The DiviTum® TKa test performed on blood serum measures thymidine kinase activity (TKa) which reflects tumor cell proliferation. The test is used as an aid in monitoring disease progression in postmenopausal female patients with metastatic hormone receptor-positive breast cancer.
Published Studies for the DiviTum® TKa Test
Metastatic Breast Cancer
SWOG S0226 Trial – New Data
Thymidine kinase activity levels in serum can identify HR+ metastatic breast cancer patients with a low risk of early progression (SWOG S0226)
Biomarkers January 2023
Background
Some patients with metastatic breast cancer (MBC) stay on endocrine therapy (ET) for years and others progress quickly. Serum thymidine kinase activity (TKa), an indicator of cell-proliferation, is a potential biomarker for monitoring ET and predicting MBC outcome. We have previously reported TKa as being prognostic in MBC in SWOG S0226. Here, new data on progression within 30/60 days post sampling, with a new, FDA approved version of DiviTum® TKa highlighting differences vs. a Research Use Only version is reported.
Methods
1,546 serum samples from 454 patients were assessed, collected at baseline and at 4 subsequent timepoints during treatment. A new predefined cut-off tested the ability to predict disease progression. A new measuring unit, DuA (DiviTum® unit of Activity) is adopted.
Results
A DiviTum® TKa score <250 DuA provides a much lower risk of progression within 30/60 days after blood draw, the negative predictive value (NPV) was 96.7% and 93.5%, respectively. Patients <250 DuA experienced significantly longer progression-free survival and overall survival, demonstrated at baseline and for all time intervals.
Conclusions
DiviTum® TKa provides clinically meaningful information for patients with HR+ MBC. Low TKa levels provide such a high NPV for rapid progression that such patients might forego additional therapy added to single agent ET.
SWOG S0226 Trial
Evaluating Serum Thymidine Kinase 1 in Patients with Hormone Receptor-Positive Metastatic Breast Cancer Receiving First-line Endocrine Therapy in the SWOG S0226 Trial
Clin Cancer Res. 2021 Nov 15;27(22):6115-6123.
Study type
A multicenter (426 sites), prospective-retrospective translational medicine study, n = 454
Objective
To demonstrate that low serum Thymidine Kinase 1 (sTK1) activity (=TKa) (measured with the DiviTum®TKa test) is associated with low risk for disease progression and long PFS and OS. We assessed the prognostic effect of sTK1 (TKa) in patients with hormone receptor-positive metastatic breast cancer (MBC) treated in a prospective randomized SWOG trial of anastrozole (A) vs. A plus fulvestrant (A+F).
Background
Combination ET (endocrine therapy) or ET plus other targeted agents is associated with increased toxicities and costs compared to single agent ET. Thus, identification of patients who may not need combination therapy would serve to spare them these adverse events. Currently, there is no tool available to help clinicians tailor treatment for each patient, underlining the compelling need for identification of biomarkers of resistance and response to ET agents
Results
Patients with high versus low BL sTK1 (TKa) had significantly worse PFS [median 11.2 vs. 17.3 months, HR = 1.76; P < 0.0001] and OS [median 30 vs. 58 months, HR = 2.38; P < 0.0001]. OS was significantly better for patients with high TKa who did not have prior adjuvant tamoxifen and who received A + F versus A alone [median 46 vs. 21 months, HR = 0.58; P = 0.0087]. Patients with low TKa had no difference in outcomes by therapy (P = 0.44). At serial timepoints, high versus low TKa had significantly worse subsequent PFS and OS [at cycle 2: PFS HR = 1.70, P < 0.0001, OS HR = 2.51, P < 0.0001]. Our results suggest that there are several potential practical applications for TKa in the care of patients with MBC.
Conclusion
The results of this translational medicine study suggest that BL sTK1 (TKa) identified patients with hormone receptor-positive MBC with a very favorable prognosis. Low BL TKa might identify patients who have indolent disease and may do well for a long time with first line ET alone and could safely be treated with ET monotherapy as upfront treatment for their metastatic disease. Delaying CDK4/6 or mTOR inhibitors might be warranted, decreasing toxicity and cost of therapy. Repetitive test-monitoring of TKa in MBC may allow early identification of patients whose tumors are resistant to therapy and who might benefit from switching to an alternative therapeutic strategy prior to detecting evidence of radiographic disease progression.
