Clinical Radiology 79 (2024) e305ee316

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Clinical Radiology
journal homepage: www.clinicalradiologyonline.net

Peritumoural MRI radiomics signature of brain

metastases can predict epidermal growth factor
receptor mutation status in lung adenocarcinoma
Z. Huang a, *, X. Tu b, T. Yu a, Z. Zhan a, Q. Lin a, X. Huang a
a
Department of Radiology, Longyan First Affiliated Hospital of Fujian Medical University, No. 105 North 91 Road,
Xinluo District, Fujian, 364000, China
b
Department of Orthopedics, Longyan First Affiliated Hospital of Fujian Medical University, No. 105 North 91 Road,
Xinluo District, Fujian, 364000, China

art icl e i nformat ion AIM: To investigate whether magnetic resonance imaging (MRI) radiomics features of brain
metastases (BMs) can predict epidermal growth factor receptor (EGFR) mutation status in lung
Article history: adenocarcinoma.
Received 4 May 2023 MATERIALS AND METHODS: Between June 2014 and December 2022, 58 histopathologically
Received in revised form confirmed lung adenocarcinoma patients (27 with EGFR wild-type, 31 with EGFR mutation)
5 October 2023 who underwent gadobenate dimeglumine-enhanced brain MRI were recruited retrospectively.
Accepted 18 October 2023 A total of 123 metastatic brain lesions were allocated randomly into the training cohort (n¼86)
and test cohort (n¼37) at a ratio of 7:3. Radiomics models based on multi-sequence MRI im-
ages in different regions such as volume of interest (VOI)enhancing tumour, VOIwholetumour,
VOIperitumour 1mm, VOIperitumour 3mm, and VOIperitumour 5mm were built. The optimal radiomics
model was integrated into the clinical or radiological indicators to construct a fusion model
through multivariable logistic regression analysis.
RESULTS: The optimal radiomics model based on the VOIperitumour 1mm, a combination of nine
features selected from the fluid-attenuated inversion recovery (FLAIR) sequence, yielded areas
under the curves (AUCs) of >0.75 in the training and test cohorts. The prediction of the fusion
model with integration of clinical factors (age) and radiomics score (the optimal radiomics
model) was not better than that of the optimal radiomics model alone in the test cohort (AUC:
0.808 and 0.785, respectively, p¼0.525).
CONCLUSION: The FLAIR radiomics model based on VOIperitumour 1mm as an effective
biomarker helps predict EGFR mutation status in lung adenocarcinoma patients with BMs and
then assists clinicians in selecting optimal treatment strategies.
Ó 2023 The Authors. Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

* Guarantor and correspondent: Z. Huang, Department of Radiology, Longyan First Affiliated Hospital of Fujian Medical University, No. 105 North 91 Road,
Xinluo District, Fujian, 364000, China. Tel.: þ8613850600215.
E-mail address: tuxuezhao@163.com (Z. Huang).

