Comparison of Prognosis Between Epidermal Growth Factor Mutation Positive and Negative Groups in Lung Adenocarcinoma Patients with Brain Metastases

doi:10.21203/rs.3.rs-5316285/v1

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Comparison of Prognosis Between Epidermal Growth Factor Mutation Positive and Negative Groups in Lung Adenocarcinoma Patients with Brain Metastases

https://doi.org/10.21203/rs.3.rs-5316285/v1

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Introduction:

Brain Metastasis (BM) in Non-Small Cell Lung Cancer (NSCLC) is still important reason of morbidity and mortality despite the advances in the cancer treatment. Using Tyrosine Kinase Inhibitors against Epidermal Growth Factor Receptors (EGFR) mutations revolutionized in NSCLC treatment. We investigated whether the presence of EGFR mutation influences survival in patients with Lung Adenocarcinoma with BM.

Material and Methods

The data of the patients with pathological diagnosis of NSCLC and BM at tertiary hospital were analyzed retrospectively in terms of survival. A total of 2554 patients diagnosed with NSCLC pathologically between 01.01.2010 and 01.01.2021 were identified. After exclusion of patients with lack of data, unknown EGFR mutation status, no brain metastasis and additional malignancy 336 patients were included to the study.

Results

It is found that EGFR (+) patients were more female dominant (48.6% vs 13.3% p < 0.0001) and were have less history of smoking (%47.2 vs %87.1, p < 0.0001) and were better survival (%79.2 vs %92.8). We found negativity of EGFR increased death risk by 1.700 times (95% CI: 1.323–2.183, p < 0.0001) in univariate analysis and by 1.724 times (95% CI 1.251–2.377, p = 0.0001) in multivariate analysis. When overall survivals have been compared estimated overall survival time of EGFR (-) patients were 10.088 (95% CI 8.571–11.606) months and of EGFR (+) patients were 11.829 months (95% CI 10.336–13.323) (p < 0.001).

Conclusion

EGFR positivity was associated with survival. Also, survival was significantly longer in EGFR-positive patients with brain metastases diagnosed with NSCLC.

Non-small cell lung cancer

adenocarcinoma

brain metastasis

EGFR

prognosis

Despite all the developments in the treatment of non-small cell lung cancers (NSCLC), the development of brain metastasis (BM) is still a noble cause of morbidity and mortality (1). When the rates of BM in NSCLC were evaluated, BM was detected in 7–10% of the patients at the time of diagnosis, and during the follow-up of lung cancer in 25–40% (2). After BM develops, the prognosis is less than 3 months in patients who do not receive any treatment and around 4.5 months on average with whole brain irradiation (3). The identification of driver mutations in the pathogenesis of lung cancer and the emerging treatment options for some of them opened a new horizon regarding the treatment of NSCLC. It was observed that the risk of developing BM during the disease in epidermal growth factor receptor (EGFR) mutant cases is higher than in non-mutant cases. There are different results in the literature about the prognosis of these cases (4–6).

In a previous study, BM was found to be a poor prognostic indicator, and neurological deaths were more common in EGFR mutant cases (7, 8). Also, a study that was published reported that EGFR mutation status does not have significant impacts on overall and progression-free survival (9). On the other hand, studies are reporting better prognosis in EGFR mutant BM cases. EGFR mutation status was reported to be associated with better survival independent of age, functional status, extracranial disease status, and BM count. It was also reported that EGFR mutation status is an independent predictor of response to radiotherapy (RT), and longer survival was detected in patients who received EGFR-tyrosine kinase inhibitor (TKI) treatment after the resection of brain and lung lesions (10).

The purpose of the present study was to investigate the impacts of EGFR mutation status on survival in patients with a diagnosis of lung adenocarcinoma with BM followed in SBU Izmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital.

The data of patients diagnosed with lung adenocarcinoma pathologically, BM detected by cranial MRI and EGFR mutation analysis at SBU Izmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital between 01.01.2010–01.02.2021 were analyzed retrospectively in one single center. The study started after the approval of the Medical Specialization Ethics Committee of our hospital, dated 26.03.2021, and numbered 07–16.

