BRAF V600E and KRAS mutations that occur in colorectal cancer (CRC) define a subpopulation of patients with an inferior prognosis. Recently, the first BRAF V600E-targeting therapy has been approved and novel agents targeting KRAS G12C are being evaluated in CRC. A better understanding of the clinical characteristics of the populations defined by those mutations is needed. We created a retrospective database that collects clinical characteristics of patients with metastatic CRC evaluated for RAS and BRAF mutations in a single laboratory. A total of 7604 patients tested between October 2017 and December 2019 were included in the analysis. The prevalence of BRAF V600E was 6.77%. Female sex, primary in the right colon, high-grade, mucinous, signet cell, partially neuroendocrine histology, perineural and vascular invasion, and surgical tissue sample were factors associated with increased mutation rates. The prevalence of KRAS G12C was 3.11%. Cancer of primary origin in the left colon and in samples from brain metastases were associated with increased mutation rates. The high prevalence of the BRAF V600E mutation in cancers with a neuroendocrine component identifies a potential candidate population for BRAF inhibition. The association of KRAS G12C with the left part of the intestine and brain metastases of CRC are new findings and require further investigation.

BACKGROUND: The clinicopathologic and genetic features of cutaneous melanoma with a BRAF V600K mutation are not well-known. We aimed to evaluate these characteristics in comparison with those associated with BRAF V600E.
METHODS: Real-time polymerase chain reaction (PCR) and/or the MassARRAY® system were used to detect BRAF V600K in 16 invasive melanomas and confirm BRAF V600E in another 60 cases. Immunohistochemistry and panel next-generation sequencing were used to evaluate protein expression and tumor mutation burden, respectively.
RESULTS: The median age of melanoma patients harboring the BRAF V600K mutation (72.5 years) was higher than those with the BRAF V600E (58.5 years). The two groups also differed in sex (13/16 [81.3%] male in the V600K group vs. 23/60 [38.3%] in V600E) and in the frequency of scalp involvement (8/16 [50.0%] in V600K vs. 1/60 [1.6%] in V600E). The clinical appearance was similar to a superficial spreading melanoma. Histopathologically, non-nested lentiginous intraepidermal spread and subtle solar elastosis were observed. One patient (1/13, 7.7%) had a pre-existing intradermal nevus. Diffuse PRAME immunoexpression was seen in only one (14.3%) of seven tested cases. Loss of p16 expression was observed in all 12 cases (100%) analyzed. The tumor mutation burden was 8 and 6 mutations/Mb in the two tested cases.
CONCLUSIONS: Melanoma carrying the BRAF V600K mutation showed the predominance on the scalp of elderly men, lentiginous intraepidermal growth, subtle solar elastosis, possible existence of intradermal nevus component, frequent loss of p16 immunoexpression, limited immunoreactivity for PRAME, and intermediate tumor mutation burden.

BACKGROUND: BRAF mutation involved 2-4% of lung adenocarcinoma. Differences in clinicopathologic features and patient outcome exist between V600E and non-V600E BRAF mutated NSCLC. Thus, we sought to assess the frequency and clinical relevance of BRAF mutations in a real-life population of advanced-NSCLC, investigating the potential prognostic significance of distinct genetic alterations.
METHODS: The present multicenter Italian retrospective study involved advanced BRAF mutant NSCLC. Complete clinicopathologic data were evaluated for BRAF V600E and non-V600E patients.
RESULTS: A total of 44 BRAFmut NSCLC patients were included (V600E, n = 23; non-V600E, n = 21). No significant differences in survival outcome and treatment response were documented, according to V600E vs. non-V600E mutations, although a trend towards prolonged PFS was observed in the V600E subgroup (median PFS = 11.3 vs. 6.0 months in non-V600E). In the overall population, ECOG PS and age significantly impacted on OS, while bone lesions were associated with shorter PFS. Compared to immunotherapy, first-line chemotherapy was associated with longer OS in the overall population, and especially in the BRAF V600E subtype.
CONCLUSIONS: Here, we report on real-life data from a retrospective cohort of advanced-NSCLC harboring BRAF alterations. Our study offers relevant clues on survival outcome, therapeutic response, and clinicopathologic correlations of BRAF-mutant NSCLC.

