Search

Cancer-Testis antigens (CTA) are immunogenic molecules with normal tissue expression restricted to testes but with aberrant expression in up to 30% of non-small cell lung cancers (NSCLCs). Regulation of CTA expression is mediated in part through promoter DNA methylation. Recently, immunotherapy has altered treatment paradigms in NSCLC. Given its immunogenicity and ability to be re-expressed through demethylation, NY-ESO-1 promoter methylation, protein expression and its association with programmed death receptor ligand-1 (PD-L1) expression and clinicopathological features were investigated. Lung cancer cell line demethylation resulting from 5-Aza-2'-deoxycytidine treatment was associated with both NY-ESO-1 and PD-L1 re-expression in vitro but not increased chemosensitivity. NY-ESO-1 hypomethylation was observed in 15/94 (16%) of patient samples and associated with positive protein expression (P < 0.0001). In contrast, PD-L1 expression was observed in 50/91 (55%) but strong expression in only 12/91 (13%) cases. There was no association between NY-ESO-1 and PD-L1 expression, despite resultant re-expression of both by 5-Aza-2'-deoxycytidine. Importantly, NY-ESO-1 hypomethylation was found to be an independent marker of poor prognosis in patients not treated with chemotherapy (HR 3.59, P = 0.003) in multivariate analysis. In patients treated with chemotherapy there were no differences in survival associated with NY-ESO-1 hypomethylation. Collectively, these results provided supporting evidence for the potential use of NY-ESO-1 hypomethylation as a prognostic biomarker in stage 3 NSCLCs. In addition, these data highlight the potential to incorporate demethylating agents to enhance immune activation, in tumours currently devoid of immune infiltrates and expression of immune checkpoint genes.

Backgrounds Victoria (Australia) and Denmark have comparable population sizes and high-quality healthcare systems. Lung cancer surgery, however, is performed in more than 20 Victorian hospitals compared to four in Denmark. Such differences in centralization may influence outcomes. We engaged clinical quality registries to enable international benchmarking by exploring patterns of lung cancer surgery including mortality and survival. Methods All patients undergoing lung cancer surgery between 2015 and 2018 registered in the Victorian Lung Cancer Registry and the Danish Lung Cancer Registry were included. Analyses on stage concordance, 30 and 90-day mortality, and overall survival were restricted to a selected subgroup with NSCLC and no neo-adjuvant therapy or metastatic disease and only one operation. Results We included 1554 Victorian and 4319 Danish patients. The resection rate was 26.3% in Victoria and 28% in Denmark, but a higher proportion of Victorian patients underwent wedge resection (19.1% versus 8.8%). Stage concordance was 59.6% and 54.9% in Victoria and Denmark, respectively. The 30- and 90-day mortality was 1.3% and 2.6% in Victoria, compared to 1.4% and 2.8% in Denmark with no difference in overall survival (p = 0.28) or risk-adjusted survival (HR: 1.10 (95% CI: 0.89-1.37); p = 0.38). Conclusion High-quality surgical lung cancer care was confirmed by similar high resection and low mortality rates including no overall survival difference. The drivers and consequences of stage discordance and differences in patterns of resection deserve further exploration. This study provides a model for international benchmarking using clinical quality registries, although caution remains in the interpretation given disparities in data completeness.

BACKGROUND: Many extrapulmonary neoplasms metastasize to the lungs. We conducted a retrospective review of all patients who underwent pulmonary metastasectomy for oligometastatic disease at two centres in order to determine long-term outcomes. METHODS: The study institutions' thoracic surgery databases were searched for all patients who underwent pulmonary metastasectomy from 2000 to 2017. RESULTS: There were a total of 476 patients who underwent pulmonary metastasectomy. Mean age at time of surgery was 57.2 ± 15.9 years. Mean number of pulmonary lesions was 1.9 ± 1.6. Mean disease-free interval (DFI) was 3.6 ± 4.3 years. The most common primary neoplasms were colorectal cancer (CRC) in 35.1% (167/476), sarcoma in 23.9% (114/476), melanoma in 16.2% (77/478), renal cell carcinoma (RCC) in 7.3% (35/476) and germ cell tumour (GCT) in 4.4% (21/476). Hospital mortality was 0.4% (2/476). Mean follow-up time was 3.8 ± 2.9 years. Survival was 88.9% (95% confidence interval 85.77-91.5) at 1 year and 49.6% (95% confidence interval 44.4-54.6) at 5 years. On multivariate Cox-regression analysis GCT (P = 0.004), CRC (P = 0.03), DFI of 36+ months (P = 0.007), R0 resection (P = 0.002) and non-anatomical, sub-lobar (wedge) resection (P = 0.002) were protective against mortality. CONCLUSION: Pulmonary metastasectomy is associated with survival of 50% at 5-year follow-up. DFI of over 36 months, R0 resections, lesions resectable by wedge resection rather than anatomic resection and GCT and CRC primary cancers were associated with improved survival.

Background Pulmonary carcinoids are rare neoplasms, accounting for approximately 1%–2% of all lung malignancies. A retrospective analysis was undertaken of all patients who underwent surgical resection of pulmonary carcinoid tumours across multiple institutions in Melbourne, Australia. Methods From May 2000 through April 2020, 241 patients who underwent surgical resection of pulmonary carcinoid tumours were retrospectively reviewed. Patient demographics, pathologic data, and long-term outcomes were recorded. Results Median age was 57.7 years and the majority of patients were female (58.9% vs. 41.1%). Typical carcinoid was present in 77.1%. Histological subtype was associated with several factors. Atypical carcinoid was more likely to have larger tumour size and nodal involvement. Overall survival for typical carcinoid at 5, 10, and 15 years was 98%, 95%, and 84%, and for atypical carcinoid was 88%, 82%, and 62%, respectively. Histological subtype and age were found to be independent predictors of overall survival, with worse outcomes for atypical and those above 60 years of age. Disease-free survival was related to sublobar resection (p Conclusion Excellent long-term outcomes can be achieved following surgical resection of pulmonary carcinoids. Atypical histology and lymph node involvement are significant prognostic factors, and sublobar resection should not be considered in patients with either of the above features. Typical carcinoid tumour without nodal involvement may be appropriate for sublobar resection. Typical and atypical carcinoid tumours should be considered distinct disease entities, and as such treated accordingly.

