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Radiographic markers of breast cancer brain metastases: relation to clinical characteristics and postoperative outcome


Abstract and Figures

Objective Occurrence of brain metastases BM is associated with poor prognosis in patients with breast cancer (BC). Magnetic resonance imaging (MRI) is the standard of care in the diagnosis of BM and determines further treatment strategy. The aim of the present study was to evaluate the association between the radiographic markers of BCBM on MRI with other patients’ characteristics and overall survival (OS). Methods We included 88 female patients who underwent BCBM surgery in our institution from 2008 to 2019. Data on demographic, clinical, and histopathological characteristics of the patients and postoperative survival were collected from the electronic health records. Radiographic features of BM were assessed upon the preoperative MRI. Univariable and multivariable analyses were performed. Results The median OS was 17 months. Of all evaluated radiographic markers of BCBM, only the presence of necrosis was independently associated with OS (14.5 vs 22.5 months, p = 0.027). In turn, intra-tumoral necrosis was more often in individuals with shorter time interval between BC and BM diagnosis (< 3 years, p = 0.035) and preoperative leukocytosis (p = 0.022). Moreover, dural affection of BM was more common in individuals with positive human epidermal growth factor receptor 2 status (p = 0.015) and supratentorial BM location (p = 0.024). Conclusion Intra-tumoral necrosis demonstrated significant association with OS after BM surgery in patients with BC. The radiographic pattern of BM on the preoperative MRI depends on certain tumor and clinical characteristics of patients.
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Acta Neurochirurgica (2022) 164:439–449
Radiographic markers ofbreast cancer brain metastases: relation
toclinical characteristics andpostoperative outcome
AnnaMichel1 · ThiemoDinger1· MarvinDarkwahOppong1· LaurèlRauschenbach1,2· CorneliusDeuschl3·
YahyaAhmadipour1· DanielaPierscianek1· KarstenWrede1· JörgHense4· ChristophPöttgen5·
AntonellaIannaccone6· RainerKimmig6· UlrichSure1· RamazanJabbarli1
Received: 6 August 2021 / Accepted: 9 October 2021 / Published online: 22 October 2021
© The Author(s) 2021, corrected publication 2022
Objective Occurrence of brain metastases BM is associated with poor prognosis in patients with breast cancer (BC). Mag-
netic resonance imaging (MRI) is the standard of care in the diagnosis of BM and determines further treatment strategy.
The aim of the present study was to evaluate the association between the radiographic markers of BCBM on MRI with other
patients’ characteristics and overall survival (OS).
Methods We included 88 female patients who underwent BCBM surgery in our institution from 2008 to 2019. Data on
demographic, clinical, and histopathological characteristics of the patients and postoperative survival were collected from
the electronic health records. Radiographic features of BM were assessed upon the preoperative MRI. Univariable and
multivariable analyses were performed.
Results The median OS was 17months. Of all evaluated radiographic markers of BCBM, only the presence of necrosis
was independently associated with OS (14.5 vs 22.5months, p = 0.027). In turn, intra-tumoral necrosis was more often in
individuals with shorter time interval between BC and BM diagnosis (< 3years, p = 0.035) and preoperative leukocytosis
(p = 0.022). Moreover, dural affection of BM was more common in individuals with positive human epidermal growth factor
receptor 2 status (p = 0.015) and supratentorial BM location (p = 0.024).
Conclusion Intra-tumoral necrosis demonstrated significant association with OS after BM surgery in patients with BC.
The radiographic pattern of BM on the preoperative MRI depends on certain tumor and clinical characteristics of patients.
Keywords Breast cancer· Brain metastases· MRI necrosis· HER2
The breast cancer [8] is one of the most frequent primary
cancer entities in women with high impact of interest and
prognostic value [6, 9, 53, 68]. Therapy concepts of BC
impacting the patients’ survival include the surgical and
(neo-) adjuvant treatment, the conventional chemotherapy,
endocrine therapy, and radiation, as well as targeted therapy
[18, 25, 34, 43, 46, 55, 56, 69, 72].
Depending on different risk factors and applied treatment,
15–50% of BC patients develop brain metastases [5, 10, 23,
35, 38]. The receptor status (RS) plays an important role for
therapy concepts and the prognosis of breast cancer brain
metastases (BCBM) patients [40, 49, 51, 53, 56]. Individu-
als with triple negative BC and positive status of human
epidermal growth factor receptor 2 (HER2) are prone to BM
[35, 38, 51]. The overall survival (OS) after BM surgery
This article is part of the Topical Collection on Brain Tumors
* Anna Michel
1 Department ofNeurosurgery andSpine Surgery, University
Hospital Essen, University Duisburg-Essen, Hufelandstraße
55, 45147Essen, Germany
2 DKFZ Division Translational Neurooncology attheWest
German Cancer Center (WTZ), DKTK Partner Site,
University Hospital Essen, Essen, Germany
3 Department ofRadiology, University Hospital Essen, Essen,
4 Department ofMedical Oncology, University Hospital Essen,
Essen, Germany
5 Department ofRadiotherapy, University Hospital Essen,
Essen, Germany
6 Department ofObstetrics andGynecology, University
Hospital Essen, Essen, Germany
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Acta Neurochirurgica (2022) 164:439–449
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depends on multiple factors like Karnofsky Performance
Status (KPS) scale score, number of BM, presence of extrac-
ranial metastases, patients’ age, timing between BC and BM,
histopathological parameters, and (neo-) adjuvant treatments
[3, 11, 20, 31, 33, 35, 60, 61]. In case of BCBM, the median
OS varies between 7.2 and 37.7months. [29, 33, 60]
Magnetic resonance imaging (MRI) is a sensitive diag-
nostic tool and increases the detection rate of BM [10, 26,
38, 57]. Moreover, MRI is commonly used to plan treatment
and to control the cancer disease [2, 22, 36, 39, 50, 52, 65].
