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Importance: Mismatch repair (MMR) deficiency (MMRD) and microsatellite instability (MSI) are prognostic for survival in many cancers and for resistance to fluoropyrimidines in early colon cancer. However, the effect of MMRD and MSI in curatively resected gastric cancer treated with perioperative chemotherapy is unknown.Objective: To examine the association among MMRD, MSI, and survival in patients with resectable gastroesophageal cancer randomized to surgery alone or perioperative epirubicin, cisplatin, and fluorouracil chemotherapy in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial.Design, Setting, and Participants: This secondary post hoc analysis of the MAGIC trial included participants who were treated with surgery alone or perioperative chemotherapy plus surgery for operable gastroesophageal cancer from July 1, 1994, through April 30, 2002. Tumor sections were assessed for expression of the MMR proteins mutL homologue 1, mutS homologue 2, mutS homologue 6, and PMS1 homologue 2. The association among MSI, MMRD, and survival was assessed.Main Outcomes and Measures: Interaction between MMRD and MSI status and overall survival (OS).Results: Of the 503 study participants, MSI results were available for 303 patients (283 with microsatellite stability or low MSI [median age, 62 years; 219 males (77.4%)] and 20 with high MSI [median age, 66 years; 14 males (70.0%)]). A total of 254 patients had MSI and MMR results available. Patients treated with surgery alone who had high MSI or MMRD had a median OS that was not reached (95% CI, 11.5 months to not reached) compared with a median OS among those who had neither high MSI nor MMRD of 20.5 months (95% CI, 16.7-27.8 months; hazard ratio, 0.42; 95% CI, 0.15-1.15; P = .09). In contrast, patients treated with chemotherapy plus surgery who had either high MSI or MMRD had a median OS of 9.6 months (95% CI, 0.1-22.5 months) compared with a median OS among those who were neither high MSI nor MMRD of 19.5 months (95% CI, 15.4-35.2 months; hazard ratio, 2.18; 95% CI, 1.08-4.42; P = .03).Conclusions and Relevance: In the MAGIC trial, MMRD and high MSI were associated with a positive prognostic effect in patients treated with surgery alone and a differentially negative prognostic effect in patients treated with chemotherapy. If independently validated, MSI or MMRD determined by preoperative biopsies could be used to select patients for perioperative chemotherapy.

Background STAMPEDE previously reported that adding upfront docetaxel (Doc) improved overall survival (OS) for locally advanced and metastatic patients (pts) starting long-term androgen deprivation therapy (ADT). We report the long-term outcomes for M0 pts using metastatic progression-free survival (mPFS) as primary outcome, previously shown to be a surrogate for OS in M0 pts. Methods Standard-of-care (SOC) was ADT +/- radical radiotherapy (RT) to the prostate. 460 SOC and 230 SOC+Doc pts were recruited with 2:1 randomised stratified allocation. Standard survival intention-to-treatment analysis methods used Cox regression models adjusted for all stratification factors, with emphasis on restricted mean survival time (RMST) for non-proportional (non-PH) hazards. There was 70% power (2-sided α = 0.05) to detect HR = 0.70 for mPFS (= new metastases, skeletal related events or PCa death). Secondary outcome measures included failure free survival (FFS) and progression free survival (PFS = mPFS or locoregional progression). Results Median follow-up was ∼6.5yr compared to ∼3.5yr when last reported, with 142 mPFS events (a 54% increase) on SOC. There was no good evidence of an advantage of SOC+Doc over SOC on mPFS (HR = 0.89, 95% CI 0.66-1.19, P = 0.425); with 5yr mPFS 82% in SOC+Doc vs. 77% SOC. Secondary outcomes showed evidence that SOC+Doc improved FFS (HR = 0.70, 95% CI 0.55-0.88, P = 0.002) and PFS (non-PH P = 0.033, RMST difference=5.8 months, 95% CI 0.5-11.2, P = 0.031). There was no good evidence of a benefit of SOC+Doc on OS (125 SOC deaths; HR = 0.88, 95% CI 0.64-1.21, P = 0.442). There was no evidence that SOC+Doc increased late toxicity compared to SOC: after 1yr, G3-5 toxicity reported for 29% SOC and 30% SOC+Doc. The impact of SOC RT (nominated prior to randomisation) with and without SOC+Doc will also be detailed by subgroup. Conclusions There is robust evidence SOC+Doc improves FFS and PFS (which we have previously shown increases Quality Adjusted Life Years). There is however no good evidence that this translates into benefit for longer-term outcomes (OS or mPFS). The benefits of upfront SOC+Doc for improved FFS and PFS with no excess late toxicity may contribute to treatment discussions. Clinical trial identification NCT00268476. Legal entity responsible for the study University College London. Funding Cancer Research UK; Sanofi; MRC; Astellas; Clovis; Janssen; Novartis; Pfizer. Disclosure N.D. James: Advisory / Consultancy: Sanofi; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Janssen. N.W. Clarke: Advisory / Consultancy: Janssen. G. Attard: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Medivation; Advisory / Consultancy: Novartis; Advisory / Consultancy: Millennium Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Abbott Laboratories; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Essa Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bayer Healthcare Pharmaceuticals; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Sanofi-Aventis; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Arno Therapeutics; Research grant / Funding (self): Innocrin Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Janssen; Advisory / Consultancy: Veridex; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche/Ventana; Advisory / Consultancy, Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), I was an employee of the ICR, where abiraterone acetate was developed, up to 8 January 2018. : The Institute of Cancer Research (ICR). W. Cross: Speaker Bureau / Expert testimony: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer. D. Dearnaley: Research grant / Funding (institution), Financial Support for Trial Recruitment: UK National Institute for Health Research Clinical Research Network (NIHR CRN); Research grant / Funding (institution): The Institute of Cancer Research (ICR); Research grant / Funding (self), C46/A3976, C46/A10588 and C33589/A19727. : Cancer Research UK; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Sandoz; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen. R. Jones: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis. M.D. Mason: Honoraria (self), Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Bayer. C. Parker: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Honoraria (self): AAA; Speaker Bureau / Expert testimony: Janssen. M.K.B. Parmar: Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Astellas; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Clovis Oncology; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Novartis; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Pfizer; Research grant / Funding (self), Unrestricted grant to contribute to STAMPEDE overall: Sanofi. M.R. Sydes: Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Astellas; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Clovis Oncology; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Novartis; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Janssen; Research grant / Funding (self), Non-remunerated activity/ies, Unrestricted grant to contribute to STAMPEDE overall: Sanofi. All other authors have declared no conflicts of interest.