BioltaLEE – New Data
Thymidine kinase 1 (TK1) is an enzyme downstream of the CDK4/6 pathway, with a critical role in DNA synthesis; serum TK1 activity (sTKa) is a novel liquid biopsy biomarker of tumor cell proliferation.
EJC March 07, 2023
Methods
The phase IIIb, BioItaLEE trial (NCT03439046) collected sera from postmenopausal patients with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC) treated with first-line ribociclib plus letrozole at baseline, day 15 of cycle 1 (C1D15), day 1 of cycle 2 (C2D1), and at first imaging (FI). Associations between sTKa assessed at different time points or sTKa dynamic patterns, and progression-free survival (PFS) were evaluated using multivariate Cox models.
Results
Overall, 287 patients were enrolled. Median follow-up was 26.9 months. High sTKa (>median) at baseline was associated with higher risk of progression (HR 2.21; 95% CI 1.45,3.37; P=0.0002); similar results were observed for patients with high sTKa levels at D15 and C2D1. Early sTKa dynamic patterns were strongly predictive of PFS. The pattern with high sTKa levels at C2D1 following initial decrease at C1D15 was associated with higher risk of progression vs. the pattern with low sTKa levels at both time points (HR 2.89; 95% CI 1.57,5.31; P=0.0006), while the pattern with high sTKa levels at C1D15 was associated with the shortest PFS (HR 5.65; CI 2.84,11.2; P<0.0001). Baseline and dynamic sTKa changes provided independent information.
Conclusions
sTKa appears to be a new promising prognostic and pharmacodynamic biomarker in patients with HR+/HER2– ABC treated with ribociclib plus letrozole as first-line therapy.
BioltaLEE
Circulating tumor DNA (ctDNA) and serum thymidine kinase 1 activity (TKa) matched dynamics in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor 2–negative (HER2-) advanced breast cancer (ABC) treated in first-line (1L) with ribociclib (RIB) and letrozole (LET) in the BioItaLEE trial
Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) 1012-1012.
Study type/Objective
A multi-center, head-to-head comparison of TKa and ctDNA as predictive biomarkers of response in pts with HR+, HER2− ABC treated with RIB+-LET enrolled in the BioItaLEE trial (NCT03439046), n = 287.
Methodology/Results
The prognostic/predictive value of both TKa and ctDNA were assessed from baseline and on-treatment cycle 1 blood samples from BioItaLEE. Baseline samples for both ctDNA and TKa were equally prognostic for PFS. Samples from patients with detectable ctDNA or high TKa levels at BL predicted for a shorter mPFS (16.59 mo vs 16.1 mo respectively) than samples from patients with undetectable ctDNA or low TKa (mPFS not reached for both biomarkers). In samples with detectable ctDNA at BL (113/263 or 43%of patients) on-treatment cycle 1 day 15 samples were assessed for clearance of ctDNA. Clearance of ctDNA at D15 was predictive for a greater mPFS (21.85 mo) vs lack of clearance at D15 (12.09 mo, HR 0.51, p=0.0228). Using on-treatment assessments of TKa at D15 and C2D1 from 92% of patients (241/263) allowed for more precise stratification of patients into 3 different prognostic patterns. Additionally, undetectable levels of TKa at both D15 and C2D1 was highly predictive for outcome with a mPFS that was not reached after 27 months of follow-up, versus a mPFS of only 10.1 mo in patients whose on-therapy samples did have detectable TKa (HR 0.18, p=<0.0001) Combining the two biomarkers did not appear to further improve prediction of patients with the best clinical outcome, but did slightly improve identification of patients predicted to have the worst clinical outcome (mPFS 6.65 mo).
Conclusion
These findings suggest that early dynamic assessments of both ctDNA and TKa can predict outcome of pts treated with RIB+LET. On-therapy measurements of TKa offer greater dynamic stratification of patients and additional predictive value versus ctDNA. TKa and ctDNA capture different features of tumor biological activity and both their individual and combined patterns warrant further evaluation in relation to other treatments, settings, and diseases. Clinical trial information: NCT03439046.