Treatment of elderly patients with lung cancer is significantly hindered by concerns about treatment tolerability, toxicity and limited clinical trial data in the elderly; potentially giving rise to treatment nihilism amongst clinicians. This study aims to describe survival in elderly patients with lung cancer and explore potential causes for excess mortality. Patients diagnosed with lung cancer in the Victorian Lung Cancer Registry between 2011–2018 were analysed (n=3481). Patients were age-categorised and compared using Cox-regression modelling to determine mortality risk, after adjusting for confounding. Probability of being offered cancer treatments was also determined, further stratified by disease stage. The eldest patients (≥80 years old) had significantly shorter median survival compared with younger age groups (, Treatment strongly determines lung cancer survival, yet nihilism may threaten treatment provision and survival outcomes. Older patients in this cohort had reduced multidisciplinary presentation, less treatment (OR 0.24) and 28% increased mortality risk. https://bit.ly/2ZGotj0

Background The COVID-19 pandemic has had a vast impact on cancer service delivery around the world. Previously reported results from our international survey of oncology clinicians, conducted through March-April 2020, found that clinicians reported altering management in both the curative and palliative settings and not in proportion to the COVID-19 case burden in their region of practice. This follow-up survey, conducted from 27th September to 7th November 2020, aimed to explore how attitudes and practices evolved over the 2020 pandemic period. Participants and methods Participants were medical, radiation and surgical oncologist and trainees. Surveys were distributed electronically via ESMO and other collaborating professional societies. Participants were asked to compare their practice prior to the pandemic to both the period of March-April 2020, referred to as the ‘early’ period, and the current survey period, referred to as the ‘later’ period. Results One hundred and seventy-two oncology clinicians completed the survey. The majority of respondents were medical oncologists (n = 136, 79%) and many were from Europe (n = 82, 48%). In the ‘early’ period, 88% (n = 133) of clinicians reported altering their practice compared to 63% (n = 96) in the ‘later’ period. Compared to prior to the pandemic, clinicians reported fewer new patient presentations in the ‘early’ period and a trend towards more patients presenting with advanced disease in the ‘later’ period. Conclusions Results indicate a swing back towards pre-COVID-19 practices despite an increase in the rate of cumulative COVID-19 cases across 2020. The impact of these changes on cancer associated morbidity and mortality remains to be measured over the months and years to come., Highlights • This collaborative international survey of oncology clinicians was conducted in October/November of 2020. • Findings indicate a swing back towards ‘pre-coronavirus disease’ practice. • Fewer clinicians altered practice compared to the ‘early’ period of the pandemic in 2020 (63% versus 88%). • Clinicians reported seeing more new patients and a greater proportion of patients presenting with advanced disease.

Advanced-stage hepatocellular carcinoma presenting with endobronchial metastases is an extremely rare phenomenon, with only a few cases reported to date. Despite endobronchial metastases being a rare occurrence, the clinically significant sequelae require prompt diagnosis and management. Therapeutic bronchoscopy represents an effective palliative treatment for malignant airway obstruction. This case report describes a 62-year-old man who presented with bilateral endobronchial metastases from advanced-stage hepatocellular carcinoma, requiring symptom palliation with laser bronchoscopy.

Author(s): Rivalland, Gareth; Mitchell, Paul; Murone, Carmel; Asadi, Khashayer; Morey, Adrienne L; Starmans, Maud; Boutros, Paul C; Walkiewicz, Marzena; Solomon, Benjamin; Wright, Gavin; Knight, Simon; John, Thomas | Abstract: BackgroundIn non-small cell lung cancer (NSCLC), mesenchyme to epithelial transition (MET) protein abundance increases with disease stage and is implicated in resistance to tyrosine kinase inhibitors. To better clarify the impact of MET overexpression on tumor behavior, we investigated a large cohort of patients who underwent curative surgical resection to determine whether MET gene amplification or protein abundance was prognostic.MethodsTissue microarrays (TMAs) were constructed using triplicate 1 mm cores of FFPE primary NSCLC specimens. TMAs underwent immunohistochemical (IHC) staining with the SP44 clone (Ventana) and cores were considered positive if g50% of tumor exhibited 2+ staining. The highest of triplicate values was used. MET gene amplification was detected using either SISH using Ventana's MET DNP probe or FISH using the D7S486/CEP 7 Abbott Probe. DNA was subjected to mutational profiling using Sequenom's LungCarta panel.ResultsData from two institutions comprising 763 patients (516; 68%) male were generated, including 360 stage I, 226 stage II, 160 stage III and 18 resected stage IV. High MET protein expression was detected in 25% (193/763), and was significantly more common in adenocarcinomas than squamous cell carcinoma (Pl0.01). MET gene copy number (GCN) correlated with high MET protein expression by IHC (P=0.01). Increased MET protein expression was associated with EGFR and KRAS mutations (Pl0.01 for both). Once polysomy was excluded, true MET gene amplification was detected in only 8/763 (1%) of samples. In multivariate analysis, neither MET protein abundance nor GCN were correlated to overall patient survival.ConclusionsMET expression by IHC and GCN amplification was not prognostic in this large Caucasian surgical series. MET's primary role remains as a therapeutic target.

Background Epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non–small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established; we sought to clarify them using a multinational patient database. Patients and Methods Patients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics. Results Among 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51%; P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval [CI], 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62). Conclusion Although phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective.

Background The decision for administering adjuvant chemotherapy (AC) in completely resected node-negative non-small cell lung cancer (NSCLC) is guided by likelihood of disease recurrence or death based on tumor, node, metastasis (TNM) stage. However, within each TNM stage are sub-groups of patients that are more or less likely to relapse than stage alone predicts. Methods In this retrospective cohort study, prospective data from 394 consecutive patients who underwent complete resection of node-negative NSCLC without adjuvant therapies, between 2002 and 2019 was retrospectively analyzed. Independent tumor and host risk factors for recurrence were subjected to multivariate analysis to develop a predictive risk model distributing patients into low-risk or high-risk categories. Results Recurrence risk was independently predicted by a neutrophil:lymphocyte ratio (NLR) of ≥3.5 [hazard ratio (HR), 1.9; 95% confidence interval (CI), 1.1-3.5], visceral pleural invasion (HR, 2.2; 95% CI, 1.3-3.8), histopathology other than adenocarcinoma or squamous cell (HR, 2.6; 95% CI, 1.2-5.5) and tumor size >33 mm (HR, 3.9; 95% CI, 2.3-6.7). The specific combination of risk factors contributed to a score for a risk model which classified 9% of Stage I and 69% of Stage ≥II patients as high-risk. The predicted 5-year disease-free survival (DFS) for high-risk and low-risk patients as scored by the predictive model was 30% and 85%, respectively. Conclusions Our readily reproducible, low-technology model, developed from individually validated tumor/host risk factors, identified sub-groups of resected node-negative NSCLC patients at significantly discordant risk of recurrence to their TNM stage category.

