Long-term impact of complications after lung resections in non-small cell lung cancer.

BACKGROUND: Postoperative complications after lung resection are common and fatal. The immediate effects of postoperative complications are related to poor prognosis; however, the long-term effects have not been assessed. Thus, this investigation aimed to clarify the long-term effects of postoperative complications among patients with resected non-small cell lung cancer (NSCLC). METHODS: This retrospective cohort study included 345 patients with resected NSCLC from a single institution. We used the Clavien-Dindo classification to classify postoperative complications. Postoperative complications were defined as complications with a Clavien-Dindo grade of ≥2. The Kaplan-Meier method was used to evaluate survival. Prognostic factors were analyzed using a Cox proportional hazard model. RESULTS: There were 110 patients with postoperative complications (31.9%). The 5-year overall survival (OS), recurrence-free survival (RFS), and cause-specific survival (CSS) rates were significantly lower in patients with complications than in those without complications [OS: 66.1%, 95% confidence interval (CI): 55.4-74.8% vs. 78.0%, 95% CI: 71.8-83.1%, P=0.001; RFS: 48.8%, 95% CI: 38.1-58.7% vs. 70.8%, 95% CI: 64.2-76.4%, P<0.001; CSS: 82.7%, 95% CI: 72.8-89.3% vs. 88.2%, 95% CI: 82.8-92.0%, P=0.005]. The 5-year OS was lower in the pulmonary complication group than in the other complication group (58.1%, 95% CI: 40.0-72.4% vs. 70.5%, 95% CI: 56.6-80.6%, P=0.033). Postoperative complications were indicated as a poor prognostic factor for OS (hazard ratio, 1.67; 95% CI: 1.11-2.53; P=0.002). CONCLUSIONS: Postoperative complications were associated with unfavorable OS because of the worse prognosis of postoperative pulmonary complications.

Postoperative C-reactive Protein Is a Predictive Biomarker for Survival After Non-small Cell Lung Cancer Resection.

BACKGROUND/AIM: Preoperative C-reactive protein (CRP) is well recognized as a prognostic factor of non-small cell lung cancer (NSCLC). The present study aimed to elucidate the prognostic impact of postoperative CRP in patients with NSCLC following lung resection. PATIENTS AND METHODS: We retrospectively reviewed 336 patients with NSCLC treated with lung resection. CRP levels were measured at postoperative week 6 (CRP6w; range: 4-8 weeks). Patients were divided into two groups based on CRP6w median value (5.0 mg/l); the 5-year overall survival (OS) as well as the recurrence-free survival (RFS) was evaluated in both groups. RESULTS: Five-year OS and RFS were worse in the high-CRP6w group than in the low-CRP6w group (62.9% vs. 82.9%; p<0.001, 48.4% vs. 76.1%; p<0.001, respectively). Subgroup analysis for pathological stage I and ≥II also revealed worse OS in the high-CRP6w group. Multivariate analysis revealed an association between high CRP6w and worse OS (hazard ratio, 2.23; p<0.001). CONCLUSION: CRP6w may serve as a prognostic biomarker in patients with resected NSCLC.

[ST Segment Elevation on Electrocardiogram (ECG) during Pleural Lavage with Distilled Water;Report of a Case].

Pleural lavage with distilled water is often employed in lung resection to eliminate malignant cells. Here we report a case of transient ST segment elevation on electrocardiogram (ECG) during pleural lavage with distilled water. A 73-year-old female was referred to our hospital because of an abnormal shadow on a chest roentogenogram. Chest computed tomography scan revealed a mass in left S4+5 segment of left upper lobe. It was proved to be adenocarcinoma of the lung by transbronchial lung biopsy and she underwent left upper lobectomy. During pleural lavage with distilled water, ST segment was elevated on ECG. In this case, it was because that the pericardium was excised and the myocardium was exposed to distilled water during pleural lavage.

Impact of the favorable prognosis of patients with lung cancer adjoining bullae.

