Article
Clinicopathological Features of Non-Small Cell Lung
Carcinoma with BRAF Mutation
Andrea Ambrosini-Spaltro 1, * , Claudia Rengucci 2 , Laura Capelli 2 , Elisa Chiadini 2 , Daniele Calistri 2 ,
Chiara Bennati 3 , Paola Cravero 4 , Francesco Limarzi 1 , Sofia Nosseir 5 , Riccardo Panzacchi 6 , Mirca Valli 7 ,
Paola Ulivi 2 and Giulio Rossi 8
1
2
3
4
5
6
7
8
*
Citation: Ambrosini-Spaltro, A.;
Rengucci, C.; Capelli, L.; Chiadini, E.;
Calistri, D.; Bennati, C.; Cravero, P.;
Limarzi, F.; Nosseir, S.; Panzacchi, R.;
et al. Clinicopathological Features of
Non-Small Cell Lung Carcinoma
with BRAF Mutation. Curr. Oncol.
2023, 30, 10019–10032. https://
doi.org/10.3390/curroncol30110728
Received: 8 October 2023
Revised: 12 November 2023
Accepted: 17 November 2023
Pathology Unit, Morgani-Pierantoni Hospital, AUSL Romagna, 47121 Forlì, Italy;
francesco.limarzi@auslromagna.it
Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”,
47014 Meldola, Italy; claudia.rengucci@irst.emr.it (C.R.); laura.capelli@irst.emr.it (L.C.);
elisa.chiadini@irst.emr.it (E.C.); daniele.calistri@irst.emr.it (D.C.); paola.ulivi@irst.emr.it (P.U.)
Oncology Unit, Santa Maria Delle Croci Hospital, AUSL Romagna, 48121 Ravenna, Italy;
chiara.bennati@auslromagna.it
Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino
Amadori”, 47014 Meldola, Italy; paola.cravero@irst.emr.it
Pathology Unit, Santa Maria Delle Croci Hospital, AUSL Romagna, 48121 Ravenna, Italy;
sofia.nosseir@auslromagna.it
Pathology Unit, Bufalini Hospital, AUSL Romagna, 47521 Cesena, Italy; riccardo.panzacchi@auslromagna.it
Pathology Unit, Infermi Hospital, AUSL Romagna, 47923 Rimini, Italy; mirca.valli@auslromagna.it
Pathology Unit, Department of Oncology, Fondazione Poliambulanza, 25124 Brescia, Italy;
giurossi68@gmail.com
Correspondence: andrea.ambrosinispaltro@auslromagna.it; Tel.: +39-0543-731703
Abstract: (1) Background: BRAF mutations affect 4–5% of lung adenocarcinomas. This study aimed to
analyze the clinicopathological features of lung carcinomas with BRAF mutations, focusing on V600E
vs. non-V600E and the presence of co-mutations. (2) Methods: All BRAF-mutated lung carcinomas
were retrieved from a molecular diagnostic unit (the reference unit for four different hospitals). The
samples were analyzed using next-generation sequencing. Statistical analyses included log-rank tests
for overall survival (OS) and progression-free survival (PFS). (3) Results: In total, 60 BRAF-mutated
lung carcinomas were retrieved: 24 (40.0%) with V600E and 36 (60.0%) with non-V600E mutations,
and 21 (35.0%) with other co-mutations and 39 (65.0%) with only BRAF mutations. Survival data were
available for 54/60 (90.0%) cases. Targeted therapy was documented in 11 cases. Patients with V600E
mutations exhibited a better prognosis than patients with non-V600E mutations (p = 0.008 for OS,
p = 0.018 for PFS); this was confirmed in PFS (p = 0.036) when considering only patients who received
no targeted therapy. Patients with co-mutations displayed no prognostic difference compared to
patients carrying only BRAF mutations (p = 0.590 for OS, p = 0.938 for PFS). (4) Conclusions: BRAFmutated lung carcinomas with V600E (40.0%) had a better prognosis than those without V600E.
Concomitant co-mutations (35.0%) did not affect the prognosis.
Keywords: NSCLC; lung; BRAF; V600E; co-mutation; prognosis; survival
Published: 19 November 2023
1. Introduction
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Lung carcinoma is one of the most common tumors globally, representing the second
most prevalent malignancy and the leading cause of cancer-related mortality worldwide [1].
Although lung carcinoma is often diagnosed at advanced and inoperable stages, many
targeted therapies have been developed over the last few decades with dramatic responses
and improvements in prognosis. In non-small cell lung carcinoma (NSCLC), targeted
therapies are mainly directed toward specific altered genes that have been thoroughly
analyzed, including EGFR, ALK, ROS1, and RET [2]. Targeted therapies against BRAF
Curr. Oncol. 2023, 30, 10019–10032. https://doi.org/10.3390/curroncol30110728
https://www.mdpi.com/journal/curroncol
Curr. Oncol. 2023, 30
10020
(vemurafenib, dabrafenib, and encorafenib) are currently available and widely used in
advanced melanomas [3] and recurrent or metastatic thyroid carcinomas [4]. Promising
results with BRAF inhibitors have also been reported for colorectal carcinomas [5,6]. In
lung carcinomas, BRAF mutations are rare and have not been extensively investigated in
the literature [7], with limited data on therapeutic options [8].
BRAF belongs to the rapidly accelerated fibrosarcoma (RAF) group of serine/threonine
kinases and plays a crucial role in cell proliferation and differentiation through the mitogenactivated protein kinase (MAPK) signaling pathway [9,10]. When mutated, BRAF may act
as an oncogene, leading to the development of cancer [11]. BRAF mutations affect from
2.2% [12] to 4.9% [13] of lung adenocarcinomas. They are usually detected in non-smokers,
females [14], and adenocarcinomas with micropapillary architecture [13]. BRAF mutations
in the lungs can be subdivided into two major groups: V600E and non-V600E. V600E mutations are located at codon 600, with the conversion of valine to glutamic acid (V600E); less
common substitutions at codon 600 include V600K/D/R/M [15]. In contrast to melanoma,
where V600E represents the majority of BRAF mutations, in NSCLC, V600E mutations
represent only approximately half of the cases, whereas the other half is composed of
other mutations, collectively named non-V600E [16]. V600E and V600D/K/R/M may be
collectively classified as class 1 mutations, whereas non-V600E mutations are composed
of different mutations and may be further classified into classes 2 and 3 [17]. V600E mutations are particularly interesting because they can be targeted using specific drugs, mainly
vemurafenib, dabrafenib, and trametinib [18]. Vemurafenib is especially effective in V600
mutations, but not in other BRAF (non-V600) mutations [19]. Dabrafenib and trametinib
have been approved as first-line treatments for patients with metastatic NSCLC harboring
the V600E mutation [20]. Non-V600 mutations can be treated with specific targeted therapies [21], but patients usually undergo immunotherapy and chemotherapy [22]. However,
treatment of non-V600E mutations has not been well documented, with limited clinical
data [22].
