Mutations

dennycee said:

The mutations that affect
The mutations that affect the development of lung cancer have not all been identified. There are issues even with known mutations. The most important thing to note is that you can eliminate the use of certain types of chemo that will not work. In the case of mutations that are identified and have a targeted therapy, the drug prohibits the formation of new cancer cells. But mutations continue to mutate and the drug may no longer be effective. Their usefulness can range anywhere from a few weeks to five years. Then there is at least one known mutation for which there is no targeted therapy.

There are no identified mutations for squamous cell nsclc, small cell lung cancer and the other rarer types of lung cancer. The known targetable mutations really only represent a very small percentage of cancers. Some patients present with lung cancers that have features of both small cell and non small cancers. (whatever that means). I hope something here helps. My own understanding of mutations is imperfect so this is more a collection of facts I retained in the course of my own reading.

There are a few people who contribute to the conversations at inspire.com with encyclopedic knowledge about mutations. You may want to visit there and search the site for threads on mutations or post this question there.

dennycee said:

Oh, Sleepless!
You have really grown so much since you joined ACS website. I am so tickled to read your posts here and at cancergrace.org. The body of knowledge you have gained and the experiences you have shared show such growth throughout this horrible disease your mom is fighting. I like reading them because they are authentically you. Trust yourself to answer these questions, too. You are an authority too, you know?

Yes, I was thinking of Craig and Greg when I wrote what I did, but they are not the only ones. When I suggest that someone go to inspire or grace I am hoping that they will learn from you too. I think you have more to share because some of them are coming from a medical background and you come from a place of having only the love of your mom motivating you. You, like me and so many here, were thrust into this with no prior knowledge. We weren't even sure what questions to ask in order to get through to the information we need. Look at you now! My love to you and your mom. I mean it.

Ps: I thought Craig was seeing Dr. Shaw and that she was the one who identified his mutation out of the 200+ she currently tests for.

dennycee said:

Oh, Sleepless!
You have really grown so much since you joined ACS website. I am so tickled to read your posts here and at cancergrace.org. The body of knowledge you have gained and the experiences you have shared show such growth throughout this horrible disease your mom is fighting. I like reading them because they are authentically you. Trust yourself to answer these questions, too. You are an authority too, you know?

Yes, I was thinking of Craig and Greg when I wrote what I did, but they are not the only ones. When I suggest that someone go to inspire or grace I am hoping that they will learn from you too. I think you have more to share because some of them are coming from a medical background and you come from a place of having only the love of your mom motivating you. You, like me and so many here, were thrust into this with no prior knowledge. We weren't even sure what questions to ask in order to get through to the information we need. Look at you now! My love to you and your mom. I mean it.

Ps: I thought Craig was seeing Dr. Shaw and that she was the one who identified his mutation out of the 200+ she currently tests for.

CraiginPA said:

hi, boating - re: mutations
Hi, boating.

Sleeping gave me a heads-up to check your qn over here. I think this is the one.

First, please don’t swamp Dr. Shaw with questions about mutations in general unless you’re thinking of using MGH’s mutation testing services or thinking of getting a 2nd opinion consultation with her (which I highly recommend) or if you are too far away to drive to Boston but need short advice on a specific decision on a subject she’s got unique research expertise in like ROS1, ALK (maybe MET and RET soon). (That’s just my opinion, but I feel she really needs to focus on her patients and her research and save a little time for her husband and kids; she’s not a public free service for the world to overwhelm.) The email address sleepless gave for Dr. Shaw is NOT correct, but I am not comfortable sharing a doctor’s private email address in a public forum. You can either google it (similar but different than sleepless said) or you can private message me via http://inspire.com/CraiginPA if you need it.

Second, sorry that I haven't had the capacity to keep tabs on all the different forums, but even on the main one I use I've had to be inactive for 2-3 weeks due to needing to direct my time to other things (incl. a big Windows7 PC to Windows8+OSX-on-Mac change that will take a few more days to get under control.

Nonetheless, you are getting some pretty good info in other's replies here already, but let me help you put it in a better context.

== Mutations ==

Yes, cancer is caused by mutations. (Semantically, some experts call these molecular rearrangements since DNA gets cut & fused back together in unnatural ways rather than altering specific amino acid pairs in DNA.) Your body adapts to mutations by trying to repair them or kill off those cells, but with cancer it has not been successful.

Most of the mutations a person has don't get dangerous until one occurs which makes the cancer start growing (and stop dying when things get too crowded). A mutation like this that unleashes the cancer tends to be called a "driving mutation." A cancer probably also has a number of supporting mutations and probably a lot of others that won't be noticed which might make the cancer tougher to treat.

