Circulating tumor cell clusters are frequently detected in women with early-stage breast cancer

Carolina Reduzzi; Serena Di Cosimo; Lorenzo Gerratana; Rosita Motta; Antonia Martinetti; Andrea Vingiani; Paolo D’amico; Youbin Zhang; Marta Vismara; Catherine Depretto; Gianfranco Scaperrotta; Secondo Folli; Giancarlo Pruneri; Massimo Cristofanilli; Maria Grazia Daidone; Vera Cappelletti

doi:10.3390/cancers13102356

Circulating tumor cell clusters are frequently detected in women with early-stage breast cancer

Carolina Reduzzi, Serena Di Cosimo, Lorenzo Gerratana, Rosita Motta, Antonia Martinetti, Andrea Vingiani, Paolo D’amico, Youbin Zhang, Marta Vismara, Catherine Depretto, Gianfranco Scaperrotta, Secondo Folli, Giancarlo Pruneri, Massimo Cristofanilli, Maria Grazia Daidone, Vera Cappelletti^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

The clinical relevance of circulating tumor cell clusters (CTC-clusters) in breast cancer (BC) has been mostly studied using the CellSearch®, a marker-dependent method detecting only epithelial-enriched clusters. However, due to epithelial-to-mesenchymal transition, resorting to marker-independent approaches can improve CTC-cluster detection. Blood samples collected from healthy donors and spiked-in with tumor mammospheres, or from BC patients, were processed for CTC-cluster detection with 3 technologies: CellSearch®, CellSieve™ filters, and ScreenCell® filters. In spiked-in samples, the 3 technologies showed similar recovery capability, whereas, in 19 clinical samples processed in parallel with CellSearch® and CellSieve™ filters, filtration allowed us to detect more CTC-clusters than CellSearch® (median number = 7 versus 1, p = 0.0038). Next, samples from 37 early BC (EBC) and 23 metastatic BC (MBC) patients were processed using ScreenCell® filters for attaining both unbiased enrichment and marker-independent identification (based on cytomorphological criteria). At baseline, CTC-clusters were detected in 70% of EBC cases and in 20% of MBC patients (median number = 2, range 0–20, versus 0, range 0–15, p = 0.0015). Marker-independent approaches for CTC-cluster assessment improve detection and show that CTC-clusters are more frequent in EBC than in MBC patients, a novel finding suggesting that dissemination of CTC-clusters is an early event in BC natural history.

Original language	English (US)
Article number	2356
Journal	Cancers
Volume	13
Issue number	10
DOIs	https://doi.org/10.3390/cancers13102356
State	Published - May 2 2021

Funding

Acknowledgments: We are really grateful to all the patients who donated their blood for this study. We thank Patrizia Miodini for skillful technical assistance in sample processing and Cinzia De Marco for preparing the mammospheres. Fondazione Banca del Monte di Lombardia supported C.R. for a six-months visit to the Northwestern University of Chicago to carry the technological comparison experiments. We thank the Lynn Sage Cancer Research Foundation and the The Foundation Blanceflor Boncompagni Ludovisi, née Bildt that supported this study. Janine Wechsler (ScreenCell, Sarcelles, France) counted the CTC-clusters present on ScreenCell filters, without knowledge of the clinical data. Daniel Adams provided technical support for cluster detection on CellSieve filters. We would like to dedicate this article to the memory of Veronica Graziani and to thank Monica Remiddi and Paolo Graziani for their activity in supporting cancer research. Funding: This research was funded by Associazione Italiana per la Ricerca sul Cancro, AIRC (IG 16900-M.G. Daidone; IG 20774-S. Di Cosimo, IG. 21694-V. Cappelletti); European Commission under the 7th Framework Programme, grant agreement N. 260791 Eurocan Platform. C.R. is the recipient of an AIRC fellowship (N. 23916).

Keywords

Circulating tumor cell clusters
Circulating tumor microemboli
Early breast cancer
Liquid biopsy
Metastatic breast cancer
Size-based enrichment

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers13102356

Cite this

Reduzzi, C., Di Cosimo, S., Gerratana, L., Motta, R., Martinetti, A., Vingiani, A., D’amico, P., Zhang, Y., Vismara, M., Depretto, C., Scaperrotta, G., Folli, S., Pruneri, G., Cristofanilli, M., Daidone, M. G., & Cappelletti, V. (2021). Circulating tumor cell clusters are frequently detected in women with early-stage breast cancer. Cancers, 13(10), Article 2356. https://doi.org/10.3390/cancers13102356