4022 Background: No large scale randomised data exists evaluating the impact of age and sex in patients (pts) undergoing potentially curative surgery and CTx for OG cancer. However, differences in age and sex may be contributing factors to variability in CTx dose-response and toxicity which could also impact survival. Methods: Data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival data, hazard ratios were calculated for pts

TPS3624 Background: There is now a body of evidence indicating a potential role for aspirin in colorectal cancer (CRC) prevention. In cardiovascular trials, effects on incidence of cancer metastases and short-term mortality suggest further possible roles in the treatment setting, supported by observational studies of aspirin use after cancer diagnosis. In the prevention setting, aspirin use has been limited by toxicity concerns, particularly of serious bleeding. In the adjuvant setting, benefits associated with reducing recurrence and subsequent treatment may outweigh these risks. The Add-Aspirin trial will investigate this, and will also consider possible mechanisms of action for aspirin effects, including the impact of PIK3CA mutations, where there are currently several theories and conflicting data. Methods: Add-Aspirin (ISRCTN74358648) is an international, phase III, double-blind, randomised, placebo-controlled trial recruiting patients who have undergone surgery and relevant adjuvant treatment for stage II or III CRC, as well as those with completely resected CRC liver metastases. Parallel randomised cohorts will address the question in breast, gastro-oesophageal and prostate cancer. Participants take aspirin 100mg daily for an 8-week run-in, to assess adherence and toxicity, and those suitable to proceed are randomised (1:1:1) to aspirin 100mg, aspirin 300mg or placebo daily for at least 5 years. A number of measures – including blood pressure control and PPI use where relevant - are in place to reduce bleeding risk. The primary outcome is disease-free survival (target hazard ratio = 0.8, n = 2600 in 5 years) with a long term analysis of survival planned across the tumour groups. Translational work includes a sub-study monitoring urinary thromboxane B2 as a marker of platelet activation in a subgroup (n = 500) to investigate mechanisms of action. Add-Aspirin opened in 2015 and recruited 1505 CRC patients during the first 3 years from 137 UK centres. 1282 (85%) proceeded to randomisation. A pre-planned feasibility analysis of run-in data (n = 2253 across all 4 tumour groups) provided reassuring data on safety, tolerability and adherence, and recruitment continues with centres in India and Republic of Ireland recently joining. Clinical trial information: 74358648.

5019 Background: The STAMPEDE trial recruits men with high risk prostate cancer commencing first line systemic therapy. In a pilot study to ascertain the feasibility of tNGS and the prevalence of common genomic aberrations, we tested a commercial clinically-accredited assay on tumor blocks and present data obtained in the largest cohort of treatment-naïve M1 CSPC to date. Methods: Archival FFPE blocks were retrieved from trial participants and a single block submitted for sequencing by a Foundation Medicine. Inc. tNGS assay that includes 395 genes. Results: We successfully obtained tNGS data on 115 (62%) of 186 patients enrolled between Nov-2011 and April-2017 at 15 UK participating centers. The median age was 70 years (IQR 44-85); 97% had de novo M1 disease and 83% Gleason score ≥8. We observed PTEN deficiency (34%) due to copy-number loss (25%) or mutation (9%); TP53 mutation or loss (33%) and aberrations in PI3K signaling (16%), genes involved in DNA repair (14%), Wnt signaling (14%) and cell cycle control (6%). In total, these aberrations were observed in 76% of patients, with 35% harboring two or more. No androgen receptor ( AR) mutations were detected. Conclusions: The prevalence of PTEN deficiency is comparable with that observed in mCRPC consistent with this being a feature of metastatic disease. In contrast, AR mutations are not observed in this treatment-naïve group. The prevalence of DNA repair deficiency is less than observed in mCRPC but more than reported in prostatectomy cohorts. Although it is possible to use FFPE biopsies for tNGS, the test failure-rate poises challenges to evaluating treatments in low prevalence biomarker-defined groups. These data will inform the design and conduct of biomarker-directed trials.

43 Background: Platinum and 5-Fluorouracil (5FU) neoadjuvant chemotherapy followed by surgery is one of the standard approaches for patients with resectable EAC. To date, there are no predictive biomarkers of chemotherapy benefit. We hypothesize that DNA methylation of genes in key biologic and oncogenic pathways predict for chemotherapy benefit in EAC. Methods: In the OE02 trial, 802 patients with resectable esophageal carcinoma were randomised to surgery alone (S) versus two cycles of cisplatin and 5FU chemotherapy followed by surgery (CS). DNA was extracted from 213 EAC resection specimens (110 from the (CS) arm, 103 from the (S) arm). DNA methylation was analyzed at 1505 CpG sites within 807 genes using the Illumina GoldenGate platform. Cox proportional hazard analysis was performed to identify predictive markers of survival in (CS) arm; non-negative matrix factorization (NMF) was used to delineate methylation signatures. Results: Methylation status of 1505 CpG sites had no statistical difference between the (CS) and (S) arms. In the (CS) arm, 87 (5.7%) CpG sites were initially identified as promising candidates in univariate analysis (p < 0.05 cutoff). NMF generated a 4 CpG site signature which divided patients into poor risk and good risk. Genes involved in the signature include RUNX1T1, CCND2, MST1R and MMP14. Survival was significantly different between poor risk and good risk in (CS) arm (HR 0.32, 95% CI: 0.21 to 0.52, p < 0.0001). No difference in survival was detected in the surgery arm (HR 1.12, 95% CI: 0.76 to 1.80, p = 0.48), suggesting the signature served as a predictive and not prognostic biomarker. Methylation signature remained an independent predictor of survival in multivariate analysis with clinicopathologic factors (along with age and vascular invasion). Conclusions: Chemotherapy does not appear to change methylation status of EAC. Hypermethylation of RUNX1T1, CCND2 and hypomethylation of MST1R and MMP14 leads to significantly decreased benefit from chemotherapy in EA. We describe an epigenetic signature which may serve as a predictive biomarker for chemotherapy benefit using data form the largest bank of DNA methylation in EA reported to date.

