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BRAF mutations in advanced cancers: clinical characteristics and outcomes.

El-Osta H, Falchook G, Tsimberidou A, Hong D, Naing A, Kim K, Wen S, Janku F, Kurzrock R - PLoS ONE (2011)

Bottom Line: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis.Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported).In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively).

View Article: PubMed Central - PubMed

Affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

ABSTRACT

Background: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic.

Methods: We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome.

Results: Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients.

Conclusions: BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation.

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Related in: MedlinePlus

Kaplan Meier estimate of overall survival from time of diagnosis comparing patients with melanoma with V600K BRAF mutation vs. other BRAF mutations.Tic marks represent patients who were alive and censored at time of last follow up. (One patient for whom the time of diagnosis was unknown was excluded.)
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pone-0025806-g006: Kaplan Meier estimate of overall survival from time of diagnosis comparing patients with melanoma with V600K BRAF mutation vs. other BRAF mutations.Tic marks represent patients who were alive and censored at time of last follow up. (One patient for whom the time of diagnosis was unknown was excluded.)

Mentions: We further investigated the behavior of mutBRAF melanoma with V600K substitution compared to other subtypes of BRAF mutation. (There were 13 patients with V600K mutations including 12 with melanoma and one with colorectal cancer). In the melanoma group, we compared patients with V600K BRAF mutations vs. non-V600K BRAF mutations (the vast majority being V600E). We found that V600K was associated with more brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007). (The single patient with colorectal cancer and V600K also had brain and lung metastases). V600K melanomas metastasized earlier (median time to metastasis = 19 months, 95%CI 0–49 vs. 53 months, 95%CI 33–72, p = 0.046), and were associated with a shorter OS from time of diagnosis (median 78 months, 95%CI 10–146 vs. 322 months, p = 0.024) (Figure 6).


BRAF mutations in advanced cancers: clinical characteristics and outcomes.

El-Osta H, Falchook G, Tsimberidou A, Hong D, Naing A, Kim K, Wen S, Janku F, Kurzrock R - PLoS ONE (2011)

Kaplan Meier estimate of overall survival from time of diagnosis comparing patients with melanoma with V600K BRAF mutation vs. other BRAF mutations.Tic marks represent patients who were alive and censored at time of last follow up. (One patient for whom the time of diagnosis was unknown was excluded.)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198456&req=5

pone-0025806-g006: Kaplan Meier estimate of overall survival from time of diagnosis comparing patients with melanoma with V600K BRAF mutation vs. other BRAF mutations.Tic marks represent patients who were alive and censored at time of last follow up. (One patient for whom the time of diagnosis was unknown was excluded.)
Mentions: We further investigated the behavior of mutBRAF melanoma with V600K substitution compared to other subtypes of BRAF mutation. (There were 13 patients with V600K mutations including 12 with melanoma and one with colorectal cancer). In the melanoma group, we compared patients with V600K BRAF mutations vs. non-V600K BRAF mutations (the vast majority being V600E). We found that V600K was associated with more brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007). (The single patient with colorectal cancer and V600K also had brain and lung metastases). V600K melanomas metastasized earlier (median time to metastasis = 19 months, 95%CI 0–49 vs. 53 months, 95%CI 33–72, p = 0.046), and were associated with a shorter OS from time of diagnosis (median 78 months, 95%CI 10–146 vs. 322 months, p = 0.024) (Figure 6).

Bottom Line: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis.Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported).In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively).

View Article: PubMed Central - PubMed

Affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

ABSTRACT

Background: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic.

Methods: We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome.

Results: Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients.

Conclusions: BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation.

Show MeSH
Related in: MedlinePlus