Recent studies showed that radiographic markers might have
additional clinical value for the prognostication of postop-
erative survival in patients with lung and breast cancer [1, 7,
8, 12, 13, 15, 24, 45]. As to BCBM, the contrast-enhanced
T1-weighted MRI features were identified as prognostic fac-
tors for therapeutic response after Gamma Knife radiosur-
gery [73]. In this context, the patient and tumor characteris-
tics associated with the radiographic pattern of BM on MRI
are also of clinical relevance. In particular, leptomeningeal
infiltration of BM was more common in individuals with
HER2-positive and triple-negative BC. [28, 30, 41]
To address the clinical value of radiographic markers of
BCBM, we analyzed the association between various radio-
graphic characteristics of BM on the preoperative MRI with
demographic, clinical, and immunohistochemical features
of BCBM patients selected for surgery. A special attention
was drawn on the potential prognostic value of radiographic
markers of BCBM for OS.
Material andmethods
This study was performed in accordance with the Declara-
tion of Helsinki and approved by the local ethics committee
of the University Hospital Essen (local registration number:
Patient population
All female patients (age ≥ 18years) who underwent BM sur-
gery in our institution from January 2008 to December 2019
were included. The cases with missing preoperative MRI
were excluded (n = 9). Treatment strategy and allocation to
BCBM surgery was discussed in the institutional interdisci-
plinary tumor conference. Common criteria for BM surgery
were the size and the mass effect from the lesion(s), presence
of considerable perifocal edema and/or neurological symp-
toms, non-eloquent location, and the KPS score.
Data management
For the evaluation of the radiographic parameters of
BCBM, the T1-, T2-, and contrast-enhanced-weighted
images of the preoperative MRI scans were reviewed by
the first author (A.M., blinded at this time to all clini-
cal, histological, and survival data) for the presence of
following radiographic characteristics of BM: number
(single vs multiple), size (maximal diameter), and loca-
tion (supratentorial vs infratentorial) of BM; intra-tumoral
hemorrhage; contrast enhancement (CE) configuration;
cystic components; necrosis; edema; midline shift; dural
affection; and the relation to the ventricles.
Then, certain clinical and histological features of
BCBM patients were recorded from the electronic health
records: age (at BC and BM diagnosis), the type of BC
surgery (mastectomy vs breast-preserving surgery (BPS)),
trastuzumab therapy of BC, the time interval between the
diagnosis of BC and BM, preoperative KPS scale, extrac-
ranial metastases, RS of BM and BC (hormone recep-
tors: estrogen (ER), progesterone (PR), and HER2), and
the receptor conversion (RC) in BM, as well as OS upon
the available follow-up data. Moreover, two laboratory
parameters at admission were also included for further
correlations as commonly evaluated laboratory markers
for disease progression and survival in BC patients: white
blood cells [16, 27, 44, 47] and lactate dehydrogenase [37,
49, 67]
Statistical analysis
Data were analyzed using SPSS (version 27, SPSS Inc.,
IBM, Chicago, IL, USA) statistical software. The variables
were reported in median values and interquartile ranges
(IQR) between 25 and 75%, or as number of cases (with
percentage), as appropriate. The significance level for the p
value was set at 0.05. Continuous data were dichotomized
according to the established criteria or using the associa-
tions in the receiver operating characteristic (ROC) curves.
In particular, WBC > 10 × 109/L was referred as leukocytosis
and LDH as pathologically increased. The patients’ age was
dichotomized at 65years. In line with the previous studies
[59], the size of peri-tumoral edema in the preoperative MRI
scans was dichotomized at 10mm.
First, the associations between preoperative MRI charac-
teristics and patients’ demographic, clinical, immunohisto-
chemical, and laboratory parameters were evaluated in uni-
variate analysis using the chi-square (χ2 test) or Fisher exact
tests. Significant associations from the univariable analysis
were transferred to multivariable binary logistic regression
analysis to control for confounders.
The associations between the radiographic markers and
OS were evaluated in the univariable and multivariable Cox
regression analysis in the same manner. To visualize the sur-
vival differences for major study results, the Kaplan–Meier
survival plots and log-rank test were performed.
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Acta Neurochirurgica (2022) 164:439–449
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Patient population
The final cohort consisted of 88 female patients. The
median OS after BM surgery was 17.0 (7.0–34.8) months.
The initial treatment of BC included BPS and trastuzumab
in 44 (50%) and 26 (29.5%) cases, respectively. Adjuvant
radiotherapy was the standard therapy after BCBM resec-
tion. In some cases, system therapy was also adapted.
In our cohort, 77 (87.5%) received postoperative radio-
therapy. Positive HER2 RS in the BM was identified in
36 cases (40.9%). Table1 summarizes the major baseline
demographic, clinical, and histological characteristics of
the patients in the final cohort. On the preoperative MRI
scans, 42 patients (47.7%) showed singular and supraten-
torial BM. The detailed information on the radiographic
features of BCBM is presented in the Fig.1.
Association betweenMRI markers andother
patients’ characteristics
Univariable analysis
Intra-tumoral hemorrhage was more frequent in individu-
als with poor KPS scale (< 80%) at admission (p = 0.040).