66 Background: In CLASSIC and MAGIC, MSI was a good prognostic factor, and adjuvant/perioperative chemotherapy had null/detrimental effect. Given the low prevalence of MSI in GCs and its association with other good prognostic variables, larger datasets are needed to draw more robust evidences on its specific prognostic/predictive impact. Methods: This was a multinational IPD meta-analysis of resectable GC pts enrolled in MAGIC, CLASSIC, ARTIST, ITACA-S. Data on pts’ demographics (age, sex, and race), primary site (stomach versus junctional), histotype (intestinal vs. other), T/N stage (7th TNM), treatment received (multimodal therapy vs. surgery alone) and MSI were pooled. Univariable and multivariable associations with disease-free survival (DFS)/overall survival (OS) were assessed. The predictive role of MSI according to treatment received was assessed overall and in the 2 RCTs with a surgery alone arm (MAGIC+CLASSIC). Results: We pooled 1,552 pts with available MSI status: 121 (7,8%) were MSI, 572 Caucasian/980 Asian. In MSI versus MSS subgroups, 5-y DFS was 71.8% (95% CI: 63.8-80.7%) versus 52.3% (49.6-55.0%) (HR = 0.50, 95% CI 0.35-0.72; p < 0.001); 5-y OS 77.4% (69.9-85.8%) versus 59.2% (56.6-62.0%) (HR = 0.50, 95% CI 0.34-0-74; p < 0.001). In multivariable analyses, MSI was independently associated with DFS (HR = 0.48 [0.33-0.70]; p < 0.001) and OS (HR = 0.48 [0.29-0.81]; p = 0.005), as T/N/race/treatment. Conclusions: In resectable primary GC, MSI is an independent good prognostic marker that should be adopted as stratification factor in future RCTs. Chemotherapy omission and/or immune checkpoint blockade should be prospectively investigated in MSI-high GCs according to the clinically-defined risk of relapse. [Table: see text]

BACKGROUND: Perioperative epirubicin, cisplatin and fluorouracil (ECF) chemotherapy improves survival in operable oesophago-gastric cancer [Adjuvant Gastric Cancer Infusional Chemotherapy (MAGIC) trial HR 0.75 (0.6-0.93)]. HER2 amplification is reported to predict enhanced benefit from anthracyclines in breast cancer. We sought to define whether HER2 predicts benefit from ECF in oesophago-gastric cancer. PATIENTS AND METHODS: Diagnostic biopsies and/or resection specimens were collected from 415 of 503 MAGIC trial patients (82.5%). HER2 was evaluated by immunohistochemistry (IHC) and brightfield dual in situ hybridisation (BDISH) in tissue microarrays. The prognostic and predictive impact of HER2 status was investigated. RESULTS: Concordance between HER2 over-expression (IHC3+) and amplification was 96%. Results of HER2 assessment in biopsy and resection specimens were concordant in 92.9% (145/156). HER2 positive rate (IHC3+, or IHC2+/BDISH positive) was 10.9% in the whole cohort and 10.4% in resection specimens. A further 4.0% of resections were IHC negative/BDISH positive. HER2 status was neither prognostic, nor (in pre-treatment biopsies) predicted enhanced benefit from chemotherapy [HER2 positive HR 0.74 (0.14-3.77); HER2 negative HR 0.58 (0.41-0.82), interaction P = 0.7]. However, the power of the predictive analysis was limited by the small number of HER2 positive pre-treatment biopsies. CONCLUSIONS: HER2 status is not an independent prognostic biomarker in early oesophago-gastric adenocarcinoma.

Summary Background Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. Methods In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 μg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784. Findings 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12–31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7–14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0–15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and −0·16 mmol/L (−2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and −0·23 mmol/L (−3·3%), respectively (p

Over 30% of patients with non-small cell lung cancer (NSCLC) develop brain metastases. If inoperable, optimal supportive care (OSC), including steroids, and whole brain radiotherapy (WBRT) are generally considered to be standard care, although there is no randomised evidence demonstrating that the addition of WBRT to OSC improves survival or quality of life.QUARTZ is a randomised, non-inferiority, phase III trial comparing OSC + WBRT versus OSC in patients with inoperable brain metastases from NSCLC. The primary outcome measure is quality-adjusted life years (QALYs). QUARTZ was threatened with both loss of funding and early closure due to poor accrual. A lack of preliminary randomised data supporting the trial's hypotheses was thought to underlie the poor accrual, so, with no knowledge of the data, the independent trial steering committee agreed to the unusual step of releasing interim data.Between March 2007 and April 2010, 151 (of the planned 534) patients were randomised (75 OSC + WBRT, 76 OSC). Participants' baseline demographics included median age 67 years (interquartile range 62-73), 60% male, 50% with a Karnofsky performance status70; steroid usage was similar in the two groups; 64/75 (85%) received WBRT (20 Gy in five fractions). Median survival was: OSC + WBRT 49 days (95% confidence interval 39-61), OSC 51 days (95% confidence interval 27-57) - hazard ratio 1.11 (95% confidence interval 0.80-1.53) in favour of WBRT. Quality of life assessed using EQ-5D showed no evidence of a difference. The estimated mean QALYs was: OSC + WBRT 31 days and OSC 30 days, difference -1 day (95% confidence interval -12.0 to +13.2 days).These interim data indicate no early evidence of detriment to quality of life, overall survival or QALYs for patients allocated to OSC alone. They provide key information for discussing the trial with patients and strengthen the argument for continuing QUARTZ to definitively answer this important clinical question.

