Bespoke polymerase chain reaction (PCR) is an emerging novel technology for the analysis of liquid biopsies — circulating tumor DNA (ctDNA) — with multiple potential applications.
The technology was used in the TRACERx (ClinicalTrials.gov Identifier:
NCT01888601) study to predict non–small cell lung cancer relapse and adjuvant treatment response.1
Matthew Rabinowitz, PhD, is the founder and CEO of Natera, the company that is developing bespoke PCR. Cancer Therapy Advisor asked Dr Rabinowitz about the bespoke PCR technology and ongoing studies.
Cancer Therapy Advisor (CTA): Can you explain the bespoke PCR technology and how it is different from other methods of ctDNA analysis?
Dr Rabinowitz: This is a derivative of our non-invasive prenatal testing. Our analysis is targeted to single-nucleotide polymorphisms and we can combine those measurements with data from the human genome project, like the HAPMAP database.
For the oncology applications, we build a customized panel for each patient that is specific to their tumor’s mutations from ctDNA. So if there’s a single molecule or fragment of DNA that comes from the tumor that has the cancer-associated mutation on it, we pick that up in a blood draw of about 5 to 10 moles of blood. We can go down to single molecule levels of sensitivity and do that with a very low cost.
CTA: What are the oncology-specific applications of bespoke PCR?
Dr Rabinowitz: The first is disease load monitoring. This would require a blood draw every couple of weeks to understand how the patient is responding. The second application is residual disease load after therapy or surgery to understand when therapy can be discontinued or whether you caught all of the cancer with surgery.
The third application, and probably the biggest, is recurrence monitoring. As we showed in the Nature paper, using cell-free DNA you can catch the recurrence of a cancer — in the case of lung cancer — an average of 4 months before you see nodules by imaging or clinical symptoms. We were able to catch recurrences as early as 11 months before you would see imaging or clinical symptoms.
CTA: Does the time of day affect the outcome of bespoke PCR?
Dr Rabinowitz: In the prenatal setting, we see that the amount of fetal DNA in the mother’s blood can vary quite a lot over the course of a few hours. We haven’t done those kinds of studies in the oncology space, but it is possible that the level of cell-free DNA could increase at different times.
CTA: Are there ongoing or future studies in oncology that are evaluating bespoke PCR?
Dr Rabinowitz: We are doing a breast cancer trial with the I-SPY study to understand how the level of cell-free DNA from the tumor corresponds to the imaging and to determine if its possibly a better marker for therapy response and imaging. We’re evaluating it as a prognostic indicator for recurrence and whether we can detect breast cancer recurrence substantially earlier than we could by mammogram. There are also trials ongoing in ovarian, liver, bladder, and renal cancers.
- Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution. Nature. 2017 Apr 26. doi: 10.1038/nature22364 [Epub ahead of print]