Clinical significance of detecting CSF-derived tumor cells in breast cancer patients with leptomeningeal metastasis
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Xuelu Li1,2,*, Yuan Zhang1,3,*, Jinlei Ding1,4,*, Min Wang1,3, Na Li1,5, Hui Yang1,5, Kainan Wang1,5, Dandan Wang6, Peter Ping Lin6, Man Li1,5, Zuowei Zhao1,2 and Pixu Liu1,3,7
1The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
2Department of Breast Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
3Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China
4Cancer Institute, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
5Department of Oncology, The Second Affiliated Hospital, Dalian Medical University, Dalian, China
6Cytelligen, San Diego, California, USA
7College of Pharmacy, Dalian Medical University, Dalian, China
*These authors contributed equally to this work
Pixu Liu, email: [email protected]
Zuowei Zhao, email: [email protected]
Man Li, email: [email protected]
Peter Ping Lin, email: [email protected]
Keywords: breast cancer; leptomeningeal metastasis; cerebrospinal fluid-derived tumor cell; SE-i•FISH
Received: July 20, 2017 Accepted: December 14, 2017 Published: December 21, 2017
Despite marked advances in breast cancer therapy, breast cancer-associated leptomeningeal metastasis (LM), a particularly aggressive syndrome with multifocal seeding of the leptomeninges by tumor cells, still carries an abysmal prognosis. A major problem with breast cancer LM surveillance is the lack of an effective and sensitive means to track dynamic changes of the disease. Cytology detection of cerebrospinal fluid (CSF) is considered the gold standard for LM diagnosis but has a high false-negative rate with a limited sensitivity. Here we applied subtraction enrichment and immunostaining-fluorescence in situ (SE-i•FISH) method, a technique previously used for isolating circulating tumor cells (CTCs) from the peripheral blood, to detect, enumerate, and track cerebrospinal fluid-derived tumor cells (CSFTCs) in CSF samples from 8 breast cancer patients. Comparing with cytology test, we found SE-i•FISH method can accurately and feasibly detect CSFTCs for the diagnosis of breast cancer-associated LM and monitor the disease progression. We also isolated and cultured CSFTCs from these cancer patients and performed genomic sequencing on CSFTCs of two patients. Genomic analysis of CSFTCs against corresponding archival primary breast tumors revealed clonal relationships with some ongoing evolution. Further drug sensitivity test on cultured CSFTCs based on genomic analysis data helped identify promising treatment options for the patient tested. Together, our results suggest that CSFTCs detection using SE-i•FISH platform could serve as a sensitive and accurate method to make the diagnosis and a promising approach to monitor tumor dynamics and treatment response for breast cancer-associated LM.
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