BRAF-V600 mutations have no prognostic impact in stage IV melanoma patients treated with monochemotherapy

Background\ud \ud The impact of BRAF tumor mutations on the natural course of disease of melanoma patients is controversial.\ud \ud Patients and Methods\ud \ud We analyzed the mutational status and overall survival of 215 patients receiving treatment with dacarbazine or temozolomide. All patients who started first-line treatment at our institution between 2000 and 2010 were included to prevent selection and bias due to thereafter arising therapeutic options.\ud \ud Results\ud \ud No patient received BRAF- or MEK-inhibitors during follow-up. Survival was associated with the pattern of visceral involvement, the presence of brain metastases and the serum lactate dehydrogenase level (all p<0.001). The BRAF-V600 mutational status was not associated with survival and no differences in overall survival were detected according to age, gender or to the cytotoxic agent used for therapy. In Cox regression analysis the presence of brain metastases (hazard ratio 2.3; p<0.001) and an elevated serum LDH (hazard ratio 2.5; p<0.001) were the only factors, which independently predicted survival.\ud \ud Conclusions\ud \ud No differences in prognosis were observed according to the BRAF mutational status in patients with distant metastasis treated with monochemotherapy

Survival according to BRAF-V600 tumor mutations : an analysis of 437 patients with primary melanoma

The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease-free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant-metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies

Multivariate analysis for disease-specific death.

#<p>95%-CI = 95% confidence interval;</p><p>*21 patients had unknown values for LDH and were excluded; the model was adjusted for the confounding effects of the site of distant metastasis; no significant interaction was detected.</p

Survival analysis for patients with brain involvement.

#<p>95%-CI = 95% confidence interval;</p>$<p>na = not available.</p><p>*4 patients had unknown values for LDH and were excluded; no confounding effects were detected.</p

Survival analysis for patients without brain involvement.

<p># 95%-CI = 95% confidence interval; * 17 patients had unknown values for LDH and were excluded; the model was adjusted for the confounding effects of the site of distant metastasis; no significant interaction was detected.</p

Univariate survival analysis.

<p>Kaplan Meier survival curves according to (A) the presence of brain metastasis, (B) serum lactate dehydrogenase (LDH) or (C) the <i>BRAF-V600</i> mutational status. Censored events are indicated by vertical lines.</p

Clinical characteristics and survival analysis.

#<p>95%-CI = 95% confidence interval;</p><p>*p-values are results of Fishers exact tests $ p-values are results of log rank tests excluding cases with missing values.</p

Overall survival stratified according to tumor thickness.

a<p>95%-CI = 95% confidence interval;</p>b<p>p-values are results of log rank tests excluding cases with missing values.</p>c<p>2 patients had unknown mitosis and in 3 cases censoring occurred before the first event was observed; the model was adjusted for the confounding effects of tumor thickness (n = 234).</p>d<p>2 patients had unknown mitosis rate and in 1 cases censoring occurred before the first event was observed; the model was adjusted for the confounding effects of mitotic rate and <i>BRAF-V600</i> mutations (n = 195).</p><p>na = not available.</p