J Neurooncol DOI 10.1007/s11060-015-1776-3
CLINICAL STUDY
The correlation between EGFR mutation status and the risk of brain metastasis in patients with lung adenocarcinoma Bo Li1 • Suo-zhu Sun2 • Ming Yang3 • Jian-ling Shi2 • Wei Xu2 • Xi-fan Wang2 Mao-min Song1 • Huo-ming Chen2
•
Received: 2 December 2014 / Accepted: 2 April 2015 Ó Springer Science+Business Media New York 2015
Abstract To explore the correlation between epidermal growth factor receptor (EGFR) mutation status and the risk of brain metastasis (BM) in patients with lung adenocarcinoma, the clinical data of 100 patients with pathologically confirmed lung adenocarcinoma and known EGFR mutation status at exon 18, 19, 20, or 21 were analyzed retrospectively. The incidence of BM was similar between patients with wild-type EGFR and those with EGFR mutations (p = 0.48). However, among patients with EGFR mutations, the incidence of BM was significantly higher in patients with mutation at exon 19 than in patients with mutation at other sites (p = 0.007). Besides, among patients with heterochronous BM, 66.7 % had EGFR mutations. Regarding brain-metastasis-free survival (BMFS), patients with EGFR sensitive mutations (mutation at exon 19/21/and dual mutation) had significantly shorter BMFS compared
with patients with wild-type EGFR (p = 0.018). For patients treated only with chemotherapy, BM was an unfavorable prognostic factor. Patients with BM had worse overall survival compared with those without BM (p = 0.035). However, in patients with BM and EGFR sensitive mutations, those treated with tyrosine kinase inhibitors (TKIs) had significantly longer overall survival compared with those treated with chemotherapy only (p = 0.0081). In conclusion, among patients with EGFR mutations, those mutated at exon 19 had the highest incidence of BM. Furthermore, patients with EGFR mutations are more likely to develop heterochronous BM. The BMFS was significantly shorter in patients with EGFR sensitive mutations. TKIs improved the survival of patients with lung adenocarcinoma and BM who harbored EGFR sensitive mutations. Keywords Non-small cell lung cancer Adenocarcinoma Brain metastasis Epidermal growth factor receptor Tyrosine kinase inhibitors Chemotherapy
Doctor Mao-min Song and Huo-ming Chen are both responsible for the content of the article. & Mao-min Song [email protected] & Huo-ming Chen [email protected] 1
Department of General Surgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, No. 6, Tiantan Xili, Dongcheng District, Beijing 100050, China
2
Department of Medical Oncology, The Second Artillery General Hospital PLA, No. 16, Xinwai Avenue, Xicheng District, Beijing 100088, China
3
College of Life Science and Technology, Beijing University of Chemical Technology, No. 15, North Third Ring Road East, Chaoyang District, Beijing 100029, China
Introduction Adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC), accounting for approximately 40 % of all patients with NSCLC, and its incidence continues to rise. Clinically, this cancer subtype is highly aggressive, with fast progression and early distant metastasis [1]. The brain is one of the most common distant sites of metastasis. Patients with brain metastasis (BM) have poor survival, with a median overall survival (OS) of 4–7 weeks without treatment [2–4]. It was reported that even after undergoing whole-brain radiation therapy (WBRT), the median OS of these patients was only extended to 3–6 months, and a vast majority of patients
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died because of uncontrolled systemic disease other than intracranial failure [5]. In recent years, tyrosine kinase inhibitors (TKIs), which target epidermal growth factor receptor (EGFR), have been included in standard NSCLC treatment. Compared with conventional chemotherapy, TKIs were not only convenient and less toxic, but also efficacious [6, 7]. Additionally, several studies reported their efficacy in NSCLC patients with BM, with an intracranial response ranging from 26.7 to 83 % when used as single agents [8–11] and 64–87 % when combined with WBRT [8, 12, 13]. Moreover, the median OS of patients with BM was also improved significantly after TKIs treatment, ranging from 11.8 to 18.8 months [10, 11, 13]. EGFR mutation status is highly associated with sensitivity to TKIs in advanced NSCLC. In patients with EGFR mutations, TKIs administration was followed by a response rate of 70–80 %, and a longer progression-free survival and OS than those obtained with conventional chemotherapy [6, 7]. Although the presence of EGFR mutation was associated with better efficacy in patients with NSCLC without BM, it is unclear whether this mutation is associated with better efficacy in such patients with BM. Furthermore, some studies suggested that patients with EGFR mutations had higher incidence of BM compared with those without this mutation [13–15]. Owing to small samples and lower proportion of patients available for EGFR mutation analyses in these studies, this question was not fully answered. To explore further the correlation between EGFR mutation status and the risk of BM and clarify the predictive role of EGFR mutation status on the efficacy of TKIs in patients with BM, a retrospective analysis was conducted in 100 patients with lung adenocarcinoma.
