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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 BRAF mutation who showed any decrease vs. no decrease in size of target lesions on phase 1 trial.(Patients who did not have tumor measurements at the time of last follow-up (N = 9) or patients who were not enrolled in a phase 1 trial after referral (N = 13) were excluded).
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pone-0025806-g002: Kaplan-Meier estimate of overall survival from time of referral to phase 1 clinic in patients with BRAF mutation who showed any decrease vs. no decrease in size of target lesions on phase 1 trial.(Patients who did not have tumor measurements at the time of last follow-up (N = 9) or patients who were not enrolled in a phase 1 trial after referral (N = 13) were excluded).

Mentions: In univariate analysis, we observed a longer OS from referral in women vs. men (not reached in both groups, p = 0.015 and HR 2.62, 95%CI 1.14–6.01; p = 0.02), RMH score of 0–1 vs. 2–3 (not reached vs. 5 months, 95%CI 3–7; p<0.001 and HR 3.69, 95%CI 1.74–7.82; p = 0.001), performance status ≤1 vs. 2–4 (not reached vs. 6 months, 95%CI 2.1–9.9; p = 0.035 and HR 2.51, 95%CI 1.01–6.28; p = 0.048), treatment with RAF/MEK targeting agents (56 of the 80 patients received RAF/MEK targeting agents including 37 with melanoma, 10 with papillary thyroid, 8 with colon cancer and 1 with ovarian cancer) vs. treatment with any other agents or no treatment (not reached vs. 5 months, 95%CI 3.4–6.6; p<0.001 and HR 0.20, 95%CI 0.095–0.43; p<0.001), papillary thyroid cancer vs. other cancers (not reached in both groups, p = 0.018 and HR 0.09, 95%CI 0.10–0.89; p = 0.04), and any decrease in tumor size on any phase I clinical trial vs. no decrease (not reached vs. 6 months, 95%CI 4.7–7.2; p<0.001 and HR 0.09, 95%CI 0.025–0.32; p<0.001) (Figure 2 and Table 4).


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 BRAF mutation who showed any decrease vs. no decrease in size of target lesions on phase 1 trial.(Patients who did not have tumor measurements at the time of last follow-up (N = 9) or patients who were not enrolled in a phase 1 trial after referral (N = 13) were excluded).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0025806-g002: Kaplan-Meier estimate of overall survival from time of referral to phase 1 clinic in patients with BRAF mutation who showed any decrease vs. no decrease in size of target lesions on phase 1 trial.(Patients who did not have tumor measurements at the time of last follow-up (N = 9) or patients who were not enrolled in a phase 1 trial after referral (N = 13) were excluded).
Mentions: In univariate analysis, we observed a longer OS from referral in women vs. men (not reached in both groups, p = 0.015 and HR 2.62, 95%CI 1.14–6.01; p = 0.02), RMH score of 0–1 vs. 2–3 (not reached vs. 5 months, 95%CI 3–7; p<0.001 and HR 3.69, 95%CI 1.74–7.82; p = 0.001), performance status ≤1 vs. 2–4 (not reached vs. 6 months, 95%CI 2.1–9.9; p = 0.035 and HR 2.51, 95%CI 1.01–6.28; p = 0.048), treatment with RAF/MEK targeting agents (56 of the 80 patients received RAF/MEK targeting agents including 37 with melanoma, 10 with papillary thyroid, 8 with colon cancer and 1 with ovarian cancer) vs. treatment with any other agents or no treatment (not reached vs. 5 months, 95%CI 3.4–6.6; p<0.001 and HR 0.20, 95%CI 0.095–0.43; p<0.001), papillary thyroid cancer vs. other cancers (not reached in both groups, p = 0.018 and HR 0.09, 95%CI 0.10–0.89; p = 0.04), and any decrease in tumor size on any phase I clinical trial vs. no decrease (not reached vs. 6 months, 95%CI 4.7–7.2; p<0.001 and HR 0.09, 95%CI 0.025–0.32; p<0.001) (Figure 2 and Table 4).

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