Summary Background The identification of circulating tumour cells correlate with poor prognosis in metastatic breast cancer, but there are few data describing the importance of circulating tumour ...cells in patients with non-metastatic disease. Our aim was to establish if circulating tumour cells predicted worse outcome in patients with non-metastatic breast cancer. Methods We prospectively collected data on circulating tumour cells at the time of definitive surgery from chemonaive patients with stage 1–3 breast cancer from February, 2005, to December, 2010. We deemed eligible all patients with operable breast cancer presenting at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients were ineligible if they had bilateral breast cancer or any other malignancy within 5 years of the diagnosis of the present cancer. We measured circulating tumour cells with the CellSearch System (Veridex, Raritan, NJ). We correlated findings of circulating tumour cells with standard tumour characteristics, including tumour size and grade; oestrogen and progesterone receptor and human epidural growth factor receptor 2 (HER2) status; and axillary lymph node status with χ2 or Fisher exact tests. We assessed outcomes at a median follow-up of 35 months. Log-rank test and Cox regression analysis was applied to establish the association of circulating tumour cells with progression-free and overall survival. Findings No patients reported adverse events or complications from blood collections. We identified one or more circulating tumour cells in 73 (24%) of 302 patients. Detection of one or more circulating tumour cells predicted both decreased progression-free survival (log-rank p=0·005; hazard ratio HR 4·62, 95% CI 1·79–11·9) and overall survival (log-rank p=0·01; HR 4·04, 1·28–12·8). Interpretation The presence of one or more circulating tumour cells predicted early recurrence and decreased overall survival in chemonaive patients with non-metastatic breast cancer. These results suggest that assessment of circulating tumour cells might provide important prognostic information in these patients. Funding Society of Surgical Oncology, Morgan Welch Inflammatory Breast Cancer Program, The University of Texas MD Anderson Cancer Center, and the State of Texas Rare and Aggressive Breast Cancer Research Program.
Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that ...demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis.
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•Epithelial ovarian cancer metastasizes to the omentum hematogenously•Elevated levels of NRG1 in the omentum promote the homing of ovarian cancer cells•ErbB3-expressing CTCs foster hematogenous metastases•ErbB3 knockdown inhibits ovarian cancer metastasis
Using a parabiosis model, Pradeep et al. find that ovarian cancer cells metastasize to the omentum most often via the blood. They show that hematogenous metastasis is dependent on an activated neuregulin 1-ErbB3 pathway, which supports localization to and growth in the omentum, suggesting ErbB3 as a therapeutic target.
ABSTRACT
Aims
Left atrial (LA) mechanical function may play a significant role in the development and progression of heart failure with preserved ejection fraction (HFpEF). We performed a systematic ...review and meta‐analysis to evaluate association of impaired LA function with outcomes in HFpEF.
Methods and results
Multiple databases were searched for original studies measuring different phases of LA function in HFpEF patients. Comparative LA function between HFpEF patients and healthy controls was assessed by pooling weighted mean differences (WMD). Adjusted hazard ratios (HRs) with 95% confidence intervals were pooled to evaluate the prognostic utility of LA function. Twenty‐two studies (2 trials, 20 observational) comprising 1974 HFpEF patients and 751 healthy controls were included. HFpEF patients had decreased LA reservoir WMD = −12.21% (−15.47, −8.95); P < 0.001, LA conduit WMD = −5.68% (−8.56, −2.79); P < 0.001, and pump WMD = −11.07% (−14.81, −7.34); P < 0.001 emptying fractions compared with controls. LA reservoir WMD = −13.38% (−16.07, −10.68); P < 0.001, conduit WMD = −4.09% (−6.77, −1.42); P = 0.003, and pump WMD = −3.53% (−4.47, −2.59); P < 0.001 strains were also significantly lower in HFpEF patients. Decreased LA reservoir strain HR 1.24 (1.02, 1.50); P = 0.03 was significantly associated with risk of composite all‐cause mortality or heart failure hospitalization.
Conclusions
Impaired LA function appears to have diagnostic and prognostic value in HFpEF, but whether indices of LA function truly refine discrimination for diagnosis or prognosis remains to be fully determined. Larger studies are needed to better evaluate associations between LA function and clinical outcomes and the role of LA function as a target for novel HFpEF therapies.
There is a need for sensitive, reproducible biomarkers for patients with stage III melanoma to guide clinical decision making. Circulating tumor cells (CTCs) can be detected in patients with ...melanoma; however, there are limited data regarding their significance in stage III disease. The aim of this study was to determine whether CTCs are associated with early relapse in stage III melanoma.
We prospectively assessed CTCs at first presentation in clinic (baseline) for 243 patients with stage III melanoma. CTCs were measured using the CellSearch System. Relapse-free survival (RFS) was compared between patients with one or more baseline CTC versus those with no CTCs. Log-rank test and Cox regression analysis were applied to establish associations of CTCs with RFS.