If I recall a recent study correctly, never-smoker lung cancer might have on the order of 100 DNA changes (mutations) and a smoker's lung cancer might be more like 1000 (yes, 10x more). Maybe that study was just saying the range of possible mutations is 10x wider (not an individual’s but collectively the possibilities), but either way smokers are more likely to have more mutations and more likely to have one that we don’t have an effective targeted drug for yet, i.e., more likely to have something going on either in the driving mutation or supporting ones which make it more stubborn. But there are a lot of smokers who are lucky and have a simpler kind anyway, and one shouldn’t be too prejudiced either way.

== Useful Mutations ==

So yes, cancer will have a mutation, probably a driving mutation and some others. The big question is whether a cancer has a *useful* driving mutation – one that (1) if stopped, could halt the cancer, and (2) for which there is a drug known to inhibit (block) it.

Researchers are going bonkers right now trying to identify as many mutations as they can, trying to find which ones are driving mutations, and finding drugs for those.

Note: I don’t think there’s any known useful driving mutations in Small Cell lung cancer. That doesn’t mean there are no treatments, it just means there’s nothing targeted to a driving mutation in SCLC. Researchers are still working on it, though. Likewise for other lung cancer where there’s isn’t a useful mutation – it doesn’t mean there’s no treatment worth trying, but just that there isn’t a mutation-targeted drug.


== When Useful to Test? ==

It is not usual to test for driving mutations in early stage cancer. Even into stage III most people are hoping they’ll be very lucky and have a chance of being cured with chemo/radiation/surgery. As long as there’s a chance of cure (complete eradication of the cancer, at least for years), most people will prefer that hard road and go for the cure. In contrast, the inhibitor drugs for driving mutations just inhibit, they don’t cure. (This can be shrinkage, even dramatic shrinkage, or mere inhibition stability, but inhibitor drugs don’t cure, they just control, and only for a number of months, e.g., median of maybe 10 months or so, but sometimes as short as 2-4 months and sometimes [rarely] several years. I’m hoping for a 2nd year from my inhibitor drug.)

If, however, your lung cancer has progressed to the point where it’s incurable (e.g., most but not everyone in Stage IV and some Stage IIIB), it would be well worth testing to find out if you’ve got a useful mutation.

== Useful Mutations: Adenocarcinoma ==

The first lung cancer progress along these lines was in adenocarcinoma:

First, the not-so-useful-yet KRAS mutation. Researchers tried working on KRAS first since it is the most common driving mutation in lung cancer, esp. in smokers (it’s uncommon in never-smokers), but no single drug seemed effective on it (either due to that mutation being difficult or supporting mutations bypassing or blocking the drug). They are still working on it and are finding new angles of attack, but progress has been difficult and there’s only a couple of promising avenues targeted at KRAS right now (promising for a good portion of people with KRAS, not everyone).
Then they found EGFR, the 2nd most common one (and by far the most common one in East Asian never-smokers), and found drugs for it – Tarceva (erlotinib) in the USA and Iressa (gefitinib) in some other countries. These drugs usually (not always) were effective at blocking the cancer for a number of months. Researchers are now making progress on extending that benefit, including 3rd generation EGFR inhibitor drugs and combos.

Next up, was ALK. This is getting rare, like 4% of lung cancer, but a higher % of never-smokers, and the odds of what’s left in a person go up when the more common was have been ruled out by tests. Xalkori (crizotinib) usually (not always) works on ALK-driven lung cancer for a number of months. There are 2nd generation drugs in clinical trials, too, but the usefulness depends on what kind of drug-resistance a person has when Xalkori stops being effective.

Next, there’s ROS1, identified pretty recently. Even rarer than ALK – a 1%-er. ALK and ROS1 are similar in some ways and Xalkori usually also works on ROS1 for a while. Yes, that was a lucky break (especially for me personally, since I have ROS1-driven stage IV lung cancer). Yes, 2nd drugs for ROS1 are in development, too (incl, ALK drugs).

It was a lucky break that Xalkori worked on ALK and then on ROS1 because Xalkori was originally designed (yes, it’s a designer-drug) to be targeted to another driving mutation called MET, but the benefits to ALK (and then ROS1) were more obvious so those uses got fast-tracked.

But that’s not the end of the list of driving mutations that researchers are trying to find drugs for. There’s MET, of course, but also RET, HER2, BRCA, BRAF, and others are being investigated, with experimental drugs offered via clinical trials (if a patient can travel to the few locations offered and meets the eligibility requirements). More mutations, possibly useful ones, are being discovered very year.

In adenocarcinoma the odds of having an identifiable mutation are slightly more than 50%. The odds of a *useful* driving mutation are lower than that, mainly because of KRAS. In smokers, the odds improve if the difficult KRAS mutation can be ruled out first. For a never-smoker adenocarcinoma, the odds a useful one are already 50% or better, and those odds will keep improving.

