PMID- 29618616
OWN - NLM
STAT- MEDLINE
DCOM- 20191220
LR  - 20191220
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 24
IP  - 14
DP  - 2018 Jul 15
TI  - Change in Topoisomerase 1-Positive Circulating Tumor Cells Affects Overall 
      Survival in Patients with Advanced Breast Cancer after Treatment with 
      Etirinotecan Pegol.
PG  - 3348-3357
LID - 10.1158/1078-0432.CCR-17-3059 [doi]
AB  - Purpose: Preplanned exploratory analyses were performed to identify biomarkers in 
      circulating tumor cells (CTC) predictive of response to the topoisomerase 1 
      inhibitor etirinotecan pegol (EP).Experimental Design: The BEACON trial treated 
      patients with metastatic breast cancer (MBC) with EP or treatment of physician's 
      choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream 
      to enrich for CTCs. A multiplex immunofluorescence assay measured expression of 
      candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), 
      Ki67, RAD51, ABCG2, gammaH2AX, and terminal deoxynucleotidyl transferase-mediated 
      dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low 
      (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation 
      of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 
      with overall survival (OS) was investigated using Cox regression and Kaplan-Meier 
      analyses.Results: Overall, 98% of samples were successfully processed, of which 
      97% had detectable CTCs (median, 47-63 CTCs/mL; range, 0-2,020 CTCs/mL). Top1, 
      Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant 
      associations with OS were observed in pretreatment samples for either group. 
      EP-treated patients with low C2D1Top1(+) CTCs had improved OS compared with those 
      with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 
      0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). 
      Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS 
      benefit from EP (HR, 0.57; P = 0.01).Conclusions: CTC Top1 expression following 
      EP treatment may identify patients with MBC most likely to have an OS benefit. 
      Clin Cancer Res; 24(14); 3348-57. (c)2018 AACR.
CI  - (c)2018 American Association for Cancer Research.
FAU - Rugo, Hope S
AU  - Rugo HS
AD  - University of California, San Francisco, San Francisco, California.
FAU - Cortes, Javier
AU  - Cortes J
AD  - Ramon y Cajal University Hospital, Madrid, and Vall D'Hebron Institute of 
      Oncology, Barcelona, Spain.
FAU - Awada, Ahmad
AU  - Awada A
AD  - Jules Bordet Institute, Universite Libre de Bruxelles, Brussels, Belgium.
FAU - O'Shaughnessy, Joyce
AU  - O'Shaughnessy J
AD  - Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, Texas.
FAU - Twelves, Chris
AU  - Twelves C
AD  - University of Leeds and Leeds Teaching Hospital Trust, Leeds, United Kingdom.
FAU - Im, Seock-Ah
AU  - Im SA
AUID- ORCID: 0000-0002-5396-6533
AD  - Seoul National University Hospital, Cancer Research Institute, Seoul National 
      University College of Medicine, Seoul, Korea.
FAU - Hannah, Alison
AU  - Hannah A
AD  - Nektar Therapeutics, San Francisco, California.
FAU - Lu, Lin
AU  - Lu L
AD  - Nektar Therapeutics, San Francisco, California.
FAU - Sy, Sherwin
AU  - Sy S
AD  - Nektar Therapeutics, San Francisco, California.
FAU - Caygill, Katie
AU  - Caygill K
AD  - Nektar Therapeutics, San Francisco, California.
FAU - Zajchowski, Deborah A
AU  - Zajchowski DA
AD  - Consultant, San Francisco, California.
FAU - Davis, Darren W
AU  - Davis DW
AD  - ApoCell, Houston, Texas.
FAU - Tagliaferri, Mary
AU  - Tagliaferri M
AD  - Nektar Therapeutics, San Francisco, California.
FAU - Hoch, Ute
AU  - Hoch U
AD  - Nektar Therapeutics, San Francisco, California. uhoch@nektar.com.
FAU - Perez, Edith A
AU  - Perez EA
AD  - Mayo Clinic, Jacksonville, Florida.
LA  - eng
PT  - Journal Article
DEP - 20180404
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Biomarkers)
RN  - 0 (Heterocyclic Compounds, 4 or More Rings)
RN  - 0 (Topoisomerase II Inhibitors)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - EC 5.99.1.2 (DNA Topoisomerases, Type I)
RN  - LJ16641SFT (etirinotecan pegol)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Biomarkers
MH  - Breast Neoplasms/drug therapy/*enzymology/*mortality/pathology
MH  - DNA Topoisomerases, Type I/*metabolism
MH  - Female
MH  - Heterocyclic Compounds, 4 or More Rings/pharmacology/therapeutic use
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Middle Aged
MH  - Molecular Imaging
MH  - Neoplasm Metastasis
MH  - Neoplasm Staging
MH  - Neoplastic Cells, Circulating/*metabolism
MH  - Polyethylene Glycols/pharmacology/therapeutic use
MH  - Prognosis
MH  - Topoisomerase II Inhibitors/pharmacology/therapeutic use
MH  - Treatment Outcome
EDAT- 2018/04/06 06:00
MHDA- 2019/12/21 06:00
CRDT- 2018/04/06 06:00
PHST- 2017/10/17 00:00 [received]
PHST- 2018/01/10 00:00 [revised]
PHST- 2018/03/26 00:00 [accepted]
PHST- 2018/04/06 06:00 [pubmed]
PHST- 2019/12/21 06:00 [medline]
PHST- 2018/04/06 06:00 [entrez]
AID - 1078-0432.CCR-17-3059 [pii]
AID - 10.1158/1078-0432.CCR-17-3059 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2018 Jul 15;24(14):3348-3357. doi: 
      10.1158/1078-0432.CCR-17-3059. Epub 2018 Apr 4.