EGFR mutation analysis was made by DNA extraction and reverse transcriptase polymerase chain reaction (RT-PCR). Samples from tissue and peripheric blood was analyzed with RT-PCR properly. The FDA-approved “Cobas®ฏ EGFR Test” designed to detect forty-two mutations in exons 18–21 of the EGFR gene, including exon 19 deletion, L858R and T790M, was used.

The demographic characteristics of the cases and all factors that affected survival were recorded.

The thoracic disease progression-free survival was taken as the time from the date of pathological diagnosis to the date of progression of the disease except brain metastasis. The BM progression-free survival was taken as the time from the date of diagnosis of BM to recurrence or progression of brain metastasis. The overall survival (OS)l was taken as the time from the date of diagnosis of BM to the date of death or the date of the last control in patients with ongoing follow-up. Mortality rate was defined as being deceased or survivor at the 01.02.2022 (one year after last date of inclusion period).

The data obtained in the study were entered into the database that was created in the SPSS (Statistical Package for Social Sciences) 18.0 program and statistical analyzes were made. The comparisons of the independent groups with the variables that had a normal distribution were made with the “student t” test and the variables that did not have a normal distribution with the “Mann-Whitney U” test, which is a nonparametric test. The receiver operating characteristic (ROC) analysis was made to calculate the cutoff values for continuous variables affecting the survival and progression process, and the most appropriate cutoff values were determined according to the Youden’s index. The univariate survival and progression-free survival were compared with Kaplan-Meier, log-rank test, and hazard ratios were calculated. The Cox regression analysis was made in the multivariate analysis with the backward stepwise method according to the Wald value. The margin of error for the first type was found to be α:0.05 and the double-tailed test was performed in all statistical comparison tests. If the “p” value was less than 0.05, the difference between the groups was considered statistically significant.

A total of 2554 patients diagnosed with NSCLC pathologically between 01.01.2010 and 01.01.2021 were identified. Among these 2554 patients, 618 were excluded because they were diagnosed with NSCLC, 969 had no brain metastases, 318 had a lack of data, 272 were without EGFR results, and 41 had an additional primary malignancy. The remaining 336 patients were analyzed retrospectively in the study (Fig. 1).

A total of 266 of the patients were male (79.2%) and the mean age was 60.6 (32–81) and 264 patients (78.6%) out of 336 lung adenocarcinoma cases were EGFR mutation negative. The general characteristics of the patients are given in Table 1.

Table 1

General characteristics of the patients.
Variables	Total (n = 336)
Age (mean ± SD)	60.16 ± 9.12
Gender	(n, %)
Female Male	70 (20.8)
Female Male	266 (79.2)
EGFR mutation status	(n, %)
Positive Negative	72 (21.4)
Positive Negative	264 (78.6)
Targeted Treatment
Received Not Received	55 (76.4)
Received Not Received	17 (23.6)
Type of Targeted Treatment
Osimertinib Erlotinib Alectinib Gefitinib Afatinib	6 (10.9)
	25 (45.5)
	2 (3.6)
	9 (16.4)
	8 (14.5)
EGFR Mutation Type
Exon 19	29 (40.3)
Exon 20 - S768I	3 (4.2)
Exon 21 - L858R	23 (31.9)
G719X	5 (6.9)
Exon 19 and Exon 20 - T790M	9 (12.5)
Exon 20 - T790M and Exon 21 - L858R	3 (4.2)
Comorbidity	(n, %)
Yes No	129 (38.4)
Yes No	207 (61.6)
Additional organ metastasis	(n, %)
Yes No	271 (80.7) 65 (19.3)
Diagnosis stage	(n, %)
Stage I Stage II Stage III Stage IV	9 (2.7)
	6 (1.8)
	44 (13.1)
	277 (82.4)
Systemic chemotherapy (n, %)
Received Not received	209 (62.2)
Received Not received	127 (37.8)
Number of chemotherapy cures (median, min-max)	6 (1–40)
Mortality (n, %)	302 (89.9)

Tumor (T) and node (N) status of the primary disease at the time of BM, clinical findings, characteristics of BM, treatments, and their comparison in EGFR (+) and EGFR (-) groups are summarized in Table 2.