== Useful Mutations: Squamous ==

What about squamous cell? The concept is the same but the odds of different mutations and the odds of having a useful drug differ. There aren’t big more-than-20%-ers like KRAS and EGFR here and the research isn’t as far along, but researchers are trying and there are clinical trials for some, e.g., applying drugs that have proven effective for the same mutation in a different kind of cancer. It’s premature, though, to put too much faith into most of them until we see more results from clinical trials, but many patients might want to know the name of their enemy so they can be aware of breakthroughs and trials that might apply to them. (That was my situation – I wanted to know my driving mutation even if there wasn’t any drug for it; that led me to MGH in Boston where they not only found my ROS1 mutation but they had a drug trial for it which I’ve been in now for a year.)

Here’s the list of some common squamous ones: FGFR (13-14%? though I saw one mention of 20%), PIK3CA (11-12%?), KRAS (6%?), PDGFR (4-5%?), DDR2 (2-3%?), EGFR (1-2%), NRAS (1-2%?), and more rarely others like ALK, etc.

(Yes, the KRAS and EGFR in that list are the same ones as in adenocarcinoma.)

== Testing for Mutations ==

So yes, I’m a fan of testing for mutations but it depends on the specific type of lung cancer and at some point it testing for rare ones a person’s smoking history can shift the odds enough to make it debatable.

No lab tests today for every possible mutation. But most of the time when a patient thinks they have no mutation it’s just because they haven’t tested for everything known and sometimes their doctor hasn’t even tested for all the useful and very-promising-to-be-useful ones. So it’s important to know exactly what was tested for and exactly the results so you can compare to known useful ones.

In adenocarcinoma, surely test for EGFR and ALK. If those are both negative (also called “wild type”), then test for KRAS to rule that one out so you’d know if it’s worth testing for very rare ones. If all three are negative, then at least in never-smokers I’d recommend testing for ROS1 and then RET and maybe a couple of others that have more experimental targeted drugs. With smokers, some of the useful mutations are rare, e.g., only about 10% of ALK is found in smokers, only about 10% of ROS1 is found in smokers, but if the smoking history wasn’t heavy or was decades ago, I would guess it might be worth a shot testing for them.

In squamous, the list might be shorter – mainly just EGFR unless you’re also interested in ones that are more experimental at this point (like I would if I were in that situation). I don’t think I’d get mutation testing if I had Small Cell lung cancer, but maybe there’ll be an interesting experimental one worth testing there, too, within a year or so. Right now it’d be hard to guess which one, maybe PIK3CA.

Why test sequentially? Usually each test uses up biopsy tissue and you don’t have an unlimited supply of good samples. But since there’s almost always only one driving mutation in a cancer (at least initially), it makes sense to try for those with the greatest odds and usefulness first and stop on the first positive result (if there is one).

== Misleading Test Results ==

Keep in mind that some small % of the time a mutation test result could be wrong for any number of reasons. When you hear that 85%-95% of ALK-positive patients respond to Xalkori, some of the people who don’t benefit might have had a false-positive result. Likewise, I’ve heard of cases of a false-negative. The odds of a reliable result are better if the tissue sample has a high % of cancer cells, the most reliable test is used (e.g., usually a FISH break-apart test), and the lab has a lot of experience striving to be excellent.

Another kind of misleading result is when the given type of mutation does exist, but the cancer is already resistant to the inhibitor drug for it. That is why I suggest that people with EGFR-driven cancer find out which specific variant it is. There are a pretty large number of variants, and some of them are known to be already drug-resistant, for example the T790M variant that account for more drug resistance than any other. Unfortunately, other useful mutations aren’t far enough along to have such testing be routine yet, but it’ll probably be coming.

== CLL mutations ==

Many kinds of cancer are being researched for driving mutations. Some of the experimental drugs for lung cancer mutations first succeeded in another kind of cancer (e.g., drugs for BRCA, HER2, and RET).

One bit of research that might be of interest to you personally is that the EGFR inhibitor drug Iressa (gefitinib) (but not Tarceva [erlotinib]) has been showing some interesting promise for a ZAP70 type of CLL, I assume for a very similar reason. Unfortunately, Iressa isn’t available in the USA, but a Canadian clinical trial for that for CLL with the right “markers” might not be too far for you to want to travel to if you have ZAP70. If you’ve got ZAP70 CLL, you might discuss this research with your oncologist:

in an AACR journal:
http://cancerres.aacrjournals.org/cgi/content/short/72/8_MeetingAbstracts/5232
or the AACR search result:
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=2898&sKey=cd876b09-4b78-478a-a175-d901fcad4a1f&cKey=5145584e-4bbb-4be1-b846-e4e40287a2d0

== Besides Mutations ==

Don’t get too crazy about mutations. It’s a great tool to have in your arsenal if it applies to a person’s cancer, but there are other tools – chemo of various kinds, surgery, radiation, and even new immunotherapy drugs of different types. (If cancer is under control with those conventional treatments, then something like Lucanix could be useful – it’s trial is underway and not taking new patients, but FDA approval might come within a year or so. There’s also an experimental category called anti-PD-1 drugs which look promising by uncloaking cancer so your immune system can find and attack it. And sometimes there are approaches for specific kinds of cancer.

Any qns?

Best hopes,

Craig in PA