Hanna Ritzén, Amy Williams, and Mattias Bergqvist from Biovica International in collaboration with international investigators, analyzed the clinical utility of thymidine kinase activity (TKa) for monitoring patient response to endocrine therapy (ET) in hormone receptor-positive (HR+) metastatic breast cancer (MBC). Their analysis, based on clinical data from the SWOG S02261 study and other trials, examined various treatment stages and approaches, including those with and without CDK4/6 inhibitors. TKa was also compared to CA 15-3 and circulating tumor DNA (ctDNA) for prognosis and monitoring in HR+ MBC patients, using data from the BioItaLEE2 trial for the latter biomarker.

The findings were presented at the ABC Global Alliance Conference in Lisbon, Portugal, November 9-11, 2023, and at the San Antonio Breast Cancer Symposium on December 5, 2023.

Below is the poster featuring insights from Biovica’s evaluation of TKa’s predictive and monitoring utility in HR+ MBC.

Circulating Thymidine Kinase Activity in HR+ Metastatic Breast Cancer
ABC 2023 poster on the utility of TKa for predicting and monitoring HR+ MBC patients’ response to anti-proliferative cancer treatments.

Context

Thymidine Kinase (TK) is an enzyme that catalyzes the phosphorylation of thymidine, a crucial step in DNA synthesis and cell division.

Biovica’s study was focused on DiviTum® TKa, an ELISA-based assay for measuring TK activity in serum or plasma samples. Samples were collected from postmenopausal patients with HR+ MBC before and at various stages during treatment with endocrine therapy +/- CDK4/6 inhibitors:

  • Baseline
  • Cycle 1, Day 15 (C1D15)
  • Cycle 2, Day 1 or Day 28 of treatment (C2D1)
  • Months 2–4
  • Month 7

DiviTum® TKa was compared to CA 15-3, a glycoprotein from the MUC1 mucin family. Additionally, the study compared TKa to ctDNA3, which consists of small DNA fragments from tumor cells found in the bloodstream. The BioItaLEE clinical trial, a Phase IIIb, open-label, multicenter study in Italy, evaluated the effectiveness of ribociclib and letrozole in treating postmenopausal women with HR+ HER2-negative advanced breast cancer, using ctDNA alterations to measure treatment effectiveness. This clinical data was used for the analysis.

Results

Below are the results for each component of the analysis.

DiviTum® TKa usability for monitoring survival of HR+ MBC patients treated with mono ET

The assessment of TKa levels for predicting disease progression in patients undergoing endocrine therapy (ET) revealed that low TKa levels (below 250 DiviTum Units of Activity, DuA) are associated with a 97% Negative Predictive Value (NPV). This suggests only a 3% chance of rapid cancer progression, indicating that patients with low TKa levels may continue benefiting from single-agent ET.

The study also found that lower TKa levels are linked to significantly longer overall survival (OS). Patients with low TKa levels had a median OS of 59.9 months, compared to 34.0 months for those with TKa levels of 250 DuA or higher.

TKa patterns for CDK4/6i HR+ MBC therapy predictions

Complete TKa suppression within two weeks of starting CDK4/6 inhibitor therapy, and maintaining it at four weeks, predicts longer treatment duration and minimal progression in HR+ MBC patients (median PFS not reached). In contrast, patients with TKa levels above the LLOQ have a median PFS of 10.1 months.

HR+ MBC PFS predictability with TKa vs ctDNA

For ctDNA, four patterns were observed:

  1. The longest progression-free survival (PFS) was not estimable (NE) at the trial point and was indicated in patients with non-mutated ctDNA, known as wild-type (WT) at both baseline and C1D15.
  2. In patients with mutations in tumor DNA detected at baseline but reverted to WT by C1D15, PFS was shorter, averaging about 21.85 months.
  3. Patients whose tumor DNA was not mutated at baseline but showed mutations by C1D15 experienced a PFS nearly 6 months shorter, averaging 15.93 months.
  4. The lowest PFS of 12.32 months was observed in patients whose tumor DNA was mutated before treatment and remained mutated by C1D15.

