NRAS and BRAF Testiing

On NRAS, so far I’ve only seen it used for about 5 clinical trials as an eligibility criteria, mostly MEK inhibitors. As far as I know from my oncologist it sonds like theyre stull trying to figure out how to target NRAS effectively. So other than trying to get into certain MEK trials I’m not sure how useful it would be, yet.

C-KIT mutation testing would be something to ask about, present in about 10% cutaneous (skin-originating) melanomas.

Some people who originally tester BRAF negative have been re-tested with a different newer test and come up positive, something else to look into.

I dont know whether melanoma that was originally, truly, BRAF negative can later evolve a new mutation like BRAF — no idea.

Several here have had severe immune reactions to IPI — NYMaren, Swannee, and a username beginning with Roxy are a few, whose situations resolved eventually with steroids.

On NRAS, so far I’ve only seen it used for about 5 clinical trials as an eligibility criteria, mostly MEK inhibitors. As far as I know from my oncologist it sonds like theyre stull trying to figure out how to target NRAS effectively. So other than trying to get into certain MEK trials I’m not sure how useful it would be, yet.

C-KIT mutation testing would be something to ask about, present in about 10% cutaneous (skin-originating) melanomas.

Some people who originally tester BRAF negative have been re-tested with a different newer test and come up positive, something else to look into.

I dont know whether melanoma that was originally, truly, BRAF negative can later evolve a new mutation like BRAF — no idea.

Several here have had severe immune reactions to IPI — NYMaren, Swannee, and a username beginning with Roxy are a few, whose situations resolved eventually with steroids.

On NRAS, so far I’ve only seen it used for about 5 clinical trials as an eligibility criteria, mostly MEK inhibitors. As far as I know from my oncologist it sonds like theyre stull trying to figure out how to target NRAS effectively. So other than trying to get into certain MEK trials I’m not sure how useful it would be, yet.

C-KIT mutation testing would be something to ask about, present in about 10% cutaneous (skin-originating) melanomas.

Some people who originally tester BRAF negative have been re-tested with a different newer test and come up positive, something else to look into.

I dont know whether melanoma that was originally, truly, BRAF negative can later evolve a new mutation like BRAF — no idea.

Several here have had severe immune reactions to IPI — NYMaren, Swannee, and a username beginning with Roxy are a few, whose situations resolved eventually with steroids.

Though tumors can continue to mutate and evolve, I don't believe melanoma mutates from being BRAF wild type to BRAF mutant.  Having said this, a lot of tests get it wrong so re-testing is not a bad idea.

About half of cutaneous melanomas have mutated BRAF, mostly in melanomas that show up with moderate UV/sun exposure and mostly associated with a lot of moles.  About 15% of cutaneous melanomas have mutated NRAS.  This is a step further up in the signaling pathway.  In other words, the cell has a number of signalling pathways that allow various messages to be transmited from the cell surface to the cell nucleus.  Each pathway has a series of steps, and one step signals the next step.  One such pathway includes NRAS, which signals BRAF, which signals MEK, which signals ERK.  In about half of melanomas, the BRAF step is turned to the "on" position even though the step before it, NRAS, is not turned on.  In about 15%, the NRAS step is stuck in the "on" position.  

Doctors now have drugs that block the function of BRAF, shutting that switch down.  They also have, in late state development, some MEK inhibitors that block the step after BRAF.  Studies suggest that combining a BRAF inhibitor and a MEK inhibitor gives better and longer responses with fewer side effects.

For NRAS mutations the challenges are greater.  One approach is to use MEK along, and that has had moderate success. Because NRAS is not easily targeted, researchers are looking for other approaches.  Another approach is to look beyond ERK to the next cascade involving a compound called CDK4.  At least one company has a small study combining a MEK inhibitor and a CDK4 inhibitor, and I believe that is open to NRAS mutations.

I know this sounds like alphabet soup, but the bottom line is this.  Melanomas should be tested for common mutations: BRAF, NRAS, and KIT.  This information will help inform the treatment approach.

Tim–MRF

Though tumors can continue to mutate and evolve, I don't believe melanoma mutates from being BRAF wild type to BRAF mutant.  Having said this, a lot of tests get it wrong so re-testing is not a bad idea.

About half of cutaneous melanomas have mutated BRAF, mostly in melanomas that show up with moderate UV/sun exposure and mostly associated with a lot of moles.  About 15% of cutaneous melanomas have mutated NRAS.  This is a step further up in the signaling pathway.  In other words, the cell has a number of signalling pathways that allow various messages to be transmited from the cell surface to the cell nucleus.  Each pathway has a series of steps, and one step signals the next step.  One such pathway includes NRAS, which signals BRAF, which signals MEK, which signals ERK.  In about half of melanomas, the BRAF step is turned to the "on" position even though the step before it, NRAS, is not turned on.  In about 15%, the NRAS step is stuck in the "on" position.  

Doctors now have drugs that block the function of BRAF, shutting that switch down.  They also have, in late state development, some MEK inhibitors that block the step after BRAF.  Studies suggest that combining a BRAF inhibitor and a MEK inhibitor gives better and longer responses with fewer side effects.

For NRAS mutations the challenges are greater.  One approach is to use MEK along, and that has had moderate success. Because NRAS is not easily targeted, researchers are looking for other approaches.  Another approach is to look beyond ERK to the next cascade involving a compound called CDK4.  At least one company has a small study combining a MEK inhibitor and a CDK4 inhibitor, and I believe that is open to NRAS mutations.

I know this sounds like alphabet soup, but the bottom line is this.  Melanomas should be tested for common mutations: BRAF, NRAS, and KIT.  This information will help inform the treatment approach.

Tim–MRF

Though tumors can continue to mutate and evolve, I don't believe melanoma mutates from being BRAF wild type to BRAF mutant.  Having said this, a lot of tests get it wrong so re-testing is not a bad idea.

About half of cutaneous melanomas have mutated BRAF, mostly in melanomas that show up with moderate UV/sun exposure and mostly associated with a lot of moles.  About 15% of cutaneous melanomas have mutated NRAS.  This is a step further up in the signaling pathway.  In other words, the cell has a number of signalling pathways that allow various messages to be transmited from the cell surface to the cell nucleus.  Each pathway has a series of steps, and one step signals the next step.  One such pathway includes NRAS, which signals BRAF, which signals MEK, which signals ERK.  In about half of melanomas, the BRAF step is turned to the "on" position even though the step before it, NRAS, is not turned on.  In about 15%, the NRAS step is stuck in the "on" position.  

Doctors now have drugs that block the function of BRAF, shutting that switch down.  They also have, in late state development, some MEK inhibitors that block the step after BRAF.  Studies suggest that combining a BRAF inhibitor and a MEK inhibitor gives better and longer responses with fewer side effects.

For NRAS mutations the challenges are greater.  One approach is to use MEK along, and that has had moderate success. Because NRAS is not easily targeted, researchers are looking for other approaches.  Another approach is to look beyond ERK to the next cascade involving a compound called CDK4.  At least one company has a small study combining a MEK inhibitor and a CDK4 inhibitor, and I believe that is open to NRAS mutations.

I know this sounds like alphabet soup, but the bottom line is this.  Melanomas should be tested for common mutations: BRAF, NRAS, and KIT.  This information will help inform the treatment approach.

Tim–MRF