Studies have reported a discordant prognostic behavior between V600E and nonV600E BRAF-mutated cases. In cases with the V600E mutation, some studies have reported a worse prognosis [13], whereas others have reported a better prognosis [23] or
no difference in prognosis [24]. Furthermore, BRAF mutations may be present either
alone or in combination with other co-mutations. The co-occurrence of BRAF mutations
and co-mutations has been marginally analyzed [23,25], with limited data on its impact
on prognosis.
The purpose of our study was to collect a series of lung carcinomas with BRAF
mutations and examine their clinicopathological features, with special emphasis on the
following: (1) distinction between V600E and non-V600E mutations, (2) distinction between
BRAF mutations alone and BRAF with co-mutations.
2. Materials and Methods
We collected all advanced/metastatic NSCLCs with BRAF mutations resulting from
routine diagnostic molecular analysis performed between 2019 and mid-2022 in AUSL
Romagna using next-generation sequencing (NGS). The cases were provided by 4 different
hospitals (Cesena, Forlì, Ravenna, and Rimini, Italy). NGS analysis was performed at the
Molecular Diagnostics Laboratory of IRST-IRCCS (Meldola, Italy). A dedicated pathologist
assessed the neoplastic content (at least 500 tumor cells) and tumor/normal tissue ratio
(more than 30%). The pathological features and clinical follow-up data were retrieved.
2.1. Clinical Data
The clinical and survival data were retrieved from an electronic database. Progression
was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST)
criteria, version 1.1 [26].
Curr. Oncol. 2023, 30
10021
2.2. NGS Analysis
We used an amplicon-based DNA/RNA NGS panel, OncomineTM Focus Assay
(Thermo Fisher Scientific, Waltham, MA, USA), which can detect 52 genes. The DNA panel
could identify hotspot mutations in 35 genes (including BRAF) and copy number variants
in 19 genes (including BRAF). The RNA panel was able to detect fusion drivers in 23 genes
(including BRAF). We focused only on BRAF-mutated cases and excluded those with BRAF
fusion and/or amplification.
To extract DNA/RNA, we used the MagMAX FFPE DNA/RNA Ultra Kit (Applied
Biosystems, Waltham, MA, USA) following the manufacturer’s protocol, with formalinfixed and paraffin-embedded (FFPE) material (6–8 tumor sections of 5 µm) or with cytological smears. The DNA concentration was calculated through fluorometric quantitation
using a Qubit 4.0 Fluorometer with a Qubit DNA HS (High Sensitivity) Assay Kit (Thermo
Fisher Scientific).
DNA library preparation was performed automatically using the library preparer “Ion
Chef™ System” (Thermo Fisher Scientific) following the manufacturer’s instructions, with
10 ng of input DNA per sample.
The template was then prepared on the Ion Chef™ System (i.e., DNA and RNA from the
same sample were combined on the same chip), and sequencing was performed on the Ion S5
Plus platform (Thermo Fisher Scientific) using Ion 520 Chips (Thermo Fisher Scientific).
The primary evaluation was performed using Torrent Suite Software™ (5.12.3) for
initial quality control, including chip loading density, median read length, and number of
mapped reads. Subsequently, each sample was analyzed using Ion Reporter™ Software
(5.16), a suite of bioinformatic tools for variants, filtering, and annotations.
2.3. IHC
We used an automated immunostainer (ULTRA, Ventana Medical Systems, Roche,
Tucson, AZ, USA) with the following antibodies: VENTANA anti-ALK (D5F3) rabbit
monoclonal primary antibody (Ventana Medical Systems, AZ, USA), ROS1 (D4D6) rabbit
monoclonal antibody (Cell Signaling Technology, Inc., Danvers, MA, USA), and PD-L1
Dako 22C3 anti-PD-L1 primary antibody (Agilent, Santa Clara, CA, USA). For PD-L1, we
relied on a laboratory-based test, which provided results comparable to those reported
in the literature, as previously described [27]. Sections of 4 µm thickness were mounted
on positively charged slides. EZ Prep solution (Ventana Medical Systems) was used to
remove paraffin and reaction buffer to rinse the slides between the staining steps. Antigen
retrieval was performed using Cell Conditioning 1 (CC1) (pH 8.0) antigen retrieval solution
(Ventana Medical Systems) for 64 min at 95 ◦ C. For ALK, specimens were incubated with
primary anti-ALK antibody (prediluted) for 16 min, using OptiView DAB Detection and
Amplification. For ROS1, specimens were incubated with primary anti-ROS1 antibody at
a concentration of 1:100 for 32 min. For PD-L1, specimens were incubated with primary
anti-PD-L1 antibody at a concentration of 1:25 for 64 min at 37 ◦ C, followed by using an
OptiView DAB IHC Detection Kit. The slides were stained with hematoxylin and covered
with coverslips. Appropriate positive controls were used for each run. In PD-L1 staining,
an internal control (normal tonsil) was added to each slide.
The staining was evaluated using a specific scoring system. For ALK, cases were scored
as positive or negative, according to the manufacturer’s instructions [28]. For ROS1, cases
were scored as moderate (2+) or strong (3+) intensity of cytoplasmic staining with at least
50% of neoplastic cells [29]. For PD-L1, cases were considered adequate if at least 100 tumor
cells were available. The slides were viewed by one qualified pathologist, with a collegial
discussion of the difficult cases. According to the Tumor Proportion Score (TPS), cases
were scored for PD-L1 in three groups: (1) less than 1% positive cells (TPS < 1%, negative),
(2) 1–49% positive cells (TPS: 1–49%, low expression), and (3) at least 50% positive cells
(TPS ≥ 50%, high expression) [30].
