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1.  Systemic Therapy, Clinical Outcomes, and Overall Survival in Locally Advanced or Metastatic Pulmonary Carcinoid 
Background
Data to guide the management of advanced pulmonary carcinoid (APC) come from retrospective reports and subgroup analyses of trials that included mainly extrapulmonary carcinoid tumors. We report the largest series to date of 49 patients with locally advanced or metastatic pulmonary carcinoid.
Methods
The Johns Hopkins Pathology Database was reviewed for APC patients treated between January 1992 and December 2012. Data on time to recurrence, progression-free survival, and overall survival were estimated by using the Kaplan–Meier method.
Results
Forty-nine patients were treated for APC in the specified time period. Median time to recurrence after surgical resection was 2.5 years (atypical carcinoid [AC] versus typical carcinoid [TC], 2.5 versus 6.3 years; p = 0.063). Median survival with advanced disease was 7.1 years and significantly longer for TC compared with AC (10.2 versus 4 years; p = 0.009). Among the diverse systemic therapies used, responses occurred in four of 17 patients (23.5%) who received platinum/ etoposide with a median progression-free survival of 7 months.
Conclusion
Although systemic chemotherapy has moderate activity for APC, novel approaches are required. TC and AC, although both classified as pulmonary carcinoid, are clearly different clinical and molecular entities and require separate treatment paradigms in the advanced/metastatic setting.
doi:10.1097/JTO.0000000000000065
PMCID: PMC4322909  PMID: 24518093
Pulmonary carcinoid; Metastatic carcinoid; Chemotherapy pulmonary carcinoid; Chemotherapy bronchial carcinoid; Therapy carcinoid; Atypical carcinoid; Typical carcinoid
2.  The Impact of Thymoma Histotype on Prognosis in a Worldwide Database 
Journal of Thoracic Oncology  2015;10(2):367-372.
Introduction:
The rarity of thymomas and lack of multi-institutional studies have hampered therapeutic progress for decades. To overcome this, the members of the International Thymic Malignancy Interest Group created a worldwide retrospective database. This database was analyzed regarding the demographic and geographic distribution of thymomas and the impact of different variables on survival and recurrence.
Methods:
This study analyzed 4221 thymomas diagnosed between 1983 and 2012 with World Health Organization histotype information from the International Thymic Malignancy Interest Group database. Associations to survival and recurrence were studied by univariate and multivariate analyses.
Results:
Type B2 thymoma is the most common (28%) and type A the least common (12%) histotypes. They are significantly more frequent in Europe and the United States than Asia. Type A and AB occur at significantly higher age than other thymomas (64 and 57 years, respectively). There are no differences in gender distribution. Stage is lower in type A (90% in stages I–II) and AB than B1 to B3 thymomas (38% of type B3 in stage III). In univariate analysis, recurrence is significantly less frequent among stage I/II tumors, in type A and AB (recurrence rates, 1–2%) than B1 to B3 thymomas (2–7%). Multivariate analysis reveals an impact of age, stage, and resection status on survival and recurrence, whereas for histology there is only a significant impact on recurrence.
Conclusion:
New findings are (1) geographic differences such as a lower incidence of type A and B2 thymoma in Asia; and (2) impact of stage and histology, the latter partially limited to early stage disease, on recurrence.
doi:10.1097/JTO.0000000000000393
PMCID: PMC4318643  PMID: 25616178
Thymoma; International Thymic Malignancy Interest Group; World Health Organization histotype; Prognosis; Epidemiology
3.  [No title available] 
PMCID: PMC4096850  PMID: 24419423
4.  A Randomized Phase II Study to Assess the Efficacy of Pemetrexed or Sunitinib or Pemetrexed Plus Sunitinib in the Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer 
Background
Second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) improves survival modestly but new strategies are needed. This trial was designed to evaluate an antivascular endothelial growth factor strategy with or without standard chemotherapy in previously treated NSCLC.
Methods
Patients with stage IIIB/IV NSCLC with performance status 0 to 1 progressive after first-line chemotherapy were eligible for randomization to pemetrexed, sunitinib, or the combination. Patients were stratified by performance status, stage, and sex. Primary objective was 18-week progression-free survival (PFS) rate; secondary objectives included response, overall survival (OS), and toxicity. Target accrual was 225. The study was terminated early because of decreasing accrual rates.