considered. Principally, TKIs were reserved for patients with advanced/relapsed disease and EGFR mutations. The same evaluations performed at baseline were repeated at the completion of planned therapy, then every 3 months for the first 2 years, and every 6 months for the next 3 years. Magnetic resonance imaging was used for BM screening. For patients with documented BM, stereotactic radiosurgery (SRS) was administered if there were less than three BM lesions. Otherwise, whole-brain radiotherapy (WBRT) was considered. After the completion of radiation, systemic therapy was recommended. The study was reviewed and approved by the institutional reviewed boards and ethics committees of Beijing Tiantan Hospital, affiliated to the Capital Medical University and The Second Artillery General Hospital of PLA. All patients provided informed consent according to the Declaration of Helsinki. EGFR mutation testing Mutation analysis was conducted separately in two hospitals and confirmed centrally in College of Life Science and Technology, Beijing University of Chemical Technology. EGFR gene mutations were analyzed in paraffin-embedded tissue sections from the primary tumor. Tumor tissue was scraped from the glass slides under direct visualization or under a dissecting microscope, and DNA was extracted with a QIAmp DNA Mini Kit (Qiagen Inc., Valencia, CA, USA). EGFR mutations were detected by using ADx EGFR Mutations Detection Kit (Amoy Diagnostics, Xiamen, China), which is based on the principle of amplified refractory mutation system. The assay was carried out according to the manufacturer’s protocol with the ABI 7500 (Applied Biosystems, Foster City, CA, USA) real-time polymerase chain reaction system. Statistical analysis
Materials and methods Clinical data of 100 consecutive patients (52 patients from the database of Beijing Tiantan Hospital, affiliated to the Capital Medical University, and 48 from the database of The Second Artillery General Hospital of PLA), diagnosed between April 2010 and September 2013 with pathologically confirmed adenocarcinoma of the lung were analyzed retrospectively. Before treatment, all patients had a baseline evaluation, including a medical history, general physical examination, complete blood count, serum chemistry, and radiographic examinations. The treatment strategy was determined according to the stage at diagnosis (American Joint Committee on Cancer, 6th ed.). Platinum-based adjuvant chemotherapy was recommended for operable patients with disease stage IB to IIIA postoperatively. For patients with disease stage IIIB to IV, systemic therapy was
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IBM SPSS Statistics 19.0 software was used for data analysis. The Kaplan–Meier method was used to estimate OS, which was determined from the date of diagnosis to the date of death or the last follow-up visit. Brain-metastasis-free survival (BMFS) was calculated from the date of diagnosis to the date at which BM were documented radiographically. The log-rank test was used to compare survival curves. X2 test was used to compare the incidence of BM between patients with different EGFR mutation statuses.
Results Patient characteristics Patient characteristics are summarized in Table 1. Of the 100 patients included in the study, 57 % were male and
J Neurooncol Table 1 Patient characteristics
Table 1 continued No.
Age, median (range)
%
53 years (29–83)
Gender Male Female
57.0 43
43.0
I
8
8.0
II
6
6.0
III
22
22.0
IV
64
64.0
Wild type Exon 18
49 1
49.0 1.0
Exon 19
26
26.0
Exon 20
3
3.0
Exon 21
18
18.0
Dual mutation (Exon 19/21)
3
3.0
Adenocarcinoma
90
90.0
Bronchioloalveolar carcinoma
6
6.0
Adenosquamous carcinoma
4
4.0
55
55.0
Current
37
37.0
Unknown
8
8.0
30
71.4
12
28.6
1
17
40.5
2–3
11
26.2
[3
14
33.3
Stage
EGFR status
Histology
Smoking status Never
Brain metastasis Synchronous Heterochronous No. of brain metastasis
RPA I
3
7.1
II
27
64.3
III
12
28.6
0–1
10
23.8
1.5–2.5
28
66.7
3
1
2.4
3.5–4
3
7.1
Gefitinib Erlotinib
23 4
58.9 10.3
Icotinib
12
30.8
16
38.1
GPA
TKIs
Treatment after BM Local therapy only
No.
%
Local therapy plus systemic therapy
19
45.2
Systemic therapy only
4
9.5
None
3
7.2
EGFR epidermal growth factor receptor, RPA recursive partitioning analysis, GPA graded prognostic assessment, TKIs tyrosine kinase inhibitors, BM brain metastasis
43 % were female. The median age at diagnosis was 53 (range, 29–83) years. Altogether, 42 patients had documented BM: 30 were synchronous and 12 were heterochronous. Of 42 patients with BM, 35 received local therapy; SRS was administered in 25 and WBRT in 10 patients. After the completion of local therapy, systemic therapy was administered thereafter in 19 patients. For the remaining seven patients with BM, four received systemic therapy only, and three received none. EGFR mutation status and BM The incidence rates of BM and BMSF in patients with different EGFR statuses were summarized in Table 2. In this cohort, EGFR mutated in 51 patients and remained wild type in 49. Among patients with mutated EGFR, one patient had mutations at exon 18; 26, at exon 19; three, at exon 20; 18, at exon 21; and three had dual mutations both at exon 19 and exon 21. The incidence of BM was 44.9 % (22/49) in patients with wild-type EGFR and 39.2 % (20/ 51) in those with EGFR mutations, although the difference was not significant (p = 0.48). However, in those with EGFR mutations, patients with mutation at exon 19 had significantly higher incidence of BM compared with those with mutations at other sites (p = 0.007). Among patients with heterochronous BM, 66.7 % (8/12) had EGFR mutations. Among patients with synchronous BM, 60 % (18/30) had wild-type EGFR. In terms of median BMFS, it was 35 (95 % CI 0–71) months for patients with wild-type EGFR, 13 (95 % CI 9–17) months for patients with mutations at exon 19, and 12 (95 % CI 7–16) months for patients with mutations at exon 21 (patients with synchronous BM were excluded). Otherwise, the median BMFS in patients with other mutations was not calculated because of the smaller samples. Survival analysis showed that the median BMFS was shorter in patients with mutations compared with patients with wild-type EGFR, although the difference was not significant (35 vs 14 months, p = 0.076). However,
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J Neurooncol Table 2 Incidence of BM and BMSF in patients with different EGFR statuses EGFR status
No.