PYTHIA
Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant
European Journal of Cancer, Volume 164, March 2022, Pages 39-51
Study type
Phase II, single-arm, multicenter trial (Italy, Belgium, UK) that enrolled 124 post-menopausal women with endocrine-resistant hormone receptor-positive/HER2-negative metastatic breast cancer.
Background
Biomarkers for cyclin-dependent kinase 4/6 inhibitors, such as palbociclib, for patients with hormone receptor-positive/HER2-negative metastatic breast cancer are lacking. Thymidine kinase is a proliferation marker downstream of the cyclin-dependent kinase 4/6 pathway.
Objective
We prospectively investigated the prognostic role of serum thymidine kinase activity (sTKa), in patients treated with Palbociclib + fulvestrant.
Results
Data from 122 women were analyzed. Pre-treatment sTKa was not associated with clinical characteristics and moderately correlated with tissue Ki-67. Palbociclib + fulvestrant markedly suppressed sTKa levels at D15, with 83% of patients recording levels below limit of detection. At D28, sTKa showed a rebound in 60% of patients. At each timepoint, higher sTKa was associated with shorter progression-free survival (each p < 0.001), with the strongest effect at D15.
Conclusion
TKa is an independent prognostic biomarker in patients treated with palbociclib. High pre-treatment sTKa and its incomplete suppression during treatment may identify patients with poorer prognosis and primary resistance. This warrants validation in prospective comparative trials.
TKa and Palbociclib
A phase II trial of an alternative schedule of palbociclib and embedded serum TK1 analysis
NPJ Breast Cancer. 2022 Mar 21;8(1):35.
Study Type
Single-arm phase II trial, patients with HR+/HER2− MBC from multiple U.S. sites (University of Nebraska, Omaha, Washington University, St. Louis), n = 54
Background
CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, have gained FDA approval based on the significant improvement in progression-free survival (PFS) when added to endocrine therapy in patients with advanced disease as front-line therapy or following disease progression on prior endocrine therapy. These agents have now become the standard of care in combination with an endocrine therapy partner for HR+/HER2− metastatic breast cancer (MBC). However, treatment-related neutropenia is a common adverse event (AE), leading to dose interruption, reduction, and at times discontinuation. An alternative palbociclb dosing schedule of 5-days-on/2-days-off weekly was investigated to determine if it could reduce grade 3 and above neutropenia.
Objective
We assessed sTK1 (TKa) dynamics for target inhibition and examined its potential prognostic value and utility in disease monitoring.
Results
We assessed treatment-induced pharmacodynamics effect: All patients with high sTK1 (TKa) at C1D15 (≥20 Du/L) had high TKa at baseline (>200 Du/L, predefined cut point for high baseline TKa). Among the 24 patients who progressed with TKa available, an TKa increase from the prior time point was detected at the time of progression in nine patients, and at an earlier time point in 13 patients.
We then assessed the prognostic significance of baseline and early on-treatment TKa:
- There was no association between levels of TKa either at baseline or C1D15 with the presence of visceral metastasis or endocrine sensitivity defined by ESMO criteria
- However, TKa at both BL and C1D15 time points were significantly correlated with clinical benefit versus not
- Baseline TKa was higher in patients with PD as the best response
- Progression within 6 months (not achieving clinical benefit) was negatively correlated with high TKa at baseline (p = 0.000419) and C1D15 (p = 8.4 × 10−5)
- High TKa at baseline (>200 Du/L), C1D15 (>20 Du/L) or C2D1 (>20 Du/L) predicted progression within 3 (or 6) months
- TKa at BL, C1D15, and C2D1 remained an independent predictor of PFS in the multivariate analysis that included age, endocrine sensitivity, and sites of metastases
Conclusions
- Our study demonstrated the potential utility of sTK1 activity (TKa) at baseline and on-treatment as a prognostic marker and in monitoring disease status for patients with MBC receiving a CDK4/6 inhibitor. High TKa at baseline or early on-treatment time point (C1D15 or C2D1), especially at C1D15, had high degrees of accuracy in predicting progression within 6 months (84% accuracy for C1D15).
