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Background: The prognosis for unresectable locally advanced pancreatic adenocarcinoma (LAPC) remains poor. There is increasing interest in modern ablative techniques to improve outcomes. We report on the potential value of integrating percutaneous irreversible electroporation (IRE) in patients undergoing systemic chemotherapy. Methods: Seventy-five patients with unresectable pancreatic carcinoma underwent percutaneous IRE after chemotherapy using computerised tomography guidance under general anaesthesia. Postoperative immediate and 30-day morbidity and mortality, progression-free (PFS) and overall survival (OS) were evaluated. Results: Post-procedural immediate and 30-day mortality rates were both zero. All-grade adverse events were 25%. Median in-patient stay was 1 day (range 1–5 days). Median OS and PFS post-IRE for LAPC were 27 and 15 months respectively. Four patients with LAPC down-staged post-IRE ablation to be surgically resectable, with R0 resections in 3 cases. Conclusions: These results suggest that percutaneous IRE ablation of unresectable LAPC is safe to integrate with standard-of-care chemotherapy and may improve survival, which provides a template for further evaluation in prospective randomized clinical trials.

Trastuzumab is a key drug in the neoadjuvant treatment of breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2). Pathological complete response (pCR) is commonly used as an endpoint in neoadjuvant clinical trials of trastuzumab as evidence suggests it may be a surrogate for long-term survival. Several biosimilar candidates of originator or 'reference' trastuzumab are in development and have used pCR as a primary endpoint to assess therapeutic equivalence between treatments. The exact definition of pCR has varied across studies. Areas covered: Here we look at the clinical relevance of pCR and compare rates of total pCR (defined as ypT0/is ypN0) and breast pCR (defined as ypT0/is) in clinical trials of reference and biosimilar trastuzumab. Expert commentary: In order to evaluate the efficacy of neoadjuvant systemic therapies in a uniform way, standardization of trial endpoints is necessary. Future studies in HER2-positive breast cancer should include full assessment of the breast and lymph node basin before and after neoadjuvant systemic therapy, and the use of total pCR as the primary outcome.

We evaluated the effect of tailoring treatments based on predictions informed by tumor molecular profiles across a range of cancers, using data from Caris Life Sciences. These included breast carcinoma, colorectal adenocarcinoma, female genital tract malignancy, lung non-small cell lung cancer, neuroendocrine tumors, ovarian surface epithelial carcinomas, and urinary tract cancers. Molecular profiles using mostly immunohistochemistry (IHC) and DNA sequencing for tumors from 841 patients had been previously used to recommend treatments; some physicians followed the suggestions completely while some did not. This information was assessed to find out if the outcome was better for the patients where their received drugs matched recommendations. The IHC biomarker for the progesterone receptor and for the androgen receptor were found to be most prognostic for survival overall. The IHC biomarkers for P-glycoprotein (PGP), tyrosine-protein kinase Met (cMET) and the DNA excision repair protein ERCC1 were also shown to be significant predictors of outcome. Patients whose treatments matched those predicted to be of benefit survived for an average of 512 days, compared to 468 days for those that did not (P = 0.0684). In the matched treatment group, 34% of patients were deceased at the completion of monitoring, whereas this was 47% in the unmatched group (P = 0.0001).

Tumor molecular profiling has enabled selection of targeted therapies in a host of solid tumors. Here we used a retrospective clinical cohort, to evaluate the benefit of tailoring treatments for female genital tract malignancy, using tumor molecular profiles. Clinical outcome data for 112 patients was retrospectively separated into two groups. These either followed a matched treatment plan that incorporated at least one drug recommended according to their tumor profile and none that were expected to have no benefit (64 patients), or was unmatched with suggested treatments and received at least one drug that was anticipated to lack benefit for that tumor (48 patients). In the group of patients whose drugs matched those recommended by molecular profiling of their tumor, their overall survival was 593 days on average, compared to 449 days for patients that did not; removing drugs predicted to have no benefit from treatment regimens received after profiling increased survival by 144 days on average (P = 0.0265). In the matched treatment group, 30% of patients had died by the last time of monitoring, whereas this was 40% in the unmatched group (P = 0.2778). The IHC biomarker for the progesterone receptor was demonstrated to be prognostic for survival.