https://doi.org/10.1016/j.crad.2023.10.022
0009-9260/Ó 2023 The Authors. Published by Elsevier Ltd on behalf of The Royal College of Radiologists. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
e306 Z. Huang et al. / Clinical Radiology 79 (2024) e305ee316
Introduction
Lung cancer remains the leading cause of cancer-related
death globally.1 Non-small-cell lung cancer (NSCLC) com-
prises 80% of primary lung cancers.2 Approximately 10e60%
of NSCLCs present with epidermal growth factor receptor
(EGFR) mutation,3 which can promote the proliferation,
adhesion, invasion, and metastasis of tumour cells.4 As the
most common pathological subtype of NSCLC, advanced lung
adenocarcinoma frequently presents with initial brain me-
tastases (BMs) and has a poor prognosis.5,6 The detection of
EGFR mutations in lung adenocarcinoma patients through
biopsies or resections of primary lesions has significant
limitations: (1) biopsy risks: invasive biopsies carry sub-
stantial risks, with a 35% occurrence of pneumothorax and a
0.07% mortality rate due to severe complications among
9,783 biopsies7; (2) biopsy accuracy: the accuracy rate of
detecting EGFR mutations in primary lesions, ranges from
65e85%, revealing potential inaccuracies and emphasises
the need for more reliable methods8; (3) impracticality of
direct BM sampling: obtaining tissue directly from BMs by
invasive biopsy or surgical resection is often impractical and
hazardous9; and (4) “lack of evidence for non-invasive
methods”: the inadequacy of current evidence on analysing
EGFR mutation status in BMs through serum or cerebrospinal
fluid underscores the lack of reliable non-invasive tech-
niques. In addition, evidence regarding the analyses of the
EGFR mutation status of BMs with serum or cerebrospinal
fluid specimens is insufficient.10 Thus, a non-invasive and
reliable method for identifying the EGFR mutation status in
lung adenocarcinoma patients with BMs is imperative.
Previous radiologists applied conventional images to
depict the number,11 size,11 distribution,12 homogeneity,13
and peritumoural oedema11,14 of BMs and then explored
whether radiological characteristics of BMs can predict
EGFR mutation status; however, evaluating those con-
ventional image characteristics is subjective and depends
on the clinical practice experience of radiologists.15
Radiomics can automatically extract high-dimensional
quantitative data from images and then mine the data to
capture the biological behaviour of the tumour.16 Addi-
tionally, radiomics has been widely used to identify the
presence of specific gene mutations in cancers.15
Currently, the application of radiomics signature of BMs
to determine EGFR mutation status in either BMs or pri-
mary lung cancers has received encouraging results.
Almost all prior studies were concerned with the contrast-
enhancing segmentation or the whole tumoural segmen-
tation (including necrotic areas) to reflect tumoural het-
erogeneity by single or multiple sequence magnetic
resonance imaging (MRI) radiomics rather than computed
tomography (CT) radiomics.8,17e19 Previously, Baumert
et al.20 and Neves et al.21 both confirmed that the NSCLC
presented a higher percentage of peritumoural infiltration
sites and smaller maximum peritumoural infiltration
depths than small-cell lung cancer (SCLC). Although Chen
et al.9 conducted research on the peritumoural region of
BMs, their study lacked a comprehensive investigation
into the MRI characteristics associated with different de-
grees of peritumoural expansion.
This study aims to develop MRI radiomics models based
on three peritumoural regions (1, 3, and 5 mm), in addition
to the entire tumour and enhancing tumour regions. The
study further evaluates whether incorporating clinical or
radiological features in a fusion model outperforms the
optimal radiomics model in predicting EGFR mutation sta-
tus of lung adenocarcinoma patients with BMs.
Materials and methods
Patients
This single-centre retrospective study received approval
from the institutional review board, and the requirement
for informed consent was waived. From June 2014 to
December 2022, 145 patients with histopathologically
confirmed lung adenocarcinoma and brain metastases were
identified via MRI; however, several patients were excluded
based on the following criteria (Fig 1): (1) absence of EGFR
genetic testing (n¼16); (2) insufficient MRI data (n¼36);
(3) unmeasurable brain metastases (n¼33); and (4) absence
of radiotherapy or chemotherapy treatment for brain me-
tastases (n¼2). Consequently, 58 eligible patients with 123
metastatic brain lesions met the inclusion criteria. These
patients were assigned randomly to the training cohort
(n¼86) and test cohort (n¼37) at a ratio of 7:3. Subse-
quently, each patient was categorised into either the EGFR
mutation group or the EGFR wild-type group.
EGFR genetic testing
Fifty-eight patients with lung adenocarcinoma underwent
EGFR genetic testing using amplification refractory mutation
systemepolymerase chain reaction and next-generation
sequencing technology. Twenty-seven patients were EGFR
wild-type, and 31 patients were EGFR mutation (one muta-
tion at exon 18, 13 at exon 19, four at exon 20, nine at exon 21,
two at exons 19 and 20, and two at exons 19 and 21).
MRI protocol
MRI was performed with either a 1.5 or 3 T MRI system
with a standard brain phased-array coil. Routine transverse
whole-brain MRI sequences were performed as follows: T1-
weighted imaging (T1WI), T2-weighted imaging (T2WI),
fluid-attenuated inversion recovery (FLAIR), diffusion-
weighted imaging (DWI), and contrast-enhanced T1WI
(CE-T1WI). DWI was acquired with transverse single-shot
spin-echo echo-planar imaging (SS SE-EPI) with three b-
values (0, 1,000, and 2,000 s/mm2). Apparent diffusion co-
efficient (ADC) maps were reconstructed automatically at
the console of the MRI device. Intravenous gadobenate
dimeglumine contrast agent was used at a dose of 0.2 ml/kg
body weight and a rate of 2 ml/s, followed by a 30 ml saline
flush. Detailed parameters of each acquisition sequence are
shown in Table 1.
 Z. Huang et al. / Clinical Radiology 79 (2024) e305ee316 e307

Figure 1 Flowchart of study cohort selection.

Radiomics model T1WI. Volumes of interest (VOIs) were delineated manu-

Fig. 2 provides a brief workflow of this study. The DICOM
MRI images were imported into a three-dimensional slicer
(version 5.3.0). After that, tumour segmentation was per-
formed on transverse T1WI, T2WI, FLAIR, ADC, and CE-
ally along the tumour surface, covering the whole tumour
(VOIwholetumour). After subtraction, the enhancing tumour
region (VOIenhancing tumour) involving solid components but
not necrosis was obtained. To explore the peritumoural
information, VOIwholetumour was dilated automatically by 1,

Table 1
Magnetic resonance imaging (MRI) protocol.

