mutations

dennycee said:

Mutations
Hi Boating, welcome to the CSN website. Mutations are related to the cell chromosome and DNA. They can be affected two ways. First, they are set at birth- like red hair, brown eyes, tall or short. You inherit from your parents. The second way is when you are exposed to something after birth, an outside agent causes the DNA in a cell to divide incorrectly and the altered cell reproduces itself over and over.

So far there have been some 200 mutations identified in cells. The mutations are named for the spot it is located on in the chromosomes. Several of these mutations are known factors in lung cancer. A drug is developed that prevents the DNA/chromosomes from communicating that it is time for the cell with the mutation to split and replicate itself. These drugs are called targeted therapies. One of the most common mutations is EGFR or epidermal growth factor receptor, the drug Tarceva was designed to treat it. Other targeted therapy is Xalkori for the ALK mutation and Alimta which I think is for KRAS.

They will use the traditional chemotherapies on your wife instead of the targeted therapy. Generally, that means a platinum drug in combination with one other chemo drug. I had cisplatin and etopiside. I, too, am stage 4. I was diagnosed 22 months ago. At that time I was told I would live 10-15 months at the outside. I am doing very well, thank you, and my quality of life improves weekly, at my last scan my tumors were still shrinking.

One more thing to think about, there are companies that will test your wife's cancer for known mutations (more than the ones an oncologist usually tests for) and a company that will test samples of your wife's cancer with known chemos to see which one destroys it faster.

My knowledge of this stuff is imperfect. There are oncologists that monitor a website called cancergrace.org, check it out, also inspire.com. Hope I was of some help.
Denny

sleepless in jersey said:

Boating
I have copied and pasted this. He is a great source of knowledge as well as all of these 3 sites. Good Luck to you both!
God Bless
Sleepless

I Am A ROS1 Mutation Success!
CraiginPA

By CraiginPA · January 6, 2012 at 2:12 am · 81 replies
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Not KRAS. Not EGFR. Not ALK.

I'm a ROS1 !

Huh? Who? What?

ROS1 is a newly-discovered drug-targetable lung cancer mutation. Lab researchers have known about ROS1 for a few years, but its usefulness in lung cancer wasn’t recognized until recently. It’s very rare (1% to 2% of adenocarcinomas vs. 4% for ALK) so not much was done with it, at least in the lung cancer world. But some wonderful researchers recently discovered that the ALK-targeted drug Xalkori (crizotinib) also seems to work for NSCLC ROS1 mutations! That is really good news for some triple-negative patients!

Those of you who have taken Xalkori know what a blessing it can be -- relatively easy side-effects and effective for about 90% of ALK cancers for a number of months. (About 60% get a shrinkage response and about 30% get stability. The remaining 10% or so that don’t respond either (a) might have had a false-positive test, i.e., they don’t really have ALK, or (b) they already have a drug-resistant variant of ALK, in which case they’ll want to try an experimental 2nd generation drug that is designed for that.)

=== The Research ====

The research that crizotinib seems to work for ROS1 is newly hot off the presses(1)(2), confirming the rumor in the discussion at
http://www.inspire.com/groups/lung-cancer-survivors/discussion/triple-neg-n sclc-xalkori-crizotinib-for-ros1-mutation/ .
That published research describes ROS1 and offers an example of crizotinib working in a ROS1 patient rather astonishingly. Even though it doesn’t provide results for a group of patients, crizotinib-for-ROS1 looks quite promising.

Patient trials began last year and seem to be progressing well, so to me it seems a bit like the progress seen by its predecessor crizotinib-for-ALK trials at an equivalent early stage. Even though it’ll be a long time before crizotinib-for-ROS1 trial data is available in a future published article, I can share this much:

=== My ROS1 Test and Trial Results ===

As some of you know, I have Stage IV incurable eventually-terminal adenocarcinoma (specifically a slow mBAC, or mostly so). Surgery would have left me worse off, so I had to nix that option. And chemo usually doesn’t work well against mBAC either (although sometimes it does). I soon learned I don’t have any of the common mutations either. It was good I didn’t have KRAS, but I also didn’t have either of the known drug-targetable mutations (EGFR and ALK). I was lucky to have a slow-moving cancer, but if nothing worked against it I’d be dead in 2 years, and it wasn’t looking like anything was likely to work.