Next generation sequencing (NGS) is becoming increasingly integrated into oncological practice and clinical research. NGS methods have also provided evidence for clonal evolution of cancers during disease progression and treatment. The number of variants associated with response to specific therapeutic agents keeps increasing. However, the identification of novel driver mutations as opposed to passenger (phenotypically silent or clinically irrelevant) mutations remains a major challenge. We conducted targeted exome sequencing of advanced solid tumors from 44 pre-treated patients with solid tumors including breast, colorectal and lung carcinomas, neuroendocrine tumors, sarcomas and others. We catalogued established driver mutations and putative new drivers as predicted by two distinct algorithms. The established drivers we detected were consistent with published observations. However, we also detected a significant number of mutations with driver potential never described before in each tumor type we studied. These putative drivers belong to key cell fate regulatory networks, including potentially druggable pathways. Should our observations be confirmed, they would support the hypothesis that new driver mutations are selected by treatment in clinically aggressive tumors, and indicate a need for longitudinal genomic testing of solid tumors to inform second line cancer treatment.

Although the major burden of disease caused by smoking is observed in the adult population, two-third of smokers start before the age of 18 years. Reducing the number of young smokers could lead to marked improvements to the health of the UK population and save billions of pounds in National Health Service finances. However, very little is known about what makes children decide to not smoke or to quit early. We believe that increased awareness of the health risks associated with smoking will reduce smoking uptake among children. This study identifies a significant lack of knowledge among children aged 11-17 years at two London secondary schools and potentially identifies an area for improving our antismoking programmes. Although 80% of pupils cited lung cancer as being a smoking-related disease, very few other conditions could be recalled. We must do all we can to reduce smoking uptake in children. Understanding their baseline knowledge is the first step towards addressing the deficits in our current antismoking programmes.

// Adam E. Frampton 1, 2, * , Mireia Mato Prado 2, * , Elena Lopez-Jimenez 2 , Ana Belen Fajardo-Puerta 1 , Zaynab A.R. Jawad 1 , Phillip Lawton 2 , Elisa Giovannetti 3, 4 , Nagy A. Habib 1 , Leandro Castellano 2, 5 , Justin Stebbing 2, # , Jonathan Krell 2, # and Long R. Jiao 1, # 1 HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, London, UK 2 Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK 3 Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands 4 Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, Italy 5 University of Sussex, School of Life Sciences, John Maynard Smith Building, Falmer, Brighton, UK * These authors share co-first authorship # These authors share co-senior authorship Correspondence to: Long R. Jiao, email: l.jiao@imperial.ac.uk Keywords: Glypican-1 (GPC1); pancreatic ductal adenocarcinoma (PDAC); exosome; biomarker; tumor size Received: October 28, 2017 Accepted: March 02, 2018 Published: April 10, 2018 ABSTRACT Background: Glypican-1 (GPC1) is expressed in pancreatic ductal adenocarcinoma (PDAC) cells and adjacent stromal fibroblasts. Recently, GPC1 circulating exosomes (crExos) have been shown to be able to detect early stages of PDAC. In this study, we investigated the usefulness of crExos GPC1 as a biomarker for PDAC. Methods: Plasma was obtained from patients with benign pancreatic disease ( n = 16) and PDAC ( n = 27) prior to pancreatectomy, and crExos were isolated by ultra-centrifugation. Protein was extracted from surgical specimens (adjacent normal pancreas, n = 13; and PDAC, n = 17). GPC1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: There was no significant difference in GPC1 levels between normal pancreas and PDAC tissues. This was also true when comparing matched pairs. However, GPC1 levels were enriched in PDAC crExos ( n = 11), compared to the source tumors ( n = 11; 97 ± 54 vs. 20.9 ± 12.3 pg/mL; P 4 cm; P = 0.012). Conclusions: High GPC1 crExos may be able to determine PDAC tumor size and disease burden. However, further efforts are needed to elucidate its role as a diagnostic and/or prognostic biomarker using larger cohorts of PDAC patients.

TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell–cell junctions’ pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis., In pancreatic ductal adenocarcinoma, TGF-β/Activin induce epithelial-to-mesenchymal transition (EMT) and stemness. Here, the authors show that TGF-β induces pro-tumourigenic miR-100 and miR-125b, but blocks anti-tumourigenic let-7a maturation via LIN28B, regulating pathways to promote stemness, EMT and tumourigenesis.

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker. Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided. Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008). Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy.

Background CT-P6 was approved by both US FDA and European Commission as a biosimilar to reference trastuzumab (RTZ). Here we report updated long term efficacy and safety. Methods 549 patients with HER2 positive EBC were randomized 1:1 to CT-P6 (n = 271) or RTZ (n = 278) with docetaxel (Cycles 1-4) and 5-fluorouracil, epirubicin and cyclophosphamide (Cycles 5-8). After surgery, patients received CT-P6 or RTZ monotherapy to complete a total of 1 year and were followed up to 3 years from enrollment of the last patient. Stratified Cox regression and Kaplan-Meier methods were used for time to event (TTE) analyses. Results 528 patients (259 in CT-P6 and 269 in RTZ) were followed up. The median duration of follow-up was 39 months. Overall, the rates of disease-free survival (DFS) and overall survival (OS) were similar between CT-P6 and RTZ in both PPS and ITT set. The number of DFS events (42 [16.3%] in CT-P6 and 36 [13.8%] in RTZ) and OS events (18 [6.6%] in CT-P6 and 18 [6.5%] in RTZ) were comparable in ITT set. Median DFS and OS have not been reached due to an insufficient number of events. The mean LVEF was more than 60% in both groups, and no new cases of heart failure were reported during the follow-up period. Table. Summary of Long Term Efficacy Endpoints. Table . 190P PPS ITT set CT-P6 n = 248 RTZ n = 256 CT-P6 n = 258 RTZ n = 261 DFS rate 1 year (95% CI) 0.95 (0.91 – 0.97) 0.96 (0.93 – 0.98) 0.95 (0.91 – 0.97) 0.96 (0.93 – 0.98) 2 years (95% CI) 0.87 (0.81 – 0.90) 0.89 (0.85 – 0.92) 0.87 (0.82 – 0.90) 0.89 (0.85 – 0.93) 3 years (95% CI) 0.82 (0.77 – 0.87) 0.82 (0.75 – 0.88) 0.83 (0.77 – 0.87) 0.83 (0.76 – 0.88) Hazard ratio (95% CI) 1.23 (0.78 – 1.94) 1.23 (0.78 – 1.93) p-value 0.3808 0.3807 CT-P6 n = 248 RTZ n = 256 CT-P6 n = 271 RTZ n = 278 OS rate 1 year (95% CI) 1.00 (1.00 – 1.00) 1.00 (0.97 – 1.00) 0.99 (0.97 – 1.00) 0.99 (0.97 – 1.00) 2 years (95% CI) 0.98 (0.95 – 0.99) 0.98 (0.96 – 0.99) 0.97 (0.93 – 0.98) 0.98 (0.96 – 0.99) 3 years (95% CI) 0.95 (0.91 – 0.97) 0.94 (0.90 – 0.96) 0.93 (0.90 – 0.96) 0.94 (0.90 – 0.96) Hazard ratio (95% CI) 0.87 (0.42 – 1.82) 1.10 (0.57 – 2.13) p-value 0.7181 0.7710 Conclusions DFS and OS rates and cardiotoxicity at a median follow-up of 39 months support the similarity of CT-P6 and reference trastuzumab in early-stage breast cancer. Clinical trial identification NCT02162667. Legal entity responsible for the study Celltrion. Funding Celltrion. Disclosure J. Stebbing: Officer / Board of Directors, Editer-in-Chief: Oncogene; Advisory / Consultancy: Celltrion; Advisory / Consultancy: Vor Biopharma; Advisory / Consultancy: Benevolent AI; Officer / Board of Directors: BB Biotech Healthcare Trust; Officer / Board of Directors: Xerion Healthcare. Y. Baranau: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Novatis. V. Moiseyenko: Speaker Bureau / Expert testimony: AstraZeneca. J. Pikiel: Travel / Accommodation / Expenses: Roche. A. Eniu: Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Celltrion; Research grant / Funding (self): Pfizer. S.J. Lee: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Stock option: Celltrion. M.J. Kim: Full / Part-time employment: Celltrion. S. Kim: Full / Part-time employment: Celltrion. S. Park: Full / Part-time employment: Celltrion. J.H. Bae: Full / Part-time employment: Celltrion. F.J. Esteva: Advisory / Consultancy: Celltrion; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.