MRI device No. of patients Magnet (T) Sequences Parameters

Repetition time (ms) Echo time (ms) Matrix Voxel size (mm)
GE Signa HDxt 13 1.5 T1WI 5,000 107 320  192 0.75  0.75  6.00
T2WI 1,800 24 320  192 0.75  0.75  6.00
FLAIR 8,600 120 288  192 0.75  0.75  6.00
DWI 8,600 120 289  192 0.75  0.75  6.00
CE-T1WI 1,750 24 320  256 0.75  0.75  6.00
Philips Prodiva 3 1.5 T1WI 585 13 252  179 0.78  1.10  6.00
T2WI 2,500 120 368  368 0.60  0.60  6.00
FLAIR 7,500 100 244  175 0.90  1.13  6.00
DWI 3,000 82 128  110 1.72  2.00  6.00
CE-T1WI 161 2.3 356  273 0.65  0.75  6.00
Philips Achieva 17 3.0 T1WI 2,000 20 288  216 0.76  0.92  7.00
T2WI 1,991 90 400  240 0.57  0.83  7.00
FLAIR 11,000 125 352  197 0.65  0.93  7.00
DWI 2,877 50 192  90 1.20  2.56  7.00
CE-T1WI 260 4.6 400  255 0.57  0.72  5.00
Philips Ingenia II 20 3.0 T1WI 1,900 20 308  173 0.75  1.07  7.00
T2WI 4,000 104 356  356 0.65  0.65  7.00
FLAIR 9,000 101 260  185 0.70  1.23  7.00
DWI 2,314 90 144  110 1.60  2.09  7.00
CE-T1WI 257 4.6 400  255 0.57  0.72  5.00
Philips Ingenia cx 5 3.0 T1WI 2,000 20 356  201 0.65  0.94  5.00
T2WI 6,278 95 272  272 0.85  0.85  5.00
FLAIR 8,000 125 352  173 0.65  1.05  5.00
DWI 3,020 86 152  98 1.51  2.35  5.00
CE-T1WI 272 2.3 356  164 0.90  1.12  5.00

