CSCO 2024 | 极往知来——生物标志物检测如何助力肺癌精准诊疗

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Dr Tony Mok: This is an important question. The development of lung cancer therapy over the last twenty years is revolutionary, and it is because of biomarkers making it assessable for us to select the right drug for the patient. We start off with the story of the EGFR mutation that we all know and that we all test for now in patients with adenocarcinoma. That changed the paradigm. In addition to that, with the availability of an ALK inhibitor since 2014, we now also test for ALK. The number of genes we are testing for upfront is increasing. Apart from those, we now have a total of around ten different genetic abnormalities that we test for. Most of this already have some first-line information, even for uncommon mutations, like RET. We now have first-line data demonstrating improvement. We also have EGFR exon 20, an uncommon mutation, but then first-line chemotherapy and amivantamab is actually very useful. I think it has become standard practice that we do a whole panel including the ten or eleven genes so we can identify the patient from the beginning.

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Dr Tony Mok: It has been proven to be successful with the genomic-based biomarkers, because the drug is targeting the abnormal gene and its product. But a future platform is actually lies beyond molecular genomics. With ADCs, we obviously need to look at the proteins, and how we do the calculation of proteins is important. But the next thing is that we also have other platforms, including cancer vaccines, CAR T-cells or other cell therapies, all of which utilize the immune system. That becomes a lot more complex, because different immune systems interact with each other as well as interacting with normal cells. How do we differentiate between this interaction of the immune system with the cancer cells versus the immune system with normal cells is very difficult. But I think we can start with one basic concept, which is HLA typing. HLA typing is actually the most basic presentation of the antigen to the T-cell. There is different HLA typing between one race versus another race - the answers are totally different - so we need to learn a little bit more, at least about this basic HLA typing and its relationship to immune-related therapy.

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Dr Tony Mok: The question is quite broad, covering treatment and diagnosis. Maybe I will speak about early detection first. As you probably know, early detection is important because curative surgery has to be done in early stage disease. Most lung cancer patients present at a later stage when surgical resection is not possible. We have established a low-dose CT scan as one of the most effective tools for the early detection of lung cancer. However, this tool is still quite expensive, and requires large equipment to perform, so I think we have to correlate use of this potential tool with plasma-based biomarkers. One possibility is using a plasma-based DNA genomic test for early detection. Previously, there has been a similar test available, but sensitivity is not high. For the future, there is novel technology called fragmentomics, which looks at fragments of DNA from which we can calculate the methylation. This technology has been demonstrated in a number of early studies to be promising with a higher sensitivity for the detection of early stage lung cancer. In the future, how we use the low-dose CT scan and fragmentomics together will be one interesting development. That is for early detection. Then, for prognosis, personally, I would say that there are so many prognostic factors and so many genes can be prognostic, but it doesn’t really help our clinical management as much. A prognostic gene does not necessarily mean it is predictive. So to me, a clinically relevant biomarker should be a predictive one, just like the genomic biomarkers I have mentioned, plus some of the immune biomarkers that we have actually been using.