Curr. Oncol. 2023, 30
10022
2.4. Statistical Analysis
Overall survival (OS) and progression-free survival (PFS) were estimated using
Kaplan–Meier survival curves. OS was defined as the time from the date of molecular analysis (corresponding to the diagnosis of metastatic/advanced disease) to the date
of death or the last follow-up for living patients. PFS was defined as the time from the
date of molecular analysis to the date of radiological/clinical progression or death from
any cause, whichever occurred first, or the last follow-up visit for patients who were alive
without disease progression. In the case of no data on disease progression, we used the
date of death to calculate PFS. The log-rank test was used to compare OS and PFS between
the different subgroups. Median OS and PFS with a 95% confidence interval (CI) were
calculated. Multivariate Cox regression analysis was subsequently performed to further
evaluate the validity of the significant variables for both OS and PFS.
We examined the differences for V600E vs. non-V600E, and BRAF alone vs. BRAF with
co-mutations. We used the Mann–Whitney test for non-parametric variables to compare
the values in different categories. Statistical significance (p) was set at 0.05, using a 2-tailed
hypothesis. Statistical analyses were performed using Microsoft Excel 2020 (Microsoft
Corp., Redmond, WA, USA) and SPSS version 25 (IBM Corp., Armonk, NY, USA).
3. Results
3.1. Case Series
A total of 60 NSCLCs with BRAF mutation were retrieved. One additional case showed
only a BRAF copy number alteration (with no BRAF mutation) and was excluded from this
series. No cases with BRAF fusion were found.
All cases were NSCLCs, predominantly adenocarcinomas (55 cases, 91.7%), with
2 (3.3%) NSCLCs not otherwise specified (NOS), 1 (1.7%) squamous cell carcinoma, 1 (1.7%)
adenosquamous carcinoma, and 1 (1.7%) carcinoma with sarcomatoid features. Detailed
information is summarized in Supplementary Table S1 for pathological features (in all
60 cases) and in Supplementary Table S2 for clinical stage (in 44/60 cases) and therapeutic
regimens (in 54/60 cases).
Molecular analysis was performed on bioptic material in 32 cases (53.3%), cytological
material (smears or cell blocks) in 19 cases (31.7%), and surgical resection in 9 cases (15.0%).
The 60 BRAF-mutated cases were subdivided into 24/60 (40.0%) V600E and 36/60
(60.0%) non-V600E. Among the non-V600E BRAF mutations, the most frequent mutations
were the following: G466A, D594N, G469A, and N581S (8,3%, 6.7%, 6.7%, and 6.7% of all
BRAF mutations, respectively). A summary of BRAF mutations is illustrated in Figure 1a,b
and specifically described in Table 1.
(a)
(b)
Figure 1. Summary of identified BRAF mutations. (a) V600E vs. non-V600E; (b) V600E and all
other non-V600E mutations.
Curr. Oncol. 2023, 30
10023
Table 1. Summary of all identified BRAF mutations.
Mutation
N. (%)
Mutation
N. (%)
V600E
24 (40.0)
V600E
24 (40.0)
G466A
5 (8.3)
non-V600E
Total
36 (60.0)
D594N
4 (6.7)
G469A
4 (6.7)
N581S
4 (6.7)
G466V
3 (5.0)
G469V
3 (5.0)
G464V
2 (3.3)
K601E
2 (3.3)
D594F
1 (1.7)
D594G
1 (1.7)
E586G
1 (1.7)
G258V
1 (1.7)
G596R
1 (1.7)
L584F
1 (1.7)
L597Q
1 (1.7)
N581I
1 (1.7)
V471F
1 (1.7)
60
BRAF mutation was present alone in 39/60 (65.0%) cases and in combination with
other co-mutations in 21/60 (35.0%) cases. Associated co-mutations included predominantly KRAS, PIK3CA, and EGFR (38.1%, 23.8%, and 9.5%, respectively). Specifically,
co-mutations involved the following genes: KRAS (8/21), PIK3CA (5/21, 1 with KRAS
as well), EGFR (2/21, 1 with KRAS as well), IDH1 (2/21), FGFR3 (2/21), MET (1/21
with KRAS as well), GNAQ (1/21), CDH4 (1/21), AKT1, and MTOR (1/21). Among
V600E-mutated cases, co-mutations were detected in 6/24 cases (25.0%), whereas among
non-V600E cases, co-mutations were slightly elevated, representing 15/36 cases (41.7%).
The types and frequencies of specific co-mutations are summarized in Table 2.
Using IHC, ALK and ROS1 were available in 42 cases, and both were negative in all
42 cases. PD-L1 was determined in 53 cases, with the following results: 7 (13.2%) negative
cases (TPS < 1%), 25 cases (47.2%) with low expression (TPS: 1–49%), and 21 cases (39.6%)
with high expression (TPS ≥ 50%).
Follow-up data on mortality and progression were available for 54/60 (90%) cases,
ranging from 0 to 49 months (mean: 13.0 ± 13.7, median: 8.0): 22 with V600E mutation
and 32 with non-V600E mutations; 18 with co-mutations and 36 without co-mutations.
Among the 22 V600E cases with follow-up, 11/22 (50.0%) received specific targeted therapy
against BRAF (alone or in combination with chemotherapy) (8 in first-line and 3 in secondline), 5/22 (22.7%) received other therapies, 5/22 (22.7%) received no therapy (only best
supportive care), and 1/22 (4.5%) had no data on the specific therapy administered. Among
non-V600E cases, no targeted therapy was administered. Overall, 36/60 (60.0%) patients
died; one 96-year-old patient was considered censored (died of other causes), whereas
the other 35/60 (58.3%) patients were considered to have died of the disease. Progression
was observed in 5/60 (8.3%) cases. Detailed information on survival data (OS and PFS) is
presented in Supplementary Table S3.
Curr. Oncol. 2023, 30
10024
Table 2. Co-mutations associated with BRAF. Summary of all detected co-mutations associated with
BRAF mutation.