Objectives\ud \ud To compare quality-of-life (QoL) outcomes at 6 months between men with advanced prostate cancer receiving either transdermal oestradiol (tE2) or luteinising hormone-releasing hormone agonists (LHRHa) for androgen-deprivation therapy (ADT).\ud \ud Patients and methods\ud \ud Men with locally advanced or metastatic prostate cancer participating in an ongoing randomised, multicentre UK trial comparing tE2 versus LHRHa for ADT were enrolled into a QoL sub-study. tE2 was delivered via three or four transcutaneous patches containing oestradiol 100 μg/24 h. LHRHa was administered as per local practice. Patients completed questionnaires based on the European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core (EORTC QLQ-C30) with prostate-specific module QLQ PR25. The primary outcome measure was global QoL score at 6 months, compared between randomised arms.\ud \ud Results\ud \ud In all, 727 men were enrolled between August 2007 and October 2015 (412 tE2, 315 LHRHa) with QoL questionnaires completed at both baseline and 6 months. Baseline clinical characteristics were similar between arms: median (interquartile range) age of 74 (68–79) years and PSA level of 44 (19–119) ng/mL, and 40% (294/727) had metastatic disease. At 6 months, patients on tE2 reported higher global QoL than those on LHRHa (mean difference +4.2, 95% confidence interval 1.2–7.1; P = 0.006), less fatigue, and improved physical function. Men in the tE2 arm were less likely to experience hot flushes (8% vs 46%), and report a lack of sexual interest (59% vs 74%) and sexual activity, but had higher rates of significant gynaecomastia (37% vs 5%). The higher incidence of hot flushes among LHRHa patients appear to account for both the reduced global QoL and increased fatigue in the LHRHa arm compared to the tE2 arm.\ud \ud Conclusion\ud \ud Patients receiving tE2 for ADT had better 6-month self-reported QoL outcomes compared to those on LHRHa, but increased likelihood of gynaecomastia. The ongoing trial will evaluate clinical efficacy and longer term QoL. These findings are also potentially relevant for short-term neoadjuvant ADT.

Patients with colorectal cancer with mutated PIK3CA, identified from two large observational cohorts, had increased cancer-specific and overall survival if they used aspirin regularly after diagnosis compared to non-users. No effect of aspirin was seen in patients with wild-type PIK3CA. Mutated PIK3CA might be a useful biomarker to select patients who would benefit from adjuvant aspirin therapy.

We read with interest the editorial by Tsao (1), and thank the author for this well considered response to our recent paper describing the results of the QUARTZ trial of whole brain radiotherapy for patients with inoperable brain metastases from non-small cell lung cancer (2). We continue to be encouraged by the amount of discussion taking place surrounding treatment options for these patients.

Aspirin inhibits the enzyme cyclooxygenase (Cox), and there is a significant body of epidemiological evidence demonstrating that regular aspirin use is associated with a decreased incidence of developing cancer. Interest focussed on selective Cox-2 inhibitors both as cancer prevention agents and as therapeutic agents in patients with proven malignancy until concerns were raised about their toxicity profile. Aspirin has several additional mechanisms of action that may contribute to its anti-cancer effect. It also influences cellular processes such as apoptosis and angiogenesis that are crucial for the development and growth of malignancies. Evidence suggests that these effects can occur through Cox-independent pathways questioning the rationale of focussing on Cox-2 inhibition alone as an anti-cancer strategy. Randomised studies with aspirin primarily designed to prevent cardiovascular disease have demonstrated a reduction in cancer deaths with long-term follow-up. Concerns about toxicity, particularly serious haemorrhage, have limited the use of aspirin as a cancer prevention agent, but recent epidemiological evidence demonstrating regular aspirin use after a diagnosis of cancer improves outcomes suggests that it may have a role in the adjuvant setting where the risk:benefit ratio will be different.

Summary Randomised controlled trials are the gold standard method for developing evidence-based medicine. Good trial design and an awareness of some potential pitfalls are likely to maximise the chances of a successful trial with a conclusion that adds meaningfully to the evidence base. This paper is aimed at people early in their research careers and focuses on some common, usually avoidable, pitfalls in trial design. The areas covered include: assessing the scientific idea; trial design; size and duration of the trial; analysis; and reporting and presentation.

58 Background: Single nucleotide polymorphisms (SNPs) in mir-608 (rs4919510) are prognostic in colorectal cancer (CRC) and hepatocellular cancer. SNPs of the let-7 complementary site 6 (LCS-6) 3'-untranslated region of KRAS (rs61764370) are associated with prognosis in CRC and platinum sensitivity in head and neck cancer. We investigated the prognostic effects of these SNPs in patients treated with surgery and with perioperative epirubicin, cisplatin and 5-fluorouracil chemotherapy plus surgery in the MRC MAGIC trial. Methods: DNA was extracted from tumour tissue using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). Samples were genotyped using the Taqman assay (Life Technologies, Carlsbad, CA) for rs4919510 in mir-608 and rs61764370 in LCS-6. SNP status was assessed for association with patient characteristics and survival. Results: 305 patients (of 456 operated) had mir-608 and/or LCS-6 results available. SNPs mir-608 and LCS-6 were in Hardy-Weinberg equilibrium. Pathological tumour regression grading was not different for any SNP genotype. No genotype was statistically significantly associated with overall survival in either surgery arm or chemotherapy plus surgery arm of the trial (Table). Conclusions: Germline polymorphisms in mir-608 and LCS-6 showed no evidence of a prognostic effect in patients with gastric and gastroesophageal cancer treated with surgery or chemotherapy plus surgery in the MAGIC trial. However, the small number of patients with selected genotypes means that these analyses may be underpowered to detect survival differences. [Table: see text]