PURPOSE: Access to trastuzumab, a valuable anti-cancer treatment, can be limited by cost. The primary aim of this study was to evaluate and compare the PK profiles of CT-P6, a biosimilar of trastuzumab, and US-licensed reference trastuzumab (Herceptin®) in healthy subjects. Secondary study aims included comparison of the safety and immunogenicity of CT-P6 and reference trastuzumab in these subjects. METHODS: We performed a single-dose, randomised, double-blind, parallel group study (NCT02665637) comparing CT-P6 with reference trastuzumab (6 mg/kg, 90 min intravenous infusion) in 70 healthy adult males. Pharmacokinetics, safety and immunogenicity were evaluated up to 10 weeks post-dose. Primary endpoints were area under the serum concentration-time curve (AUC) from time 0 to infinity (AUCinf); AUC from time 0 to last quantifiable concentration (AUClast); and observed maximum serum concentration (Cmax). The pre-determined equivalence criterion was a 90% confidence interval of 80-125% for ratios of geometric least squares (LS) means. RESULTS: Equivalence of CT-P6 and reference trastuzumab was demonstrated. Ratios (CT-P6/reference trastuzumab) of geometric LS means (90% confidence interval) were: AUCinf 99.05 (93.00, 105.51); AUClast 99.30 (92.85, 106.20); Cmax 96.58 (90.93, 102.59). Safety profiles were similar; treatment-emergent adverse events occurred in ten subjects (28.6%) in the CT-P6 group and 11 (31.4%) in the reference trastuzumab group. No serious adverse events or deaths occurred. No subjects tested positive for anti-drug antibodies. CONCLUSIONS: These data add to the totality of evidence required to demonstrate biosimilarity. A phase III study of CT-P6-in which equivalent neoadjuvant efficacy to reference trastuzumab has been demonstrated-is ongoing.

// Philip Carter 1 , Costi Alifrangis 2 , Pramodh Chandrasinghe 1, 3, 4 , Biancastella Cereser 1 , Lisa Del Bel Belluz 1 , Cosimo Alex Leo 4 , Nina Moderau 1 , Neha Tabassum 1 , Janindra Warusavitarne 4 , Jonathan Krell 1 and Justin Stebbing 1 1 Department of Surgery and Cancer, Imperial College, London, UK 2 Department of Medical Oncology, Imperial College, London, UK 3 Department of Surgery, University of Kelaniya, Kelaniya, Sri Lanka 4 Department of Colorectal Surgery, St Mark’s Hospital, London, UK Correspondence to: Philip Carter, email: phil.carter@imperial.ac.uk Keywords: tumor profiling; colorectal adenocarcinoma; cancer treatment Received: July 29, 2017 Accepted: November 15, 2017 Published: January 16, 2018 ABSTRACT We evaluated the benefit of tailoring treatments for a colorectal adenocarcinoma cancer cohort according to tumor molecular profiles, by analyzing data collected on patient responses to treatments that were guided by a tumor profiling technology from Caris Life Sciences. DNA sequencing and immunohistochemistry were the main tests that predictions were based upon, but also fragment analysis, and in situ hybridization. The status of the IHC biomarker for the thymidylate synthase receptor was a good indicator for future survival. Data collected for the clinical treatments of 95 colorectal adenocarcinoma patients was retrospectively divided into two groups: the first group was given drugs that always matched recommended treatments as suggested by the tumor molecular profiling service; the second group received at least one drug after profiling that was predicted to lack benefit. In the matched treatment group, 19% of patients were deceased at the end of monitoring compared to 49% in the unmatched group, indicating a benefit in mortality by tumor molecular profiling colorectal adenocarcinoma patients.