Gene
N. (%)
KRAS
KRAS, EGFR
KRAS, MET
KRAS, PAM2K1
KRAS, PIK3CA
4 (19.0)
1 (4.8)
1 (4.8)
1 (4.8)
1 (4.8)
KRAS (all)
PIK3CA
N. (%)
8 (38.1)
4 (19.0)
PIK3CA (all)
IDH1
FGFR3
EGFR
5 (23.8)
2 (9.5)
2 (9.5)
1 (4.8)
EGFR (all)
2 (9.5)
ESR1
GNAQ
CDH4
AKT1, MTOR
1 (4.8)
1 (4.8)
1 (4.8)
1 (4.8)
Total
21
3.2. Statistical Analysis
Using the log-rank test, survival analyses revealed a significantly better prognosis in
22 V600E patients than in 32 non-V600E patients, in terms of both OS (p = 0.008, Figure 2a)
and PFS (p = 0.018, Figure 2b). The median OS was 23 months in V600E (95% CI 12.8–33.2)
and 6 months in non-V600E (95% CI 2.0–10.0). The median PFS was 17 months in V600E
(95% CI 6.0–28.0) and 5 months in non-V600E (95% CI 3.0–7.0). The better prognosis of
patients with V600E compared to those with non-V600E was further confirmed when the
analysis was restricted to patients who did not receive anti-BRAF targeted therapy (12 cases
with V6000E and 32 cases with non-V600E), with significance for PFS (p = 0.036, Figure 3b)
but not for OS (p = 0.103, Figure 3a). In this comparison, we excluded one case from the
V600E subgroup since we did not have detailed information on specific treatment. We did
not exclude any cases from the non-V600E subgroup because they were not treated with
anti-BRAF targeted therapy in the institutions enrolled in this study (anti-BRAF targeted
therapy was administered only in V600E cases). Multivariate Cox regression analysis of
40/60 cases showed that V600E (p = 0.008 for OS, p = 0.017 for PFS) and type of therapy
(p = 0.006 for OS, p = 0.009 for PFS) were significant variables, whereas stage reached statistical significance only for OS (p = 0.049) and not for PFS (p = 0.055). Detailed information
on the Cox regression analysis is summarized in Supplementary Table S4.
In contrast, co-mutations did not affect prognosis, neither in terms of OS (p = 0.590,
Figure 4a) nor PFS (p = 0.938, Figure 4b). The median OS was 8 months in 18 cases with
co-mutations (95% CI 0–27.6) and 10 months in 36 cases without co-mutations (95% CI
3.7–16.3). The median PFS was 6 months in 18 cases with co-mutations (95% CI 3.2–8.8)
and 6 months in 36 cases without co-mutations (95% CI 0–12.8).
We subsequently examined the differences in various parameters between V600E and
non-V600E mutations, and between co-mutated and non-co-mutated cases. Using the
Mann–Whitney test, age, sex, histotype, material, smoking status, and PD-L1 expression
were variably distributed, with no significant difference between V600E and non-V600E
cases, or BRAF alone and BRAF with co-mutations (Table 3). Co-mutations were slightly
more frequent in non-V600E cases (15/36, 41.7%) than in V600E cases (6/24, 25.0%); however, this difference was not statistically significant. Values close to significant (but still not
significant) were found in comparisons of smoking status, both in V600E vs. non-V600E
(p = 0.08) and in co-mutated vs. non-co-mutated (p = 0.07). However, this comparison was
not relevant because the vast majority of these patients were current smokers or ex-smokers,
and only 2/35 (5.7%) were non-smokers.
Curr. Oncol. 2023, 30
10025
(a)
(b)
Figure 2. Survival curves comparing V600E and non-V600E mutations. Cases with V600E mutations
tt
(22 cases, blue lines) showed better prognosis than those with non-V600E mutations (32 cases, red
lines): (a) overall survival (OS) (p = 0.008); (b) progression-free survival (PFS) (p = 0.018).
(a)
(b)
Figure 3. Survival curves comparing V600E and non-V600E mutations without targeted therapy. Targeted therapy may be used in BRAF-mutated patients, especially in those harboring V600E. Without
tt
targeted therapy, cases with V600E mutations (12 cases, blue lines) exhibited a better prognosis than
cases with non-V600E mutations (32 cases, red lines): (a) overall survival (OS), without statistical
significance (p = 0.103); (b) progression-free survival (PFS), with statistical significance (p = 0.036).
ff
(a)
(b)
Figure 4. Cases with co-mutations (18 cases, blue lines) and without co-mutations (36 cases, red lines)
showed no significant differencesff in prognosis: (a) overall survival (OS) (p = 0.590); (b) progressionfree survival (PFS) (p = 0.938).
ff
ff
Curr. Oncol. 2023, 30
10026
Table 3. Clinicopathological features of BRAF-mutated carcinoma, focusing on differences of V600E vs. non-V600E and with vs. without co-mutations. No significant
differences were observed in any of the comparisons (SD: standard deviation).
Overall
V600E
Non-V600E
N.
60
24/60 (40.0%)
36/60 (60.0%)
Age (mean ± SD)
71.2 ± 9.9
71.3 ± 11.1
71.1 ± 9.1
0.92
0.13
Sex
Histotype
Material
Smoking status (data
available in 35 cases)
PD-L1 (total: 53)
ALK (total: 42)
ROS1 (total: 42)
Co-mutations
male
37/60 (61.7%)
12/24 (50.0%)
25/36 (69.4%)
female
23/60 (38.3%)
12/24 (50.0%)
11/36 (30.6%)
p-Value
without
Co-Mutations
21/60 (35.0%)
39/60 (65.0%)
70.0 ± 10.8
71.8 ± 9.5
0.74
15/21 (71.4%)
22/39 (56.4%)
0.26
6/21 (28.6%)
17/39 (43.6%)
adenocarcinoma
55/60 (91.7%)
24/24 (100.0%)
31/36 (86.1%)
18/21 (85.7%)
37/39 (94.9%)
squamous cell carcinoma
1/60 (1.7%)
0/24
1/36 (2.8%)
0/21
1/39 (2.6%)
NSCLC, NOS and other
histotypes
4 (6.7%)
0/24
4/36 (11.1%)
3/21 (14.3%)
1/39 (2.6%)
cytological
19/60 (31.7%)
8/24 (33.3%)
11/36 (30.6%)
5/21 (23.8%)
14/39 (35.9%)
bioptic
32/60 (53.3%)
11/24 (45.8%)
21/36 (58.3%)
15/21 (71.4%)
17/39 (43.6%)
surgical
9/60 (15.0%)
5/24 (20.8%)
4/36 (11.1%)
1/21 (4.8%)
8/39 (20.5%)
non-smokers
2/35 (5.7%)
2/14 (14.3%)
0/21
current smokers
11/35 (31.4%)
3/14 (21.4%)
8/21 (38.1%)
0.6
with Co-Mutations
0.76
0.86
1/13 (7.7%)
1/22 (4.5%)
1/13 (7.7%)
10/22 (45.5%)
11/13 (84.6%)
11/22 (50.0%)
1/13 (7.7%)
1/22 (4.5%)
12/13 (92.3%)
21/22 (95.5%)
4/19 (21.1%)
3/34 (8.8%)
ex-smokers
22/35 (62.9%)
9/14 (64.3%)
13/21 (61.9%)
non-smokers
2/35 (5.7%)
2/14 (14.3%)
0/21
smokers (current and ex-)
33/35 (94.3%)
12/14 (85.7%)
21/21 (100.0%)
TPS < 1%
7/53 (13.2%)
3/21 (14.3%)
4/32 (12.5%)
TPS 1–49%
25/53 (47.2%)
9/21 (42.9%)
16/32 (50.0%)
7/19 (36.8%)
18/34 (52.9%)
TPS ≥ 50%
21/53 (39.6%)
9/21 (42.9%)
12/32 (37.5%)
8/19 (42.1%)
13/34 (38.2%)
negative
42 (100%)
17
25
16
26
17
25
16
26
6/24 (25.0%)
15/36 (41.7%)
positive
0
negative
42 (100%)
positive
0.08
0.81
0
21/60 (35.0%)
0.19
p-Value
0.21
0.97
0.07
0.7
0.79
Curr. Oncol. 2023, 30
10027
4. Discussion
This study showed that among BRAF-mutated NSCLCs:
1.