OBJECTIVE: To assess the hormonal effects of Fem7® (Merck, KGaA, Darmstadt, Germany) 100 µg transdermal oestrogen patches on men undergoing first-line androgen-deprivation therapy for prostate cancer. PATIENTS AND METHODS: PATCH is a multicentre, randomized, phase II trial for men with locally advanced or metastatic prostate cancer, comparing luteinizing hormone-releasing hormone agonist therapy with oestrogen patches. To assess the dosing schedule for the patches, as this was the first time that this brand of patch had been used in men, and to reassure patients and participating clinicians, the Independent Data Monitoring Committee agreed to early release of hormonal data from this study. RESULTS: Oestradiol, testosterone and prostate-specific antigen (PSA) levels are presented for the first group of 14 patients who received the patches (with 1 withdrawal) and for whom there were ≥12 weeks of follow-up by March 2007. After 12 weeks, testosterone levels (nmol/L) in eight of the 13 patients were 2. The median (range) serum oestradiol levels was 442 (52.1–1542) pmol/L and all patients had a PSA response, with eight having a PSA level of

BACKGROUND: The most frequent site of metastases from prostate cancer is bone. Adjuvant bisphosphonate treatment improves outcomes of patients with bone metastasis-negative breast cancer, but the effects of bisphosphonates on bone metastases in prostate cancer are not known. METHODS: We performed a randomized double-blind placebo-controlled trial to determine whether a first-generation bisphosphonate could improve symptomatic bone metastasis-free survival (time to symptomatic bone metastases or death from prostate cancer) in men with nonmetastatic prostate cancer who were at high risk of developing bone metastases. Between June 1, 1994, and December 31, 1997, 508 men from 26 UK sites and one New Zealand site who were within 3 years of initial prostate cancer diagnosis with no evidence of metastases from current bone scanning were randomly assigned to daily oral sodium clodronate (2080 mg/day, n = 254) or placebo (n = 254) for a maximum of 5 years. Estimates of outcome risks were compared using Kaplan-Meier analyses. RESULTS: The groups allocated to each treatment were well balanced. After a median follow-up of nearly 10 years, no evidence of benefit to the clodronate group was observed in terms of bone metastases-free survival (clodronate versus placebo, 80 events versus 68 events; hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 0.88 to 1.68) or overall survival (clodronate versus placebo, 130 deaths versus 127 deaths; HR = 1.02; 95% CI = 0.80 to 1.30). Adverse events, notably gastrointestinal problems and increased lactate dehydrogenase levels, were more frequent in the clodronate group than in the placebo group; otherwise, clodronate was well tolerated. Modification of trial drug dose was more frequent in the clodronate group than the placebo group (HR = 1.63, 95% CI = 1.21 to 2.19). CONCLUSION: Adjuvant sodium clodronate does not modify the natural history of nonmetastatic prostate cancer.

Background Systematic reviews of RCTs are recognised as the optimal way to resolve or confirm uncertainty about the effects of interventions. They can provide the rationale for the design of a new trial, inform the conduct of an ongoing trial, and help place trial results in the context of those from related trials. However, empirical evidence suggests that few trials use systematic reviews in these ways.

Professor Peter Rothwell of Oxford University chaired the annual Scientific Conference of the International Aspirin Foundation in London on 28 August 2015. It took the form of four sessions.\ud \ud Aspirin has more than one action in its effects on disease. Its acetylation of cyclooxygenase 2 (COX-2) in platelets leads to the blockade of pro-inflammatory chemicals and generation of anti-inflammatory mediators and increase in nitrous oxide (NO) production, which helps to preserve arterial endothelium. But platelets are not its only target. There is now evidence that aspirin has a direct antitumour effect on intestinal mucosal cells that block their potential transformation into cancer cells.\ud \ud Randomised placebo-controlled trials (RCTs) in people with histories of colorectal neoplasia have shown that aspirin reduces the risk of recurrent adenomas and reduces long-term cancer incidence in patients with Lynch syndrome. Among women given aspirin for cardiovascular disease, there were fewer cancers than in those given placebo. Epidemiological evidence has suggested that aspirin treatment after cancer is diagnosed reduces the incidence of metastases and prolongs survival, and long-term studies of anticancer treatment with aspirin are under way to confirm this.\ud \ud Apart from cancer studies, aspirin use is now firmly established as treatment for antiphospholipid syndrome (Hughes syndrome) and is being used to prevent and treat the heightened risk of cardiovascular disease in diabetes mellitus and in patients with HIV.

Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa.To compare BMD change in men receiving either LHRHa or oestradiol patches (OP).Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006-2011; 1:1, thereafter) were recruited into a BMD study (2006-2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr.LHRHa as per local practice, OP (FemSeven 100μg/24h patches).The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance.A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was -0.021g/cm(3) for patients randomised to the LHRHa arm (mean percentage change -1.4%) and +0.069g/cm(3) for the OP arm (+6.0%; p0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa -3.0% and OP +7.9% (p0.001).Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial.This study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial.ISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).

