What we do
About our project
Around 25-35% of breast cancer (BC) patients will have or develop metastatic disease (MBC). For newly diagnosed patients with estrogen receptor (ER-) positive MBC (60-70% of MBC patients) endocrine therapy is the mainstay systemic treatment. Addition of CDK4/6 inhibitors to endocrine therapy greatly increases the progression free survival (PFS) of these patients. However, 10-15% of patients on CDK4/6 inhibitors progress within 6 months after therapy start, whereas 25% of patients on endocrine monotherapy achieve a PFS comparable to that of CDK4/6 inhibitor-treated patients. CDK4/6 inhibitors are associated with increased toxicity compared to endocrine monotherapy and are expensive.
The nation-wide SONIA trial will determine the optimal placement (i.e. line of treatment) for CDK4/6 inhibition in ER-positive MBC patients. Irrespective of its outcome, methods are needed for identification of unresponsive patients. CT- and bone scans lack sensitivity to show progression early on, particularly in women with bone metastasis only. Liquid biopsies (blood) can contain tumor-derived material and could be used to determine whether a patient is responding to the treatment. Therefore blood will be collected in consenting SONIA patients before treatment start, 2 and 12 weeks after treatment start, and at time of progressive disease.
We hypothesize that early dynamics in the level of circulating tumor DNA (ctDNA) in the blood can be used to predict early progression (within 6 months after treatment start) in MBC patients. Therefore, we aim to measure changes in patient-specific tumor mutation blood levels 2 weeks and 3 months after treatment start relative to baseline in patients from the SONIA trial.
In addition, we aim to identify potential CDK4/6 inhibitor resistance mechanisms in selected patients by investigating the extent of genetic heterogeneity and the emergence of specific genetic variants during treatment with a CDK4/6 inhibitor.
Expected outcomeNotwithstanding the promising results obtained with liquid biopsy research, scientific support of their clinical utility is urgently needed for clinical implication. In this respect, large-scale prospective clinical trials like the SONIA trial provide a unique opportunity as they recruit patients according to predefined inclusion criteria, follow them over time, and generate high quality clinical data. Our results will pave the way for routine use of liquid biopsies for treatment monitoring in MBC patients. In addition, more insight will be gained into the currently poorly understood palbociclib resistance mechanisms, enabling better patient selection, and potentially novel treatment options.
Our research focus
CDK4/6-inhibitors in ER-positive MBC
Clinical trials showed that addition of CDK4/6-inhibitors to endocrine therapy in first or second line treatment of women with ER-positive MBC substantially prolonged their PFS.
Additional important observations from these studies:
- no benefit in overall survival was found yet
- many patients do well on endocrine monotherapy
- none of the tested parameters distinguish between good and poorly responding patients
Grade 3-4 toxicity (mostly neutropenia) according to the Common Terminology Criteria for Adverse Events (CTCAE) was experienced by 60-70% of patients treated with the combination compared to 20% of patients treated with endocrine monotherapy.
Clinical utility of ctDNA
CtDNA is DNA that is derived from tumor cells and circulates cell-free in the peripheral blood. Potential clinical applications of ctDNA include monitoring of treatment response, detection of the emergence of drug resistance, and quantification of minimal residual disease.
It was recently shown that in a subgroup of palbociclib-treated patients, early PIK3CA ctDNA dynamics were highly predictive of response, where ESR1 ctDNA dynamics were not. These results indicate the potential of ctDNA measurements for prediction of early progression in this patient population but also suggest it is important to focusing on so-called trunk mutations.
Palbociclib resistance mechanisms
Palbociclib induces cell cycle arrest through specific inhibition of CDK4 and CDK6. Normally, the CDK4/6-Cyclin D1 complex phosphorylates pRb thereby activating the cell cycle inducing transcription factor E2F family members.
Palbociclib resistance is not fully understood but appears associated with loss- and gain-of-function of proteins involved in the pRb and PI3K pathways. The serial sample series we envision to collect will provide us with an unprecedented opportunity to investigate the molecular effects of palbociclib treatment on the tumor’s molecular make-up within the patient.
Funds & Grants
Breast Cancer Now PCC1286: “The value of circulating tumor DNA dynamics in patient selection for palbociclib treatment”
- Dr Agnes Jager
- Prof Dr John Martens
- Drs Lisa Jongbloed
- Prof Dr Stefan Sleijfer
- Dr Maurice Jansen
- Dr Jaco Kraan
- Dr Saskia Wilting