Dan J. Raz

A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies.

BACKGROUND The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging. METHODS A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I-III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC). FINDINGS Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5-80·0) in low-risk, 58·3% (48·9-66·6) in intermediate-risk, and 49·2% (42·2-55·8) in high-risk patients (p(trend)=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0-80·6) in low-risk, 57·4% (48·3-65·5) in intermediate-risk, and 44·6% (40·2-48·9) in high-risk patients (p(trend)<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages. INTERPRETATION Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection. FUNDING UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.

Update on the molecular biology of malignant mesothelioma.

Malignant mesothelioma (MM) is a highly aggressive tumor with a very poor prognosis. The disease is largely unresponsive to conventional chemotherapy or radiotherapy, and most patients die within 10–17 months of the first symptoms. Novel, more effective therapeutic strategies are needed for this inexorably fatal disease. Improvement in our understanding of the molecular biology of MM has identified promising new candidates for targeted treatments. In this review the key molecular signaling pathways, including vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), Wnt, and the cell cycle control genes p53, pRb, and bcl‐2 that appear to play an important role in the pathogenesis of MM are explored. Cancer 2007.

Three-Gene Expression Signature Predicts Survival in Early-Stage Squamous Cell Carcinoma of the Lung

Purpose: Adjuvant treatment may improve survival in early-stage squamous cell carcinoma (SCC) of the lung; however, the absolute gain is modest and mainly limited to stage II-IIIA. Current staging methods are imprecise indications of prognosis, but high-risk patients can be identified by gene expression profiling and considered for adjuvant therapy. Experimental Design: The expression of 29 genes was assessed by reverse transcriptase quantitative PCR in frozen primary tumor specimens obtained from 66 SCC patients who had undergone surgical resection. Expression values were dichotomized using the median as a cutoff value. We used a risk score to develop a gene expression model for the prediction of survival. Results: The univariate analysis of gene expression in the training cohort identified 10 genes with significant prognostic value: CSF1, EGFR, CA IX, PH4, KIAA0974, ANLN, VEGFC, NTRK1, FN1, and INR1. In the multivariate Cox model, CSF1 (hazard ratio, 3.5; P = 0.005), EGFR (hazard ratio, 2.7; P = 0.02), CA IX (hazard ratio, 0.2; P < 0.0001), and tumor size >4 cm (hazard ratio, 2.7; P = 0.02) emerged as significant markers for survival. The high prognostic value of a risk score based on the expression of the three genes (CSF1, EGFR, and CA IX) was positively validated in a separate cohort of 26 patients in an independent laboratory (P = 0.05). Conclusions: The three-gene signature is strongly associated with prognosis in early-stage SCC. Positive independent validation suggests its suitability for selecting SCC patients with an increased risk of death who might benefit from adjuvant treatment.

Clinical, Radiological, and Manometric Profile in 145 Patients with Untreated Achalasia

BackgroundEsophageal achalasia is characterized by the absence of esophageal peristalsis and by a dysfunctional lower esophageal sphincter (LES). Descriptions of clinical, radiological, and manometric findings in patients with achalasia usually have been based on small numbers of patients. This study was designed to determine in patients with untreated achalasia: (1) clinical presentation; (2) how often a diagnosis of gastroesophageal reflux disease (GERD) was erroneously made based on the presence of heartburn; (3) manometric profile; (4) relationship between chest pain and the manometric finding of vigorous achalasia.MethodsBetween 1990 and 2004, a diagnosis of esophageal achalasia was established in 145 patients. None of them had been previously treated (no previous endoscopic or surgical treatment). We evaluated the demographic and clinical characteristics, as well as the results of the endoscopy, barium swallow, esophageal manometry, and ambulatory pH monitoring. We also compared the clinical and the manometric profile of patients with classic and patients with vigorous achalasia.ResultsMost patients with untreated achalasia had dysphagia (94%). Regurgitation was present in 76% and heartburn in 52%. Chest pain (41%) and weight loss (35%) were less common. Acid-suppressing medications had been prescribed to 65 patients (45%) who complained of heartburn on the assumption that GERD was present. The LES was hypertensive in 43% of patients only. There was no significant difference in the prevalence, severity, and duration of chest pain in patients with classic and with vigorous achalasia.ConclusionsThese results show that in patients with untreated achalasia: (1) dysphagia was the most frequent complaint, but regurgitation and heartburn were frequently present; (2) a diagnosis of GERD based on the presence of heartburn was highly unreliable; (3) the LES was hypertensive in less than half of patients; and (4) the prevalence, severity, and duration of chest pain did not correlate with the manometric finding of vigorous achalasia.