2.
Patients with the V600E mutation had a better prognosis than those with non-V600E
mutations.
Associated co-mutations were not rare (35.0%) and did not affect prognosis.
BRAF mutations are seldom detected in lung tumors, with frequencies varying from
2.2% [12] to 4.9% [13] in lung adenocarcinoma and reaching up to 5.4% [31] in NSCLC.
Overall, BRAF mutations in NSCLC show an intermediate frequency between EGFR
mutations and ROS1 rearrangements, similar to ALK rearrangement [25], and deserve
special attention for the possible use of targeted therapy.
BRAF mutations are subdivided into V600E and non-V600E mutations. In our series
(54 cases with FU), we reported a significantly better prognosis for V600E patients than
for non-V600E patients, both in terms of OS (p = 0.008) and PFS (p = 0.018). Studies in the
literature have reported conflicting results. In a series of 36 BRAF-mutated cases, Cardarella
et al. described no prognostic difference between V600E and non-V600E [24]. Among
36 BRAF-mutated cases, Marchetti et al. reported a worse prognosis in V600E cases [13].
Conversely, in 380 BRAF-mutated cases, Sakai et al. detected a better prognosis in V600E
cases [23]. The discrepancies may be due to the evolving role of specific targeted therapies
that mainly address V600E cases. In our series, we repeated the survival analyses in V600E
patients who did not receive any targeted therapy, and the prognostic advantage of V600E
was statistically confirmed only in PFS (p = 0.036, Figure 3b); a better prognosis was also
evident in OS even if it was not statistically significant (Figure 3a). These conflicting results
may also be partially explained by the limited number of cases examined in different studies,
given the relatively low frequency of these mutations in the landscape of all NSCLCs.
However, the study with the most cases examined in the literature was that described
by Sakai [23], who provided results apparently in accordance with ours, underlining the
overall better prognosis of cases harboring the V600E mutation.
The better prognosis of V600E cases is clinically important and may be useful in correctly evaluating patients affected by NSCLCs. In NSCLCs, targeted therapy (BRAF/MEK
inhibitors) is usually administered to patients carrying the V600E mutation [32]. When
evaluating the responsiveness to a specific therapy, the better prognosis intrinsically associated with V600E may represent an important bias. This was also confirmed in our series by
the better prognosis of V600E-mutated patients who were not treated with targeted therapy,
especially when examined for PFS. For future studies, it may be clinically important to
consider the better prognosis associated with V600E cases by not directly comparing them
with non-V600E cases or using adequate statistical corrections.
BRAF-mutated NSCLSs may be associated with co-mutations in other genes. In
our study, BRAF-mutated NSCLCs were associated with co-mutations in a considerable
proportion of cases: 21/60 (35.0%). Co-mutations mainly involved KRAS and PIK3CA,
as described by Sakai [23], who also found p53 mutations that were not detected in our
series. Sheikine described the co-occurrence of SETD2, SMAD4, and PIK3CA in V600E and
of KEAP1, NF1, MET, RICTOR, KRAS, MYC, STK11, and TP53 in non-V600E [25]. The
role of co-mutations has recently become more important in the development of cancer,
as their presence may change the development of neoplastic disease, its prognosis, and
response to therapy [33]. In lung cancer, co-occurring genomic alterations, particularly in
TP53 and LKB1 (also known as STK11), have been proven to be core determinants of the
molecular and clinical heterogeneity of oncogene-driven subgroups [34]. Co-mutations may
modulate responsiveness to immune checkpoint inhibitors [35]. Co-mutations (particularly
p53) may reduce responsiveness to anti-EGFR tyrosine kinase inhibitors in EGFR-mutated
NSCLCs [36,37]. However, little is known about the prognostic role of co-mutations in
BRAF-mutated NSCLCs and their possible role in developing resistance to BRAF inhibitors.
The detection of co-mutations may raise suspicion if their presence reduces the efficacy of
therapies that specifically target BRAF. In our study, the presence of co-mutations associated
Curr. Oncol. 2023, 30
10028
with BRAF did not affect prognosis, neither in OS nor in PFS. Furthermore, the number of
co-mutations was slightly higher in non-V600E patients than in V600E patients; however,
this difference was not statistically significant. Hence, the presence of co-mutations did not
affect the prognosis of BRAF-mutated NSCLCs, without significant differences between
V600E and non-V600E cases. A clinical consequence may be that the detection of possible
co-mutations may not change the therapeutic approach for BRAF-mutated NSCLCs (both
V600E and non-V600E).
