David H. Harpole

Oncogenic pathway signatures in human cancers as a guide to targeted therapies

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.

Adjuvant Paclitaxel Plus Carboplatin Compared With Observation in Stage IB Non–Small-Cell Lung Cancer: CALGB 9633 With the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups

PURPOSE Adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC. PATIENTS AND METHODS Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m(2) intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival. RESULTS Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors > or = 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043). CONCLUSION Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors > or = 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.

Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: A propensity-matched analysis from the STS database

BACKGROUND Several single-institution series have demonstrated that compared with open thoracotomy, video-assisted thoracoscopic lobectomy may be associated with fewer postoperative complications. In the absence of randomized trials, we queried the Society of Thoracic Surgeons database to compare postoperative mortality and morbidity following open and video-assisted thoracoscopic lobectomy. A propensity-matched analysis using a large national database may enable a more comprehensive comparison of postoperative outcomes. METHODS All patients having lobectomy as the primary procedure via thoracoscopy or thoracotomy were identified in the Society of Thoracic Surgeons database from 2002 to 2007. After exclusions, 6323 patients were identified: 5042 having thoracotomy, 1281 having thoracoscopy. A propensity analysis was performed, incorporating preoperative variables, and the incidence of postoperative complications was compared. RESULTS Matching based on propensity scores produced 1281 patients in each group for analysis of postoperative outcomes. After video-assisted thoracoscopic lobectomy, 945 patients (73.8%) had no complications, compared with 847 patients (65.3%) who had lobectomy via thoracotomy (P < .0001). Compared with open lobectomy, video-assisted thoracoscopic lobectomy was associated with a lower incidence of arrhythmias [n = 93 (7.3%) vs 147 (11.5%); P = .0004], reintubation [n = 18 (1.4%) vs 40 (3.1%); P = .0046], and blood transfusion [n = 31 (2.4%) vs n = 60 (4.7%); P = .0028], as well as a shorter length of stay (4.0 vs 6.0 days; P < .0001) and chest tube duration (3.0 vs 4.0 days; P < .0001). There was no difference in operative mortality between the 2 groups. CONCLUSIONS Video-assisted thoracoscopic lobectomy is associated with a lower incidence of complications compared with lobectomy via thoracotomy. For appropriate candidates, video-assisted thoracoscopic lobectomy may be the preferred strategy for appropriately selected patients with lung cancer.

Data from The Society of Thoracic Surgeons General Thoracic Surgery database: the surgical management of primary lung tumors.

OBJECTIVE Our objective was to investigate the surgical management of primary lung cancer by board-certified thoracic surgeons participating in the general thoracic surgery portion of The Society of Thoracic Surgeons database. METHODS We identified all pulmonary resections recorded in the general thoracic surgery prospective database from 1999 to 2006. Among the 49,029 recorded operations, 9033 pulmonary resections for primary lung cancer were analyzed. RESULTS There were 4539 men and 4494 women with a median age of 67 years (range 20-94 years). Comorbidity affected 79% of patients and included hypertension in 66%, coronary artery disease in 26%, body mass index of 30 kg/m2 or more in 25.7%, and diabetes mellitus in 13%. The type of resection was a wedge resection in 1649 (18.1%), segmentectomy in 394 (4.4%), lobectomy in 6042 (67%), bilobectomy in 357 (4.0%), and pneumonectomy in 591 (6.5%). Mediastinal lymph nodes were evaluated in 5879 (65%) patients; via mediastinoscopy in 1928 (21%), nodal dissection 3722 (41%), nodal sampling in 1124 (12.4%), and nodal biopsy in 729 (8%). Median length of stay was 5 days (range 0-277 days). Operative mortality was 2.5% (179 patients). One or more postoperative events occurred in 2911 (32%) patients. CONCLUSION The patients in the general thoracic surgery database are elderly, gender balanced, and afflicted by multiple comorbid conditions. Mediastinal lymph node evaluation is common and the pneumonectomy rate is low. The length of stay is short and operative mortality is low, despite frequent postoperative events.

