Yeun-Chung Chang

Specific EGFR Mutations Predict Treatment Outcome of Stage IIIB/IV Patients With Chemotherapy-Naive Non–Small-Cell Lung Cancer Receiving First-Line Gefitinib Monotherapy

PURPOSE To explore predictive factors for time to treatment failure (TTF) in chemotherapy-naive non-small-cell lung cancer (NSCLC) patients receiving gefitinib treatment. PATIENTS AND METHODS We designed a phase II study to test gefitinib antitumor efficacy in advanced-stage, chemotherapy-naive NSCLC patients. Patients were treated with gefitinib 250 mg/d. Tumor assessments were performed every 2 months. Responding or stable patients were treated until progression or unacceptable toxicity. All scans were reviewed independently. EGFR exons 18-21 sequence, K-ras exon 2 sequence, and MET gene copy numbers were examined in available samples. Clinical or molecular predictors of TTF were examined by multivariate analysis. RESULTS One hundred six patients were enrolled. Ninety patients had tumor samples for biomarker tests. Overall response rate was 50.9% (95% CI, 41.4% to 60.4%). Median TTF was 5.5 months, and median overall survival (OS) was 22.4 months. The response rate and median TTF of the patients with exon 19 deletion (n = 20) were 95.0% and 8.9 months, for exon 21 L858R mutation (n = 23) were 73.9% and 9.1 month, and for other types of EGFR mutations (N = 12) were 16.7% and 2.3 months, respectively. In multivariate analysis, the presence of EGFR deletion exon 19 or L858R EGFR mutations in adenocarcinoma patients predicted longer TTF. High copy number of MET seemed to correlate with shorter TTF in patients with gefitinib-sensitive activating EGFR mutations. CONCLUSION In this prospective study, EGFR exon 19 deletion or L858R mutations in adenocarcinoma were the best predictors for longer TTF in stage IIIB/IV chemotherapy-naive NSCLC patients receiving first-line gefitinib monotherapy.

Effectiveness of Tyrosine Kinase Inhibitors on “Uncommon” Epidermal Growth Factor Receptor Mutations of Unknown Clinical Significance in Non–Small Cell Lung Cancer

Purpose: Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non–small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance. Patients and Methods: Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations. Results: Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months). Conclusions: Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed. Clin Cancer Res; 17(11); 3812–21. ©2011 AACR.

Radiotherapy in Lung Adenocarcinoma with Brain Metastases: Effects of Activating Epidermal Growth Factor Receptor Mutations on Clinical Response

Purpose: Whole-brain radiation therapy (WBRT) has been applied to inoperable brain metastases in lung adenocarcinoma. Recently, an in vitro study showed reduced clonogenic survival of mutant epidermal growth factor receptor (EGFR) lung cancer cell lines in response to ionizing radiation compared with that of the wild type. To elucidate the role of EGFR mutations in radiation treatment, we evaluated the clinical response to WBRT and survival of lung adenocarcinoma patients with brain metastases. Experimental Design: This was a retrospective analysis of 63 patients with brain metastases from lung adenocarcinoma who were treated with WBRT. Demographic data, EGFR mutation status, response to WBRT, and survival data were collected. Clinical response was assessed 1 month after the start of WBRT. Univariate and logistic regression models were used to test potential predictive factors associated with clinical response. Log-rank test and Cox regression were analyzed to identify factors that affected survival. Results: Clinical response to WBRT was observed in 29 patients (46%), with 34 nonresponder patients (54%). Patients with EGFR mutations had higher response rates to WBRT compared with those with the wild-type (54% versus 24%; P = 0.045). Both the administration of EGFR tyrosine kinase inhibitor (P = 0.034) and EGFR mutation (P = 0.029) were independently associated with response to WBRT. In Cox regression analysis, WBRT responder (P = 0.010) and absence of extracranial metastases (P = 0.002) were associated with better survival. Conclusions: Both the EGFR mutations and the administration of EGFR TKI during WBRT were independent predictors of response to WBRT in brain metastases of lung adenocarcinoma.

Computer-Aided Diagnosis with Deep Learning Architecture: Applications to Breast Lesions in US Images and Pulmonary Nodules in CT Scans.

This paper performs a comprehensive study on the deep-learning-based computer-aided diagnosis (CADx) for the differential diagnosis of benign and malignant nodules/lesions by avoiding the potential errors caused by inaccurate image processing results (e.g., boundary segmentation), as well as the classification bias resulting from a less robust feature set, as involved in most conventional CADx algorithms. Specifically, the stacked denoising auto-encoder (SDAE) is exploited on the two CADx applications for the differentiation of breast ultrasound lesions and lung CT nodules. The SDAE architecture is well equipped with the automatic feature exploration mechanism and noise tolerance advantage, and hence may be suitable to deal with the intrinsically noisy property of medical image data from various imaging modalities. To show the outperformance of SDAE-based CADx over the conventional scheme, two latest conventional CADx algorithms are implemented for comparison. 10 times of 10-fold cross-validations are conducted to illustrate the efficacy of the SDAE-based CADx algorithm. The experimental results show the significant performance boost by the SDAE-based CADx algorithm over the two conventional methods, suggesting that deep learning techniques can potentially change the design paradigm of the CADx systems without the need of explicit design and selection of problem-oriented features.