Results
Between April 2008 and September 2011, 130 patients were registered and randomized; of this, 125 patients were treated. Baseline characteristics in the three arms were well balanced. Toxicity was higher in the sunitinib-containing arms. The 18-week PFS rate in the pemetrexed, sunitinib, and combination arms was 54% (95% confidence interval [CI], 40–71), 37% (95% CI, 25–54), and 48% (95% CI, 35–66), respectively (p= 0.25). Median PFS in the pemetrexed, sunitinib, and combination arms in months was 4.9 (2.1–8.8), 3.3 (2.3–4.2), and 3.7 (2.5–5.8), respectively (p= 0.18). There was an overall statistically significant difference in OS between the three arms: median OS in months was 10.5 (8.3–20.2) for pemetrexed, 8.0 (6.8–13.5) for sunitinib, and 6.7 (4.1–10.1) for the combination (p= 0.03).
Conclusion
Pemetrexed had a superior toxicity profile to either sunitinib or the combination of pemetrexed and sunitinib. The 18-week PFS rate was not significantly different between the arms. OS was significantly better with pemetrexed alone compared with the two sunitinib-containing arms, with the doublet performing worst for OS.
doi:10.1097/JTO.0000000000000071
PMCID: PMC4284815  PMID: 24419419
CALGB 30704; Lung cancer
5.  Randomized Phase II Study of Palifermin for Reducing Dysphagia in Patients Receiving Concurrent Chemoradiotherapy for Locally Advanced Unresectable Non-small Cell Lung Cancer 
Introduction
Dysphagia is a common, dose-limiting toxicity of combined chemoradiotherapy (CT/RT) in patients with locally advanced non-small cell lung cancer (NSCLC). This study assessed the efficacy and safety of palifermin in reducing dysphagia from CT/RT followed by consolidation chemotherapy (CT).
Methods
This randomized, double-blind, phase II trial enrolled adults with unresectable stage III NSCLC. Subjects received weekly paclitaxel (50 mg/m2) and carboplatin (AUC 2.0) with concurrent daily radiation (RT) of 6000 to 6600 cGy, followed by consolidation CT. Palifermin (n = 49) or placebo (n = 46) was administered before starting concurrent CT/RT and once weekly for 6 weeks. The primary end points were the incidence of grade ≥2 dysphagia and safety.
Results
The incidence of grade ≥2 and ≥3 dysphagia was numerically lower in palifermin subjects versus placebo subjects (61% versus 70%; p = 0.36; 22% versus 28%, p = 0.50, respectively). Mean duration of dysphagia (grade ≥2) was 25 days for palifermin subjects and 32 days for placebo subjects (p = 0.32). The incidence of adverse events was similar in the two treatment groups, and median overall survival and progression-free survival were not adversely affected by palifermin treatment (overall survival: 513 versus 319 days; progression-free survival: 262 versus 235 days for palifermin versus placebo arms, respectively). The palifermin arm received more doses of CT per study design and significantly more patients received RT doses ≥6000 cGy (84% versus 61%, p = 0.01).
Conclusions
The results of this exploratory trial suggest that additional larger studies may be warranted to further evaluate the effect of palifermin on dysphagia, exposure to CT/RT, and long-term survival.
doi:10.1097/JTO.0b013e31822f6526
PMCID: PMC4284819  PMID: 22011667
Non-small cell; Lung; Dysphagia
7.  A Randomized, Placebo-Controlled, Multicenter, Biomarker-Selected, Phase 2 Study of Apricoxib in Combination with Erlotinib in Patients with Advanced Non–Small-Cell Lung Cancer 
Cyclooxygenase-2 (COX-2) overexpression is associated with a poor prognosis in non–small-cell lung cancer (NSCLC) and may promote resistance to epidermal growth factor receptor inhibitors. This randomized phase 2 trial evaluated apricoxib, a novel COX-2 inhibitor, in combination with erlotinib in biomarker-selected patients. Patients with stage IIIB/IV NSCLC previously treated with platinum-based chemotherapy were randomized (2:1) to 400 mg/day apricoxib plus 150 mg/day erlotinib (AP/E) or placebo plus erlotinib (P/E) in 21-day cycles until disease progression or unacceptable toxicity. The primary endpoint was time to progression (TTP). A decrease of 50% or more from baseline urinary prostaglandin E2 metabolite after a 5-day, open-label, run-in period was used to select eligible patients. One hundred twenty patients (median age 64 years) were randomized (78 to AP/E and 42 to P/E). Overall median TTP was 1.8 months in the AP/E group and 2.1 months in the P/E group, with a 12% objective response rate in both groups (intent-to-treat analysis). A subgroup analysis in patients aged 65 years or younger demonstrated a statistically significant TTP benefit for AP/E (hazard ratio 0.5 [95% confidence interval: not applicable–0.9]; p=0.018) and overall survival advantage at minimum 1-year follow-up (median 12.2 versus 4.0 months; hazard ratio=0.5; p=0.021). The most common adverse events were rash, diarrhea, fatigue, and nausea. Toxicity contributed to early discontinuations in patients aged more than 65 years treated with AP/E. This is the first randomized placebo-controlled study of a COX-2 inhibitor in NSCLC to use a prospective patient-selection strategy. Although AP/E seemed to improve TTP and overall survival in a subset of patients aged 65 years or younger, the primary endpoint of the trial was not met.
