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Life Extension Magazine April 2010

Circulating Tumor Cells

Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality-adjusted survival.

BACKGROUND: Adjuvant tamoxifen for early breast cancer provides an improvement in relapse-free (RFS) and overall survival (OS), especially for older women. We carried out a meta-analysis to find out whether the benefit of adding chemotherapy to tamoxifen outweighs its costs in terms of toxic effects for postmenopausal patients. METHODS: The meta-analysis of quality-adjusted survival was based on data from 3,920 patients aged 50 years or older with node-positive breast cancer randomly assigned in nine trials that compared combination chemotherapy plus tamoxifen with tamoxifen alone. The nine trials were included in the worldwide overview conducted by the early breast cancer trialists’ collaborative group (EBCTCG). The quality-adjusted time without symptoms or toxicity (Q-TWiST) method was used to provide treatment comparisons incorporating differences in quality of life associated with subjective toxic effects of treatment and symptoms of disease relapse. FINDINGS: Within 7 years of follow-up the modest benefit of increased RFS and OS for patients who received chemotherapy just balanced the costs in terms of acute toxic side-effects. Chemotherapy-treated patients gained an average of 5.4 months of RFS and 2 months of OS (neither statistically significant), but had to receive cytotoxic treatment for between 2 and 24 months to achieve these gains. No values of preference weights for time spent undergoing chemotherapy and time after relapse gave significantly more Q-TWiST with chemotherapy plus tamoxifen than with tamoxifen alone. INTERPRETATION: Within 7 years of follow-up, adjuvant chemoendocrine therapy did not provide more quality-adjusted survival time than tamoxifen alone for women aged 50 years or older with node-positive breast cancer. Better selection and administration of chemotherapy regimen, different scheduling of chemotherapy and tamoxifen, and appropriate use of patient and tumour characteristics may increase the therapeutic advantage of the combination.

Lancet. 1996 Apr 20;347(9008):1066-71

HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials.

BACKGROUND: Adjuvant chemotherapy with anthracyclines improves disease-free and overall survival compared with non-anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer. The role of HER2 status as a marker of anthracycline responsiveness has been explored by subset analyses within randomized clinical trials, with inconsistent results. We performed a pooled analysis of the interaction between HER2 status and the efficacy of adjuvant anthracyclines based on the published subset data. METHODS: We searched literature databases to identify randomized trials that compared anthracycline-based with non-anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer and reported efficacy data according to HER2 status. Log hazard ratios (HRs) for disease-free and overall survival were pooled across the studies according to HER2 status by inverse variance weighting. A pooled test for treatment by HER2 status interaction was performed by weighted linear meta-regression. All statistical tests were two-sided. RESULTS: Eight studies (with 6564 randomly assigned patients, of whom 5,354 had HER2 status information available) were eligible for this analysis. In HER2-positive disease (n = 1536 patients), anthracyclines were superior to non-anthracycline-based regimens in terms of disease-free (pooled HR of relapse = 0.71; 95% confidence interval [CI] = 0.61 to 0.83; P < .001) and overall (pooled HR of death from any cause = 0.73; 95% CI = 0.62 to 0.85; P < .001) survival. In HER2-negative disease (n = 3818 patients), anthracyclines did not improve disease-free (HR = 1.00; 95% CI = 0.90 to 1.11; P = .75) or overall (HR = 1.03; 95% CI = 0.92 to 1.16; P = .60) survival. The test for treatment by HER2 status interaction yielded statistically significant results: for disease-free survival, the chi-square statistic for interaction was 13.7 (P < .001), and for overall survival, it was 12.6 (P < .001). CONCLUSIONS: The added benefits of adjuvant chemotherapy with anthracyclines appear to be confined to women who have HER2 overexpressed or amplified breast tumors.

Natl Cancer Inst. 2008 Jan 2;100(1):14-20

Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.

BACKGROUND: Doxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug. A large-scale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7% of patients developed doxorubicin-related congestive heart failure (CHF) after a cumulative dose of 550 mg/m(2). To assess whether this estimate is reflective of the incidence in the broader clinical oncology setting, the authors evaluated data from three prospective studies to determine both the incidence of doxorubicin-related CHF and the accumulated dose of doxorubicin at which CHF occurs. METHODS: A group of 630 patients who were randomized to a doxorubicin-plus-placebo arm of three Phase III studies, two studies in patients with breast carcinoma and one study in patients with small cell lung carcinoma, were included in the analysis. RESULTS: Thirty-two of 630 patients had a diagnosis of CHF. Analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin-related CHF at a cumulative dose of 550 mg/m(2). Age appeared to be an important risk factor for doxorubicin-related CHF after a cumulative dose of 400 mg/m(2), with older patients (age > 65 years) showing a greater incidence of CHF compared with younger patients (age < or = 65 years). In addition, > 50% of the patients who experienced doxorubicin-related CHF had a reduction < 30% in left ventricular ejection fraction (LVEF) while they were on study. CONCLUSIONS: Doxorubicin-related CHF occurs with greater frequency and at a lower cumulative dose than previously reported. These findings further indicate that LVEF is not an accurate predictor of CHF in patients who receive doxorubicin.

