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This lunchtime workshop aims to build on the opening plenary debate to examine the role and impact that integrated care can make in helping to re-orient health and care systems so that they enable better care experiences and care outcomes for people in financially sustainable ways. The workshop will examine the role of public policy to enable innovations in value-based care in Australia and beyond.The workshop will be led by Annette Schmiede, BUPA Health Foundation, and Zoe Wainer, BUPA ANZ with support from Professor Nick Goodwin, Director, Central Coast Research Institute and Alison Verhoeven, Chief Executive of AHHA.

We discovered a novel somatic gene fusion, CD74–NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74–NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2–ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P < 0.0001). Ectopic expression of CD74–NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K–AKT pathway, and led to increased colony formation in soft agar. Thus, CD74–NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment. Significance: CD74–NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415–22. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 377

Background Expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 has been functionally associated with a stem cell phenotype in normal and malignant cells. The prevalence of such cells in solid tumours should therefore correlate with recurrence and/or metastasis following definitive surgical resection. The aim of this study was to evaluate the prognostic significance of ALDH1A1 and CD133 in surgically resected, early stage non-small cell lung cancer (NSCLC). Methods A retrospective analysis of ALDH1A1 and CD133 expression in 205 patients with pathologic stage I NSCLC was performed using immunohistochemistry. The association between the expression of both markers and survival was determined. Results We identified 62 relapses and 58 cancer-related deaths in 144 stage 1A and 61 stage 1B patients, analysed at a median of 5-years follow-up. Overexpression of ALDH1A1 and CD133, detected in 68.7% and 50.7% of primary tumours, respectively, was an independent prognostic indicator for overall survival by multivariable Cox proportional hazard model (p=0.017 and 0.039, respectively). Overexpression of ALDH1A1, but not of CD133, predicted poor recurrence-free survival (p=0.025). When categorised into three groups according to expression of ALDH1A1/CD133, patients with overexpression of both ALDH1A1 and CD133 belonged to the group with the shortest recurrence-free and overall survival (p=0.015 and 0.017, respectively). Conclusions Expression of ALDH1A1 and CD133, and coexpression of ALDH1A1 and CD133, is strongly associated with poor survival in early-stage NSCLC following surgical resection. These data are consistent with the hypothesis that expression of stem cell markers correlates with recurrence as an indirect measure of self-renewal capacity.

Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids.

Background Surgical resection (usually lobectomy) is considered the treatment of choice for individuals with stage I and II non-small cell lung cancer (NSCLC) and for some patients with resectable stage IIIA NSCLC. However much of the evidence supporting surgery is observational. Objectives To determine whether, in patients with early stage non-small cell lung cancer, surgical resection of cancer improves disease-specific and all-cause mortality compared with no treatment, radiotherapy or chemotherapy. To compare the effectiveness of different surgical approaches (e.g. lobectomy versus limited resection) in improving disease-specific or all-cause mortality in patients with early stage lung cancer. Search strategy Electronic databases (the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE (1966 to December 2003)), bibliographies, handsearching of a journal and discussion with experts were used to identify published and unpublished trials. Selection criteria Randomised controlled trials comparing surgery alone (or in combination with other therapy) with non-surgical therapy and randomised trials comparing different surgical approaches. Data collection and analysis A pooled hazard ratio was calculated where possible. Tests for statistical heterogeneity were performed. Main results Eleven trials were included with a total of 1910 subjects. There were no studies with an untreated control group. In a pooled analysis of three trials, four-year survival was superior in patients with resectable stage I to IIIA NSCLC who underwent resection and complete mediastinal lymph node dissection compared with those undergoing resection and lymph node sampling, the hazard ratio was estimated to be 0.78 (95% CI 0.65-0.93, P = 0.005). A further trial found an increased rate of local recurrence in patients with stage I NSCLC treated with limited resection compared with lobectomy. One small trial found a survival advantage in favour of chemotherapy followed by surgery compared to chemotherapy followed by radiotherapy in patients with stage IIIA NSCLC. However none of the other trials included in the review demonstrated a significant improvement in survival in patients treated with surgery compared with non surgical therapy. Several of the included trials had potential methodological weaknesses. Authors' conclusions Conclusions about the efficacy of surgery for local and loco-regional NSCLC are limited by the small number of participants studied to date and potential methodological weaknesses of trials. Current evidence suggests that lung cancer resection combined with complete mediastinal lymph node dissection is associated with a small to modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I to IIIA NSCLC.

Introduction We investigated the relationship between predominant subtype, according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Lung Adenocarcinoma Classification; mutation status; and patient outcome in stage III (N2) lung adenocarcinoma. Methods We identified 69 patients with stage III (N2) lung adenocarcinoma operated on with curative intent between 1993 and 2011 who had adequate tumor tissue for molecular analysis and adequate follow-up time for survival analysis. DNA was isolated and tested for mutations using Sequenom's OncoCarta Panel (v1.0; Sequenom, San Diego, CA). Results The majority of tumors were acinar (26 of 69 tumors; 38%), solid (24 of 69 tumors; 35%), and micropapillary predominant (13 of 69 tumors; 19%) subtypes. EGFR and KRAS mutations were identified in 17 of 59 tumors (29%) and 13 of 59 tumors (22%), respectively. EGFR mutations occurred most often in acinar (11 of 25 tumors; 44%) and micropapillary predominant tumors (five of 13 tumors; 38%) ( p = 0.009), whereas KRAS mutations occurred most often in solid predominant tumors (nine of 21 tumors; 43%) ( p = 0.016). Patients with acinar predominant tumors had significantly improved overall survival compared with those with non-acinar predominant tumors (hazard ratio: 0.45; 95% confidence interval: 0.22–0.91; p = 0.026), which remained significant after adjustment for EGFR status, T-stage, sex, and age. Patients with EGFR -mutant micropapillary predominant tumors had similar survival to those with EGFR -mutant acinar predominant tumors. The predominant subtype in the primary tumor was most often seen in the N2 node in micropapillary and solid predominant tumors but not in acinar predominant tumors. Conclusions The predominant subtype in the primary tumor was associated with overall survival in resected stage III (N2) lung adenocarcinoma and was independent of mutation status. Histologic subtyping provides important prognostic information and potentially molecular correlates.