Introduction Erythema nodosum is often associated with a distressing symptomatology, including painful subcutaneous nodules, polyarthropathy, and significant fatigue. Whilst it is a well-documented side-effect of estrogen therapy in females, we describe what we believe to be the first report in the literature of erythema nodosum as a result of estrogen therapy in a male. Case presentation A 64-year-old Afro-Caribbean man with locally advanced carcinoma of the prostate agreed to participate in a randomized controlled trial comparing estrogen patches with luteinizing hormone-releasing hormone analogs to achieve androgen deprivation, and was allocated to the group receiving estrogen patches. One month later he presented with tender lesions on his shins and painful swelling of his ankles, wrists, and left shoulder. This was followed by progressive severe fatigue that required hospital admission, where he was diagnosed with erythema nodosum by a rheumatologist. Two months after discontinuing the estrogen patches the erythema nodosum, and associated symptoms, had fully resolved, and to date he remains well with no further recurrence. Conclusion Trial results may establish transdermal estrogen as an alternative to luteinizing hormone-releasing hormone analogs in the management of prostate cancer, and has already been established as a therapy for male to female transsexuals. It is essential to record the toxicity profile of transdermal estrogen in men to ensure accurate safety information. This case report highlights a previously undocumented toxicity of estrogen therapy in men, of which oncologists, urologists, and endocrinologists need to be aware. Rheumatologists and dermatologists should add estrogen therapy to their differential diagnosis of men presenting with erythema nodosum.

Background A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. Methods We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. Results ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P = 0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P

Purpose To compare the effectiveness and tolerability of epirubicin and paclitaxel (EP) with epirubicin and cyclophosphamide (EC) as first-line chemotherapy for metastatic breast cancer (MBC). Patients and Methods Patients previously untreated with chemotherapy (except for adjuvant therapy) were randomly assigned to receive either EP (epirubicin 75 mg/m2 and paclitaxel 200 mg/m2) or EC (epirubicin 75 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously every 3 weeks for a maximum of six cycles. The primary outcome was progression-free survival; secondary outcome measures were overall survival, response rates, and toxicity. Results Between 1996 and 1999, 705 patients (353 EP patients and 352 EC patients) underwent random assignment. Patient characteristics were well matched between the two groups, and 71% of patients received six cycles of treatment. Objective response rates were 65% for the EP group and 55% for the EC group (P = .015). At the time of analysis, 641 patients (91%) had died. Median progression-free survival time was 7.0 months for the EP group and 7.1 months for the EC group (hazard ratio = 1.07; 95% CI, 0.92 to 1.24; P = .41), and median overall survival time was 13 months for the EP group and 14 months for the EC group (hazard ratio = 1.02; 95% CI, 0.87 to 1.19; P = .8). EP patients, compared with EC patients, had more grade 3 and 4 mucositis (6% v 2%, respectively; P = .0006) and grade 3 and 4 neurotoxicity (5% v 1%, respectively; P < .0001). Conclusion In terms of progression-free survival and overall survival, there was no evidence of a difference between EP and EC. The data demonstrate no additional advantage to using EP instead of EC as first-line chemotherapy for MBC in taxane-naïve patients.

Background: There is a significant body of in vitro evidence and pre-clinical data which demonstrates that aspirin inhibits the growth of tumours and prevents the development of metastases[1]. A recent meta-analysis using individual patient data from randomized trials evaluating the cardiovascular effects of aspirin reports a reduction in cancer deaths after 5 years (hazard ratio 0.46, 95% confidence interval 0.27-0.77)[2]. Effects on risk of metastases and death following a cancer diagnosis have also been observed[3]. An analysis of the Nurses’ Health Study found that aspirin use following a diagnosis of stage I-III breast cancer was associated with a lower risk of breast cancer death (for those taking aspirin 2-5 times per week, relative risk 0.27, 95% confidence interval 0.15-0.47)[4]. Concerns over toxicity have limited the use of aspirin as a primary prevention agent against cancer. In the adjuvant setting the benefit:risk ratio will be different with higher morbidity and mortality from recurrent cancer potentially outweighing the risks associated with regular aspirin use. The Add-Aspirin trials will investigate whether regular aspirin use after curative treatment for localised malignancy can prevent tumour recurrence and prolong survival. As an inexpensive drug with a potential therapeutic role in several common cancers, aspirin could have a huge impact on the global cancer burden. Trial design: Multicentre, international, phase III, double-blind, placebo-controlled randomized trial in patients with early breast cancer. Participants will be randomised to enteric-coated aspirin 100mg, aspirin 300mg or matching placebo daily for at least 5 years. Parallel trials based on a common infrastructure will be conducted in colorectal, gastro-oesophageal and prostate cancer. Eligibility criteria: Patients who have undergone primary therapy, including curative surgery and appropriate neoadjuvant/adjuvant therapies for histologically confirmed invasive breast cancer which is node positive or node negative with high-risk features. Patients who have already participated in other primary treatment trials may be eligible subject to agreement from the trial management groups. Specific aims: The primary outcome will be disease-free survival. Secondary endpoints include overall survival, toxicity, cardiac morbidity and assessment of overall healthcare benefits. Translational work will investigate mechanisms of action and biomarkers for toxicity and treatment efficacy (including PIK3CA mutation status and COX-2 expression). Statistical methods: Approximately 3100 patients will be needed to test for a 4% improvement in DFS associated with aspirin use. [1] Langley RE et al. Br J Cancer. 2011;105(8):1107-13. [2] Rothwell PM et al. Lancet. 2011;377(9759):31-41. [3] Rothwell PM et al. Lancet. 2012;379(9826):1591-601. [4] Holmes MD et al. J Clin Oncol 2010;28(9):1467-72. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-4-01.

