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Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4–12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 μg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25·6 months (95% CI 22·5–29·2) with tecemotide versus 22·3 months (19·6–25·5) with placebo (adjusted HR 0·88, 0·75–1·03; p=0·123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30·8 months (95% CI 25·6–36·8) compared with 20·6 months (17·4–23·9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0·78, 0·64–0·95; p=0·016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19·4 months [95% CI 17·6–23·1] vs 24·6 months [18·8–33·0], respectively; adjusted HR 1·12, 0·87–1·44; p=0·38). Grade 3–4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. Merck KGaA (Darmstadt, Germany).

Purpose Few large-scale studies have investigated sex differences in cancer survival and little is known about their temporal and age-related patterns. Methods We used cancer registry data for first primary cancers diagnosed between 1982 and 2015 in Victoria, Australia. Cases were followed until the end of 2015 through linkage to death registries. Differences in survival were assessed for 25 cancers using the Pohar-Perme estimator of net survival and the excess mortality rate ratio (EMRR) adjusting for age and year of diagnosis. Results Five-year net survival for all cancers combined was lower for men (47.1%; 95% CI 46.9–47.4) than women (52.0%; 95% CI 51.7–52.3); EMRR 1.13 (95% CI 1.12–1.14; p  < 0.001). A survival disadvantage for men was observed for 11 cancers: head and neck, esophagus, colorectum, pancreas, lung, bone, melanoma, mesothelioma, kidney, thyroid, and non-Hodgkin lymphoma. In contrast, women had lower survival from cancers of the bladder, renal pelvis, and ureter. For the majority of cancers with survival differences, the EMRR decreased with increasing age at diagnosis; for colorectal, esophageal, and kidney cancer, the EMRR increased with time since diagnosis. Conclusion Identifying the underlying reasons behind sex differences in cancer survival is necessary to address inequalities, which may improve outcomes for men and women.

False-positive T790M mutations have been reported in formalin-fixed lung tumors, but the cause of the false positives has not been identified. The T790M mutation results from a C>T change at the cytosine of a CpG dinucleotide. The presence or absence of methylation at this cytosine has different consequences following deamination, resulting in a thymine or uracil, respectively, both of which however result in an artifactual change. Uracil-DNA glycosylase (UDG) can be used to eliminate DNA templates with uracil residues but is not active against artifactual thymines. We therefore investigated the use of thymine-DNA glycosylase (TDG) to reduce artifactual T790M mutations. Formalin-fixed normal lung tissues and lung squamous cell carcinomas were tested to measure the frequency of false-positive mutations by use of droplet digital PCR before and after treatment with either UDG or TDG. Methylation at the cytosine at T790 was assessed by pyrosequencing and by analysis of public databases. Artifactual T790M mutations were detected in all of the archival formalin-fixed normal lung and lung squamous cell carcinomas at mutant allele frequencies of 1% or lower. The cytosine at T790 showed high levels of methylation in all lung cancer samples and normal tissues. Pretreatment of the formalin-fixed DNA with either UDG or TDG reduced the false T790M mutations, but a greater reduction was seen with the TDG treatment. Both U:G and T:G lesions in formalin-fixed tissue are sources of false-positive T790M mutations. This is the first report of the use of TDG to reduce sequence artifacts in formalin-fixed DNA and is applicable to the accurate detection of mutations arising at methylated cytosines.

Cancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival. We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post-operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs. NY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28-5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07-0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression. NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.

Purpose We evaluated whether 18 F-FDG-PET altered stage classification, management, and prognostic stratification of newly diagnosed small cell lung cancer (SCLC). Procedures We identified 46 consecutive patients undergoing staging positron emission tomography for SCLC from 1993–2008 inclusive. Updated survival data from the state Cancer Registry was available on 42 of 46 patients. Results PET altered stage classification in 12 of 46 (26%) patients. PET altered treatment modality in nine patients, and the target mediastinal radiation field in another three patients. Therefore, PET altered management in 12 of 46 (26%) patients. Patients with limited disease (LD) on pre-PET staging had significantly longer overall survival (OS) than those upstaged to extensive disease (ED; median 18.6 months versus 5.7 months; log-rank p  < 0.0001). In patients with ED on pre-PET staging, those downstaged to LD by PET had significantly longer OS than those with ED on PET (median 10.9 months versus 5.9 months; log-rank p  = 0.037). Conclusion PET had a major impact on stage classification, management, and prognostic stratification of newly diagnosed SCLC.

DNA repair genes that have been inactivated by promoter methylation offer potential therapeutic targets either by targeting the specific repair deficiency, or by synthetic lethal approaches. This study evaluated promoter methylation status for eight selected DNA repair genes ( ATM , BRCA1 , ERCC1 , MGMT , MLH1 , NEIL1 , RAD23B and XPC ) in 56 non-small cell lung cancer (NSCLC) tumours and 11 lung cell lines using the methylation-sensitive high resolution melting (MS-HRM) methodology. Frequent methylation in NEIL1 (42%) and infrequent methylation in ERCC1 (2%) and RAD23B (2%) are reported for the first time in NSCLC. MGMT methylation was detected in 13% of the NSCLCs. Contrary to previous studies, methylation was not detected in ATM , BRCA1, MLH1 and XPC . Data from The Cancer Genome Atlas (TCGA) was consistent with these findings. The study emphasises the importance of using appropriate methodology for accurate assessment of promoter methylation.

In the original publication of the article, the concluding paragraph of the Discussion section was inadvertently missed and is provided below.In the original publication of the article, the concluding paragraph of the Discussion section was inadvertently missed and is provided below.

Background Mucin 1 antigen, highly expressed by epithelial ovarian cancer (EOC), is a potential target for immunotherapy. A previous successful phase 1 trial was conducted in patients with adenocarcinoma who were injected with Cvac, autologous monocyte-derived dendritic cells (DCs) incubated with mannosylated mucin 1 protein (M-FP). The present study was a phase 2 trial of Cvac in patients with advanced EOC. Methods Eligible patients had EOC with progressive disease, defined as an increase in CA125 of ≥ 25% in 1 month. The primary endpoint was CA125 response or stabilization. Peripheral blood mononuclear cells were collected by leukapheresis and cultured to generate DCs. The DC were incubated with M-FP, and after washing were prepared for injection into the patient intradermally every 4 weeks for 3 doses, then every 10 weeks for up to 12 months. Results All 28 patients recruited were evaluable for safety and 26 for efficacy. All had undergone surgery and platinum-based chemotherapy, and 57% of patients received ≥ 3 chemotherapy regimens. There were no Grade 3 or 4 toxicities considered related to Cvac. Four patients showed CA125 response or stabilization (2 patients with major responses, 1 minor response, 1 stabilization) of median duration 10.3 months (5.3–16.3 months). An additional patient had > 25% CA125 reduction (not confirmed). Conclusions Cvac immunotherapy was well tolerated. Clinical activity in EOC was evident based on decline or stabilization of CA125 in some patients, supporting ongoing development of Cvac in ovarian carcinoma and planning of additional trials of patients in remission is currently underway.