Purpose: Although unequivocal evidence has shown the prognostic relevance of circulating tumor cells (CTC) in the peripheral blood of patients with metastatic breast cancer, less evidence is available for the prognostic relevance of CTCs at the time of primary diagnosis.Experimental Design: We conducted a pooled analysis of individual data from 3,173 patients with nonmetastatic (stage I-III) breast cancer from five breast cancer institutions. The prevalence and numbers of CTCs were assessed at the time of primary diagnosis with the FDA-cleared CellSearch System (Janssen Diagnostics, LLC). Patient outcomes were analyzed using meta-analytic procedures, univariate log-rank tests, and multivariate Cox proportional hazard regression analyses. The median follow-up duration was 62.8 months.Results: One or more CTCs were detected in 20.2% of the patients. CTC-positive patients had larger tumors, increased lymph node involvement, and a higher histologic tumor grade than did CTC-negative patients (all P < 0.002). Multivariate Cox regressions, which included tumor size, nodal status, histologic tumor grade, and hormone receptor and HER2 status, confirmed that the presence of CTCs was an independent prognostic factor for disease-free survival [HR, 1.82; 95% confidence interval (CI), 1.47-2.26], distant disease-free survival (HR, 1.89; 95% CI, 1.49-2.40), breast cancer-specific survival (HR, 2.04; 95% CI, 1.52-2.75), and overall survival (HR, 1.97; 95% CI, 1.51-2.59).

IntroductionThe presence of circulating tumor cells (CTC) is an independent prognostic factor for progression-free survival and breast cancer-related death (BRD) for patients with metastatic breast cancer beginning a new line of systemic therapy. The current study was undertaken to explore whether the presence of CTC at the time of diagnosis was associated with recurrence-free survival (RFS) and BRD.MethodsIn a prospective single center study, CTC were enumerated with the CellSearch system in 30 ml of peripheral blood of 602 patients before undergoing surgery for breast cancer. There were 97 patients with a benign tumor, 101 did not meet the inclusion criteria of which there were 48 patients with DCIS, leaving 404 stage I to III patients. Patients were stratified into unfavorable (CTC ≥1) and favorable (CTC = 0) prognostic groups.Results≥1 CTC in 30 ml blood was detected in 15 (15%) benign tumors, in 9 DCIS (19%), in 28 (16%) stage I, 32 (18%) stage II and in 16 (31%) patients with stage III. In stage I to III patients 76 (19%) had ≥1 CTC of whom 16 (21.1%) developed a recurrence. In 328 patients with 0 CTC 38 (11.6%) developed a recurrence. Four-year RFS was 88.4% for favorable CTC and 78.9% for unfavorable CTC (P = 0.038). A total of 25 patients died of breast cancer-related causes and 11 (44%) had ≥1 CTC. BRD was 4.3% for favorable and 14.5% for unfavorable CTC (P = 0.001). In multivariate analysis ≥1 CTC was associated with distant disease-free survival, but not for overall recurrence-free survival. CTC, progesterone receptor and N-stage were independent predictors of BRD in multivariate analysis.ConclusionsPresence of CTC in breast cancer patients before undergoing surgery with curative intent is associated with an increased risk for breast cancer-related death.

The authors' full names, academic degrees, and affiliations are listed in the Appendix. Dr. Peffault de Latour can be contacted at regis .

BACKGROUND: The treatment of recurrent transitional cell carcinoma (TCC) remains an unmet clinical need. This study assessed lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER‐2, as second‐line therapy in patients with locally advanced or metastatic TCC. METHODS: This was a single‐arm, multicenter, open‐label, prospective phase 2 study. Patients with TCC whose disease progressed on prior platinum‐based chemotherapy received lapatinib until disease progression or unacceptable toxicity, with evaluations for response by Response Evaluation Criteria In Solid Tumors criteria performed every 8 weeks. The primary endpoint of the current study was objective tumor response rate. Secondary endpoints included safety, time to disease progression, and overall survival. RESULTS: Fifty‐nine patients were enrolled in the study, 25 of whom (42%) could not be evaluated for response. The primary endpoint of an objective response rate (ORR) >10% was observed in 1.7% (95% confidence interval [95% CI], 0.0%‐9.1%) of patients; however, 18 (31%; 95% CI, 19%‐44%) patients achieved stable disease (SD). The median time to disease progression and overall survival (OS) were 8.6 weeks (95% CI, 8.0 weeks‐11.3 weeks) and 17.9 weeks (95% CI, 13.1 weeks‐30.3 weeks), respectively. Clinical benefit (ORR and SD) was found to be correlated with EGFR overexpression (P = .029), and, to some extent, HER‐2 overexpression. The median OS was significantly prolonged in patients with tumors that overexpressed EGFR and/or HER‐2 (P = .0001). Lapatinib was well tolerated. CONCLUSIONS: The study was considered to be negative because it did not meet its primary endpoint; however, further analysis demonstrated an improvement in OS in a subset of patients with tumors overexpressing EGFR and/or HER‐2, which is encouraging and warrants further investigation. Cancer 2009. © 2009 American Cancer Society.

BackgroundPresence of circulating tumor cells (CTC) in patients with metastatic breast, colorectal and prostate cancer is indicative for poor prognosis. An automated CTC (aCTC) algorithm developed previously to eliminate the variability in manual counting of CTC (mCTC) was used to extract morphological features. Here we validated the aCTC algorithm on CTC images from prostate, breast and colorectal cancer patients and investigated the role of quantitative morphological parameters.MethodologyStored images of samples from patients with prostate, breast and colorectal cancer, healthy controls, benign breast and colorectal tumors were obtained using the CellSearch system. Images were analyzed for the presence of aCTC and their morphological parameters measured and correlated with survival.ResultsOverall survival hazard ratio was not significantly different for aCTC and mCTC. The number of CTC correlated strongest with survival, whereas CTC size, roundness and apoptosis features reached significance in univariate analysis, but not in multivariate analysis. One aCTC/7.5 ml of blood was found in 7 of 204 healthy controls and 9 of 694 benign tumors. In one patient with benign tumor 2 and another 9 aCTC were detected.Significance of the studyCTC can be identified and morphological features extracted by an algorithm on images stored by the CellSearch system and strongly correlate with clinical outcome in metastatic breast, colorectal and prostate cancer.