Moreover, younger age at BC diagnosis (p = 0.033), BC
therapy with trastuzumab (p = 0.019), infratentorial BM
(p = 0.027), and positive HER2 RS in BM (p = 0.017) were
associated with dural affection in the preoperative MRI.
Circular CE was identified more commonly in older
patients at BC diagnosis (p = 0.001), in patients without
trastuzumab therapy (p = 0.048), and with negative HER2
RS in BC (p = 0.050). Then, negative HER2 (p = 0.017)
and ER (p = 0.001) RS in BM was also associated with
circular CE in BCBM.
Cystic components in BM were detected more often in
BM with negative ER RS (p = 0.001).
BM with necrosis in MRI showed associations with
poorer initial clinical condition (p = 0.053), trastuzumab
therapy for BC (p = 0.046), shorter time interval between
BC and BM (p = 0.009), negative ER RS in BM (p = 0.049),
and higher rate of leukocytosis at admission (p = 0.007).
BCBM patients without extracranial metastases
(p = 0.027), shorter time interval between BC and BM mani-
festation (p = 0.024), and negative ER RS in BM (p = 0.030)
as well as identic HR status in BC and BM (p = 0.047)
showed more often BM with perifocal edema > 10mm.
Finally, none of the patients’ characteristics showed sig-
nificant associations with the relation of BM to the ventri-
cles (see supplementary table1 and 2).
Multivariable analysis
For dural affection, the following associations remained
significant: supratentorial location of (aOR 3.10, 95% CI
1.16–8.27, p = 0.024) and positive HER2 RS in BM (aOR
3.30, 95% CI 1.26–8.62, p = 0.015). Age ≥ 65years at BC
diagnosis (aOR 5.66, 95% CI 1.18–27.14, p = 0.030) and
negative ER RS in BM (aOR 21.84, 95% CI 2.37–201.49,
p = 0.007) were significantly associated with circular CE.
Table 1 Baseline characteristics of BCBM patients
Abbreviations: Nr. number of cases, BC breast cancer, BM brain
metastasis, IQR interquartile ranges 25–75%, OS overall survival, RS
receptor status, HER2 human epidermal growth factor receptor 2, ER
estrogen receptor, PR progesterone receptor, HR hormone receptors
(= ER and PR), RC receptor conversion
Parameter Median (IQR) or Nr. (%)
Clinical parameters
Number of patients 88 (100%)
OS (months) 17.0 (7.0–34.8)
Preoperative KPS ≥ 80% 77 (87.5%)
Age at BC diagnosis (years) 65.0 (45.0–62.0)
Age at BM diagnosis (years) 55.0 (51.0–68.8)
Time interval BC to BM (months) 42.0 (22.0–100.0)
Number of BM
Singular 58 (65.9%)
Multiple 30 (34.1%)
BM location
Supratentorial 55 (62.5%)
Infratentorial 33 (37.5%)
Surgical treatment of BC
 Mastectomy 42 (47.7%)
 Breast-preserving surgery (BPS) 46 (52.3%)
Trastuzumab therapy of BC 26 (29.5%)
Adjuvant radiotherapy of BM 77 (87.5%)
Extracranial metastases 35 (39.8%)
Immunohistochemically parameters
 Positive 36 (40.9%)
 Negative 52 (59.1%)
 Positive 45 (51.1%)
 Negative 43 (48.9%)
 Positive 17 (19.3%)
 Negative 71 (80.7%)
 Identic 69 (78.4%)
 Converted 9 (10.2%)
 Identic 39 (44.3%)
 Converted 39 (44.3%)
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Acta Neurochirurgica (2022) 164:439–449
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Fig. 1 Radiological informa-
tion’s in preoperative MRI.
a Preoperative radiological
parameters of operated BCBM
patients. The following distribu-
tion of radiological charac-
teristics are available: ven-
tricular contact (19/88, 21.6%),
ventricular infiltration (9/88,
10.2%), intraventricular lesion
(2/88, 2.3%), necrosis (50/88,
56.8%), midline shift (16/88,
18.2%), edema > 10mm (71/88,
80.7%), cystic components
(23/88, 26.1%), circular CE
(19/88, 21.6%), dural affection
(47/88, 53.4%), BM diam-
eter > 30mm (44/88, 50.0%),
and hemorrhage (3/88, 3.4%). b
Preoperative MRI scans: b1 and
b2 demonstrate central necrosis
(hash symbol), perifocal edema
is seen in b3 (black arrowhead)
and b4 shows the circular CE
exemplary. Abbreviation: CE,
contrast enhancement; BM,
brain metastases
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Acta Neurochirurgica (2022) 164:439–449
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Moreover, two baseline parameters remained significant
in the multivariable analysis for the predictors of necrosis
in preoperative MRI: time interval between BC and BM
(< 3years, aOR 3.10, 95% CI 1.08–8.85, p = 0.035) and
preoperative leukocytosis (aOR 3.44, 95% CI 1.19–9.94,
p = 0.022). Finally, negative ER RS in BM (aOR 3.78, 95%
CI 0.99–14.43, p = 0.05) was the only parameter indepen-
dently associated with peri-tumoral edema in the multivari-
able analysis (see Table2).
Association betweenMRI markers andOS
Univariable analysis: Patients with BM necrosis showed
poorer outcome (median OS 14.50 vs 22.50 months,
p = 0.051). Other radiographic parameters showed no sig-
nificant associations with OS (Fig.2). As to the remaining
patient and tumor characteristics, only the positive HER2
RS in BM (median OS 23.5 vs 13.5months, p = 0.017) and
favorable preoperative KPS scale (≥ 80%, median OS 22.00
vs 7.00months, p = 0.001) showed significant associations
with OS (see supplementary table3).