Relations of Epicardial Adipose Tissue Measured by Multidetector Computed Tomography to Components of the Metabolic Syndrome Are Region-Specific and Independent of Anthropometric Indexes and Intraabdominal Visceral Fat

CONTEXT Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot. Its distribution is asymmetrical and primarily concentrated in the grooves. To date, it remains unclear which measurement of EAT best reflects its metabolic risk. OBJECTIVE We aimed to examine the correlations between various multidetector computed tomographic measurements of EAT, metabolic syndrome components, and plasma levels of high-sensitivity C-reactive protein and adipokines. DESIGN, SETTING, AND PARTICIPANTS This study included 148 consecutive patients undergoing multidetector computed tomography prior to diagnostic coronary angiography. Thickness in the grooved segments, cross-sectional areas, and total volume of EAT were measured. The cross-sectional areas of sc and visceral abdominal fat depots were additionally measured in 70 randomly selected patients. RESULTS Thickness of EAT in the left atrioventricular groove was the only EAT measurement significantly correlated with all three metabolic syndrome components (blood pressure, lipid, and glucose components) and plasma levels of resistin and high-sensitivity C-reactive protein after age and gender adjustments. The association between left atrioventricular groove thickness and increasing number of metabolic syndrome components remained significant after additional adjustments for body mass index, waist circumference, and intraabdominal visceral fat area. By using the receiver operating characteristic analysis, the optimal cutoff point for left atrioventricular groove thickness to predict the presence of at least two metabolic syndrome components was 12.4 mm. CONCLUSIONS A simple measurement of EAT thickness in the left atrioventricular groove may provide a more accurate assessment of metabolic risk associated with EAT, which could not be accounted for by anthropometric indexes and intraabdominal visceral fat.

Evaluating swallowing dysfunction using a 100-ml water swallowing test.

This study used comparison with videofluoroscopic examination of swallowing (VFES) to examine the validity of a 100-ml water swallowing test (WST) in assessing swallowing dysfunction. Fifty-nine consecutive outpatients (15 females, 44 males) with clinically suspected dysphagia were enrolled in this study. Each subject underwent a 100-ml WST followed by VFES. Data was obtained on swallowing speed and signs of choking (coughing and a wet-hoarse voice). The analytical results revealed that 49 subjects had abnormal swallowing speeds (< 10 ml/s) in the 100-ml WST, and 47 of them were identified as having dysphagia by VFES. Among the ten participants with normal swallowing speed (> 10 ml/s), eight were diagnosed with dysphagia by VFES. Notably, 14 participants choked in the 100-ml WST, 11 of whom exhibited aspiration or penetration in VFES. Among the 45 participants without choking in WST, 12 displayed aspiration or penetration in VFES. The sensitivity of swallowing speed in detecting the swallowing dysfunction was 85.5%, and the specificity was 50%. Moreover, the sensitivity of using choking or wet-horse voice in the 100-ml WST as the sole factor for predicting the presence of aspiration was 47.8%, while the specificity was 91.7%. Therefore, this study concluded that swallowing speed is a sensitive indicator for identifying patients at risk for swallowing dysfunction. Moreover, choking in the 100-ml WST may be a potential specific indicator for followup aspiration.

Dysphagia in Patients with Nasopharyngeal Cancer After Radiation Therapy: A Videofluoroscopic Swallowing Study

This study evaluated swallowing status and the factors influencing swallowing in patients with nasopharyngeal carcinoma (NPC) after radiation therapy. During the period from July 1995 to June 1999, this cross-sectional study used videofluoroscopic swallowing study (VFSS) to evaluate 184 NPC patients who had completed radiation therapy [113 cases had completed radiation therapy ≤12 months prior to evaluation (acute group) and 71 cases had completed radiation therapy >12 months prior to evaluation (chronic group)]. The numbers of patients with tumors in each of the four stages were as follows: 24 in stage I, 45 in stage II, 41 in stage III, and 74 in stage IV. Swallowing abnormalities of the acute and chronic groups were correlated with multiple variables, including gender, age, the stage of the tumor, use of either neoadjuvant chemotherapy or radiosensitizer, and radiation modality. The analytical results indicated that the chronic group had a significantly higher proportion of swallowing abnormalities. Radiation modality, chemotherapy, and tumor staging were not significantly associated with swallowing dysfunction. Trend analysis revealed a progressive deterioration of most parameters of swallowing function in this group of patients. These findings indicate that swallowing function continues to deteriorate over time, even many years after radiation therapy in patients with NPC. Our results indicate that the time elapsed since radiation therapy correlates with the severity of dysphagia in NPC patients.

