Hyo Sup Shim

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.

Histopathologic characteristics of lung adenocarcinomas with epidermal growth factor receptor mutations in the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification.

CONTEXT The proposed International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinomas has been published. OBJECTIVE To evaluate the correlation between epidermal growth factor receptor mutations and histologic subtypes of lung adenocarcinomas according to the upcoming new classification of lung adenocarcinomas. DESIGN Medical records and pathologic slides were reviewed for a total of 107 surgically resected lung adenocarcinomas. All tumors were reclassified according to the predominant histologic subtype, and comprehensive histologic subtyping with semiquantitative assessment of each of the histologic subtypes in increments of 5% was performed. Correlations with epidermal growth factor receptor status were then evaluated. RESULTS Epidermal growth factor receptor mutations were found in 54 cases (50.5%). Epidermal growth factor receptor mutations were significantly associated with the micropapillary-predominant subtype (P  =  .02) and with the presence (any amount) of the lepidic component (P  =  .02). CONCLUSION The upcoming International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma is relevant in that it shows a phenotype-genotype correlation. Comprehensive histologic subtyping should be recommended because of the association of particular subtypes with epidermal growth factor receptor mutations.

Molecular proteomics imaging of tumor interfaces by mass spectrometry

The specific molecular profiles of ovarian cancer interface zones (IZ), the region between tumors and normal tissues, were evaluated using a new method involving matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS). We analyzed three ovarian serous carcinomas using MALDI-IMS. Principal component analysis (PCA) was used to evaluate the quality of tissue spatial features based on MALDI-IMS, and for analysis of large data sets of MALDI-IMS. Two-dimensional gel electrophoresis and fluorescence microscopy were used to verify interface-specific proteins. Unique profiles were identified for the tumors, the normal zone, and the IZ. Through MALDI analysis, two interface-specific proteins, plastin 2 and peroxiredoxin 1 (PRDX 1), were identified as differentially regulated between zones. Fluorescence microscopy revealed high expression levels of plastin 2 and PRDX 1 along the IZ of ovarian tumors. This comparative proteomics study using tissue MALDI-IMS suggested that the IZ is different from the adjacent tumor and normal zones, and that plastin 2 and PRDX 1 may be interface markers specific to ovarian tumors.

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.

Molecular portraits of intratumoral heterogeneity in human ovarian cancer

One of the most common characteristic profiles of cancer is intratumoral heterogeneity (ITH). We aimed to clarify the molecular profiles and biological significance of ITH with relation to cancer stem cell (CSC). We analyzed five primary cultured clones generated from different spatial zones, front and rear zone, of a fresh-frozen ovarian tumor tissue, performing ATP-CRA, conventional RT-PCR, side population (SP) analysis, flow cytometry immunophenotyping, and cell proliferation assays. We also carried out array CGH and Ingenuity Pathways Analysis (IPA) between SP and non-SP (NSP) cells. Clones from tumor front zone showed phenotypically and genetically distinct subpopulations with relatively higher SP proportions, CD24(+) and CD117(+) expression, and chemotherapeutic resistance. We demonstrate that phenotype of SP cells in heterogeneous clones of human ovarian cancer was closely related to CD24(+), CD117(+), and combined CD117(+)/CD24(+) fractions. Chromosomal alterations in SP cells relative to NSP cells were closely related to the novel core networks of cancer stem cell-like cells (CSCs), such as cycle checkpoint regulation, notch, PTEN, wnt/β-catenin, PI3K/AKT, integrin, and cytokine and chemokine signaling. ITH could arise from clonal diversity closely related to CSC-like molecules, as evidenced by accumulated genetic, transcriptional and gene products alterations in SP.

Screening of ROS1 rearrangements in lung adenocarcinoma by immunohistochemistry and comparison with ALK rearrangements.