In the final multivariable Cox regression analysis, MRI
necrosis (aHR 1.78, 95% CI 1.07–2.96, p = 0.027), negative
HER2 RS in BM (aHR 1.88, 95% CI 1.10–3.21, p = 0.020),
and poor preoperative KPS scale scores (aHR 3.33, 95%
CI 1.57–7.06, p = 0.002) were confirmed as independent
predictors for poor OS after BCBM surgery (See Table3).
Figure3 visualizes the association between the number of
present independent predictors and patients’ survival at 1,
2, and 3years.
Currently, MRI is the standard of care in the diagnosis and
the evaluation of treatment response in patients with BM.
Increasing epidemiologic relevance of BC in the developed
countries and considerable survival differences necessitate
the identification of simple and reliable prognostic mark-
ers for BC patients which might help to predict the disease
course at its early stage. In this retrospective study, we evalu-
ated the prognostic value of easily assessable radiological
markers of BCBM and found that the necrosis in the preop-
erative MRI scan is independently associated with postop-
erative survival in BCBM patients.
It is generally accepted that patients’ age, BC subtype,
preoperative KPS scale scores, and the presence of extrac-
ranial metastases influence the treatment decisions and
survival in individuals with BCBM [3, 11, 3133, 35, 42,
51, 60]. The location and the number of BM are also rel-
evant parameters for treatment decision and prognosis. So,
infratentorial BM were associated with higher morbidity and
complications rates in surgical series. [14, 63, 70] Different
risk scores based on the patients’ age, KPS scale values,
and BC subtype, as well as the patterns of intracranial and
extracranial metastases were also confirmed as reliable prog-
nostic markers for BCBM patients [17, 60, 62, 63, 66].
CE MRI is the gold standard in the diagnostics of BM
patients and is crucial for the selection of proper treatment
strategy. Furthermore, different (MRI-based) imaging char-
acteristics of BM were reported as prognostic markers for
survival and treatment response. The radiographic param-
eters which were previously addressed as clinically relevant
markers for cancer patients include the tumor volume; pres-
ence of necrotic, perifocal, and cystic components; peri-focal
edema; and dural affection, as well as the pattern of CE [4,
8, 15, 54, 58, 59, 64, 71, 73].
Several studies demonstrated the impact of CE-weighted
MRIs for the prediction of local tumor control following
Gamma Knife radiosurgery and underlined the correla-
tions between EGFR mutation status and clinical aspects
with radiological features like CE and mass effect of BM in
Table 2 Multivariate analysis of radiological features with clinical,
immunohistochemically, and laboratory parameters
Abbreviations: BC breast cancer, BM brain metastasis, RS receptor
status, HER2 human epidermal growth factor receptor 2, ER estrogen
receptor, HR hormone receptors (= ER and PR (progesterone recep-
tor)), CE contrast enhancement, TI time interval, KPS Karnofsky
Performance status, Preop. preoperative, aOR adjusted odds ratio, CI
confidence interval
Parameter p-value aOR 95% CI
Dural affection
Age at BC diagnosis ≥ 65years 0.097 2.80 0.83–9.41
BM location supratentorial 0.024 3.10 1.16–8.27
BM HER2 RS negative 0.015 3.30 1.26–8.62
Circular CE
Age at BC diagnosis ≥ 65years 0.030 5.66 1.18–27.14
Trastuzumab BC therapy 0.425 2.21 0.32–15.48
BC HER2 RS negative 0.969 1.06 0.06–18.75
BM HER2 RS negative 0.651 1.90 0.12–30.84
BM ER RS negative 0.007 21.84 2.37–201.49
KPS < 90% 0.118 2.35 0.80–6.84
Trastuzumab BC therapy 0.301 1.82 0.58–5.70
TI BC-BM < 3years 0.035 3.10 1.08–8.85
BM ER RS negative 0.268 1.80 0.64–5.08
Preop. WBC (> 10/nL) 0.022 3.44 1.19–9.94
Edema > 10mm
Extracranial metastases 0.108 0.35 0.09–1.26
TI BC-BM < 5years 0.106 2.83 0.80–10.00
BM ER RS negative 0.052 3.78 0.99–14.43
HR RC identic 0.091 3.19 0.83–12.31
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Acta Neurochirurgica (2022) 164:439–449
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non-small cell lung carcinoma [13, 15, 19, 21]. However,
the data on the clinical value of radiographic BCBM char-
acteristics for the estimation of postoperative survival was
still missing.
In the present study, we have identified heterogeneous
radiological characteristics of BM which can be easily
assessed upon the preoperative MRI imaging without the
application of cost- and time-consuming software solu-
tions. We analyzed the relationship between these simple
radiographic markers with other baseline parameters and OS
of BCBM patients. Of all radiographic BCBM features, only
the presence of intra-tumoral necrosis showed independent
association with postoperative survival in our cohort. Inter-
estingly, BM necrosis was already reported as prognostic
factor for poor local tumor control after Gamma Knife radio-
surgery of lung cancer BM [19, 48].
Although the remaining MRI markers of BCBM showed
no predictive value for OS, but the observed independent
Fig. 2 Prediction for OS in
patients with operated BCBM:
Kaplan Meier curves demon-
strate the radiological param-
eters and their influence on OS.