Sarcomas, despite being a disparate group of malignant diseases, share a common propensity to metastasise to the lungs, regardless of origin of the primary. This risk correlates with location, size, grade and histological subtype [1]. Often this is the only clinical evidence of disease in patients after appropriate complete resection of their primary sarcoma. They may appear at the time of local recurrence in an incompletely resected or inappropriately treated primary sarcoma.

Objectives: To report clinician-perceived changes to cancer service delivery in response to COVID-19. Design: Multidisciplinary Australasian cancer clinician survey in collaboration with the European Society of Medical Oncology. Setting: Between May and June 2020 clinicians from 70 countries were surveyed; majority from Europe (n=196; 39%) with 1846 COVID-19 cases per million people, Australia (AUS)/New Zealand (NZ) (n=188; 38%) with 267/236 per million and Asia (n=75; 15%) with 121 per million at time of survey distribution. Participants Medical oncologists (n=372; 74%), radiation oncologists (n=91; 18%) and surgical oncologists (n=38; 8%). Results: Eighty-nine per cent of clinicians reported altering clinical practices; more commonly among those with versus without patients diagnosed with COVID-19 (n=142; 93% vs n=225; 86%, p=0.03) but regardless of community transmission levels (p=0.26). More European clinicians (n=111; 66.1%) had treated patients diagnosed with COVID-19 compared with Asia (n=20; 27.8%) and AUS/NZ (n=8; 4.8%), pConclusion: Clinicians reported widespread changes to oncology services, in regions of both high and low COVID-19 case numbers. Clinician concerns of potential negative impacts on patient outcomes warrant objective assessment, with system and policy implications for healthcare delivery at large.

One reason that lung cancer is the leading cause of cancer mortality worldwide, is that surgical intervention is highly dependent on earlier tumor stage and good patient condition. As large proportion of cases are already metastatic at presentation and many are locally advanced, curative surgery is only possible in a minority of fit patients. Increasing the number of patients achieving complete resection is one of the avenues to increase overall survival using our existing technology. In the past, complex cases may have been sporadically discussed between various specialists in order to achieve better outcomes. More recently, the idea of discussing those cases on a routine basis, rather than an accident of geography or referral pattern, gave rise to the multidisciplinary team. Lung cancer management is now increasingly complex, especially with novel modalities such as targeted therapies, immune checkpoint inhibitors and stereotactic body radiotherapy delivery. Likewise, in thoracic surgery, minimally invasive techniques, early recovery after surgery protocols and complex techniques for resecting locally advanced tumours or preserving lung parenchyma must all be deployed appropriately to continue our incremental gains in survival and quality of life. To highlight the role of specialist thoracic surgeon in the multidisciplinary care of locally advanced non-small cell lung cancer, we conducted a search of English language publications for its multidisciplinary-based surgical management. We limited our search to the last decade, then hand-searched relevant references. In addition, we used our large prospective database as a team-oriented specialized thoracic surgical service to benchmark and demonstrate the benefits of specialist surgeons in the modern multidisciplinary team. In conclusion, patients with locally advanced non-small cell lung cancer should have any surgical option withheld without a specialist thoracic surgical opinion as part of the multidisciplinary team discussion.

Lung cancer poses the greatest cancer-related death risk and males have poorer outcomes than females, for unknown reasons. Patient sex is not a biological variable considered in lung cancer standard of care. Correlating patient genetics with outcomes is predicted to open avenues for improved management. Using a bioinformatics approach across non-small cell lung cancer (NSCLC) subtypes, we identified where patient sex, mutation of the major tumor suppressor gene, Tumour protein P53 (TP53), and immune signatures stratified outcomes in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), among datasets of The Cancer Genome Atlas (TCGA). We exposed sex and TP53 gene mutations as prognostic for LUAD survival. Longest survival in LUAD occurred among females with wild-type (wt) TP53 genes, high levels of immune infiltration and enrichment for pathway signatures of Interferon Gamma (INF-&gamma, ), Tumour Necrosis Factor (TNF) and macrophages-monocytes. In contrast, poor survival in men with LUAD and wt TP53 genes corresponded with enrichment of Transforming Growth Factor Beta 1 (TGFB1, hereafter TGF-&beta, ) and wound healing signatures. In LUAD with wt TP53 genes, elevated gene expression of immune checkpoint CD274 (hereafter: PD-L1) and also protein 53 (p53) negative-regulators of the Mouse Double Minute (MDM)-family predict novel avenues for combined immunotherapies. LUSC is dominated by male smokers with TP53 gene mutations, while a minor population of TCGA LC patients with wt TP53 genes unexpectedly had the poorest survival, suggestive of a separate etiology. We conclude that advanced approaches to LUAD and LUSC therapy lie in the consideration of patient sex, TP53 gene mutation status and immune signatures.

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma. Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin. The treatment of lung cancer cells with chloropyramine, a compound that increases SASH1 protein concentrations, reduced cellular proliferation and increased sensitivity to cisplatin in a SASH1-dependent manner. In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.