// Philip Carter 1 , Costi Alifrangis 2 , Biancastella Cereser 1 , Pramodh Chandrasinghe 1, 3 , Lisa Del Bel Belluz 1 , Christina Fotopoulou 1 , Andreja Frilling 1 , Thomas Herzog 4, 5 , Nina Moderau 1 , Neha Tabassum 1 , Jonathan Krell 1 and Justin Stebbing 1 1 Department of Surgery and Cancer, Imperial College, London, UK 2 Department of Oncology, University College Hospital, London, UK 3 Department of Surgery, University of Kelaniya, Kelaniya, Sri Lanka 4 Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, USA 5 University of Cincinnati Cancer Institute, University of Cincinnati, Cincinnati, USA Correspondence to: Philip Carter, email: phil.carter@imperial.ac.uk Keywords: tumor profiling; female genital tract malignancy; cancer treatment Abbreviations: ER: estrogen receptor; IHC: immunohistochemistry; OS: overall survival; PR: progesterone receptor Received: July 29, 2017 Accepted: November 14, 2017 Published: December 27, 2017 ABSTRACT Tumor molecular profiling has enabled selection of targeted therapies in a host of solid tumors. Here we used a retrospective clinical cohort, to evaluate the benefit of tailoring treatments for female genital tract malignancy, using tumor molecular profiles. Clinical outcome data for 112 patients was retrospectively separated into two groups. These either followed a matched treatment plan that incorporated at least one drug recommended according to their tumor profile and none that were expected to have no benefit (64 patients), or was unmatched with suggested treatments and received at least one drug that was anticipated to lack benefit for that tumor (48 patients). In the group of patients whose drugs matched those recommended by molecular profiling of their tumor, their overall survival was 593 days on average, compared to 449 days for patients that did not; removing drugs predicted to have no benefit from treatment regimens received after profiling increased survival by 144 days on average ( P = 0.0265). In the matched treatment group, 30% of patients had died by the last time of monitoring, whereas this was 40% in the unmatched group ( P = 0.2778). The IHC biomarker for the progesterone receptor was demonstrated to be prognostic for survival.

Tyrosine kinases (TKs) are central regulators in cellular activities and perturbations of TK signaling contribute to oncogenesis. However, less than half of the TKs have been thoroughly studied and a global functional analysis of their proteomic portrait is lacking. Here we conducted a combined approach of RNA interference (RNAi) and stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics to decode the TK-regulated proteome and associated signaling dynamics. As a result, a broad proteomic repertoire modulated by TKs was revealed, upon silencing of the 65 TKs expressed in MCF7 breast cancer cells. This yielded 10 new distinctive TK clusters according to similarity in TK-regulated proteome, each characterized by a unique signaling signature in contrast to previous classifications. We provide functional analyses and identify critical pathways for each cluster based on their common downstream targets. Analysis of different breast cancer subtypes showed distinct correlations of each cluster with clinical outcome. From the significantly up- and down-regulated proteins, we identified a number of markers of drug sensitivity and resistance. These data supports the role of TKs in regulating major aspects of cellular activity, but also reveals redundancy in signaling, explaining why kinase inhibitors alone often fail to achieve their clinical aims. The TK-SILACepedia provides a comprehensive resource for studying the global function of TKs in cancer.

