Monitoring CDK 4/6 Inhibitors in Breast Cancer

Feb 13, 2020

Inhibitors of Cyclin Dependent Kinases type 4 and 6 (CDK 4/6Is) have revolutionised the therapy of breast cancer. Combined with anti-oestrogen therapy they have significantly extended the mean and median life expectancies of women with breast cancer. This combination is now recommended as first-line therapy for breast cancer.

A recent study from the US FDA1 has reviewed the data used in the registration of these drugs to evaluate if the response differed between different types of cancer and different combinations of CDK 4/6Is and anti-oestrogens. The finding was that this drug combination is very effective in women with all forms of breast cancer. Another important question that they asked, but could not answer, was which women being treated with anti-oestrogen therapy did not need or received no benefit from additional CDK 4/6Is?

This is a very important question as CDK 4/6Is are expensive (the article mentions $180 000 for two years of therapy) and they have side effects such as neutropenia and diarrhoea. Critically, it is not possible at present to identify in advance women who will show no additional response to CDK 4/6Is. The authors state a need for biomarkers.

In the article they state:

Implications of all the available evidence

These results are important in informing clinical decision-making regarding the risks and benefits of adding a CDKI to endocrine therapy versus endocrine therapy alone.

They show that we are unable to identify patients for whom endocrine therapy alone might result in similar outcomes to endocrine therapy plus a CDKI and that further study of biomarkers predictive of response to CDKIs is therefore needed to improve risk-benefit for individual patients and reduce health-care costs.

Fortunately, there is a biomarker for the effects of CDK 4/6Is – Thymidine Kinase 1 (TK1). CDK 4/6 inhibitors block the cell cycle at the G1-S phase boundary, the point at DNA synthesis occurs and TK1 activity is induced. Studies have shown that therapy with CDK 4/6Is causes a rapid fall in cellular and serum TK1 activities which rise again after therapy is terminated2. TK1 is a mechanistic biomarker for the inhibition of CDK 4/6Is.

AroCell has a leading position in the development and application of TK1 assays and it is actively engaged in studies on their use to monitor cancer therapy, including CDK 4/6 inhibitors. The AroCell TK 210 ELISA is a CE marked kit for precise measurement of TK1 in serum.

AroCell’s CEO, Michael Brobjer, stated “The application of precision medicine is revolutionising cancer therapy, saving costs, reducing patient morbidity and increasing life expectancy. This review shows that there is still an unmet need for an important class of drugs in a major disease, an unmet need that the AroCell’s Technology can help to fill.”

[1] Gao JJ et al. (2019) CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis. Lancet Oncol. pii: S1470-2045(19)30804-6.
[2] Bagegni N et al. (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 (2017) 19:123