Viera’s article on the polypill focused exclusively on cardiovascular benefits.1 Yet several candidates for inclusion in such a formulation, such as aspirin and metformin, have shown anticancer activity in recent years. Randomised trials show that aspirin prevents the development of colorectal cancer,23 and long term follow-up from vascular trials indicates that aspirin inhibits development of …

The purpose of this review is to assess recent evidence that demonstrates that aspirin has the potential to be an effective preventive and therapeutic agent in gastrointestinal malignancy.Long-term follow-up of previous randomized trials of aspirin show that it decreases cancer incidence and mortality with the greatest effects seen on cancers that arise from the gastrointestinal tract. Reduction in distant metastasis and improvements in cancer outcomes appear within 5 years of randomization indicating that aspirin affects tumour growth or the development and spread of metastases from existing cancers or both. In Lynch syndrome (hereditary nonpolyposis colon cancer), aspirin reduces cancer incidence and should be considered standard care. Mutations in the PIK3CA gene may be a potential predictive marker of response to aspirin after a cancer diagnosis, though pharmacological considerations suggest that platelets may be central to the antitumour efficacy of aspirin.These findings have re-awakened interest in the role of aspirin in the primary prevention of cancer and in the treatment of cancer. Randomized controlled trials are underway to assess the role of aspirin within the treatment algorithms of several solid common cancers.

Androgen deprivation therapy (ADT) resulting in testosterone suppression is central to the management of prostate cancer (PC). As PC incidence increases, ADT is more frequently prescribed, and for longer periods of time as survival improves. Initial approaches to ADT included orchiectomy or oral estrogen (diethylstilbestrol [DES]). DES reduces PC-specific mortality, but causes substantial cardiovascular (CV) toxicity. Currently, luteinizing hormone-releasing hormone agonists (LHRHa) are mainly used; they produce low levels of both testosterone and estrogen (as estrogen in men results from the aromatization of testosterone), and many toxicities including osteoporosis, fractures, hot flashes, erectile dysfunction, muscle weakness, increased risk for diabetes, changes in body composition, and CV toxicity. An alternative approach is parenteral estrogen, it suppresses testosterone, appears to mitigate the CV complications of oral estrogen by avoiding first-pass hepatic metabolism, and avoids complications caused by estrogen deprivation. Recent research on the toxicity of ADT and the rationale for revisiting parenteral estrogen is discussed.

DOI: 10.1111/jsm.12330The recent comprehensive review by Trost et al. highlighting theimpact of androgen deprivation therapy (ADT) with luteinisinghormone-releasing hormone agonists (LHRHa) on quality of life(QoL) of prostate cancer survivors is timely in view of increasingusage and accumulating evidence of its harms [1]. LHRHa weredeveloped because oral estrogen, a major option for treating pros-tate cancer through ADT in the second half of the 20th century,was discontinued due to its excessive cardiovascular (CVS) mor-tality [2]. The authors report a wide range of adverse events withLHRHa and include advice for monitoring and managementoptions [1]. That contemporary ADT using LHRHa suppressesendogenous testosterone levels (by about 95%) is well known butthat estrogen is derived from testosterone via aromatization andendogenous estrogen levels are consequently also reduced (byabout80%)isfarlessappreciated[3,4].Thusinadditiontoachiev-ingthetreatmentobjectiveofarrestingprostatetumorgrowth,thecastrated male suffers unwanted side effects from this iatrogenichypogonadism including sarcopenia, anemia, and erectile dysfunc-tion (testosterone lack) and osteoporosis (with high risk of frac-tures), hot flushes and probably, cognitive impairment (estrogenlack) [5]. We concur that definitive evidence for the impact ofcastration on CVS mobidity/mortality remains wanting, butseveral observational studies support an increased risk of CVScomplications [1,6]. Ironically, alternatives to LHRHa are nowsoughtfollowingthemultiplecomorbiditiesconsequentonitsuse.Parenteral administration of estrogen (intramuscular or trans-dermal) for ADT appears to mitigate the CVS toxicity associatedwith oral estrogen by circumventing first-pass liver metabolism[7–9]. By contrast, oral estrogen leads to direct exposure of theliver to high levels of estrogen through the portal circulationresulting in a hypercoaguable state through upregulation of liverbiosynthesis including procoagulant proteins, and increasing therisk of serious CVS events [10]. Parenteral exogenous estrogenadministration has the added benefit of replacing the reducedendogenous estrogen, thereby potentially avoiding the meno-pausal (estrogen lack) symptoms seen with LHRHa while simul-taneously delivering the beneficial arterial effects associated withestrogen therapy [11]. Thus exogenous parenteral estrogen asmonotherapy (especially important in older age groups) has thepotential of both treating prostate cancer and reducing side effectswhen compared with LHRHa.More recent evidence supporting parenteral estrogen therapycomesfromthePATCH(ProstateAdenocarcinomaTransCutane-ous Hormones) study; a phase II randomized clinical trial compar-ingtransdermalestrogenpatcheswithLHRHainlocallyadvancedandmetastaticprostatecancer.Inthefirststageofthetrial(n = 254,medianfollow-uptime19months,primaryoutcomemeasureCVSevents),therateofCVSeventswassimilarinthetwotrialarms[12].Testosterone suppression rates were also similar. At 6 and 12months,meanfastingcholesterolincreasedintheLHRHaarmbutdecreased in the estrogen arm whereas high-density lipoproteincholesterolincreasedinboth.MeanfastingglucoseincreasedintheLHRHa group at 6 months and again further at 12 months butshowed a decrease in the estrogen group at 6 months, which wasmaintainedunchangedat12months.ThesecondstageofthephaseII study with a planned recruitment target of 730 men assessingprogression-free survival as the primary outcome measure isnearingcompletionandwillinformthedesignofaphaseIIIclinicaltrial with overall survival as primary end point.Further research should lead to the re-emergence of estrogen,in parenteral form, as an effective and cheaper alternative toLHRHa for the treatment of prostate cancer with reduced adverseevents, enhancing patient choice when considering ADT. Untilthe availability of definitive results, effective monitoring isrequired for instituting timely prophylactic and/or therapeuticinterventions for CVS and other serious toxicities of contempo-rary ADT with LHRHa.Syed I.A. Shah, MPhil,* Fay H. Cafferty, PhD

Comment on ‘Endocrine therapy in prostate cancer: time for re-appraisal of risks, benefits and cost-effectiveness?’

