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Breast Cancer Research

, 18:20

First Online: 12 February 2016Received: 09 October 2015Accepted: 29 January 2016DOI: 10.1186-s13058-016-0679-3

Cite this article as: Kasimir-Bauer, S., Bittner, AK., König, L. et al. Breast Cancer Res 2016 18: 20. doi:10.1186-s13058-016-0679-3


BackgroundPatients with breast cancer BC undergoing neoadjuvant chemotherapy NACT may experience metastatic relapse despite achieving a pathologic complete response. We analyzed patients with BC before and after NACT for disseminated tumor cells DTCs in the bone marrowBM; comprehensively characterized circulating tumor cells CTCs, including stem cell–like CTCs slCTCs, in blood to prove the effectiveness of treatment on these cells; and correlated these findings with response to therapy, progression-free survival PFS, and overall survival OS.

MethodsCTCs n = 135 and slCTCs n = 91 before and after NACT were analyzed using the AdnaTest BreastCancer, AdnaTest TumorStemCell, and epithelial–mesenchymal transition QIAGEN Hannover GmbH Germany. The expression of estrogen receptor, progesterone receptor, and the resistance marker excision repair cross-complementing rodent repair deficiency, complementation group 1 ERCC1, nuclease were studied in separate single-plex reverse transcription polymerase chain reaction experiments. DTCs were evaluated in 142 patients before and 165 patients after NACT using the pan-cytokeratin antibody A45-B-B3 for immunocytochemistry.

ResultsThe positivity rates for DTCs, CTCs, and slCTCs were 27 %, 24 %, and 51 % before and 20 %, 8 %, and 20 % after NACT, respectively. Interestingly, 72 % of CTCs present after therapy were positive for ERCC1, and CTCs before p = 0.005 and after NACT p = 0.05 were significantly associated with the presence of slCTCs. Whereas no significant associations with clinical parameters were found for CTCs and slCTCs, DTCs were significantly associated with nodal status p = 0.03 and histology 0.046 before NACT and with the immunohistochemical subtype p = 0.02 after NACT. Univariable Cox regression analysis revealed that age p = 0.0065, tumor size before NACT p = 0.0473, nodal status after NACT p = 0.0137, and response to NACT p = 0.0136 were significantly correlated with PFS, whereas age p = 0.0162 and nodal status after NACT p = 0.0243 were significantly associated with OS. No significant correlations were found for DTCs or any CTCs before and after therapy with regard to PFS and OS.

ConclusionsAlthough CTCs were eradicated more effectively than DTCs, CTCs detected after treatment seemed to be associated with tumor cells showing tumor stem cell characteristics as well as with resistant tumor cell populations that might indicate a worse outcome in the future. Thus, these patients might benefit from additional second-line treatment protocols including bisphosphonates for the eradication of DTCs.

KeywordsBreast cancer Circulating tumor cells Disseminated tumor cells Minimal residual disease neoadjuvant therapy Stem cells EMT AbbreviationsALDH1aldehyde dehydrogenase 1

BCbreast cancer

BMbone marrow

CTCcirculating tumor cell

DCISductal carcinoma in situ

DTCdisseminated tumor cell

EMTepithelial–mesenchymal transition

EpCAMepithelial cell adhesion molecule

ERestrogen receptor

ERCC1excision repair cross-complementing rodent repair deficiency, complementation group 1

HER2human epidermal growth factor receptor 2

HRhazard ratio



MUC1mucin 1, cell surface associated

NACTneoadjuvant chemotherapy

ORodds ratio

OSoverall survival

pCRpathological complete response

PFSprogression-free survival

PI3Kphosphoinositide 3-kinase

pNRpathological no response

pPRpathological partial response

PRprogesterone receptor

RT-PCRreverse transcription polymerase chain reaction

slCTCstem cell–like circulating tumor cell

TNMtumor, node, metastasis stage

TWIST1Twist-related protein 1

ZOLzoledronic acid

Electronic supplementary materialThe online version of this article doi:10.1186-s13058-016-0679-3 contains supplementary material, which is available to authorized users.

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Autor: Sabine Kasimir-Bauer - Ann-Kathrin Bittner - Lisa König - Katharina Reiter - Thomas Keller - Rainer Kimmig - Oliver Hoffma


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