Japanese Journal of Clinical Oncology Advance Access originally published online on January 31, 2006
Japanese Journal of Clinical Oncology 2006 36(2):69-75; doi:10.1093/jjco/hyi228
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© 2006 Foundation for Promotion of Cancer Research
A Correlation between EGFR Gene Mutation Status and Bronchioloalveolar Carcinoma Features in Japanese Patients with Adenocarcinoma
1 Department of Surgery II, Nagoya City University Medical School, Nagoya, Japan, 2 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA and 3 Department of Pathology II, Nagoya City University Medical School, Nagoya, Japan
For reprints and all correspondence: Hidefumi Sasaki, Department of Surgery II, Nagoya City University Medical School, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. E-mail: hisasaki{at}med.nagoya-cu.ac.jp
Received August 16, 2005; accepted December 1, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Background: The presence of epidermal growth factor receptor (EGFR) mutations in gefitinib-naive lung cancer patients has been reported to be higher in females, in non-smokers, in Japanese, and in adenocarcinoma patients, especially in bronchioloalveolar carcinoma (BAC). To further investigate the prevalence of EGFR mutations in relation to pathological factors, we evaluated EGFR mutations in series of Japanese adenocarcinoma patients who had never been treated with gefitinib.
Methods: In the previous studies, we examined mutation status in the tyrosine kinase domain of EGFR, exon18 through exon21, in 112 primary lung adenocarcinoma samples. Using these data, adenocarcinomas were histologically classified according to the presence or absence of bronchioloalveolar components.
Results: Among 112 patients, 48 had adenocarcinoma with BAC components. Those with adenocarcinomas with BAC components had higher frequency of EGFR mutation (28/48, 58%) than those with non-BAC adenocarcinoma (24/64, 37%, P = 0.036). Male patients had the same trend; 12/23 (52%) male patients with adenocarcinoma with BAC components and 10/47 (21%) of those with non-BAC adenocarcinoma had EGFR mutation (P = 0.0135) but there was no correlation between the EGFR mutation status and with/without BAC components in 42 female patients (P = 0.30). Among 11 male non-smokers, patients with adenocarcinoma with BAC components had a tendency to have EGFR mutation more frequently than those with non-BAC adenocarcinoma (P = 0.061). In clear contrast, the frequency of EGFR mutation did not differ significantly between male smoker patients with adenocarcinoma with BAC components and those with non-BAC. Among patients with adenocarcinoma with BAC components, those with adenocarcinoma with EGFR gene mutation had a significantly better 5 year survival than those with adenocarcinoma with wild-type (85.7 versus 46.0%, P = 0.0017).
Conclusions: Adenocarcinomas with BAC components in male non-smokers seem to predict the presence of EGFR mutation. Half of female adenocarcinoma patients with EGFR mutation exhibit adenocarcinomas with non-BAC suggesting a different behavior from those in males. The prognosis of patients with adenocarcinoma with BAC components with EGFR gene mutation is predicted to be better than that of patients with adenocarcinoma with BAC components with wild-type EGFR gene.
Key Words: lung cancer • EGFR • mutation • BAC
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Bronchioloalveolar carcinoma (BAC) is a form of adenocarcinoma (1). In the past, BAC was a rarely diagnosed neoplasm that accounted for
3% of lung cancers; however, several studies documented a dramatic increase in its incidence (14.7–24% of all lung cancers) (2). Further distinguishing BAC from other types of non-small cell lung cancer (NSCLC) is a higher percentage of females, a younger age distribution and a higher incidence in non-smokers (3). Although the revised WHO definition strictly defines BAC as having absolutely no evidence of invasion, adenocarcinoma can display a range of BAC features from predominant BAC with only a small focus of invasion to a lesion that has BAC features only at the peripheral of the tumor (4). Previous work demonstrated that BAC, BAC with focal invasion and adenocarcinoma with BAC features have similar clinical course characterized by relatively long survival, a higher incidence of intrathoracic recurrence and second primary lung cancers, and less frequent distant metastasis (5). Gefitinib, a synthetic anilinoquinazoline that specifically inhibits epidermal growth factor receptor (EGFR) tyrosine kinase, has been used to treat advanced, chemotherapy-refractory NSCLC, yielding clinical responses of 9–19% (6,7). The partial clinical responses to gefitinib have been observed most frequently in Japanese, in females, in non-smokers, and in patients with adenocarcinoma (6,8,9), especially in patients with BAC (9). Last year, the molecular mechanisms underlying clinical responsiveness to gefitinib in NSCLC have been shown to correlate with somatic mutations in the kinase domain of EGFR gene by two groups (10,11). Lynch et al. (10) reported that most of their EGFR mutations occurred in BAC (they regarded an adenocarcinoma with any element of BAC as BAC). However, EGFR mutations were detected in only one case of BAC not treated with gefitinib in the series of Paez et al. (11). Thus, the relationship between the EGFR mutation and BAC components in adenocarcinoma is not yet clear. To further investigate possible pathological factors related to the presence of EGFR mutations, we evaluated a series of 112 Japanese lung adenocarcinoma patients who had never been treated with gefitinib with special reference to the presence of BAC components.