BACKGROUND: Lung cancer adjoining bullae (LC-AB) is an uncommon manifestation. The clinical characteristics and prognosis of LC-AB remain unclear. The aim of this study is to investigate the clinical features and overall survival (OS) of patients with LC-AB following lung resection compared to non-LC-AB group. METHODS: We retrospectively investigated 291 consecutive patients with lung cancer who underwent curative resection in a single institution between April 2007 and March 2015. A total of LC-AB was 52 patients. LC-AB was determined using thin slice computed tomography (CT) imaging and pathological findings. Survival analysis was calculated using the Kaplan-Meier method. We used a Cox proportional hazards model for the univariate and multivariate analysis to identify prognostic factors. RESULTS: The LC-AB group showed a higher frequency of younger patients (P=0.017), former or current smokers (P=0.011), men (P=0.021), tumor location in the upper lobe (P=0.031), moderately or poorly differentiated tumor histology (P<0.001), pleural indentation (P=0.007), and non-adenocarcinoma histology (P=0.016) than the non-LC-AB group. The 5-year survival and recurrence-free survival (RFS) rates were significantly higher in the LC-AB group than the non-LC-AB group (88.5% vs. 74.9%, P=0.010, 75.4% vs. 61.3%, P=0.030, respectively). Multivariate analysis using a Cox proportional hazard model of OS showed that LC-AB was an independent prognostic factor [hazard ratio (HR): 0.30, 95% confidence interval (CI): 0.12-0.77, P=0.012]. CONCLUSIONS: Patients with LC-AB had better OS than those with non-LC-AB. Thus, LC-AB may be an independent favorable prognostic factor following curative resection.

Impact of Postoperative Pneumonia Developing After Discharge on Long-Term Follow-up for Resected Lung Cancer.

BACKGROUND: Postoperative nosocomial pneumonia is a common immediate complication following lung resection. However, the incidence and mortality of pneumonia developing after discharge (PDAD) for lung-resected patients during long-term observation remain unclear. The aim of this study was to investigate the clinical features of PDAD in patients with resected lung cancer. METHODS: We conducted a retrospective cohort study of 357 consecutive patients with lung cancer who had undergone lung resection at a single institution, between April 2007 and December 2016. The clinical characteristics, pathological features, and overall survival were analyzed. Propensity score matched analysis was used for the evaluation of overall survival between PDAD and non-PDAD groups with adjusted relevant confounding factors. RESULTS: PDAD was observed in 66 patients (18.5%). The cumulative incidence of PDAD was 14.9% at 3 years and 21.6% at 5 years. Mortality of PDAD was 30.3%. Multivariate analysis demonstrated that the risk factors for PDAD were age (OR 1.07; P = 0.005), oral steroid use (OR 5.62; P = 0.046), and lower-lobe resection (OR 1.87; P = 0.034). After propensity score matching, 52 patients with PDAD and 52 patients without it were compared. The incidence of PDAD resulted in a worse 5-year overall survival (56.1 vs. 69.3%; P = 0.024). The Cox proportional hazards model indicated that PDAD was associated with poor overall survival (HR 1.99, P = 0.027). CONCLUSIONS: Our findings revealed a high incidence and mortality of PDAD among patients who had undergone lung resection with long-term follow-up. Therefore, PDAD could be associated with poorer overall survival.

Prognostic Impact of Postoperative C-reactive Protein for Non-small Cell Lung Cancer Following Lobectomy.

BACKGROUND/AIM: C-reactive protein (CRP) is associated with cancer progression; however, the prognostic impact of postoperative CRP remains controversial. The aim of this study was to investigate the prognostic significance of postoperative CRP in patients with resected non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 198 consecutive patients with NSCLC that had undergone lobectomy were retrospectively reviewed. CRP was measured on postoperative days 1, 3, and 5. Patients were divided into two groups according to the median of CRP on postoperative day 3 (CRP3); the high and low CRP3 groups (n=99, respectively). RESULTS: Five-year overall survival was significantly higher in the high CRP3 group than the low CRP3 (75.3% vs. 86.5%; p=0.016), as was the 5-year recurrence-free survival (62.7% vs. 73.0%; p=0.016). Multivariate analysis revealed that high CRP3 was associated with a favorable prognosis (hazard ratio(HR)=0.36; p<0.001). CONCLUSION: High CRP3 may be a favorable prognostic predictor in patients with NSCLC following lobectomy.

Detection of EGFR and K-ras mutations for diagnosis of multiple lung adenocarcinomas.

