Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib

Nusayba Bagegni, Shana Thomas, Ning Liu, Jingqin Luo, Jeremy Hoog, Donald W Northfelt, Matthew Philip Goetz, Andres Forero, Mattias Bergqvist, Jakob Karen, Magnus Neumüller, Edward M. Suh, Zhanfang Guo, Kiran Vij, Souzan Sanati, Matthew Ellis, Cynthia X. Ma

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774). Methods: Patients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was>10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3-5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA)levels. Results: Despite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per literDu/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2%-96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% -100%) and 84% (95% CI 69.6%-98.4%), respectively. The Κ-statistic was 0.76 (p<0.001) between TK1 and Ki-67, indicating substantial agreement. Conclusions: Serum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation. Trial registration: ClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.

Original languageEnglish (US)
Article number123
JournalBreast Cancer Research
Volume19
Issue number1
DOIs
StatePublished - Nov 21 2017

Fingerprint

Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinase 4
Breast Neoplasms
Serum
Neoplasms
palbociclib
thymidine kinase 1
Biomarkers

Keywords

  • Anastrozole
  • Biomarker
  • Breast cancer
  • Neoadjuvant
  • Palbociclib
  • Thymidine kinase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. / Bagegni, Nusayba; Thomas, Shana; Liu, Ning; Luo, Jingqin; Hoog, Jeremy; Northfelt, Donald W; Goetz, Matthew Philip; Forero, Andres; Bergqvist, Mattias; Karen, Jakob; Neumüller, Magnus; Suh, Edward M.; Guo, Zhanfang; Vij, Kiran; Sanati, Souzan; Ellis, Matthew; Ma, Cynthia X.

In: Breast Cancer Research, Vol. 19, No. 1, 123, 21.11.2017.

Research output: Contribution to journalArticle

Bagegni, N, Thomas, S, Liu, N, Luo, J, Hoog, J, Northfelt, DW, Goetz, MP, Forero, A, Bergqvist, M, Karen, J, Neumüller, M, Suh, EM, Guo, Z, Vij, K, Sanati, S, Ellis, M & Ma, CX 2017, 'Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib', Breast Cancer Research, vol. 19, no. 1, 123. https://doi.org/10.1186/s13058-017-0913-7
Bagegni, Nusayba ; Thomas, Shana ; Liu, Ning ; Luo, Jingqin ; Hoog, Jeremy ; Northfelt, Donald W ; Goetz, Matthew Philip ; Forero, Andres ; Bergqvist, Mattias ; Karen, Jakob ; Neumüller, Magnus ; Suh, Edward M. ; Guo, Zhanfang ; Vij, Kiran ; Sanati, Souzan ; Ellis, Matthew ; Ma, Cynthia X. / Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. In: Breast Cancer Research. 2017 ; Vol. 19, No. 1.
@article{03e9fa2c811e4894a49197bbf87ba34a,
title = "Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib",
abstract = "Background: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774). Methods: Patients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was>10{\%}, in which case patients went off study owing to inadequate response. Surgery occurred following 3-5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA)levels. Results: Despite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per literDu/L) in 92{\%} of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8{\%} (95{\%} CI: 79.2{\%}-96.2{\%}), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1{\%} (95{\%} CI 86.2{\%} -100{\%}) and 84{\%} (95{\%} CI 69.6{\%}-98.4{\%}), respectively. The Κ-statistic was 0.76 (p<0.001) between TK1 and Ki-67, indicating substantial agreement. Conclusions: Serum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation. Trial registration: ClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.",
keywords = "Anastrozole, Biomarker, Breast cancer, Neoadjuvant, Palbociclib, Thymidine kinase",
author = "Nusayba Bagegni and Shana Thomas and Ning Liu and Jingqin Luo and Jeremy Hoog and Northfelt, {Donald W} and Goetz, {Matthew Philip} and Andres Forero and Mattias Bergqvist and Jakob Karen and Magnus Neum{\"u}ller and Suh, {Edward M.} and Zhanfang Guo and Kiran Vij and Souzan Sanati and Matthew Ellis and Ma, {Cynthia X.}",
year = "2017",
month = "11",
day = "21",
doi = "10.1186/s13058-017-0913-7",
language = "English (US)",
volume = "19",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib

AU - Bagegni, Nusayba

AU - Thomas, Shana

AU - Liu, Ning

AU - Luo, Jingqin

AU - Hoog, Jeremy

AU - Northfelt, Donald W

AU - Goetz, Matthew Philip

AU - Forero, Andres

AU - Bergqvist, Mattias

AU - Karen, Jakob

AU - Neumüller, Magnus

AU - Suh, Edward M.

AU - Guo, Zhanfang

AU - Vij, Kiran

AU - Sanati, Souzan

AU - Ellis, Matthew

AU - Ma, Cynthia X.

PY - 2017/11/21

Y1 - 2017/11/21

N2 - Background: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774). Methods: Patients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was>10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3-5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA)levels. Results: Despite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per literDu/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2%-96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% -100%) and 84% (95% CI 69.6%-98.4%), respectively. The Κ-statistic was 0.76 (p<0.001) between TK1 and Ki-67, indicating substantial agreement. Conclusions: Serum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation. Trial registration: ClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.

AB - Background: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774). Methods: Patients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was>10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3-5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA)levels. Results: Despite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per literDu/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2%-96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% -100%) and 84% (95% CI 69.6%-98.4%), respectively. The Κ-statistic was 0.76 (p<0.001) between TK1 and Ki-67, indicating substantial agreement. Conclusions: Serum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation. Trial registration: ClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.

KW - Anastrozole

KW - Biomarker

KW - Breast cancer

KW - Neoadjuvant

KW - Palbociclib

KW - Thymidine kinase

UR - http://www.scopus.com/inward/record.url?scp=85034785786&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85034785786&partnerID=8YFLogxK

U2 - 10.1186/s13058-017-0913-7

DO - 10.1186/s13058-017-0913-7

M3 - Article

C2 - 29162134

AN - SCOPUS:85034785786

VL - 19

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 123

ER -