding of the clinical and biologic behavior of MBC. PATIENTS AND METHODS We retrospectively analyzed 517 MBC patients treated at a single institution. Subtypes of primary tumors were analyzed by immunohistochemical (IHC) or fluorescent in situ hybridization analyses and CTCs were enumerated by CellSearch® at starting a new therapy. Overall survival (OS) and progression-free survival durations for each IHC subtype were determined. RESULTS At a median follow-up of 24.6 months, 276 of 517 (53%) patients had died. The median OS for patients with <5 and ≥5 CTCs were 32.4 and 18.3 months, respectively (P < 0.001). Except in HER2+ patients, the prognostic value of CTCs was independent of disease subtype and disease site. CONCLUSIONS In this large retrospective study, CTCs were strongly predictive of survival in all MBC subtypes except HER2+ patients who had been treated with targeted therapy. Our results clearly demonstrate the value of enumerating CTCs in MBC and strongly suggest an interesting biological implication in the HER2+ subset of patients that need to be further explored.BACKGROUND Circulating tumor cells (CTCs) are associated with inferior prognosis in metastatic breast cancer (MBC). We hypothesized that the relationship between CTCs and disease subtype would provide a better understanding of the clinical and biologic behavior of MBC. PATIENTS AND METHODS We retrospectively analyzed 517 MBC patients treated at a single institution. Subtypes of primary tumors were analyzed by immunohistochemical (IHC) or fluorescent in situ hybridization analyses and CTCs were enumerated by CellSearch(®) at starting a new therapy. Overall survival (OS) and progression-free survival durations for each IHC subtype were determined. RESULTS At a median follow-up of 24.6 months, 276 of 517 (53%) patients had died. The median OS for patients with <5 and ≥ 5 CTCs were 32.4 and 18.3 months, respectively (P < 0.001). Except in HER2+ patients, the prognostic value of CTCs was independent of disease subtype and disease site. CONCLUSIONS In this large retrospective study, CTCs were strongly predictive of survival in all MBC subtypes except HER2+ patients who had been treated with targeted therapy. Our results clearly demonstrate the value of enumerating CTCs in MBC and strongly suggest an interesting biological implication in the HER2+ subset of patients that need to be further explored.

Circulating tumor cells and bone metastases as detected by FDG–PET/CT in patients with metastatic breast cancer

BACKGROUND We evaluated the relationship between the detection and prognostic significance of circulating tumor cells (CTCs) and sites of metastases detected by 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS From May 2004 to January 2008, 195 patients with relapsed/progressive MBC underwent whole-body FDG-PET/CT and provided blood samples for assessment of CTC count. RESULTS Higher CTC numbers were detected in patients with bone metastases relative to those with no bone lesions (mean 65.7 versus 3.3, P = 0.0122) and in patients with multiple bone metastases relative to those with one or two bone lesions (mean 77.7 versus 2.6, P < 0.001). CTCs predicted overall survival (OS) in 108 patients with multiple sites of metastases including bone (P = 0.0008) but not in 58 without bone metastases (P = 0.4111) and in 29 with bone involvement only (P = 0.3552). All 15 patients but one with human epidermal growth factor receptor 2 (HER-2) positive tumors who were treated with trastuzumab-based regimens had <5 CTCs at progression. In multivariate analysis, CTCs, but not bone metastases, remained a significant predictor of OS. CONCLUSION Presence of extensive bone metastases as detected by FDG-PET/CT is associated with increased CTC numbers in MBC.

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.

18F-FDG PET/CT Findings and Circulating Tumor Cell Counts in the Monitoring of Systemic Therapies for Bone Metastases from Breast Cancer

Our objective was to compare the predictive significance of 18F-FDG PET/CT findings and circulating tumor cell (CTC) count in patients with bone metastases from breast cancer treated with standard systemic therapy. Methods: Breast cancer patients with progressive bone-only metastatic disease without visceral metastases starting a new line of systemic therapy underwent 18F-FDG PET/CT and had CTC counts determined before and during treatment. Disease status was reassessed by CTC count (≥5 vs. <5 CTC/7.5 mL of blood) and 18F-FDG PET/CT approximately 2–4 mo after initiation of the new systemic therapy. Results: CTC counts at follow-up agreed with the 18F-FDG PET/CT assessment in 43 (78%) of the 55 evaluable patients. Of the 12 patients with discordant CTC and 18F-FDG PET/CT results, 8 (66%) had ≥5 CTCs, with no evidence of progressive disease at the time of the 18F-FDG PET/CT study, whereas 4 (33%) had <5 CTCs, with evidence of progressive disease by 18F-FDG PET/CT. 18F-FDG PET/CT findings and follow-up CTC counts were found to be significantly associated with both progression-free survival (P = 0.02 and P < 0.0001, respectively) and overall survival (P = 0.02 and P = 0.01, respectively). In multivariate analysis, the 18F-FDG PET/CT assessment remained as the only predictive factor for progression-free survival (P < 0.0001), whereas estrogen receptor status was the only predictive factor for overall survival (P = 0.01). Conclusion: 18F-FDG PET/CT is a useful tool for therapeutic monitoring in patients with bone metastases from breast cancer. Prospective studies are needed to define the role of 18F-FDG PET/CT and CTC in the setting of response discordance to establish bone-dominant disease as a tumor-response measurable disease.