Outcomes after esophagectomy: a ten-year prospective cohort

BACKGROUND The Department of Veterans Affairs National Surgical Quality Improvement Program is a unique resource to prospectively analyze surgical outcomes from a cross-section of surgical services nationally. We used this database to assess risk factors for morbidity and mortality after esophagectomy in Veterans Affairs Medical Centers from 1991 to 2001. METHODS A total of 1,777 patients underwent an esophagectomy at 109 Veterans Affairs hospitals with complete in-hospital and 30-day outcomes recorded. Bivariate and multivariable analyses were completed. RESULTS Thirty-day mortality was 9.8% (174/1,777) and the incidence of one or more of 20 predefined complications was 49.5% (880/1,777). The most frequent postoperative complications were pneumonia in 21% (380/1,777), respiratory failure in 16% (288/1,777), and ventilator support more than 48 hours in 22% (387/1,777). Preoperative predictors of mortality based on multivariable analysis included neoadjuvant therapy, blood urea nitrogen level of more than 40 mg/dL, alkaline phosphatase level of more than 125 U/L, diabetes mellitus, alcohol abuse, decreased functional status, ascites, and increasing age. Preoperative factors impacting morbidity were increasing age, dyspnea, diabetes mellitus, chronic obstructive pulmonary disease, alkaline phosphatase level of more than 125 U/L, lower serum albumin concentration, increased complexity score, and decreased functional status. Intraoperative risk factors for mortality included the need for transfusion; intraoperative risk factors for morbidity included the need for transfusion and longer operative time. CONCLUSIONS These data constitute the largest prospective outcomes cohort in the literature and document a near 50% morbidity rate and 10% mortality rate after esophagectomy. Data from this study can be used to better stratify patients before esophagectomy.

Thoracoscopic Lobectomy Is a Safe and Versatile Procedure: Experience With 500 Consecutive Patients

Objective:Advantages of thoracoscopic lobectomy for early stage non-small cell lung cancer (NSCLC), as compared with lobectomy by conventional thoracotomy, include less postoperative pain and shorter length of hospitalization. The outcomes after thoracoscopic lobectomy in patients with more complex pulmonary conditions are analyzed to determine safety, efficacy, and versatility. Methods:A prospective database of 500 consecutive patients who underwent thoracoscopic lobectomy between June 1999 and January 2006 was queried. Demographic, histopathologic, perioperative, and outcome variables were assessed using standard descriptive statistics and Kaplan-Meier survival analyses. Results:Thoracoscopic lobectomy was successfully performed in 492 patients (conversion rate, 1.6%). Pathologic analysis included primary NSCLC in 416 patients (83.2%), centrally located secondary pulmonary malignancy in 37 patients (7.4%), and a variety of benign conditions in 45 patients (9%). Among the 416 patients with NSCLC, pathologic analysis demonstrated stage I in 330 patients (55.3%), stage II in 40 patients (9.6%), and stage III or greater NSCLC in 44 patients (10.6%). The operative and perioperative (30-day) mortality was 0% and 1%, respectively. The overall 2-year survival rate for the entire cohort was 80%, and the 2-year overall survival rates for stage I NSCLC, stage II or greater NSCLC, secondary pulmonary malignancy, and granulomatous disease patients were 85%, 77%, 73%, and 89%, respectively. Conclusions:Thoracoscopic lobectomy is applicable to a spectrum of malignant and benign pulmonary disease and is associated with a low perioperative morbidity and mortality rate. Survival rates are comparable to those for lobectomy with thoracotomy.

Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients

Early stage lung cancer has a variable prognosis, and there are currently no markers that predict which patients will recur. This study examined the relation between tumor‐regulatory T (Treg) cells and total tumor‐infiltrating T‐cell lymphocytes (TIL) to determine whether they correlated with recurrence.

Prognostic models of thirty-day mortality and morbidity after major pulmonary resection ☆ ☆☆ ★

BACKGROUND A part of the prospective, multi-institutional National Veterans Affairs Surgical Quality Improvement Program was developed to predict 30-day mortality and morbidity for patients undergoing a major pulmonary resection. METHODS Perioperative data were acquired from 194,319 noncardiac surgical operations at 123 Veterans Affairs Medical Centers between October 1, 1991, and August 31, 1995. Current Procedural Terminology code-based analysis was undertaken for major pulmonary resections (lobectomy and pneumonectomy). Preoperative, intraoperative, and outcome variables were collected. The 30-day mortality and morbidity models were developed by means of multivariable stepwise logistic regression with the preoperative and intraoperative variables used as independent predictors of outcome. RESULTS A total of 3516 patients (mean age 64 9 years) underwent either lobectomy (n = 2949) or pneumonectomy (n = 567). Thirty-day mortality was 4.0% for lobectomy (119/2949) and 11.5% for pneumonectomy (65/567). The preoperative predictors of 30-day mortality were albumin, do not resuscitate status, transfusion of more than 4 units, age, disseminated cancer, impaired sensorium, prothrombin time more than 12 seconds, type of operation, and dyspnea. When the intraoperative variables were considered, intraoperative blood loss was added to the preoperative model. In the presence of these intraoperative variables in the model, do not resuscitate status and prothrombin time more than 12 seconds were only marginally significant. Thirty-day morbidity, defined as the presence of 1 or more of the 21 predefined complications, was 23.8% for lobectomy (703/2949) and 25.7% for pneumonectomy (146/567). In multivariable models, independent preoperative predictors (P <.05) of 30-day morbidity were age, weight loss greater than 10% in the 6 months before surgery, history of chronic obstructive pulmonary disease, transfusion of more than 4 units, albumin, hemiplegia, smoking, and dyspnea. When intraoperative variables were added to the preoperative model, the duration of operation time and intraoperative transfusions were included in the model and albumin became marginally significant. CONCLUSIONS This analysis identifies independent patient risk factors that are associated with 30-day mortality and morbidity for patients undergoing a major pulmonary resection. This series provides an initial risk-adjustment model for major pulmonary resections. Future refinements will allow comparative assessment of surgical outcomes and quality of care at many institutions.

