According to the National Cancer Institute, ovarian cancer only has a 50.8% five-year survival rate, and one of the leading causes of cancer death in women. One reason for these high rates is that the cancer’s symptoms, which can include bloating and lower back pain, often can be chalked up to something else, and so the cancer is not discovered until it’s in later stages.
Researchers have identified homologous recombination deficiency (HRD) as a biomarker that can guide treatment in high grade cancer. Yann Christinat, PhD, a clinical bioinformatician at the Geneva University Hospitals, Switzerland spoke to CLN about the significance of cytogenetic analysis for HRD scoring and how he uses the OncoScan platform for research.
What is HRD and why is it relevant for human cancers?
HRD represents a deficiency in one of the pathways that repair DNA in the cell. This defect affects the cells’ capability to repair double strand breaks in DNA. That means HRD-positive ovarian cancer cells also have a harder time repairing themselves. We can target them with PARP inhibitors, drugs that through synthetic lethality target only HRD-positive tumor cells. These inhibitors block the cancer cells’ repair mechanism further, leading to more of them dying.
The cancer that benefits the most from detection of this biomarker is high grade ovarian cancer. Many ovarian cancers are discovered very late, so they often are lethal. Determining the HRD scoring can also be helpful in breast cancer and prostate cancer.
How do you research HRD?
In general, we use only one technology, the OncoScan platform, a whole-genome microarray research solution. On top of that, we developed our own score, which we also validated on retrospective data from a large clinical trial.
OncoScan does not call BRCA mutations, does this hinder your analysis?
We don’t really look at the BRCA genes for our HRD analysis. That’s because when you have BRCA mutations, you also will have HRD. When there is not a BRCA mutation, a patient still could have HRD due to something else happening in the cells.
We can also find BRCA mutations when we use our NGS panel. The BRCA mutation is really the confirmation.
What are the main advantages of microarray-based technology to understand the HRD cytogenetic signature?
What makes this technology really cool is that the lab doesn’t need to amplify or treat FFPE DNA before running the assay. This technology works because it has a probe that links to DNA. You fill in the gap, and then you amplify the probe. If there is low quality DNA, and it’s amplified, you get low quality results. With OncoScan, even with low quality FFPE DNA, if you can bind to the probe’s small footprint, then it’s clean DNA with a clean result.
Quite often when next-generation sequencing was not working for mutation detection, we could get a result with OncoScan, but almost never the other way around. Now we have better representative results with low quality DNA, and it’s also more reliable and better for low tumor content.
You used OncoScan within the scope of a clinical trial. What did you find?
We participated in a European HRD tests evaluation trial where we verified the Geneva HRD method. On a funny note, the validation project was run by sending samples to several laboratories in Europe and each test got nicknamed after its city of origin.
We found, and published last year, that the Geneva method is similar to reference NGS methods in terms of positivity, but the Geneva method has a lower error rate, which allows a 10% increase in samples that receive a conclusive laboratory result.
We have a new paper we’re currently writing with respect to the results we saw in our clinical study on overall survival. In this paper, we report results where the Geneva method has a greater impact on overall survival in treatment of high grade ovarian cancer patients.
What is your hope for this technology in the future?
We are going to continue developing this assay and making our method even better. We have collaborations with researchers in Switzerland to develop version 2.0 that will integrate BRCA mutations and drug resistance mechanisms.
Note to readers:
OncoScanTM is labeled For Research Use Only. Not for Use in Diagnostic Procedures.
The use of OncoScan platform in this research does not imply an endorsement or recommendation of Thermo Fisher Scientific Inc. and its subsidiaries for the utilization of any specific algorithm or methodology with the OncoScan platform for HRD analysis. Thermo Fisher Scientific Inc. and its subsidiaries make no claims regarding the suitability, performance or efficacy of any algorithms or methodologies used in conjunction with the OncoScan platform for HRD analysis. Furthermore, Thermo Fisher Scientific Inc. and its subsidiaries have not conducted any searches or investigations into the existence of any third-party rights which may affect the use of any specific algorithms or methodologies in conjunction with the OncoScan platform for HRD analysis, and users are solely responsible for ensuring that such use is in compliance with applicable laws, regulations and intellectual property rights.