Change in topoisomerase 1–positive circulating tumor cells affects overall survival in patients with advanced breast cancer after treatment with etirinotecan pegol

Hope S. Rugo, Javier Cortes, Ahmad Awada, Joyce O'Shaughnessy, Chris Twelves, Seock Ah Im, Alison Hannah, Lin Lu, Sherwin Sy, Katie Caygill, Deborah A. Zajchowski, Darren W. Davis, Mary Tagliaferri, Ute Hoch, Edith A. Perez

Research output: Contribution to journalArticle

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Abstract

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, gH2AX, 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 C2D1Top1þ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P ¼ 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P ¼ 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P ¼ 0.01). Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit.

Original languageEnglish (US)
Pages (from-to)3348-3357
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number14
DOIs
StatePublished - Jul 15 2018

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Circulating Neoplastic Cells
Breast Neoplasms
Survival
Therapeutics
Biomarkers
Topoisomerase I Inhibitors
Physicians
Tumor Biomarkers
etirinotecan pegol
Fluorescent Antibody Technique
Research Design
Regression Analysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Change in topoisomerase 1–positive circulating tumor cells affects overall survival in patients with advanced breast cancer after treatment with etirinotecan pegol. / Rugo, Hope S.; Cortes, Javier; Awada, Ahmad; O'Shaughnessy, Joyce; Twelves, Chris; Im, Seock Ah; Hannah, Alison; Lu, Lin; Sy, Sherwin; Caygill, Katie; Zajchowski, Deborah A.; Davis, Darren W.; Tagliaferri, Mary; Hoch, Ute; Perez, Edith A.

In: Clinical Cancer Research, Vol. 24, No. 14, 15.07.2018, p. 3348-3357.

Research output: Contribution to journalArticle

Rugo, HS, Cortes, J, Awada, A, O'Shaughnessy, J, Twelves, C, Im, SA, Hannah, A, Lu, L, Sy, S, Caygill, K, Zajchowski, DA, Davis, DW, Tagliaferri, M, Hoch, U & Perez, EA 2018, 'Change in topoisomerase 1–positive circulating tumor cells affects overall survival in patients with advanced breast cancer after treatment with etirinotecan pegol', Clinical Cancer Research, vol. 24, no. 14, pp. 3348-3357. https://doi.org/10.1158/1078-0432.CCR-17-3059
Rugo, Hope S. ; Cortes, Javier ; Awada, Ahmad ; O'Shaughnessy, Joyce ; Twelves, Chris ; Im, Seock Ah ; Hannah, Alison ; Lu, Lin ; Sy, Sherwin ; Caygill, Katie ; Zajchowski, Deborah A. ; Davis, Darren W. ; Tagliaferri, Mary ; Hoch, Ute ; Perez, Edith A. / Change in topoisomerase 1–positive circulating tumor cells affects overall survival in patients with advanced breast cancer after treatment with etirinotecan pegol. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 14. pp. 3348-3357.
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title = "Change in topoisomerase 1–positive circulating tumor cells affects overall survival in patients with advanced breast cancer after treatment with etirinotecan pegol",
abstract = "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, gH2AX, 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{\th} CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P ¼ 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P ¼ 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P ¼ 0.01). Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit.",
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T1 - Change in topoisomerase 1–positive circulating tumor cells affects overall survival in patients with advanced breast cancer after treatment with etirinotecan pegol

AU - Rugo, Hope S.

AU - Cortes, Javier

AU - Awada, Ahmad

AU - O'Shaughnessy, Joyce

AU - Twelves, Chris

AU - Im, Seock Ah

AU - Hannah, Alison

AU - Lu, Lin

AU - Sy, Sherwin

AU - Caygill, Katie

AU - Zajchowski, Deborah A.

AU - Davis, Darren W.

AU - Tagliaferri, Mary

AU - Hoch, Ute

AU - Perez, Edith A.

PY - 2018/7/15

Y1 - 2018/7/15

N2 - 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, gH2AX, 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 C2D1Top1þ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P ¼ 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P ¼ 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P ¼ 0.01). Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit.

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, gH2AX, 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 C2D1Top1þ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P ¼ 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P ¼ 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P ¼ 0.01). Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit.

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