mutations

boating

Could someone please help undestand mutations. Our onc tells this my wife is unmutated their are limited, if any, drugs that will help her Is this true? While I am a vet on cll lung cancer I,m a newbie. My wife is stage 4. Thanks and God Bless us all

dennycee

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

boating

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

mutations
Thanks for your informative response. NOW ARE YOU MUTATED OR UNMUTATED

Dan620

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

Thank s
Denny i also thank you, learn something from this site every day..... Dan

dennycee

boating said:

mutations
Thanks for your informative response. NOW ARE YOU MUTATED OR UNMUTATED

Moi?
Hi Boating, it is always good to know that what you write down makes sense to others too. Sometimes I read what I wrote and think "Wha?".

Actually, my surgeon did not get a large enough sample to test for mutations. We will be waiting for the cancer to begin growing again before we do another biopsy and run the tests. It's an insurance thing. My oncologist and I have already discussed this. Smokers, rarely get the EGFR mutation so they frequently do not test former smokers for it. That said, it is not a hard and fast rule that they cannot get it so I would urge everyone to request or argue for it- I will. Tarceva, the targeted therapy for EGFR still successfully shrinks tumors in 8% of patients who do not have EGFR mutations. Ask your wife's oncologist which mutations were tested for.

I have made a point of studying this stuff so that I can be more active in decision making process down the line. If/when the time comes that my 3rd and 4th lines of chemo fail, I will be requesting to try a drug trial.

Best regards, Denny

ps: The answer to whether I am mutated or not depends on who you are talking to. My siblings still insist I am a mutant.

Dan, thanks I will take that as a compliment. We learn so much here don't we.

sleepless in jersey

Boating
Denny is right. My Mom is negative ALK,K-RAS & EGRF. Dr. Alice Shaw in Mass. general Hospital as well as Colorado and I think the 3rd place is Ca.that does a lot more gene mutation testing that the rest of the states do not. As Denny mentioned there are those 2 other sites and there is Graig from PA. who's on inspire.com who has been written up on his mutation that Dr. Shaw has found. Mom was to go there til recent brain MRI showing poss. Leptomeningeal disease, so she is no longer make any sense to take the trip unless she is driven to find out, which she is not.
God Bless
Sleepless

My Mom who’s 62 now. Has been DX 1/3/11 NSCLC (Adeno) Triple mutation neg. 10 days of WBR and brain surgery 1/11, started Carboplatin/Alimta/Zameta and B12, showed 1 tumor growing switched TX to Taxotere/Zameta 5/11 too many side effects, tumors have grown, port put in 8/11, thoracenteses x2 neg.- CA, pleurodesis on both lungs 8/11 & 10/11. Gemzar 8/11 growth and too many side effects.11/16/11 started Navelbine. 5//12 scans showed some growth to chest wall, switch to Topotecan. 7/12 progression with several brain mets, poss leptomeningeal disease (declined lumbar puncture). Tarceva 7/12

sleepless in jersey

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.

dennycee

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.

Sleepless! So good to hear from you!
You have amassed a great deal of knowledge in the days since your mom's dx. You have been an amazing advocate for your mom.

sleepless in jersey

dennycee said:

Sleepless! So good to hear from you!
You have amassed a great deal of knowledge in the days since your mom's dx. You have been an amazing advocate for your mom.

Thanks Denny
Unfortunately my family has been put on the back burner while I have put my Mom 1st. I don't know if that was right or wrong, but I did it!
Nobody is going to be my Mom's advocate, but me. Dad owns his own business and works all day and my 2 bros. forget about it. I have spent numerous hours on the computer and have spoken to so many people who have been so amazing and warm through this journey!