Introduction: Non–small-cell lung cancer (NSCLC) has disproportionately negative outcomes in men compared with women. The importance of the relationship between sex and tumor, node, metastases (TNM) staging system remains unknown. The objective of this study was to investigate the effect of sex on NSCLC survival for each stage in the eighth edition of the TNM staging system in NSCLC. Patients and Methods: Two cohorts treated surgically with curative intent between 2000 and 2010 were analyzed. The primary cohort was from Australia with a second population set from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses of putative and validated prognostic factors were undertaken to investigate sex-dependent prognostication with detailed analyses of sex differences in each TNM stage. The primary outcome was disease-specific survival (DSS) at 5 years. Results: Inclusion criteria were met by 555 patients in the Australian cohort, 335 men (60.4%) and 220 (39.6%) women; and 47,706 patients from the SEER cohort, 24,671 men (51.7%) and 23,035 women (48.3%). Five-year DSS was significantly worse for men in multivariate analyses for the Australian (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.04-1.98; P =.026) and SEER (HR, 1.24; 95% CI, 1.20-1.28; P

BACKGROUND Pulmonary metastases are a sign of advanced malignant disease. Interdisciplinary management of metastatic cancer mandates the consideration of all treatment options, and in selected patients pulmonary metastasectomy can be performed with curative intent. This study aims to analyze the prognostic factors associated with survival and optimize the selection of surgical candidates. The sarcoma subset analysis aims to examine the role of multiple repeat resections for pulmonary metastatic recurrence. METHODS A total of 243 patients were analyzed in this retrospective cohort study. Overall survival was estimated using Kaplan-Meier analysis. Univariate analyses with log-rank tests and multivariate analysis with Cox proportional hazards model were undertaken to determine the independent prognostic factors for survival. RESULTS Multivariate analyses identified germ cell cancer (P = 0.01) and a disease-free interval of >36 months (P = 0.006) as significant independent prognostic factors for improved survival, whilst synchronous metastases (P = 0.04), multiple metastases (P = 0.005) and incomplete resection (P

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms., The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Here, Alcala and colleagues present a multi-omics analysis of these tumours, revealing distinct molecular and prognostic subgroups.

Introduction Four different programmed death ligand 1 immunohistochemical assays are approved or in development as companion or complementary diagnostics to different immunotherapeutic agents in lung carcinoma. We sought to determine whether these assays are technically equivalent and whether one antibody can be used on an alternate staining platform. Methods Serial sections of tissue microarrays constructed from 368 cases of resected lung cancer were stained for 22C3 and 28-8 on the Dako Link 48 platform (Dako, Carpinteria, Ca) and for SP142 and SP263 on the Ventana Benchmark Ultra platform (Ventana Medical Systems, Tucson, AZ) strictly as per product insert. A protocol was developed to use the 22C3 antibody on the Ventana Benchmark Ultra platform. Results Differences in mean tumor cell and immune cell staining were observed between the four assays ( p Conclusions Concordance between the four programmed death ligand 1 immunohistochemical assays when performed and scored as intended show that apart from 28-8 and 22C3, they cannot be used interchangeably in clinical practice. A protocol was successfully developed to use 22C3 on an alternate platform, which may help to overcome some barriers to implementation.

We investigated correlations between diagnosis according to the 2015 World Health Organization (WHO) classification of unresected lung tumours, molecular analysis and TTF1 expression in small biopsy and cytology specimens from 344 non-small cell lung carcinoma (NSCLC) patients. One case failed testing for EGFR, KRAS and ALK abnormalities and six had insufficient tumour for ALK testing. Overall mutation rate in 343 cases was 48% for the genes tested, with 19% EGFR, 33% KRAS and 4% BRAF mutations, and 5% ALK rearrangements detected. More EGFR-mutant (78%) and ALK-rearranged (75%) tumours had morphologic adenocarcinoma than KRAS-mutant (56%) tumours. Despite no significant difference in the overall rate of any molecular abnormality between morphologic adenocarcinoma (52%) and NSCLC, favour adenocarcinoma (47%) (p = 0.18), KRAS mutations were detected more frequently in the latter group. No significant difference in the overall rate of any molecular abnormality between TTF1 positive (49%) and TTF1 negative tumours (44%) (p = 0.92) was detected, but more EGFR-mutant (97%) and ALK-rearranged tumours (92%) were TTF1 positive than KRAS-mutant tumours (68%). Rates of EGFR, KRAS and BRAF mutations and ALK rearrangements in this Australian NSCLC patient population are consistent with the published international literature. Our findings suggest that 2015 WHO classification of unresected tumours may assist in identifying molecular subsets of advanced NSCLC.

Background The association between socioeconomic status (SES) and lung cancer is internationally established but in Australia this relationship remains ill defined. Aims To examine the association between SES, place of residence and lung cancer outcomes in a large Australian cohort. Methods 2369 consecutive lung cancer patients managed by St Vincent's Hospital lung multidisciplinary meeting between 2001–2014 were included. Postcode data stratified participants by Socio-Economic Indexes for Areas, a validated measure of SES, and by geographical location, an important socioeconomic factor in Australia. Results There was no difference between socioeconomic groups in age (68 years), sex (63% males) or presentation (75% symptomatic). Low socioeconomic patients had increased smoking rates and a trend towards less adenocarcinoma. More low SES patients were from rural locations, had a greater frequency of earlier stage disease and curative treatment with higher overall survival even after multivariate analysis. When stratified for socioeconomic status, overall 5-year survival was significantly better in the low SES group (33% vs 24%, n = 2275, p = 0.02), although stage-stratified survival was similar in all socioeconomic groups. Conclusions Low SES patients were more frequently from rural locations and unexpectedly had earlier stage disease and higher overall survival. The excellent outcomes in rural and lower SES patients is reassuring but suggests that there is a population of these patients with advanced lung cancer who are not referred for multidisciplinary care. Further studies are required to better define this group and determine the barriers to referral to improve overall lung cancer outcomes.

The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. The identification of dependencies borne through common co-occurring mutations are sought to more effectively target KRAS-mutant lung cancer. Approximately 20% of KRAS-mutant LUAD carry loss-of-function mutations in KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate that Keap1-deficient KrasG12D lung tumors arise from a bronchiolar cell-of-origin, lacking pro-tumorigenic macrophages observed in tumors originating from alveolar cells. Keap1 loss activates the pentose phosphate pathway, inhibition of which, using 6-AN, abrogated tumor growth. These studies highlight alternative therapeutic approaches to specifically target this unique subset of KRAS-mutant LUAD cancers., Lung adenocarcinomas frequently harbour KRAS mutations, of which a subset are characterized by co-mutation of KEAP1. Here the authors show, in mice, that KrasG12D mutant tumours are metabolically distinct, with a bronchiolar cell-of-origin.

