Cancer Res Treat.  2022 Jul;54(3):782-792. 10.4143/crt.2021.843.

Selection Strategies and Practical Application of BRAF V600E-Mutated Non–Small Cell Lung Carcinoma

• Hwang I
• Choi YL
• Lee H
• Hwang S
• Lee B
• Yang H
• Chelakkot C
• Han J

• KMID: 2531324
• DOI: http://doi.org/10.4143/crt.2021.843

Abstract

Purpose
The incidence of BRAF V600E mutation in non-small cell lung carcinoma (NSCLC) is lower than 2%, which poses difficulties in finding legitimate patients for targeted therapy. We investigated the predictive factors pertaining to BRAF V600E and the effectiveness of the VE1 antibody as a screening method for patient selection.
Materials and Methods
The study was designed into two steps. In a first group, BRAF-mutated NSCLCs were identified from sequencing data to determine the features of BRAF V600E mutation. The results of the first group helped the collection of adenocarcinomas with a papillary or micropapillary pattern but without EGFR or ALK alterations as a second group so that the frequency of BRAF V600E mutation could be calculated. The sensitivity and specificity of the VE1 were compared with BRAF V600E status.
Results
Among 39 BRAF-mutated NSCLCs in the first group, 20 (51%) were V600E. BRAF V600E mutation was more common in female patients and showed no significant correlation with smoking status. Nineteen cases were adenocarcinomas without EGFR and ALK alterations. The most common patterns of invasion were papillary and micropapillary along with central fibrosis. The sensitivity and specificity of the VE1 were 90.0% and 92.3%, respectively. In the second group, 6.7% of cases were VE1-positive, indicating that the prevalence was significantly higher than that reported in previous studies (0.3-1.8%).
Conclusion
BRAF V600E-mutated NSCLCs could be enriched with the application of clinicopathologic parameters, which are not perfect. Therefore, additional VE1 immunohistochemistry may be useful as a screening method.

Keyword

V600E; Non-small-cell lung carcinoma; Adenocarcinoma of lung; Histology

Figure

• 

  Fig. 1 Overview of the patient selection process (the excluded specimens are not described here). Two out of the 29 specimens (6.9%) were positive for VE1 immunohistochemistry based on our selection criteria. Due to the small number, the surgically resected specimens in the first and the second groups were analyzed together to determine the clinicopathologic features, which are presented in Table 2. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; NGS, next-generation sequencing; NSCLC, non–small cell lung carcinoma.

• 

  Fig. 2 Various invasive patterns of adenocarcinoma with or without BRAF V600E mutation. (A) Acinar pattern. The entire sections of this tumor showed micropapillary and papillary predominant patterns with focal (less than 30%) acinar patterns. VE1 immunohistochemistry (IHC) was weak positive and BRAF V600E was confirmed by real-time polymerase chain reaction. (B) Most areas of this adenocarcinoma showed a papillary pattern. A micropapillary pattern was also presented but not predominant. VE1 antibody staining was strong positive. (C) A micropapillary dominant adenocarcinoma. The tumor also had a focal acinar pattern within central fibrosis (not shown), but the area’s volume did not exceed 30% of the total volume. VE1 IHC was diffuse and intermediate to strong positive. (D) The adenocarcinoma was mainly composed of a solid pattern. The tumor had high-grade nuclear atypia with abundant pale eosinophilic cytoplasm, and the stroma showed dense lymphocytic infiltration. VE1 IHC was diffuse and strong positive. (E) BRAF V600E–negative adenocarcinoma with papillary and micropapillary patterns. VE1 immunostaining was negative. (F) Solid pattern with VE1-negative staining (A–F, H&E staining and VE1 immunostaining, scale bar=200 μm).

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  Fig. 3 The recurrence-free survival (A) and overall survival (B) of BRAF V600E–mutated and V600E–negative adenocarcinomas with a papillary or micropapillary pattern but without epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations. After surgical resection, there was no difference in the recurrence-free survival and overall survival between BRAF V600E–mutated and V600E–negative adenocarcinomas (recurrence-free survival, p=0.146; overall survival, p=0.782).

Reference

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