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Kasi Highlights Potential Impact of Detecting Resistance Mechanisms With Liquid Biopsies

Danielle Ternyila
Published Online:2:49 PM, Wed May 22, 2019
Pashtoon M. Kasi, MD, MBBS, MS
Pashtoon M. Kasi, MD, MBBS, MS
Liquid biopsies have a number of advantages over tissue biopsies in patients with both gastrointestinal (GI) and other types of cancer, according to Pashtoon M. Kasi, MD, MBBS, MS. Moreover, liquid biopsies can more efficiently detect mechanisms of resistance to certain targeted therapies that can help in determining if a patient should be rechallenged with an agent they previously failed.

In patients with colorectal cancer (CRC), for example, anti-EGFR agents may eventually stop working. RAS mutations can cause resistance to these drugs and can develop over time. RAS mutations would not be seen in the initial tissue biopsy as they are acquired after treatment with agents such as cetuximab (Erbitux) or panitumumab (Vectibix).

Collecting tissue samples again for another tissue biopsy can be difficult as it is time consuming and relatively invasive; however, a liquid biopsy can be used at time of progression on an anti-EGFR drug to determine whether or not a RASmutation has been acquired.

Liquid biopsies can be done in-house or sent out, with results returning within 7 to 10 days. These results can help in determining the next treatment option for a patient. For example, if the patient developed a RASmutation after progression on an anti-EGFR agent, the mutation may decay over time when the drug is stopped, giving the physician the option to rechallenge the patient with another anti-EGFR agent again.

In an interview with Targeted Oncology, Kasi, assistant professor of oncology and senior associate consultant in the Division of Hematology/Oncology at the University of Iowa, Holden Comprehensive Cancer Center, discussed the current role of liquid biopsies in patients with CRC, GI, and other types of cancers. He also highlights the advantages to making treatment decisions based on results from liquid biopsies.

TARGETED ONCOLOGY: What mutations can be identified with liquid biopsy assays?

Kasi: Most of the commercially available assays are not necessarily specific to a particular tumor type, so they are what we call a next-generation sequencing assay. Most of them are panel-based, so they at least have most if not all mutations, aberrations, or fusions that are listed by the NCCN in terms of what you should be testing for when you have a particular patient with any particular diagnosis. The way some of these companies have designed their panels are anywhere between 50 to 75 genes if you add in the deletions or fusions; it’s usually in the ballpark of that range. They haven’t really narrowed it down to 1 or 2 tumor types here; they’ve ended up with a lot of actionable findings as well as meaningful findings. For example, by default, panels have the BRAFV600E, which is important for CRC as well as melanoma. It’s the same BRAFV600E that’s noted in the patients with cholangiocarcinoma or thyroid cancers. Same goes for the RASmutations or, similarly, microsatellite instability (MSI) which some assays are able to detect, which is a biomarker for mismatch repair deficiency (dMMR) and the use of immunotherapy.

TARGETED ONCOLOGY: What would you say is important to know about using a liquid biopsy assay?

Kasi: It’s important to know the assay you are ordering and the disease context in question because if you are just reading off the report, it’s possible that the particular assay may not be capturing what you’re asking for. For example, some of the genes in breast cancer like the ATM gene have large genes. Some of these liquid biopsy assays are not necessarily all inclusive or all comprehensive for that particular gene. It may have the most common mutations and aberrations, but it wouldn’t necessarily have all of them. If you come back with a negative report, it could mean 1 of 2 things: the gene really is not present, or the assay was not even in the capacity or ability to know that.

TARGETED ONCOLOGY: How can these results help inform treatment decisions?

Kasi: Knowing the limitations of the assay can at least help guide the use in a more informed way so that you know which genes or assays you can rely on. For example, in CRC, when we talk about clinically meaningful mutations and aberrations, we need to know which patients have BRAFV600E, both from a prognostic and now from a predictive standpoint, since we know that we have combination regimens and trials for patients with BRAFV600E-positive CRC.