The TKa patterns are more straightforward. By assessing C1D15 TKa and C2D1 TKa, the following patterns were identified:

  1. The lowest TKa levels at both time points corresponded to the longest PFS, with median PFS not reached.
  2. Patients with TKa levels above LLOQ at C2D1 after an initial decrease at C1D15 had a median PFS of 22.1 months, associated with a higher risk of progression.
  3. The shortest PFS, with a median of 10.1 months, was experienced by patients with TKa levels above LLOQ at both C1D15 and C2D1.

PFS predictability with TKa vs CA 15-3

The SWOG S0226 study shows that baseline TKa levels are highly prognostic for patients with HR+ metastatic breast cancer starting first-line endocrine therapy, with low baseline TKa indicating a better prognosis. TKa measured at 2, 3, 4, and 7 months during treatment consistently predicts outcomes. In contrast, baseline CA 15-3 levels do not provide a consistent prognosis for PFS but become prognostic after three treatment cycles.

Highlights

DiviTum® TKa is an FDA-cleared and CE-labeled ELISA-based assay for accurate measurement of TKa levels in serum.

  • The SWOG S0226 trial, focused on post-menopausal women with HR+ metastatic breast cancer (MBC). Acceptable prior treatments included adjuvant or neoadjuvant therapy with aromatase inhibitors or fulvestrant, provided these were completed more than 12 months before randomization.
  • While ctDNA can be collected from blood via a non-invasive liquid biopsy, its measurement is more complex than that of TKa and requires a significantly larger sample volume.
  • Current studies, including TK IMPACT, a prospective, real-time study at Washington University in St. Louis (WashU), PDM-MBC at Christie Hospital, Manchester, UK, and four centers in Sweden, and TIRESIAS in Italy are focused on evaluating the effectiveness of the TKa adoption for MBC monitoring.
  • The YALE MBC trial, guided by Yale School of Medicine, is assessing the correlation between DiviTum® TKa levels and medication non-compliance, potential drug-drug interactions, and the effects of medication dose reductions in MBC patients receiving CDK4/6 inhibitor therapy.

Implications for future breast cancer research

Results demonstrate that TKa is a strong predictor of PFS and OS in HR+ MBC patients, with lower levels linked to better outcomes. Its relative ease of testing and strong correlation with cancer proliferation make TKa a promising biomarker that could reduce the need for frequent imaging. TKa offers an earlier prognostic value compared to CA 15-3 and greater precision than ctDNA for predicting CDK4/6 inhibitor efficacy. However, elevated TKa levels require further investigation to verify treatment adherence, explore genetic mutations affecting therapy, and adjust treatment as needed.

Ongoing studies such as TK IMPACT, PDM-MBC, TIRESIAS, and YALE MBC will confirm the clinical utility of DiviTum® TKa.

References

  1. Phase III Randomized Trial of Anastrozole Versus Anastrozole and Fulvestrant as First Line Therapy for Post Menopausal Women with Metastatic Breast Cancer.” SWOG Cancer Research Network. https://www.swog.org/clinical-trials/s0226
  2. Bianchini G et al. “Abstract GS3-07: Circulating tumor DNA (ctDNA) dynamics in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first line with ribociclib (R) and letrozole (L) in the BioItaLEE trial”. American Association for Cancer Research Journals. 2022. 82(4)
    https://aacrjournals.org/cancerres/article/82/4_Supplement/GS3-07/680174/Abstract-GS3-07-Circulating-tumor-DNA-ctDNA
  3. Liquid biopsies: Understanding ctDNA and circulating tumor cells”. The University of Texas MD Anderson Cancer Center. https://www.mdanderson.org/cancerwise/liquid-biopsies–understanding-ctdna-and-circulating-tumor-cells.h00-159463212.html

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