Pulmonary metastases are a sign of advanced malignancy and an omen of poor prognosis. Once primary tumors metastasize, they become notoriously difficult to treat and interdisciplinary management often involves a combination of chemotherapy, radiotherapy, and surgery. Over the last 25 years, the emerging body of evidence has recognized the curative potential of pulmonary metastasectomy. Surgical resection of pulmonary metastases is now commonly considered for patients with controlled primary disease, absence of widely disseminated extrapulmonary disease, completely resectable lung metastases, sufficient cardiopulmonary reserve, and lack of a better alternative systemic therapy. Since the development of these selection criteria, other prognostic factors have been proposed to better predict survival and optimize the selection of surgical candidates. Disease-free interval (DFI), completeness of resection, surgical approach, number and laterality of lung metastases, and lymph node metastases all play a dynamic role in determining patient outcomes. There is a definite need to continue reviewing these prognosticators to identify patients who will benefit most from pulmonary metastasectomy and those who should avoid unnecessary loss of lung parenchyma. This literature review aims to explore and synthesize the last 25 years of evidence on the long-term survival, prognostic factors, and patient selection process for pulmonary metastasectomy.

Thoracotomy is acknowledged as one of the most painful procedures in surgical practice, with the potential to result in significant acute and chronic sequelae, which become especially relevant in high-risk patient populations. Certain pathologies necessitate this surgical approach, and in those circumstances we must aim to mitigate postoperative complications by employing surgical techniques that decrease the risk of nerve injury, rib fracture, and unnecessary soft tissue trauma. We describe an approach to thoracotomy that incorporates evidence-based strategies to lessen the risk of these potential complications, which resulted in rapid postoperative recovery in a nonagenarian.

We describe a novel technique for the creation of a pleural tent and pleurectomy via the use of a laparoscopic hernia balloon. In this method a Spacemaker™ Structural Balloon Trocar (Covidien, USA) is tunnelled under the pleura at the site of thoracotomy or video assisted thoracoscopic surgery port and incrementally inflated under vision. This method is less traumatic than traditional methods, is more likely to provide an intact pleural tent, and allows the surgeon to operate in a near bloodless operative field.

BACKGROUND/OBJECTIVE: Given the poor overall survival (OR) and progression-free survival (PFS) rates for lung cancers managed with surgical resection, there is a need to identify the prognostic markers that would improve the risk stratification of patients with operable lung cancer to inform treatment decisions. We investigate the prognostic utility of two established inflammation-based scores, the neutrophil–lymphocyte ratio (NLR) and the change in neutrophil–lymphocyte ratio (ΔNLR), throughout the operative period in a prospective cohort of patients with lung cancer who underwent surgical resection. METHODS: Demographic, clinical, and treatment details for 345 patients with lung cancer who underwent surgical resection between 2000 and 2019 at multiple centers across Melbourne, Victoria (Australia), were prospectively collected. Preoperative NLR and ΔNLR were calculated after which Cox univariate and multivariate analyses were conducted for OS and PFS against the known prognostic factors. RESULTS: Both univariate and multivariate analyses showed that preoperative NLR >4.54, as well as day 1 and day 2 postoperative NLR (P < 0.01), was associated with increased risk for postoperative mortality (hazard ratio 1.8; P < 0.01) and PFS (P < 0.05), whereas ΔNLR was not a significant predictor of OS or PFS. CONCLUSION: Elevated NLR among patients with lung cancer who underwent surgical resection was prognostic for poor OS and PFS, whereas ΔNLR was not found to be prognostic for either OS or PFS. Further research may yet reveal a prognostic value for ΔNLR when compared across a greater time period.

BackgroundLung cancer has markedly poorer survival in men. Recognized important prognostic factors are divided into host, tumour and environmental factors. Traditional staging systems that use only tumour factors to predict prognosis are of limited accuracy. By examining sex-based patterns of disease-specific survival in non-small cell lung cancer patients, we determined the effect of sex on the prognostic value of additional host factors.

Background Lung cancer accounts for significant morbidity and mortality worldwide. The effect of recent changes in demographics and management on outcomes in Australia has not been clearly defined. Aims To compare three consecutive lung cancer cohorts to evaluate emergent differences in diagnosis, management and mortality. Methods For comparative analysis, 2119 lung cancer patients were divided into three successive cohorts. Current death data were sought from the Victorian Cancer Registry. Results Age at diagnosis, mode of presentation and pathology did not significantly differ between the groups. Significantly more females were diagnosed with lung cancer in the most recent cohort (P = 0.04). Amongst non-small-cell lung cancer patients, there were more adenocarcinomas and less large cell carcinomas in the latest cohort (P =

We sought to investigate the frequency of mutations in epidermal growth factor receptor (EGFR) and Kirsten-RAS (KRAS) by each pathological subtype for patients with resected pulmonary adenocarcinoma as defined by the IASLC/ATS/ERS classification. Histological examination determined the predominant subtype according to the IASLC/ATS/ERS classification. EGFR and KRAS mutations were determined by high-resolution melting and Sanger sequencing. Clinical data were collected from medical records and clinicians. The 178 consecutive patients consisted of 48% males, median age 68 years (range 20-87) and smoking history 78%. The tumour stage was I in 62%, II in 18% and III in 20%. The mutation rates were: EGFR 30%; KRAS 28%. The rate of EGFR mutations in the acinar predominant reference group (n=76), was 37%. The solid predominant subtype showed significantly fewer EGFR mutations [3/33 (9%), odds ratio 0.17 (0.05-0.61), p=0.007]. No differences in mutation rate were observed in other subtypes. No association was found between KRAS mutations and predominant histological subtype. Advanced stage and solid predominant subtype were negative prognostic factors. EGFR mutations can be present in adenocarcinoma of any predominant subtype, however rarely in solid predominant tumours. No association was found between KRAS mutation and the predominant histological subtype.

Background: Prehabilitation to maximize exercise capacity before lung cancer surgery has the potential to improve operative tolerability and patient outcomes. However, translation of this evidence into clinical practice is limited. Aims: To determine the acceptability and perceived benefit of prehabilitation in lung cancer among thoracic surgeons. Procedure: 198 cardiothoracic surgeons within Australia and New Zealand were surveyed to evaluate their attitudes and perceived benefits of prehabilitation in lung cancer. Results: Response rate was 14%. A moderate proportion of respondents reported that there is a need to refer lung resection patients to preoperative physiotherapy/prehabilitation, particularly high-risk patients or those with borderline fitness for surgery. 91% of surgeons were willing to delay surgery (as indicated by cancer stage/type) to optimize patients via prehabilitation. The main barriers to prehabilitation reported were patient comorbidities and access to allied health professionals, with 33% stating that they were unsure who to refer to for prehabilitation in thoracic surgery. This is despite 60% of the cohort reporting that pulmonary rehabilitation is available as a preoperative resource. 92% of respondents believe that further research into prehabilitation in lung cancer is warranted. Conclusion: The benefits of prehabilitation for the oncology population have been well documented in the literature over recent years and this is reflected in the perceptions surgeons had on the benefits of prehabilitation for their patients. This survey demonstrates an interest among cardiothoracic surgeons in favor of prehabilitation, and therefore further research and demonstration of its benefit is needed in lung cancer to facilitate implementation into practice.