We need to know MSI or dMMR. We need to know RASmutations, not that we have drugs for RASmutations, but because we have drugs that will not work if you have a RASmutation; it’s a negative predictor, where the absence of RASmutations will guide the use of anti-EGFR drugs. Along those lines, what is interesting is when you give an anti-EGFR drug like cetuximab or panitumumab, which are both approved, to these patients who do not have any RASmutations to begin with, such as RASKRASNRAS, or HRAS, the problem is we know that it’s not that these drugs don’t work; it’s that they just stop working. What’s happening with the liquid biopsy is that it is able to capture what transpired. What’s happening in these patients – and it is a subject of publication and debate in many papers that have come forward in the last year or so – is the fact that your cancer acquires new RAS clones. If you’re relying just on the tissue biopsy from before that did not have any RASmutations to begin with, but at progression after an anti-EGFR drug stops working, the patient can acquire RAS. Acquired RASand acquired EGFRmutations can be picked up by the liquid biopsy.

TARGETED ONCOLOGY: Is this seen in cases outside of patients with CRC?

Kasi: In other instances when you use targeted therapy, when you hit these road blocks in the cancer pretty much all around, it acquires these RASmutations or mechanisms of resistance which were not present at the baseline tissue but are present now at progression. The really interesting thing is, which was presented in a poster at ASCO last year by MD Anderson Cancer Center looking at the half-life of these clones, the clones that obviously came around to overcome these drugs as a mechanism of resistance will disappear anywhere between 4 to 7 months when we stop using that drug. In practice, we see this all the time. We have patients that fail a particular therapy, and they’re not on that particular chemotherapy or targeted therapy for 3 to 6 months or perhaps even longer, then we always “recycle” or rechallenge patients with the same drug even though they stopped working a year ago. The rationale behind this is that maybe what transpired is not there, so they can use that drug again.

With liquid biopsy, you can track that. You know that at the time of acquisition of resistance, these mutations happened, but if you know these clones disappeared, you could rechallenge the patient with the same anti-EGFR drug, and there are numerous studies that have presented this and have shown that if on the repeat liquid biopsy whatever clones were gone, the chances of anti-EGFR drug working again is higher as opposed to if you still have RAS clones even though your tissue was negative. At the baseline when you are detecting something, you don’t necessarily have to do the tissue in-house or try to arrange for a tissue biopsy that may or may not be feasible. You can fill that void by getting a liquid biopsy that has results coming back in 7 to 10 days. That’s helpful.

Obviously in these situations where we have these acquired instances of resistance with the rising instance of CRC in young metastatic patients, the median survival now is 3 years at least, if not more. For the patients who are young in their 20s, 30s, and 40s, that could put them on the right end of the curve. To rely on the genetic tests that were conducted on a specimen that is at least 3 to 4 years old or older, you can argue if that really is depicting what’s going on in the patient’s tumor today. Technically speaking, you can’t go around and biopsy the patient’s tissue every so often because it is not practical; it is an invasive procedure. Liquid biopsy could be done easily, and some people argue it could be not necessarily doing a biopsy; it’s just a blood test. That’s where I see its value in terms of being able to apply care safely and reliably in the advanced and metastatic instances of GI cancers.

TARGETED ONCOLOGY: Is there anything else you’d like to add about liquid biopsies?

Kasi: Beyond just the education of liquid biopsy, there are active trials that are ongoing right now formally studying the utility [of liquid biopsy]. Before you rechallenge a patient with a drug that stopped working [the trials are looking] to see if liquid biopsy could be a measure of determining accurately if those mechanisms of resistance are still there or if should you consider something else. That’s something that many abstracts and posters at ASCO, and even before this year’s [meeting], are focusing on. I think the data that will come out will further inform us of the utility of liquid biopsy, how to use it effectively, and what dynamics mean in these patients.

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