A Multigene Assay Is Prognostic of Survival in Patients with Early-Stage Lung Adenocarcinoma

Purpose: Clinical staging does not adequately risk stratify patients with early stage non–small cell lung cancer. We sought to generate a real-time PCR (RT-PCR)–based prognostic model in patients with early stage lung adenocarcinoma, the dominant histology of lung cancer in the United States. Experimental Design: We studied gene expression of 61 candidate genes in 107 patients with completely surgically resected lung adenocarcinoma using RT-PCR. We used crossvalidation methods to select and validate a prognostic model based on the expression of a limited number of genes. A risk score was generated based on model coefficients, and survival of patients with high- and low-risk scores were analyzed. Results: We generated a four-gene model based on expression of WNT3a, ERBB3, LCK, and RND3. Risk score predicted mortality better than clinical stage or tumor size (adjusted hazard ratio, 6.7; 95% confidence interval, 1.6-28.9; P = 0.001). Among 70 patients with stage I disease, 5-year overall survival was 87% among patients with low-risk scores, and 38% among patients with high-risk scores (P = 0.0002). Among all patients, 5-year overall survival was 62% and 41%, respectively (P = 0.0054). Disease-free survival was also significantly different among low- and high-risk score patients. Conclusions: This multigene assay predicts overall and disease-free survival significantly better than clinical stage and tumor size in patients with early stage lung adenocarcinoma and performs especially well in patients with stage I disease. Prospective clinical trials are needed to determine whether high-risk patients with stage I disease benefit from adjuvant chemotherapy.

Interdisciplinary Palliative Care for Patients With Lung Cancer

CONTEXT Palliative care, including symptom management and attention to quality of life (QOL) concerns, should be addressed throughout the trajectory of a serious illness such as lung cancer. OBJECTIVES This study tested the effectiveness of an interdisciplinary palliative care intervention for patients with Stage I-IV non-small cell lung cancer (NSCLC). METHODS Patients undergoing treatments for NSCLC were enrolled in a prospective, quasi-experimental study whereby the usual care group was accrued first followed by the intervention group. Patients in the intervention group were presented at interdisciplinary care meetings, and appropriate supportive care referrals were made. They also received four educational sessions. In both groups, QOL, symptoms, and psychological distress were assessed at baseline and 12 weeks using surveys which included the Functional Assessment of Cancer Therapy-Lung and the Lung Cancer Subscale, the 12-item Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being, and the Distress Thermometer. RESULTS A total of 491 patients were included in the primary analysis. Patients who received the intervention had significantly better scores for QOL (109.1 vs. 101.4; P < 0.001), symptoms (25.8 vs. 23.9; P < 0.001) spiritual well-being (38.1 vs. 36.2; P = 0.001), and lower psychological distress (2.2 vs. 3.3; P < 0.001) at 12 weeks, after controlling for baseline scores, compared to patients in the usual care group. Patients in the intervention group also had significantly higher numbers of completed advance care directives (44% vs. 9%; P < 0.001), and overall supportive care referrals (61% vs. 28%; P < 0.001). The benefits were seen primarily in the earlier stage patients vs. those with Stage IV disease. CONCLUSION Interdisciplinary palliative care in the ambulatory care setting resulted in significant improvements in QOL, symptoms, and distress for NSCLC patients.

