Shawn M. Stoddard

Correlation of IHC and FISH for ALK Gene Rearrangement in Non-small Cell Lung Carcinoma: IHC Score Algorithm for FISH

Introduction: Accurate, cost-effective methods for testing anaplastic lymphoma kinase gene rearrangement (ALK+) are needed to select patients with non-small cell lung carcinoma for ALK-inhibitor therapy. Fluorescent in situ hybridization (FISH) is used to detect ALK+, but it is expensive and not routinely available. We explored the potential of an immunohistochemistry (IHC) scoring system as an affordable, accessible approach. Methods: One hundred one samples were obtained from an enriched cohort of never-smokers with adenocarcinoma from the Mayo Clinic Lung Cancer Cohort. IHC was performed using the ALK1 monoclonal antibody with ADVANCE detection system (Dako) and FISH with dual-color, break-apart probe (Abbott Molecular) on formalin-fixed, paraffin-embedded tissue. Results: Cases were assessed as IHC score 0 (no staining; n = 69), 1+ (faint cytoplasmic staining, n = 21), 2+ (moderate, smooth cytoplasmic staining; n = 3), or 3+ (intense, granular cytoplasmic staining in ≥10% of tumor cells; n = 8). All IHC 3+ cases were FISH+, whereas 1 of 3 IHC 2+ and 1 of 21 IHC 1+ cases were FISH+. All 69 IHC 0 cases were FISH−. Considering FISH a gold-standard reference in this study, sensitivity and specificity of IHC were 90 and 97.8%, respectively, when 2+ and 3+ were regarded as IHC positive and 0 and 1+ as IHC negative. Conclusions: IHC scoring correlates with FISH and may be a useful algorithm in testing ALK+ by FISH in non-small cell lung carcinoma, similar to human epidermal growth factor-2 testing in breast cancer. Further study is needed to validate this approach.

Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma

Introduction: The EML4–anaplastic lymphoma kinase (ALK) translocation is a recognized oncogenic driver in non-small cell lung cancer. We investigated immunohistochemistry (IHC) screening with fluorescence in situ hybridization (FISH) confirmation for ALK detection and estimated the prevalence of ALK positivity in our patient cohort of never-smokers, together with differences in clinical outcomes and prognostic factors for patients with ALK-positive and ALK-negative tumors. Methods: We designed a three-phase study (training, validation, and testing) in 300 never-smokers with lung adenocarcinoma from the observational Mayo Clinic Lung Cancer Cohort. Tumor samples were tested using IHC and FISH, and concordance between the methods was assessed. Clinical outcomes were assessed via 5-year progression- or recurrence-free survival from diagnosis. Prognostic factors for ALK-positive tumors and metastases were also investigated. Results: ALK-positive patients were significantly (p < 0.05) younger and had higher grade tumors than ALK-negative patients. ALK positivity was 12.2% by IHC and confirmed at 8.2% of tumors by FISH, with complete concordance between IHC 3+/0 and FISH+/− assessments, respectively. Five-year risk of progression or recurrence was doubled for patients with ALK-positive compared with ALK-negative tumors; ALK-positive tumors also appeared to be associated with a higher risk of brain and liver metastases. Conclusions: Our findings suggest that ALK positivity is associated with a significantly poor outcome in nonsmoking-related adenocarcinoma and that ALK-positive tumors may be associated with an increased risk of brain and liver metastases compared with ALK-negative disease. Consequently, an unmet medical need exists in ALK-positive lung cancer patients, and effective ALK-specific therapies are needed.

Network-based approach identified cell cycle genes as predictor of overall survival in lung adenocarcinoma patients

Lung adenocarcinoma is the most common type of primary lung cancer. The purpose of this study was to delineate gene expression patterns for survival prediction in lung adenocarcinoma. Gene expression profiles of 82 (discovery set) and 442 (validation set 1) lung adenocarcinoma tumor tissues were analyzed using a systems biology-based network approach. We also examined the expression profiles of 78 adjacent normal lung tissues from 82 patients. We found a significant correlation of an expression module with overall survival (adjusted hazard ratio or HR=1.71; 95% CI=1.06-2.74 in discovery set; adjusted HR=1.26; 95% CI=1.08-1.49 in validation set 1). This expression module contained genes enriched in the biological process of the cell cycle. Interestingly, the cell cycle gene module and overall survival association were also significant in normal lung tissues (adjusted HR=1.91; 95% CI, 1.32-2.75). From these survival-related modules, we further defined three hub genes (UBE2C, TPX2, and MELK) whose expression-based risk indices were more strongly associated with poor 5-year survival (HR=3.85, 95% CI=1.34-11.05 in discovery set; HR=1.72, 95% CI=1.21-2.46 in validation set 1; and HR=3.35, 95% CI=1.08-10.04 in normal lung set). The 3-gene prognostic result was further validated using 92 adenocarcinoma tumor samples (validation set 2); patients with a high-risk gene signature have a 1.52-fold increased risk (95% CI, 1.02-2.24) of death than patients with a low-risk gene signature. These results suggest that a network-based approach may facilitate discovery of key genes that are closely linked to survival in patients with lung adenocarcinoma.