T1WI, T1-weighted imaging; T2WI, T2-weighted imaging; FLAIR, fluid-attenuated inversion recovery; DWI, diffusion-weighted imaging; CE-T1WI, contrast-
enhanced T1-weighted images.
e308 Z. Huang et al. / Clinical Radiology 79 (2024) e305ee316
Figure 2 A brief workflow of the study.
3, and 5 mm (VOIperitumour 1mm, VOIperitumour 3mm, and
VOIperitumour 5mm), excluding the tumour region. Addition-
ally, the MRI images of 20 patients were selected randomly
for re-segmentation 1 month later. Meanwhile, the VOIs in
20 cases were re-delineated by another radiologist with 11
years of experience in neurology.
Image pre-processing was performed before feature
extraction. First, the images were resampled to a voxel size
of 3  3  3 mm3 using B-spline interpolation to address
inconsistent spatial resolutions. Following the spatial
resampling, intensity values of the MRI were normalised
and discretised using Z-score standardisation and five-bins
histogram discretisation, respectively.
Radiomics features were extracted from each VOI of
every single sequence using the FeAture Explorer soft-
ware (version 0.4.2). Each set of 107 radiomics features
retrieved from the original images, including the first-
order intensity,18 three-dimensional (3D) shape fea-
tures,14 and textural features (grey-level co-occurrence
matrix [24], grey-level size zone matrix [16], grey-level
run length matrix [16], grey-level dependence matrix
[14], and neighbourhood grey-tone difference matrix [5])
were obtained. Z-score normalisation of the extracted
radiomics features was performed before feature selec-
tion. If the feature pair’s Pearson correlation coefficient
(PCC) value was more significant than 0.99, one of them
was removed enough for adequate dimension reduction
to allow model fitting. The first selected features were
again screened using the recursive feature elimination
(RFE) algorithm. The optimal radiomics parameters were
selected by the logistic regression (LR) with fivefold cross-
validation in the training cohort and were applied to the
test cohort.
For each model, the discrimination performance was
evaluated by the area under the receiver operating
characteristic curve (ROC AUC) and other diagnostic
indices, such as accuracy, sensitivity, and specificity.
Moreover, the AUC values of different models were
compared using the DeLong test. Additionally, the diag-
nostic performance of models was then quantified by
diagnostic integrated discrimination improvement (IDI).
The calibration curve and the HosmereLemeshow test
were applied to describe the agreement between radio-
mics model prediction and actual EGFR mutation.
Moreover, decision curve analysis (DCA) and clinical
impact curve (CIC) were used to assess the clinical use-
fulness and effectiveness of the radiomics model. Finally,
the radiomics score (R-score) predicting the probability
of EGFR mutation was calculated for each patient via a
linear combination of the selected features by their
respective coefficients, which was defined as the radio-
mics signature. In addition, EGFR mutational probabilities
in the training and test cohorts were detected by the
ManneWhitney U-test.
 Z. Huang et al. / Clinical Radiology 79 (2024) e305ee316
Fusion model
First, the candidate clinicaleradiological characteristics
and R-score measured from the FLAIR sequence in VOI per-
itumour 1mm were grouped using the median and cut-off
values, respectively. Next, the clinicaleradiological signa-
tures associated with EGFR mutation by univariate and
multivariate logistic regression analysis were constructed
into a fusion model. Subsequently, the output of the fusion
model was also converted into a nomogram score, which
indicated the individual probability of EGFR mutation.
Lastly, five verifications of the diagnostic nomogram used as
a graphical representation of the fusion model were per-
formed: ROC, IDI, calibration curve, the HosmereLemeshow
test, DCA, and CIC.
Statistical analyses
All numerical data were converted to categorical data,
expressed as relative distribution frequency and percent-
age. The chi-square test or Fisher’s exact test was used to
compare the baseline characteristics of the categorical var-
iables. The intraclass correlation coefficient (ICC) was used
to evaluate the intra- and interobserver reproducibility of
radiomics features.
The statistical analyses were performed using the soft-
ware IBM SPSS Statistics 22 and R software (version 4.2.0). A
two-sided p-value of <0.05 was considered statistically
significant.
Results
Clinical and radiological characteristics
The baseline clinical and radiological characteristics are
summarised in Table 2. There was no significant difference
in clinical and radiological features between the training
and test cohorts (p¼0.091e0.948). Results of the chi-square
test or Fisher’s exact test showed no significant impact of
the categorical variables on the EGFR mutation in the test
cohort (p¼0.313e1.000), whereas two radiological variables
(enhancement pattern and necrosis component) and one
clinical variable (gender) were significantly related to EGFR
mutation in the training cohort (p¼0.003e0.035).
Radiomics analysis
The detailed results of the 25 single-sequence radiomics
models based on different regions using the RFE-LR algo-
rithm are presented in Table 3 and Fig 3. The five radiomics
features derived from the FLAIR radiomics model in
VOIperitumour 1mm (radiomics model 1) showed good perfor-
mance, with a cut-off value of 0.576. In the training cohort,
the sensitivity, specificity, and accuracy were 0.711, 0.780,
and 0.744, respectively; in the test cohort, the sensitivity,
specificity, and accuracy were 0.737, 0.778, and 0.757,
respectively. The ROC curve showed AUC values of 0.746
(95% confidence interval [CI]: 0.616e0.875, p¼0.000) and
0.757 (95% CI: 0.562e0.952, p¼0.001) in the training and
e309
test cohorts, respectively. The nine radiomics features
derived from the FLAIR radiomics model in VOIperitumour 1mm
(radiomics model 2) had AUCs of 0.756 (95% CI:
0.627e0.884, p¼0.000) in the training cohort and 0.785 (95%
CI: 0.600e0.970, p¼0.000) in the test cohort. The sensitivity,
specificity, and accuracy in the training and test cohorts
were 0.756, 0.756, 0.756, 0.737, 0.833, and 0.784, respec-
tively, with a cut-off value of 0.583. The above radiomics
features demonstrated good intra- and interobserver reli-
ability, with an ICC of >0.75; however, the AUCs of radiomics
models 1 and 2 did not differ in either the training (Elec-
tronic Supplementary Material Fig. S1a, c) or test (Electronic
Supplementary Material Fig. S1b, d) cohorts (DeLong test,
p¼0.239 and p¼0.810, respectively). In addition, IDI indi-
cated no significant improvement in the predictive value of
radiomics model 2 compared to radiomics model 1 (training
cohort: IDI [95% CI] ¼ 0.035 [-0.009e0.078] and p¼0.116;
test cohort: IDI [95% CI] ¼ 0.089 [-0.001e0.180] and
p¼0.053). Although the calibration curve analysis of radio-
mics model 1 in the training (Electronic Supplementary
Material Fig. S1e) and test (Electronic Supplementary
Material Fig. S1f) cohorts did not have good agreement
(HosmereLemeshow test, p¼0.774 and p¼0.033, respec-
tively), radiomics model 2 showed good agreement between
predicted and actual EGFR mutation status in the training
(Electronic Supplementary Material Fig. S1g) and test
(Electronic Supplementary Material Fig. S1h) cohorts (Hos-
mereLemeshow test, p¼0.157 and 0.155, respectively).
Moreover, the DCA demonstrated that radiomics models 1
and 2 (Fig. S1i and k in the training cohort, Electronic
Supplementary Material Fig. S1j and l in the test cohort)
could increase the net benefits and exhibit a wide range of
threshold probabilities. The CIC showed that the clinical
effectiveness of the two radiomics models 1 and 2 (Elec-
tronic Supplementary Material Fig. S1m and o in the training
cohort, Electronic Supplementary Material Fig. S1n and p in
the test cohort) was also good.
Fig. 4a shows the nine selected features in radiomics
model 2 and corresponding coefficients. The diagnostic
nomogram was used to represent radiomics model 2
(Fig 4b). The ManneWhitney U-test demonstrated that the
R-score (cut-off value of 0.583) in the training and test co-
horts had diagnostic performance for EGFR mutation status
(Fig 4c).
Performance of fusion model
In the univariate and multivariate analyses of the training
cohort, male gender (OR¼0.214, 95% CI: 0.067e0.686,
p¼0.009) and R-score (cut-off value 0.583) (OR¼10.155, 95%
CI: 3.541e29.121, p¼0.000) were identified as independent
risk factors for EGFR mutation in the fusion model (Table 4).
The AUCs (95% CI) of 0.762 (0.642e0.881) in the training
cohort with a cut-off of 0.339 and 0.725 (0.541e0.909) in the
test cohort, with the sensitivity of 0.889 and 0.895, speci-
ficity of 0.634 and 0.556, and accuracy of 0.767 and 0.730,
respectively.
Fig. 4d provides a diagnostic nomogram. The nomogram
score (the optimal cut-off value of 0.339) in the training
 e310
Table 2
The comparison of clinical and radiological characteristics between the training cohort and test cohort.