4064Background: MMRd and MSI are prognostic for survival in many cancers and predict resistance to fluoropyrimidines in colon cancer. We examined the relationship between MMRd, MSI and survival in ...

Background REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluourouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. Patients and methods Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. Results RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%) , PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS , BRAF and PIK3CA and loss of PTEN ( phosphatase and tensin homolog ) were found in 6.3%, 1.0% , 5.0% and 10.9%, respectively, and were not associated with survival. Conclusions The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor.ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity.Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up).Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P combined = 4.09 × 10-9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P combined = 2.74 × 10-10; OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus. © 2012 Nature America, Inc. All rights reserved.

Background. Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. Methods. We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. Findings. 459 patients were randomly assigned (115 to each of groups A–C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3–7·5] vs 4·5 months [2·8–6·4]; hazard ratio 0·84, 95% CI 0·69–1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14–1·52), less widespread disease (1·51, 1·05–2·19), and use of oxaliplatin (0·57, 0·39–0·82) were predictive of better OTU. Interpretation. FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit. Funding. Cancer Research UK and the Medical Research Council.

MRC Clinical TrialsUnit, London, UKDear Editor,In this era of emerging novel, complex prostatecancer treatments, it was refreshing to review a his-torical perspective of the merits of oestrogen, the firstpharmacological agent used as androgen deprivationtherapy (ADT), i.e. suppression of testosterone byabout 95% to castrate levels [1]. Prescribed for oraluse as diethylstilboestrol, it had to be discontinuedbecause of the resulting high cardiovascular toxicityand deaths, despite evidence of greater efficacy thanorchiectomy as a prostate cancer treatment [2].Although oestrogen suppresses testosterone primarilythrough the hypothalamic–pituitary–gonadal axis,additional mechanisms similar to those of some ofthe newest therapies under investigation may accountfor this greater efficacy, e.g. inhibition of 17,20-lyaseand consequent extragonadal steroid synthesis, anabiraterone-like action [1].ADT was subsequently achieved by replacing oraloestrogenwithluteinizinghormone-releasinghormoneagonist (LHRHa), which also suppresses testosteronetocastratelevels.Therateoftestosteronesuppressioniseven more marked with an LHRH antagonist [3].However, this reduction in testosterone also results insuppression of the endogenously produced oestrogenby about 80%. Oestrogen in men is derived fromaromatization of testosterone [4,5]. The resulting iat-rogenic hypogonadism (of both male and female sexhormones) causes unwanted side-effects includingsarcopenia, anaemia and erectile dysfunction (fromtestosterone depletion), and osteoporosis (with a highrisk of fractures), hot flushes and, probably, cognitiveimpairment (from oestrogen depletion) [6].Can the potential benefits of oestrogen berealized without the cardiovascular andhypogonadal risks of the oral route?Parenteraloestrogenadministration(intramuscularaspolyoestradiolphosphateortransdermalasoestradiol)avoids first pass through the liver and the consequenthepatic overexpression of proteins, includingthose affecting coagulation, thereby diminishingcardiovascular toxicity substantially [7,8]. Exogenousoestrogen also replaces suppressed endogenousoestrogen, potentially diminishing the oestrogendepletion-relatedtoxicityofLHRHa.Thus,parenteraloestrogen as single-agent therapy offers potential ben-efits over either oral diethylstilboestrol or LHRHathrough (i) treating the cancer, by suppressing testos-terone to castrate levels, (ii) reducing the risk ofcardiovascular hazards of oral oestrogen, and (iii)possiblyavoidingsomeoftheadverseeffectsofLHRHaby maintaining endogenous levels of oestrogen.The Prostate Adenocarcinoma TransCutaneousHormones (PATCH) study, funded by CancerResearch UK, is a randomized phase II trial compar-ing LHRHa with transdermal oestrogen patches inmen with locally advanced or metastatic prostatecancer. Stage 1 of this study (n = 254) specificallyaddressed cardiovascular toxicity as the primary out-come, and data showed similar rates of cardiovascular

Purpose OEO2 is a randomized, controlled trial of preoperative chemotherapy in patients undergoing radical surgery for esophageal cancer. Random assignment was to surgery alone (S) or to two cycles of combination cisplatin and fluorouracil before surgery (CS). Initial results reported in 2002 demonstrated an advantage for both disease-free and overall survival in the CS group. The analysis has now been updated after a median follow-up of 6 years. Patients and Methods OEO2 recruited 802 patients, 400 on CS and 402 on S. The nature of the first recurrence event and cause of death are detailed. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. Survival by extent of resection is presented. Results There were 655 deaths, 335 for S and 320 for CS. The survival benefit has been maintained with a hazard ratio (HR) of 0.84 (95% CI, 0.72 to 0.98; P = .03) which in absolute terms is a 5-year survival of 23.0% for CS compared with 17.1% for S. The treatment effect is consistent in both adenocarcinoma and squamous cell carcinoma. The first disease-free survival event was macroscopic residual disease from incomplete resection (R2) or no resection in 26.4% of the S group versus 14.3% of the CS P < .001. Three-year survival by type of resection was R0 42.4%, R1 was 18.0%, and R2 was 8.6%. Conclusion Long-term follow-up confirms that preoperative chemotherapy improves survival in operable esophageal cancer and should be considered as a standard of care.

Despite both the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development during the last 10 years, the number of new treatments that have been approved for patients has not increased as expected. We propose the multi-arm, multi-stage trial design as a way to evaluate treatments faster and more efficiently than current standard trial designs. By using intermediate outcomes and testing a number of new agents (and combinations) simultaneously, the new design requires fewer patients. Three trials using this methodology are presented.