Table 2

The characteristics of the brain metastasis and comparison between groups.
Variables	Total (n = 336)	EGFRmut (+) (n = 72)	EGFRmut (-) (n = 264)	p-value
Number of brain metastases (n, %)
Single Multiple	130 (38.7 )	22 (30.6)	108 (40.9)	0.110
Single Multiple	206 (61.3)	50 (69.4)	156 (59.1)	0.110
Brain metastasis symptoms (n, %)
Seizures	45 (13.4)	7 (9.7)	38 (14.4)	0.403
Consciousness change	37 (11)	11 (15.3)	26 (9.8 )	0.275
Hemiplegia	38 (11.3)	4 (5.6)	34 (12.9)	0.126
Paraplegia	15 (4.5)	2 (2.8)	13 (4.9)	0.747
Headache	49 (14.6)	18 (25)	31 (11.7)	0.008
Dizziness	37 (11)	17 (23.6)	20 (7.6)	< 0.001
Brain metastasis size (mm) (median, min-max)	16 (2-288)	15 (2–40)	17 (2-288)	0.008
Hemorrhage into brain metastasis (n, %)
Yes	8 (6.5)	3 (4.2)	5 (1.9)	0.376
No	328 (93.5)	69 (95.8)	259 (98.1)	0.376
Rim-type involvement in brain metastasis (n, %)
Yes	75 (22.3)	14 (19.4)	61(23.1)	0.616
No	261 (77.7)	58 (80.6)	203 (76.9)	0.616
Treatment (n, %)
Metastasectomy	34 (10.1)	9 (12.5)	25 (9.5)	0.592
Cranial radiotherapy	323 (84.2)	68 (92.6)	255 (96.5)	0.488
Brain metastasis relapse or progression (n, %)
Yes	51 (15.2)	9 (12.5)	42 (15.9)	0.475
No	285 (96.1)	63 (87.5)	222 (84.)	0.475

The variables that could affect survival were compared in the mortality and survivor groups, and their relationship with survival was evaluated and summarized in the Table 3.