Characteristics Whole cohort Training cohort Test cohort Training cohort (n¼86) p-Value Test cohort (n¼37) p-Value
(n¼123) No (%) (n¼86) No (%) (n¼37) No. (%)
EGFR mutation EGFR wild-type EGFR mutation EGFR wild-type
(n¼45) No (%) (n¼41) No (%) (n¼19) No (%) (n¼18) No (%)
Age, p-value 0.111 0.643 0.737
56 years 63 (51.2) 40 (46.5) 23 (62.2) 22 (48.9) 18 (43.9) 11 (57.9) 12 (66.7)
>56 years 60 (48.8) 46 (53.5) 14 (37.8) 23 (51.1) 23 (56.1) 8 (42.1) 6 (33.3)
Gender, p-value 0.091 0.003 0.330
Female 46 (37.4) 28 (32.6) 18 (48.6) 21 (46.7) 7 (17.1) 11 (57.9) 7 (38.9)
Male 77 (62.6) 58 (67.4) 19 (51.4) 24 (53.3) 34 (82.9) 8 (42.1) 11 (61.1)
Smoking history, p-value 0.827 0.220 0.313
Never smoker 78 (63.4) 54 (62.8) 24 (64.9) 31 (68.9) 23 (56.1) 14 (73.7) 10 (55.6)
Active and former smoker 45 (36.6) 32 (37.2) 13 (35.1) 14 (31.1) 18 (43.9) 5 (26.3) 8 (44.4)

Z. Huang et al. / Clinical Radiology 79 (2024) e305ee316

Interval from primary diagnosis to 0.589 0.969 1.000
brain metastasis, p-value
>6 months 89 (72.4) 61 (70.9) 28 (75.7) 32 (71.1) 29 (70.7) 14 (73.7) 14 (77.8)
6 months 34 (27.6) 25 (29.1) 9 (24.3) 13 (28.9) 12 (29.3) 5 (26.3) 4 (22.2)
Tumour location, p-value 0.200 0.859 1.000
Anterior circulation: frontal, 81 (65.9) 59 (68.6) 22 (59.5) 32 (71.1) 27 (65.9) 11 (57.9) 11 (61.1)
parietal, and temporal lobes
Posterior circulation: occipital lobes, 38 (30.9) 23 (26.7) 15 (40.5) 11 (24.4) 12 (29.3) 8 (42.1) 7 (38.9)
cerebellum, and brain stem
Deep grey nucleus: caudate and 4 (3.25) 4 (4.65) 0 (0.0) 2 (4.44) 2 (4.88) 0 (0.0) 0 (0.0)
thalamus
Enhancement pattern, p-value 0.511 0.035 0.734
Homogeneous 47 (38.2) 30 (34.9) 17 (45.9) 20 (44.4) 10 (24.4) 10 (52.6) 7 (38.9)
Heterogeneous 57 (46.3) 42 (48.8) 15 (40.5) 16 (35.6) 26 (63.4) 7 (36.8) 8 (44.4)
Ring 19 (15.4) 14 (16.3) 5 (13.5) 9 (20.0) 5 (12.2) 2 (10.5) 3 (16.7)
Whole tumour volume, p-value 0.162 0.112 1.000
2 cm3 58 (47.2) 37 (43.0) 21 (56.8) 23 (51.1) 14 (34.1) 11 (57.9) 10 (55.6)
>2 cm3 65 (52.8) 49 (57.0) 16 (43.2) 22 (48.9) 27 (65.9) 8 (42.1) 8 (44.4)
Necrosis component, p-value 0.302 0.032 0.515
Absent 48 (39.0) 31 (36.0) 17 (45.9) 21 (46.7) 10 (24.4) 10 (52.6) 7 (38.9)
Present 75 (61.0) 55 (64.0) 20 (54.1) 24 (53.3) 31 (75.6) 9 (47.4) 11 (61.1)
Intratumoural necrotic volume, 0.541 0.089 0.743
p-value
0.2 cm3 68 (55.3) 46 (53.5) 22 (59.5) 28 (62.2) 18 (43.9) 12 (63.2) 10 (55.6)
>0.2 cm3 55 (44.7) 40 (46.5) 15 (40.5) 17 (37.8) 23 (56.1) 7 (36.8) 8 (44.4)
Oedema component, p-value 0.948 0.862 0.660
Absent 17 (13.8) 12 (14.0) 5 (13.5) 6 (13.3) 6 (14.6) 2 (10.5) 3 (16.7)
Present 106 (86.2) 74 (86.0) 32 (86.5) 39 (86.7) 35 (85.4) 17 (89.5) 15 (83.3)
Peritumoural oedema volume, 0.188 0.976 0.508
p-value
3 cm3 62 (50.4) 40 (46.5) 22 (59.5) 21 (46.7) 19 (46.3) 10 (52.6) 12 (66.7)
>3 cm3 61 (49.6) 46 (53.5) 15 (40.5) 24 (53.3) 22 (53.7) 9 (47.4) 6 (33.3)

EGFR, epidermal growth factor receptor.