The incidence of multiple primary lung adenocarcinoma (MPLA) is increasing, and it is important to distinguish MPLA from intrapulmonary metastasis (IPM) in order to determine the therapeutic strategy. However, there is no reliable method to differentiate between the two. The purpose of this study was to distinguish MPLA from IPM based on the gene status of EGFR and K-ras and the morphological Noguchi classification system. Sixty-eight tumors from 34 cases of clinical MPLA were evaluated. Of them, 11 cases (32.4%) were diagnosed as biological MPLA (bMPLA) by EGFR/K-ras mutation analyses, and 12 cases (35.3%) by morphological analysis. In all, 23 of the 34 cases (67.6%) were diagnosed as bMPLA. The remaining 11 cases were diagnosed as biological IPM (bIPM). The 5-year survival rates of bMPLA and bIPM were 90.9% and 63.6%, respectively (p=0.04). These findings suggest that the combination method including gene mutation and morphological analysis can guide treatment decisions and that there is a need for systemic chemotherapy, and surveillance monitoring.

Lack of direct association between EGFR mutations and ER beta expression in lung cancer.

BACKGROUND: Positive expression of estrogen receptor (ER) beta is correlated with a favorable prognosis for patients with epidermal growth factor receptor (EGFR) mutations and predicts a good clinical outcome for patients with lung cancer after treatment with an EGFR-tyrosine kinase inhibitor (TKI), suggesting that it may be a candidate surrogate marker. The molecular mechanism underlying the apparent link between EGFR mutations and ER beta expression in lung cancer cell lines was investigated. MATERIALS AND METHODS: Four different human lung cancer cell lines were used, including one with an exon19 delE746-A750, one with a substitution of Leu for Arg at codon 858 in exon 21 (L858R), one with a L858R+ threonine-to-methionine mutation at codon 790 of EGFR (T790M) and one with wild-type EGFR. The EGFR mutations were investigated by direct sequencing. The expression levels of ER beta in the cell lines, in tumors from SCID mice and in primary human tissue specimens were evaluated by immunohistochemistry. Cell growth was compared after treatment with 17-beta-estradiol. The proliferative activity following knockdown of ER beta by siRNA was also examined. Furthermore, the cell inhibition assay was performed for cells treated with gefitinib after knockdown of ER beta. To investigate the relevant pathways for ER beta, the expression of apoptosis-related molecules was evaluated by Western blotting analysis. RESULTS: All the cell lines showed positive expression of ER beta, the cancer cells from SCID mice, and the original primary tumors showed positive expression of ER beta. All of the cell lines revealed a similar proliferative pattern, regardless of the presence of EGFR mutations. Although the suppression of ER beta slightly increased the proliferative activity, no statistically significant effect on proliferation was observed in any of the cell lines. Moreover, no significant changes in any cell signaling or apoptosis-related molecules were observed following ER beta knockdown. CONCLUSION: A direct association between EGFR mutations and ER beta expression in lung cancer cell lines is lacking. Further investigation will be necessary to clarify the role of the ER in the EGFR signaling pathway.

Molecular diagnosis of MACC1 status in lung adenocarcinoma by immunohistochemical analysis.

BACKGROUND: Recently, we reported that overexpression of metastasis-associated colon cancer-1 (MACC1) mRNA may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery. However, the biological significance of mRNA overexpression is difficult to determine and is not widely used because mRNA expression analysis is relatively expensive and time- and labor-intensive. On the other hand, immunohistochemical (IHC) staining is easy to perform, well-established, inexpensive, and is a useful method which can be routinely applied in solid tumor diagnosis in clinical laboratories. PATIENTS AND METHODS: Tumor specimens were collected from 197 consecutive patients who underwent a complete resection for lung adenocarcinoma from 1998 to 2007. We analyzed the MACC1 status of the primary lung adenocarcinoma by IHC analysis. RESULTS: The average postoperative observation period was 46.7 months. Forty (20.3%) of the 197 patients developed recurrences after surgery. Positive expression of MACC1 was identified in 129 (65.5%) patients. Furthermore, MACC1 IHC was positive in 33 (82.5%) out of the 40 patients and 96 (61.1%) out of the 157 patients, with and without recurrence, respectively (p=0.011). Both univariate and multivariate logistic regression models indicated that positive staining for MACC1 was an independent factor for tumor recurrence. Furthermore, positive staining for MACC1 was associated with poorer disease-free survival (DFS), according to the univariate survival analysis (p=0.080). CONCLUSION: Positive staining for MACC1 expression in resected specimens was associated with a poorer DFS. Therefore, positive staining of IHC for MACC1 may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery.

