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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 referral to phase 1 clinic in patients with mutBRAF treated with RAF/MEK targeting agents or other phase 1 trials.Tic marks represent patients still alive at the last follow-up. (Of 80 patients with BRAF mutations, 56 received a RAF/MEK targeting agents, 11 received a non RAF/MEK targeting agents and 13 were not enrolled on a phase 1 trial).
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pone-0025806-g003: Kaplan-Meier estimate of overall survival from time of referral to phase 1 clinic in patients with mutBRAF treated with RAF/MEK targeting agents or other phase 1 trials.Tic marks represent patients still alive at the last follow-up. (Of 80 patients with BRAF mutations, 56 received a RAF/MEK targeting agents, 11 received a non RAF/MEK targeting agents and 13 were not enrolled on a phase 1 trial).

Mentions: By excluding patients who did not get enrolled into a phase 1 trial after referral (13 patients total), we found that mutBRAF patients treated with RAF/MEK targeting agents has improved survival after referral compared to mutBRAF patients treated with any other agents (not reached vs. 5 months, 95%CI 4–6; p = 0.002 and HR 0.26, 95%CI 0.10–0.66; p = 0.005) (Figure 3).


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 referral to phase 1 clinic in patients with mutBRAF treated with RAF/MEK targeting agents or other phase 1 trials.Tic marks represent patients still alive at the last follow-up. (Of 80 patients with BRAF mutations, 56 received a RAF/MEK targeting agents, 11 received a non RAF/MEK targeting agents and 13 were not enrolled on a phase 1 trial).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025806-g003: Kaplan-Meier estimate of overall survival from time of referral to phase 1 clinic in patients with mutBRAF treated with RAF/MEK targeting agents or other phase 1 trials.Tic marks represent patients still alive at the last follow-up. (Of 80 patients with BRAF mutations, 56 received a RAF/MEK targeting agents, 11 received a non RAF/MEK targeting agents and 13 were not enrolled on a phase 1 trial).
Mentions: By excluding patients who did not get enrolled into a phase 1 trial after referral (13 patients total), we found that mutBRAF patients treated with RAF/MEK targeting agents has improved survival after referral compared to mutBRAF patients treated with any other agents (not reached vs. 5 months, 95%CI 4–6; p = 0.002 and HR 0.26, 95%CI 0.10–0.66; p = 0.005) (Figure 3).

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