Mi Kyung Bae

Fibroblast Growth Factor Receptor 1 Gene Amplification Is Associated With Poor Survival and Cigarette Smoking Dosage in Patients With Resected Squamous Cell Lung Cancer

PURPOSE To investigate the frequency and the prognostic role of fibroblast growth factor receptor 1 (FGFR1) amplification in patients with surgically resected squamous cell carcinoma of the lung (SCCL) and the association between smoking and FGFR1 amplification. PATIENTS AND METHODS Gene copy number of FGFR1 was investigated in microarrayed tumors from 262 patients with SCCL who had tumor tissue as well as smoking and survival data available. Gene copy number was evaluated by fluorescent in situ hybridization, and an FGFR1-amplified tumor (FGFR1 amp(+)) was prespecified as a tumor with nine or more copies of FGFR1. RESULTS Among 262 patients, the frequency of FGFR1 amp(+) was 13.0%. Patients with FGFR1 amp(+) had significantly shorter disease-free survival (DFS; 26.9 v 94.6 months; P < .001) as well as shorter overall survival (OS; 51.2 v 115.0 months; P = .002) than those without FGFR1 amp(+). Multivariate modeling confirmed that patients with FGFR1 amp(+) had a significantly greater risk of recurrence and death than those without FGFR1 amp(+) after adjusting for sex, smoking status, pathologic stage, and adjuvant chemotherapy (DFS: adjusted hazard ratio [AHR], 2.24; 95% CI, 1.45 to 3.45; P < .001; OS: AHR, 1.83; 95% CI, 1.15 to 2.89; P = .01). The frequency of FGFR1 amp(+) was significantly higher in current smokers than in former smokers and never-smokers (28.9% v 2.5% v 0%; P(trend) < .001). As the smoking dosage increased, so did the incidence of FGFR1 amp(+) (P(trend) = .002). CONCLUSION FGFR1 amplification is an independent negative prognostic factor in surgically resected SCCL and is associated with cigarette smoking in a dose-dependent manner. FGFR1 amplification is a relevant therapeutic target in Asian patients with SCCL.

The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma

BACKGROUND To determine the frequency and predictive impact of ROS1 rearrangements on treatment outcomes in never-smoking patients with lung adenocarcinoma. PATIENTS AND METHODS We concurrently analyzed ROS1 and ALK rearrangements and mutations in the epidermal growth factor receptor (EGFR), and KRAS in 208 never smokers with lung adenocarcinoma. ROS1 and ALK rearrangements were identified by fluorescent in situ hybridization. RESULTS Of 208 tumors screened, 7 (3.4%) were ROS1 rearranged, and 15 (7.2%) were ALK-rearranged. CD74-ROS1 fusions were identified in two patients using reverse transcriptase-polymerase chain reaction. The frequency of ROS1 rearrangement was 5.7% (6 of 105) among EGFR/KRAS/ALK-negative patients. Patients with ROS1 rearrangement had a higher objective response rate (ORR; 60.0% versus 8.5%; P = 0.01) and a longer median progression-free survival (PFS; not reached versus 3.3 months; P = 0.008) to pemetrexed than those without ROS1/ALK rearrangement. The PFS to EGFR-tyrosine kinase inhibitors in patients harboring ROS1 rearrangement was shorter than those without ROS1/ALK rearrangement (2.5 versus 7.8 months; P = 0.01). CONCLUSIONS The frequency of ROS1 rearrangements in clinically selected patients is higher than that reported for unselected patients, suggesting that ROS1 rearrangement is a druggable target in East-Asian never smokers with lung adenocarcinoma. Given the different treatment outcomes to conventional therapies and availability of ROS1 inhibitors, identification of ROS1 rearrangement can lead to successful treatment in ROS1-rearranged lung adenocarcinomas.

Preoperative C-reactive protein levels are associated with tumor size and lymphovascular invasion in resected non-small cell lung cancer