Table 3

The comparison of the variables that might affect survival in the surviving and mortality groups.
Variable	Mortality (n = 302)	Survivor (n = 34)	p-value
Age	60.22 ± 9.30	59.68 ± 7.42	0.743
Gender (n, %)
Male Female	244 (80.8)	22 (64.7)	0.049
Male Female	58 (19.2)	12 (35.3)	0.049
Comorbidity (n, %)
Yes No	112 (37.1)	17 (50)	0.200
Yes No	190 (62.9)	17 (50)	0.200
EGFR status (n, %)
Positive Negative	57 (18.9)	15 (44.2)	0.001
Positive Negative	245 (81.1)	19 (55.8)	0.001
Performance status (n, %)
ECOG 0 ECOG 1-2-3-4	123 (40.7)	27 (79.4)	< 0.0001
ECOG 0 ECOG 1-2-3-4	179 (59.3)	7 (20.6)	< 0.0001
Diagnostic sequence (n, %)
Later brain metastasis	208 (68.9)	23 (67.6)	1
Simultaneous diagnosis	94 (31.1)	11 (32.4)	1
Clinical manifestation due to cranial metastasis (n, %)
Yes	179 (59.3)	10 (29.4)	0.002
No	123 (40.7)	24 (70.6)	0.002
Cranial radiotherapy (n, %)
Received Not received	292 (96.7)	31 (91.2)	0.134
Received Not received	10 (3.3)	3 (8.8)	0.134
Cranial Metastasectomy
Yes No	30 (9.9)	4 (11.8)	0.763
Yes No	272 (90.1)	30 (88.2)	0.763
Chemotherapy
Received	188 (62.3)	21 (61.8)	1
Not received	114 (37.7)	13 (38.2)	1
T status at diagnosis (n, %)
T1 T2 T3 T4	41 (13.5)	9 (26.5)	0.164
	83(27.5)	10 (29.4)
	43 (14.2)	5 (14.7)
	135 (44.8)	10 (29.4)
N status at diagnosis (n, %)
N0 N1 N2 N3	46 (15.2)	13 (38.2)	0.002
	34 (11.3)	6 (17.6)
	92 (30.5)	9 (26.5)
	130 (43.0)	6 (17.6)
M status at diagnosis (n, %)
M0 M1	50 (16.6)	10 (29.4)	0.105
M0 M1	252 (83.4)	24 (70.6)	0.105
Additional organ metastasis (n, %)
Yes No	251 (83.1)	20 (58.8)	0.002
Yes No	51 (16.9)	14 (41.2)	0.002
T status at the time of brain metastasis (n, %)
T1 T2, 3, 4	37 (12.3)	11 (32.4)	0.004
T1 T2, 3, 4	265(87.2)	23 (67.6)	0.004
N status at the time of brain metastasis (n, %)
N0 N1 N2 N3	52 (17.2)	12 (35.3)	0.006
	30 (9.9)	6 (17.6)
	82 (27.2)	10 (29.5)
	138 (45.7)	6 (17.6)
M status at the time of brain metastasis
M1a, M1b M1c	85 (28.1)	17 (50)	0.015
M1a, M1b M1c	217 (71.9)	17 (50)	0.015
LDH U/L (median, min-max)	220 (65-2322)	189 (118–1522)	0.009
Albumin g/dL (median, min-max)	3.80 (2-5.1)	4.13 (3.34–5.3)	0.001
NLR (median, min-max)	3.61 (0,24–161)	3.06 (0.18–22.2)	0.213
LDH threshold value U/L (n, %)
> 218 ≤ 218	154 (51)	8 (23.5)	0.004
> 218 ≤ 218	148 (49)	26 (76.5)	0.004
Total protein threshold g/dL (n, %)
> 6.87 ≤ 6.87	142 (47)	21 (61.8)	0.147
> 6.87 ≤ 6.87	160 (53)	13 (38.2)	0.147
Albumin threshold g/dL (n, %)
> 3.96 ≤ 3.96	123 (40.7)	23 (67.6)	0.005
> 3.96 ≤ 3.96	179 (59.3)	11 (32.4)	0.005
NLR threshold value (n, %)
> 4.2 ≤ 4.2	135 (44.7)	10 (29.4)	0.128
> 4.2 ≤ 4.2	167 (55.3)	24 (70.6)	0.128
ECOG: Eastern Cooperative Oncology Group; Patient performance status score.
T: Tumor size, N: Lymph node metastasis, M: Metastasis status.
LDH: Lactate dehydrogenase, NLR: Neutrophil/lymphocyte ratio.

The comparison of the tumor-node-metastasis (TNM) status, stage, and presence of additional organ metastasis at the time of diagnosis, TNM status at the time of BM, and stage in the mortality and survival groups are given in Table 3.

The characteristics of the laboratory parameters were examined in the mortality and survival groups. The threshold values of parameters were calculated with the Youden’s index. The comparisons made according to these threshold values are given in Table 3.

The relationship between the demographic, clinical, laboratory, and radiological characteristics of the patients and their survival was evaluated with univariate analysis. Multivariate analysis was made based on the variables obtained according to univariate analysis results and clinical significance. Multivariate analysis results are given in Table 4.