Summary Background Increased detection of small-sized, peripheral, non-small-cell lung cancer has renewed interest in sublobar resection instead of lobectomy, the traditional standard of care for early-stage lung cancer. We aimed to assess morbidity and mortality associated with lobar and sublobar resection for early-stage lung cancer. Methods CALGB/Alliance 140503 is a multicentre, international, non-inferiority, phase 3 trial in patients with peripheral non-small-cell lung cancer clinically staged as T1aN0. Patients were recruited from 69 academic and community-based institutions in Australia, Canada, and the USA. Patients were randomly assigned intraoperatively to either lobar or sublobar resection. The random assignment was based on permuted block randomisation without concealment and was stratified according to radiographic tumour size, histology, and smoking status. The primary endpoint of the trial is disease-free survival; here, we report a post-hoc, exploratory, comparative analysis of perioperative mortality and morbidity associated with lobar and sublobar resection. Perioperative mortality was defined as death from any cause within 30 days and 90 days of surgical intervention and was calculated for all randomised patients. Morbidity was graded using Common Terminology Criteria for Adverse Events version 4.0. All analyses were done on an intention-to-treat basis for randomised patients with data available. This trial is registered with ClinicalTrials.gov, number NCT00499330. Findings Between June 15, 2007, and March 13, 2017, 697 patients were randomly allocated to either lobar resection (n=357) or sublobar resection (n=340; 59% wedge resection). Six (0·9%) patients died by 30 days, four (1·1%) after lobar resection and two (0·6%) after sublobar resection; by 90 days, ten (1·4%) patients had died, six (1·7%) after lobar resection and four (1·2%) after sublobar resection (difference at 30 days, 0·5%, 95% CI −1·1 to 2·3; difference at 90 days, 0·5%, 95% CI −1·5 to 2·6). An adverse event of any grade occurred in 193 (54%) of 355 patients after lobar resection and 172 (51%) of 337 patients after sublobar resection. Adverse events of grade 3 or worse occurred in 54 (15%) patients assigned lobar resection and in 48 (14%) patients assigned sublobar resection. No differences between surgical approaches were noted in cardiac or pulmonary complications. Grade 3 haemorrhage (requiring transfusion) occurred in six (2%) patients assigned lobar resection and eight (2%) patients assigned sublobar resection. Prolonged air leak occurred in nine (3%) patients after lobar resection and two (1%) patients after sublobar resection. Interpretation Our post-hoc analysis showed that perioperative mortality and morbidity did not seem to differ between lobar and sublobar resection in physically and functionally fit patients with clinical T1aN0 non-small-cell lung cancer. These data may affect the daily choices made by patients and their doctors in establishing the best treatment approach for stage I lung cancer. Funding National Cancer Institute.

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors., The molecular nature of large-cell neuroendocrine lung carcinomas (LCNEC) has remained unclear. Here, the authors show LCNECs represent a distinct transcriptional subgroup among lung cancers and comprise two molecular subgroups, type I (TP53 and STK11/KEAP1 alterations) and type II (TP53 and RB1 inactivation).

Non-small cell lung cancer (NSCLC) is the fourth most commonly diagnosed cancer in males and the fourth most commonly diagnosed cancer in females in Australia. It is the leading cause of cancer-related mortality, being responsible for more deaths than breast, colorectal and prostate cancer combined. Pulmonary resection provides the best chance of a cure for patients with early stage lung cancer. However, pulmonary resection is associated with significant impairment in functional capacity along with a moderate risk of postoperative morbidity, particularly in frail or deconditioned patients. Prehabilitation is defined as “a process on the continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment that, in the perioperative setting, aims to enhance functional capacity of the individuals to enable them to withstand the stress associated with a procedure”. Prehabilitation can include a care bundle incorporating smoking cessation, diet optimization, psychosocial support and exercise, and aims to identify impairments and deliver targeted interventions that improve patient outcomes. It provides an opportunity to decrease treatment-related morbidity, increase available treatment options for patients who would not otherwise be surgical candidates and facilitate return of patients to the highest possible functional level. There is a growing body of evidence that supports prehabilitation as a means of preparing patients with newly diagnosed cancer for surgery by optimizing their health preoperatively. Enhancing a patient’s preoperative condition may help them withstand the stressors of surgery. Evidence supports the implementation of prehabilitation in the preoperative care pathway of other cancer cohorts, for example colorectal, breast and prostate cancers. Unfortunately, the evidence for the effects of prehabilitation in lung cancer has lagged behind and the use of prehabilitation (specifically the exercise component) for patients with lung cancer is now an emerging area. To date, exercise prior to lung cancer surgery has been shown to be safe and associated with improvements in functional capacity as well as postoperative morbidity (hospital length of stay) and rates of postoperative pulmonary complications), however the feasibility and acceptability of prehabilitation for patients with lung cancer is still unclear. The two studies within this thesis focus on the exercise component of prehabilitation in the context of surgical management of lung cancer in Australia.

Introduction: SASH1 (SAM and SH3 domain-containing protein 1) is a putative tumor suppressor functioning in the control of apoptosis and cellular proliferation. Previously SASH1 has been shown to be down-regulated in approximately 90% of lung cancers, however little is known about the role of SASH1 in the pathogenesis of the disease. Our previously published data has shown that Chloropyramine a known competitive reversible H1-receptor antagonist, increases SASH1 protein level in breast cancer cells.

