Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Prognostic impact of circulating tumor cell apoptosis and clusters in serial blood samples from patients with metastatic breast cancer in a prospective observational cohort

Authors: Sara Jansson, Pär-Ola Bendahl, Anna-Maria Larsson, Kristina E. Aaltonen, Lisa Rydén

Published in: BMC Cancer | Issue 1/2016

Login to get access

Abstract

Background

Presence of circulating tumor cells (CTCs) is a validated prognostic marker in metastatic breast cancer. Additional prognostic information may be obtained by morphologic characterization of CTCs. We explored whether apoptotic CTCs, CTC clusters and leukocytes attached to CTCs are associated with breast cancer subtype and prognosis at base-line (BL) and in follow-up (FU) blood samples in patients with metastatic breast cancer scheduled for first-line systemic treatment.

Methods

Patients with a first metastatic breast cancer event were enrolled in a prospective observational study prior to therapy initiation and the CellSearch system (Janssen Diagnostics) was used for CTC enumeration and characterization. We enrolled patients (N = 52) with ≥5 CTC/7.5 ml blood at BL (median 45, range 5–668) and followed them with blood sampling for 6 months during therapy. CTCs were evaluated for apoptotic changes, CTC clusters (≥3 nuclei), and leukocytes associated with CTC (WBC-CTC, ≥1 CTC + ≥1 leukocytes) at all time-points by visual examination of the galleries generated by the CellTracks Analyzer.

Results

At BL, patients with triple-negative and HER2-positive breast cancer had blood CTC clusters present more frequently than patients with hormone receptor-positive cancer (P = 0.010). No morphologic characteristics were associated with prognosis at BL, whereas patients with apoptotic CTCs or clusters in FU samples had worse prognosis compared to patients without these characteristics with respect to progression-free (PFS) and overall survival (OS) (log-rank test: P = 0.0012 or lower). Patients with apoptotic or clustered CTCs at any time-point had impaired prognosis in multivariable analyses adjusting for number of CTCs and other prognostic factors (apoptosis: HROS = 25, P < 0.001; cluster: HROS = 7.0, P = 0.006). The presence of WBC-CTCs was significantly associated with an inferior prognosis in terms of OS at 6 months in multivariable analysis.