Table 4

The impacts of the demographic, clinical, and radiological characteristics of patients on mortality according to multivariate analysis.
Variables	Multivariate Analysis
	HR (95% CI)				p-value
Age (> 72 years)	2.1	1.5	-	3.1	< 0.001
EGFR mutation status (Negative)	1.7	1.3	-	2.4	0.0001
Smoking history (Yes)	1.5	1.1	-	2.0	0.017
Brain metastasis diagnosis (Following lung diagnosis)	1.6	1.2	-	2.1	0.001
Brain metastasis size (> 19 mm)	1.3	1.0	-	1.7	0.029
Clinical manifestation related to brain metastasis (Yes)	1.5	1.2	-	1.9	0.002
Chemotherapy (Not received)	1.5	1.2	-	1.9	0.002
LDH U/L (> 218)	1.3	1.0	-	1.6	0.042
Stage at diagnosis (Stage IV)	1.5	1.1	-	2.1	0.017
T status at the time of brain metastasis (T II, III, IV)	1.6	1.1	-	2.3	0.016
N status at the time of brain metastasis (N2, 3)	1.4	1.1	-	1.8	0.018
M status at the time of brain metastasis (M1c)	1.9	1.5	-	2.4	< 0.0001
LDH: Lactate dehydrogenase, EGFR (Epidermal Growth Factor Receptor): T: Tumor size, N: Lymph node metastasis, M: Metastasis status, HR: Hazard ratio, CI: Confidence interval.

The mean thoracic disease progression-free survival of all patients was found to be 11.199 (9.84–12.55) months. The mean thoracic disease progression-free survival times were 9.72 months (95% CI 8.329–11.111) in the EGFR (-) group and 16.625 months (95% CI 13.185–20.065) in the EGFR (+) group (p < 0.0001).

The brain metastasis progression status of the patients was evaluated. Although no recurrence or progression of brain metastasis was detected in 283 patients (84.2%), it was seen in 51 patients (15.2%). Progression-free survival times of 51 patients with relapse/progression in brain metastases were evaluated. The mean brain metastasis recurrence or progression-free survival time was 34.105 months (95% CI: 30.604–37.605). This period was 28.966 (95% CI 29.668–42.662) months in the EGFR (-) Group and 36.165 (95% CI 30.627–43.361) months in the EGFR (+) Group.

The mean value of the overall survival time of the patients was found to be 11.83 (95% CI: 10.33–13.32). When overall survival was compared, the mean expected time in the EGFR (-) group was 10.088 (95% CI 8.571–11.606) months, and 11.829 months (95% CI 10.336–13.323) months in the EGFR (+) Group (p < 0.001) (Fig. 2).

The survival of 72 patients with positive EGFR was evaluated according to their targeted treatment status. 55 patients received targeted treatment; 17 patients did not receive targeted treatment. While the mortality rate was 88.24% in those who did not receive targeted treatment, the mortality rate in those who received targeted treatment was 76.36%. The median expected overall survival was found to be 7.929 months (95% CI: 4.794–11.065) in the no-treatment group, and it was 21.209 months (95% CI: 16.672–25.747) in the group that received targeted treatment. EGFR-positive patients were 4 times more (95% CI: 1.767–9.058) in the group that did not receive targeted treatment than in the group that received the targeted treatment (p = 0.0009) (Fig. 2).

In our study, the impacts of EGFR mutation on survival were investigated in patients with lung adenocarcinoma with brain metastases.

In the present study, there were 72 (21.4%) patients out of the group of 336 patients in the patient group were found to be EGFR positive, and 55 (76.4%) of this group received targeted treatment. In studies conducted in Türkiye, the EGFR positivity rate ranges between 22–42% (12).

In the present study, the rate of women in EGFR-positive patients was higher than in the EGFR-negative group (48.8%; 13.3%) and the smoking history was less in EGFR-positive patients (47.2%; 87.1%). It is already known that driver mutation positivity is more common in women and non-smokers (varying between 29–66% in the literature) (13, 14).

It is also known that tumors with EGFR positivity cause a predisposition to metastasis regardless of tumor size, especially brain metastasis when compared to those without EGFR (15, 16). In the present study although additional organ metastases were more common in the EGFR-negative group, this difference was not statistically significant.