I wasn’t expecting much when I decided to go to the Harvard-affiliated Massachusetts General Hospital in Boston to be tested for up to 120 mutations by the team behind 'superdoc' Alice Shaw MD PhD. I expected my odds of having a really useful mutation were slim to none, but at least I’d find out the name of my enemy. . . . And that’s when everything changed:

Alice (Dr. Shaw) nailed it on the very first test: A ROS1 (“c-ROS oncogene 1”) mutation (actually a rearrangement) was driving my cancer, a receptor tyrosine kinase mutation so rare that less than 2% of adenocarcinomas have it. I then became one of the first dozen patients in Alice’s crizotinib-for-ROS1 drug trial.

Like some ALK patients have experienced, within 24 to 36 hours of starting the drug my primary symptom vanished. (Instead of a couple of capfuls of fluid spilling out of my lungs when I bent over, it now felt like just a couple of drops and they weren’t going anywhere.) Within a couple of weeks my SpO2 oxygen levels seemed to bump up a couple of points, too (although that varies so much it’s hard to know for sure). Later, my 7th week CT scan showed great improvement (consolidated mass shrinkage and reduced GGO density, even though the overall GGO footprint didn’t improve much).

My response may have been less dramatic than what the patient in the research article had, but crizotinib was a miracle drug for me, too. It’s extending my life and my health feels almost normal. And even though my cancer will develop resistance sooner or later, there’s a good chance that one of the 2nd generation ALK drugs will repeat the miracle for me once more.

I urge all other late-stage adenocarcinoma patients (and maybe some other NSCLC patients) who might have the ROS1 mutation to seek testing for this mutation. And if do you have the ROS1 mutation, please join the crizotinib-for-ROS1 trial, even if you have to travel a long way to it . . . not only for your sake, but for the sake of all future ROS1 patients who have to wait for the FDA to approve it for them after the trials shows many dozens (or hundreds) more successes.

=== Who Has ROS1? ===

So who might have ROS1? As with ALK, the odds of ROS1 might be best for a younger-than-average never-smoker adenocarcinoma that is triple-negative for the more common mutations (not KRAS, not EGFR, not ALK). Based on my own experience, I'd guess there’s a chance that having the BAC subtype of adenocarcinoma might help a little, too. But that doesn’t mean there couldn’t be exceptions. (After all, it might only be that those are the patients the researchers happened to test and found so far.)

It’s adenocarcinomas that have a reasonable chance of ROS1. I’d speculate exceptions might be found in other NSCLC’s (at least), but at this point the odds of ROS1 are so tiny to begin with that it seems unlikely. In any case, though, it can be good to know your cancer’s driving mutation, whatever it is, in case it becomes useful at a later time . . . like my mutation turned out to be.

ROS1 is the driving mutation for less than 2% of adenocarcinomas, but being triple-negative increases your [remaining] chances of having ROS1. And the closer you come to fitting the most common profile of other known ROS1 patients, the more likely you’d have a “fair chance” of having ROS1.

For what it’s worth, there are some other mutations besides KRAS, EGFR, and ALK that are more common than ROS1, but none seem so close to being effectively treated with a targeted drug (and 2nd generation drugs after that). (HER2 might be the next closest – see http://cancergrace.org/lung/2011/03/19/her2-by-m/ ). Again, it can be good to know your cancer’s driving mutation in case it becomes useful at a later time

=== Where’s the Trial? ===

The trial I’m in was expanded from being just for ALK mutations to also accept ROS1 (and MET, a.k.a. c-MET). For some reason this is still a Phase I trial, but patients get the dose amount that prior Phase I work with ALK already established has the best balance of safety and effectiveness. (I expect the Phase II or III versions will eventually be expanded for ROS1, too.)

I copied and pasted this from inspire. I hope this helps a bit. Good Luck to you both.
God Bless
Sleepless
This trial ID is Pfizer NCT00585195 – “A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer.” You can find a description of it here, including eligibility criteria and site locations: http://clinicaltrials.gov/ct2/show/NCT00585195

I believe Dr. Alice Shaw’s team at Massachusetts General Hospital in Boston is leading the ROS1 trial, and according to the trial description there are partners in Aurora, Colorado (U. of Colorado, I think); Orange, California; Chicago, Illinois; 4 cities in Michigan; NYC; East Melbourne, Australia; and Seoul, Korea.