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MATERIALS AND METHODS |
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PATIENTS
We studied 112 surgically resected adenocarcinomas. These surgical resections were undertaken at the Department of Surgery II, Nagoya City University Hospital between 1997 and 2002. The research was approved by the Institutional Review Board of Nagoya City University Hospital. Patients' age ranged from 38 to 82 years old (mean 64.3 years). There were 70 male and 42 female patients. ‘Non-smoker’ was defined as those who had never smoked until the operation, and ‘smoker’ was defined as those who had smoked by the time of the operation (including the ex-smokers). Forty-nine (44%) patients were non-smokers. Eleven (15%) of 70 males were non-smokers, whereas 38 (90%) of 42 females were non-smokers. Using genomic DNA prepared from these 112 samples, DNA sequencing was already performed (11,12,13).
PATHOLOGIC EVALUATION
BAC feature was defined pathologically as exclusively papillolepidic and/or replacement type growth. Pathology specimens of all the patients were examined independently by an in-house pathologist and one out-house pathologist (N.L.) who were unaware of the patient's outcome. The final decision for adenocarcinoma classification was made by N.L. Adenocarcinomas were classified into one of the following: ‘non-BAC’ (adenocarcinoma without BAC), ‘adenocarcinoma with BAC features’ (adenocarcinoma with both solid and BAC features) or ‘BAC’(tumor was basically composed of BAC). In all analysis, adenocarcinoma with BAC features and BAC were combined and shown as ‘adenocarcinoma with BAC components’ as opposed to ‘non-BAC’. Zero percent of area of BAC features was the threshold to discriminate adenocarcinoma with BAC components from non-BAC.
STATISTICAL ANALYSIS
Fisher's exact test and multivariate analysis using the logistic regression model were used to compare frequencies of clinicopathologic variables or to analyze the contribution of each variables with EGFR mutation using Stat View (version 5; SAS Institute, Inc., Cary, NC, USA) software, and the difference was considered significant when the P-value was <0.05. The post-operative 5 year overall survival rate was analyzed using the Kaplan–Meier method, and differences in survival rates were assessed using the log-rank test. When the P-value was <0.05, it was concluded that there was significant difference.
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RESULTS |
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EGFR MUTATION AND PATHOLOGIC CLASSIFICATION
Mutations in the kinase domain of the EGFR gene were detected in 52 of 112 (46.0%) adenocarcinomas (Table 1). Fifty-two EGFR gene mutations consisted of 1 G719S mutation in exon18, 29 deletion and 1 insertion type mutations in exon19, 2 insertion type mutations in exon20, 1 L861Q and 18 L858R mutations in exon20 (Table 2). There were no correlations between the exon carrying mutation and clinicopathological factors (gender, smoking status and pathological findings) (Table 3). Also there were no correlations between the pattern of mutation and clinicopathological factors (Table 3). We have previously reported the EGFR mutation percentage as 15/58 (25.9%) among Japanese NSCLC. The EGFR mutation status from adenocarcinoma was significantly higher than our previous data from all NSCLC (P = 0.0130). The mutation was higher in females (30/42, 71.4%) than in males (22/70, 31.0%) (P < 0.0001) (Table 1).
