How Lung Cancer Treatment in Malaysia Has Changed with Technology Like Next Generation Sequencing (NGS)

Professor Dr Pathmanathan Rajadurai, Consultant Pathologist | Dr Matin Mellor Abdullah, Consultant Clinical Oncologist

For too long, lung cancer has been burdened by its reputation of poor survival and outcomes for patients. But the treatment of lung cancer has come a long way since the days when only surgery, radiotherapy or chemotherapy was available.

There are now advancements in diagnostic and treatment methods which can save more lives than ever. We speak to SJMC’s Professor Dr Pathmanathan Rajadurai, Consultant Pathologist, and Dr Matin Mellor Abdullah, Consultant Clinical Oncologist about game-changers in lung cancer treatment and how to ensure patients are able to access them.

Q: Smoking has long been linked to the main cause of lung cancer, but who else is at risk today of lung cancer?

Dr Matin Mellor:

Smoking remains, by far the most common cause of lung cancer, but there are other causes like second-hand smoking for example, which is becoming more prevalent as well. Gas exposures in certain mining activities and industries, in fact causes more lung cancer in those who are exposed. There is also genetic susceptibility and also those patients who have scars in their lungs owing to previous infections like tuberculosis, they are also at a slightly increased risk of lung cancer. But I stress again, smoking is still by far the most common cause of lung cancer.

Q: What are some early and late signs of lung cancer?

Dr Matin Mellor:

The signs and symptoms of lung cancer unfortunately cannot be differentiated between early and late stage. By the time they are symptomatic, a lot of the symptoms may indicate advanced lung cancer. Some of the symptoms that may indicate lung cancer include cough that doesn’t go away or gets worse over time, this thing called haemoptysis where one coughs up blood in their phlegm, chest pain, discomfort, difficulty in breathing, wheezing, hoarseness of voice, lost of appetite, weight loss, these are symptoms which are by no means specific to lung cancer. And they are usually not the early signs.

Q: Could you describe to us what’s actually happening in the lung cells of someone who has cancer? How are the cancer cells taking over our lungs? 

Professor Dr Pathmanathan:

Most lung cancers occur because of what we term as driver mutations. These are genetic events that occur very early on, and these mutations are what propels the cancer cells to grow, to become much more aggressive, to invade the tissue around the neighbouring normal lung. They acquire as they grow additional mutations, which gives them a survival advantage, the ability to get it to the blood stream and go to other parts of the body. We are now at a point where we understand that although we talk about lung cancer as a general disease, everybody’s lung cancer is different. Lung cancers at the molecular level are different and are distinguished by unique genetic mutations that propel that cancer to grow, to proliferate, to invade, and to metastasise (spread to other parts of the body). Some of the agents that can cause these mutations are things like smoking, radiation, environmental pollutants, asbestos and so on. There is probably a very small subset of patients who are at genetic risk of lung cancer, but these are a very small percentage.

Q: How does knowing that every person’s lung cancer is different genetically help doctors like you or Dr Matin in treating a patient?

Professor Dr Pathmanathan:

The typical process is that a person who is symptomatic will go and get an examination and if lung cancer is suspected, they will have a biopsy where a bit of tissue is removed from the tumour and analysed by a pathologist like myself. We would first of all confirm that it’s cancer, we will then confirm that it’s a cancer that is originating in the lung, and we would want to be sure it’s a type of tumour that is called a non-small cell lung cancer.

Because these 2 large groups, the small cells and the non-small cells are different. And it’s critical that we make that distinction because non-small cell lung cancers are the ones that we now believe are driven by the mutations where we have drugs readily available.

The story is unfolding for small cell carcinomas or small cell lung cancers as well, but it’s not as far advanced and there are still clinical trials that are on-going. So, once we have made the diagnosis that this is a non-small cell lung cancer, the next step would be to identify which are the specific mutations that are responsible for propelling the cancer and so on. Because if we can identify that mutation, if there is a drug that is readily available that exquisitely targets that mutation, then that is a realisation of precision medicine or targeted therapy.

Q: What are the challenges you are facing in getting people with potential early-stage lung cancer to getting themselves diagnosed?