TS expression predicts postoperative recurrence in adenocarcinoma of the lung.

BACKGROUND: Not all patients with lung cancer require postoperative adjuvant chemotherapy after a complete resection. However, no useful markers for either selecting appropriate candidates or for predicting clinical recurrence exist. METHODS: Tumor specimens were collected from 183 consecutive patients who underwent a complete resection for lung adenocarcinoma from 2003 to 2007 in our department. We analyzed the thymidylate synthase (TS) and dihydrofolate reductase (DHFR) expressions in the primary lung adenocarcinoma by immunohistochemisty. RESULTS: The strong expression of TS and DHFR was identified in 39 (21.3%) and 120 (65.6%) patients, respectively. The strong TS expression was identified in 11 (39.3%) of 28 patients and 28 (18.1%) of 155 patients in patients with and without recurrence, respectively (p=0.012). The strong DHFR expression was also identified in 23 (82.1%) and 97 (62.6%) of the patients with and without recurrence, respectively (p=0.045). Logistic regression models indicated the strong TS expression to be an independent factor for tumor recurrence. The strong TS and DHFR expression was associated with a poorer disease-free survival (DFS) according to the survival analysis. A multivariate analysis demonstrated the strong TS expression to be independently associated with an increased risk for poor DFS. CONCLUSIONS: The strong TS expression may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma following surgery.

Insulin-like growth factor receptor-1 expression predicts postoperative recurrence in adenocarcinoma of the lung.

Not all patients with lung cancer require postoperative adjuvant chemotherapy after a complete resection. However, no useful markers exist for either selecting appropriate candidates or for predicting clinical recurrence. The purpose of the present study was to clarify the clinical role of insulin-like growth factor receptor-1 (IGFR1) in lung adenocarcinoma. Tumor specimens were collected from 182 patients who underwent a complete resection for adenocarcinoma of the lung. The expression of IGFR1 was evaluated by immunohistochemistry. The genetic status of the epidermal growth factor receptor (EGFR) and K-ras genes was also investigated by PCR-based analyses. Immunohistochemistry and real-time PCR assays were used to evaluate the MET gene association with tyrosine phosphorylation and hepatocyte growth factor (HGF) status, and amplification, respectively. Positive expression of IGFR1 was detected in 43 (23.6%) of the 182 cases. A positive IGFR1 expression was also identified in 12 (42.9%) and 31 (20.1%) of the patients with and without recurrence, respectively (p=0.009). Logistic regression models indicated that positive staining for IGFR1 expression was an independent factor associated with tumor recurrence. IGFR1 expression was associated with a poorer disease-free survival (DFS). Multivariate analysis demonstrated positive IGFR1 expression to be independently associated with an increased risk for poor DFS. The tumors appearing positive for IGFR1 were more frequent among those with K-ras mutations when compared with the wild-type group. IGFR1 expression was associated with reduced DFS correlating with postoperative recurrence. Therefore, the expression status of IGFR1 can be a candidate surrogate marker to select patients who may benefit from adjuvant chemotherapy.

Overexpression of MACC1 mRNA in lung adenocarcinoma is associated with postoperative recurrence.