%
No. of BM
Synchronous BM
Heterochronous BM
Incidence of BM
p value
BMFS
95 % CI
0.48a Wild type
0.018b
49
49.0
22
18
4
44.9
35
Exon 18
1
1.0
0
0
0
0
–
–
Exon 19
26
26.0
13
8
5
50.0
13
9–17
0–71
Exon 20
3
3.0
1
0
1
33.3
–
–
Exon 21
18
18.0
5
4
1
27.8
12
7–16
3
3.0
1
0
1
33.3
–
–
Dual mutation (19/21)
p value
EGFR epidermal growth factor receptor, BM brain metastasis, BMFS brain-metastasis-free survival a
Incidence comparison between patients with wild-type and mutated EGFR
b
BMFS comparison between patients with wild-type and EGFR sensitive mutations
patients with mutation at exon 19 (p = 0.035) or exon 21 (p = 0.040) had significantly shorter median BMFS compared with patients with wild-type EGFR. Furthermore, patients with EGFR sensitive mutation (19/21/dual mutation) had significantly shorter median BMFS compared with patients with wild-type EGFR (13 vs 35 months, p = 0.018) (Fig. 1). Survival analysis Recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) were still valuable for prognosis assessment in patients with BM. In our cohort, the median survival times for the RPA classes I–III were: not reached,
26 and 16 months, respectively (p = 0.0048). The median survival times according to the GPA score were: GPA 0–1, 12 months; GPA 1.5–2.5, 23 months; GPA 3, none (only one patient); and GPA 3.5–4.0, not reached (p = 0.039). On univariate analysis, the difference of median OS between patients with or without BM was not significant (23 vs 44 months, p = 0.84). However, if patients treated with TKIs were excluded, the survival difference between patients with or without BM did reach significance (17 months vs not reached, p = 0.035). Altogether, 39 patients received TKIs at some point of treatment; gefitinib was administered in 23, erlotinib in four, and icotinib in 12 patients. Patients with EGFR sensitive mutations, who received TKIs (n = 11) before BM, had longer median BMFS compared with patients, who received conventional chemotherapy only (n = 24). However, the difference was not significant (13 vs 12 months, p = 0.42). Among patients with BM and EGFR sensitive mutations, those treated with TKIs (n = 12), had significantly longer OS than patients treated with conventional chemotherapy only (n = 7) (22 vs 4 months, p = 0.0081) (Fig. 2). In patients treated with local therapy after BM, 19 patents received systemic therapy thereafter. Among patients with wild-type EGFR, those treated with chemotherapy only had longer OS than patients treated with TKIs (26 vs 7 months, p = 0.64). While among patients with EGFR mutations, those treated with TKIs had longer OS than patients treated with chemotherapy only (12 vs 4 months, p = 0.36). Unfortunately, both differences did not reach the significant level.
Discussion Fig. 1 Brain-metastasis-free survival (BMFS) comparison between patients with (epidermal growth factor receptor) EGFR sensitive mutation and wild type (p = 0.018)
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Adenocarcinoma has a significantly higher incidence of BM compared with other histological types of NSCLC [1, 16–18]. The reasons are not only associated with the
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Fig. 2 OS comparison between patients with BM with EGFR sensitive mutation treated with tyrosine kinase inhibitors and conventional chemotherapy only (p = 0.0081)
aggressive biological behavior of the tumor itself, but also to the prolonged long-term survival achieved since the advent of novel agents, such as TKIs. In recent years, several authors have reported a growing number of cases of partial and complete response among patients with BM treated with TKIs [8–11]. However, the correlation of EGFR status and risk of BM was not clear. Although some authors addressed the issue in their studies, it was hard to draw definitive conclusions because of the lower EGFR mutation rate in western populations and the few patients with EGFR mutations evaluated in those studies. Therefore, we explored the issue in adenocarcinoma patients from eastern populations who are known to present a higher prevalence of EGFR mutations. Similar to the data reported by other studies concerning eastern populations, the mutation rate of EGFR in our cohort was 51 %, and the most common mutations occurred at exon 19 and exon 21 [19–21]. Although patients with or without EGFR mutations had comparable incidence of BM, we found that patients with EGFR mutations at exon 19 had the highest incidence of BM among patients with mutations. Besides, patients with EGFR mutations were more likely to develop heterochronous BM compared with those with wild-type EGFR. To further explore the correlation between EGFR status and the risk of BM, we analyzed the difference of BMFS between patients with different EGFR statuses. The results showed that patients with mutation at exon 19 or exon 21 had significantly shorter BMFS compared with patients with wild-type EGFR. Because patients with mutation at exon 19 and exon