Cancer. 2003 Jun 1;97(11):2869-79

HER-2 gene amplification can be acquired as breast cancer progresses.

Amplification and overexpression of the HER-2 oncogene in breast cancer is felt to be stable over the course of disease and concordant between primary tumor and metastases. Therefore, patients with HER-2-negative primary tumors rarely will receive anti-Her-2 antibody (trastuzumab, Herceptin) therapy. A very sensitive blood test was used to capture circulating tumor cells (CTCs) and evaluate their HER-2 gene status by fluorescence in situ hybridization. The HER-2 status of the primary tumor and corresponding CTCs in 31 patients showed 97% agreement, with no false positives. In 10 patients with HER-2-positive tumors, the HER-2/chromosome enumerator probe 17 ratio in each tumor was about twice that of the corresponding CTCs (mean 6.64 +/- 2.72 vs. 2.8 +/- 0.6). Hence, the ratio of the CTCs is a reliable surrogate marker for the expected high ratio in the primary tumor. Her-2 protein expression of 10 CTCs was sufficient to make a definitive diagnosis of the HER-2 gene status of the whole population of CTCs in 19 patients with recurrent breast cancer. Nine of 24 breast cancer patients whose primary tumor was HER-2-negative each acquired HER-2 gene amplification in their CTCs during cancer progression, i.e., 37.5% (95% confidence interval of 18.8-59.4%). Four of the 9 patients were treated with Herceptin-containing therapy. One had a complete response and 2 had a partial response.

Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9393-8

HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients.

PURPOSE: Early metastasis in node-negative breast cancer indicates that breast cancer cells obviously can bypass the lymph nodes and disseminate directly hematogenous to distant organs. For this purpose, we evaluated the prognostic value of blood-borne, HER2-positive circulating tumor cells (CTC) in the peripheral blood from 42 breast cancer patients with a median follow-up of 95 months. EXPERIMENTAL DESIGN: Cells were isolated by the patented combined buoyant density gradient and immunomagnetic separation procedure and analyzed by immunocytochemistry. RESULTS: We detected one to eight CTCs in the peripheral blood of 17 of 35 patients (48.6%) presenting no overt metastasis. As a positive control, 7 of 7 (100%) patients with metastatic disease presented positive. Healthy persons and patients (n = 32) operated for nonmalignant diseases presented negative for CTCs. The presence and frequency of HER2-positive CTCs correlated with a significantly decreased disease-free survival (P < 0.005) and overall survival (P < 0.05). Interestingly, in 12 patients with HER2-positive CTCs, the primary tumor was negative for HER2 as assessed by immunohistochemical score and fluorescence in situ hybridization. CONCLUSIONS: This study provides some evidence of a prognostic effect of HER2-positive CTCs in stage I to III breast cancer. Future studies have to determine the outcome of patients treated with HER2-targeting therapies with respect to HER2-positive CTC levels because it is not unlikely that high levels of HER2-positive CTCs reflect the activity of the tumor and may predict response to trastuzumab.

Clin Cancer Res. 2006 Mar 15;12(6):1715-20

Prognostic value of circulating prostate cells in patients with a rising PSA after radical prostatectomy.

BACKGROUND: To predict poor outcome in patients with a biochemical recurrence (rising PSA) after radical prostatectomy (RP), urologists rely primarily on Gleason score, PSA doubling time, and time from surgery to biochemical (i.e., PSA) recurrence. In the present study, we assess the value of RT-PCR detection circulating prostate cells in blood of patients with a rising PSA. METHODS: RNA from blood samples was obtained from 55 patients with a rising PSA and from 45 patients without evidence of biochemical failure (PSA < 0.1 ng/ml). Both groups were matched for age, Gleason score, pT stage, and interval between radical prostatectomy and PCR testing. RESULTS: PSA positive cells were detected in 1/45 (2%) patients without a PSA recurrence and 19/55 (34%) patients with a PSA recurrence. In the rising PSA group, mean PSA doubling time was significantly shorter in patients with positive RT-PCR (5 months) than in patients with negative RT-PCR (16 months; P = 0.001). An earlier onset of recurrence was also detected in patients with a positive RT-PCR (31 months for positive RT-PCR vs. 50 months for negative RT-PCR) but this result did not achieve statistical significance (P = 0.102). Salvage radiation therapy was administered in 15 patients. Three of the five patients with a positive RT-PCR progressed during radiotherapy whereas 7 of the 10 patients with a negative RT-PCR obtained a complete response and none have progressed. CONCLUSIONS: These preliminary results suggest that RT-PCR detection of prostate cells in blood of patients after RP correlates with rapidly progressing biochemical failure after RP.