Table 3
Predictive efficacy of single-sequence radiomics models based on different regions using the RFE-LR algorithm.

Region Best sequence Radiomics features Cohort Cut-off Radiomics model

value
Optimal Top 3 important features Sensitivity Specificity Accuracy AUC (95%CI) P value
feature
number
VOIperitumour 1mm FLAIR 4 original_shape_SurfaceVolumeRatio Train ＞0.619 0.600 0.780 0.686 0.690 (0.555e0.825) 0.000
original_shape_Maximum2DDiameterRow Test 0.421 0.722 0.568 0.572 (0.357e0.786) 0.189
original_glrlm_RunPercentage
5 original_shape_SurfaceVolumeRatio Train ＞0.576 0.711 0.780 0.744 0.746 (0.616e0.875) 0.000
original_shape_Maximum2DDiameterRow Test 0.737 0.778 0.757 0.757 (0.562e0.952) 0.001
original_firstorder_Minimum
6 original_shape_SurfaceVolumeRatio Train ＞0.656 0.600 0.878 0.733 0.739 (0.617e0.861) 0.000
original_glrlm_RunPercentage Test 0.421 0.833 0.622 0.627 (0.430e0.824) 0.954

Z. Huang et al. / Clinical Radiology 79 (2024) e305ee316

original_shape_Maximum2DDiameterRow
7 original_shape_SurfaceVolumeRatio Train ＞0.666 0.578 0.878 0.721 0.728 (0.606e0.850) 0.000
original_glrlm_RunPercentage Test 0.421 0.833 0.622 0.627 (0.430e0.824) 0.954
original_shape_Maximum2DDiameterRow
8 original_shape_SurfaceVolumeRatio Train ＞0.674 0.578 0.878 0.721 0.728 (0.606e0.850) 0.000
original_glrlm_RunPercentage Test 0.368 0.833 0.595 0.601 (0.406e0.795) 0.090
original_shape_Maximum2DDiameterRow
9 original_shape_SurfaceVolumeRatio Train ＞0.583 0.756 0.756 0.756 0.756 (0.627e0.884) 0.000
original_shape_Maximum2DDiameterRow Test 0.737 0.833 0.784 0.785 (0.600e0.970) 0.000
original_ngtdm_Coarseness
T1WI 8 original_shape_SurfaceVolumeRatio Train ＞0.528 0.778 0.756 0.767 0.767 (0.640e0.893) 0.000
original_glszm_SizeZoneNonUniformityNormalised Test 0.684 0.611 0.649 0.648 (0.431e0.865) 0.964
original_shape_Maximum2DDiameterRow
VOIperitumour 3mm T2WI 9 original_glcm_SumSquares Train ＞0.533 0.778 0.732 0.756 0.755 (0.626e0.883) 0.000
original_shape_Maximum2DDiameterRow Test 0.579 0.722 0.649 0.651 (0.436e0.865) 0.967
original_glcm_ClusterTendency
VOIperitumour 5mm FLAIR 5 original_firstorder_Minimum Train ＞0.534 0.733 0.756 0.744 0.745 (0.614e0.875) 0.000
original_glcm_Id Test 0.737 0.444 0.595 0.591 (0.377e0.804) 0.131
original_glcm_Imc1
6 original_firstorder_Minimum Train ＞0.509 0.756 0.732 0.744 0.744 (0.613e0.874) 0.000
original_glcm_Id Test 0.737 0.444 0.595 0.591 (0.377e0.804) 0.131
shape_Maximum2DDiameterSlice
7 original_firstorder_Minimum Train ＞0.526 0.756 0.756 0.756 0.756 (0.627e0.884) 0.000
original_glcm_Id Test 0.737 0.444 0.595 0.591 (0.377e0.804) 0.131
original_glcm_Imc1
8 original_glcm_Imc1 Train ＞0.507 0.756 0.732 0.744 0.744 (0.613e0.874) 0.000
original_glcm_Id Test 0.737 0.444 0.595 0.591 (0.377e0.804) 0.131
original_shape_Maximum2DDiameterColumn
9 original_glcm_Id Train ＞0.507 0.756 0.732 0.744 0.744 (0.613e0.874) 0.000
original_glcm_DifferenceAverage Test 0.737 0.444 0.595 0.591 (0.377e0.804) 0.131
original_firstorder_Minimum

VOI, volume of interest; AUC, area under the curve; FLAIR, fluid-attenuated inversion recovery; T1WI, T1-weighted imaging; T2WI, T2-weighted imaging; RFE, recursive feature elimination; LR, logistic
regression.