BACKGROUND This study focused on the association between preoperative serum C-reactive protein (CRP) levels and pathologic parameters in patients with resected non-small cell lung cancer (NSCLC). Our primary objective was to find pathologic factors that may explain poor prognosis in patients with preoperative serum CRP elevation. METHODS The records of 102 patients who had undergone pulmonary resection of NSCLC were reviewed. The association between preoperative serum CRP levels and variables that had p-values of less than 0.05 in t-test or one-way ANOVA was examined using multiple linear regression analysis. RESULTS Mean serum CRP level prior to surgery was 3.8+/-4.9 (range, 0.1-19.8) mg/dL. The Pearson correlation coefficient indicated that serum CRP level and pathologic tumor diameter are positively correlated (r=0.487, p<0.001). Serum CRP levels were associated with sex (male vs. female, p=0.003), smoking status (smoker vs. never smoker, p=0.007), histology (squamous vs. non-squamous, p=0.001), tumor size (size>3 cm vs. size< or =3, p<0.001), tumor necrosis (yes vs. no, p<0.001), lymphovascular invasion (yes vs. no, p<0.001), and pleural invasion (P0 vs. P1 vs. P2 vs. P3, p=0.013), but not with age (age>64.5 vs. age< or =64.5, p=0.508), atelectasis or obstructive pneumonia (yes vs. no, p=0.119), location of tumor (peripheral vs. central, p=0.474), and lymph node involvement (N0 vs. N1 vs. N2 vs. N3, p=0.558). Multiple linear regression analysis indicated that pathologic tumor size (beta=0.583, p=0.005) and lymphovascular invasion (beta=3.002, p=0.009) were associated with preoperative serum CRP level. CONCLUSION Our results indicate that lymphovascular invasion and pathologic tumor size are associated with preoperative serum CRP level, which may be considered a prognostic factor in patients with NSCLC. This additional information might serve as a basis to explain poor prognosis in patients with preoperative serum CRP elevation.

Early Masaoka stage and complete resection is important for prognosis of thymic carcinoma: a 20-year experience at a single institution

OBJECTIVE Prognosis of primary thymic carcinomas is poor due to advanced stage progression at diagnosis and highly malignant behavior. We retrospectively evaluated patients with thymic carcinoma to determine the prognostic factors. METHODS Sixty patients diagnosed and treated for thymic carcinoma from 1986 to 2005 were reviewed retrospectively. Influences of demographic characteristics, Masaoka stage, histologic grade, completeness of resection and adjuvant treatment on survival were evaluated. We defined complete resection as macroscopically and microscopically total resection of a tumor (R0 resection) and incomplete resection was subdivided into microscopic incomplete resection (R1 resection) or macroscopically incomplete resection (R2 resection). RESULTS There were 42 male and 18 female patients and mean age was 53.9 (+/-14.4) years old. The 5-year overall survival rate was 38.8% and median survival time was 35.6 months. The most common histologic type was squamous cell carcinoma (n=29). In our study, 5 patients (8.3%) were in Masaoka stage I, 5 (8.3%) were in stage II, 19 (31.7%) were in stage III, 15 (25.0%) were stage in IVa, and 16 (26.7%) were in stage IVb. Among 40 patients who underwent surgical resection, complete resection was achieved in 14 patients. The 5-year survival rate after complete resection was 85.1% and was considered significantly better than those after incomplete resection (29.0%, p=0.001) and non-surgical treatment (16.7%, p<0.001). But, no survival difference could be found between the incomplete resection group and non-surgical treatment group (p=0.15). The 5-year survival rates of early Masaoka stage patients were significantly higher than advanced Masaoka stage (90.0% vs 28.3%, p=0.001). The recurrence rates within 3 years after R1 resection (75.0%) were significantly higher than that after R0 resection (14.9%, p=0.008). CONCLUSIONS In thymic carcinoma, complete resection of early Masaoka stage lesions is the most important factor for disease control and long-term survival of patients.

Impact of cigarette smoking on response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in lung adenocarcinoma with activating EGFR mutations.

OBJECTIVES The aim of this study is to evaluate the predictive impact of cigarette smoking on treatment outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma patients with activating EGFR mutations. METHODS We retrospectively analyzed 222 consecutive recurrent or unresectable lung adenocarcinoma patients who harbored activating EGFR mutations (exon 19 deletion or exon 21 L858R) and had received gefitinib or erlotinib. Detailed smoking histories were obtained from all patients according to a standard protocol. RESULTS Of 222 EGFR-mutated patients, 65.3% were never-smokers, 19.8% were smokers with < 30 pack-years, and 14.9% were smokers with ≥ 30 pack-years smoking dosage. The disease control rate (DCR) and objective response rate (ORR) of smokers with ≥ 30 pack-years were significantly lower than never-smokers and smokers with < 30 pack-years (DCR, 78.8% vs. 93.1%, p = 0.016; ORR, 45.5% vs. 62.4%, p = 0.020). Smokers with ≥ 30 pack-years showed significantly shorter PFS than never-smokers (6.4 vs. 11.8 months, p = 0.001) and smokers with < 30 pack-years (6.4 vs. 11.4 months, p = 0.033), as well as shorter overall survival from the time of metastatic diagnosis than never-smokers (33.6 vs. 46.2 months, p = 0.003). There was no survival difference between smokers with < 30 pack-year and never smokers. In the multivariate analysis adjusted for age, sex, performance status, initial stage, and line of EGFR-TKI, the presence of smoking dosage ≥ 30 pack-years was an independent predictive factor for the disease progression to EGFR-TKIs (hazard ratio, 1.87; 95% confidence interval, 1.15-3.05; p = 0.012). CONCLUSIONS Cigarette smoking dosage of ≥ 30 pack-years is an independent negative predictive factor of EGFR-TKI treatment outcome in lung adenocarcinoma patients with activating EGFR mutations.