Recently, retrospective analysis began to shed light on metastatic colorectal cancers (mCRCs) harboring rare BRAF non-V600 mutations, documenting a distinct phenotype and a favorable prognosis. This study aimed to confirm features and prognosis of rare BRAF non-V600 mCRCs compared to BRAF V600E and BRAF wild-type mCRCs treated at two Italian Institutions. Overall, 537 cases were retrospectively evaluated: 221 RAS/BRAF wild-type, 261 RAS mutated, 46 BRAF V600E and 9 BRAF non-V600. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided, had a lower tumor burden and displayed a lower grade and an MMR proficient/MSS status. In addition, non-V600 mCRC patients underwent more frequently to resection of metastases with radical intent. Median overall survival (mOS) was significantly longer in the non-V600 compared to the V600E group. At multivariate analysis, only age < 65 years and ECOG PS 0 were identified as independent predictors of better OS. BRAF V600E mCRCs showed a statistically significant worse mOS when compared to BRAF wild-type mCRCs, whereas no significant difference was observed between BRAF non-V600 and BRAF wild-type mCRCs. Our study corroborates available evidence concerning incidence, clinicopathologic characteristics and prognosis of BRAF-mutated mCRCs.

UNASSIGNED: Data describing therapeutic outcomes in patients with non-small cell lung cancers (NSCLC) with BRAF mutations remains limited.
UNASSIGNED: We conducted a retrospective cohort study of 31 patients with metastatic NSCLC treated at Duke University Hospital who had been identified by next-generation sequencing methods to bear a BRAF mutation in their tumor in order to evaluate clinical response to immunotherapy and chemotherapy.
UNASSIGNED: Sixty-five percent of patients identified in this cohort were current or former smokers. Fourteen (45.2%) of patients had a BRAF V600E mutation and 17 (54.8%) had a non-V600E mutation. Median progression-free survival (PFS) in the 23 patients who received first-line chemotherapy was 6.4 months [95% confidence interval (CI), 2.3 to 13.0]. Overall survival (OS) in patients who received first-line chemotherapy showed a median survival of 18 months (95% CI, 7.4 to 28.6). OS comparing patients who had never received immunotherapy at any point was 18.4 months (95% CI, 4.1 to NE) compared to 19.0 months (95% CI, 9.9 to 28.6) in those who had received immunotherapy. We did not find a statistically significant difference in OS in patients with BRAF V600E, BRAF amplification, or non-V600E mutations. There was also no difference in OS in patients treated with targeted BRAF inhibitors compared to those who were not treated with targeted BRAF inhibitors.
UNASSIGNED: We describe therapeutic outcomes for patients with metastatic NSCLC with BRAF mutations treated with either cytotoxic chemotherapy or immunotherapy. Although the sample size is small, the survival curves do not suggest improved clinical activity in this population when treated with immunotherapy.

Patients with stage IV non-small-cell lung cancer (NSCLC) and BRAF V600 mutations may benefit from targeted therapies. Chemotherapy outcomes are little known in this population.
The French Cooperative Thoracic Intergroup (IFCT) Biomarkers France study was a national prospective cohort study aiming to describe the molecular characteristics and clinical outcome of all consecutive NSCLC patients (N = 17,664) screened for molecular alterations. We used this data set to set up a case-control analysis. Cases had stage IV BRAF-mutated (BRAF-MT) NSCLC, whereas controls had NSCLC that was wild-type for EGFR, KRAS, HER2, BRAF, PIK3CA and ALK. Each case was matched for sex, age at diagnosis and smoking status to two controls randomly selected.
Overall, 83 cases with BRAF mutant disease (66.3% V600E) were matched to 166 controls. Five cases received tyrosine kinase inhibition in the first-line and 16 in the second-line. All others were treated with standard chemotherapy. There was no significant difference in first-line and second-line progression-free survival (PFS) between the groups, as well as in the disease control rate, BRAF mutation was not found to be prognostic of overall survival. We found no significant difference in outcome between the treatment types used in first-line or second-line in patients with BRAF-MT disease compared with controls nor between BRAF V600E or non-V600E compared with controls.
BRAF mutation is not a strong prognostic factor in NSCLC. Although taxan-based therapy shows poorest PFS in first-line, no chemotherapy regimen was associated with prognosis.