Prostate. 2003 Aug 1;56(3):163-70

Prognostic significance of reverse transcriptase polymerase chain reaction for prostate-specific antigen in metastatic prostate cancer: a nested study within CALGB 9583.

PURPOSE: To determine whether reverse transcriptase polymerase chain reaction (RT-PCR) to detect circulating prostate-specific antigen (PSA)-positive cells is a prognostic factor for survival in hormone refractory prostate cancer and to validate the prognostic importance of this test in relation to other known prognostic factors. PATIENTS AND METHODS: A single centralized laboratory received and analyzed whole blood for RT-PCR for PSA for a subset of patients enrolled on two Cancer and Leukemia Group B (CALGB) randomized trials (CALGB 9583 and CALGB 9480). Using 9583, a prognostic model was developed and an independent data set (CALGB 9480) was used to validate the fitted model. RESULTS: Of 162 patients in 9,583, 91 (56%) patients were negative for RT-PCR for PSA and 71 (44%) patients were positive. The median survival time was 21 months (95% confidence interval [CI], 18 to 27 months) for RT-PCR-negative patients compared with 11 months (95% CI, 8 to 15 months) for RT-PCR-positive patients (P < or =.001). In multivariable analysis, the hazard ratio (HR) for death was 1.7 (95% CI, 1.2 to 2.4; P =.006) for positive RT-PCR patients compared with negative RT-PCR patients. A fitted model that incorporated RT-PCR for PSA and other factors was used to classify patients from 9,480 into one of two risk groups: low or high. We observed good agreement between the observed and predicted survival probabilities for the two risk groups. CONCLUSION: RT-PCR to detect PSA-positive circulating cells is confirmed to be a significant prognostic factor of survival in patients with hormone refractory prostate cancer. This model could be used to stratify patients in randomized phase III trials.

J Clin Oncol. 2003 Feb 1;21(3):490-5

Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer.

PURPOSE: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. EXPERIMENTAL DESIGN: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We estimated the probability of survival over time by the Kaplan-Meier method. The concordance probability estimate was used to gauge the discriminatory strength of the informative prognostic factors. RESULTS: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. CONCLUSIONS: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.

Clin Cancer Res. 2007 Dec 1;13(23):7053-8

Circulating tumor cells versus imaging—predicting overall survival in metastatic breast cancer.

PURPOSE: The presence of >or=5 circulating tumor cells (CTC) in 7.5 mL blood from patients with measurable metastatic breast cancer before and/or after initiation of therapy is associated with shorter progression-free and overall survival. In this report, we compared the use of CTCs to radiology for prediction of overall survival. EXPERIMENTAL DESIGN: One hundred thirty-eight metastatic breast cancer patients had imaging studies done before and a median of 10 weeks after the initiation of therapy. All scans were centrally reviewed by two independent radiologists using WHO criteria to determine radiologic response. CTC counts were determined approximately 4 weeks after initiation of therapy. Specimens were analyzed at one of seven laboratories and reviewed by a central laboratory. RESULTS: Interreader variability for radiologic responses and CTC counts were 15.2% and 0.7%, respectively. The median overall survival of 13 (9%) patients with radiologic nonprogression and >or=5 CTCs was significantly shorter than that of the 83 (60%) patients with radiologic nonprogression and <5 CTCs (15.3 versus 26.9 months; P=0.0389). The median overall survival of the 20 (14%) patients with radiologic progression and <5 CTCs was significantly longer than the 22 (16%) patients with >or=5 CTCs that showed progression by radiology (19.9 versus 6.4 months; P=0.0039). CONCLUSIONS: Assessment of CTCs is an earlier, more reproducible indication of disease status than current imaging methods. CTCs may be a superior surrogate end point, as they are highly reproducible and correlate better with overall survival than do changes determined by traditional radiology.

Clin Cancer Res. 2006 Nov 1;12(21):6403-9

Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival.