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abstract = "The clinical relevance of circulating tumor cell clusters (CTC-clusters) in breast cancer (BC) has been mostly studied using the CellSearch{\textregistered}, a marker-dependent method detecting only epithelial-enriched clusters. However, due to epithelial-to-mesenchymal transition, resorting to marker-independent approaches can improve CTC-cluster detection. Blood samples collected from healthy donors and spiked-in with tumor mammospheres, or from BC patients, were processed for CTC-cluster detection with 3 technologies: CellSearch{\textregistered}, CellSieve{\texttrademark} filters, and ScreenCell{\textregistered} filters. In spiked-in samples, the 3 technologies showed similar recovery capability, whereas, in 19 clinical samples processed in parallel with CellSearch{\textregistered} and CellSieve{\texttrademark} filters, filtration allowed us to detect more CTC-clusters than CellSearch{\textregistered} (median number = 7 versus 1, p = 0.0038). Next, samples from 37 early BC (EBC) and 23 metastatic BC (MBC) patients were processed using ScreenCell{\textregistered} filters for attaining both unbiased enrichment and marker-independent identification (based on cytomorphological criteria). At baseline, CTC-clusters were detected in 70% of EBC cases and in 20% of MBC patients (median number = 2, range 0–20, versus 0, range 0–15, p = 0.0015). Marker-independent approaches for CTC-cluster assessment improve detection and show that CTC-clusters are more frequent in EBC than in MBC patients, a novel finding suggesting that dissemination of CTC-clusters is an early event in BC natural history.",

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Reduzzi, C, Di Cosimo, S, Gerratana, L, Motta, R, Martinetti, A, Vingiani, A, D’amico, P, Zhang, Y, Vismara, M, Depretto, C, Scaperrotta, G, Folli, S, Pruneri, G, Cristofanilli, M, Daidone, MG & Cappelletti, V 2021, 'Circulating tumor cell clusters are frequently detected in women with early-stage breast cancer', Cancers, vol. 13, no. 10, 2356. https://doi.org/10.3390/cancers13102356

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AU - Reduzzi, Carolina

AU - Di Cosimo, Serena

AU - Gerratana, Lorenzo

AU - Motta, Rosita

AU - Martinetti, Antonia

AU - Vingiani, Andrea

AU - D’amico, Paolo

AU - Zhang, Youbin

AU - Vismara, Marta

AU - Depretto, Catherine

AU - Scaperrotta, Gianfranco

AU - Folli, Secondo

AU - Pruneri, Giancarlo

AU - Cristofanilli, Massimo

AU - Daidone, Maria Grazia

AU - Cappelletti, Vera

PY - 2021/5/2

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N2 - The clinical relevance of circulating tumor cell clusters (CTC-clusters) in breast cancer (BC) has been mostly studied using the CellSearch®, a marker-dependent method detecting only epithelial-enriched clusters. However, due to epithelial-to-mesenchymal transition, resorting to marker-independent approaches can improve CTC-cluster detection. Blood samples collected from healthy donors and spiked-in with tumor mammospheres, or from BC patients, were processed for CTC-cluster detection with 3 technologies: CellSearch®, CellSieve™ filters, and ScreenCell® filters. In spiked-in samples, the 3 technologies showed similar recovery capability, whereas, in 19 clinical samples processed in parallel with CellSearch® and CellSieve™ filters, filtration allowed us to detect more CTC-clusters than CellSearch® (median number = 7 versus 1, p = 0.0038). Next, samples from 37 early BC (EBC) and 23 metastatic BC (MBC) patients were processed using ScreenCell® filters for attaining both unbiased enrichment and marker-independent identification (based on cytomorphological criteria). At baseline, CTC-clusters were detected in 70% of EBC cases and in 20% of MBC patients (median number = 2, range 0–20, versus 0, range 0–15, p = 0.0015). Marker-independent approaches for CTC-cluster assessment improve detection and show that CTC-clusters are more frequent in EBC than in MBC patients, a novel finding suggesting that dissemination of CTC-clusters is an early event in BC natural history.

AB - The clinical relevance of circulating tumor cell clusters (CTC-clusters) in breast cancer (BC) has been mostly studied using the CellSearch®, a marker-dependent method detecting only epithelial-enriched clusters. However, due to epithelial-to-mesenchymal transition, resorting to marker-independent approaches can improve CTC-cluster detection. Blood samples collected from healthy donors and spiked-in with tumor mammospheres, or from BC patients, were processed for CTC-cluster detection with 3 technologies: CellSearch®, CellSieve™ filters, and ScreenCell® filters. In spiked-in samples, the 3 technologies showed similar recovery capability, whereas, in 19 clinical samples processed in parallel with CellSearch® and CellSieve™ filters, filtration allowed us to detect more CTC-clusters than CellSearch® (median number = 7 versus 1, p = 0.0038). Next, samples from 37 early BC (EBC) and 23 metastatic BC (MBC) patients were processed using ScreenCell® filters for attaining both unbiased enrichment and marker-independent identification (based on cytomorphological criteria). At baseline, CTC-clusters were detected in 70% of EBC cases and in 20% of MBC patients (median number = 2, range 0–20, versus 0, range 0–15, p = 0.0015). Marker-independent approaches for CTC-cluster assessment improve detection and show that CTC-clusters are more frequent in EBC than in MBC patients, a novel finding suggesting that dissemination of CTC-clusters is an early event in BC natural history.

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KW - Circulating tumor microemboli

KW - Early breast cancer

KW - Liquid biopsy

KW - Metastatic breast cancer

KW - Size-based enrichment

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Circulating tumor cell clusters are frequently detected in women with early-stage breast cancer

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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