21 achieved favorable response from TKI therapy, they were grouped for further analysis. Accordingly, patients with EGFR sensitive mutations also had significantly shorter BMFS compared with patients with wild-type EGFR. By far, the largest cohort study to explore a similar issue was a study conducted by Hendriks et al. from the Netherlands, in which 62 patients with EGFR mutation (at exon 19 or 21) and 62 patients with wild-type metastatic NSLCL were included [22]. Unfortunately, neither the incidence of BM nor BMFS was significantly different between patients with or without EGFR mutation. Compared with our data, the incidence of BM was lower in their study. Furthermore, a higher proportion of patients included had a histological type other than adenocarcinoma and metastatic disease. These factors may have potentially compromised the difference of BM between patients with wild-type EGFR and mutated EGFR. However, since both the study by Hendriks et al. and our own were retrospective, any results should be interpreted carefully. Moreover, it would be premature to conclude that the discrepancy of tumor behavior between both populations would be the probable cause for the lack of significant differences in the former. Therefore, more studies with larger samples are warranted to elucidate this issue. Patients with BM are known to have poor survival. Without treatment, their median survival is only 4–7 weeks [2–4]. By far, RPA and GPA are still the most widely accepted models for prognosis evaluation in patients with BM [4, 23, 24]. As it was shown in our cohort, the OS of patients in different RPA classes and GPA groups differed significantly. RPA and GPA prognostic indices assess the prognosis of patients with BM in terms of factors more than BM itself. However, the prognostic value of BM as a single variant is still controversial. In our cohort, BM was an unfavorable prognostic factor for patients treated with chemotherapy only. Patients with BM had significantly shorter median OS compared with those without BM. This result indicated two things: first, the prognostic value of BM is probably confined to patients with lung adenocarcinoma treated with conventional chemotherapy. Second, for patients with BM, conventional chemotherapy seems incapable of improving their poor survival. After further analysis, we found that patients with BM and sensitive EGFR mutations benefited from the treatment with TKIs based on their significantly longer median OS compared with those treated with conventional chemotherapy only (p = 0.0081). However, the survival difference was not significant (p = 0.67) for patients with BM and wild-type EGFR. Furthermore, among patients treated with local therapy (WBRT/SRS) after BM, those with EGFR mutations had longer OS when TKIs were chosen as subsequent systemic therapy. Several studies have explored the EGFR status between primary and intracranial lesions of patients
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with NSCLC. As their results showed, extremely high concordance rates were reported, varying from 93.3 to 100 % [15, 25, 26]. Further, in a study including 136 Chinese patients with NSCLC and BM, the EGFR mutation rate of BM lesions was 52.9 %, which is similar to the data from extracranial lesions [25]. Furthermore, many studies found that patients with BM could benefit from TKI treatment, which not only reduced the nodule size, but also prolonged patient survival [8–11, 13]. Additionally, the efficacy was much better in selected populations, such as in Eastern Asians, those with adenocarcinoma histology, and never-smokers [10]. Thus, based on these reports, it is suggested that tumors from both primary and intracranial lesions shared similar biological characteristics. Combined with the results of our study, we consider that it is reasonable to tailor TKI use according to the EGFR status determined from extracranial lesions in patients with NSCLC and BM, especially when samples from intracranial lesions are not available. Moreover, we consider that patients with adenocarcinoma and BM, who present EGFR sensitive mutation, could benefit more from the TKI treatment than from conventional chemotherapy. Prophylactic cranial irradiation (PCI) has been a standard treatment for patients with SCLC. It can decrease the cumulative incidence of BM, and significantly improve OS rates in patients with either limited-stage disease or extensive-stage disease who responded to first-line treatment [27, 28]. However, in NSCLC patients, the use of PCI has only reduced the cumulative incidence of BM compared with that in control groups, but it has not improved OS [29, 30]. This is in part because of differences in tumor biology across different types of cancer. For NSCLC patients, the incidence of BM is about 18–38 % [29–32], which is lower than that reported in SCLC patients, ranging from 40 to 58 % [27, 28, 33]. Furthermore, even within NSCLC, the incidence of BM varies notably among different histological types. For patients with adenocarcinoma, the incidence of BM is about 20–45 %, while for those with squamous cell carcinoma it is only 8–28 % [1, 16, 31, 32]. Based on these findings, it is thought that only patients with higher risk of developing BM may benefit from treatment with PCI. We found in our series that patients with EGFR mutations (at exon 19 or 21) had higher incidence of BM and shorter BMFS. Therefore, patients with adenocarcinoma histology, especially those with EGFR mutation at exon 19 or 21, should be the candidates for future studies concerning PCI treatment in NSCLC. Given the fact that TKIs have the ability to penetrate the blood–brain barrier and induce intracranial response, TKI treatment may be a potential method to prevent BM [34, 35]. In our cohort, patients with sensitive EGFR mutation treated with TKIs before BM had longer BMFS compared with patients treated conventional
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chemotherapy only, but the difference was not significant. This negative result can probably be attributed to the relatively small number of patients included in our analysis. Further studies are strongly warranted to clarify this issue. Altogether, our study indicated that adenocarcinoma patients from eastern populations with EGFR mutation at exon 19 or exon 21 had higher risk of BM. For these patients, conventional chemotherapy had limited ability to improve their poor survival. TKI treatment should be considered for patients with NSCLC with BM and EGFR sensitive mutation. Acknowledgments This work was supported by the Special Foundation for Capital Health Development (Grant number: 2014-4-5082). Conflict of interest of interest.
