NRAS and TP53

Hi Lucy, 

I do not have any personal experience with that, but you may want to check Tony's posts, he is BRAF wild too and he seems to be looking into some promising options:
https://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/pog-targeted-therapy

Also, if you have not heard of it already, immunotherapy options work for BRAF wild patients as well as they do for the BRAF positive ones. 

Good Luck 🙂

I am BRAF Negative, ipi/nivo worked fantastic for me.

Hi Lucy,

My husband was diagnosed stage 4 in October 2018.  He had an enlarged submandibular lymph node and he also had no primary site.  He has the p53 mutation also and BRAF wild.  We are also at Emory with Dr. Kudchadkar.  He completed the 4 rounds of ipi/nivo and is now on nivo once a month.  We just got the results from his 6 month scans today and we've probably seen a tumor load reduction of about 90% so far.  He had metastis in his liver, bone, and lungs.  The neck lymph node mass was 5cm and is now 1 cm.  We are down to a couple of 1cm nodules in the lung and the 1cm residual in the original lymph node.  We are hoping he continues to have such a great success with this treatment!!!!  His eyebrows and beard have gone completely white.

Janice (Jim's wife)

Hi Lucy,

My husband was diagnosed stage 4 in October 2018.  He had an enlarged submandibular lymph node and he also had no primary site.  He has the p53 mutation also and BRAF wild.  We are also at Emory with Dr. Kudchadkar.  He completed the 4 rounds of ipi/nivo and is now on nivo once a month.  We just got the results from his 6 month scans today and we've probably seen a tumor load reduction of about 90% so far.  He had metastis in his liver, bone, and lungs.  The neck lymph node mass was 5cm and is now 1 cm.  We are down to a couple of 1cm nodules in the lung and the 1cm residual in the original lymph node.  We are hoping he continues to have such a great success with this treatment!!!!  His eyebrows and beard have gone completely white.

Janice (Jim's wife)

Hi Lucy,

My husband's genetic testing also showed the NRAS mutation.  It's been a while since I delved into the research, but I really delved into it five years ago and was freaked out at first, but what I remember is a found a lot of variance in the research regarding prognostic differences per mutation status.  My final conclusion was there wasn't enough certainty to say one mutation was different from another prognostically and there was a lot of high-risk bias in the research.  High-risk is high risk and low risk is low risk!  My husband is high risk based on all of his pathology criteria.  What has been really different is that they found a treatment specific to BRAF with BRAF inhibitors (but I think these develop some sort of resistance after a certain amount of time)  I know a bunch of research is going on for NRAS but no drug/treatment yet specific to that part of the regulation pathway (please forgive terminology, i have to reread this stuff to really get the process to sink in but with your background this is probably second nature to you)  .  And what i understand, now with immunotherapy (which wasn't available during older research), this is the great equalizer across mutations so to speak.  This particular study shows that NRAS may have some benefit a benefit to response to immunotherapy.  but what i'm taking from it is that immunotherapy works on melanoma regardless of mutation status.  Here is the link to an interesting research article talking about the different mutational status.  Expression of PD-L1 seems to be an important factor to success as well but I'll let our experts on the board speak to the science.

I just remember feeling the same thoughts you have just had, some of the older research was very scary around NRAS (more aggressive tumors, nodular, survival times etc) but it seems like the newer immunotherapies work regardless.  Many hugs, Jackie

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351797/pdf/nihms-657047.pdf

We hypothesized that ‘driver mutation’ status may influence response to immune therapies, specifically examining the cohort of melanoma patients harboring activating NRAS mutations. Data from our multi-institutional retrospective analysis suggest that patients with Johnson et al.Page 6Cancer Immunol Res. Author manuscript; available in PMC 2016 March 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscript
NRAS-mutant melanoma experience higher rates of objective response or prolonged stable disease from immune therapy compared to those with BRAF-mutant and NRAS/BRAF WT melanoma. This benefit was particularly notable for the novel immune checkpoint inhibitors (ipilimumab and anti-PD-1/PD-L1). Although only small numbers were treated, the clinical benefit rate was unexpectedly high with anti-PD-1 or anti-PD-L1, occurring in 8 of 11 patients with NRAS-mutant melanoma compared to only 13 of 37 patients in the non-NRAS-mutant cohorts. This finding could have implications for molecular testing, treatment decision making, and provides early insights into the complex relationship between tumor genetics and the immune response.In contrast to BRAF-mutant melanoma, no effective molecularly-targeted therapeutic strategies have yet been approved for NRAS-mutant or WT melanoma. Immune therapies, therefore, are the cornerstones of therapy for these subtypes. A recent study by Joseph and colleagues showed that IL2 treatment provided superior efficacy for patients with NRAS-mutant compared to patients with BRAF/NRAS WT melanoma (ORR of 47% vs. 15%), although this analysis included only 15 NRAS-mutant melanoma patients (19). Our study is much larger and extends to the immune checkpoint inhibitors. It should be noted that while several clinical endpoints strongly favored the NRAS population (ORR to first-line therapy, CBR to any and first-line therapy), only a trend was observed for several others (ORR to any therapy, PFS, OS)