OBJECTIVE: The purpose of this study was to clarify the role and clinical significance of metastasis associated in colon cancer 1 in resected stage I non-small cell lung cancers. METHODS: Tumor specimens were collected from 146 consecutive patients who underwent a complete resection for stage I lung adenocarcinoma from 1998 to 2007 at the University of Occupational and Environmental Health. We analyzed the expression of metastasis associated in colon cancer 1 mRNA of primary lung adenocarcinomas by real-time reverse transcriptase-polymerase chain reaction. RESULTS: The average postoperative observation period was 49.4 months. Thirteen (8.9%) of 146 patients had recurrences after surgery. Overexpression of metastasis associated in colon cancer 1 mRNA was identified in 62 patients (42.5%). Metastasis associated in colon cancer 1 was overexpressed in 9 (69.2%) of 13 patients and 53 (39.9%) of 133 patients with and without recurrence, respectively (P = .004). The median metastasis associated in colon cancer 1 copy number was 3.0 and 1.4 in patients with and without tumor recurrence, respectively. Metastasis associated in colon cancer 1 overexpression was associated with poorer disease-free survival according to the survival analysis (P = .033). CONCLUSIONS: Metastasis associated in colon cancer 1 gene overexpression may be a useful marker for predicting postoperative recurrence in patients with lung adenocarcinoma after surgery.

TS, DHFR and GARFT expression in non-squamous cell carcinoma of NSCLC and malignant pleural mesothelioma patients treated with pemetrexed.

BACKGROUND: Recently, pemetrexed (PEM), a new generation antifolate, has been used for the treatment of patients with advanced non-squamous cell carcinoma (SQ) of non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). However, no useful markers for selecting appropriate candidates exist at present. MATERIALS AND METHODS: Tumor specimens were collected from 5 lung non-SQ and 8 MPM patients who underwent surgery and received PEM. Real-time PCR and immunohistochemical (IHC) staining of the primary tumor were used to analyze the mRNA and protein expressions of thymidylate synthase (TS)/dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), and to compare the expression status and clinical outcomes. RESULTS: TS, DHFR, and GARFT mRNA levels had a median value of 2.39, 1.70, and 1.40 in non-SQ samples of NSCLC patients. The TS and DHFR protein levels had a mean total score of 2 and 4 in non-SQ of NSCLC patients. TS, DHFR, and GARFT mRNA levels had a median value of 5.55, 3.73, and 3.52 in MPM patients. TS and DHFR protein levels had a mean total expression score of 1 and 3 in MPM patients. No significant correlation was identified between the expression levels of TS/DPD/GARFT mRNA and clinical response for the non-SQ of NSCLC and MPM patients treated with PEM. CONCLUSION: TS, DHFR, and GARFT mRNA and protein expression may not be useful markers for predicting clinical response in Japanese patients with non-SQ of NSCLC and MPM. Further investigations are necessary in order to develop biomarkers to determine the clinical benefits of PEM treatment.

Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma.

BACKGROUND: The epithelial to mesenchymal transition (EMT) may well play a part in determining the sensitivity to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). However to date, no study has investigated the association between the EMT status and acquired resistance using cancer specimens. PATIENTS AND METHODS: Immunohistochemical (IHC) staining was used to analyse the protein expression of epithelial and mesenchymal markers in tumour samples from lung adenocarcinoma patients. Mutations in the EGFR and K-ras gene were also examined. RESULTS: All patients showed a positive expression of epithelial markers in sensitive tumours. Tumour in 4 (44.4%) out of 9 patients showed down-regulation of epithelial markers or up-regulation of mesenchymal markers. The change in the EMT status between pre-and post-treatment was shown in 2 cases each with and without the T790M mutation. CONCLUSION: EMT plays a role in approximately half of the cases of resistance to EGFR-TKI, independent of T790M mutation.

Identification of a tumour associated antigen in lung cancer patients with asbestos exposure.

BACKGROUND: This study analysed the humoral immune response in asbestos exposed lung cancer patients to identify new surrogate markers of the carcinogenic risk in populations exposed to asbestos. METHODS AND RESULTS: A serological analysis identified five distinct antigens reactive with IgG derived from a lung cancer patient with high asbestos exposure. In one of the isolated antigens, quantitative RT-PCR indicated that annexin A2 (AnxA2) was overexpressed in lung cancer tissues and normal lung from patients with high asbestos exposure. Antibody against AnxA2 was detected in 9/15 (60%) of lung cancer patients with high asbestos exposure; however, in only 1/12 (8%) of lung cancer patients with low asbestos exposure. AnxA2 was also overexpressed in malignant mesothelioma cells, and the antibody was also positive in 8/15 (53%) of patients with malignant mesothelioma. CONCLUSION: The antibody titer against AnxA2 may be a potentially useful new diagnostic surrogate marker for asbestos-related lung cancer and malignant mesothelioma.