ROS1 rearrangement is a predictive biomarker for response to the tyrosine kinase inhibitor, crizotinib. We investigated the usefulness of ROS1 immunohistochemistry (IHC) for the detection of patients who harbor ROS1 rearrangements in two separate cohorts. We also compared ROS1 IHC with ALK IHC in terms of diagnostic performance to predict each gene rearrangement. In a retrospective cohort, IHC was performed in 219 cases of lung adenocarcinoma with already known genetic alterations. In a prospective cohort, we performed IHC for 111 consecutive cases of lung adenocarcinoma and confirmed the results by subsequent FISH. In the retrospective cohort, all 8 ROS1-rearranged tumors were immunoreactive, and 14 of 211 ROS1-wild cases were immunoreactive (sensitivity 100% and specificity 93.4%). In the prospective cohort, all IHC-negative cases were FISH-negative, and 5 of 34 ROS1 immunoreactive cases were ROS1-rearranged (sensitivity 100% and specificity 72.6%). In ROS1-wild tumors, ROS1 protein was more expressed in the tumors of ever-smokers than in those of never-smokers (p = 0.003). ALK IHC showed 100% sensitivity and 98.1 to 100% specificity in both patient cohorts. In conclusion, ROS1 IHC is highly sensitive, but less specific compared with ALK IHC for detection of the corresponding rearrangement. ROS1 IHC-reactive tumors, especially when the tumor is stained with moderate to strong intensity or a diffuse pattern, are recommended to undergo FISH to confirm the gene rearrangement.

High EGFR Gene Copy Number and Skin Rash as Predictive Markers for EGFR Tyrosine Kinase Inhibitors in Patients with Advanced Squamous Cell Lung Carcinoma

Purpose: This study aimed to search for predictors of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) efficacy in previously treated patients with advanced squamous cell lung carcinoma in which EGFR mutations are very rare. Experimental Design: EGFR gene copy numbers were assessed by FISH and evaluated as predictors of EGFR-TKI efficacy in 71 patients with advanced squamous cell lung cancer who received gefitinib or erlotinib as a second-line or higher therapy. The tumors were classified into EGFR/FISH-positive (high polysomy/gene amplification) and EGFR/FISH-negative (other) groups. Results: EGFR/FISH was positive in 19 (26.7%) patients. Only EGFR/FISH positive status was correlated with the EGFR-TKIs response (EGFR/FISH+ vs. EGFR/FISH−, 26.3% vs. 2.0%; P = 0.005). In a multivariate analysis, the risk of progression was lower in EGFR/FISH-positive patients (HR of EGFR/FISH+ vs. EGFR/FISH−, 0.57; P = 0.057) or patients experiencing grade 2 or more rash (HR for rash grade 2 or more vs. less than 2, 0.54; P = 0.042), compared with EGFR/FISH-negative patients or those experiencing grade of less than 2 rash, respectively. When the combined criteria of EGFR/FISH and skin rash severity were analyzed, EGFR/FISH-negative patients with grade less than 2 rash had poorer clinical outcomes than patients with positive EGFR/FISH or grade 2 or more rash, apparent as a lower response rate (0.0% vs. 21.4%; P = 0.003) and a shorter median progression-free survival (1.13 months vs. 3.90 months; P = 0.0002). Conclusions: EGFR/FISH and skin rash severity may be used to identify which patients are likely to gain a benefit from EGFR-TKIs in this population. Clin Cancer Res; 18(6); 1760–8. ©2012 AACR.

Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status.