It was found in the present study that EGFR-negative patients had larger brain metastases. In the study of Yeop-shin et al., no correlation was detected between the size of brain metastasis and EGFR positivity (17).

In our study, symptoms such as seizures, changes in consciousness, hemiplegia, paraplegia, and visual impairment symptoms were not associated with EGFR status. However, headache and dizziness complaints were statistically and significantly higher in the EGFR-positive group. Luo D et al. found that intracranial hypertension, paresthesia, aphasia, and distraction were higher in the EGFR-positive group, but not at statistically significant levels (18).

The relationship between the demographic, clinical, laboratory, and radiological characteristics of the patients and survival was examined. There are publications in the literature reporting that the female gender is a positive prognostic characteristic in survival (19). In this study, even though the male gender was found to be a risk factor for death in univariate analysis, it was not found as a risk factor for mortality in multivariate analysis. This can be explained by the fact that male patients were older and had less EGFR positivity than female patients.

Age over 72 was found to be a risk factor for mortality in the univariate and multivariate analyses. EGFR mutation is seen at a higher rate in younger patients. Also, age was found to be a factor that negatively affected survival in the EGFR-negative and EGFR-positive NSCLC (20, 21).

The impacts of co-morbidities on the prognosis of lung cancer are less researched considering the stage and treatment modalities. Although there are publications in the literature reporting a relationship between comorbidity and mortality in lung cancer (22, 23), no correlation was detected between comorbidity and survival in our study.

Smoking was found to be a factor that increased the risk of mortality in the multivariate analyses in our study like other studies (24).

It is already known that poor performance status (ECOG (Eastern Cooperative Oncology Group ≥ 1) negatively affects survival in NSCLC and all cancer types and tend to be older and more EGFR-negative (25–27). Performance status was found to be statistically and significantly risky for mortality in univariate analysis, but not found to be significantly risky in multivariate analysis in the present study. This change may be occurred by retrospective design of the study.

T ≥ 2 or N ≥ 2 disease at the time of diagnosis and at the time of brain metastasis, M1c disease at the time of brain metastasis, presence of additional organ metastases, and Stage IV disease at the time of diagnosis were found to be risky in terms of mortality in univariate analysis.

It is already known that active extracranial metastasis is associated with decreased survival in NSCLC patients with brain metastases. Eichler et al. reported that active extracranial metastasis has a poor impact on survival (10) was supported by the fact that M1c is associated with decreased survival at the time of brain metastasis in the univariate and multivariate analyses.

It is already known that the nutritional status of the patient or the presence of cachexia affects the prognosis and survival of lung cancer patients (28). The total protein and albumin levels were used to measure cachexia in the present study with the threshold values for total protein ≤ 6.87 g/dL and albumin ≤ 3.96 g/dL. No relationship was detected between total protein and survival.

As an intracellular enzyme, LDH was shown to be associated with a poor prognostic factor because it shows increased catabolism and mitotic activity (29–30). And NLR level is an indicator of the increased systemic inflammatory response, it was found to be associated with poor prognosis in lung cancer (31). LDH > 218 U/L and NLR > 4.2 appear to increase the risk of mortality in univariate analysis. It was also seen that having an LDH > 218 U/L increased the risk of mortality in multivariate analysis.

In our study it is found that tumor size > 19 mm and the presence of clinical symptoms because of brain metastasis decreased survival in multivariate analysis. It is concordant with other studies (32).

Brain metastasis development during follow-up rather than brain metastasis at the time of diagnosis was found to be a risk factor in terms of mortality in univariate and multivariate analyzes in the present study. In the study of Jünger et al. it was found that time of BM in NSCLC did not affect the mortality (32). This study contradicts our study in this regard.

