Thymidine kinase 1 in breast cancer monitoring

Thymidine kinase 1 (TK1) is an essential component of nucleotide metabolism, playing a significant role in cell proliferation. Specifically, in the context of breast cancer, TK1 is vital in facilitating DNA replication during cancer cell division, and the serum of cancer patients has been shown to contain higher levels of TK1 activity than those of healthy persons¹.

This rise in TK1 enzyme activity may be a diagnostic marker for hematological malignancies and prostate, lung, and breast cancers, and indeed, TK1 is a breast cancer biomarker. Poorer clinical outcomes, a higher chance of metastasis, and more aggressive malignancies are frequently linked to higher levels of TK1 expression or activity².

Cell cycle dysregulation is a common part of breast cancer cells, which causes uncontrolled growth³. Many checkpoints closely control the course of the cell cycle, and changes to these regulatory processes can lead to aberrant proliferation. An essential enzyme for DNA synthesis, TK1, is activated to meet the increased demand for nucleotides by faster cell division. Increased TK1 levels in blood or breast cancer tissues indicate proliferative activity. The aggressiveness of breast cancers based on the higher proliferation index, denotes fast cell growth and division, correlate with greater TK1 expression⁴.

Tumor aggressiveness, including fast development, infiltration of adjacent tissues, and metastasis, is indicated by the tumor’s grade and stage. Research has shown that in many cancer types, tumors with more advanced stages and higher histological grades are often associated with elevated TK1 levels⁵.

The presence of an aggressive tumor, and is linked to a dismal prognosis for the patient⁶. Due to their greater proliferative and invasive characteristics, tumors with elevated TK1 expression and TK cell division activity may have increased potential for metastazising⁴. Heightened TK1 levels can also predict adverse outcomes and assist in identifying individuals who need more intensive care or constant observation, making it an essential method within breast cancer monitoring.

TK1’s involvement in the origin of cancer: 2 case studies

Recent research has also suggested that TK1 may be involved in the origin of cancer. In 2023, at the Columbia University Irving Medical Center in the United States, an investigation of the possible connection(s) between TK1 expression and cancer-promoting pathways implicated in the pathophysiology of breast cancer was conducted⁷.

As HCC 1806 cells are naturally aggressive, they were chosen as the main breast cancer cell line. To determine which TK1-influenced cancer-promoting pathways may be of interest, HCC 1806 wild-type and HCC 1806 TK1-knockdown (L133) cells were examined.

The study’s findings indicate that significant quantities of TK1 are endogenously expressed by HCC 1806 cells and that this expression is a factor in the cells’ pathogenic nature. The findings seen in vitro were confirmed by a breast cancer tissue array of patient samples, which also showed that increased TK1 expression influences the course of ductal and lobular breast cancer7.

Another study done in the UK in 2018 showed similar patterns, wherein researchers used flow cytometry to assess the membrane TK1 expression levels on lung and breast cell lines⁸. The therapeutic significance of TK1 was further evaluated by evaluating the expression levels of TK1 in both normal and malignant tissue. Findings pointed to TK1 enzyme activity as a possible target for immunotherapy, suggesting that the location of TK1 on the cell surface could be specific to cancer and unrelated to cell growth⁸.

Furthermore, the study demonstrated that TK1 expression is elevated in cancer patients relative to normal healthy individuals and that TK1 is increased in a sizable population of breast cancer patient tissues⁸.

An immunoassay system that involves ELISA also improves specificity in the measurement of serum TK1 levels in breast cancer patients while simultaneously removing the need for special handling and expensive equipment⁴.

A study conducted in 2016 involved a newly developed TK 210 ELISA from AroCell AB, which was was used to analyze TK1 protein and TK1 activity levels in sera from both breast cancer patients and healthy donors by the 3[H]-deoxythymidine (dThd) phosphorylation assay. Findings suggested that TK1 levels found in sera from breast cancer patients with T1 to T4 stage disease were significantly different from healthy controls, and they pointed to the possibility of more accurate measurement of TK1 levels associated with solid tumors⁹.

The management of patient outcomes with breast cancer can be improved by TKa testing, which can help with risk assessment, therapy selection, and disease progression tracking.

TK1 activity measurement to influence treatment approach

Patients with breast cancer who are more prone to experience metastases, relapse, or disease progression can be identified with the use of TK1 level measurement¹⁰. For example, individuals with higher TK1 levels may perhaps need closer monitoring or more aggressive treatment plans.

Another potential of measuring TK1 activity when monitoring breast cancer development is to allow clinicians to employ targeted treatments and chemotherapy regimens for patients. Additionally, TK1 enzyme activity measurement may be used to identify people who are at high risk for breast cancer, particularly those who have BRCA1 mutations. Individuals with BRCA1 mutations may have elevated TK1 enzyme activity, which may function as a biomarker for enhanced proliferation and perhaps signify an increased risk of cancer development¹¹.