ROS1 is rare and few places other than MGH in Boston (and maybe U of Colorado) are qualified to test ROS1 eligibility for the trial. Based on my experience, I highly recommend MGH for ROS1 testing (and for all other rare or difficult-to-test mutations), and I highly recommend Alice Shaw, MD, PhD in particular as a ‘superdoc’ lung cancer clinical oncologist and top expert in molecular testing and mutation-targeted drug research (and a super nice person, too). She’s the person whose work is saving my life for a while longer. I'd be glad to put you in touch with her if you'd like.

sleepless in jersey said:

Boating
I have copied and pasted this. He is a great source of knowledge as well as all of these 3 sites. Good Luck to you both!
God Bless
Sleepless

I Am A ROS1 Mutation Success!
CraiginPA

By CraiginPA · January 6, 2012 at 2:12 am · 81 replies
Recommend Follow replies Problem
More options
Shared with members

Not KRAS. Not EGFR. Not ALK.

I'm a ROS1 !

Huh? Who? What?

ROS1 is a newly-discovered drug-targetable lung cancer mutation. Lab researchers have known about ROS1 for a few years, but its usefulness in lung cancer wasn’t recognized until recently. It’s very rare (1% to 2% of adenocarcinomas vs. 4% for ALK) so not much was done with it, at least in the lung cancer world. But some wonderful researchers recently discovered that the ALK-targeted drug Xalkori (crizotinib) also seems to work for NSCLC ROS1 mutations! That is really good news for some triple-negative patients!

Those of you who have taken Xalkori know what a blessing it can be -- relatively easy side-effects and effective for about 90% of ALK cancers for a number of months. (About 60% get a shrinkage response and about 30% get stability. The remaining 10% or so that don’t respond either (a) might have had a false-positive test, i.e., they don’t really have ALK, or (b) they already have a drug-resistant variant of ALK, in which case they’ll want to try an experimental 2nd generation drug that is designed for that.)

=== The Research ====

The research that crizotinib seems to work for ROS1 is newly hot off the presses(1)(2), confirming the rumor in the discussion at
http://www.inspire.com/groups/lung-cancer-survivors/discussion/triple-neg-n sclc-xalkori-crizotinib-for-ros1-mutation/ .
That published research describes ROS1 and offers an example of crizotinib working in a ROS1 patient rather astonishingly. Even though it doesn’t provide results for a group of patients, crizotinib-for-ROS1 looks quite promising.

Patient trials began last year and seem to be progressing well, so to me it seems a bit like the progress seen by its predecessor crizotinib-for-ALK trials at an equivalent early stage. Even though it’ll be a long time before crizotinib-for-ROS1 trial data is available in a future published article, I can share this much:

=== My ROS1 Test and Trial Results ===

As some of you know, I have Stage IV incurable eventually-terminal adenocarcinoma (specifically a slow mBAC, or mostly so). Surgery would have left me worse off, so I had to nix that option. And chemo usually doesn’t work well against mBAC either (although sometimes it does). I soon learned I don’t have any of the common mutations either. It was good I didn’t have KRAS, but I also didn’t have either of the known drug-targetable mutations (EGFR and ALK). I was lucky to have a slow-moving cancer, but if nothing worked against it I’d be dead in 2 years, and it wasn’t looking like anything was likely to work.

I wasn’t expecting much when I decided to go to the Harvard-affiliated Massachusetts General Hospital in Boston to be tested for up to 120 mutations by the team behind 'superdoc' Alice Shaw MD PhD. I expected my odds of having a really useful mutation were slim to none, but at least I’d find out the name of my enemy. . . . And that’s when everything changed:

Alice (Dr. Shaw) nailed it on the very first test: A ROS1 (“c-ROS oncogene 1”) mutation (actually a rearrangement) was driving my cancer, a receptor tyrosine kinase mutation so rare that less than 2% of adenocarcinomas have it. I then became one of the first dozen patients in Alice’s crizotinib-for-ROS1 drug trial.