The impact of chemotherapy and targeted treatment on survival was also examined. Chemotherapy increases survival when compared to patients who cannot receive chemotherapy (33). In the present study, patients who did not receive chemotherapy had a higher risk of mortality in both univariate and multivariate analyses. Cranial metastasectomy is beneficial in selected patients (especially in those with brain metastases without lymph node involvement) (34). In the present study, cranial metastasectomy reduced mortality risk in univariate analysis, but this impact was not detected in multivariate analysis, which may be because of the number of patients who underwent cranial metastasectomy. Radiotherapy was not found to be associated with the risk of mortality in the present study. This result is similar to the results of the study conducted by Jiang et al. that investigated the impacts of radiotherapy on survival in EGFR-positive patients (35).

When the survival rates of the patients were examined, the thoracic disease progression-free survival time (9.7 months to 16.6 months) and the brain metastasis recurrence or progression-free survival time (29.0 months to 36.2 months) were statistically and significantly longer in the EGFR-positive group. Unlike our study, no difference was reported between progression-free survival times in Luo et al.’s study (18). Similar to our study, disease progression-free survival time was found to be longer in the EGFR-positive group than in the KRAS-positive or EGFR-negative groups in the study of Cadranel et al. (36).

In the present study, the mean OS time of the patients was found to be 11.8 (95% CI: 10.3–13.3) months. These results are similar to the OS times of metastatic NSCLC (19, 54). There are studies suggests that EGFR positivity is associated with better outcome (37). In the study of Eichler et al., EGFR mutation was found to be one of the prognostic factors affecting survival along with performance status, age, and the prevalence of extracranial disease (10). In the present study, it was found that EGFR positivity was associated with prolonged survival, and this relationship was also significant in multivariate analysis. In this way, it was found that EGFR mutation status is a factor affecting survival as much as age, additional organ metastasis at the time of brain metastasis, and smoking history.

Among EGFR-positive patients who received EGFR treatment appears to significantly improve survival (mean survival 21.2 vs. 7.9 months). The risk of mortality of patients who were EGFR positive and did not receive EGFR treatment was four times higher than the other group. It was observed during Stage III drug trials that treatments for EGFR prolonged progression-free survival but did not have a statistically significant impact on OS. In studies in which real-life data were evaluated, these agents were also found to provide advantages in OS, which was also explained by the addition of patients with advanced age, poor performance status, and rare EGFR mutation, which were excluded in real-life Stage III studies (37).

Data loss occurred in the present study because of its retrospective nature. Also, the number of patients in this single-center study remained at a certain level. These two situations are the limitations of the study.

NSCLC, which has advanced brain metastases, is a difficult disease to manage and has a high mortality rate. The discovery of driver mutations in NSCLC classification and treatment changed treatment radically. Publications report that EGFR mutation has positive prognostic values in NSCLC patients with BM. The impact of EGFR positivity on survival in patients diagnosed with NSCLC with brain metastases was examined in the study. Advanced age (age > 72), poor performance status at the time of diagnosis (ECOG > 0), smoking history, development of brain metastases in the follow-up, brain metastasis size (> 19 mm), neurological clinical presence because of brain metastasis, not receiving Chemotherapy, and LDH > 218 U/L had negative prognostic value and decreased survival. EGFR positivity was found to be associated with prolonged survival and was found to be a prognostic factor in multivariate analysis in the present study. It was shown in the present study that patients who received targeted treatment had significantly longer survival among EGFR-positive patients. This area must be supported by prospective and multicenter studies.

Conflict of interest: There is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

The manuscript is written with contributions of all authors. And the manuscript is approved by all authors.

Funding: This scientific publication has received no financial support. Additionally, there are no conflicts of interest, and the authors have not received any personal financial support.

AUTHOR CONTRUBITIONS

DSU made prominent contributions to the concept of work. DSU also made significant contributions to the collection of data and writing process. SA made significant contributions to the interpretation of data and reviewed the paper. OK made important contributions to the interpretation and collection of data. GB played a role in the writing and editing processes. SE made significant contributions to the collection of data. AM played a vital role in the conception of work, interpretation of data and reviewing of paper. All authors have approved the submitted version of the manuscript.

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Comparison of Prognosis Between Epidermal Growth Factor Mutation Positive and Negative Groups in Lung Adenocarcinoma Patients with Brain Metastases

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