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Among 112 patients, 48 patients had adenocarcinomas with BAC components (adenocarcinoma with BAC features and BAC); 25 (60%) of 42 females and 23 (33%) of 70 males had adenocarcinomas with BAC components (P = 0.001) (Table 4). Among patients with adenocarcinoma with BAC components, 10 (43%) of 23 males had BAC, and 12 (48%) of 25 females had BAC (P = 0.7799) (Table 4). EGFR mutations were found in 24 of 64 patients with non-BAC adenocarcinoma (Table 1), including 16 at exon19, 1 at exon20 and 7 at exon21 (Table 2), and in 28 of 48 patients with adenocarcinoma with BAC components (Table 1), including 1 at exon18, 14 at exon19, 1 at exon20 and 12 at exon21 (Table 2).
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In all adenocarcinoma patients, there was a correlation between EGFR mutation and adenocarcinoma with BAC components (P = 0.0358). In female patients, both patients with adenocarcinoma with BAC components (16/25) and with non-BAC (14/17, P = 0.3) had similar EGFR mutation status. But in male patients, there was a higher percentage of EGFR mutation in patients with adenocarcinoma with BAC components (12/23) than with non-BAC (10/47, P = 0.0135) (Table 1). There was a tendency towards a higher EGFR mutations ratio at exon21 in patients with adenocarcinoma with BAC components (12/48) when compared to patients with non-BAC (7/64, P = 0.0737) (Table 3).
PATHOLOGIC CLASSIFICATION AND CLINICAL FACTORS
There was a higher ratio of patients with adenocarcinoma with BAC components in non-smokers than smokers (65.3 versus 25.4%, P < 0.0001). Similarly in male patients, non-smokers had a significantly higher ratio of adenocarcinoma with BAC components compared with smokers (72.7 versus 25.4%, P = 0.0041). But in female patients, there was no correlation between smoking habit and BAC components (P = 0.286) (Table 4).
EGFR MUTATION AND CLINICAL FACTORS
In all patients, there was a higher percentage of EGFR mutation in non-smokers than smokers (67.3 versus 30.2%, P = 0.0001). In male patients, there were a tendency towards a higher ratio of EGFR mutation in non-smokers than smokers (54.5 versus 27.1%, P = 0.0877), but in female patients, there was no correlation between EGFR mutation and smoking status (P > 0.9999) (Table 1). It is of note that among male non-smokers, those with EGFR mutation were exclusively with adenocarcinoma with BAC components. In clear contrast, both in female non-smokers, patients with BAC components and with non-BAC had similar frequencies of EGFR mutation (Table 4).
We constructed a multivariate logistic regression model to determine factors that are significantly associated with EGFR mutation. This result revealed that in all patients gender had a tendency to be an independent factor that affected EGFR mutation (P = 0.0512). In male patients BAC components was an independent factor (P = 0.032), but in female patients neither BAC components nor smoking status were independent factors (P = 0.188 and P = 0.886, respectively).
THE SURVIVAL ANALYSIS ACCORDING TO EGFR MUTATION
In all patients, the 5 year survival rate for the patients with adenocarcinomas with wild-type EGFR gene was 54.8%, while that for those with mutation was 71.5% (P = 0.0109). In male patients, 5 year survival of those with wild-type EGFR gene and those with mutation was 55.7 and 74.0%, respectively (P = 0.0203). In female patients, 5 year survival of those with wild-type EGFR gene and those with mutation was 53.6 and 69.9%, respectively (P = 0.4079) (Fig. 1).
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For Stage I patients, the 5 year survival rate for those with wild-type EGFR gene was 75.0%, while that for those with mutation was 86.1% (P = 0.1219). In male Stage I patients, 5 year survival for those with wild-type EGFR gene and those with mutation was 72.9 and 85.7%, respectively (P = 0.2505). In female Stage I patients, 5 year survival for those with wild-type and those with mutation was 83.3 and 87.7%, respectively (P = 0.6891) (Fig. 2).
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In the patient group with non-BAC tumor, there were no significant differences in survival between those with EGFR wild-type and those with mutation (5 year survival rate 60.7 and 56.8%, respectively, P = 0.5832). In marked contrast, in patient group with adenocarcinoma with BAC components, there was a significant difference in survival rate between those with wild-type EGFR gene and those with mutation (5 year survival rate 46.0 and 85.7%, respectively, P = 0.0017) (Fig. 3).
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ANALYSIS OF EGFR DNA COPY NUMBER
The EGFR gene amplification of 61 samples was analyzed by quantitative real-time PCR. Four of 61 cases were found to have EGFR DNA amplification (EGFR copy number >3). All four patients were male, two were non-smokers and had EGFR mutation (L858R), and three had BAC components. The EGFR amplification did not correlate with EGFR mutation or with any of the clinicopathological factors.