Dr Matin Mellor:

Dr Pathmanathan has alluded to the steps involved when somebody comes with symptoms suspecting of lung cancer. The steps involved would be to do scans, identify the presence of the abnormality, do a biopsy of the abnormality to confirm the diagnosis of lung cancer. Part of the clinical workup also involves staging the disease, basically a scan of the whole body to see where it has spread—whether it has spread within the lung, or to the other lung, or to other parts of the body. Based on the scans, we are able to establish what stage the cancer is at, and whether we are able to offer treatment that is curative.

The biopsy is vital to make a diagnosis in lung cancer, there are 3 levels of identification: 1. Identify the presence of lung cancer, 2. Make sure the disease that is found in the lung arise from the lung cells, 3. Identify what is driving that cancer using molecular profiling. Then only we can decide what treatment is appropriate for the individual.

Q: How many people with early lung cancer symptoms are not being picked up?

Dr Matin Mellor:

With lung cancer, there are a lot of data that suggest that by the time the patient presents themselves at the clinical level, majority of them are at an advanced stage. Unfortunately for lung cancer, there aren’t any screening programs that are widely available.

There have been many clinical trials that look at different screening and tests to see if that would impact the diagnosis, staging and outcome when treated. It has been shown more recently that with targeted CT scan screening of individuals at high risk of developing lung cancer (i.e., the smokers), that we may be able to pick up the disease early enough that when treated, you can achieve a chance of cure.

In the absence of this screening program, by and large the early lung cancer that are being picked up are usually picked up incidentally when the patients are being investigated for something else or during medical check-ups. In that situation, we may find something in the lung that potentially may be curative as they are presented at an early stage without symptoms.

Q: So there are no screenings like mammograms for breast cancer or Pap smears for cervical cancer?

Dr Matin Mellor:

Unfortunately, there is nothing like that.

Q: So how to we change the trend of people coming in with lung cancer at later stages?

Dr Matin Mellor:

I think for the groups who are working in high-risk environments, the awareness should be high. Those who are smoking, they should also be aware that they are high-risk at developing lung cancer and those are the groups that should potentially go for screening as indicated. For the rest of us who don’t smoke, then going for a lung cancer screening doesn’t make sense at all.

Q: Does the technology called Next Generation Sequencing (NGS) help to identify specific mutations in individuals?

Professor Dr Pathmanathan:

Next Generation Sequencing is a technology that looks at genetic mutations. Theoretically hundreds, maybe even thousands of different molecular aberrations in a cell and technically in a cancer cell. It’s a sophisticated technology and there are many different platforms out there. Depending on the platform you use, what we are trying to do is to determine the presence of driver mutations. Since we are talking about lung cancer, we are trying to detect unique driver mutations which are targetable, which means that there are drugs available that can specifically target cancer cells that carry that mutation. Again, depending on the size of the panel, you can cast a very wide net to pick up all the important molecular mutations that have been described thus far for lung cancer.

Q: Has all the possible mutations linked to lung cancer been identified?

Professor Dr Pathmanathan:

I don’t think so. More and more are being discovered every day. And there is probably about 35% of lung cancers where still we do not know what the driver mutations are. Certainly, for squamous cell carcinomas, the presence of driver mutations is even less than adeno carcinomas. Within the non-small cell groups there are these 2 different subgroups, the squamous and the adeno. Squamous being more common in smokers, adeno less often associated with smoking. Adeno carcinomas tend to be bio-marker rich, and therefore the focus has been to try as far as possible to pick up the driver mutations that are present in non-small cell lung cancer of the adeno type.

Even then, half, or slightly more than half of the driver mutations are detected. The caveat is that you must use a technology that is capable of picking up all the important driver mutations. And there are panels out there that look at maybe 20 gene mutations, others look at 50, or some far more. So, how wide a net you cast is going to have some implication to what your success rate at picking up genetic mutations are.

Q: Why wouldn’t it be standard that you cast a wide as net as possible?

Professor Dr Pathmanathan:

Different technologies have different systems and not all the sytems are equal. Some are capable of picking up more mutations that others, some are more sensitive than others. Especially for lung cancer, because the disease progress happens quickly, it’s important that we have a platform to detect these driver mutations in the shortest possible of time so that we can start targeted therapy as soon as possible. Larger panels takes a longer time to complete as opposed to smaller panels.

Q: How does this information lead to precision treatment for a patient?

Dr Matin Mellor:

As far as treatment is concerned, they are molecular driven. With someone recently diagnosed with lung cancer, typical steps would be to diagnose lung cancer, confirm it’s from the lungs and with the NGS, establish what are the driver mutations that are present in that individual’s cancer.