doi:10.1097/JTO.0000000000000082
PMCID: PMC4271824  PMID: 24736085
Non–small-cell lung cancer; Apricoxib; Erlotinib; Cyclooxygenase-2 inhibitor; Prostaglandin E2 metabolite
8.  Validation of a Molecular and Pathological Model for Five-Year Mortality Risk in Patients with Early Stage Lung Adenocarcinoma 
Journal of Thoracic Oncology  2014;10(1):67-73.
Introduction:
The aim of this study was to validate a molecular expression signature [cell cycle progression (CCP) score] that identifies patients with a higher risk of cancer-related death after surgical resection of early stage (I-II) lung adenocarcinoma in a large patient cohort and evaluate the effectiveness of combining CCP score and pathological stage for predicting lung cancer mortality.
Methods:
Formalin-fixed paraffin-embedded surgical tumor samples from 650 patients diagnosed with stage I and II adenocarcinoma who underwent definitive surgical treatment without adjuvant chemotherapy were analyzed for 31 proliferation genes by quantitative real-time polymerase chain reaction. The prognostic discrimination of the expression score was assessed by Cox proportional hazards analysis using 5-year lung cancer-specific death as primary outcome.
Results:
The CCP score was a significant predictor of lung cancer-specific mortality above clinical covariates [hazard ratio (HR) = 1.46 per interquartile range (95% confidence interval = 1.12–1.90; p = 0.0050)]. The prognostic score, a combination of CCP score and pathological stage, was a more significant indicator of lung cancer mortality risk than pathological stage in the full cohort (HR = 2.01; p = 2.8 × 10−11) and in stage I patients (HR = 1.67; p = 0.00027). Using the 85th percentile of the prognostic score as a threshold, there was a significant difference in lung cancer survival between low-risk and high-risk patient groups (p = 3.8 × 10−7).
Conclusions:
This study validates the CCP score and the prognostic score as independent predictors of lung cancer death in patients with early stage lung adenocarcinoma treated with surgery alone. Patients with resected stage I lung adenocarcinoma and a high prognostic score may be candidates for adjuvant therapy to reduce cancer-related mortality.
doi:10.1097/JTO.0000000000000365
PMCID: PMC4272230  PMID: 25396679
Carcinoma; Nonsmall cell lung cancer; Real-time polymerase chain reaction; Risk stratification
9.  Therapy resistant cancer stem cells have differing sensitivity to photon versus proton beam radiation 
Background
Cancer stem cells (CSCs) play an important role in non–small cell lung cancer (NSCLC) recurrence and metastasis. We sought to determine whether CSC-like cells respond differentially to proton and photon beam therapies.
Materials and methods
CSC-enriched cells from paclitaxel-resistant human H460 and A549 cell lines were irradiated with the same relative biological effectiveness dose and analyzed for cell viability, clonogenic survival, apoptosis, cell migration, cell invasiveness, tumor sphere formation, and CSC markers. The intracellular concentration of reactive oxygen species (ROS) was measured before and after irradiation.
Results
Compared with photons, protons caused significantly lower cell viability in chemoresistant cells and, in CSC-like cells, significantly lower clonogenic survival, invasiveness, and number of tumor spheres; less migration and CSC markers (CAR, β-catenin, and side population cells); more apoptosis; and higher ROS level. CSC-like cells contained less than half the ROS levels of parental cancer cells or normal human bronchial epithelial cells.
Conclusions
CSC-like cells may be more sensitive to irradiation with protons than photons. The increased sensitivity could be caused by the greater ROS generated by protons. Because chemoresistant CSCs play an important role in tumor recurrence, protons may be more effective than photons in eliminating recurrent or persistent NSCLC.
doi:10.1097/JTO.0b013e3182a5fdcb
PMCID: PMC3882687  PMID: 24389430
NSCLC; cancer stem cells; treatment resistance; proton therapy; photon therapy
10.  Contributions of KRAS and RAL in Non-Small Cell Lung Cancer growth and progression 
Introduction
KRAS mutations are poor prognostic markers for patients with non-small cell lung cancer (NSCLC). RALA and RALB GTPases lie downstream of RAS and are implicated in RAS mediated tumorigenesis. However, their biological or prognostic role in the context of KRAS mutation in NSCLC is unclear.