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DISCUSSION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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In this paper, pathological features having BAC components correlated with EGFR mutation status in all patients and male patients; 28/48 (58%) patients with adenocarcinoma with BAC components and 24/64 (38%) patients with non-BAC adenocarcinoma had EGFR mutation (P = 0.0358). This result was not in agreement with another report from a Japanese group, which showed 10.8% (4/37) patients with adenocarcinoma with BAC components and 41.9% (13/31) patients with invasive adenocarcinoma had EGFR mutations (14). In agreement with our result, Marchetti et al. (15) and Sonobe et al. (16) have demonstrated that BAC histology was associated with EGFR mutations. Yatabe et al. (17) also reported that the characteristics of terminal-respiratory-unit type adenocarcinoma were likely to correspond to the BAC reported as a predictor of gefitinib response. The reason for these differences is not clear at present; however, the small number of patients and different patient selection may have caused the difference.
BACs are lung tumors believed to arise from bronchiolar and alveolar epithelium, with a characteristic growth pattern along the alveolar walls. Compared with other subtypes of lung cancers, BAC is characterized by distinct clinical presentation, radiographic appearance and natural history. Patients with BAC tend to be younger at diagnosis and are more likely to be female and non-smokers when compared with other lung cancers. Actually, this population was correlated with gefitinib sensitivity. These differences raise the question of whether BAC represents a separate biologic entity. It has shown that there are differences in the distribution and quality of p53, K-ras and FHIT mutations between BAC and conventional adenocarcinoma.
Previous limited data suggested that chemotherapy for BAC provides modest benefit; however, anecdotal reports of swift and durable responses after treatment with EGFR tyrosine kinase (TK) inhibitor in patients with BAC have prompted further investigation in this subset of patients (18). Two Japanese groups using the EGFR TK inhibitor gefitinib have demonstrated encouraging results (19,20). Thus, we investigated the correlation between EGFR mutation, gender, smoking status and BAC components. Gender and smoking status were correlated with EGFR mutation status, and there was a correlation between pathological BAC components and EGFR mutation status in all the patients and male patients, but not in female patients. Particularly of note is that among 11 male non-smokers, patients with adenocarcinoma with BAC components had a tendency to have EGFR mutation more frequently than those with non-BAC (P = 0.061). In clear contrast, the frequency of EGFR mutation did not differ significantly between male smoker patients with adenocarcinoma with BAC components and those with non-BAC. These results seem to suggest that in male non-smokers EGFR mutation tended to give rise to adenocarcinomas with BAC components, which rarely proceed to exhibit non-BAC adenocarcinoma. In females, the presence of non-BAC adenocarcinomas in half of adenocarcinomas with EGFR mutation suggests that the underlying oncogenic mechanisms may differ according to gender.
In male patients, the prognosis of patients with adenocarcinoma with EGFR mutation was better than that of patients with adenocarcinomas with wild-type, but in female patients, the prognosis of patients with adenocarcinoma with EGFR mutation was similar to that of patients with adenocarcinoma with wild-type. Similarly, among patients with adenocarcinoma with BAC components, the prognosis of patients with adenocarcinoma with EGFR mutation was better than that of patients with adenocarcinoma with wild-type, but this difference was not seen in patients with non-BAC adenocarcinoma.
These data suggest that EGFR mutation plays a different role in oncogenesis in male and female patients, in patients with non-BAC adenocarcinoma compared to those with adenocarcinoma with BAC components.
Our result may be useful to identify patients with possible benefit from therapy using gefitinib. For example, six of eight male non-smokers with adenocarcinoma had an EGFR mutation and thus may be good candidates for gefitinib therapy. However, different mechanisms other than EGFR mutations may exist to explain the good response of gefitinib therapy for patients with adenocarcinoma with BAC components. Actually, a case that responded using gefitinib in BAC in the absence of EGFR mutation has been reported (21).
In summary, BAC components in male non-smokers may predict the presence of EGFR mutations in adenocarcinomas. BAC components with EGFR gene mutation in patients with adenocarcinoma predict a better survival.
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Acknowledgments |
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This study was supported by a grant for cancer research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Astra Zeneca Research grant 2004.
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References |
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