If the driver mutation is present, there are specific targeted therapy that’s prescribed for that particular driver mutation and they are treated based on that.

But we have to remember that although targeted therapy has improved overall survival, there are a significant number of patients who do not have driver mutations identified. In such patients, the choice of treatment still remains the standard chemotherapy, that has been the standard for the last 30 years. Generally, the outcomes for such patients are not as good as those in whom a driver mutation has been identified.

There are enough clinical studies now to show that individuals with lung cancer with the presence of a driver mutation and receive the targeted therapy specific to that driver mutation generally do much better than those who do not. Overall survival has been shown to be much better in individuals who receive the appropriate treatment.

Q: Are researchers working on identifying more driver mutations?

Professor Dr Pathmanathan:

Yes, and not only that. We are discovering mutations that drive the tumour forward, and NGS has enabled us to discover mutations that adversely affect your therapies. So, you may for example have a driver mutation and you have a drug that targets that driver mutation, but now we are finding that there are other mutations within this patient’s tumour, which mitigate that effort to have a successful therapeutic response.

They are adverse predictive markers. Patients who harbour these adverse mutations do not do as well as those who don’t have these additional mutations. That is also an important part of the whole equation. Not only do you want to find driver mutations, but you also want to be able to identify mutations which may not give you a good therapeutic response as you would expect.

The second point is, as these new driver mutations are detected, more and more drugs are coming into the market. Newer companies are coming out and we’ve seen first generation therapies and there are now second and third generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI) and so on.

But cancer cells are clever, they become resistant and NGS is useful because we are now able to deploy this powerful technology to pick up resistance mutations. So that is the challenge and also the promise of how we handle this constantly evolving tumour that is finding ways to survive.

Q: Dr Matin, so what exactly does targeted therapy look like then? And Professor Pathmanathan talked about first line, second line, how different are these from chemotherapy?

Dr Matin Mellor:

Targeted therapy for driver mutations are more specific so much so the drugs are being described as designer drugs. You design a drug to target a particular mutation. Chemotherapy on the other hand is described as like carpet bombing—nonspecific, you hope that the chemotherapy would have acted on the cancer cells which are dividing rapidly.

Because of the way it works, chemotherapy has much more side effects and many people are fearful of chemotherapy and the side effects that they produce. Targeted therapy on the other hand is more targeted and because it’s designed to attack a particular driver mutation, the side effects of these drugs tend to be slightly different from chemotherapy, but on the whole the side effects are generally milder compared to chemotherapy. And most patients, if they respond, can remain on this drug for years. Thus, indicating that the degree of side effects they may experience is tolerable and doesn’t affect their quality of life as much.

Q: Earlier you mentioned the word “curative”. Do you mean that the cancer can be cured and the patient will be cancer free?

Dr Matin Mellor:

Cure in lung cancer is difficult. For us we only talk about cure for patients if they are operable. So, stage 1 and 2 lung cancers are potentially curable because they can undergo surgery that can potentially remove all the known disease sites. However, even those who have undergone curative surgery, the relapse rate for such individuals is quite high. As much as 40% - 50% in patients who have the disease who are operable.

In the past, those patients who are operated on who had complete recession of the tumour still undergo chemotherapy because there had been a big study which studied two groups with operable cancer, one which received chemotherapy and one which didn’t receive chemotherapy--those who did chemotherapy do very slightly better than those who did not receive chemotherapy. And this study was done before the era of targeted therapy.

The presence of targeted therapy and molecular precision medicine has complicated this a little bit. Now, for those who have undergone curative surgery, their specimen is still sent for molecular profiling to see whether there are any molecular drivers for their cancers. In groups of patients who have molecular drivers for their cancers, they would also receive the targeted therapy in an adjuvant setting and there are also enough studies to show that those who receive adjuvant therapy do better than those who do not do adjuvant therapy. So that is how things have changed over the years.

Q: When you say “do better”, are we talking about survival?

Dr Matin Mellor:

Basically, we “do better” at 2 levels. The first level is the rate of relapse—When they relapse? Do they relapse? If they do relapse, what is the timeframe in which they relapse? So, on both counts, those who receive targeted therapy on whom they are operated, if they do relapse, they relapse much later and the overall survival is also better compared to those who did not.

In that sense, when we talk about cure with “lung cancer”, if the disease does not come back within the next 5-years, generally one would say the disease would not come back. But, one has to be mindful when talking about this because some causes of the lung cancer, especially for those who smoke, if they continue to smoke their outcomes will also not be as good because they can develop second cancers and so on.