The authors declare that they have no conflict
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CLINICAL STUDY
The correlation between EGFR mutation status and the risk of brain metastasis in patients with lung adenocarcinoma Bo Li1 • Suo-zhu Sun2 • Ming Yang3 • Jian-ling Shi2 • Wei Xu2 • Xi-fan Wang2 Mao-min Song1 • Huo-ming Chen2
•
Received: 2 December 2014 / Accepted: 2 April 2015 Ó Springer Science+Business Media New York 2015
Abstract To explore the correlation between epidermal growth factor receptor (EGFR) mutation status and the risk of brain metastasis (BM) in patients with lung adenocarcinoma, the clinical data of 100 patients with pathologically confirmed lung adenocarcinoma and known EGFR mutation status at exon 18, 19, 20, or 21 were analyzed retrospectively. The incidence of BM was similar between patients with wild-type EGFR and those with EGFR mutations (p = 0.48). However, among patients with EGFR mutations, the incidence of BM was significantly higher in patients with mutation at exon 19 than in patients with mutation at other sites (p = 0.007). Besides, among patients with heterochronous BM, 66.7 % had EGFR mutations. Regarding brain-metastasis-free survival (BMFS), patients with EGFR sensitive mutations (mutation at exon 19/21/and dual mutation) had significantly shorter BMFS compared
with patients with wild-type EGFR (p = 0.018). For patients treated only with chemotherapy, BM was an unfavorable prognostic factor. Patients with BM had worse overall survival compared with those without BM (p = 0.035). However, in patients with BM and EGFR sensitive mutations, those treated with tyrosine kinase inhibitors (TKIs) had significantly longer overall survival compared with those treated with chemotherapy only (p = 0.0081). In conclusion, among patients with EGFR mutations, those mutated at exon 19 had the highest incidence of BM. Furthermore, patients with EGFR mutations are more likely to develop heterochronous BM. The BMFS was significantly shorter in patients with EGFR sensitive mutations. TKIs improved the survival of patients with lung adenocarcinoma and BM who harbored EGFR sensitive mutations. Keywords Non-small cell lung cancer Adenocarcinoma Brain metastasis Epidermal growth factor receptor Tyrosine kinase inhibitors Chemotherapy
Doctor Mao-min Song and Huo-ming Chen are both responsible for the content of the article. & Mao-min Song [email protected] & Huo-ming Chen [email protected] 1
Department of General Surgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, No. 6, Tiantan Xili, Dongcheng District, Beijing 100050, China
2
Department of Medical Oncology, The Second Artillery General Hospital PLA, No. 16, Xinwai Avenue, Xicheng District, Beijing 100088, China
3
College of Life Science and Technology, Beijing University of Chemical Technology, No. 15, North Third Ring Road East, Chaoyang District, Beijing 100029, China
Introduction Adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC), accounting for approximately 40 % of all patients with NSCLC, and its incidence continues to rise. Clinically, this cancer subtype is highly aggressive, with fast progression and early distant metastasis [1]. The brain is one of the most common distant sites of metastasis. Patients with brain metastasis (BM) have poor survival, with a median overall survival (OS) of 4–7 weeks without treatment [2–4]. It was reported that even after undergoing whole-brain radiation therapy (WBRT), the median OS of these patients was only extended to 3–6 months, and a vast majority of patients
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died because of uncontrolled systemic disease other than intracranial failure [5]. In recent years, tyrosine kinase inhibitors (TKIs), which target epidermal growth factor receptor (EGFR), have been included in standard NSCLC treatment. Compared with conventional chemotherapy, TKIs were not only convenient and less toxic, but also efficacious [6, 7]. Additionally, several studies reported their efficacy in NSCLC patients with BM, with an intracranial response ranging from 26.7 to 83 % when used as single agents [8–11] and 64–87 % when combined with WBRT [8, 12, 13]. Moreover, the median OS of patients with BM was also improved significantly after TKIs treatment, ranging from 11.8 to 18.8 months [10, 11, 13]. EGFR mutation status is highly associated with sensitivity to TKIs in advanced NSCLC. In patients with EGFR mutations, TKIs administration was followed by a response rate of 70–80 %, and a longer progression-free survival and OS than those obtained with conventional chemotherapy [6, 7]. Although the presence of EGFR mutation was associated with better efficacy in patients with NSCLC without BM, it is unclear whether this mutation is associated with better efficacy in such patients with BM. Furthermore, some studies suggested that patients with EGFR mutations had higher incidence of BM compared with those without this mutation [13–15]. Owing to small samples and lower proportion of patients available for EGFR mutation analyses in these studies, this question was not fully answered. To explore further the correlation between EGFR mutation status and the risk of BM and clarify the predictive role of EGFR mutation status on the efficacy of TKIs in patients with BM, a retrospective analysis was conducted in 100 patients with lung adenocarcinoma.