Baseline TK1 activity can be assessed before starting therapy with experimental medications. This can determine the patient’s original state of illness and offer a point of reference. TK1 activity level can also be routinely checked during therapy, and changes over time may indicate how the patient’s cancer cells react to the experimental medication. A drop in TK1 activity levels, for example, might indicate tumor regression or decreased proliferation, which would be a sign of a successful therapeutic outcome.

Furthermore, early signs of therapy response before traditional endpoints are seen might be obtained from TK1 kinetics. In a shorter amount of time, changes in TKa levels can serve as a prognostic marker for therapy success before radiographic or clinical indications of response¹². This can lead to the potential of therapy continuation, modification, or cessation decisions made more quickly, reducing extended exposure to ineffective medications or facilitating swift escalation to alternate treatments.

TK1 activity measurement in clinical trials

In clinical trials, gene expression patterns linked to TK1 expression levels or activities can be found by integrating TK1 data with transcriptome profiles. By identifying putative regulators or downstream effectors of TK1, differential gene expression analysis can shed light on the protein’s function in cancer development or the response to therapy⁷. TK1 expression levels may be linked to metabolic pathways, protein-protein interactions, or biomarker signatures that may be found by integrated analysis. These findings could provide new targets for biomarker development or therapeutic intervention. These studies, which incorporate several molecular levels, can improve our comprehension of disease biology and pinpoint new targets for treatment.

TK1 is involved in illness diagnosis, risk assessment, and therapy selection, among other aspects of personalized medicine, with enzyme activity influencing the choice of breast cancer treatment. For example, elevated TK1 enzyme activity can suggest a more aggressive tumor phenotype, leading physicians to select more intense treatment alternatives such as targeted therapy or chemotherapy¹². On the other hand, low TK1 enzyme activity indicates a less aggressive tumor, which can call for active surveillance or less hazardous treatment choices.

Combining thymidine kinase 1 (TK1) data with genetic and tumor features in ongoing treatment studies may improve our understanding of cancer biology. Several clinical trials have been conducted on this matter. For example, a study used a series of bioinformatics analyses using public multi-omics datasets to assess the relationships of TK1 expression level with glioma prognosis and clinicopathological variables¹³. It was found that, in comparison to standard samples or regular cell lines, TK1 expression was more significant in glioma tissue samples and cell lines. Furthermore, elevated TK1 expression was detected in several other cancers and shown to relate to a worse prognosis¹³.

The use of TK1 testing in the early diagnosis and identification of different tumors shows potential. Increased TK1 levels may be a sensitive biomarker for early cancer detection, enabling prompt treatment and better patient outcomes. Furthermore, TK1 levels offer valid prognostic data that aid in forecasting the course, likelihood of recurrence, and overall survival of the illness². Routine care that includes TK1 testing improves risk assessment and guides clinical judgment, resulting in better patient care. With TK1 testing, doctors may monitor treatment response in real-time, evaluating the efficacy of therapy and modifying treatment regimens as necessary.

Challenges of TK1 clinical utility

Despite these potentials, there are some challenges with confirming the clinical utility of TK1.

Several factors must be considered when interpreting the findings of TK1 tests. These include the patient’s clinical history, demographics, and current medicines. Clinicians must analyze TK1 levels with other diagnostic and prognostic indicators to prevent misunderstanding and make well-informed therapeutic decisions.

Issues with cost-effectiveness and reimbursement may also prevent TK1 testing from being widely used in standard medical treatment. Robust data establishing clinical benefits and cost reductions associated with TK1-based methods is necessary to establish the economic value of TK1 tests. Realizing the full potential of TK1 testing in standard clinical treatment will require addressing these obstacles.

Facing these challenges

More investigation and validation are essential to completely comprehend the potential and constraints of thymidine kinase 1 (TK1) as a biomarker in cancer detection. First, efforts to create uniform methods across laboratories are required as variations in assay platforms and protocols can impact the precision and repeatability of TK1 measurements. More investigation is also needed to clarify the relationship between TK1 enzyme activity and clinical outcomes such as overall survival, progression-free survival, and responsiveness to therapy. Finally, longitudinal studies undertaken can reveal new information about the prognostic importance and predictive usefulness of TK1 in directing treatment choices. This can be done to evaluate TK1 kinetics over time and their correlation with patient outcomes.

With testing done via a simple blood test, TK1 has strong potential to be used for monitoring, prognostic, diagnostic, and predictive purposes to be used as a tool for individualized approaches to treatment. Much has been done to suggest TK1’s therapeutic usefulness. To maximize its incorporation into clinical practice, pharmaceutical companies can further conduct validation studies.

The DiviTum® TKa test is a diagnostic, prognostic, and monitoring tool designed to measure TK activity in blood samples. This produces a DiviTum activity score, which can provide valuable information regarding the disease proliferative status, particularly in mBC patients who are hormone receptor-positive and postmenopausal. Learn more about the clinical trials we have undertaken thus far, or enquire about the suitability of the test in your clinical study.

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