In our study, PD-L1 immunoreactivity showed no significant variation among different
classes. We did not observe any trend or statistical significance in PD-L1 expression between
the V600E and non-V600E subgroups; high PD-L1 expression was present in 42.9% of
V600E cases and in 37.5% of non-V600E cases (p = 0.81). Perrone et al. found no statistical
significance but described a trend towards increased PD-L1 expression in the non-V600E
population [31]. They reported high PD-L1 expression in 30% of V600E cases and 47% of
non-V600E cases. Dudnik et al. reported a slight association between non-V600E cases and
elevated PD-L1 expression (42% in V600E and 50% in non-V600E), even though the values
were close to significance (p = 0.051) [38]. In contrast, Gibson et al. observed higher PD-L1
expression in V600E (60% of cases) than in non-V600E (39% of cases), but again with no
statistical significance (p = 0.27) [39]. Independently from PD-L1 expression, recent reports
have underlined the important use of immune checkpoint inhibitors in BRAF-mutated
NCSLCs, with a limited distinction between V600E and non-V600E [40].
The limitations of this study may be related to the fact that the samples were collected
from four different centers using different pre-analytical procedures. However, a centralized
molecular laboratory carried out all analyses in this study. Another critical point may be
related to the subdivisions of BRAF mutations, which were classified as V600E or nonV600E. A more precise classification subdivides BRAF mutations into three classes [17],
with V600 in class 1 and non-V600 in classes 2 and 3. We did not use this more complex
classification, even though it is more precise, because we wanted to analyze the impact of
V600E on prognosis considering its important role in therapeutic decisions. Finally, the
evaluation of PFS may be limited by the fact that when data on progression were lacking,
we used the date of death instead of the date of progression. However, most significant
analyses were also confirmed for OS, which also plays a more important role than PFS in
prognosis evaluation.
5. Conclusions
This study shows that BRAF-mutated NSCLCs are a heterogeneous group that can
be subdivided into two main subgroups: those with V600E mutations and those with
non-V600E mutations. Patients with the V600E mutations show a better prognosis than
those with non-V600E mutations. Conversely, the presence of associated co-mutations does
not affect prognosis. These features may have clinical implications. Most importantly, the
presence of a co-mutation in BRAF-mutated NSCLCs does not seem to affect the natural
history of the disease. The conflicting results reported in the literature may be better defined
by more extensive studies.
Supplementary Materials: The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/curroncol30110728/s1, Table S1: Pathological features of all cases;
Table S2: Clinical stages and therapeutic regimens of all cases; Table S3: Data on OS and PFS; Table
S4: Summary of the Cox regression multivariate analysis.
Author Contributions: Conceptualization, G.R. and A.A.-S.; methodology, A.A.-S., C.R. and P.U.;
software, A.A.-S. and F.L.; validation, A.A.-S. and P.U.; formal analysis, A.A.-S.; investigation (pathological evaluation), A.A.-S., F.L., S.N., R.P. and M.V.; investigation (molecular analysis), C.R., L.C.,
E.C. and D.C.; investigation (clinical follow-up), C.B. and P.C.; resources, C.R.; data curation, C.R.;
writing—original draft preparation, A.A.-S.; writing—review and editing, P.U. and G.R.; visualization,
A.A.-S.; supervision, G.R.; project administration, G.R. and A.A.-S. All authors have read and agreed
to the published version of the manuscript.
Curr. Oncol. 2023, 30
10029
Funding: This research received no external funding.
Institutional Review Board Statement: This study was conducted in accordance with the Declaration
of Helsinki. Ethical review and approval were waived for this study. Data were already collected for
internal controls, completely anonymized, and subsequently organized for statistical purposes. No
additional analyses were performed for this specific study. No identified information of patients was
used; hence, the ethical approval was not required for this study.
Informed Consent Statement: Due to the retrospective nature of this study and since the data were
anonymized, the need for informed consent was waived.
Data Availability Statement: The data that support the findings of this study are available from the
corresponding author upon reasonable request.
Acknowledgments: The graphical abstract was partly generated using Servier Medical Art (https:
//smart.servier.com, accessed on 28 September 2023), provided by Servier, licensed under a Creative
Commons Attribution 3.0 unported license.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or
in the decision to publish the results.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Ibodeng, G.; Uche, I.N.; Mokua, R.; Galo, M.; Odigwe, B.; Galeas, J.N.; Dasgupta, S. A Snapshot of Lung Cancer: Where Are We
Now?—A Narrative Review. Ann. Transl. Med. 2023, 11, 261. [CrossRef]
Singh, N.; Temin, S.; Baker, S.; Blanchard, E.; Brahmer, J.R.; Celano, P.; Duma, N.; Ellis, P.M.; Elkins, I.B.; Haddad, R.Y.; et al.
Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline. J. Clin. Oncol. 2022, 40,
3310–3322. [CrossRef] [PubMed]
Proietti, I.; Skroza, N.; Michelini, S.; Mambrin, A.; Balduzzi, V.; Bernardini, N.; Marchesiello, A.; Tolino, E.; Volpe, S.; Maddalena,
P.; et al. BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions. Cancers 2020, 12, 1823. [CrossRef] [PubMed]
Crispo, F.; Notarangelo, T.; Pietrafesa, M.; Lettini, G.; Storto, G.; Sgambato, A.; Maddalena, F.; Landriscina, M. BRAF Inhibitors in
Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives. Cancers 2019, 11, 1388. [CrossRef]
Van Cutsem, E.; Cervantes, A.; Adam, R.; Sobrero, A.; Van Krieken, J.H.; Aderka, D.; Aranda Aguilar, E.; Bardelli, A.; Benson, A.;
Bodoky, G.; et al. ESMO Consensus Guidelines for the Management of Patients with Metastatic Colorectal Cancer. Ann. Oncol.
2016, 27, 1386–1422. [CrossRef] [PubMed]
Grassi, E.; Corbelli, J.; Papiani, G.; Barbera, M.A.; Gazzaneo, F.; Tamberi, S. Current Therapeutic Strategies in BRAF-Mutant
Metastatic Colorectal Cancer. Front. Oncol. 2021, 11, 601722. [CrossRef]
Malapelle, U.; Rossi, G.; Pisapia, P.; Barberis, M.; Buttitta, F.; Castiglione, F.; Cecere, F.L.; Grimaldi, A.M.; Iaccarino, A.; Marchetti,
A.; et al. BRAF as a Positive Predictive Biomarker: Focus on Lung Cancer and Melanoma Patients. Crit. Rev. Oncol./Hematol. 2020,
156, 103118. [CrossRef]
Guaitoli, G.; Zullo, L.; Tiseo, M.; Dankner, M.; Rose, A.A.; Facchinetti, F. Non-Small-Cell Lung Cancer: How to Manage
BRAF-Mutated Disease. Drugs Context 2023, 12, 1–19. [CrossRef] [PubMed]
Puri, M.; Gawri, K.; Dawar, R. Therapeutic Strategies for BRAF Mutation in Non-Small Cell Lung Cancer: A Review. Front. Oncol.