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e312 Z. Huang et al. / Clinical Radiology 79 (2024) e305ee316

Figure 3 The heat map of AUCs in a single-sequence radiomics model based on five regions using the RFE-LR algorithm. PCC, pearson correlation
coefficient; RFE, recursive feature elimination; LR, logistic regression.

and test cohorts also demonstrated diagnostic perfor- The fusion model (AUC ¼ 0.814; Electronic Supple-
mance for EGFR mutation status by the ManneWhitney U mentary Material Fig. S2a) was better than radiomics
test (Fig 4e). model 2 (AUC ¼ 0.756) in the training cohort, and this
 Z. Huang et al. / Clinical Radiology 79 (2024) e305ee316 e313

Figure 4 (aec) The optimal radiomics model based on the peritumour region of 1 mm, which was a combination of nine features selected from
the FLAIR sequence. (a) Selected features in the optimal radiomics model and corresponding coefficients. (b) EGFR nomogram. (c) Distribution of
R-scores between EGFR mutation and EGFR wild-type in the training and test cohorts. (d,e) The fusion model of EGFR mutation status. (d) EGFR
nomogram. (e) Violin and box plots of EGFR mutation probabilities in the training and test cohorts.

difference was statistically significant (DeLong test, Discussion

p¼0.010). Electronic Supplementary Material Fig. S2e
shows the fusion model with a superior AUC of 0.808
compared with radiomics model 2 (AUC ¼ 0.785) in the
test cohort, but the p-value of the DeLong test was 0.525.
In the training cohort, IDI manifested a significant
difference in the predictive value between the fusion
model and radiomics model 2 (IDI [95% CI] ¼ 0.067
[0.015e0.119], p¼0.012); however, there was no statistical
difference in predictive value between the fusion model
and radiomics model 2 in the test cohort (IDI [95%
CI] ¼ 0.009 [-0.020e0.037], p¼0.554). The DCA curve
showed that as the threshold probability was above 0.1,
this fusion model and radiomics model 2 both obtained a
more significant net benefit than either the “none” or
“all” scheme (Electronic Supplementary Material Fig.
S2b,f). The calibration curve analysis of this fusion
model had good agreement between predicted and actual
EGFR mutation status (HosmereLemeshow test, p¼1.000
in the training cohort and p¼0.965 in the test cohort;
Electronic Supplementary Material Fig. S2c,g). The CIC
demonstrated the clinical effectiveness of the fusion
model, which showed that the number of high-risk
subjects predicted by the fusion model was highly
matched with the number of high-risk subjects with
event subjects (Electronic Supplementary Material
Fig. S2d,h).
This study aimed to investigate the value of the radio-
mics signature of BMs for predicting EGFR mutation status
in lung adenocarcinoma. Radiomics model 2 converted into
a quantitative R-score can be considered an independent
risk predictor for EGFR mutation status. The predictive
performance of the fusion model integrating clinical factors
(gender) and R-score (radiomics model 2) was not better
than that of radiomics model 2 alone.
Due to the infiltrative nature of NSCLC, the present study
explored the size of the peritumoural region to provide
adequate to cover of the infiltrative zones. Previously,
Matsuo et al.22 reported that viable tumour cells could be
observed at the margin. Another survey by Baumert et al.13
demonstrated that BMs from lung cancer had a possible
infiltration outside of the contrast-enhancing tumour
margin on imaging. Subsequently, some studies have dis-
cussed the role of the peritumoural region as a promising
indicator of underlying infiltration of BMs from lung cancer.
For instance, Zakaria et al.14 and Spanberger et al.23 both
divided the peritumoural region into “near” as <1 cm from
the tumour edge versus “far” as 1 cm from the edge using
conventional MRI images. Nowosielski et al.24 used ADC
metrics to subdivide the peritumoural region into three
adjacent ring-shaped spaces with a width of 3 mm each;
however, previous studies omitted the importance of the 1
e314 Z. Huang et al. / Clinical Radiology 79 (2024) e305ee316

Table 4
Univariate and multivariate analyses of characteristics related to EGFR mutation status.

Characteristics Univariate Multivariate

OR (95% CI) p-Value OR (95% CI) p-Value

Age
56 years 1.000
>56 years 0.818 (0.350e1.914) 0.643
Gender
Female 1.000
Male 0.235 (0.086e0.641) 0.005 0.214 (0.067e0.686) 0.009
Smoking history
Never smoker 1.000
Active and former smoker 0.577 (0.239e1.395) 0.222
The interval from primary diagnosis to brain metastasis
>6 months 1.000
6 months 0.982 (0.387e2.493) 0.969
Tumour location
Anterior circulation: frontal, parietal, and temporal lobes 1.000
Posterior circulation: occipital lobes, cerebellum, and brain stem 0.773 (0.295e2.031) 0.602
Deep grey nucleus: caudate and thalamus 0.844 (0.111e6.398) 0.869
Enhancement pattern
Homogeneous 1.000
Heterogeneous 0.308 (0.115e0.821) 0.019
Ring 0.900 (0.238e3.406) 0.877
Whole tumour volume
2 cm3 1.000
>2 cm3 0.496 (0.208e1.185) 0.114
Necrosis component
Absent 1.000
Present 0.369 (0.147e0.927) 0.034
Intra tumoural necrotic volume
0.2 cm3 1.000
>0.2 cm3 0.475 (0.201e1.126) 0.091
Oedema component
Absent 1.000
Present 1.114 (0.329e3.775) 0.862
Peritumoural oedema volume
3 cm3 1.000
>3 cm3 0.987 (0.423e2.306) 0.976
Radiomic score cut-off value
0.583 1.000
>0.583 9.582 (3.578e25.659) 0.000 10.155 (3.541e29.121) 0.000