Q: How does liquid biopsy fit into the picture of what we are discussing today?

Professor Dr Pathmanathan:

I believe in some situations it is going to be a game-changer. The technique requires that you take the patient’s blood, extract the DNA and that DNA will contain the patient’s DNA which is normal and also a bit from the tumour cells. We have technology in place that with fragments of circulating tumour DNA (cell-free DNA), we are now able to retrieve that even though in miniscule amounts and in the laboratory, make a number of copies of that DNA so there is a significant amount for us to analyse it. This is what we mean by liquid biopsy.

Where tissue biopsy requires you pass a needle into the tumour and take it out for analysis, here what we are doing is in situations where the patient is too sick, it’s hazardous to do a biopsy or maybe the tumour is in a site that is difficult to do biopsy, then what we could do is take the patient’s blood, extract the circulating tumour DNA and subject that to analysis.

NGS can be used for this, and the same kind of driver mutations can be investigated for. And if present, liquid biopsy has a high degree of specificity. That means if you find it, it’s real, it’s true; you can start treating the patient. However, the sensitivity level is still not as close as that of tissue biopsy. So, if it’s about about 85-90% in the best of hands, there is chance you will get a false negative result. It means that it may be there in the tumour but for some reason, it’s not appearing in the blood. If you don’t find it in the blood and you are really intent of chasing this to the limits then under those circumstances, a tissue biopsy will be mandated because we really don’t want to miss a driver mutation that may be life-changing for the patient.

Q: But this is something we are looking at only in the future?

Professor Dr Pathmanathan:

No, we have been doing this for the past couple of years and we are offering it as a routine diagnostic service. But we use it judiciously, because tissue is always still the gold standard; and liquid biopsy is in these special circumstances where you are for some health reason unable to get a tissue biopsy.

Liquid biopsy holds great promise for the future because there is nothing better than to take a patient’s blood and then see whether they actually have lung cancer developing very early on. So it may come a that point where we can use it as a screening test. It’s not there yet but it may be possible in the future because I can see how the technology is evolving.

I’ve already talked about how it may be used for diagnosis, the other way it’s being used is monitoring. After we detect a driver mutation and the disease goes away, we can periodically test the patient’s blood to see if the tumour is coming back. Because if it is, even small quantities of tumour cells may shed the DNA and this facilitates early detection of recurrence. So that makes it a monitoring tool. NGS is powerful enough to detect even resistance tones that may be emerging, allowing us to opportunity to intervene early.

I think this is an evolving technology and soon it will get into the good practice guidelines and therefore provide some kind of criteria for us to fall back on and deploy this technology.

Q: What happens if patients can’t afford the costs of these technology?

Dr Matin Mellor: 

All these cutting-edge technology treatment does come at a fairly high cost and that’s why the setting in which most of these treatments are available is mainly in the private setting. It would be very good if this could be available in the public sector setting. And that’s one of the reasons why with regards to the outcome as a nation, our outcome is not likely to be different over the next couple of years, because all these cutting edge technology and the treatment itself is not available to the masses.

It is available in the public sector but only in a limited area. With regards to the cancer centres in the country, many parts of the country are still not covered by any cancer centres that are able to treat them in a comprehensive fashion. Unfortunately, that is the current situation we are in.

That being said, the pharmaceutical companies are trying to bring down the cost. NGS as well, there is a collaboration between our lab and the pharmaceutical companies making NGS more affordable. But when we talk about being more affordable, it’s not at the level of a few hundred ringgit, but a few thousand ringgit.

With regards to the targeted therapy, they are also very costly. Pharmaceutical companies are providing some sort of patient support program. But having said that, they do come at a high price unfortunately.

Q: Does it cost a few thousand ringgit just for NGS testing?

Professor Dr Pathmanathan:

Well, when we first deploying this technology, offering it as a service, the cost was somewhere near RM8,000 – RM10,000 depending on which centre was doing it. This is unrealistic. And so, we decided that because the technology is so powerful and at the moment beyond the reach of most lung cancer patients, something must be done to make it more affordable. And so, this was an initiative that we started in our healthcare facility, basically partnering with pharma and with instrument vendors and trying to get a buy-in from them so that everybody contributes, and we are able to offer the technology at a cost that would not break the bank for most patients.

