Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients.
Circulating tumor cells (CTCs) are promising biomarkers for diagnosis and therapy in systemic cancer. However, their infrequent and unreliable detection, especially in nonmetastatic cancer, currently impedes the clinical use of CTCs. Because leukapheresis (LA) targets peripheral blood mononuclear cells, which have a similar density to CTCs, and usually involves processing the whole circulating blood, we tested whether LA could substantially increase CTC detection in operable cancer patients. Therefore, we screened LA products generated from up to 25 L of blood per patient in two independent studies, and found that CTCs can be detected in more than 90% of nonmetastatic breast cancer patients. Interestingly, complete white blood cell sampling enabled determining an upper level for total CTC numbers of about 100,000 cells (median, 7,500 CTCs) per patient and identified a correlation of CTC numbers with anatomic disease spread. We further show that diagnostic leukapheresis can be easily combined with the US Food and Drug Administration-approved CellSearch system for standardized enumeration of CTCs. Direct comparison with 7.5 mL of blood revealed a significantly higher CTC frequency in matched LA samples. Finally, genomic single-cell profiling disclosed highly aberrant CTCs as therapy-escaping variants in breast cancer. In conclusion, LA is a clinically safe method that enabled a reliable detection of CTCs at high frequency even in nonmetastatic cancer patients, and might facilitate the routine clinical use of CTCs as in the sense of a liquid biopsy. Combined with technologies for single-cell molecular genetics or cell biology, it may significantly improve prediction of therapy response and monitoring of early systemic cancer.
Institute for Transplantation Diagnostics and Cell Therapeutics and Departments of Obstetrics and Gynecology and General, Visceral and Pediatric Surgery, Medical Faculty, University Hospital, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
Johannes C
JC
Fischer
Dieter
D
Niederacher
Stefan A
SA
Topp
Ellen
E
Honisch
Sarah
S
Schumacher
Norma
N
Schmitz
Luisa
L
Zacarias Föhrding
Christian
C
Vay
Imke
I
Hoffmann
Nikola S
NS
Kasprowicz
Philip G
PG
Hepp
Svjetlana
S
Mohrmann
Ulrike
U
Nitz
Antje
A
Stresemann
Thomas
T
Krahn
Tanja
T
Henze
Evelyn
E
Griebsch
Katharina
K
Raba
Jutta M
JM
Rox
Folker
F
Wenzel
Christoph
C
Sproll
Wolfgang
W
Janni
Tanja
T
Fehm
Christoph A
CA
Klein
Wolfram Trudo
WT
Knoefel
Nikolas H
NH
Stoecklein
D014408:Biomarkers, Tumor / Q000097:blood*; D001943:Breast Neoplasms / Q000097:blood / Q000175:diagnosis*; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D019937:Diagnostic Techniques and Procedures; D005260:Female; D005858:Germany; D006801:Humans; D007937:Leukapheresis / Q000379:methods*; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011446:Prospective Studies; D012189:Retrospective Studies; D018709:Statistics, Nonparametric
D014408:Biomarkers, Tumor
comparative genomic hybridization; gastrointestinal cancer; metastasis; minimal residual disease; single-cell analysis