Methods
Using expression analysis of human tumors and a panel of cell lines coupled with functional in vivo and in vitro experiments, we evaluated the prognostic and functional importance of RAL in NSCLC and their relationship to KRAS expression and mutation.
Results
Immunohistochemical (N=189) and transcriptomic (N=337) analyses of NSCLC patients revealed high RALA and RALB expression was associated with poor survival. In a panel of 14 human NSCLC cell lines, RALA and RALB had higher expression in KRAS mutant cell lines while RALA but not RALB activity was higher in KRAS mutant cell lines. Depletion of RAL paralogs identified cell lines that are dependent on RAL expression for proliferation and anchorage independent growth. Overall, growth of NSCLC cell lines which carry a glycine to cystine (G12C) KRAS mutation were more sensitive to RAL depletion than those with wild-type KRAS. Using gene expression and outcome data from 337 human tumors, RAL-KRAS interaction analysis revealed that KRAS and RAL paralog expression jointly impact patient prognosis.
Conclusion
RAL GTPase expression carries important additional prognostic information to KRAS status in NSCLC patients. Simultaneously targeting RAL may provide a novel therapeutic approach in NSCLC patients harboring G12C KRAS mutations.
doi:10.1097/JTO.0000000000000007
PMCID: PMC3934792  PMID: 24389431
RAL; RAS; non-small cell lung cancer; GTPase; prognosis
11.  Clinician Perceptions of Care Difficulty, Quality of Life, and Symptom Reports for Lung Cancer Patients: An Analysis from ECOG E2Z02 (Symptom Outcomes and Practice Patterns; SOAPP) 
Introduction
Despite recent therapeutic advances, lung cancer is a difficult disease to manage. This study assessed clinicians’ perceptions of care difficulty, quality of life (QOL), and symptom reports for their lung cancer patients compared to their patients with breast, prostate and colon cancer.
Materials and Methods
This report focused on secondary analyses from the ECOG Symptom Outcomes and Practice Patterns (SOAPP) study (E2Z02); outcome measures included clinician ratings of 3106 solid tumor patients. Univariate analyses focused on patterns of disease-specific perceptions; multivariable analyses examined whether disease-specific differences persisted after covariate inclusion.
Results
In univariate comparisons, clinicians rated lung cancer patients as more difficult to treat than other solid tumor patients, with poorer QOL and higher symptom reports. After adjusting for covariates, odds of clinicians perceiving lower QOL for their lung cancer patients were 3.6 times larger than for patients with other solid tumors (OR = 3.6 [95% CI, 2.0 to 6.6], p < 0.0001). Clinicians also perceived weight difficulties 3.2 times more for lung cancer patients (OR = 3.2 [95% CI, 1.7 to 6.0], p = 0.0004). No other outcome showed significant lung versus other differences in multivariable models.
Discussion
Clinicians were more pessimistic about the well-being of their lung cancer patients compared to patients with other solid tumors. Differences remained for clinician perceptions of patient QOL and weight difficulty, even after controlling for such variables as stage, performance status, and patient-reported outcomes. These continuing disparities suggest possible perception bias. More research is needed to confirm this disparity and explore the underpinnings.
doi:10.1097/01.JTO.0000437501.83763.5d
PMCID: PMC3936653  PMID: 24189514
12.  Esophageal Cancer Recurrence Patterns and Implications for Surveillance 
Introduction
After definitive treatment of esophageal cancer, patients are at high risk for recurrence. Consistent follow-up is important for detection and treatment of recurrence. The optimal surveillance regimen remains undefined. We investigated posttreatment recurrence patterns and methods of detection in survivors of esophageal cancer.
Methods
We retrospectively studied a cohort of patients who had undergone surgical resection for esophageal cancer at our institution between 1996 and 2010. Routine computed tomography (CT) scan and upper endoscopy were performed for surveillance.
Results
In total, 1147 patients with resected esophageal adenocarcinoma or squamous cell carcinoma were included (median follow-up, 46 months). Of these, 723 (63%) had received neoadjuvant therapy before surgery. During follow-up, there were 595 deaths (52%) and 435 recurrences (38%) (distant [55%], locoregional [28%], or both [17%]). Half of recurrences were detected as a result of symptoms (n = 217), 45% by routine chest and abdominal CT scan (n = 194), and 1% by surveillance upper endoscopy (n = 6). The recurrence rate decreased from 27 per 100 person-years in posttreatment year 1 to 4 per 100 person-years in year 6. In the first 2 years, the rate of recurrence was higher among patients who had received neoadjuvant therapy (35 per 100 person-years) than among those who had not (14 per 100 person-years) (p < 0.001).