We booked the family vacation for Mom in Lake George for next Mos. for 3 nights (all 14 of us,tot's and all) When I got Onc's bad new's call last mos. re:poss lepto. she suggested to cancel trip, but if she's fine I don't want you to be angry either. So I sent the final pymt yest. God willing she will be fine and not in much pain!! (I have been so positive through this journey, but now with this poss. lepto and watching Mom go down real quick, I feel like this trip is the movie "The last song")

CRAIGINPA said he's on inspire more often so if anybody is trying to contact him, start there.
God Bless
Sleepless

My Mom who’s 62 now. Has been DX 1/3/11 NSCLC (Adeno) Triple mutation neg. 10 days of WBR and brain surgery 1/11, started Carboplatin/Alimta/Zameta and B12, showed 1 tumor growing switched TX to Taxotere/Zameta 5/11 too many side effects, tumors have grown, port put in 8/11, thoracenteses x2 neg.- CA, pleurodesis on both lungs 8/11 & 10/11. Gemzar 8/11 growth and too many side effects.11/16/11 started Navelbine. 5//12 scans showed some growth to chest wall, switch to Topotecan. 7/12 progression with several brain mets, poss leptomeningeal disease (declined lumbar puncture). Tarceva 7/12

CraiginPA

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.

I'm CraiginPA
Hi, boating.

FYI - I'm CraiginPA, that ROS1 guy. ( http:inspire.com/CraiginPA ) Thought I'd pop in over here at sleeplessinjersey's suggestion. Didn't realize there was a LC forum over here. It's hard for me to keep up with the many smaller lung cancer forums, so I don't expect to be a frequent visitor here, but it is about time I at least had an account over here, too.

Can you help me understand your or your wife's situation more clearly? Your 1st message in this discussion mentioned both CLL (leukemia or lymphoma?) and lung cancer, is that right?

I think you might be saying your wife has Stage IV lung cancer, some type in the non-small cell lung cancer category, and it's been tested for some mutations but came back negative (sometimes also called "wild type").

From that description, I'm going to make a guess the specific type is adenocarcinoma although maybe squamous cells instead. Which?

Although there well over 100 known possible mutations (actually called molecular rearrangements or sometimes fusions) in lung cancer, only a few are potentially useful at this point. The ones people focus on are "driving mutations" because if you block them with an appropriate inhibitor drug you'd usually halt the cancer's nasty behavior for a while (until the cancer finds a way around the inhibitor drug).

The commonly tested mutations are EGFR, ALK, and the not-so-useful-yet KRAS. In adenocarcinoma, all 3 are worth testing. In contrast, for squamous cell LC they might test for EGFR and KRAS (and maybe different experimental ones), but maybe not ALK because that one is so rare in squamous cell LC.

For EGFR, the inhibitor drug is Tarceva (and/or Iressa in some other countries). For ALK, it's Xalkori.

The KRAS mutation isn't so useful yet, but if KRAS is the one then it rules out rarer ones and would make you aware of experimental trials for KRAS that might eventually prove to be helpful. (Only a couple seem potentially promising right now.) KRAS is common in smokers, uncommon in neversmokers.

So I can't guess which specific driving mutations have been tested in your wife. EGFR? ALK? KRAS? If all three, then the driving mutation mutation might be something rarer for which there might be an experimental clinical trial of a drug for the mutation.

If triple-negative for EGR, ALK, and KRAS, another one that is worth testing at least in never-smokers is the ROS1 mutation that I have. It's also possible in smokers (about 10% of ROS1 is found in smokers, although more likely they are light smokers), so it might be worth a shot because the drug for it, Xalkori (the same one as for ALK) usually works well for a number of months (as short a 3 months or as long as, well, it might be years but is probably about a year).

Driving mutation-targeted inhibitor drugs don't cure cancer, so it isn't a good choice for someone who has a chance of being cured with surgery, chemo, radiation. But if the cancer is thought to be incurable, then if an inhibitor drug would be effective against the driving mutation there's a good chance it could add months of time (in my case perfectly-healthy time), and there's a chance that researchers will find another drug to try after that.

So which specific mutations were tested? And is there a smoking history? Age can also be an influence since ALK and ROS1 are somewhat more common in people who are closer to 50 than 60, but both have been found in people of any age or gender or ethinic group.

Best hopes,

Craig in PA