A biologic risk model for stage I lung cancer: immunohistochemical analysis of 408 patients with the use of ten molecular markers.

OBJECTIVE The standard treatment of patients with stage I non-small cell lung cancer is resection of the primary tumor; however, the recurrence rate is 28% to 45%. This study evaluates a panel of molecular markers in a large population of patients with stage I non-small cell lung cancer to determine the prognostic value of each marker and to create a biologic risk model. METHODS Pathologic specimens were collected from 408 consecutive patients after complete resection for stage I non-small cell lung cancer at a single institution, with follow-up of at least 5 years. A panel of 10 molecular markers was chosen for immunohistochemical analysis of the primary tumor on the basis of differing oncogenic mechanisms. Local tumor expansion requires growth regulating proteins (epidermal growth factor receptor, the protooncogene erb-b2); apoptosis proteins (p53, bcl-2); and cell cycle regulating proteins (retinoblastoma recessive oncogene, KI-67). Local tumor invasion requires angiogenesis (factor viii). The development of distant metastases involves the expression of adhesion proteins (CD-44, sialyl-Tn, blood group A). Cox proportional hazards regression analysis was used to construct an independent risk model for cancer recurrence and death. RESULTS Multivariable analysis demonstrated significantly elevated risk for the following molecular markers: p53 (hazard ratio, 1.68; P =.004); factor viii (hazard ratio, 1.47 P =. 033); erb-b2 (hazard ratio, 1.43; P =.044); CD-44 (hazard ratio, 1. 40; P =.050); and retinoblastoma recessive oncogene (hazard ratio, 0. 747; P =.084). CONCLUSIONS Five molecular markers were associated with the risk of recurrence and death, representing independent metastatic pathways: apoptosis (p53), angiogenesis (factor viii), growth regulation (erb-b2), adhesion (CD-44), and cell cycle regulation (retinoblastoma recessive oncogene). This study demonstrates the validity of this molecular biologic risk model in patients with stage I non- small cell lung cancer.

Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients.

OBJECTIVE The authors examine the feasibility and efficacy of trimodality therapy in the treatment of malignant pleural mesothelioma and identify prognostic factors. BACKGROUND Mesothelioma is a rare, uniformly fatal disease that has increased in incidence in recent decades. Single and bimodality therapies do not improve survival. METHODS From 1980 to 1995, 120 patients underwent treatment for pathologically confirmed malignant mesothelioma at Brigham and Womens Hospital and Dana-Farber Cancer Institute (Boston, MA). Initial patient evaluation was performed by a multimodality team. Patients meeting selection criteria and with resectable disease identified by computed tomography scan or magnetic resonance imaging underwent extrapleural pneumonectomy followed by combination chemotherapy and radiotherapy. RESULTS The cohort included 27 women and 93 men with a mean age of 56 years. Operative mortality rate was 5.0%, with a major morbidity rate of 22%. Overall survival rates were 45% at 2 years and 22% at 5 years. Two and 5-year survival rates were 65% and 27%, respectively, for patients with epithelial cell type, and 20% and 0%, respectively, for patients with sarcomatous or mixed histology tumors. Nodal involvement was a significant negative prognostic factor. Patients who were node negative with epithelial histology had 2- and 5-year survival rates of 74% and 39%, respectively. Involvement of margins at time of resection did not affect survival, except in the case of full-thickness, transdiaphragmatic invasion. Classification on the basis of a revised staging system stratified median survivals, which were 22, 17, and 11 months for stages I, II, and III, respectively (p = 0.04). CONCLUSIONS Extrapleural pneumonectomy with adjuvant therapy is appropriate treatment for selected patients with malignant mesothelioma selected using a revised staging system.