Clinical Features of Bronchioloalveolar Carcinoma with New Histologic and Staging Definitions

Introduction: To assess clinical features of bronchioloalveolar carcinoma (BAC) based on the 1999 World Health Organization Classification (“pure BAC”), compare patients with pure BAC with patients previously diagnosed as BAC not meeting the 1999 definition, and compare survival changes of pure BAC based on the old and new (2009) staging systems. Methods: A pulmonary pathologist reviewed each BAC tumor diagnosed between January 1, 1997, and December 31, 2007, identifying cases meeting the new criteria. Cases were restaged according to the seventh edition of the tumor, node, metastasis classification introduced in 2009. Patients with pure BAC were analyzed under both staging systems for changes in overall survival estimation. Results: Of 338 total patients who were diagnosed with BAC, 117 were classified as pure and 221 were non-pure BAC. Seventy-eight of the 117 and 178 of the 221 had no other primary lung cancer. One-year and 5-year survival for the 78 patients with pure BAC were 94.8 and 83.5%, and for the 178 patients were 92.6 and 46.4%, respectively. Restaging for pure BAC cases resulted in nine of the 78 cases (12%) changing stage. Compared with the old staging, patients with advanced stage under the new stage had a worse 5-year survival (53% versus 45%), but no change was observed for stage IA. Conclusions: For patients with pure BAC, the new pathologic system favorably affects survival and the new staging system may more accurately reflect prognosis in advanced stage cancer. Our results have important implications for researchers, clinicians, and patients.

Tobacco smoking as a risk factor of bronchioloalveolar carcinoma of the lung: pooled analysis of seven case–control studies in the International Lung Cancer Consortium (ILCCO)

BackgroundThe International Lung Cancer Consortium (ILCCO) was established in 2004, based on the collaboration of research groups leading large molecular epidemiology studies of lung cancer that are ongoing or have been recently completed. This framework offered the opportunity to investigate the role of tobacco smoking in the development of bronchioloalveolar carcinoma (BAC), a rare form of lung cancer.MethodsOur pooled data comprised seven case–control studies from the United States, with detailed information on tobacco smoking and histology, which contributed 799 cases of BAC and 15,859 controls. We estimated the odds ratio of BAC for tobacco smoking, using never smokers as a referent category, after adjustment for age, sex, race, and study center.ResultsThe odds ratio of BAC for ever smoking was 2.47 (95% confidence interval [CI] 2.08, 2.93); the risk increased linearly with duration, amount, and cumulative cigarette smoking and persisted long after smoking cessation. The proportion of BAC cases attributable to smoking was 0.47 (95% CI 0.39, 0.54).ConclusionsThis analysis provides a precise estimate of the risk of BAC for tobacco smoking.

Clinical outcomes and changes in lung function after segmentectomy versus lobectomy for lung cancer cases

OBJECTIVE We compared the clinical outcomes and changes in pulmonary function test (PFT) results after segmentectomy or lobectomy for non-small cell lung cancer. METHODS The retrospective study included 212 patients who had undergone segmentectomy (group S) and 2336 patients who had undergone lobectomy (group L) from 1997 to 2012. The follow-up and medical record data were collected. We used all the longitudinal PFT data within 24 months postoperatively and performed linear mixed modeling. We analyzed the 5-year overall and disease-free survival in stage IA patients. We used propensity score case matching to minimize the bias due to imbalanced group comparisons. RESULTS During the perioperative period, 1 death (0.4%) in group S and 7 (0.3%) in group L occurred. The hospital stay for the 2 groups was similar (median, 5.0 vs 5.0 days; range, 2-99 vs 2-58). The mean overall and disease-free survival period of those with T1a after segmentectomy or lobectomy seemed to be similar (4.2 vs 4.5 years, P=.06; and 4.1 vs 4.4 years, P=.07, respectively). Compared with segmentectomy, lobectomy yielded marginally significantly better overall (4.4 vs 3.9 years, P=.05) and disease-free (4.1 vs 3.6 years; P=.05) survival in those with T1b. We did not find a significantly different effect on the PFTs after segmentectomy or lobectomy. CONCLUSIONS Both surgical types were safe. We would advocate lobectomy for patients with stage IA disease, especially those with T1b. A retrospective study with a large sample size and more detailed information should be conducted for PFT evaluation, with additional stratification by lobe and laterality.

Trends in the proportion of patients with lung cancer meeting screening criteria.