Like some ALK patients have experienced, within 24 to 36 hours of starting the drug my primary symptom vanished. (Instead of a couple of capfuls of fluid spilling out of my lungs when I bent over, it now felt like just a couple of drops and they weren’t going anywhere.) Within a couple of weeks my SpO2 oxygen levels seemed to bump up a couple of points, too (although that varies so much it’s hard to know for sure). Later, my 7th week CT scan showed great improvement (consolidated mass shrinkage and reduced GGO density, even though the overall GGO footprint didn’t improve much).

My response may have been less dramatic than what the patient in the research article had, but crizotinib was a miracle drug for me, too. It’s extending my life and my health feels almost normal. And even though my cancer will develop resistance sooner or later, there’s a good chance that one of the 2nd generation ALK drugs will repeat the miracle for me once more.

I urge all other late-stage adenocarcinoma patients (and maybe some other NSCLC patients) who might have the ROS1 mutation to seek testing for this mutation. And if do you have the ROS1 mutation, please join the crizotinib-for-ROS1 trial, even if you have to travel a long way to it . . . not only for your sake, but for the sake of all future ROS1 patients who have to wait for the FDA to approve it for them after the trials shows many dozens (or hundreds) more successes.

=== Who Has ROS1? ===

So who might have ROS1? As with ALK, the odds of ROS1 might be best for a younger-than-average never-smoker adenocarcinoma that is triple-negative for the more common mutations (not KRAS, not EGFR, not ALK). Based on my own experience, I'd guess there’s a chance that having the BAC subtype of adenocarcinoma might help a little, too. But that doesn’t mean there couldn’t be exceptions. (After all, it might only be that those are the patients the researchers happened to test and found so far.)

It’s adenocarcinomas that have a reasonable chance of ROS1. I’d speculate exceptions might be found in other NSCLC’s (at least), but at this point the odds of ROS1 are so tiny to begin with that it seems unlikely. In any case, though, it can be good to know your cancer’s driving mutation, whatever it is, in case it becomes useful at a later time . . . like my mutation turned out to be.

ROS1 is the driving mutation for less than 2% of adenocarcinomas, but being triple-negative increases your [remaining] chances of having ROS1. And the closer you come to fitting the most common profile of other known ROS1 patients, the more likely you’d have a “fair chance” of having ROS1.

For what it’s worth, there are some other mutations besides KRAS, EGFR, and ALK that are more common than ROS1, but none seem so close to being effectively treated with a targeted drug (and 2nd generation drugs after that). (HER2 might be the next closest – see http://cancergrace.org/lung/2011/03/19/her2-by-m/ ). Again, it can be good to know your cancer’s driving mutation in case it becomes useful at a later time

=== Where’s the Trial? ===

The trial I’m in was expanded from being just for ALK mutations to also accept ROS1 (and MET, a.k.a. c-MET). For some reason this is still a Phase I trial, but patients get the dose amount that prior Phase I work with ALK already established has the best balance of safety and effectiveness. (I expect the Phase II or III versions will eventually be expanded for ROS1, too.)

I copied and pasted this from inspire. I hope this helps a bit. Good Luck to you both.
God Bless
Sleepless
This trial ID is Pfizer NCT00585195 – “A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer.” You can find a description of it here, including eligibility criteria and site locations: http://clinicaltrials.gov/ct2/show/NCT00585195

I believe Dr. Alice Shaw’s team at Massachusetts General Hospital in Boston is leading the ROS1 trial, and according to the trial description there are partners in Aurora, Colorado (U. of Colorado, I think); Orange, California; Chicago, Illinois; 4 cities in Michigan; NYC; East Melbourne, Australia; and Seoul, Korea.

ROS1 is rare and few places other than MGH in Boston (and maybe U of Colorado) are qualified to test ROS1 eligibility for the trial. Based on my experience, I highly recommend MGH for ROS1 testing (and for all other rare or difficult-to-test mutations), and I highly recommend Alice Shaw, MD, PhD in particular as a ‘superdoc’ lung cancer clinical oncologist and top expert in molecular testing and mutation-targeted drug research (and a super nice person, too). She’s the person whose work is saving my life for a while longer. I'd be glad to put you in touch with her if you'd like.