considered. Principally, TKIs were reserved for patients with advanced/relapsed disease and EGFR mutations. The same evaluations performed at baseline were repeated at the completion of planned therapy, then every 3 months for the first 2 years, and every 6 months for the next 3 years. Magnetic resonance imaging was used for BM screening. For patients with documented BM, stereotactic radiosurgery (SRS) was administered if there were less than three BM lesions. Otherwise, whole-brain radiotherapy (WBRT) was considered. After the completion of radiation, systemic therapy was recommended. The study was reviewed and approved by the institutional reviewed boards and ethics committees of Beijing Tiantan Hospital, affiliated to the Capital Medical University and The Second Artillery General Hospital of PLA. All patients provided informed consent according to the Declaration of Helsinki. EGFR mutation testing Mutation analysis was conducted separately in two hospitals and confirmed centrally in College of Life Science and Technology, Beijing University of Chemical Technology. EGFR gene mutations were analyzed in paraffin-embedded tissue sections from the primary tumor. Tumor tissue was scraped from the glass slides under direct visualization or under a dissecting microscope, and DNA was extracted with a QIAmp DNA Mini Kit (Qiagen Inc., Valencia, CA, USA). EGFR mutations were detected by using ADx EGFR Mutations Detection Kit (Amoy Diagnostics, Xiamen, China), which is based on the principle of amplified refractory mutation system. The assay was carried out according to the manufacturer’s protocol with the ABI 7500 (Applied Biosystems, Foster City, CA, USA) real-time polymerase chain reaction system. Statistical analysis
Materials and methods Clinical data of 100 consecutive patients (52 patients from the database of Beijing Tiantan Hospital, affiliated to the Capital Medical University, and 48 from the database of The Second Artillery General Hospital of PLA), diagnosed between April 2010 and September 2013 with pathologically confirmed adenocarcinoma of the lung were analyzed retrospectively. Before treatment, all patients had a baseline evaluation, including a medical history, general physical examination, complete blood count, serum chemistry, and radiographic examinations. The treatment strategy was determined according to the stage at diagnosis (American Joint Committee on Cancer, 6th ed.). Platinum-based adjuvant chemotherapy was recommended for operable patients with disease stage IB to IIIA postoperatively. For patients with disease stage IIIB to IV, systemic therapy was
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IBM SPSS Statistics 19.0 software was used for data analysis. The Kaplan–Meier method was used to estimate OS, which was determined from the date of diagnosis to the date of death or the last follow-up visit. Brain-metastasis-free survival (BMFS) was calculated from the date of diagnosis to the date at which BM were documented radiographically. The log-rank test was used to compare survival curves. X2 test was used to compare the incidence of BM between patients with different EGFR mutation statuses.
Results Patient characteristics Patient characteristics are summarized in Table 1. Of the 100 patients included in the study, 57 % were male and
J Neurooncol Table 1 Patient characteristics
Table 1 continued No.
Age, median (range)
%
53 years (29–83)
Gender Male Female
57.0 43
43.0
I
8
8.0
II
6
6.0
III
22
22.0
IV
64
64.0
Wild type Exon 18
49 1
49.0 1.0
Exon 19
26
26.0
Exon 20
3
3.0
Exon 21
18
18.0
Dual mutation (Exon 19/21)
3
3.0
Adenocarcinoma
90
90.0
Bronchioloalveolar carcinoma
6
6.0
Adenosquamous carcinoma
4
4.0
55
55.0
Current
37
37.0
Unknown
8
8.0
30
71.4
12
28.6
1
17
40.5
2–3
11
26.2
[3
14
33.3
Stage
EGFR status
Histology
Smoking status Never
Brain metastasis Synchronous Heterochronous No. of brain metastasis
RPA I
3
7.1
II
27
64.3
III
12
28.6
0–1
10
23.8
1.5–2.5
28
66.7
3
1
2.4
3.5–4
3
7.1
Gefitinib Erlotinib
23 4
58.9 10.3
Icotinib
12
30.8
16
38.1
GPA
TKIs
Treatment after BM Local therapy only
No.
%
Local therapy plus systemic therapy
19
45.2
Systemic therapy only
4
9.5
None
3
7.2
EGFR epidermal growth factor receptor, RPA recursive partitioning analysis, GPA graded prognostic assessment, TKIs tyrosine kinase inhibitors, BM brain metastasis
43 % were female. The median age at diagnosis was 53 (range, 29–83) years. Altogether, 42 patients had documented BM: 30 were synchronous and 12 were heterochronous. Of 42 patients with BM, 35 received local therapy; SRS was administered in 25 and WBRT in 10 patients. After the completion of local therapy, systemic therapy was administered thereafter in 19 patients. For the remaining seven patients with BM, four received systemic therapy only, and three received none. EGFR mutation status and BM The incidence rates of BM and BMSF in patients with different EGFR statuses were summarized in Table 2. In this cohort, EGFR mutated in 51 patients and remained wild type in 49. Among patients with mutated EGFR, one patient had mutations at exon 18; 26, at exon 19; three, at exon 20; 18, at exon 21; and three had dual mutations both at exon 19 and exon 21. The incidence of BM was 44.9 % (22/49) in patients with wild-type EGFR and 39.2 % (20/ 51) in those with EGFR mutations, although the difference was not significant (p = 0.48). However, in those with EGFR mutations, patients with mutation at exon 19 had significantly higher incidence of BM compared with those with mutations at other sites (p = 0.007). Among patients with heterochronous BM, 66.7 % (8/12) had EGFR mutations. Among patients with synchronous BM, 60 % (18/30) had wild-type EGFR. In terms of median BMFS, it was 35 (95 % CI 0–71) months for patients with wild-type EGFR, 13 (95 % CI 9–17) months for patients with mutations at exon 19, and 12 (95 % CI 7–16) months for patients with mutations at exon 21 (patients with synchronous BM were excluded). Otherwise, the median BMFS in patients with other mutations was not calculated because of the smaller samples. Survival analysis showed that the median BMFS was shorter in patients with mutations compared with patients with wild-type EGFR, although the difference was not significant (35 vs 14 months, p = 0.076). However,
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J Neurooncol Table 2 Incidence of BM and BMSF in patients with different EGFR statuses EGFR status
No.
