Episode 1: The utility of comprehensive genomic profiling in routine oncology practice - Dr. Beer
Historically the first biomarkers in cancer patients were tested on an individual level by PCR. As we get knowledge of more and more actionable biomarkers, the parallel testing of them via NGS has become an integral part of molecular cancer diagnostics. Also, the size of genomic panels is constantly increasing.
Dr. Philip Beer is a renowned physician, scientist, and precision oncology expert from the UK. In this first episode of your ONCOmmunity podcast, he will share his opinion and experience of this trend.
He will dig into the benefits of running a single comprehensive biomarker test rather than multiple small gene sequencing panel assays and argue why the optimal time to undertake comprehensive biomarker tests on cancer patients along their clinical pathway is at initial diagnosis.
“There are promising uses of liquid biopsy, however, still under investigation in clinical trials. But the use of liquid biopsies is likely to find its way into routine clinical practice within the next couple of years, so is certainly one to watch”, he will conclude with regards to further technologies beyond tissue testing.
0:06 Welcome to ONCOmmunity, the molecular oncology podcast by ONCODNA. In these podcast series, we would like to explore some aspects of molecular diagnostics and genomics in cancer. Therefore, we are happy to welcome the expert Dr. Philip Beer, physician, scientist, and precision oncology expert, live on our telephone line from UK.
Dr. Philip Beer
0:29 It’s great to be here.
0:31 Historically, the first biomarkers in cancer patients were tested on an individual level by PCR. As we gain knowledge of more and more actionable biomarkers, the parallel testing of them via NGS has become an integral part of molecular cancer diagnostics.
Also, the size of gene panels is constantly increasing. Could you illustrate for us your opinion and some of your experience on this trend?
Dr. Philip Beer
0:57 There are a number of reasons why the use of large comprehensive assays is of benefit to patients. Where you have cancers such as lung cancer, where there are a number of different biomarkers that are associated with approved therapies, deploying a single assay that captures all of these biomarkers at the same time can be cheaper. It also saves time. And it also uses the patient’s tissue in a better way.
So one of the problems with performing different tests, a number of different tests, is that the tissue material can be exhausted, particularly in cancers such as lung cancers, where biopsies are often small.
So the deployment of a single assay makes sure that the patients get all the testing that they need, both to inform standard of care therapy, but also to give information about clinical trials that they may be eligible for.
2:04 The use of a single comprehensive assay also allows the inclusion of biomarkers that are less common, things like microsatellite instability or NTRK fusions. NTRK fusions in common solid tumors are really quite rare, being found at around 0.5 percent of cases or even less.
So to deploy a dedicated single assay to find NTRK fusions in patients with solid tumors is not economically viable, whereas such testing can be included as part of a large comprehensive assay without adding significant cost.
2:47 The same goes for microsatellite instability, where in a number of tumor types, the prevalence is only 1 or 2 percent. So again, deploying a dedicated assay to find these patients is not cost effective, whereas any appropriately designed genomic assay can detect microsatellite unstable disease without adding any additional cost to the assay.
Another important biomarker is tumor mutational burden. And there has been a recent drug approval in the US for checkpoint inhibitor therapy for any tumors, regardless of the type, that have a tumor mutation burden above a certain level of 10 mutations per megabase.
3:34 In order to accurately estimate tumor mutation burden, it’s necessary to sequence around 1 megabase of DNA to get good predictions.
So this again is roughly the size of the comprehensive genomic profiling assays that are being used in clinical practice. So this additional biomarker information of tumor mutation burden is essentially provided for free by this approach.
4:01 Could you please elaborate for us when such comprehensive testing is best timed along the clinical pathway?
Dr. Philip Beer
4:08 The optimal time for comprehensive molecular profiling for patients with metastatic cancer is at initial diagnosis. This allows the physician and the patient to have all the information at the beginning of the patient journey to identify biomarkers that are associated with approved therapies, biomarkers associated with therapies that are in the process of being approved and are on the near horizon, and also biomarkers associated with drugs in clinical development.
Having all of this information at diagnosis allows the physician and their patient to plan out their treatment pathway through approved therapies and then looking at the potential to enroll in a clinical trial.
4:57 And in some circumstances, biomarkers may be discovered that are associated with drugs in clinical development that are showing significant promise. And in this situation, the patient might decide that they would like to be enrolled in a clinical trial earlier in their treatment pathway in order to benefit from drugs that look like they may show good efficacy.
The problem we have often in clinical practice is that clinical trials and indeed molecular profiling are only undertaken when the patient has no standard of care therapy options. And at this point in time, it is often too late, too late to find a suitable clinical trial because the patient is no longer so well.
So at diagnosis is the best time to undertake this kind of testing to allow the patient with that physician to have a view of the whole treatment pathway right from the start.
5:58 Those are indeeds and very good arguments how to fine tune cancer therapies and bring treatment decisions on an individual personalized level. Are there particular technologies you would like to mention?
Dr. Philip Beer
6:09 The use of liquid biopsy or analysis of circulating tumor DNA to comprehensively profile tumors is topical at the moment. The use of liquid biopsies has been put forward as an alternative to tumor sequencing. It is less invasive. It is easier to get hold of the sample and often easier to process.
The main drawback of using liquid biopsy at diagnosis is reduced sensitivity. And independent studies have shown that liquid biopsy analysis misses around 30 percent of the mutations that are present in the tumor.
So at initial diagnosis or the first time the patient has a comprehensive genomic profile, then the use of a tissue sample is optimal.
7:06 Where liquid biopsy can be useful is in patients with progressive disease, especially those who have received molecularly targeted therapy, such as an eGFR inhibitor for lung cancer, or hormone-directed therapy, such as in breast cancer or prostate cancer.
And here, analysis of circulating tumor DNA can be useful in detecting genomic alterations that are associated with resistance to targeted therapy. And this information can then help the physician to guide the choice of the next line of therapy.
Because resistance mutations to targeted or hormone-directed therapy arise in a small number of cells in the tumor, i.e. they’re subclonal, then a liquid biopsy is potentially the best assay in order to capture this information, the reason being that the liquid biopsy samples DNA from all the tumor sites throughout the body, including the primary tumor and the metastatic sites.
8:13 Another potentially interesting application of liquid biopsy is in the detection of minimal residual disease, residual cancer in patients who have been treated with surgery for localized disease, such as colorectal and breast cancer.
In this situation, the identification of residual tumor by liquid biopsy can be used to help the physician to choose whether the patient would benefit from adjuvant chemotherapy or not.
This is a promising use of liquid biopsy that is still under investigation in clinical trials and not yet ready for routine clinical practice, but is likely to find its way into routine clinical practice within the next couple of years, so is certainly one to watch.
9:03 Thank you, Dr. Beer, for your insights and explanations. We will look even closer behind the scene of molecular genomics testing in the next episodes of ONCOmmunity, the molecular oncology podcast by ONCODNA.