Plasma Thymidine Kinase Activity as a Biomarker in Patients with Luminal Metastatic Breast Cancer Treated with Palbociclib within the TREnd Trial

Purpose: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC. Experimental Design: Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor–positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the “To Reverse ENDocrine Resistance” (TREnd) trial (n = 46). Results: Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients (n = 8) showing an increase—correlating with a worse outcome than those with decreased/stable TKa (n = 33; mPFS 3.0 vs 9.0 months; P = 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months; P = 0.05). Conclusions: TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.

[1]  L. Chow,et al.  Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. , 2019, The New England journal of medicine.

[2]  M. Piccart,et al.  Prognostic role of serum thymidine kinase 1 activity in patients with hormone receptor-positive metastatic breast cancer: Analysis of the randomised phase III Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT). , 2019, European journal of cancer.

[3]  G. Curigliano,et al.  Clinical outcomes after palbociclib with or without endocrine therapy in postmenopausal women with hormone receptor positive and HER2-negative metastatic breast cancer enrolled in the TREnd trial , 2019, Breast Cancer Research.

[4]  J. Abraham,et al.  Real-world evidence evaluating continuation of CDK4/6 inhibitors beyond first progression in hormone receptor-positive (HR+) metastatic breast cancer. , 2019, Journal of Clinical Oncology.

[5]  S. Loi,et al.  Cyclin E1 Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor–Positive Metastatic Breast Cancer , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  Shudong Wang,et al.  Overcoming CDK4/6 inhibitor resistance in ER positive breast cancer. , 2019, Endocrine-related cancer.

[7]  R. Schiff,et al.  Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer , 2018, npj Breast Cancer.

[8]  S. Loi,et al.  Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer , 2018, The New England journal of medicine.

[9]  L Biganzoli,et al.  Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive, HER2-negative metastatic breast cancer: TREnd trial , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[10]  Bing-he Xu,et al.  Abstract CT048: Biomarker analysis from a phase 1 study of palbociclib (PAL) plus letrozole (L) as first-line treatment for ER+/HER2– advanced breast cancer (ABC) in Chinese women , 2018, Clinical Trials.

[11]  P. Fasching,et al.  Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  G. Hortobagyi,et al.  First-line ribociclib (RIB) + letrozole (LET) in hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC): MONALEESA-2 biomarker analyses. , 2018 .

[13]  M. Pestrin,et al.  Plasma thymidine kinase-1 activity predicts outcome in patients with hormone receptor positive and HER2 negative metastatic breast cancer treated with endocrine therapy , 2018, Oncotarget.

[14]  M. Ellis,et al.  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 , 2017, Breast Cancer Research.

[15]  M. Goetz,et al.  MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  P. Neven,et al.  MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  Zachary L. Skidmore,et al.  NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor–Positive Breast Cancer , 2017, Clinical Cancer Research.

[18]  K. Gelmon,et al.  Palbociclib and Letrozole in Advanced Breast Cancer. , 2016, The New England journal of medicine.

[19]  E. Winer,et al.  Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. , 2016, The New England journal of medicine.

[20]  Laura M. Heiser,et al.  FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer , 2016, Proceedings of the National Academy of Sciences.

[21]  K. Gelmon,et al.  Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib (P) with letrozole (L) compared with placebo (PLB) plus L in postmenopausal women with ER + /HER2– advanced breast cancer (ABC) , 2016 .

[22]  M. Dowsett,et al.  Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer. , 2016, Cancer research.

[23]  S. Loi,et al.  Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. , 2016, The Lancet. Oncology.

[24]  M. Fernö,et al.  Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial , 2013, Breast Cancer Research and Treatment.

[25]  K. Krohn,et al.  Monitoring tumor cell proliferation by targeting DNA synthetic processes with thymidine and thymidine analogs. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[26]  B Asselain,et al.  Thymidine kinase as a proliferative marker: clinical relevance in 1,692 primary breast cancer patients. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  M. Bolla,et al.  Prognostic of DNA‐synthesizing enzyme activities (thymidine kinase and thymidylate synthase) in 908 T1–T2, N0–N1, M0 breast cancers: A retrospective multicenter study , 2000, International journal of cancer.

[28]  R. Blamey,et al.  Thymidine kinase in breast cancer. , 1990, British Journal of Cancer.

[29]  Xin Huang,et al.  The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. , 2015, The Lancet. Oncology.