The aim of this study was to investigate the prevalence of fibroblast growth factor receptor 1 (FGFR1) amplification by fluorescence in situ hybridization (FISH) in a lung cancer patient cohort and to correlate results with morphology, silver in situ hybridization (SISH), and patient outcome. FGFR1 FISH and SISH were performed in 406 and 385 lung cancer cases, respectively, and the results were compared. High-level FGFR1 amplification was defined as the ratio of FGFR1/centromere 8 ≥2, or tumor cell percentage with ≥15 signals ≥10%, or average number of signals/tumor cell nucleus ≥6. Low-level amplification was defined as tumor cell percentage with ≥5 signals ≥50%. Of 406 tumors tested, there were 191 squamous cell carcinomas, 28 carcinomas with focal squamous morphology, 24 large cell carcinomas with squamous immunoprofile, 115 adenocarcinomas, 17 neuroendocrine tumors, and 31 carcinomas without squamous morphology or immunoprofile. FGFR1 FISH was assessable in 368 tumors, with FGFR1 amplification identified in 50, including 48 tumors with either squamous morphology or immunoprofile (48 of 225, 21.3%), and two 'marker-null' tumors without squamous or glandular morphology or immunoprofile (2 of 143, 1.4%; P

Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) against EGFR mutant lung adenocarcinoma develops after a median of nine to thirteen months. Upregulation of the interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway may be a potential source of resistance to EGFR TKIs. We undertook a detailed assessment of the IL-6/JAK1/phosphorylated STAT3 (pSTAT3) pathway in resected lung adenocarcinoma specimens, with special interest in whether the presence of an EGFR mutation enriched for pSTAT3 positivity. Tumours from 143 patients with resected lung adenocarcinoma were assessed. EGFR and KRAS mutation status were scanned for with high-resolution melting and confirmed by polymerase chain reaction. Immunohistochemisty (IHC) was performed for IL-6, gp130, JAK1 and pSTAT3. Two methods for assigning IHC positivity were assessed (the presence of any positivity, and the presence of positivity at an H score >40). We found statistically significant associations between IL-6, JAK1 and pSTAT3 measured by IHC, consistent with the activation of the pathway in clinical specimens. No relationship was demonstrated between members of this pathway and oncogenic mutations in EGFR or KRAS. However, a proportion of tumours with EGFR mutations showed staining for IL-6, JAK1 and pSTAT3. No correlations with clinicopathologic features or survival outcomes were found for IL-6, JAK1 or pSTAT3 staining. The presence of EGFR or KRAS mutations did not enrich for the activation of IL-6, JAK1 or pSTAT3. pSTAT3 may still play a role in resistance to EGFR TKIs in clinical practice.

Introduction/Background An individual patient data metaanalysis was performed to determine clinical outcomes, and to propose a risk stratification system, related to the comprehensive treatment of patients with oligometastatic NSCLC. Materials and Methods After a systematic review of the literature, data were obtained on 757 NSCLC patients with 1 to 5 synchronous or metachronous metastases treated with surgical metastectomy, stereotactic radiotherapy/radiosurgery, or radical external-beam radiotherapy, and curative treatment of the primary lung cancer, from hospitals worldwide. Factors predictive of overall survival (OS) and progression-free survival were evaluated using Cox regression. Risk groups were defined using recursive partitioning analysis (RPA). Analyses were conducted on training and validating sets (two-thirds and one-third of patients, respectively). Results Median OS was 26 months, 1-year OS 70.2%, and 5-year OS 29.4%. Surgery was the most commonly used treatment for the primary tumor (635 patients [83.9%]) and metastases (339 patients [62.3%]). Factors predictive of OS were: synchronous versus metachronous metastases ( P P = .002), and adenocarcinoma histology ( P = .036); the model remained predictive in the validation set (c-statistic = 0.682). In RPA, 3 risk groups were identified: low-risk, metachronous metastases (5-year OS, 47.8%); intermediate risk, synchronous metastases and N0 disease (5-year OS, 36.2%); and high risk, synchronous metastases and N1/N2 disease (5-year OS, 13.8%). Conclusion Significant OS differences were observed in oligometastatic patients stratified according to type of metastatic presentation, and N status. Long-term survival is common in selected patients with metachronous oligometastases. We propose this risk classification scheme be used in guiding selection of patients for clinical trials of ablative treatment.

Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.

// Gavin M. Wright 1 , Hongdo Do 2 , Jonathan Weiss 2 , Naveed Z. Alam 1 , Vivek Rathi 3 , Marzena Walkiewicz 4 , Thomas John 4 , Prudence A. Russell 3 , Alexander Dobrovic 2 1 University of Melbourne Department of Surgery, St Vincent’s Hospital Melbourne, Victoria, Australia. 2 Translational Genomics and Epigenomics Laboratory Ludwig Institute for Cancer Research Olivia Newton-John Cancer and Wellness Centre Heidelberg, Victoria, Australia. 3 Department of Anatomical Pathology St Vincent’s Hospital Melbourne, Victoria, Australia. 4 Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre Heidelberg, Victoria, Australia. 5 Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia. Correspondence: Gavin M. Wright, email: // Keywords : BRAF, EGFR, KRAS, high resolution melting, polymerase chain reaction, tumor heterogeneity. Received : Febuary 25, 2014 Accepted : March 20, 2014 Published : March 22, 2014 Abstract Precision medicine depends on the accurate identification of actionable mutations in a tumor sample. It is unknown how heterogeneous the distribution of such mutations can be in a tumor. Morphological (i.e. histopathological) heterogeneity is well described in lung adenocarcinoma and has been specifically recognized in the most recent official clinico-pathological classification. The most predominant subtype present is now used to classify each lung adenocarcinoma. No molecular profile exists to explain the intratumoral differences in lung adenocarcinoma morphology, despite the consistently observed association between specific predominant subtypes and poorer survival. Given a recent proposal stratifying lung adenocarcinoma into subtypes of differing metastatic potential, we questioned the assumption that major mutations are present uniformly throughout tumors; especially those showing discrete different subtypes. We selected formalin-fixed paraffin embedded lung adenocarcinoma specimens that showed discrete areas of different subtypes, extracted subtype DNA samples from those areas and screened for mutations in hotspot regions of the EGFR , KRAS and BRAF genes using high resolution melting. Sanger sequencing was used to confirm all identified mutations. Chromogenic in situ hybridization (CISH) was used to identify mutant allele specific imbalances in tumors with EGFR mutations. Interestingly, we found that KRAS and BRAF mutations could be confined to morphological domains of higher grade. On the other hand, EGFR mutations were found through all histological subtypes in each tumor consistent with the driver status of this mutation. Intratumoral heterogeneity has major implications for tumorigenesis, chemoresistance and the role of histopathology in molecular screening for precision medicine. This study not only confirms that intratumoral mutational heterogeneity does occur, but also that it is associated with morphologically distinct regions in some tumors. From a practical perspective, small biopsies may not adequately represent a tumor’s full mutational profile, particularly for later arising but prognostically important mutations such as those in the KRAS and BRAF genes.