%
No. of BM
Synchronous BM
Heterochronous BM
Incidence of BM
p value
BMFS
95 % CI
0.48a Wild type
0.018b
49
49.0
22
18
4
44.9
35
Exon 18
1
1.0
0
0
0
0
–
–
Exon 19
26
26.0
13
8
5
50.0
13
9–17
0–71
Exon 20
3
3.0
1
0
1
33.3
–
–
Exon 21
18
18.0
5
4
1
27.8
12
7–16
3
3.0
1
0
1
33.3
–
–
Dual mutation (19/21)
p value
EGFR epidermal growth factor receptor, BM brain metastasis, BMFS brain-metastasis-free survival a
Incidence comparison between patients with wild-type and mutated EGFR
b
BMFS comparison between patients with wild-type and EGFR sensitive mutations
patients with mutation at exon 19 (p = 0.035) or exon 21 (p = 0.040) had significantly shorter median BMFS compared with patients with wild-type EGFR. Furthermore, patients with EGFR sensitive mutation (19/21/dual mutation) had significantly shorter median BMFS compared with patients with wild-type EGFR (13 vs 35 months, p = 0.018) (Fig. 1). Survival analysis Recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) were still valuable for prognosis assessment in patients with BM. In our cohort, the median survival times for the RPA classes I–III were: not reached,
26 and 16 months, respectively (p = 0.0048). The median survival times according to the GPA score were: GPA 0–1, 12 months; GPA 1.5–2.5, 23 months; GPA 3, none (only one patient); and GPA 3.5–4.0, not reached (p = 0.039). On univariate analysis, the difference of median OS between patients with or without BM was not significant (23 vs 44 months, p = 0.84). However, if patients treated with TKIs were excluded, the survival difference between patients with or without BM did reach significance (17 months vs not reached, p = 0.035). Altogether, 39 patients received TKIs at some point of treatment; gefitinib was administered in 23, erlotinib in four, and icotinib in 12 patients. Patients with EGFR sensitive mutations, who received TKIs (n = 11) before BM, had longer median BMFS compared with patients, who received conventional chemotherapy only (n = 24). However, the difference was not significant (13 vs 12 months, p = 0.42). Among patients with BM and EGFR sensitive mutations, those treated with TKIs (n = 12), had significantly longer OS than patients treated with conventional chemotherapy only (n = 7) (22 vs 4 months, p = 0.0081) (Fig. 2). In patients treated with local therapy after BM, 19 patents received systemic therapy thereafter. Among patients with wild-type EGFR, those treated with chemotherapy only had longer OS than patients treated with TKIs (26 vs 7 months, p = 0.64). While among patients with EGFR mutations, those treated with TKIs had longer OS than patients treated with chemotherapy only (12 vs 4 months, p = 0.36). Unfortunately, both differences did not reach the significant level.
Discussion Fig. 1 Brain-metastasis-free survival (BMFS) comparison between patients with (epidermal growth factor receptor) EGFR sensitive mutation and wild type (p = 0.018)
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Adenocarcinoma has a significantly higher incidence of BM compared with other histological types of NSCLC [1, 16–18]. The reasons are not only associated with the
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Fig. 2 OS comparison between patients with BM with EGFR sensitive mutation treated with tyrosine kinase inhibitors and conventional chemotherapy only (p = 0.0081)
aggressive biological behavior of the tumor itself, but also to the prolonged long-term survival achieved since the advent of novel agents, such as TKIs. In recent years, several authors have reported a growing number of cases of partial and complete response among patients with BM treated with TKIs [8–11]. However, the correlation of EGFR status and risk of BM was not clear. Although some authors addressed the issue in their studies, it was hard to draw definitive conclusions because of the lower EGFR mutation rate in western populations and the few patients with EGFR mutations evaluated in those studies. Therefore, we explored the issue in adenocarcinoma patients from eastern populations who are known to present a higher prevalence of EGFR mutations. Similar to the data reported by other studies concerning eastern populations, the mutation rate of EGFR in our cohort was 51 %, and the most common mutations occurred at exon 19 and exon 21 [19–21]. Although patients with or without EGFR mutations had comparable incidence of BM, we found that patients with EGFR mutations at exon 19 had the highest incidence of BM among patients with mutations. Besides, patients with EGFR mutations were more likely to develop heterochronous BM compared with those with wild-type EGFR. To further explore the correlation between EGFR status and the risk of BM, we analyzed the difference of BMFS between patients with different EGFR statuses. The results showed that patients with mutation at exon 19 or exon 21 had significantly shorter BMFS compared with patients with wild-type EGFR. Because patients with mutation at exon 19 and exon
21 achieved favorable response from TKI therapy, they were grouped for further analysis. Accordingly, patients with EGFR sensitive mutations also had significantly shorter BMFS compared with patients with wild-type EGFR. By far, the largest cohort study to explore a similar issue was a study conducted by Hendriks et al. from the Netherlands, in which 62 patients with EGFR mutation (at exon 19 or 21) and 62 patients with wild-type metastatic NSLCL were included [22]. Unfortunately, neither the incidence of BM nor BMFS was significantly different between patients with or without EGFR mutation. Compared with our data, the incidence of BM was lower in their study. Furthermore, a higher proportion of patients included had a histological type other than adenocarcinoma and metastatic disease. These factors may have potentially compromised the difference of BM between patients with wild-type EGFR and mutated