2023, 13, 1141876. [CrossRef]
Melosky, B.; Wheatley-Price, P.; Juergens, R.A.; Sacher, A.; Leighl, N.B.; Tsao, M.-S.; Cheema, P.; Snow, S.; Liu, G.; Card, P.B.; et al.
The Rapidly Evolving Landscape of Novel Targeted Therapies in Advanced Non-Small Cell Lung Cancer. Lung Cancer 2021, 160,
136–151. [CrossRef]
Owsley, J.; Stein, M.K.; Porter, J.; In, G.K.; Salem, M.; O’Day, S.; Elliott, A.; Poorman, K.; Gibney, G.; VanderWalde, A. Prevalence
of Class I–III BRAF Mutations among 114,662 Cancer Patients in a Large Genomic Database. Exp. Biol. Med. 2021, 246, 31–39.
[CrossRef] [PubMed]
Villaruz, L.C.; Socinski, M.A.; Abberbock, S.; Berry, L.D.; Johnson, B.E.; Kwiatkowski, D.J.; Iafrate, A.J.; Varella-Garcia, M.;
Franklin, W.A.; Camidge, D.R.; et al. Clinicopathologic Features and Outcomes of Patients with Lung Adenocarcinomas
Harboring BRAF Mutations in the Lung Cancer Mutation Consortium: BRAF Mutations in Lung Adenocarcinomas. Cancer 2015,
121, 448–456. [CrossRef] [PubMed]
Marchetti, A.; Felicioni, L.; Malatesta, S.; Grazia Sciarrotta, M.; Guetti, L.; Chella, A.; Viola, P.; Pullara, C.; Mucilli, F.; Buttitta, F.
Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Harboring BRAF Mutations. J. Clin. Oncol. 2011, 29,
3574–3579. [CrossRef] [PubMed]
Chen, D.; Zhang, L.-Q.; Huang, J.-F.; Liu, K.; Chuai, Z.-R.; Yang, Z.; Wang, Y.-X.; Shi, D.-C.; Liu, Q.; Huang, Q.; et al. BRAF
Mutations in Patients with Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. PLoS ONE 2014, 9, e101354.
[CrossRef] [PubMed]
Curr. Oncol. 2023, 30
15.
16.
17.
10030
Sholl, L.M. A Narrative Review of BRAF Alterations in Human Tumors: Diagnostic and Predictive Implications. Precis. Cancer
Med. 2020, 3, 26. [CrossRef]
Nguyen-Ngoc, T.; Bouchaab, H.; Adjei, A.A.; Peters, S. BRAF Alterations as Therapeutic Targets in Non–Small-Cell Lung Cancer.
J. Thorac. Oncol. 2015, 10, 1396–1403. [CrossRef]
Dankner, M.; Wang, Y.; Fazelzad, R.; Johnson, B.; Nebhan, C.A.; Dagogo-Jack, I.; Myall, N.J.; Richtig, G.; Bracht, J.W.P.; Gerlinger,
M.; et al. Clinical Activity of Mitogen-Activated Protein Kinase–Targeted Therapies in Patients With Non–V600 BRAF-Mutant
Tumors. JCO Precis. Oncol. 2022, 6, e2200107. [CrossRef]
Curr. Oncol. 2023, 30
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
10031
Leonetti, A.; Facchinetti, F.; Rossi, G.; Minari, R.; Conti, A.; Friboulet, L.; Tiseo, M.; Planchard, D. BRAF in Non-Small Cell Lung
Cancer (NSCLC): Pickaxing Another Brick in the Wall. Cancer Treat. Rev. 2018, 66, 82–94. [CrossRef]
Mazieres, J.; Cropet, C.; Montané, L.; Barlesi, F.; Souquet, P.J.; Quantin, X.; Dubos-Arvis, C.; Otto, J.; Favier, L.; Avrillon, V.; et al.
Vemurafenib in Non-Small-Cell Lung Cancer Patients with BRAFV600 and BRAFnonV600 Mutations. Ann. Oncol. 2020, 31,
289–294. [CrossRef]
Odogwu, L.; Mathieu, L.; Blumenthal, G.; Larkins, E.; Goldberg, K.B.; Griffin, N.; Bijwaard, K.; Lee, E.Y.; Philip, R.; Jiang, X.; et al.
FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring
BRAF V600E Mutations. Oncologist 2018, 23, 740–745. [CrossRef]
Noeparast, A.; Teugels, E.; Giron, P.; Verschelden, G.; De Brakeleer, S.; Decoster, L.; De Grève, J. Non-V600 BRAF Mutations
Recurrently Found in Lung Cancer Predict Sensitivity to the Combination of Trametinib and Dabrafenib. Oncotarget 2017, 8,
60094–60108. [CrossRef]
Abuali, I.; Lee, C.-S.; Seetharamu, N. A Narrative Review of the Management of BRAF Non-V600E Mutated Metastatic Non-Small
Cell Lung Cancer. Precis. Cancer Med. 2022, 5, 13. [CrossRef]
Sakai, T.; Matsumoto, S.; Ueda, Y.; Shibata, Y.; Ikeda, T.; Nakamura, A.; Kodani, M.; Ohashi, K.; Furuya, N.; Izumi, H.; et al.