We investigated if gene copy number (GCN) alterations of the epidermal growth factor receptor (EGFR), as detected by silver enhanced in situ hybridisation (SISH), could be used to select patients for EGFR mutation testing. Resected lung adenocarcinoma specimens with adequate tumour were identified. EGFR SISH was performed using the Ventana Benchmark Ultra platform. EGFR GCN was classified according to the Colorado Classification System. EGFR mutations were scanned by high resolution melting and confirmed by Sanger sequencing. Thirty-four of 96 tumours were EGFR SISH positive (35%), and 31 of 96 tumours harboured one or more EGFR mutations (32%). Of 31 EGFR-mutant tumours, 18 were EGFR SISH positive (58%). There was a statistically significant relationship between the presence of an EGFR mutation and EGFR GCN (p = 0.003). Thirteen of 31 EGFR-mutant tumours were EGFR SISH negative (42%), and 16 of 65 EGFR-wild type tumours were EGFR SISH positive (24%). The sensitivity, specificity, positive predictive value and negative predictive value were 58%, 75%, 52.9% and 79%, respectively. Despite a significant relationship between EGFR GCN alterations and EGFR mutations, our results indicate that EGFR GCN as detected by SISH is not a suitable way to select patients for EGFR mutation testing.

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

e20097 Background: Recent success with the use of checkpoint inhibition in SCLC has increased the importance of understanding the immunological tumour microenvironment. In many tumours gene expression profiling (GEP) of T-cell inflammation and IFN-gamma is correlated with response to checkpoint inhibitors. We present GEP results in a SCLC cohort and correlation of gene expression with IHC analysis of common checkpoints. Methods: SCLC tissue microarrays from 105 histologically confirmed SCLC specimens were scored for IHC staining of immune checkpoints on tumour and tumour infiltrating lymphocytes (TILs). A subgroup of 30 patients had sufficient tissue for GEP. Nanostring nCounter Pan-cancer immune panel, using the previously described RUVIII normalisation method, was used to examine GEP. A 28-gene IFN-G related signature was examined. Results: Median age 67y (range 53 – 86); male: 16/30 (53%); stage: limited 22/30 (73%), 5/30 (17%) extensive, 3/30 (10%) stage unknown. Significant heterogeneity was observed in gene expression. Pearson correlation co-efficients between IHC analysis and corresponding mRNA of PD-L1, PD-L2, LAG3 and TIM3, on both tumour and TILs, were not statistically significant. Significant positive correlation was found for mRNA levels of HAVCR2 (TIM3) with LAG3 and with PDCD1LG2 (PD-L2). As in the larger cohort, TIL co-expression of PD-L1, PD-L2, TIM3 and LAG3 were all associated with improved survival; med OS 89.3 v 15.7 mo; p < 0.01. The cohort clustered into 4 groups with respect to the IFN-G GEP. The group with the highest level of gene expression (5/30 pts, 16.7%) had numerically improved OS; 89.3 v 21.3 mo, p = 0.23. Conclusions: In this limited cohort, gene expression did not consistently correlate with IHC. Co-ordinated expression of T-cell inflamed/IFN-G immune checkpoints occurred in 16.7% SCLC and was associated with improved survival.

Aim A survey of management of lung cancer diagnosed in Victoria in 2003 was commissioned by the Victorian Cooperative Oncology Group to identify gaps in the management of this disease. Results from a similar survey in 1993 were available to identify differences in the disease, management and outcomes. This paper details results of the surgically managed subset within the larger study. Methods All patients diagnosed with lung cancer in the first 6 months of 2003 were identified from the Victorian Cancer Registry. Registry research staff completed a detailed questionnaire using primary source documents from hospitals and consulting rooms. The survey data were then de-identified with respect to patient and treating clinician prior to statistical analysis by the investigators. Results From eligible cases identified, non-small cell lung cancer was confirmed in 655 cases with a minimum of 6 years of follow-up. Thoracotomy was performed in 145 cases (22%), but only 130 received the intended resection. Compared with 1993, significant differences were increased use of preoperative positron emission tomography (PET) scanning (79% vs 0%), relatively fewer resections (20% vs 25%), lower pneumonectomy rate (14% vs 25%) and higher sub-lobar resection rate (22% vs 11%). The 30-day mortality remained below 2%. Positive resection margin (21%) and abandoned resection rates (10%) were much higher than expected. Overall 5-year survival was 42%, unchanged from 1993. Conclusion Irrespective of widespread introduction of PET scanning, thoracotomy without resection was common. While operative mortality and overall survival were well within benchmark standards, futile thoracotomy and positive resection margin rates were unacceptably high.

Introduction A Simplified Comorbidity Score (SCS) provided additional prognostic information to the established factors in patients with non-small cell lung cancer lung cancer. We undertook this analysis to test the prognostic value of the SCS in a population-based study. Patients and methods Retrospective survey of all Victorians diagnosed with lung cancer in January–June 2003, identified from the Victorian Cancer Registry. Results There were 921 patients, with data available for 841 (91.3%). Median age was 72 years (range 30–94) and 63.1% were male. A tissue diagnosis was made for 89.9%, of which 86.6% were non-small cell (NSCLC), and 13.4% small cell carcinoma (SCLC). Comorbidities on which the SCS is based were distributed: cardiovascular 54.6%; respiratory 38.9%; neoplastic 19.9%; renal 4.6%; diabetes 11.7%; alcoholism 5.5%; and tobacco 83.1%. In patients with NSCLC, higher SCS score (>9) was associated with increasing stage, ECOG performance status, male sex, increasing age, tobacco consumption and not receiving treatment. Using Cox regression, survival was analysed by SCS score after adjusting for the effect of age, sex, cell type (NSCLC, SCLC, no histology), ECOG performance status and stage for all patients and then restricted to NSCLC. As a continuous or dichotomous (≤ or >9) variable, SCS was not a significant prognostic factor for all patients or when restricted to NSCLC. Conclusion In this retrospective analysis of population based registry patients, SCS did not provide additional prognostic information in patients with lung cancer. ECOG performance status may be a substitute for the effect of comorbidity.