So, we brought the cost down from RM8,000 to RM2,000. And that was the sponsored price we basically offered to qualified patients, these are patients who are newly diagnosed with lung cancer. Moving forward, we’ve done at least 3 iterations of this program, each of them more successful than the previous. We are at that point in re-strategizing as to how we can drop that RM2,000 price point further. This would be we recruit more pharma partners, because as more driver mutations as discovered, this is another opportunity for them to provide drugs to patients who are qualified.

This is an on-going effort, and we hope to be able to bring the cost down. I am quite confident to say that no where in the world has this kind of initiative being replicated. Partly because there are many legislations that are in place in other countries which prohibit pharma participation because they feel there is vested interest. In Malaysia I think we are fortunate that the greater good has prevailed, that more patients will benefit through public, private, pharma & industry partnership, a smart partnership where everybody wins.

This how we have been able to offer the technology at 20% of the cost.

Q: Does insurance cover the diagnosis?

Professor Dr Pathmanathan:

At least one insurance company has come forward to say that they will support precision medicine testing, which means Next Generation Sequencing (NGS) provided is it recommended for by the oncologist and he feels that it is the necessary way forward for the patient to have the best standard of care.

Dr Matin Mellor:

That remains an on-going discussion, because the pharmaceutical companies may have got some leverage in the discussion with insurance companies to get them to sponsor the testing. As far as treatment is concerned, it’s much more precise and hopefully will bring bigger benefit to the patient without unnecessarily giving treatment that may not benefit the patient. I think the insurance companies are realising that and Dr Pathmanathan talked about one company, but I know of a few others who if you lobby them hard enough at the individual patient level, might cover the cost of the NGS.

Q: What is your final message on what all of us need to look out for when it comes to early detection of lung cancer?

Professor Dr Pathmanathan:

For me early detection would mean having a good enough biomarker test, a liquid biopsy test that could help us discover the lung at the time of its genesis. At the moment it is still high in the sky and there is a lot of activity going on, but I’m sure we will close that gap sometime in the future. Dr Matin has already talked about imaging, self-awareness, periodic check-ups, looking at susceptible populations and having them subjected to maybe low-dose CTs. These technologies are still being tested in the real world.

We spent a lot of time talking about Next Generation Sequencing (NGS) and looking at driver mutations, but we also have to understand there is an explosion of knowledge on immunotherapy. For patients who do not have driver mutations, immunotherapy is a promising avenue for these patients who do not have driver mutations and who have a biomarker called PD-L1 for example that is expressed from the surface of the cells. We have good studies that show that if tumour cells express these proteins at a high enough level, more than 50%, some of them are disease free for up to 5 years. So that is good information to have, so if you don’t have a driver mutation, all is not lost. Science is evolving and there are therapies that are looming in the horizon.

Dr Matin Mellor:

I think it remains challenging to get an early diagnosis in lung cancer as majority at a much later stage and there are no specific signs and symptoms indicating the presence of lung cancer. I’ve alluded to the fact that most of the screening studies that looked at patients to detect early lung cancer had failed except for the low-dose CT scan in individuals who are smokers and are at higher risk of developing lung cancer. I suppose at this point in time that remains the subgroup that one needs to be concentrating on because there are good clinical data available in those group of patients where you screen them, you pick it up early, you treat them early, you can achieve a higher cure rate in them as opposed to when they present symptomatically. But I suppose all is not lost, we know that the advancement in treatment comes at all stages of the disease. We know that with early-stage disease, even if the patients are not able to undergo surgery, there are other forms of treatment available, for example what is called stereotactic radiosurgery (SRS) can be done for patients who have complications from the lung. With regards to surgery itself, there is also robotic surgery & keyhole surgery which is more acceptable and has less complications.

In those who are advanced, we talk about targeted therapy. But a significant number of patients who do not have driver mutations are given chemotherapy as a standard of care. However, there are now advances in which the chemotherapy is combined with immunotherapy, where the overall survival is improved for patients who do not have driver mutations.

For those who have high PD-L1, there was a study and the 5 years survival rate of those who received immunotherapy vs those who did not in patients with high PD-L1, the survival rate is higher for those who did receive immunotherapy. Basically, for patients with lung cancer, there are many things we can do. But lung cancer remains a very challenging disease to treat and if you are not able to institute curative surgery, the disease can still cut short an individual’s life. If they can stop smoking, it will be very good.