Conclusions
The incidence of recurrence is high after esophagectomy for cancer. Surveillance endoscopy has limited value for detection of asymptomatic local recurrence. The yield from follow-up scans diminishes significantly after the sixth year; surveillance scans after that point are likely unnecessary.
doi:10.1097/01.JTO.0000437420.38972.fb
PMCID: PMC4066875  PMID: 24389438
Esophageal Cancer; Surveillance; Endoscopy
13.  Primary Lung Adenocarcinomas in Children and Adolescents Treated for Pediatric Malignancies 
Introduction
Primary lung adenocarcinoma is extremely rare in the pediatric age group. There have been anecdotal reports of lesions that are histologically indistinguishable from adult-type pulmonary adenocarcinoma in young patients after treatment for nonpulmonary cancers. Herein, we present clinical, histopathologic, and molecular data on eight such cases.
Methods
Histopathologic evaluation of the tumors was performed according to the World Health Organization classification. Molecular studies for EGFR and KRAS mutations were performed on six patients with sufficient material.
Results
All eight patients were never smokers, four males and four females. Median age at nonpulmonary cancer diagnosis was 14 years (range, 3–23 years). Pulmonary adenocarcinomas were diagnosed at a median age of 15 years (range, 10–24 years); tumors were 0.1 to 2.0 cm in size and in some cases coexisted with metastases from the original cancer. Retrospective review showed that in at least three patients, the nodules were radiographically present before chemotherapy. Of six patients whose tumors were tested for common EGFR and KRAS mutations, two were positive for the former and one for the latter. At a median follow-up of 11 months (range, 2–29 months), six patients remained well without lung nodules and two had additional small, peripheral lung nodules that have not been biopsied.
Conclusions
Pulmonary lesions found in young patients with pediatric cancers can be histologically indistinguishable from lung adenocarcinoma seen in adults, may display typical adenocarcinoma-associated mutations of EGFR and KRAS, and may precede the administration of cytotoxic chemotherapy.
doi:10.1097/JTO.0b013e3181f69f08
PMCID: PMC4243865  PMID: 20975376
Bronchioloalveolar carcinoma; Lung cancer; Adenocarcinoma; Secondary malignancies; Osteosarcoma; EGFR; KRAS
14.  A Phase II First-Line Study of Gemcitabine, Carboplatin, and Bevacizumab in Advanced Stage Non-squamous Non-small Cell Lung Cancer 
Background
Bevacizumab improves responses and progression-free survival when added to first-line paclitaxel/carboplatin or cisplatin/gemcitabine for patients with advanced nonsquamous non-small cell lung cancer. This study was designed to evaluate toxicities and efficacy of gemcitabine/carboplatin/bevacizumab.
Methods
Patients with untreated advanced nonsquamous non-small cell lung cancer, with no evidence of brain metastases and not on anticoagulation were eligible. Patients received gemcitabine 1000 mg/m2 on days 1 and 8; carboplatin area under the curve 5 day 1; and bevacizumab 15 mg/kg day 1 every 3 weeks for up to six cycles. Bevacizumab was then continued every 3 weeks until disease progression or unacceptable toxicity.
Results
From July 2006 to December 2008, 48 patients were enrolled: 23 (48%) men, 25 (52%) women, and 19 (40%) never smokers. One patient never received therapy and is not included in the analysis. Median cycle number was 8 (1– 42) with 37 patients (78.7%) completing ≥4 cycles of three drugs. Dose reductions occurred in 34 (72.3%) patients. Grade 3/4 toxicities included neutropenia (47%/15%), thrombocytopenia (11%/15%), anemia (6%/0%), dyspnea (6%/2%), bacterial pneumonia (4%/0%), and hypertension (4%/2%). No neutropenic fevers occurred. One patient died of hemoptysis. Grade 3 bleeding occurred in three other patients. There were seven (14.9%) partial responses. Median time to first event (progression/death/toxicity requiring discontinuation) was 6.4 months (95% confidence interval: 4.8 –7.9 months). The median overall survival (OS) was 12.8 months (95% confidence interval: 10.0 –16.5). The OS is 57% at 1 year and 10% at 2 years.
Conclusions
Although perhaps skewed by a high proportion of nonsmokers and women, treatment with gemcitabine/carboplatin/bevacizumab has an acceptable toxicity profile with promising median OS despite a low response rate.
doi:10.1097/JTO.0b013e3181f1d23c
PMCID: PMC4241413  PMID: 20881641
Lung cancer; Non-small cell; Antiangiogenic agents
15.  Diagnostic Accuracy of MALDI Mass Spectrometric Analysis of Unfractionated Serum in Lung Cancer 
Purpose
There is a critical need for improvements in the noninvasive diagnosis of lung cancer. We hypothesized that matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) analysis of the most abundant peptides in the serum may distinguish lung cancer cases from matched controls.