Only necrosis presents as inde-
pendent prognostic factor for
OS for operated BCBM patients
(necrosis status in preoperative
MRI, log-rank test: p = 0.045).
a BM diameter (log-rank test:
p = 0.285), b cystic components
(log-rank test: p = 0.281), c
dural affection (log-rank test:
p = 0.485), d edema (log-rank
test: p = 0.591), e hemorrhage
(log-rank test: p = 0.792),
f necrosis (log-rank test:
p = 0.045), g ventricular contact
(log-rank test: p = 0.303), and
h circular CE (log-rank test:
p = 0.842). Abbreviations: BM,
brain metastasis; RS, receptor
status; HER2, human epidermal
growth factor receptor 2; KPS,
Karnofsky Performance status;
Preop., preoperative
a BM diameter (log-rank test: p=0.285) bcystic components(log-rank test: p=0.281)
dural affection (log-rank test: p=0.485)d edema (log-rank test: p=0.591)
hemorrhage (log-rank test: p=0.792) f necrosis (log-rank test: p=0.045)
ventricular contact (log-rank test: p=0.303)h circular CE (log-rank test: p=0.842)
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Acta Neurochirurgica (2022) 164:439–449
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associations with other patient and tumor characteristics
might also be of clinical relevance. On one side, BCBM
patients with negative ER RS presented more often with
circular CE and considerable perifocal edema. On another
side, BM with dural affection was more common in HER2-
positive and supratentorial BM. In turn, higher rate of tumor
recurrence was reported for BM with dural contact [64]. In
summary, our findings show that certain histological charac-
teristics (and, possibly, related adjuvant treatment strategies)
might influence the radiographic pattern of BCBM.
Accordingly, the observed association between the
tumor necrosis and OS in our cohort might be related to
certain tumor- and patient-specific characteristics.So,
individuals with shorter time interval between BC and
BM diagnosis showed more often necrotic components
in MRI. Shorter time interval is well established as rel-
evant prognostic factor for BCBM. [20] Another tumor
necrosis-related baseline parameter, the leukocytosis at
admission, was also previously reported as a significant
survival predictor for BC patients [27, 44, 47]. Finally,
the RS and preoperative KPS scale scores which showed
the associations with the necrosis in univariable analy-
sis are acknowledged survival predictors of BC [31, 40,
51, 60]. For the clarification of the biological background
of the association between the tumor features in the MRI
scans with the other patients’ characteristics and postop-
erative survival, further clinical and experimental studies
are mandatory.
The retrospective design and the information bias with
regard to non-unique technical features of analyzed preop-
erative MRI scans and partially missing follow-up data are
the major limitations of this monocentric study. Moreover,
imaging interpretation without the use of threshold-based
automated analyses always impairs the risk of investiga-
tor bias. Another limitation of our study is the inability
of assessment of the extent of metastasis resection with
a MRI imaging, since only postoperative computed
tomography scans were routinely performed. However,
according to the surgical reports, complete resection of
BM could be achieved in all cases of the analyzed cohort.
Then, the standard perioperative steroid treatment could
have impacted the development of leukocytosis. However,
the blood sampling and begin of steroid therapy mostly
on the admission day lowers the probability of steroid-
induced leukocytosis in the analyzed patients. Finally,
center-specific selection criteria for BCBM surgery which
might vary between the clinics, particularly, in different
countries, also limit the generalizability of our results.
Therefore, external validation of the analyzed radiographic
markers of BCBM is necessary for the clarification of the
prognostic value of MRI markers for BCBM patients.
Table 3 Multivariate analysis for independent predictors of OS after
BCBM surgery
Abbreviations: aHR adjusted hazard ratio, CI confidence interval, RS
receptor status, BM brain metastases, HER2 human epidermal growth
factor receptor 2, KPS Karnofsky Performance status, preop preop-
erative, MRI magnetic resonance imaging, OS overall survival
Parameter aHR 95% CI p-value
MRI necrosis 1.78 1.07–2.96 0.027
BM HER2 RS negative 1.88 1.10–3.21 0.020
Preop. KPS < 80% 3.33 1.57–7.06 0.002
Fig. 3 Significant survival
predictors in operated BCBM
patients. BM HER2 negative
RS, preoperative KPS < 80%,
and necrosis in preoperative
MRI are predictors for poor
outcome. Prognostic relevant
predictors demonstrate (1year,
2years, 3years) survival rates
[in %] in different subgroups (0,
1, 2, 3 risk factors). Abbrevia-
tions: BM, brain metastases;
HER2, human epidermal
growth factor receptor 2; KPS,
Karnofsky Performance status;
neg, negative; pos, positive
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Acta Neurochirurgica (2022) 164:439–449
1 3
The radiographic pattern of BCBM on the preoperative MRI
depends on certain baseline patient and tumor characteristics
like the RS for ER and HER2, patient’s age, time interval
between BC and BM diagnosis, and preoperative leukocy-
tosis. In turn, tumor necrosis is independently associated
with OS after BCBM surgery. The observed associations
between the radiographic tumor characteristics with other
clinical and immunohistochemical parameters and patients’
survival might be useful for better understanding of tumor
biology in individuals with BCBM.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s00701- 021- 05026-4.
Author contribution Conceptualization, AM and RJ; methodology,
AM, RJ, and MDO; formal analysis, AM, RJ, and LR; supervision,
RJ; writing (original draft preparation), AM; writing (review and edit-
ing), RJ, MDO, LR, DP, TFD, YA, CD JH, CP, AI, RK, KW, and US.
Funding Open Access funding enabled and organized by Projekt
Ethics approval The study was conducted according to the guidelines
of the Declaration of Helsinki and approved by the Ethics Committee of
University Hospital Essen (protocol code: 17–7855-BO, 05.05.2020).
Informed consent Informed consent was obtained from all subjects
involved in the study.
Conflict of interest The authors declare no competing interests.
