Expert Says Next Generation Sequencing Revolutionizing Molecular Diagnostics

Next generation sequencing has drastically changed the lung cancer patient track, allowing healthcare practitioners to create a precise molecular profile for patients.

CancerNetwork^® spoke with Bob T. Li, MD, Memorial Sloan Kettering Cancer Center, about this revolutionary step in the diagnosis of lung cancer that he presented on at the NY Lung Patient Focused Sessions.

CancerNetwork^®: What do you believe is the most important point in the patient track?Li: In the patient track, molecular testing, biomarker testing, is incredibly important. This is going beyond just what the cancer looks like under the microscope in terms of histologic diagnosis. That’s an important first step, but we need to go beyond that to give the patient the right therapy. So next generation sequencing is really the best way to do the molecular diagnostics and get every driver alteration that’s potentially druggable in one go. And there is an evolving list of drivers that we can target. So, this is an important step in the diagnosis of lung cancer that every patient with non-small cell lung cancer needs to have.

In terms of choosing chemotherapy or immunotherapy or targeted therapy, it should be based on the precise molecular profile of the tumors for these patients. Even immunotherapy is now becoming a more precise tool in the treatment of lung cancer.

Liquid biopsy [is another] emerging biomarker tool that’s already helping patients with advanced metastatic small-cell lung cancer in terms of picking up those oncogenic drivers quicker, earlier, and getting them treated earlier as a complement to tissue based next generation sequencing testing.

So, the final message is that getting a tissue biopsy is important, it’s an important first step, but simply knowing you having lung cancer or what type of lung cancer under the microscope is not good enough. We need to go a step further to find out the precise molecular profile of the tumors in order to treat the patient in the most effective way and produce the best possible outcome.

How do you go about explaining all of this to patients in a way that helps them to understand their diagnosis?
Communication is very, very important, especially at that point in the patient’s journey, because that’s when their life is essentially turned upside down. And most of the time it’s very sudden. And so, they’re in a tough situation at that point, and it’s very important for the physician to be compassionate, to have empathy to understand what they’re going through, and to really walk with them through that situation, showing them there’s light at the end of that tunnel. Their life could be turned, flipped backwards, back on track to a normal state and the physician should be dedicated, the practice team should be dedicated, to that cause. Getting patients’ life back on track and then selecting the right treatment, that’s going to help them as a first treatment.

So that explanation I think should start off with that overview in mind. Otherwise, it’s very easy to just get lost in this. They’re already overwhelmed with the diagnosis, their life is upside down, and then if you if you overwhelm them with jargon, they’re going to get so lost and this is just causing extra stress for the particular patient. So, I think it’s important to put that framework into place in the outset.

And then I think the rest could be made with ease. And therefore, all of those tools and technologies should be communicated to the patient in a way that’s helpful to them. It actually should be communicated in a way to relieve their stress, give them hope, and encourage them to fight on with this war on cancer. So, the communication is a very important aspect of diagnosis.

With that, what advice do you give patients looking to do more research on their diagnosis?
I tell my patients first of all, you can read everything, but read everything with a grain of salt and don’t trust anything straight away, and that’s certainly my advice to my patients. In reality, they’re all going to google and some of them really get overwhelmed by google because there’s good information, there’s bad information, there’s true, and there’s a lot of fake information out there as well. And most of the time it’s talking about other people’s illness, not them, so it doesn’t apply. But then they get overwhelmed and they see the statistics, or they see someone else’s cancer, and emotionally it could be very harmful to be stuck with that.

There are a lot of readily available information booklets for patients at cancer centers, so those are the things that I try to help my patients with. Especially at that initial part where they’re so stressed out, the whole family is so stressed out. But the message is that it’s not the end of the world, we can turn this around, and, yes, it’s a terrible diagnosis, but we can fight it, and there’s certainly hope at the end of that tunnel.

Stepping back from patient care, what research is exciting you the most when it comes to lung cancer?
KRAS is the commonest oncogenic mutation in all of cancers, human cancers, the commonest oncogenic driver. And despite close to 40 years of research, we’ve not been able to crack it until very recently. And the research recently, in the last few years, including those done at Memorial-Sloan Kettering in the lab had shown that we are able to trap the KRAS G12C protein in an inactive sleep state instead of the active one. It prefers to go to active state, but when it’s inactive, there’s a little pocket that we can fit a pill in; and we can actually block and trap its state in inactive, therefore switching off the cancer signal and therefore [the KRAS G12C] die. And so, I am the principle investigator of the first in class KRAS G12C inhibitor AMG510 at Memorial Sloan Kettering, and we had shown some very encouraging tumor shrinkages in patients now with this mutation that were heavily pretreated with other drugs. None of them had worked and were no longer working, and suddenly they take this pill and their tumors shrink. This is the very first with certainly not a homerun, but it’s a very giant step forward and this could potentially help many patients, should it be developed further towards regulatory approval. And it could certainly help many patients, because KRAS G12C is looking at about 10-13% of non-small cell lung cancers, that’s a lot of patients. And then there are emerging ways, not only single agent, but in combination with other pathway inhibitors that could really lock the KRAS protein in inactive state permanently and shutting it down. That’s incredibly exciting and I think that’s a near future, potentially a near future breakthrough for patients.