Current Concepts in Bronchioloalveolar Carcinoma Biology

Bronchioloalveolar carcinoma (BAC) has a unique clinical and radiological presentation and a different response to systemic treatments compared with conventional lung adenocarcinoma. Although tobacco-related, BAC is found disproportionately in never-smokers, women, and Japanese patients ([1][1]).

Epidemiology of Non-small Cell Lung Cancer in Asian Americans: Incidence Patterns Among Six Subgroups by Nativity

Background: Differences in the epidemiology of lung cancer between Asians and non-Hispanic whites have brought to light the relative influences of genetic and environmental factors on lung cancer risk. We set out to describe the epidemiology of non-small cell lung cancer (NSCLC) among Asians living in California, and to explore the effects of acculturation on lung cancer risk by comparing lung cancer rates between U.S.-born and foreign-born Asians. Methods: Age-adjusted incidence rates of NSCLC were calculated for Chinese, Filipino, Japanese, Korean, Vietnamese, and South Asians in California between 1988 and 2003 using data from the California Cancer Registry. Incidence rates were calculated and stratified by sex and nativity. We analyzed population-based tobacco smoking prevalence data to determine whether differences in rates were associated with prevalence of tobacco smoking. Results: Asians have overall lower incidence rates of NSCLC compared with whites (29.8 and 57.7 per 100,000, respectively). South Asians have markedly low rates of NSCLC (12.0 per 100,000). Foreign-born Asian men and women have an approximately 35% higher rate of NSCLC than U.S.-born Asian men and women. The incidence pattern by nativity is consistent with the population prevalence of smoking among Asian men; however, among women, the prevalence of smoking is higher among U.S.-born, which is counter to their incidence patterns. Conclusions: Foreign-born Asians have a higher rate of NSCLC than U.S.-born Asians, which may be due to environmental tobacco smoke or nontobacco exposures among women. South Asians have a remarkably low rate of NSCLC that approaches white levels among the U.S.-born. More studies with individual-level survey data are needed to identify the specific environmental factors associated with differential lung cancer risk occurring with acculturation among Asians.

Rewiring of human lung cell lineage and mitotic networks in lung adenocarcinomas

Analysis of gene expression patterns in normal tissues and their perturbations in tumors can help to identify the functional roles of oncogenes or tumor suppressors and identify potential new therapeutic targets. Here, gene expression correlation networks were derived from 92 normal human lung samples and patient-matched adenocarcinomas. The networks from normal lung show that NKX2-1 is linked to the alveolar type 2 lineage, and identify PEBP4 as a novel marker expressed in alveolar type 2 cells. Differential correlation analysis shows that the NKX2-1 network in tumors includes pathways associated with glutamate metabolism, and identifies Vaccinia-related kinase (VRK1) as a potential drug target in a tumor-specific mitotic network. We show that VRK1 inhibition cooperates with inhibition of PARP signaling to inhibit growth of lung tumor cells. Targeting of genes that are recruited into tumor mitotic networks may provide a wider therapeutic window than that seen by inhibition of known mitotic genes.

Side-to-side stapled intra-thoracic esophagogastric anastomosis reduces the incidence of leaks and stenosis.

Trans-hiatal esophagectomy with a hand-sewn anastomosis was for 2 decades the preferred approach in our institution for patients with esophageal cancer. In our experience, this anastomotic technique was associated with a 12% leak rate and a 48% rate of stricture requiring dilatation. We sought to determine if a side-to-side intra-thoracic anastomosis was associated with a lower rate of anastomotic stricture and leak. Thirty-three consecutive patients with distal esophageal cancer or Barretts esophagus with high grade dysplasia underwent a trans-thoracic esophagectomy with a side-to-side stapled intra-thoracic anastomosis. The overall morbidity was 27%, with no anastomotic stricture or leaks. One patient died (3%). The median time to the resumption of an oral diet was 7 days (range 5-28), and the median length of stay in hospital was 9 days (range 6-45). Trans-thoracic esophagectomy with a side-to-side stapled anastomosis is safe and it is associated with a very low rate of anastomotic complications. We consider this to be the procedure of choice for patients with distal esophageal cancers.