New Technology Eases Information Overload in Precision Medicine

R. Steven Paulson, MD

As the use of precision medicine continues to expand, liquid biopsies are beginning to become more standardized across oncology, says R. Steven Paulson, MD.

"[We need to] focus on the changing nature of oncology," says Paulson. "When I first started [practicing medicine], there were one or two drugs [approved] each year in oncology, and to have any kind of major advance was great but it wasn't that difficult to keep up with. Today, we have drugs that are highly effective for certain mutations and a subset of patients who can be parsed out from the overall group. You can specifically deal with these folks in a much more effective fashion."

In an interview during the 2019 OncLive^® State of the Science Summit™ on Precision Medicine, Paulson, a physician at Texas Oncology, discussed how to adapt to the era of precision medicine, the latest with liquid biopsies, and a unique diagnostic tool with the potential to revolutionize oncology.

OncLive: Could you expand the conversation surrounding tissue biopsy versus liquid biopsy?

Paulson: Technically, tissue biopsy is the gold standard, but there are challenges in regard to tissue specimens. There may not be enough of the original tissue to do a test, so you would have to do an invasive procedure to obtain more tissue.

If the patient is already somewhat unhealthy, that may not be a palatable option for the practicing physician. Therefore, liquid biopsy does two things: first, it gives you the option of a fairly noninvasive test—a blood draw—and allows you to test the blood for circulating tumor DNA (ctDNA). The ctDNA may not reflect the presence of the tumor, but if it is positive, it is usually a reliable test. The challenge is that there is some [disconnect] between different laboratories in terms of reporting the same result.

You can't take a negative result as a reliable outcome, but a positive result that reflects a certain mutation should be reliable as a means for initiating therapy for patients who are quite ill while you wait for the tissue specimens from the hospital.

[Liquid biopsy] gives you a quick, if somewhat dirty, answer that allows you to make a clinical determination. If the test is negative, you haven’t lost anything, you are just waiting on the original tissue to show up—or you're going to have to proceed with an invasive procedure to get more tissue.

Therefore, it is not a question of which test to use, but rather how to incorporate both?

That is the way we have our diagnostic tools set up at Texas Oncology. Essentially, liquid biopsy is the default position and [then we follow up with] tissue testing. If the liquid biopsy is positive, you may be able to act on that to initiate therapy, typically if an EGFR mutation is found.

If the liquid biopsy is negative, then you have to wait for the tissue. You still do the tissue testing because you want to know the full spectrum of variants that are present in the tissue.

You specialize in gastrointestinal malignancies. Do you see a growing role for precision medicine in that space?

Precision medicine in general is being used, not just in lung or GI cancers, but essentially in all malignancies to refine therapy.

I grew up in an era where everything looked like a nail because all you had was a hammer. In the current climate where we have 20 to 25 new targeted agents coming out each year, refining therapy is going to give us more options to profile a patient.

Based on what has happened at the last two ASCO Annual Meetings, we have tumor-agnostic indications for immunotherapy and for target therapy. It's irrational not to broaden the use of molecular testing to better treat our patients either with standard of care or to optimize their ability to participate in clinical trials.

Could you expand on the data from the 2019 ASCO Annual Meeting pertaining to that?

Primarily, the information on microsatellite instability (MSI) and the ability to treat all tumors regardless of their origin [was important]. Pembrolizumab (Keytruda) was the agent in this particular study but generally speaking, it is believed that the immuno-oncology agents can be somewhat interchangeable in that space.

Therefore, if you have a patient with a MSI-high tumor, regardless of the type of cancer, all [agents] should be investigated, especially if they have stage III or IV disease. They should be candidates for molecular testing, and they should be considered for a checkpoint inhibitor or targeted agent that you could specifically treat them with.

What key assays are you using in practice?

There are challenges dealing with the testing because of governmental payers that limit the number of markers that can be done. We use a 50SEQ gene panel that includes, essentially, all but 3 of the actionable genes that you can target at this point in time.

That said, we have relationships with other laboratories that allows us to look for a broad number of genes, upwards of 400 to 500.

Even if there is not a targeted therapy specifically for those genes, the ability to identify them emphasizes what the pharmaceutical companies should look for to develop agents that match those targets, especially if they are common.

The cost of testing is coming down significantly, and it is not the cost of testing that puts off payers. It is the potential for opening “Pandora's box” with non-indicated therapies. For example, a breast cancer that might have a mutation for which there is not an approved drug in breast cancer, but there is a drug that targets that specific marker [in another disease], you have the opportunity put that patient on therapy. This opens a whole difficult decision-making process for payers who are trying to keep the lid on the cost of cancer therapy.

On the physician's side, what are the challenges with uptake of these tests?

The biggest challenge is that there are a lot of physicians who are somewhat long in the tooth, such as myself, who did not grow up in this era looking at variants and specific genetic mutations in the tumor DNA.

We have worked to create a diagnostic pathways tool that allows us to enter the type of tumor and some specific indications about the advanced nature of the disease, and then be able to quickly pull up a listing of all the National Comprehensive Cancer Network-approved tests for that particular diagnosis. The laboratory can then give you the best result and tell you what test to order.

Secondarily, they can tell you what to do with that test result when you get it back, because that is not very clear either. The whole spectrum of targeted therapy is exploding right now, and for a physician who sees a broad range of diseases, there is no way they can possibly keep up with it all. Having a crutch to understand what the result of a test means and how to effectively use it for the patient's best benefit is tremendous.

It also tells you whether or not there are clinical trials the patient could potentially qualify for. Clinical trials are critically important to advance the nature of what we are using.

Is that tool something specific to your institution or is it being used all over?

It is something that our Precision Medicine Program has developed in conjunction with a company called Intervention Insights. It is an electronic, cloud-based tool that allows us to enter the specifics of the diagnosis and then tells us whether or not there is molecular testing should be ordered. It allows our practicing physicians stay abreast of what is going on in precision medicine and how do we best optimize the management of the patient.

Right now, with our Precision Medicine Program, we have created a database that allows us to interrogate and look for rare mutations. For example, the KRAS mutations that were previously thought to be very rare, our database showed we have more than 170 patients with a KRAS mutation. We are trying to make sure the patient remains the center of the universe with regard to treatment, while making sure the standard of care and access to clinical trials is driving our search to find more effective ways to use precision medicine.