Clinico-Genomic Features and Targetable Mutations in Non-Small Cell Lung Cancers Harboring BRAF Non-V600E Mutations: A
Multi-Institutional Genomic Screening Study (LC-SCRUM-Asia). J. Thorac. Oncol. 2023, 18, 1538–1549. [CrossRef] [PubMed]
Cardarella, S.; Ogino, A.; Nishino, M.; Butaney, M.; Shen, J.; Lydon, C.; Yeap, B.Y.; Sholl, L.M.; Johnson, B.E.; Jänne, P.A. Clinical,
Pathologic, and Biologic Features Associated with BRAF Mutations in Non–Small Cell Lung Cancer. Clin. Cancer Res. 2013, 19,
4532–4540. [CrossRef]
Sheikine, Y.; Pavlick, D.; Klempner, S.J.; Trabucco, S.E.; Chung, J.H.; Rosenzweig, M.; Wang, K.; Velcheti, V.; Frampton, G.M.; Peled,
N.; et al. BRAF in Lung Cancers: Analysis of Patient Cases Reveals Recurrent BRAF Mutations, Fusions, Kinase Duplications, and
Concurrent Alterations. JCO Precis. Oncol. 2018, 2, 1–15. [CrossRef] [PubMed]
Eisenhauer, E.A.; Therasse, P.; Bogaerts, J.; Schwartz, L.H.; Sargent, D.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney,
M.; et al. New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (Version 1.1). Eur. J. Cancer 2009, 45,
228–247. [CrossRef]
Ambrosini-Spaltro, A.; Dubini, A.; Pieri, F.; Ravaglia, C.; Delmonte, A.; Poletti, V. PD-L1 Expression in NSCLC: Role of Cell Blocks
and Concordance between Samples. Diagn. Cytopathol. 2021, 49, 303–310. [CrossRef]
Wong, D.W.-S.; Leung, E.L.-H.; So, K.K.-T.; Tam, I.Y.-S.; Sihoe, A.D.-L.; Cheng, L.-C.; Ho, K.-K.; Au, J.S.-K.; Chung, L.-P.; Pik
Wong, M.; et al. The EML4-ALK Fusion Gene Is Involved in Various Histologic Types of Lung Cancers from Nonsmokers with
Wild-Type EGFR and KRAS. Cancer 2009, 115, 1723–1733. [CrossRef] [PubMed]
Jain, D.; Nambirajan, A.; Borczuk, A.; Chen, G.; Minami, Y.; Moreira, A.L.; Motoi, N.; Papotti, M.; Rekhtman, N.; Russell, P.A.;
et al. Immunocytochemistry for Predictive Biomarker Testing in Lung Cancer Cytology. Cancer Cytopathol. 2019, 127, 325–339.
[CrossRef]
Herbst, R.S.; Baas, P.; Kim, D.-W.; Felip, E.; Pérez-Gracia, J.L.; Han, J.-Y.; Molina, J.; Kim, J.-H.; Arvis, C.D.; Ahn, M.-J.; et al.
Pembrolizumab versus Docetaxel for Previously Treated, PD-L1-Positive, Advanced Non-Small-Cell Lung Cancer (KEYNOTE010): A Randomised Controlled Trial. Lancet 2016, 387, 1540–1550. [CrossRef]
Perrone, F.; Mazzaschi, G.; Minari, R.; Verzè, M.; Azzoni, C.; Bottarelli, L.; Nizzoli, R.; Pluchino, M.; Altimari, A.; Gruppioni, E.;
et al. Multicenter Observational Study on Metastatic Non-Small Cell Lung Cancer Harboring BRAF Mutations: Focus on Clinical
Characteristics and Treatment Outcome of V600E and Non-V600E Subgroups. Cancers 2022, 14, 2019. [CrossRef]
O’Leary, C.G.; Andelkovic, V.; Ladwa, R.; Pavlakis, N.; Zhou, C.; Hirsch, F.; Richard, D.; O’Byrne, K. Targeting BRAF Mutations in
Non-Small Cell Lung Cancer. Transl. Lung Cancer Res. 2019, 8, 1119–1124. [CrossRef]
Jiang, L.; Yu, H.; Ness, S.; Mao, P.; Guo, F.; Tang, J.; Guo, Y. Comprehensive Analysis of Co-Mutations Identifies Cooperating
Mechanisms of Tumorigenesis. Cancers 2022, 14, 415. [CrossRef] [PubMed]
Skoulidis, F.; Heymach, J.V. Co-Occurring Genomic Alterations in Non-Small-Cell Lung Cancer Biology and Therapy. Nat. Rev.
Cancer 2019, 19, 495–509. [CrossRef] [PubMed]
Zhang, F.; Wang, J.; Xu, Y.; Cai, S.; Li, T.; Wang, G.; Li, C.; Zhao, L.; Hu, Y. Co-Occurring Genomic Alterations and Immunotherapy
Efficacy in NSCLC. NPJ Precis. Oncol. 2022, 6, 4. [CrossRef] [PubMed]
Canale, M.; Andrikou, K.; Priano, I.; Cravero, P.; Pasini, L.; Urbini, M.; Delmonte, A.; Crinò, L.; Bronte, G.; Ulivi, P. The Role of
TP53 Mutations in EGFR-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy. Cancers 2022,
14, 1143. [CrossRef]
Stockhammer, P.; Grant, M.; Wurtz, A.; Foggetti, G.; Expósito, F.; Gu, J.; Zhao, H.; Choi, J.; Chung, S.; Li, F.; et al. Co-Occurring
Alterations in Multiple Tumor Suppressor Genes Are Associated with Worse Outcomes in Patients with EGFR-Mutant Lung
Cancer. J. Thorac. Oncol. 2023. [CrossRef]
Dudnik, E.; Peled, N.; Nechushtan, H.; Wollner, M.; Onn, A.; Agbarya, A.; Moskovitz, M.; Keren, S.; Popovits-Hadari, N.;
Urban, D.; et al. BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression, Tumor Mutational Burden, Microsatellite
Instability Status, and Response to Immune Check-Point Inhibitors. J. Thorac. Oncol. 2018, 13, 1128–1137. [CrossRef]
Curr. Oncol. 2023, 30
39.
40.
10032
Gibson, A.J.W.; Pabani, A.; Dean, M.L.; Martos, G.; Cheung, W.Y.; Navani, V. Real-World Treatment Patterns and Effectiveness of
Targeted and Immune Checkpoint Inhibitor-Based Systemic Therapy in BRAF Mutation-Positive NSCLC. JTO Clin. Res. Rep.
2023, 4, 100460. [CrossRef]
Wang, H.; Cheng, L.; Zhao, C.; Zhou, F.; Jiang, T.; Guo, H.; Shi, J.; Chen, P.; Tang, Z.; Mao, S.; et al. Efficacy of Immune Checkpoint
Inhibitors in Advanced Non-Small Cell Lung Cancer Harboring BRAF Mutations. Transl. Lung Cancer Res. 2023, 12, 219–229.
[CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.