Thoracoscopic lobectomy is associated with superior compliance with adjuvant chemotherapy in lung cancer

BACKGROUND Although the survival benefit of adjuvant chemotherapy for nonsmall-cell lung cancer has been proved, 50% to 86% of patients received all planned cycles of chemotherapy. A thoracoscopic procedure may enable more effective administration of adjuvant chemotherapy than a thoracotomy. However, a well-balanced comparison is lacking. METHODS Patients who underwent pulmonary resection and received platinum-based double adjuvant chemotherapy for nonsmall-cell lung cancer were identified from a prospective database. A propensity score-matched analysis was performed to obtain a well-balanced comparison between thoracoscopy and thoracotomy to determine compliance of adjuvant chemotherapy. RESULTS Seventy-four patients (group A) with thoracoscopy and 278 patients with thoracotomy received adjuvant chemotherapy. Through 1:1 matching, 74 patients (group B) were selected from the thoracotomy group. A higher percentage of group A received four cycles of the planned adjuvant chemotherapy (95.9% versus 82.4%, p = 0.015). There was a trend toward better compliance in group A with four cycles of adjuvant chemotherapy without reduced dose (83.8% versus 73.0%, p = 0.162), and four cycles of adjuvant chemotherapy without delayed or reduced dose (70.3% versus 62.2%, p = 0.385). CONCLUSIONS Thoracoscopy showed better compliance with adjuvant chemotherapy after pulmonary resection for nonsmall-cell lung cancer.

Efficacy of platinum-based adjuvant chemotherapy in T2aN0 stage IB non-small cell lung cancer

BackgroundAlthough overall survival for non-small cell lung cancer (NSCLC) has increased, survival rate for pathologically staged T2aN0M0 stage IB NSCLC remains low. Adjuvant chemotherapy is not a standard treatment for stage IB NSCLC. Our purpose was to determine the efficacy of platinum-based adjuvant chemotherapy in stage IB NSCLC.MethodsWe retrospectively reviewed the medical records of 119 stage IB patients who underwent lobectomy and mediastinal lymph node dissection. Among these, 60 patients underwent platinum-based adjuvant chemotherapy (adjuvant group) and 59 did not receive chemotherapy (observation group).ResultsParticipants had a mean age of 62.12 ± 11.51 years and 73 (61.3%) were male. The median follow-up period was 49.04 months. Mean age was higher in the observation group whereas patients in the adjuvant group had larger tumors, more dissected lymph nodes, and better performance status. The 5-year overall survival was 64.7% in the observation group and 88.2% in the adjuvant group (p = 0.010). The 5-year disease-free survival was 51.3% in the observation group and 74.0% in the adjuvant group (p = 0.011). In multivariate analysis, only platinum-based adjuvant chemotherapy was a risk factor for overall survival [hazard ratio (HR) = 0.428, p = 0.049] and disease-free survival (HR = 0.57, p = 0.043). In subset analysis, patients with a larger tumor (greater than 3.2 cm), moderate to poor differentiation, and good performance status (Eastern Cooperative Oncology Group, 0) benefitted from platinum-based adjuvant chemotherapy.ConclusionsPlatinum-based adjuvant chemotherapy for surgically treated stage IB NSCLC might offer better survival than observation alone. A large-scale randomized clinical trial is needed to validate these findings.