At least one baseline CTC was identified in 90 of 243 (37%) patients. Forty-five (19%), 67 (28%), 118 (49%), and 13 (5%) patients were stage IIIA, IIIB, IIIC, or IIID, respectively. CTC detection was not associated with substage, or primary tumor characteristics. Multivariable analysis demonstrated that the detection of ≥1 baseline CTC was significantly associated with decreased 6-month RFS log-rank,
< 0.0001; HR, 3.62, 95% confidence interval (CI), 1.78-7.36;
< 0.0001 and 54-month RFS (log-rank,
= 0.01; HR, 1.69; 95% CI, 1.13-2.54;
= 0.01).
≥1 CTC was independently associated with melanoma relapse, suggesting that CTC assessment may be useful to identify patients at risk for relapse who could derive benefit from adjuvant therapy.
Abstract
Background
We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) ...detection as a prognostic marker.
Methods
We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease–free survival, locoregional relapse–free interval, and pathological complete response. All statistical tests were two-sided.
Results
Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease–free survival (P < .001), and locoregional relapse–free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval CI = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease–free survival (P < .001), and locoregional relapse–free interval (P = .008).
Conclusions
CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy.
Detailed experimental and computational studies of the high selectivity for functionalization of primary over secondary sp3 C−H bonds in alkanes by borane reagents catalyzed by Cp*Rh complexes are ...reported. Prior studies have shown that Cp*Rh(X)(Bpin) (X = H or Bpin), generated from Cp*Rh(H)2(Bpin)2 and Cp*Rh(H)2(Bpin)3, are likely intermediates in these catalytic reactions. To allow analysis of the system by H/D exchange, the current studies focused on reactions of Cp*Rh(D)2(Bpin)2 through the 16-electron species Cp*Rh(D)(Bpin). Density functional theory (DFT) calculations of the reaction between Cp*Rh(H)(BO2C2H4) and the primary and secondary C−H bonds of propane indicate that the lowest energy pathway for C−H bond cleavage occurs to form an isomer in which the alkyl and boryl groups are trans to each other, while the lowest energy pathway for functionalization of the primary C−H bond occurs by formation of the isomer in which these two groups are cis to each other. The barrier for formation of the rhodium complex by cleavage of secondary C−H bonds is higher than that by cleavage of primary C−H bond. The alkyl intermediates are formed reversibly, and steric effects cause the barrier for B−C bond formation from the secondary alkyl intermediate to be higher than that from the primary alkyl intermediate. Experimental studies are consistent with this computational analysis. H/D exchange occurs between (Cp*d 15)Rh(D)2(Bpin)2 and n-octane, indicating that C−H bond cleavage occurs reversibly and occurs faster at primary over secondary C−H bonds. The observation of small amounts of H/D exchange into the secondary C−H bonds of linear alkanes and the clear observation of H/D exchange into the secondary positions of cyclic alkanes without formation of products from functionalization are consistent with the high barrier calculated for B−C bond formation from the secondary alkyl intermediate. A series of kinetic experiments are consistent with a mechanism for H/D exchange between (Cp*d 15)Rh(D)2(Bpin)2 and n-octane occurring by dissociation of borane-d 1 to form (Cp*d 15)Rh(D)(Bpin). Thus, the origin of the selectivity for borylation of primary over secondary C−H bonds is due to the cumulative effects of selective C−H bond cleavage and selective C−B bond formation.
Purpose
New biomarkers are emerging to predict recurrence risk in women with early-stage breast cancer. High Oncotype DX Recurrence Score® (RS) is associated with worse disease-free and overall ...survival. Similarly, circulating tumor cells (CTCs, blood) and disseminated tumor cells (DTCs, bone marrow) have prognostic value in breast cancer. We investigated the association between high RS and CTCs or DTCs.
Methods
Using a prospective database, we evaluated patients with hormone receptor-positive/HER2-negative, node-negative invasive breast cancer from 1/2005 to 1/2017. RS was classified using TAILORx study cutoff points: low (< 11), intermediate (11–25), and high (> 25). CTCs were assessed using CellSearch® and DTCs using cytospin specimens of bone marrow aspirates. Positive result was defined as one or more CTCs or DTCs identified. Chi-square analyses were utilized to evaluate the relationship between RS and CTCs or DTCs.
Results
233 patients were identified from a prospective database, of which 96 had RS results. Of these patients, 88 had CTC results and 58 had DTC results. CTCs were detected in 17/88 (19%) patients, while DTCs were detected in 20/58 (34%). Patients with high RS were not more likely to have CTCs (18%) compared to patients with low/intermediate RS (20%;
p
= 0.919). Similarly, high RS was not associated with DTC detection, with DTCs present in 40% of patients with high RS versus 33% with low/intermediate RS (
p
= 0.687). In the subgroup of patients ≤ 50 years, no associations were found between high RS and CTCs (
p
= 0.383) or DTCs (
p
= 0.234).
Conclusions
High Oncotype DX RS did not correlate with CTCs in blood or DTCs in bone marrow in our study.