- In addition, we demonstrated that a rise in TKa predicted subsequent clinical/RECIST progression. Our data demonstrate TKa a promising biomarker of prognosis and disease monitoring in patients receiving CDK4/6 inhibitors.
Other breast cancer references:
Larsson, AM., Bendahl, PO., Aaltonen, K., Jansson S., Forsare C., Bergqvist M., Tykjaer Jorgensen C., Ryden L. Serial evaluation of serum thymidine kinase activity is prognostic in women with newly diagnosed metastatic breast cancer. Sci Rep 10, 4484 (2020). https://doi.org/10.1038/s41598-020-61416-1
McCartney A, Bonechi M, De Luca F, Biagioni C, Curigliano G, Moretti E, Minisini AM, Bergqvist M, Benelli M, Migliaccio I, Galardi F, Risi E, De Santo I, Romagnoli D, Biganzoli L, Di Leo A, Malorni L. Plasma Thymidine Kinase Activity as a Biomarker in Patients with Luminal Metastatic Breast Cancer Treated with Palbociclib within the TREnd Trial. Clin Cancer Res. 2020 May 1;26(9):2131-2139. doi: 10.1158/1078-0432.CCR-19-3271. Epub 2020 Jan 14. PMID: 31937617.
McCartney A, Biagioni C, Schiavon G, Bergqvist M, Mattsson K, Migliaccio I, Benelli M, Romagnoli D, Bonechi M, Boccalini G, Pestrin M, Galardi F, De Luca F, Biganzoli L, Piccart M, Gradishar WJ, Chia S, Di Leo A, Malorni L. 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). Eur J Cancer. 2019 Jun;114:55-66. doi: 10.1016/j.ejca.2019.04.002. Epub 2019 May 3. PMID: 31059974.
Cabel L, Rosenblum D, Lerebours F, Brain E, Loirat D, Bergqvist M, Cottu P, Donnadieu A, Bethune A, Kiavue N, Rodrigues M, Pierga JY, Tanguy ML, Bidard FC. Plasma thymidine kinase 1 activity and outcome of ER+ HER2- metastatic breast cancer patients treated with palbociclib and endocrine therapy. Breast Cancer Res. 2020 Sep 14;22(1):98. doi: 10.1186/s13058-020-01334-2. PMID: 32928264; PMCID: PMC7489000.
Bonechi M., Galardi F., Biagioni C., De Luca F., Bergqvist M., Neumüller M., Guarducci C., Boccalini G., Gabellini S., Migliaccio I., Di Leo A., Pestrin M., Malorni L. 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. Oncotarget. 2018; 9: 16389-16399 https://www.oncotarget.com/article/24700/text/
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. 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 Res. 2017 Nov 21;19(1):123. doi: 10.1186/s13058-017-0913-7. PMID: 29162134; PMCID: PMC5699111.
Knudsen ES, Shapiro GI, Keyomarsi K., Selective CDK4/6 Inhibitors: Biologic Outcomes, Determinants of Sensitivity, Mechanisms of Resistance, Combinatorial Approaches, and Pharmacodynamic Biomarkers, DOI: 10.1200/EDBK_281085 American Society of Clinical Oncology Educational Book 40 (May 18, 2020) 115-126. https://ascopubs.org/doi/full/10.1200/EDBK_281085
McCartney, A., Malorni, L. Potential through simplicity: thymidine kinase-1 as a biomarker for CDK4/6 inhibitors. Br J Cancer 123, 176–177 (2020). https://doi.org/10.1038/s41416-020-0858-y
McCartney, A., Malorni, L. Thymidine Kinase-1 as a biomarker in breast cancer: estimating prognosis and early recognition of treatment resistance. Biomarkers In Med. Vol. 14, No. 7, Editorial. 7 May 2020. https://doi.org/10.2217/bmm-2020-0072
Other Malignancies
Some of our Collaborations
>4,500
Numbers of patients in studies
25+
Publications
10
Pharma Contracts