Association between lymphangiogenesis-/micrometastasis- and adhesion-related molecules in resected stage I NSCLC.

BACKGROUND: The purpose of this study was to clarify the role and clinical significance of lymphangiogenesis/micrometastases and adhesion molecules in resected stage I non-small cell lung cancer (NSCLC). METHODS: Immunohistochemical (IHC) staining was used to analyze the protein expression of vascular endothelial growth factor-C (VEGF-C), VEGF, E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin in paraffin-embedded tumor samples from 117 well-characterized stage I NSCLC patients and to compare the protein expression, clinical variables and survival outcome. As a micrometastatic parameter in lymph nodes (LNs), cytokeratin (CK) staining was performed. RESULTS: The positive expression of VEGF-C and VEGF were detected in 54 (48.7%) and 86 (73.5%), respectively. We identified micrometastatic tumor cells in pathological N0 LNs in 34 (29.1%) of 117 patients. E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin were identified in 70 (59.8%), 41 (35.0%), 83 (70.9%), and 61 (52.1%) specimens, respectively. The VEGF-C expression was found more frequently in squamous cell carcinoma (SQ) and in the tumors with negative expression of beta-catenin than counter features. The VEGF expression was found more frequently in the tumors with a negative expression of E-cadherin. Micrometastasis was found more frequently in a pathological T2 status and in the tumors with a negative expression of alpha-catenin. Beta-catenin and gamma-catenin expressions were found less and more frequently in SQ, respectively. A univariate and multivariate survival analysis demonstrated that old age, pathological T2 status, and micrometastasis were independently associated with an increased risk of poor survival in the patients who underwent a surgical resection of stage I NSCLC. CONCLUSIONS: Complicated relationships exist between lymphangiogenesis/micrometastases and adhesion molecules with a specific histology. The detection of lymph nodal micrometastasis by CK may therefore be a useful marker for predicting a poor prognosis in patients who undergo a complete resection of stage I NSCLC.

Comprehensive molecular analyses of lung adenocarcinoma with regard to the epidermal growth factor receptor, K-ras, MET, and hepatocyte growth factor status.

BACKGROUND: The mutation and amplification of oncogenic genes are associated with carcinogenesis and tumor growth. The purpose of this study was to clarify the role of the epidermal growth factor receptor (EGFR), K-ras, MET, and hepatocyte growth factor (HGF) status in lung adenocarcinoma. METHODS: Tumor specimens were collected from 183 patients who underwent a complete resection for adenocarcinoma of the lung from 2003 to 2007 in our department. The genetic status of the EGFR and K-ras genes were investigated by polymerase chain reaction (PCR)-based analyses. Immunohistochemistry and real time PCR assays were used to evaluate the MET gene regarding to tyrosine phosphorylation and amplification, respectively. HGF status was evaluated by immunohistochemistry. RESULTS: The mutations of EGFR and K-ras were detected in 64 (35%) and 17 patients (9%), respectively. The tyrosine 1234/1235 phosphorylation of MET (p-MET 1234/1235) and MET amplification was identified in 12 (7%) and 8 (4%) specimens, respectively. Positive expression of HGF was identified in 104 specimens (57%). An EGFR mutation was found significantly more frequently in females and in tumors with wild type of K-ras and without MET amplification. A p-MET 1234/1235 was found significantly more frequently in the tumors with a positive expression of HGF. A multivariate survival analysis demonstrated that the wild type of K-ras, negative p-MET 1234/1235, and positive HGF expression were independently associated with an increased risk of poor survival. CONCLUSIONS: The occurrence of MET amplification and EGFR/ K-ras mutations might be mutually exclusive suggesting several distinct mechanisms in the development of lung adenocarcinoma. The wild type of K-ras, negative p-MET 1234/1235, and positive expression of HGF may be a useful marker for predicting poor prognosis of patients who underwent surgical resection of lung adenocarcinoma.

Acquired resistance to gefitinib: the contribution of mechanisms other than the T790M, MET, and HGF status.