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... All female patients (age ≥ 18 years) who underwent BC BM surgery between January 2008 and December 2019 in a single institution were included. The selection process of individuals for BC BM surgery within the institutional interdisciplinary neuro-oncologic tumor board was reported previously [19,20]. Patients with synchronous cerebral metastases were excluded from the study. ...
... The following patient and tumor characteristics were collected from the electronic health records: patients' previous medical history (documented comorbidities) and specific laboratory parameters at admission to assess the presence of anemia (hemoglobin), renal function (creatinine), and inflammatory status (white blood cells); BC-related variables: time of BC diagnosis, the type of surgical and (neo-) adjuvant treatment, histopathological features (invasive ductal, invasive lobular), tumor stage, and RS; BM-related variables: time of BM diagnosis, preoperative Karnofsky performance status (KPS) scale, number (singular vs. multiple) and location of BM, RS, and radiographic features in the preoperative magnetic resonance imaging (MRI) as reported previously [20]. In addition, all available follow-up data after BM surgery was recorded to assess the patients' OS. ...
... Except for TI, which remains the contrary discussed survival predictor, other significant results of our study are in line with current evidence in the literature. So, higher age [2,6] and tumor subtype [2], Trastuzumab therapy [1,22], brain radiation [18], and tumor necrosis [20] are acknowledged survival predictors for BC BM patients undergoing surgery. Moreover, the relevance of these factors has also been shown for survival prognosis and treatment response of different cancer types, particularly with regard to patients' age and adjuvant therapy [18]. ...
Full-text available
Purpose Breast cancer (BC) is the most frequently diagnosed tumor entity in women. Occurring at different time intervals (TI) after BC diagnosis, brain metastases (BM) are associated with poor prognosis. We aimed to identify the risk factors related to and the clinical impact of timing on overall survival (OS) after BM surgery. Methods We included 93 female patients who underwent BC BM surgery in our institution (2008–2019). Various clinical, radiographic, and histopathologic markers were analyzed with respect to TI and OS. Results The median TI was 45.0 months (range: 9–334.0 months). Fifteen individuals (16.1%) showed late occurrence of BM (TI ≥ 10 years), which was independently related to invasive lobular BC [adjusted odds ratio (aOR) 9.49, 95% confidence interval (CI) 1.47–61.39, p = 0.018] and adjuvant breast radiation (aOR 0.12, 95% CI 0.02–0.67, p = 0.016). Shorter TI (< 5 years, aOR 4.28, 95% CI 1.46–12.53, p = 0.008) was independently associated with postoperative survival and independently associated with the Union for International Cancer Control stage (UICC) III–IV of BC (aOR 4.82, 95% CI 1.10–21.17, p = 0.037), midline brain shift in preoperative imaging (aOR10.35, 95% CI 1.09–98.33, p = 0.042) and identic estrogen receptor status in BM (aOR 4.56, 95% CI 1.35–15.40, p = 0.015). Conclusions Several factors seem to influence the period between BC and BM. Occurrence of BM within five years is independently associated with poorer prognosis after BM surgery. Patients with invasive lobular BC and without adjuvant breast radiation are more likely to develop BM after a long progression-free survival necessitating more prolonged cancer aftercare of these individuals.
Full-text available
Background: Brain metastases are associated with poor survival. Molecular genetic testing informs on targeted therapy and survival. The purpose of this study was to perform a MR imaging-based radiomic analysis of brain metastases from non-small cell lung cancer (NSCLC) to identify radiomic features that were important for predicting survival duration. Methods: We retrospectively identified our study cohort via an institutional database search for patients with brain metastases from EGFR, ALK, and/or KRAS mutation-positive NSCLC. We segmented the brain metastatic tumors on the brain MR images, extracted radiomic features, constructed radiomic scores from significant radiomic features based on multivariate Cox regression analysis (p < 0.05), and built predictive models for survival duration. Result: Of the 110 patients in the cohort (mean age 57.51 ± 12.32 years; range: 22–85 years, M:F = 37:73), 75, 26, and 15 had NSCLC with EGFR, ALK, and KRAS mutations, respectively. Predictive modeling of survival duration using both clinical and radiomic features yielded areas under the receiver operative characteristic curve of 0.977, 0.905, and 0.947 for the EGFR, ALK, and KRAS mutation-positive groups, respectively. Radiomic scores enabled the separation of each mutation-positive group into two subgroups with significantly different survival durations, i.e., shorter vs. longer duration when comparing to the median survival duration of the group. Conclusion: Our data supports the use of radiomic scores, based on MR imaging of brain metastases from NSCLC, as non-invasive biomarkers for survival duration. Future research with a larger sample size and external cohorts is needed to validate our results.
Full-text available
PurposeGamma Knife radiosurgery (GKRS) is a non-invasive procedure for the treatment of brain metastases. This study sought to determine whether radiomic features of brain metastases derived from pre-GKRS magnetic resonance imaging (MRI) could be used in conjunction with clinical variables to predict the effectiveness of GKRS in achieving local tumor control.Methods We retrospectively analyzed 161 patients with non-small cell lung cancer (576 brain metastases) who underwent GKRS for brain metastases. The database included clinical data and pre-GKRS MRI. Brain metastases were demarcated by experienced neurosurgeons, and radiomic features of each brain metastasis were extracted. Consensus clustering was used for feature selection. Cox proportional hazards models and cause-specific proportional hazards models were used to correlate clinical variables and radiomic features with local control of brain metastases after GKRS.ResultsMultivariate Cox proportional hazards model revealed that higher zone percentage (hazard ratio, HR 0.712; P = .022) was independently associated with superior local tumor control. Similarly, multivariate cause-specific proportional hazards model revealed that higher zone percentage (HR 0.699; P = .014) was independently associated with superior local tumor control.Conclusions The zone percentage of brain metastases, a radiomic feature derived from pre-GKRS contrast-enhanced T1-weighted MRIs, was found to be an independent prognostic factor of local tumor control following GKRS in patients with non-small cell lung cancer and brain metastases. Radiomic features indicate the biological basis and characteristics of tumors and could potentially be used as surrogate biomarkers for predicting tumor prognosis following GKRS.