Background Circulating tumor cells (CTCs) can be identified in approximately 25% of nonmetastatic breast cancer patients, and data are emerging regarding their prognostic significance. We ...hypothesized that CTCs identified before resection of the primary tumor would predict worse outcomes in nonmetastatic breast cancer patients. Study Design We performed CTC enumerations on 509 patients with nonmetastatic breast cancer as part of an IRB-approved study. The CTCs (per 7.5 mL blood) were identified using the CellSearch System (Janssen). The presence of ≥1 CTC meeting morphologic criteria for malignancy was considered a positive result. Log-rank test and Cox regression analysis were applied to establish the association of CTCs with relapse-free and overall survival. Results Median follow-up was 48 months and mean age was 53 years. Fifty-nine percent of patients (299 of 509) had tumors larger than 2 cm, and 46% (234 of 509) had positive lymph nodes. One hundred sixty-six patients received neoadjuvant chemotherapy (NACT) before CTC assessment, and 343 patients were chemonaïve. One or more CTC was identified in 43 of 166 (26%) NACT treated patients, and in 81 of 343 (24%) chemonaïve patients. Circulating tumor cells were not associated with tumor size, grade, or lymph node status (p = NS). Detection of 1 or more CTCs predicted decreased relapse-free (log-rank p < 0.001, hazard ratio HR 2.72, 95% CI 1.57 to 4.72; p < 0.001) and overall survival (log-rank p = 0.02, HR 2.29, 95% CI 1.12 to 4.67; p = 0.03) at 48 months of follow-up. Conclusions One or more CTCs identified before resection of the primary breast tumor predicted worse relapse-free and overall survival, irrespective of primary tumor size, grade, or lymph node positivity.
Background Cyclooxygenase-2 (COX-2) expression in primary breast cancer predicts tumor cell dissemination to bone marrow, which is a risk factor for recurrence and distant metastasis. “Stem-like” ...phenotype may be important in cancer metastasis. Methods To investigate the role of COX-2 protein in breast cancer stem-like cells, we analyzed it by co-immunofluorescence in tumorospheres derived from the MCF7 estrogen receptor-positive breast cancer cell line. To evaluate COX-2 function we utilized a COX-2 inhibitor in a clonogenicity assay performed with tumorospheres-derived cells. Results We detected rare cells in tumorospheres (one cell per tumorosphere) with very high COX-2 expression (COX-2high ). COX-2 transfected MCF7 cells were able to generate long-term tumorospheres culture, even though transfection efficiency was only one in a million cells. We detected expression of OCT4 in some COX-2high cells, supporting the hypothesis that these cells could be cancer stem-like cells. It is important that COX-2high cells showed less expression of Ki-67 than did neighboring cells, indicating that COX-2high cells may be progenitors of tumorospheres. Celecoxib inhibited the growth of tumorosphere cultures and the ability of tumorosphere-derived cells to form colonies in vitro , indicating an active role of COX-2 in these processes. However, 2 μM celecoxib failed to eradicate tumorosphere-initiating cells. Finally, we detected rare COX-2high cells among SUM149 inflammatory breast cancer cells growing on plastic in serum-containing medium; the SUM149 cell line produces a very high level of COX-2 protein. Conclusion Our results support a role for COX-2 in stem-like breast cancer cells and suggest a mechanism behind a role for COX-2 in disseminated tumor cells, which are known to exhibit characteristic biomarkers and functional properties of stem-like cells.
Circulating Tumor Cells in Stage IV Melanoma Patients Hall, Carolyn S.; Ross, Merrick; Bowman Bauldry, Jessica B. ...
Journal of the American College of Surgeons,
July 2018, 2018-07-00, 20180701, Volume:
227, Issue:
1
Journal Article
Peer reviewed
Management of stage IV melanoma patients remains a challenge. In spite of promising new therapies, many patients develop resistance and progression. The aim of this pilot study was to determine if ...circulating tumor cells (CTCs) are associated with shortened (180-day) progression-free survival (PFS) after a baseline CTC assessment in stage IV melanoma patients.
A baseline CTC assessment was performed in 93 stage IV melanoma patients using a commercially available immunomagnetic system. The presence of 1 or more CTC was considered a positive result. A Cox multivariable regression model was used to evaluate the association between presence of CTCs at baseline and PFS, after adjusting for covariables. Kaplan-Meier curves and a log-rank test were used to summarize and compare unadjusted PFS for patients stratified by CTC positivity.
Median follow-up was 17 months; mean age was 55 years. Thirteen of 93 (14%) patients had no evidence of disease (NED) at baseline CTC assessment. One or more CTC was detected in 39 of 93 (42%) of patients at baseline; CTCs were not associated with primary melanoma features or NED status. Twenty-eight of 93 (30%) patients progressed within 180 days of baseline draw, with 20 of 39 (51%) of the CTC-positive patients relapsing compared with 8 of 54 (15%) of the CTC-negative patients. In adjusted Cox models, a significant association was found suggesting worse PFS within 180 days for CTC-positive patients at baseline (vs CTC-negative) (hazard ratio 4.69, 95% CI 1.59 to 13.77, p = 0.005).
One or more CTCs at baseline were associated with progression within 180 days in stage IV melanoma patients. This information warrants further study of CTCs as a means of identifying patients at high-risk for disease progression.
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