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Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

Mangana J, Cheng PF, Schindler K, Weide B, Held U, Frauchiger AL, Romano E, Kähler KC, Rozati S, Rechsteiner M, Moch H, Michielin O, Garbe C, Hauschild A, Hoeller C, Dummer R, Goldinger SM - PLoS ONE (2015)

Bottom Line: Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67).The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment.Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

ABSTRACT
Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

No MeSH data available.


Related in: MedlinePlus

Impact of mutation status on overall survival (OS), defined from initiation of anti-CTLA-4 treatment (Fig 2a) and from stage IV melanoma (Fig 2b) according to BRAF and NRAS mutation status in all patients (n = 101).The Fig 2c represents the OS according to mutation status from diagnosis of metastatic melanoma in the subgroup of patients (n = 76) with no access to BRAF/MEK inhibition treatment.
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pone.0139438.g002: Impact of mutation status on overall survival (OS), defined from initiation of anti-CTLA-4 treatment (Fig 2a) and from stage IV melanoma (Fig 2b) according to BRAF and NRAS mutation status in all patients (n = 101).The Fig 2c represents the OS according to mutation status from diagnosis of metastatic melanoma in the subgroup of patients (n = 76) with no access to BRAF/MEK inhibition treatment.

Mentions: As pointed in the material and methods section, OS was defined from the date of therapy initiation with the anti-CTLA-4 Abs treatment to death or till last follow up. In the complete study cohort (n = 101), the median OS was 10.08 months. BRAFV600 or NRASmut patients had a prolonged mOS (mOS = 10.12months, 95% CI 6.78–13.2) compared to BRAFV600/NRASwt patients (mOS = 8.26 months, 95% CI 6.02–19.9) but did not differ significantly (p = 0.67) (Fig 2A). This difference remained non-significant in a multivariate analysis adjusted for age and gender (Table 4). Also for patients with known LDH and S100 serum levels, there was no statistically significant difference in the OS when adjusting for high LDH serum levels (n = 80, HR = 1.52, 95% CI 0.8–2.7, p = 0.152) and high S100 levels (n = 67, HR = 1.570, 95% CI 0.89–2.77, p = 0.120).


Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

Mangana J, Cheng PF, Schindler K, Weide B, Held U, Frauchiger AL, Romano E, Kähler KC, Rozati S, Rechsteiner M, Moch H, Michielin O, Garbe C, Hauschild A, Hoeller C, Dummer R, Goldinger SM - PLoS ONE (2015)

Impact of mutation status on overall survival (OS), defined from initiation of anti-CTLA-4 treatment (Fig 2a) and from stage IV melanoma (Fig 2b) according to BRAF and NRAS mutation status in all patients (n = 101).The Fig 2c represents the OS according to mutation status from diagnosis of metastatic melanoma in the subgroup of patients (n = 76) with no access to BRAF/MEK inhibition treatment.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591284&req=5

pone.0139438.g002: Impact of mutation status on overall survival (OS), defined from initiation of anti-CTLA-4 treatment (Fig 2a) and from stage IV melanoma (Fig 2b) according to BRAF and NRAS mutation status in all patients (n = 101).The Fig 2c represents the OS according to mutation status from diagnosis of metastatic melanoma in the subgroup of patients (n = 76) with no access to BRAF/MEK inhibition treatment.
Mentions: As pointed in the material and methods section, OS was defined from the date of therapy initiation with the anti-CTLA-4 Abs treatment to death or till last follow up. In the complete study cohort (n = 101), the median OS was 10.08 months. BRAFV600 or NRASmut patients had a prolonged mOS (mOS = 10.12months, 95% CI 6.78–13.2) compared to BRAFV600/NRASwt patients (mOS = 8.26 months, 95% CI 6.02–19.9) but did not differ significantly (p = 0.67) (Fig 2A). This difference remained non-significant in a multivariate analysis adjusted for age and gender (Table 4). Also for patients with known LDH and S100 serum levels, there was no statistically significant difference in the OS when adjusting for high LDH serum levels (n = 80, HR = 1.52, 95% CI 0.8–2.7, p = 0.152) and high S100 levels (n = 67, HR = 1.570, 95% CI 0.89–2.77, p = 0.120).

Bottom Line: Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67).The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment.Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

ABSTRACT
Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

No MeSH data available.


Related in: MedlinePlus