BACKGROUND: Some types of somatic mutation of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). However, most of the patients with this type of sensitive mutations in their tumor show acquired resistance during the TKI treatment. METHODS: The mutations in exons 19-21 of the EGFR gene were examined in both the pre-treatment and the post-treatment gefitinib resistant tumors in 10 patients with lung adenocarcinoma. Eight patients were recurrent cases after surgery, and two patients were non-surgical cases whose tumor specimens were obtained from the metastatic lymph node and endobronchially invading tumor. RESULTS: In 10 patients, 5 patients had a deletion in exon 19 and another 5 did L858R mutation in exon 21 of EGFR in gefitinib pre-treatment tumors. The mutation status did not change in the gefitinib-resistant tumors. In 7 of 10 patients, the gefitinib-resistant tumors had a secondary T790M mutation, which was not detected in the gefitinib pre-treatment tumors. In one patient, only one of the 4 gefitinib-resistant tumors showed the T790M mutation. Neither other novel secondary mutations of EGFR nor the K-ras were observed in their gefitinib-resistant tumors. Neither MET gene amplification nor HGF were observed in their gefitinib-resistant tumors without T790M mutation. CONCLUSIONS: The T790M mutation in the EGFR is relatively common in the patients with acquired resistance to gefitinib. However, mechanisms other than T790M, MET, and HGF status are involved in resistance to gefitinib.

Prospective phase II study of gefitinib in non-small cell lung cancer with epidermal growth factor receptor gene mutations.

BACKGROUND: This study prospectively assessed the efficacy of gefitinib and the survival benefit for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. METHOD: Patients with either recurrent disease after undergoing surgery or advanced NSCLC disease (IIIB or IV) which demonstrated EGFR mutations were eligible for this study. EGFR mutations in exons 19-21 were examined. The patients with EGFR mutations were enrolled in this study after obtaining their informed consent a second time, and they were thereafter treated with gefitinib. RESULTS: EGFR mutations were detected in 20 of 48 patients with NSCLC, and 19 patients were enrolled onto this study and treated with gefitinib. Seven patients had an exon 19 deletion, 10 had L858R, 1 had both, and 1 had an exon 19 deletion and G796A. The overall response rate was 63.2%, and the disease control rate was 89.5%. In patients with an exon 19 del and L858R, the response rates were 71.4% and 60.0%, respectively. The median progression-free survival time was 7.1 months, and the median survival time was 20.0 months. No life-threatening toxicity was observed. Four of five acquired resistant tumors showed an acquired T790M mutation. CONCLUSIONS: EGFR mutations in exons 19 or 21 are considered to be a good predictor of the efficacy of gefitinib.

Association between estrogen receptor-beta expression and epidermal growth factor receptor mutation in the postoperative prognosis of adenocarcinoma of the lung.

PURPOSE: Adenocarcinoma of the lung unrelated to a smoking habit occurs more frequently in women than men, thus suggesting an association between female hormones and development of these tumors. The aim of this study was to elucidate the correlation between expression of estrogen receptor (ER) and clinicopathologic factors, including a mutation in the tyrosine kinase domain of epidermal growth factor receptor (EGFR), and prognosis in adenocarcinoma of the lung. PATIENTS AND METHODS: This study evaluated 447 resected primary lung adenocarcinoma specimens. The expression of ERalpha and ERbeta was evaluated with an immunohistochemical method. The EGFR mutation was evaluated with polymerase chain reaction. RESULTS: A strong cytoplasmic expression of ERalpha and nuclear expression of ERbeta were detected in 49.4% and 48.5% of all patients, respectively. A strong nuclear expression of ERbeta was independently associated with the EGFR mutations (odds ratio = 2.947; 95% CI, 1.97 to 4.57; P < .001) and good differentiation (odds ratio = 1.84; 95% CI, 1.21 to 2.80; P = .004) and was correlated with an increasing disease-free survival in patients with EGFR mutations (hazard ratio = 2.18; 95% CI, 1.18 to 4.06; P = .014). However, no prognostic significance was identified in patients without EGFR mutations. No clinicopathologic and/or prognostic significance of a strong expression of cytoplasmic ERalpha was found. CONCLUSION: A strong nuclear expression of ERbeta correlates with EGFR mutations, and its favorable prognostic significance was influenced by the EGFR mutations in adenocarcinoma of the lung.