Patients and Methods
We used MALDI MS to analyze unfractionated serum from a total of 288 cases and matched controls split into training (n = 182) and test sets (n = 106). We used a training–testing paradigm with application of the model profile defined in a training set to a blinded test cohort.
Results
Reproducibility and lack of analytical bias was confirmed in quality-control studies. A serum proteomic signature of seven features in the training set reached an overall accuracy of 78%, a sensitivity of 67.4%, and a specificity of 88.9%. In the blinded test set, this signature reached an overall accuracy of 72.6 %, a sensitivity of 58%, and a specificity of 85.7%. The serum signature was associated with the diagnosis of lung cancer independently of gender, smoking status, smoking pack-years, and C-reactive protein levels. From this signature, we identified three discriminatory features as members of a cluster of truncated forms of serum amyloid A.
Conclusions
We found a serum proteomic profile that discriminates lung cancer from matched controls. Proteomic analysis of unfractionated serum may have a role in the noninvasive diagnosis of lung cancer and will require methodological refinements and prospective validation to achieve clinical utility.
doi:10.1097/JTO.0b013e31814b8be7
PMCID: PMC4220686  PMID: 17909350
Mass spectrometry; Biomarker; Blood; Diagnosis
16.  CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small cell lung cancer 
Introduction
CDKN2A(p16) inactivation is common in lung cancer and occurs via homozygous deletions (HD), methylation of promoter region, or point mutations. While p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown.
Methods
We determined all three p16 inactivation mechanisms using multiple methodologies for genomic status, methylation, RNA and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary NSCLC. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation.
Results
p16 inactivation was the major mechanism of RB pathway perturbation in NSCLC, with HD being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking.
Conclusions
Our results confirm that all of the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status.
doi:10.1097/JTO.0b013e3182a46c0c
PMCID: PMC3951422  PMID: 24077454
p16; CDKN2A; inactivation; homozygous deletion; methylation; lung cancer; adenocarcinoma; meta-analysis
17.  BRIEF REPORT: Adequacy of lymph node transbronchial needle aspirates using convex probe endobronchial ultrasound for multiple tumor genotyping techniques in non-small-cell lung cancer 
Introduction
Adequate tumor acquisition is essential to identify somatic molecular alterations in non-small-cell lung cancer (NSCLC), such as EGFR mutations and ALK translocations. The success and failure rates for tumor genotyping of tissue obtained from fine needle aspirates of nodal tissue using a convex probe endobronchial ultrasound (CP-EBUS) and other diagnostic modalities in routine NSCLC care have not been described.
Methods
Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 207 patient-tumor samples sent for routine tumor genotype in clinical practice, including 42 patient-tumor samples obtained from hilar or mediastinal lymph nodes using CP-EBUS.
Results
The median age was 65 years, 62.3% were women, 77.8% were white, 26.6% were never smokers, 73.9% had advanced NSCLC and 84.1% had adenocarcinoma histology. Tumor tissue was obtained from CP-EBUS-derived hilar or mediastinal nodes in 42 cases (20.2% of total). In this latter cohort, the overall success rate for EGFR mutation analysis was 95.2%, for KRAS mutation 90.5%, and for ALK FISH 90.5%. In the complete 207 tumors, the success rate for EGFR was 92.3%, for KRAS 91.8%, and for ALK 89.9%. The failure rates were not significantly different when comparing CP-EBUS-derived nodal tissue versus all other samples or versus surgical biopsies of mediastinal nodes, but were significantly lower than image-guided percutaneous transthoracic core-needle biopsies.
Conclusions
The success rate of multiple tumor genomic analyses techniques for EGFR, KRAS and ALK gene abnormalities using routine lung cancer tissue samples obtained from hilar or mediastinal lymph nodes by means of CP-EBUS exceeds 90%, and this method of tissue acquisition is not inferior to other specimen types. Tumor genotype techniques are feasible in most CP-EBUS-derived samples and therefore further expansion of routine tumor genotype for the care of patients with NSCLC may be possible using targeted sample acquisition through CP-EBUS.
doi:10.1097/JTO.0b013e3182a471a9
PMCID: PMC3800048  PMID: 24128714
lung cancer; non-small-cell lung cancer; endobronchial ultrasound; EBUS; mediastinoscopy; never smokers; epidermal growth factor receptor; EGFR; anaplastic lymphoma kinase; ALK; KRAS; tumor genotype; failure; bone specimen; core biopsy; transbronchial needle aspiration; computed tomography; molecular testing
18.  Treatment-related Toxicities in a Phase II Trial of Dasatinib in Patients with Squamous Cell Carcinoma of the Lung: A Brief Report 
Introduction
Advanced squamous cell lung cancer (SqCC) carries a poor prognosis and new therapeutic targets are needed. Several studies have examined dasatinib in NSCLC; these report significant toxicities, but also responses in patients found to harbor mutations in DDR2 or BRAF. An open-label phase II trial with dasatinib was carried out to determine the response rates in patients with SqCC who had previously failed standard chemotherapy and to correlate responses with patient genotype.