Preoperative serum CYFRA 21-1 level as a prognostic factor in surgically treated adenocarcinoma of lung

BACKGROUND High preoperative serum CYFRA 21-1 has been reported as diagnostic marker and poor prognostic factor in non-small cell lung cancer, especially in squamous cell carcinoma. However, the prognostic value in adenocarcinoma of lung has not been reported. This study is performed to investigate the prognostic impact of CYFRA 21-1 in adenocarcinoma of lung. METHODS We retrospectively reviewed 298 patients who underwent lobectomy or above with complete mediastinal lymph node dissection for adenocarcinoma of lung, between 2004 and 2009. The patients were divided into 2 groups, by receiver operating characteristic (ROC) curve analysis. RESULTS There were 145 male patients and mean age was 62.2 ± 26.4 years. The median follow-up period was 43.3 months. Mean and median value of CYFRA 21-1 were 2.16 ± 1.97 ng/mL and 1.68 ng/mL (range, 0.37-15.10), respectively. The optimal cut-off value of CYFRA 21-1 for overall survival was 1.95 ng/mL which was determined by ROC curve analysis. One hundred fourteen (38.4%) patients showed high level of CYFRA 21-1. Preoperative serum CYFRA 21-1 was higher in advanced stage (p=0.004). The high CYFRA 21-1 was also correlated with bigger tumor size (p<0.001) and poor differentiation (p=0.008). The 5-year overall survival of low group and high group was 79.1% and 58.4% (p<0.001), respectively. Univariate and multivariate analysis showed that CYFRA 21-1 level was related to the poor prognosis for overall survival (hazard ratio=1.1, p=0.033) in adenocarcinoma of lung. The concordance index for Cox model was also higher in multivariate analysis model with CYFRA 21-1 level than in model without CYFRA 21-1 level (0.722, 95% CI 0.718-0.726 vs. 0.701, 95% CI 0.697-0.705). CONCLUSIONS High preoperative CYFRA 21-1 may be a determinant for poor prognosis in operated adenocarcinoma of lung.

Clinical and prognostic implications of ALK and ROS1 rearrangements in never-smokers with surgically resected lung adenocarcinoma

OBJECTIVES The aim of this study is to evaluate the prevalence and prognostic significance of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement in never-smokers with surgically resected lung adenocarcinoma. METHODS We retrospectively analyzed 162 consecutive never-smokers who underwent curative resection for stage IB to IIIA lung adenocarcinoma at a single institution. We concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes, and investigated ALK rearrangements by fluorescence in situ hybridization assay. ROS1 rearrangement was also determined in all triple (EGFR/KRAS/ALK)-negative tumors. RESULTS Of 162 never smokers with lung adenocarcinoma, 14 (8.6%) and 5 (3.1%) had ALK and ROS1 rearrangements, respectively. Nineteen of the 74 (25.7%) EGFR and KRAS mutation-negative patients were fusion-positive (ALK or ROS1 fusion). Fusion-positive patients tended to have shorter median disease-free survival (DFS) than fusion-negative patients (28.0 vs. 33.9 months; p=0.128). In multivariate analysis, fusion-positive patients had significantly poorer DFS than fusion-negative patients after adjustment for age, sex, T stage, N stage, and adjuvant chemotherapy use (p=0.022; hazard ratio, 2.11; 95% confidence interval, 1.19-4.30). The first recurrence sites were not significantly different between fusion-positive and fusion-negative patients in this study. CONCLUSION This study shows significantly poorer DFS of ALK or ROS1 fusion-positive lung adenocarcinoma in never-smokers after curative surgery.

Identification of somatic mutations in EGFR

BackgroundLung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers has not been conducted.MethodsWe analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohort sets. Candidate loci were validated by target capture and Sanger sequencing. Gene set analysis was performed using Ingenuity Pathway Analysis.ResultsWe identified 27 genes potentially implicated in the pathogenesis of lung adenocarcinoma. These included targetable genes involved in PI3K/mTOR signaling (TSC1, PIK3CA, AKT2) and receptor tyrosine kinase signaling (ERBB4) and genes not previously highlighted in lung adenocarcinomas, such as SETD2 and PBRM1 (chromatin remodeling), CHEK2 and CDC27 (cell cycle), CUL3 and SOD2 (oxidative stress), and CSMD3 and TFG (immune response). In the expansion cohort (N = 70), TP53 was the most frequently altered gene (11%), followed by SETD2 (6%), CSMD3 (6%), ERBB2 (6%), and CDH10 (4%). In pathway analysis, the majority of altered genes were involved in cell cycle/DNA repair (P <0.001) and cAMP-dependent protein kinase signaling (P <0.001).ConclusionsThe genomic makeup of EGFR/KRAS/ALK-negative lung adenocarcinomas in never-smokers is remarkably diverse. Genes involved in cell cycle regulation/DNA repair are implicated in tumorigenesis and represent potential therapeutic targets.