INTRODUCTION PD-L1 expression is a predictive biomarker for response to anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors and can be evaluated by immunohistochemistry. Results of the clinicopathologic characteristics of PD-L1-positive lung adenocarcinoma have been inconsistent in previous studies, and there are no reports on the relationship between PD-L1 expression and p53 status in lung adenocarcinoma. METHODS We examined PD-L1 and p53 expression in a total of 323 surgically resected lung adenocarcinoma cases using anti-PD-L1 (clone SP142) and anti-p53 (clone DO-7) antibodies, and analyzed the clinicopathologic characteristics of PD-L1-positive cases and their relationship with p53 status. RESULTS PD-L1 expression in tumor cells was positive in 60 of 323 cases (18.6%). Higher PD-L1 expression (≥50%) was more prevalent in former or current smokers (p=0.026) and was associated with more pack-years (p=0.016). PD-L1-positive tumors were significantly associated with solid predominant type (p<0.001), p53 aberrant expression (p<0.001), and PD-L1 expression in tumor-infiltrating immune cells (p<0.001). Patients with stage I to III tumors harboring PD-L1-positive tumor cells showed poor recurrence-free survival (p<0.001) and overall survival (p<0.001) on univariate analysis. CONCLUSIONS PD-L1 expression in tumor cells, solid predominant histology, p53 aberrant expression, and PD-L1 expression in tumor-infiltrating immune cells are closely related. These variables should be considered when analyzing the clinical outcomes of patients with lung adenocarcinomas treated with anti-PD1/PD-L1 immune checkpoint inhibitors.

Open-label, multicenter, phase II Study of ceritinib in patients with non–small-cell lung cancer harboring ROS1 rearrangement

Purpose ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC. Patients and Methods We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization. Ceritinib 750 mg was administered once daily. The primary end point was objective response rate. The secondary end points were disease control rate; duration of response; progression-free survival; overall survival; toxicity; and concordance among fluorescent in situ hybridization, immunohistochemistry, and next-generation sequencing. Results Between June 7, 2013, and February 1, 2016, 404 patients underwent ROS1 prescreening, and 32 patients with ROS1 rearrangement were enrolled. All patients except two were crizotinib-naïve. At the time of data cutoff, the median follow-up was 14.0 months, and 18 patients (56%) had discontinued treatment. Of the 32 patients enrolled, 28 were evaluable for response by independent radiologic review. Objective response rate was 62% (95% CI, 45% to 77%), with one complete response and 19 partial responses; duration of response was 21.0 months (95% CI, 17 to 25 months); and disease control rate was 81% (95% CI, 65% to 91%). The median progression-free survival was 9.3 months (95% CI, 0 to 22 months) for all patients and 19.3 months (95% CI, 1 to 37 months) for crizotinib-naïve patients. The median overall survival was 24 months (95% CI, 5 to 43 months). Of the eight patients with brain metastases, intracranial disease control was reported in five (63%; 95% CI, 31% to 86%). The most common adverse events (majority, grade 1 or 2) for all treated patients were diarrhea (78%), nausea (59%), and anorexia (56%). Conclusion Ceritinib demonstrated potent clinical activity in patients with ROS1-rearranged NSCLC who were heavily treated previously with multiple lines of chemotherapy.

Histopathologic findings of transbronchial biopsy in usual interstitial pneumonia.

The role of transbronchial biopsy in diagnosis of usual interstitial pneumonia (UIP) is controversial. In this study, we retrospectively reviewed transbronchial biopsy specimens according to the similar criteria of previous studies, and evaluated whether diagnostic findings of UIP could be found in transbronchial biopsies. Thirty two patients with usual interstitial pneumonia, confirmed by surgical lung biopsy, were identified. In three cases (9.4%), there were combinations of interstitial fibrosis and fibroblast foci, and these findings were considered consistent with usual interstitial pneumonia. No patchwork fibrosis or honeycomb change was found. Diagnostic findings of usual interstitial pneumonia were not frequently manifested in transbronchial biopsy specimens in our study (3 out of 32 cases, 9.4%), compared with a previous report (9 out of 22 cases, 41%). In conclusion, it cannot be claimed that transbronchial biopsy is more useful in confirming usual interstitial pneumonia than previously recognized. The primary and main role of transbronchial biopsy in diagnosis of usual interstitial pneumonia is thought not to confirm a diagnosis, but to exclude other infiltrative diseases, such as malignancy, sarcoidosis or infections.