title: Prospective assessment of the prognostic value of circulating tumor cells and their clusters in patients with advanced-stage breast cancer.
abstract: The enumeration of circulating tumor cells (CTCs) provides important prognostic values in patients with metastatic breast cancer. Recent studies indicate that individual CTCs form clusters and these CTC-clusters play an important role in tumor metastasis. We aimed to assess whether quantification of CTC-clusters provides additional prognostic value over quantification of individual CTCs alone. In 115 prospectively enrolled advanced-stage (III and IV) breast cancer patients, CTCs and CTC-clusters were counted in 7.5 ml whole blood using the CellSearch system at baseline before first-line therapy. The individual and joint effects of CTC and CTC cluster counts on patients' progression-free survival (PFS) were analyzed using Cox proportional hazards modeling. Of the 115 patients, 36 (31.3 %) had elevated baseline CTCs (≥5 CTCs/7.5 ml) and 20 (17.4 %) had CTC-clusters (≥2 CTCs/7.5 ml). Patients with elevated CTCs and CTC-clusters both had worse PFS with a hazard ratio (HR) of 2.76 [95 % confidence interval (CI) 1.57-4.86, P log-rank = 0.0005] and 2.83 (1.48-5.39, P log-rank = 0.001), respectively. In joint analysis, compared with patients with <5 CTCs and without CTC-clusters, patients with elevated CTCs but without clusters, and patients with elevated CTCs and with clusters, had an increasing trend of progression risk, with an HR of 2.21 (1.02-4.78) and 3.32 (1.68-6.55), respectively (P log-rank = 0.0006, P trend = 0.0002). The additional prognostic value of CTC-clusters appeared to be more pronounced in patients with inflammatory breast cancer (IBC), the most aggressive form of breast cancer with the poorest survival. Baseline counts of both individual CTCs and CTC-clusters were associated with PFS in advanced-stage breast cancer patients. CTC-clusters might provide additional prognostic value compared with CTC enumeration alone, in patients with elevated CTCs.
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Zhaomei
authors.initials: Z
authors.lastname: Mu
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Austin
authors.affiliation: Department of Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Civan
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, 27710, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Hyslop
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Palazzo
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Jaslow
authors.affiliation: Department of Molecular Physiology & Biophysics, Center for Human Genetics Research, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Bingshan
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Myers
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Juntao
authors.initials: J
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. hushan.yang@jefferson.edu.
authors.forename: Hushan
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. Massimo.cristofanilli@nm.org.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000401:mortality* / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000401:mortality / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011379:Prognosis; D011446:Prospective Studies
chemical_list: D014408:Biomarkers, Tumor
keywords: Circulating tumor cell clusters (CTC-clusters); Circulating tumor cells (CTCs); Inflammatory breast cancer (IBC)