Methods
Patients were treated with dasatinib 140mg daily in 28 day cycles. Patients were included if they had stage IIIb/IV SqCC, ECOG performance status of 0 or 1, and failed standard chemotherapy.
Results
The study was halted after enrolling 5 patients, all of whom were discontinued from the trial due to excess toxicity of dasatinib administered at 140mg per day. The patients were treated for 9, 14, 24, 40, and 42 days. 3 of 5 (60%) patients experienced ≥ grade 3 toxicities (dyspnea, fatigue, AST elevation, anorexia, nausea). Intolerable grade 2 pleural effusions were noted in 2 of 5 patients. 4 of 5 patients died after 44, 52, 127, and 226 days; one patient remains alive at 279 days. No deaths were associated with the study drug.
Conclusions
Dasatinib administered at 140mg per day for the treatment of advanced SqCC of the lung is associated with excess adverse events, similar to other studies, so is not recommended in unselected patients. Further work to identify patients likely to benefit from dasatinib and in managing dasatinib-related toxicities is needed.
doi:10.1097/JTO.0b013e3182a47162
PMCID: PMC3801424  PMID: 24128713
squamous cell cancer; dasatinib; lung neoplasms; discoidin receptor
20.  [No title available] 
PMCID: PMC3800250  PMID: 24077456
21.  A Randomized Phase II Study of Gemcitabine and Carboplatin With or Without Cediranib as First-Line Therapy in Advanced Non-Small Cell Lung Cancer: North Central Cancer Treatment Group Study N0528 
Purpose
To assess the safety and efficacy of gemcitabine (G) and carboplatin (C) with (arm A) or without (arm B) daily oral cediranib as first-line therapy for advanced non-small cell lung cancer (NSCLC).
Methods
A lead-in phase to determine the tolerability of G 1000 mg/m2 on days 1 and 8, and C on day 1 at AUC 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 (B) randomized phase II study. The primary endpoint was confirmed overall response rate (ORR), with 6-month progression-free survival (PFS6) rate in arm A as secondary endpoint. Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome.
Results
Based on the safety assessment, 30mg daily cediranib was used in the phase II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3+ non-hematologic adverse events, 71% vs 45%, p=0.01. The ORR was 19% (A) vs. 20% (B) (p=1.0). PFS6 in A was 48% (95% CI: 35%-62%), thus meeting the protocol specified threshold of at least 40%. The median OS was 12.0 vs. 9.9 months (p=0.10). FGFR1 rs7012413, FGFR2 rs2912791, and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased OS (HR 2.78-5.01, p=0.0002-0.0095).
Conclusions
The trial did not meet its primary endpoint of ORR but met its secondary endpoint of PFS6. Combination with cediranib 30 mg daily resulted in increased toxicity. Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival.
doi:10.1097/JTO.0b013e318274a85d
PMCID: PMC4193613  PMID: 23232491
22.  Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable non-squamous non-small cell lung cancers 
Introduction
Bevacizumab improves survival in patients with advanced non-small cell lung cancer (NSCLC). This phase II clinical trial assessed the effects of the addition of bevacizumab to neoadjuvant chemotherapy in resectable non-squamous NSCLC.
Methods
Patients with resectable stage IB-IIIA non-squamous NSCLC were treated with bevacizumab followed by imaging 2 weeks later to assess single agent effect. They then received 2 cycles of bevacizumab with 4 cycles of cisplatin and docetaxel followed by surgical resection. Resected patients were eligible for adjuvant bevacizumab. The primary endpoint was the rate of pathological downstaging (decrease from pretreatment clinical stage to post-treatment pathological stage). Secondary endpoints included overall survival, safety and radiologic response.