Full-text available
Importance Higher overall leukocyte counts in women may be associated with increased risk of breast cancer, but the association of specific leukocyte subtypes with breast cancer risk remains unknown. Objective To determine associations between circulating leukocyte subtypes and risk of breast cancer. Design, Setting, and Participants Between 2003 and 2009, the Sister Study enrolled 50 884 women who had a sister previously diagnosed with breast cancer but were themselves breast cancer free. A case-cohort subsample was selected in July 2014 from the full Sister Study cohort. Blood samples were obtained at baseline, and women were followed up through October 2016. Data analysis was performed in April 2019. Main Outcomes and Measures The main outcome was the development of breast cancer in women. Whole-blood DNA methylation was measured, and methylation values were deconvoluted using the Houseman method to estimate proportions of 6 leukocyte subtypes (B cells, natural killer cells, CD8⁺ and CD4⁺ T cells, monocytes, and granulocytes). Leukocyte subtype proportions were dichotomized at their population median value, and Cox proportional hazard models were used to estimate associations with breast cancer. Results Among 2774 non-Hispanic white women included in the analysis (mean [SD] age at enrollment, 56.6 [8.8] years), 1295 women were randomly selected from the full cohort (of whom 91 developed breast cancer) along with an additional 1479 women who developed breast cancer during follow-up (mean [SD] time to diagnosis, 3.9 [2.2] years). Circulating proportions of B cells were positively associated with later breast cancer (hazard ratio [HR], 1.17; 95% CI, 1.01-1.36; P = .04). Among women who were premenopausal at blood collection, the association between B cells and breast cancer was significant (HR, 1.38; 95% CI, 1.05-1.82; P = .02), and an inverse association for circulating proportions of monocytes was found (HR, 0.75; 95% CI, 0.57-0.99; P = .05). Among all women, associations between leukocyte subtypes and breast cancer were time dependent: higher monocyte proportions were associated with decreased near-term risk (within 1 year of blood collection, HR, 0.62; 95% CI, 0.43-0.89; P = .01), whereas higher B cell proportions were associated with increased risk 4 or more years after blood collection (HR, 1.38; 95% CI, 1.15-1.67; P = .001). Conclusions and Relevance Circulating leukocyte profiles may be altered before clinical diagnoses of breast cancer and may be time-dependent markers for breast cancer risk, particularly among premenopausal women.
PurposeBrain metastases (BM) occur in 15–35% of patients with metastatic breast cancer, conferring poor prognosis and impairing quality of life. Clinical scores have been developed to classify patients according to their prognosis. We aimed to check the utility of the Breast Graded Prognostic Assessment (B-GPA) and its modified version (mB-GPA) and compare them in routine clinical practice. Methods This is an ambispective study including all patients with breast cancer BM treated in a single cancer comprehensive center. We analyzed the overall survival (OS) from BM diagnosis until death. The Kaplan–Meier method and Cox proportional hazard regression model were used in the analyses. ROC curves were performed to compare both scores.ResultsWe included 169 patients; median age was 50 years. HER2-positive and triple negative patients were 33.7% and 20.7%, respectively. At the last follow-up, 90% of the patients had died. Median OS was 12 months (95% confidence interval 8.0–16.0 months). OS was worse in patients with > 3 BM and in patients with triple negative subtype. Conclusions In our series, we confirm that B-GPA and mB-GPA scores correlated with prognosis. ROC curves showed that B-GPA and mB-GPA have similar prognostic capabilities, slightly in favor of mB-GPA.
Specific biological properties of those circulating cancer cells that are the origin of brain metastases (BM) are not well understood. Here, single circulating breast cancer (BC) cells were fate-tracked during all steps of the brain metastatic cascade in mice after intracardial injection over weeks. A novel in vivo two-photon microscopy methodology was developed that allowed to determine the specific cellular and molecular features of BC cells that homed in the brain, extravasated, and successfully established a brain macrometastasis. Those BM-initiating breast cancer cells (BMICs) were mainly originating from a slow-cycling subpopulation that included only 16-20% of all circulating cancer cells. BMICs showed enrichment of various markers of cellular stemness. As a proof-of-principle for the principal usefulness of this approach, expression profiling of BMICs vs. non-BMICs was performed, which revealed up-regulation of NDRG1 in the slow-cycling BMIC subpopulation in one BM model. Here, BM development was completely suppressed when NDRG1 expression was downregulated. In accordance, in primary human BC, NDRG1 expression was heterogeneous, and high NDRG1 expression was associated with shorter metastasis-free survival. In conclusion, our data identifies temporary slow-cycling BC cells as the dominant source of brain and other metastases and demonstrates that this can lead to better understanding of BMIC-relevant pathways, including potential new approaches to prevent BM in patients. Implications: Cancer cells responsible for successful brain metastasis outgrowth, are slow-cycling and harbor stemness features. The molecular characteristics of these metastasis-initiating cells can be studied using intravital microscopy technology.
Purpose: Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. Methods: A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. Results: Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation (P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. Conclusion: Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).