Mutations in BRAF are rare oncogene mutations, found in 2% of non-small-cell lung cancers (nsclcs). Little information is available about the management of patients with BRAF-mutated nsclc, except for those included in clinical trials. We undertook the present study to assess the clinical characteristics, management, and outcomes of those patients in a real-life setting.
This retrospective multicentre observational study included all patients with BRAF-mutated nsclc diagnosed between January 2012 and December 2014.
Patients (n = 59) from 24 centres were included: 57.6% men; mean age: 64.5 ± 14.5 years; 82% with a performance status of 0-1 at diagnosis; smoking status: 40.3% current, 32.6% former; 93% with adenocarcinoma histology; 75% stage iv; 78% with V600E mutations; 2 with EGFR and 2 with ALK co-mutations. Of the stage iv patients, 79% received first-line therapy (14.2% anti-BRAF), and 48% received second-line treatment (23.8% anti-BRAF). Response rate and progression-free survival were, respectively, 51.7% and 8.7 months [95% confidence interval (ci): 6.4 months to 15.2 months] for first-line therapy and 35.3% and 4.1 months (95% ci: 2 months to 10.9 months) for second-line treatments. The 2-year overall survival was 58.5% (95% ci: 45.8% to 74.8%). Outcomes in patients with stage iv nsclc harbouring BRAF V600E mutations (n = 32) did not differ significantly from those of patients with other BRAF mutations.
In this real-world analysis, most nsclc patients with a BRAF mutation were men and current or former smokers. Survival appears to be better in these BRAF-mutated patients than in nsclc patients without an oncogenic driver.

Recent advances in next-generation sequencing have enabled the detection of BRAF V600E mutations as well as BRAF non-V600E mutations in a single assay. The present work aimed to describe the clinicopathological characteristics and clinical outcome of the BRAF non-V600E mutant-type in colorectal cancer (CRC).
CRC samples from 111 Stage IV patients were analyzed for somatic mutations using a 415-gene comprehensive genomic sequencing panel. Patients were classified according to BRAF status as wild-type, V600E mutant-type, or non-V600E mutant-type. Differences between clinicopathological characteristics and genetic alterations were analyzed among the three groups. Overall survival (OS) and the response to anti-EGFR therapy were also analyzed.
Comprehensive genomic sequencing revealed that 98 patients (88%), 7 patients (6%), and 6 patients (6%) were wild-type, V600E mutant-type, and non-V600E mutant-type, respectively. Non-V600E mutant-type tumors were frequently left-sided (83%), while V600E mutant-type tumors were frequently right-sided (86%; P = 0.025). Non-V600E mutant-type showed better OS than V600E mutant-type (P = 0.038), with no significant difference compared with wild-type tumors. The two patients with non-V600E mutations who underwent repeated metastasectomies showed no evidence of disease at final follow-up. Regarding the efficacy of anti-EGFR therapy, the patient with an I326V mutation had progressive disease (+115%) despite no genetic alterations detected in the EGFR pathway that could drive resistance, suggesting an alternate resistance mechanism.
Non-V600E mutant-type is more likely to be left-sided and demonstrates better OS than V600E mutant-type. Further preclinical and clinical investigations are needed to clarify the role of non-V600E mutations in CRC.

Among brain tumors, the BRAF (V600E) mutation is frequently associated with pleomorphic xanthoastrocytomas (PXAs) and gangliogliomas (GGs). This oncogenic mutation is also detected in ~5 % of other pediatric low-grade gliomas (LGGs) including pilocytic astrocytomas (PAs) and diffuse astrocytomas. In the current multi-institutional study of 56 non-PXA/non-GG diencephalic pediatric LGGs, the BRAF (V600) mutation rate is 36 %. V600-mutant tumors demonstrate a predilection for infants and young children (