EGFR. However, since both the study by Hendriks et al. and our own were retrospective, any results should be interpreted carefully. Moreover, it would be premature to conclude that the discrepancy of tumor behavior between both populations would be the probable cause for the lack of significant differences in the former. Therefore, more studies with larger samples are warranted to elucidate this issue. Patients with BM are known to have poor survival. Without treatment, their median survival is only 4–7 weeks [2–4]. By far, RPA and GPA are still the most widely accepted models for prognosis evaluation in patients with BM [4, 23, 24]. As it was shown in our cohort, the OS of patients in different RPA classes and GPA groups differed significantly. RPA and GPA prognostic indices assess the prognosis of patients with BM in terms of factors more than BM itself. However, the prognostic value of BM as a single variant is still controversial. In our cohort, BM was an unfavorable prognostic factor for patients treated with chemotherapy only. Patients with BM had significantly shorter median OS compared with those without BM. This result indicated two things: first, the prognostic value of BM is probably confined to patients with lung adenocarcinoma treated with conventional chemotherapy. Second, for patients with BM, conventional chemotherapy seems incapable of improving their poor survival. After further analysis, we found that patients with BM and sensitive EGFR mutations benefited from the treatment with TKIs based on their significantly longer median OS compared with those treated with conventional chemotherapy only (p = 0.0081). However, the survival difference was not significant (p = 0.67) for patients with BM and wild-type EGFR. Furthermore, among patients treated with local therapy (WBRT/SRS) after BM, those with EGFR mutations had longer OS when TKIs were chosen as subsequent systemic therapy. Several studies have explored the EGFR status between primary and intracranial lesions of patients
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with NSCLC. As their results showed, extremely high concordance rates were reported, varying from 93.3 to 100 % [15, 25, 26]. Further, in a study including 136 Chinese patients with NSCLC and BM, the EGFR mutation rate of BM lesions was 52.9 %, which is similar to the data from extracranial lesions [25]. Furthermore, many studies found that patients with BM could benefit from TKI treatment, which not only reduced the nodule size, but also prolonged patient survival [8–11, 13]. Additionally, the efficacy was much better in selected populations, such as in Eastern Asians, those with adenocarcinoma histology, and never-smokers [10]. Thus, based on these reports, it is suggested that tumors from both primary and intracranial lesions shared similar biological characteristics. Combined with the results of our study, we consider that it is reasonable to tailor TKI use according to the EGFR status determined from extracranial lesions in patients with NSCLC and BM, especially when samples from intracranial lesions are not available. Moreover, we consider that patients with adenocarcinoma and BM, who present EGFR sensitive mutation, could benefit more from the TKI treatment than from conventional chemotherapy. Prophylactic cranial irradiation (PCI) has been a standard treatment for patients with SCLC. It can decrease the cumulative incidence of BM, and significantly improve OS rates in patients with either limited-stage disease or extensive-stage disease who responded to first-line treatment [27, 28]. However, in NSCLC patients, the use of PCI has only reduced the cumulative incidence of BM compared with that in control groups, but it has not improved OS [29, 30]. This is in part because of differences in tumor biology across different types of cancer. For NSCLC patients, the incidence of BM is about 18–38 % [29–32], which is lower than that reported in SCLC patients, ranging from 40 to 58 % [27, 28, 33]. Furthermore, even within NSCLC, the incidence of BM varies notably among different histological types. For patients with adenocarcinoma, the incidence of BM is about 20–45 %, while for those with squamous cell carcinoma it is only 8–28 % [1, 16, 31, 32]. Based on these findings, it is thought that only patients with higher risk of developing BM may benefit from treatment with PCI. We found in our series that patients with EGFR mutations (at exon 19 or 21) had higher incidence of BM and shorter BMFS. Therefore, patients with adenocarcinoma histology, especially those with EGFR mutation at exon 19 or 21, should be the candidates for future studies concerning PCI treatment in NSCLC. Given the fact that TKIs have the ability to penetrate the blood–brain barrier and induce intracranial response, TKI treatment may be a potential method to prevent BM [34, 35]. In our cohort, patients with sensitive EGFR mutation treated with TKIs before BM had longer BMFS compared with patients treated conventional
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chemotherapy only, but the difference was not significant. This negative result can probably be attributed to the relatively small number of patients included in our analysis. Further studies are strongly warranted to clarify this issue. Altogether, our study indicated that adenocarcinoma patients from eastern populations with EGFR mutation at exon 19 or exon 21 had higher risk of BM. For these patients, conventional chemotherapy had limited ability to improve their poor survival. TKI treatment should be considered for patients with NSCLC with BM and EGFR sensitive mutation. Acknowledgments This work was supported by the Special Foundation for Capital Health Development (Grant number: 2014-4-5082). Conflict of interest of interest.
The authors declare that they have no conflict
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