Lung cancer screening using low-dose computed tomography is recommended for high-risk individuals by professional associations including the US Preventive Services Task Force (USPSTF).1 The implications of the USPSTF screening criteria were investigated in a retrospective study of a well-defined population to demonstrate trends in the proportion of lung cancer patients meeting the criteria over 28 years.

Receptivity and Preferences for Lifestyle Programs to Reduce Cancer Risk among Lung Cancer Family Members.

Background Lifestyle factors and genetic information has been found to contribute to the occurrence of lung cancer. This study assessed receptivity to participating in lifestyle programs to reduce cancer risk among unaffected lung cancer family members. We also explored demographic, medical, and psychosocial correlates of willingness to participate in lifestyle programs. Methods Family members who are part of a lung Cancer Family Registry were asked to fill out a survey assessing their receptivity to cancer risk reduction programs including preferences for an individual or family-based program. Results Of the 583 respondents, 85% were “Somewhat” or “Definitely” willing to participate in a lifestyle program. Among those receptive, about half (56%) preferred a family-based approach. Preferred programs included weight management (36%) and nutritional information (30%). Preferred delivery channels were Internet (45%) and mail-based (29%) programs. On multivariate analysis, those definitely/somewhat receptive reported greater exercise self-efficacy scores (p=0.025). Conclusion The majority of the sample was receptive to lifestyle programs that might decrease cancer risk. There was a large preference for family-based weight management and nutritional programs. Further research is indicated to determine how to best incorporate a family-based approach to lifestyle programs for cancer family members.

Chest wall resection for non-small cell lung cancer: A case-matched study of postoperative pulmonary function and quality of life

BACKGROUND To assess the pulmonary function and quality of life (QOL) after chest wall resection for non-small cell lung cancer. MATERIAL AND METHODS One hundred and thirty-five patients (cases) who underwent pulmonary resection with chest wall removal were identified from January 1997 to December 2015. Propensity score matching (1:3) was applied to balance known confounders for pulmonary function and QOL between the cases and the control group who underwent pulmonary resection without chest wall invasion. Matched analyses were performed to compare perioperative mortality and morbidity, postoperative pulmonary function, overall QOL, and specific symptoms. RESULTS Perioperative mortality and morbidity did not differ significantly between cases and controls, but the hospital stay was longer in cases than in controls (mean, 12.8 vs 8.9days; p<0.001), The decline of postoperative pulmonary forced vital capacity (FVC) and the percentage of predicted FVC (FVC%) was more obvious in cases than in controls at 6 months and 2 years after surgery, but there was no obvious decline in the forced expiratory volume in one second (FEV1), the percentage of predicted FEV1 (FEV1%), the diffusion capacity of the lung for carbon monoxide (DLCO) and the percentage of predicted DLCO (DLCO%) in cases compared with controls. No significant difference was observed between the two groups in scores for overall QOL, pain, fatigue, cough, dyspnea, appetite, hemoptysis, lung cancer symptoms, and normal activities. CONCLUSIONS When chest wall resection is inevitable, it does not worse the QOL and pulmonary function of patients who underwent pulmonary resection with chest wall removal obviously compared with patients underwent pulmonary resection without chest wall invasion.

Regional Emphysema Score Predicting Overall Survival, Quality of Life, and Pulmonary Function Recovery in Early-Stage Lung Cancer Patients

Introduction: Pulmonary emphysema is a frequent comorbidity in lung cancer, but its role in tumor prognosis remains obscure. Our aim was to evaluate the impact of the regional emphysema score (RES) on a patients overall survival, quality of life (QOL), and recovery of pulmonary function in stage I to II lung cancer. Methods: Between 1997 and 2009, a total of 1073 patients were identified and divided into two surgical groups—cancer in the emphysematous (group 1 [n = 565]) and nonemphysematous (group 2 [n = 435]) regions—and one nonsurgical group (group 3 [n = 73]). RES was derived from the emphysematous region and categorized as mild (≤5%), moderate (6%–24%), or severe (25%–60%). Results: In group 1, patients with a moderate or severe RES experienced slight decreases in postoperative forced expiratory volume in 1 second, but increases in the ratio of forced expiratory volume in 1 second to forced vital capacity compared with those with a mild RES (p < 0.01); however, this correlation was not observed in group 2. Posttreatment QOL was lower in patients with higher RESs in all groups, mainly owing to dyspnea (p < 0.05). Cox regression analysis revealed that patients with a higher RES had significantly poorer survival in both surgical groups, with adjusted hazard ratios of 1.41 and 1.43 for a moderate RES and 1.63 and 2.04 for a severe RES, respectively; however, this association was insignificant in the nonsurgical group (adjusted hazard ratio of 0.99 for a moderate or severe RES). Conclusions: In surgically treated patients with cancer in the emphysematous region, RES is associated with postoperative changes in lung function. RES is also predictive of posttreatment QOL related to dyspnea in early‐stage lung cancer. In both surgical groups, RES is an independent predictor of survival.