Biomarkers for Guiding Treatment in NSCLC: Liquid Biopsy Versus Tissue-Based Testing

A comprehensive discussion on the value and limitations of tissue-based versus liquid-based biomarker testing in non–small cell lung cancer.


Tony S.K. Mok, MD: Since we’re on liquid biopsy, Tetsuya, can you comment on what is the difference, or what are the pitfalls of using liquid instead of tissue in some circumstances? What are the things to watch out for when you choose between the liquid vs tissue?

Tetsuya Mitsudomi, MD, PhD: I think that, in general, the liquid biopsy is testing for the DNA that is released into the bloodstream, so the amount of the DNA in general compared to the tissue. Sometimes the sensitivity is a problem. But the specificity is now very good. Sometimes if the tumor burden is not enough, then the blood testing will give you negative results. So that’s 1 thing. Also, in the case of the ctDNA [circulating tumor DNA] analysis you will understand the whole picture of the heterogeneity of the body so that you can get the information of the origin. Some of the origin status of the body, so that’s a good thing. Of course, the invasiveness is less compared to the tissue biopsy, so you can repeat the biopsy several times. You can know the change of the of the gene status responding to the drug treatment, so that would be very convenient. As a surgeon, I’m very interested in MRD [minimal residual disease] detection using liquid biopsy, so there’s some benefits and some disadvantages in liquid biopsy.

Tony S.K. Mok, MD: How good is liquid biopsy for detection of the translocations? mRNA [messenger RNA] is supposed to be more sensitive, but most of the commercial platform available are actually DNA-based. Are they good enough to detect the translocations?

Tetsuya Mitsudomi, MD, PhD: I don’t have the personal experience, but I can guess the RNA in the blood would be unstable. So maybe some fusion may be missed.

Myung-Ju Ahn, MD: In our experience with that, the comparison with tissue and [INAUDIBLE] to detect their fusion, the sensitivity is around 70%. The liquid biopsy sometimes miss their fusion.

Tony S.K. Mok, MD: I agree with you. Once it’s positive, the specificity is very high. The B-FAST data that we published on the plasma positive ALK and they got very high response rate to [INAUDIBLE] as well. So I think, in a way, that we may be losing some sensitivity, but we are actually having reasonable specificity.

Tetsuya Mitsudomi, MD, PhD: In a sense, I think that the liquid and tissue biopsies have complementary roles. One is not perfect or better, but if you do them both, then you’ll have more information.

Yi-Long Wu, MD, PhD: I have 1 question for [INAUDIBLE]. If 1 patient’s pathology, the tissue, is very difficult to get, but the median shows this is lung cancer, in this stage, we’re only getting the biomarker for [INAUDIBLE]. That’s all the EGFR mutation patient but know the pathology. So in this situation, how to treat a patient?

Tony S.K. Mok, MD: You’re asking a very important question. Can we use liquid biopsy to replace the histological diagnosis? Excellent point. Let me just hear from your colleague from Shanghai first. Will you allow that to happen?

Shun Lu, MD, PhD: I would not treat these patients. Although I suspect that this is a lung cancer, but with no pathology diagnosis for lung cancer, I would not treat this kind of patient.

Tony S.K. Mok, MD: What if the patient is not physically fit for the biopsy? It’s not that they don’t want to, but that they cannot. Would you make an exception for that case?

Shun Lu, MD, PhD: Maybe if the patient has a very small nodule or something like that. This is the early stage. This is the baby for the SBRT [stereotactic body radiation therapy]. I would not exactly be using the systemic treatment for this kind of patient, if the patient had no pathologic diagnosis for lung cancer. Even with cancer with EGFR built in the patient, I would not do it.

Tony S.K. Mok, MD: One of your colleagues in Beijing is actually trying to do a paper to see whether liquid biopsy can replace histological diagnosis. You should talk to your colleague in Beijing about this.

Shun Lu, MD, PhD: But I also know some paper that it’s a benign disease. Something like the EGFR built in, especially some germline EGFR-mutant patients. We will also publish some papers, some cases. So if the germline is the EGFR-mutant, but you see that this is not lung cancer, we will not repeat this.

Tony S.K. Mok, MD: Let’s see, Korea. Would that ethically [be] acceptable to use a liquid biopsy to replace histology in patients who were not suitable for biopsy?

Myung-Ju Ahn, MD: I don’t think so. The pathologist will be very angry about that. I’m not sure how many patients are not eligible for the biopsy. Even though there is a small nodule, we try to get enough tissue even just for the pathology diagnosis. You know that without the treatment, just like that, so I think the tissue is very important.

Tony S.K. Mok, MD: How about if I push you a bit harder? What if I got a circulating tumor cell [CTC]? Would that be good enough? Would that be sufficient, if I got a circulating tumor cell and also plasma positive EGFR. Would that be sufficient?

Myung-Ju Ahn, MD: Well that’s very interesting, but I think we have to consider when I see the patient, and [INAUDIBLE] is really compatible with the lung cancer and then ctDNA, or the CTC show the EGFR mutation. Maybe I can. It’s imaginable.

Tony S.K. Mok, MD: Last but not least, in Japan. Would that be ethically—you guys have lot of guidelines. I’m sure that you are not allowed for histology, right?

Tetsuya Mitsudomi, MD, PhD: Yeah. Personally, I think that I think a bit different way. The more flexible person, I am. These days, the imaging study is very nice. You can be very sure that this can be the lung cancer by the imaging study only. Then you have the EGFR mutation in your patient blood. So I’m happy to use the easier TKI [tyrosine kinase inhibitor], especially when the patient is symptomatic. Also, if I were a patient and my blood test was positive for the EGFR mutation 19, I don’t want to have a biopsy. So it’s sometimes very invasive. It may take some time and I want to start my therapy as quick as possible. I think that these days that kind of the approach will be allowed.

Tony S.K. Mok, MD: Well, honestly, I agree with all of you that in principle, we should not. But in my practice, I’ve done it maybe twice. Seldom before, but in very special circumstances I’ve done it. You have to put a human touch to the situation.

Transcript edited for clarity.

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