Conclusions

Patients with a continuous presence of apoptotic or clustered CTCs in FU samples after systemic therapy initiation had worse prognosis than patients without these CTC characteristics. In patients with ≥5 CTC/7.5 ml blood at BL, morphologic characterization of persistent CTCs could be an important prognostic marker during treatment, in addition to CTC enumeration alone.
Clinical Trials (NCT01322893), registration date 21 March 2011
Appendix
Available only for authorised users
Literature
1.
Bidard FC, Peeters DJ, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;15(4):406–14.CrossRefPubMed
2.
de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302–9.CrossRefPubMed
3.
Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse MA, Mitchell E, Miller MC, et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol. 2009;20(7):1223–9.CrossRefPubMed
4.
Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, Priest LJ, Greystoke A, Zhou C, Morris K, et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012;30(5):525–32.CrossRefPubMed
5.
Krebs MG, Sloane R, Priest L, Lancashire L, Hou JM, Greystoke A, Ward TH, Ferraldeschi R, Hughes A, Clack G, et al. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol. 2011;29(12):1556–63.CrossRefPubMed
6.
Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen LW. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res. 2006;12(14 Pt 1):4218–24.CrossRefPubMed
7.
Nole F, Munzone E, Zorzino L, Minchella I, Salvatici M, Botteri E, Medici M, Verri E, Adamoli L, Rotmensz N, et al. Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications. Ann Oncol. 2008;19(5):891–7.CrossRefPubMed
8.
Pierga JY, Hajage D, Bachelot T, Delaloge S, Brain E, Campone M, Dieras V, Rolland E, Mignot L, Mathiot C, et al. High independent prognostic and predictive value of circulating tumor cells compared with serum tumor markers in a large prospective trial in first-line chemotherapy for metastatic breast cancer patients. Ann Oncol. 2012;23(3):618–24.CrossRefPubMed
9.
Nakamura S, Yagata H, Ohno S, Yamaguchi H, Iwata H, Tsunoda N, Ito Y, Tokudome N, Toi M, Kuroi K, et al. Multi-center study evaluating circulating tumor cells as a surrogate for response to treatment and overall survival in metastatic breast cancer. Breast Cancer. 2010;17(3):199–204.CrossRefPubMed
10.
Ligthart ST, Coumans FA, Bidard FC, Simkens LH, Punt CJ, de Groot MR, Attard G, de Bono JS, Pierga JY, Terstappen LW. Circulating Tumor Cells Count and Morphological Features in Breast, Colorectal and Prostate Cancer. PLoS One. 2013;8(6):e67148.CrossRefPubMedPubMedCentral
11.
Park S, Ang RR, Duffy SP, Bazov J, Chi KN, Black PC, Ma H. Morphological differences between circulating tumor cells from prostate cancer patients and cultured prostate cancer cells. PLoS One. 2014;9(1):e85264.CrossRefPubMedPubMedCentral
12.
Paoletti C, Li Y, Muniz MC, Kidwell KM, Aung K, Thomas DG, Brown ME, Abramson VG, Irvin WJ, Jr., Lin NU, et al. Significance of Circulating Tumor Cells in Metastatic Triple-Negative Breast Cancer Patients within a Randomized, Phase II Trial: TBCRC 019. Clin Cancer Res. 2015;21(12):2771–9.CrossRefPubMed
13.
Hou JM, Krebs M, Ward T, Sloane R, Priest L, Hughes A, Clack G, Ranson M, Blackhall F, Dive C. Circulating tumor cells as a window on metastasis biology in lung cancer. Am J Pathol. 2011;178(3):989–96.CrossRefPubMedPubMedCentral
14.
Mu Z, Wang C, Ye Z, Austin L, Civan J, Hyslop T, Palazzo JP, Jaslow R, Li B, Myers RE, et al. Prospective assessment of the prognostic value of circulating tumor cells and their clusters in patients with advanced-stage breast cancer. Breast Cancer Res Treat. 2015;154(3):563-571.
15.
16.
Phillips KG, Kolatkar A, Rees KJ, Rigg R, Marrinucci D, Luttgen M, Bethel K, Kuhn P, McCarty OJ. Quantification of cellular volume and sub-cellular density fluctuations: comparison of normal peripheral blood cells and circulating tumor cells identified in a breast cancer patient. Front Oncol. 2012;2:96.PubMedPubMedCentral
17.
Phillips KG, Velasco CR, Li J, Kolatkar A, Luttgen M, Bethel K, Duggan B, Kuhn P, McCarty OJ. Optical quantification of cellular mass, volume, and density of circulating tumor cells identified in an ovarian cancer patient. Front Oncol. 2012;2(72):00072.
18.
Marrinucci D, Bethel K, Kolatkar A, Luttgen MS, Malchiodi M, Baehring F, Voigt K, Lazar D, Nieva J, Bazhenova L, et al. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys Biol. 2012;9(1):016003.CrossRefPubMedPubMedCentral
19.
Marrinucci D, Bethel K, Bruce RH, Curry DN, Hsieh B, Humphrey M, Krivacic RT, Kroener J, Kroener L, Ladanyi A, et al. Case study of the morphologic variation of circulating tumor cells. Hum Pathol. 2007;38(3):514–9.CrossRefPubMed
20.
Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014;158(5):1110–22.CrossRefPubMedPubMedCentral
21.
Coumans FA, Doggen CJ, Attard G, de Bono JS, Terstappen LW. All circulating EpCAM + CK + CD45- objects predict overall survival in castration-resistant prostate cancer. Ann Oncol. 2010;21(9):1851–7.CrossRefPubMed
22.
Ulukaya E, Yilmaztepe A, Akgoz S, Linder S, Karadag M. The levels of caspase-cleaved cytokeratin 18 are elevated in serum from patients with lung cancer and helpful to predict the survival. Lung Cancer (Amsterdam, Netherlands). 2007;56(3):399–404.CrossRef
23.