EGFR, epidermal growth factor receptor; OR, odds ratio; CI, confidence interval.

mm peritumoural area. The results of the survey by Bau-
mert et al.13 showed that the highest percentage of infil-
tration was present in NSCLC (70%). There were several
infiltration sites of NSCLC metastasis, but NSCLC showed a
maximum infiltration depth of <1 mm. This finding was
consistent with the observations of Neves et al. showing an
infiltration zone of 1 mm for five of 24 BMs from NSCLC.21
Among constructed multiple VOI models, the FLAIR radio-
mics model obtained from the VOIperitumour 1mm (radiomics
model 2) was superior to other radiomics models in pre-
dicting EGFR mutation status. The AUCs of radiomics model
2 were 0.756 in the training cohort and 0.785 in the test
cohort. It was suggested that a peritumoural region of 1 mm
might be associated with high tumour aggressiveness,
coinciding with previous studies.13,22 In the present
research, the FLAIR radiomics model outperformed other
single-sequence radiomics models, in agreement with the
findings of Wang et al.,17 a FLAIR radiomics model yielded
AUCs of 0.987 and 0.871 in the training and test cohorts,
respectively; however, the optimal radiomics model based
on VOIperitumour 1mm was not the same as the findings of
Wang et al.,17 who found the excellent performance of
VOIentire tumour. This disagreement may be related to the
influence of EGFR mutation subtypes on radiomics features
of BMs. Although both studies retrospectively analysed lung
adenocarcinoma patients with EGFR mutations who were
initially diagnosed with BMs, patients with different EGFR
mutation subtypes may have close relationship with
different types of BMs, consistent with literature reported
by Sekine et al.11 Additionally, the optimal radiomics model
was established based on the VOIperitumour 1mm, which was a
combination of nine features selected from the FLAIR
sequence, including one first-order feature, five textural
features and three shape features. Previous researchers
revealed that NSCLC patients with deletion of exon 19 had
miliary BMs, which presented more multiple and smaller
metastatic lesions with smaller peritumoural oedema than
did those with EGFR wild-type.11,25e27 This finding was
similar to the results of the present study that the FLAIR_-
VOIperitumour 1mm_original_shape_SurfaceVolumeRatio with
 Z. Huang et al. / Clinical Radiology 79 (2024) e305ee316
a coefficient of -1.34 (p¼0.031) may reflect the size of
tumour.
Goodman et al.13 described that the pattern of
enhancement on CE-T1WI (homogeneous, heterogeneous,
or ring) or percent necrosis of BMs, were effective pre-
dictors to predict freedom from progression (FFP) of BMs,
and the lowest FFP was more likely to occur in ring-
enhancing lesions. In the present study, only enhance-
ment patterns and necrosis of brain metastases were
significantly associated with EGFR mutations in the training
cohort according to univariate analysis; however, no sta-
tistical significance was observed in two radiological pre-
dictors at multivariate analysis. The enhancement pattern,
or necrotic volume in patients with BMs, depends on the
pathological type of the primary site. Unlike the study by
Goodman et al.13 in which BMs originated from various
primary tumours, such as lung (36%), melanoma (31%),
breast 80 (15%), kidney (7%), colorectal (4%), and other un-
known primaries (7%), the present patients with BMs only
derived from lung adenocarcinoma. Moreover, univariate
and multivariate analyses supported gender as an inde-
pendent risk factor to predict the EGFR mutation status in
the present study. It was consistent with the findings of Liu
et al.,28 who reported that gender, smoking status, histo-
logical subtype, and pathological grade were significant
predictors of EGFR mutations in peripheral lung adenocar-
cinoma. Notably, they found a higher rate of EGFR muta-
tions in female patients than in male patients. The
discrepancy in research findings could be attributed to
differences in sample sizes; the present study had a smaller
sample size.
Several constraints limit this study. It is based on a
retrospective design from a single centre with a small
sample size, and internal validation was performed using
fivefold cross-validation in the training cohort. To address
these limitations and improve the model, utilising a larger
prospective dataset and conducting external validation is
essential. Additionally, exploring various EGFR mutation
subtypes was not possible due to limited sample availability.
In conclusion, the FLAIR radiomics signature in VOIper-
itumour 1mm shows promise as a potential biomarker for
predicting EGFR mutation status in lung adenocarcinoma
patients with BMs. It can significantly assist clinicians in
tailoring treatment strategies based on individual patient
characteristics and conditions.
Conflict of interest
The authors declare the following financial interests/
personal relationships which may be considered as poten-
tial competing interests:
Zhenhuan Huang reports financial support was provided
by Fujian provincial health technology project.
Acknowledgements
Thea authors thank Lanmei Gao, Qiuyuan Yue, Chuan
Yan, and Hanting Dai for their assistance with the radiomics
e315
analysis. This work was supported by Fujian Provincial
Health Technology Project (grant no.: 2020QNA090).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.crad.2023.10.022.
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