Results
Fifty patients were enrolled. Thirty-four (68%) were clinical stage IIIA. All 3 doses of neoadjuvant bevacizumab were delivered to 40/50 patients. Six (12%) patients discontinued due to bevacizumab-related adverse events. The rate of downstaging (38%), response to chemotherapy (45%), and perioperative complications (12%) were comparable to historical data. No partial responses were observed to single-agent bevacizumab but 18% developed new intratumoral cavitation with a trend toward improved pathologic response (57% vs. 21%, p=0.07). A major pathologic response (≥90% treatment effect) was associated with survival at 3 years (100% vs. 49%, p=0.01). No patients with KRAS-mutant NSCLC (0/10) had a pathologic response as compared with 11/31 with wild-type KRAS.
Conclusions
While preoperative bevacizumab plus chemotherapy was feasible, it did not improve downstaging in unselected patients. New cavitation after single-agent bevacizumab is a potential biomarker. Alternative strategies are needed for KRAS-mutant tumors.
doi:10.1097/JTO.0b013e31829923ec
PMCID: PMC4191830  PMID: 23857398
23.  An International Interpretation Study Using the ALK IHC Antibody D5F3 and a Sensitive Detection Kit Demonstrates High Concordance between ALK IHC and ALK FISH and between Evaluators 
Introduction
The goal of personalized medicine is to treat patients with a therapy predicted to be efficacious based on the molecular characteristics of the tumor, thereby sparing the patient futile or toxic therapy. Anaplastic lymphoma kinase (ALK) inhibitors are effective against ALK-positive non–small-cell lung cancer (NSCLC) tumors, but to date the only approved companion diagnostic is a break-apart fluorescence in situ hybridization (FISH) assay. Immunohistochemistry (IHC) is a clinically applicable cost-effective test that is sensitive and specific for ALK protein expression. The purpose of this study was to assemble an international team of expert pathologists to evaluate a new automated standardized ALK IHC assay.
Methods
Archival NSCLC tumor specimens (n =103) previously tested for ALK rearrangement by FISH were provided by the international collaborators. These specimens were stained by IHC with the anti-ALK (D5F3) primary antibody combined with OptiView DAB IHC detection and OptiView amplification (Ventana Medical Systems, Inc., Tucson, AZ). Specimens were scored binarily as positive if strong granular cytoplasmic brown staining was present in tumor cells. IHC results were compared with the FISH results and interevaluator comparisons made.
Results
Overall for the 100 evaluable cases the ALK IHC assay was highly sensitive (90%), specific (95%), and accurate relative (93%) to the ALK FISH results. Similar results were observed using a majority score. IHC negativity was scored by seven of seven and six of seven evaluators on three and two FISH-positive cases, respectively. IHC positivity was scored on two FISH-negative cases by seven of seven readers. There was agreement among seven of seven and six of seven readers on 88% and 96% of the cases before review, respectively, and after review there was agreement among seven of seven and six of seven on 95% and 97% of the cases, respectively.
Conclusions
On the basis of expert evaluation the ALK IHC test is sensitive, specific, and accurate, and a majority score of multiple readers does not improve these results over an individual reader’s score. Excellent inter-reader agreement was observed. These data support the algorithmic use of ALK IHC in the evaluation of NSCLC.
doi:10.1097/JTO.0000000000000115
PMCID: PMC4186652  PMID: 24722153
Non–small-cell lung cancer; Anaplastic lymphoma kinase; Immunohistochemistry; Fluorescence in situ hybridization; Companion diagnostics; Biomarkers; Crizotinib
25.  Stage-adjusted Lung Cancer Survival Does Not Differ Between Low-Income Blacks and Whites 
Introduction
Few lung cancer studies have focused on lung cancer survival in underserved populations. We conducted a prospective cohort study among 81,697 racially diverse and medically underserved adults enrolled in the Southern Community Cohort Study throughout an 11-state area of the Southeast from March 2002 to September 2009.
Methods
Using linkages with state cancer registries, we identified 501 incident non-small cell lung cancer cases. We applied Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals for subsequent mortality among black and white participants.
Results
The mean observed follow-up time (the time from diagnosis to death or end of follow up) was 1.25 years (range 0-8.3 years) and 75% (N=376) of cases died during follow-up. More blacks were diagnosed at distant stage than whites (57% versus 45%) (p = 0.03). In multivariable analyses adjusted for pack-years of smoking, age, BMI, health insurance, socioeconomic status and disease stage, the lung cancer mortality HR was higher for men vs women (HR = 1.41, 95% CI: 1.09 – 1.81) but similar for blacks vs. whites (HR = 0.99, 95% CI: 0.74 – 1.32).
Conclusions
These findings suggest that although proportionally more blacks present with distant stage disease there is no difference in stage-adjusted lung cancer mortality between blacks and whites of similar low socioeconomic status.
doi:10.1097/JTO.0b013e3182a406f6
PMCID: PMC3901948  PMID: 24457235
lung cancer; race; disparities; survival; socioeconomic status

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