Krawczyk N, Hartkopf A, Banys M, Meier-Stiegen F, Staebler A, Wallwiener M, Rohm C, Hoffmann J, Hahn M, Fehm T. Prognostic relevance of induced and spontaneous apoptosis of disseminated tumor cells in primary breast cancer patients. BMC Cancer. 2014;14:394.CrossRefPubMedPubMedCentral
24.
Smerage JB, Budd GT, Doyle GV, Brown M, Paoletti C, Muniz M, Miller MC, Repollet MI, Chianese DA, Connelly MC, et al. Monitoring apoptosis and Bcl-2 on circulating tumor cells in patients with metastatic breast cancer. Mol Oncol. 2013;7(3):680–92.CrossRefPubMed
25.
Brandt B, Junker R, Griwatz C, Heidl S, Brinkmann O, Semjonow A, Assmann G, Zanker KS. Isolation of prostate-derived single cells and cell clusters from human peripheral blood. Cancer Res. 1996;56(20):4556–61.PubMed
26.
Kats-Ugurlu G, Roodink I, de Weijert M, Tiemessen D, Maass C, Verrijp K, van der Laak J, de Waal R, Mulders P, Oosterwijk E, et al. Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinoma. J Pathol. 2009;219(3):287–93.CrossRefPubMed
27.
Molnar B, Ladanyi A, Tanko L, Sreter L, Tulassay Z. Circulating tumor cell clusters in the peripheral blood of colorectal cancer patients. Clin Cancer Res. 2001;7(12):4080–5.PubMed
28.
Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339(6119):580–4.CrossRefPubMedPubMedCentral
29.
Stott SL, Hsu C-H, Tsukrov DI, Yu M, Miyamoto DT, Waltman BA, Rothenberg SM, Shah AM, Smas ME, Korir GK, et al. Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci. 2010;107(43):18392–7.CrossRefPubMedPubMedCentral
30.
Noman MZ, Messai Y, Muret J, Hasmim M, Chouaib S. Crosstalk between CTC, Immune System and Hypoxic Tumor Microenvironment. Cancer Microenviron. 2014;7(3):153–60.CrossRefPubMedPubMedCentral
31.
Smith HA, Kang Y. The metastasis-promoting roles of tumor-associated immune cells. J Mol Med (Berl). 2013;91(4):411–29.CrossRef
32.
Gros A, Turcotte S, Wunderlich JR, Ahmadzadeh M, Dudley ME, Rosenberg SA. Myeloid Cells Obtained from the Blood but Not from the Tumor Can Suppress T-cell Proliferation in Patients with Melanoma. Clin Cancer Res. 2012;18(19):5212–23.CrossRefPubMed
33.
Gassmann P, Haier J. The tumor cell-host organ interface in the early onset of metastatic organ colonisation. Clin Exp Metastasis. 2008;25(2):171–81.CrossRefPubMed
34.
Camerer E, Qazi AA, Duong DN, Cornelissen I, Advincula R, Coughlin SR. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood. 2004;104(2):397–401.CrossRefPubMed
35.
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LWMM, et al. Circulating Tumor Cells, Disease Progression, and Survival in Metastatic Breast Cancer. N Engl J Med. 2004;351(8):781–91.CrossRefPubMed
36.
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–57.CrossRefPubMedPubMedCentral
37.
Lobbezoo DJ, van Kampen RJ, Voogd AC, Dercksen MW, van den Berkmortel F, Smilde TJ, van de Wouw AJ, Peters FP, van Riel JM, Peters NA, et al. Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer? Br J Cancer. 2015;112(9):1445–51.CrossRefPubMedPubMedCentral
38.
Wallwiener M, Hartkopf AD, Baccelli I, Riethdorf S, Schott S, Pantel K, Marme F, Sohn C, Trumpp A, Rack B, et al. The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast Cancer Res Treat. 2013;137(2):503–10.CrossRefPubMed
39.
40.
Fidler IJ. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer (Oxford, England : 1990). 1973;9(3):223–7.CrossRef
41.
Bergenfelz C, Larsson AM, von Stedingk K, Gruvberger-Saal S, Aaltonen K, Jansson S, Jernstrom H, Janols H, Wullt M, Bredberg A, et al. Systemic Monocytic-MDSCs Are Generated from Monocytes and Correlate with Disease Progression in Breast Cancer Patients. PLoS One. 2015;10(5):e0127028.CrossRefPubMedPubMedCentral
42.
Rossi E, Basso U, Celadin R, Zilio F, Pucciarelli S, Aieta M, Barile C, Sava T, Bonciarelli G, Tumolo S, et al. M30 neoepitope expression in epithelial cancer: quantification of apoptosis in circulating tumor cells by Cell Search analysis. Clin Cancer Res. 2010;16(21):5233–43.CrossRefPubMed
Metadata
Title
Prognostic impact of circulating tumor cell apoptosis and clusters in serial blood samples from patients with metastatic breast cancer in a prospective observational cohort
Authors
Sara Jansson
Pär-Ola Bendahl
Anna-Maria Larsson
Kristina E. Aaltonen
Lisa Rydén
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2406-y

Other articles of this Issue 1/2016

BMC Cancer 1/2016 Go to the issue

Research article

Randomized phase III trial of APF530 versus palonosetron in the prevention of chemotherapy-induced nausea and vomiting in a subset of patients with breast cancer receiving moderately or highly emetogenic chemotherapy

Research article

Increasing incidence of thyroid cancer in the Nordic countries with main focus on Swedish data

Study protocol

Effectiveness and cost-utility of a guided self-help exercise program for patients treated with total laryngectomy: protocol of a multi-center randomized controlled trial

Research article

Mitogen-activated protein kinase signaling causes malignant melanoma cells to differentially alter extracellular matrix biosynthesis to promote cell survival

Research article

Comparative immunogenicity and structural analysis of epitopes of different bacterial L-asparaginases

Case report

Simultaneous existence of acute myeloid leukemia and chronic lymphocytic leukemia: a case report
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits