Towards a future of oncology pharmacodynamics monitoring and detection of aggressive transformation
“The only man who behaves sensibly is my tailor; he takes my measurements anew every time he sees me, while all the rest go on with their old measurements and expect me to fit them.” -- George Bernard Shaw
An era of precision medicine is upon us, but absent in today’s diagnostic tests are the aspects of time resolution and the assessment of temporal heterogeneity (i.e. the idea that therapy alters tumors through tumor selection and tumor evolution). Much like George Bernard Shaw’s tailor, we too should take multiple biopsies of a patient’s tumor to ensure that we understand a patient’s evolving tumor biology over time.
However, to have patients undergo multiple tissue biopsies longitudinally is hazardous, expensive and often unethical. Fluid biopsies provide the opportunity to perform sequential evaluation on CTCs to assess drug-induced changes and mechanisms of drug resistance.
In a study with Institute of Cancer Research, we used Epic technology to enumeration and molecularly characterize of CTCs from metastatic castration-resistant prostate cancer (mCRPC) patients. We showed that using our technology during treatment is feasible and could detect drug-induced changes associated with variability in CTC count and androgen receptor (AR) expression levels.
We saw that patients who responded to therapy had the highest decrease in CTC counts, which was observable just one week after the drug administration. Conversely, patients who exhibited no decrease in CTC counts or had increasing CTC counts did not respond to therapy.
GU14 Abstract #78: Sequential monitoring and characterization of circulating tumor cells (CTCs) using the Epic Sciences platform in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with recently approved therapeutics.
Figure from Abstract #78 showing pharmacodynamic (PD) activity at baseline vs. 1 week utilizing Epic CTC vs. CellSearch compared to patients who exhibited a >50% PSA decline at 12 weeks. For Epic, CTC drop predicted the 12 week PSA response in 18/19 patients.
Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer that commonly arises in later stages of mCRPC. It is estimated that 25% of prostate cancer deaths can be attributed to NEPC, yet there are no reliable serum markers to identify patients that are transforming to NEPC, and metastatic tissue biopsies are rarely assessed due to cost, complexity and patient co-morbidities. Further confounding this issue is that CTCs are rarely seen in NEPC patients with the CellSearch® platform which uses EpCAM protein expression to identify CTCs.
Epithelial plasticity potentially arising from epithelial to mesenchymal transition may explain the lack of detection using conventional CTC assays. In our study with oncologists and pathologists at Weill Cornell Medical College, Epic’s CTC technology could detect CTCs from patients with pathologically defined NEPC, and these CTCs were shown to be molecularly similar to metastatic biopsies.
GU14 Abstract #177: Molecular characterization of circulating tumor cells (CTCs) of patients with neuroendocrine prostate cancer (NEPC).
Figure from Abstract #177 identifying a CTC from a NEPC patient which has abnormal morphology, is CK+ (weak), CD45-, and EpCAM-. CTCs from NEPC patients appear to have a down-regulation of epithelial markers (CK & EpCAM). Bottom plot identifies common prostate cancer cell lines compared to NEPC patients plotted for CK protein expression.
Summary:
Real-time, pharmacodynamic monitoring of patients tumors through Epic CTC technology can prognosticate true responders three months later with a high degree of accuracy. This has implications for the improvement of clinical trial design and understanding which patients are true responses and enabling the identification of acquired resistance mechanisms months prior to clinical observation.
Additionally, the detection of NEPC has clinical implications as these patients do not respond to approved androgen receptor targeting therapies. CTCs from NEPC patients harbored unique morphology that can be utilized to help identify NEPC CTCs in real-time, allowing for a fast monitoring of tumor cell selection and/or evolution. If validated, detection of confirmed NEPC-specific CTC could be utilized as a strategy to transition patients from androgen receptor targeted therapies to chemotherapies that have demonstrated efficacy to NEPC tumors.
Read the final blog post from GU14 + AACR-PCF:
Patient selection & predictive medicine from a tube of blood?