Angiogenic response of locally advanced breast cancer to neoadjuvant chemotherapy evaluated with parametric histogram from dynamic contrast-enhanced MRI

The aim of this study was to evaluate angiogenic compositions and tumour response in the course of neoadjuvant chemotherapy in patients with locally advanced breast cancer (LABC) using dynamic contrast-enhanced (DCE) MRI. Thirteen patients with LABC underwent serial DCE MRI during the course of chemotherapy. DCE MRI was quantified using a two-compartment model on a pixel-by-pixel basis. Analysis of parametric histograms of amplitude, exchange rate k(out) and peak enhancement over the whole tumour was performed. The distribution patterns of histograms were correlated with the tumour response. Initial kurtosis and standard deviation of amplitude before chemotherapy correlated with tumour response, r = 0.63 and r = 0.61, respectively. Comparing the initial values with the values after the first course of chemotherapy, tumour response was associated with a decrease in standard deviation of amplitude (r = 0.79), and an increase in kurtosis and a decrease in standard deviation of k(out) (r = 0.57 and 0.57, respectively). Comparing the initial values with the values after completing the chemotherapy, tumours with better response were associated with an increase in kurtosis (r = 0.62), a decrease in mean (r = 0.84) and standard deviation (r = 0.77) of amplitude, and a decrease in mean of peak enhancement (r = 0.71). Our results suggested that tumours with better response tended to alter their internal compositions from heterogeneous to homogeneous distributions and a decrease in peak enhancement after chemotherapy. Serial analyses of parametric histograms of DCE MRI-derived angiogenic parameters are potentially useful to monitor the response of angiogenic compositions of a tumour throughout the course of chemotherapy, and might predict tumour response early in the course.

First- or second-line therapy with gefitinib produces equal survival in non-small cell lung cancer.

RATIONALE Gefitinib is effective in treating patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Deletions in exon 19 and L858R in exon 21 are the best-documented EGFR mutations that are associated with effective gefitinib responsiveness. OBJECTIVES To clarify the influence of gefitinib timing, we conducted a study to compare the outcomes of different lines of gefitinib treatment in patients with exon 19 deletions or L858R. METHODS We surveyed the clinical data and mutational studies of patients with NSCLC with EGFR mutations in the National Taiwan University Hospital (Taipei, Taiwan). MEASUREMENTS AND MAIN RESULTS Three hundred and twenty-eight patients, who received gefitinib for stage IIIb or IV NSCLC, were adequately sequenced for EGFR mutations; 192 patients had mutant EGFR, including 77 patients with exon 19 deletions and 75 patients with L858R. The 152 patients with exon 19 deletions or L858R and who were receiving gefitinib were classified into a chemonaive group (91 patients) or a chemotherapy-treated group (61 patients). Chemonaive status before gefitinib and female sex were associated with clinical response to gefitinib (P = 0.006 and 0.053, respectively). Neither overall survival after the start of antitumor therapy nor progression-free survival after gefitinib therapy was significantly different between these two groups (P = 0.207 and 0.804, respectively). Clinical response to gefitinib was the only factor associated with better overall survival (P = 0.001). CONCLUSIONS This study suggests that gefitinib is effective in patients with EGFR mutations. The gefitinib response rate in chemonaive patients is higher than in chemotherapy-treated patients; however, there is no difference in overall survival.

Comparison of gefitinib and erlotinib in advanced NSCLC and the effect of EGFR mutations

INTRODUCTION Erlotinib and gefitinib are tyrosine kinase (TK) inhibitors of epidermal growth factor receptor (EGFR) that are effective in treating non-small cell lung cancer (NSCLC). This study aimed to compare their clinical uses and the influence of EGFR mutation. METHODS The usages of erlotinib and gefitinib in advanced NSCLC were analyzed. Clinical data and EGFR mutational status of tumors were collected. RESULTS Seven hundred and sixteen (716) patients received gefitinib (n=440) or erlotinib (n=276) for stage IIIb or IV NSCLC. Erlotinib was prescribed more frequently than gefitinib in males (58.2% vs. 41.8%, p<0.001), smokers (60.5% vs. 39.5%, p<0.001), and non-adenocarcinoma (70.6% vs. 29.4%, p<0.001). Of the 716 study patients, 327 underwent testing for EGFR mutations (170 with mutant EGFR and 157 with wild-type EGFR). Adenocarcinoma in patients with mutant EGFR and non-smoker status in patients with wild-type EGFR were associated with better overall survival after TK inhibitor treatment. In both patient groups with mutant EGFR or wild-type EGFR, the effectiveness of gefitinib and erlotinib, including drug response or overall survival, were not different. CONCLUSIONS Our study revealed the obvious disparity in drug selection between erlotinib and gefitinib in clinical practice. Type of TK inhibitors did not influence treatment outcomes in patients with EGFR mutation or wild-type EGFR.