PURPOSE: We reported previously that >or=5 circulating tumor cells (CTC) in 7.5 mL blood at baseline and at first follow-up in 177 patients with metastatic breast cancer (MBC) were associated with poor clinical outcome. In this study, additional follow-up data and CTC levels at subsequent follow-up visits were evaluated. EXPERIMENTAL DESIGN: CTCs were enumerated in 177 MBC patients before the initiation of a new course of therapy (baseline) and 3 to 5, 6 to 8, 9 to 14, and 15 to 20 weeks after the initiation of therapy. Progression-free survival (PFS) and overall survival (OS) times were calculated from the dates of each follow-up blood draw. Kaplan-Meier plots and survival analyses were done using a threshold of >or=5 CTCs/7.5 mL at each blood draw. RESULTS: Median PFS times for patients with <5 CTC from each of the five blood draw time points were 7.0, 6.1, 5.6, 7.0, and 6.0 months, respectively. For patients with >or=5 CTC, median PFS from these same time points was significantly shorter: 2.7, 1.3, 1.4, 3.0, and 3.6 months, respectively. Median OS for patients with <5 CTC from the five blood draw time points was all >18.5 months. For patients with >or=5 CTC, median OS from these same time points was significantly shorter: 10.9, 6.3, 6.3, 6.6, and 6.7 months, respectively. Median PFS and OS times at baseline and up to 9 to 14 weeks after the initiation of therapy were statistically significantly different. CONCLUSIONS: Detection of elevated CTCs at any time during therapy is an accurate indication of subsequent rapid disease progression and mortality for MBC patients.

Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4218-24

Breast cancer-specific mRNA transcripts presence in peripheral blood after adjuvant chemotherapy predicts poor survival among high-risk breast cancer patients treated with high-dose chemotherapy with peripheral blood stem cell support.

PURPOSE: To study the prognostic significance of the presence of breast cancer-specific mRNA transcripts in peripheral blood (PB), defined by serial analysis of gene expression, in high-risk breast cancer (HRBC) patients undergoing high-dose chemotherapy after receiving adjuvant chemotherapy. METHODS: From 1994 to 2000, 84 HRBC patients (median age, 44 years; > 10 nodes; 74%) received adjuvant chemotherapy (fluorouracil, epirubicin, and cyclophosphamide for six cycles [83%] or doxorubicin and cyclophosphamide followed by paclitaxel) before undergoing one course of cyclophosphamide plus thiotepa plus carboplatin (STAMP V). Radiotherapy or hormone therapy was administered whenever indicated. Aliquots of apheresis-mononuclear blood cells were frozen from each patient. mRNA was isolated using an automatic nucleic acid extractor based on the magnetic beads technology; reverse transcription was performed using random hexamers. Cytokeratin 19, HER-2, P1B, PS2, and EGP2 transcripts were quantified to B-glucuronidase by real-time polymerase chain reaction (RT-PCR) using a linear DNA probe marked with a quencher and reporter fluorophores used in RT-PCR. Presence of PB micrometastases, estrogen receptor and progesterone receptor status, tumor size, age, tumor grade, number of nodes affected, and treatment with paclitaxel were included in the statistical analysis. RESULTS: Median follow-up was 68.3 months (range, 6 months to 103 months). Forty-seven relapses (56%) and 35 deaths (41.7%) were registered. Both tumor size and presence of micrometastases reached statistical significance according to the Cox multivariate model. Relapse hazard ratio (HR) for those patients with PB micrometastases was 269% (P = .006); death HR, 300% (P = .011). Time relapse was 53 months longer for patients without micrometastases: 31.3 v 84.2 months (P = .021). CONCLUSION: PB micrometastases presence after adjuvant chemotherapy predicts both relapse and death more powerful than classical factors in HRBC patients undergoing high-dose chemotherapy. Micrometastases search using a gene panel appears to be a more accurate procedure than classical approaches involving only one or two genes.

J Clin Oncol. 2006 Aug 1;24(22):3611-8

Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse.

PURPOSE: To demonstrate that it is possible to monitor the response to adjuvant therapy by repeated analysis of circulating epithelial tumor cells (CETCs) and to detect patients early who are at risk of relapse. PATIENTS AND METHODS: In 91 nonmetastatic primary breast cancer patients, CETCs were quantified using laser scanning cytometry of anti-epithelial cell adhesion molecule-stained epithelial cells from whole unseparated blood before and during adjuvant chemotherapy. RESULTS: Numbers of CETCs were analyzed before therapy, before each new cycle, and at the end of chemotherapy. The following three typical patterns of response were observed: (1) decrease in cell numbers (> 10-fold); (2) marginal changes in cell numbers (< 10-fold); and (3) an (sometimes saw-toothed) increase or an initial decrease with subsequent reincrease (> 10-fold) in numbers of CETCs. Twenty relapses (22%) were observed within the accrual time of 40 months, including one of 28 patients from response group 1, five of 30 patients from response group 2, and 14 of 33 patients from response group 3. The difference in relapse-free survival was highly significant for CETC (hazard ratio = 4.407; 95% CI, 1.739 to 9.418; P < .001) between patients with decreasing cell numbers and those with marginal changes and between patients with marginal changes and those with an increase of more than 10-fold (linear Cox regression model). CONCLUSION: These results show that peripherally circulating tumor cells are influenced by systemic chemotherapy and that an increase (even after initial response to therapy) of 10-fold or more at the end of therapy is a strong predictor of relapse and a surrogate marker for the aggressiveness of the tumor cells.

J Clin Oncol. 2008 Mar 10;26(8):1208-15