Background: Gamma Knife radiosurgery (GKS) was recommended for treating patients with breast cancer brain metastasis (BCBM), but predictions of the existing prognostic models for therapeutic responsiveness vary substantially. Purpose: To investigate the prognostic value of pretreatment clinical, MRI radiologic, and texture features in patients with BCBM undergoing GKS. Material and methods: The data of 81 BCBMs in 44 patients were retrospectively reviewed. Progressive disease was defined as an increase of at least 20% in the longest diameter of the target lesion or the presence of new intracranial lesions on contrast-enhanced T1-weighted (CE-T1W) imaging. Radiomic features were extracted from pretreatment CE-T1W images, T2-weighted (T2W) images, and ADC maps. Cox proportional hazard analyses were performed to identify independent predictors associated with BCBM-specific progression-free survival (PFS). A nomogram was constructed and its calibration ability was assessed. Results: The cumulative BCBM-specific PFS was 52.27% at six months and 11.36% at one year, respectively. Age (hazard ratio [HR] 1.04; 95% confidence interval [CI] 1.01-1.06; P = 0.004) and CE-T1W-based kurtosis (HR 0.72; 95% CI 0.57-0.92; P = 0.008) were the independent predictors. The combination of CE-T1W-based kurtosis and age displayed a higher C-index (C-index 0.70; 95% CI 0.63-0.77) than did CE-T1W-based kurtosis (C-index 0.65; 95% CI 0.57-0.73) or age (C-index 0.63; 95% CI 0.56-0.70) alone. The nomogram based on the combinative model provided a better performance over age (P < 0.05). The calibration curves elucidated good agreement between prediction and observation for the probability of 7- and 12-month BCBM-specific PFS. Conclusion: Pretreatment CE-T1W-based kurtosis combined with age could improve prognostic ability in patients with BCBM undergoing GKS.
Lung cancer metastases comprise most of all brain metastases in adults and most brain metastases are diagnosed by magnetic resonance (MR) scans. The purpose of this study was to conduct an MR imaging-based radiomic analysis of brain metastatic lesions from patients with primary lung cancer to classify mutational status of the metastatic disease. We retrospectively identified lung cancer patients with brain metastases treated at our institution between 2009 and 2017 who underwent genotype testing of their primary lung cancer. Brain MR Images were used for segmentation of enhancing tumors and peritumoral edema, and for radiomic feature extraction. The most relevant radiomic features were identified and used with clinical data to train random forest classifiers to classify the mutation status. Of 110 patients in the study cohort (mean age 57.51 ± 12.32 years; M: F = 37:73), 75 had an EGFR mutation, 21 had an ALK translocation, and 15 had a KRAS mutation. One patient had both ALK translocation and EGFR mutation. Majority of radiomic features most relevant for mutation classification were textural. Model building using both radiomic features and clinical data yielded more accurate classifications than using either alone. For classification of EGFR, ALK, and KRAS mutation status, the model built with both radiomic features and clinical data resulted in area-under-the-curve (AUC) values based on cross-validation of 0.912, 0.915, and 0.985, respectively. Our study demonstrated that MR imaging-based radiomic analysis of brain metastases in patients with primary lung cancer may be used to classify mutation status. This approach may be useful for devising treatment strategies and informing prognosis.
Background: Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment, GPA) for breast cancer patients with brain metastases (BCBM), based on cohort A (1985-2007, n=642), then updated it, reporting the impact of tumor subtype in cohort B (1993-2010, n=400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the three cohorts. Methods: A multi-institutional (19) multi-national (3) retrospective database of 2473 breast cancer patients with newly-diagnosed brain metastases (BCBM) diagnosed from 1/1/2006-12/31/2017 was created and compared to prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated, such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively. Results: Median survival (MS) for cohorts A, B and C improved over time [from 11, to 14 to 16 months, respectively (p<0.01)] despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, KPS, age, number of BCBM and extracranial metastases (all p<0.01). MS for GPA 0-1.0, 1.5-2.0, 2.5-3.0 and 3.5-4.0 was 6, 13, 24 and 36 months, respectively. Between cohorts B & C, the proportion of HER2+ subtype decreased from 31% to 18% (p<0.01) and MS in this subtype increased from 18 to 25 months (p<0.01). Conclusion: MS has improved modestly, but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free on-line calculator available at The Breast-GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest HER2-targeted therapies improve clinical outcomes in some patients with BCBM.
Background: We aimed to validate the clinical significance of locoregional surgery in improving the prognosis of primary metastatic breast cancer (pMBC). Methods: We conducted a population-based retrospective study by analyzing clinical data obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. Stratification analysis was employed to assess the effect of breast surgery on breast cancer-specific survival and overall survival. Then propensity score matching and COX regression models were employed to evaluate the survival advantages of breast surgery, if any in patients with pMBC. Results: The median BCSS and OS in the surgery group were almost twice of that in the group without surgery. Breast surgery provided a survival advantage for patients with a single metastasis in the bone, liver or lung, but not in the brain. We found that axillary lymph node dissection performed in combination with specific breast surgical procedures did not result in a significant improvement in survival. Additionally, when combined with radiotherapy and/or chemotherapy, surgery significantly improved the survival and was not influenced by the molecular subtype and tumor size. Finally, using COX regression models before and after propensity score matching, breast surgery was found to reduce the risk of mortality in patients with MBC by more than 40%. Conclusions: The effect of locoregional surgery has been underestimated in pMBC patients. Surgical procedures should be seriously considered when planning combination treatments for pMBC patients with a single metastasis except for brain metastasis.