Nuclear receptors belong to a superfamily of proteins that play central roles in human biology, orchestrating a large variety of biological functions in both health and disease. Understanding the interactions and regulatory pathways of NRs will allow development of potential therapeutic interventions for a multitude of disease processes. Non-coding RNAs have recently been discovered to have significant interactions with NR signalling pathways via a variety of biological connections. This review summarises the known interactions between ncRNAs and the NR superfamily in health, embryogenesis and a plethora of human diseases.

Reports have described the prognostic relevance of microRNAs (miRNAs) in patients treated for pancreatic ductal adenocarcinoma (PDAC). However, many of these include small numbers of patients. To increase statistical power and improve translation, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of miRNAs on overall survival (OS) and disease-free survival (DFS) in PDAC.Eligible studies were identified and quality assessed using multiple search strategies (last search December 2014). Data were collected from studies correlating clinical outcomes with dysregulated tumoural or blood miRNAs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations.Twenty studies involving 1525 patients treated for PDAC were included. After correcting for publication bias, OS was significantly shortened in patients with high tumoural miR-21 (adjusted HR = 2.48; 1.96-3.14). This result persisted when only studies adjusting for adjuvant chemotherapy were combined (adjusted HR = 2.72; 1.91-3.89). High miR-21 also predicted reduced DFS (adjusted HR = 3.08; 1.78-5.33). Similarly, we found significant adjusted HRs for poor OS for high miR-155, high miR-203, and low miR-34a; and unadjusted HRs for high miR-222 and high miR-10b. The small number of studies, limited number of miRNAs and paucity of multivariate analyses are the limitations of our study.This is the first rigorous pooled analysis assessing miRNAs as prognostic biomarkers in PDAC. Tumoural miR-21 overexpression emerged as an important predictor of poor prognosis after PDAC resection independent of other clinicopathologic factors, including adjuvant chemotherapy use.

PURPOSE/OBJECTIVES: A growing body of evidence demonstrates that patient-derived xenografts (PDXs) represent living tumor models that accurately reflect the biology of the primary patient tumor. More importantly, we have previously shown that PDX models show responses to therapeutic agents that are concordant with patient clinical response and can be used to direct personalized cancer treatments (Stebbing, 2014). Here we report the ability of PDX models to predict for patient response to drug treatment in a cohort of breast cancer patients. MATERIALS/METHODS: Tumors were resected from patients with either primary or metastatic breast cancer and implanted into immunodeficient mice to establish PDX models. Successfully engrafted PDX models were expanded and randomized for drug sensitivity testing. Tumor growth inhibition and tumor regression were captured and results were correlated with a patient’s clinical response. In some cases, PDX results were used to personalize cancer treatment and some patients used PDX-directed treatments over multiple lines of therapy. RESULTS: A total of 42 tumors from 40 patients were implanted resulting in 21 successfully engrafted PDX models (50% engraftment rate). Notably, engraftment rates were much higher for patients with triple negative breast cancer (TNBC) and resulted in 7 successful PDX models from 8 TNBC patients (87.5% engraftment rate). Drug sensitivity testing was offered to patients with established PDX models. Drugs and drug combinations tested included standard and nonstandard chemotherapy as well as biologics. At that time of this publication, 4 patients (3 TNBC and 1 HER2+) with completed drug sensitivity tests also had clinical data available resulting in 7 clinical correlations; 4 retrospective and 3 prospective. In all 7 cases, the PDX model accurately predicted patient clinical response demonstrating an accuracy of 100%. Five of the drug tests predicted drug sensitivity and 2 tests predicted resistance, indicating the potential of the PDX platform to predict for both sensitivity and resistance to therapy. The 3 prospective correlations resulted in concordant clinical benefit in 2 patients for duration greater than 6 months each. CONCLUSIONS: These data support the use of the personalized PDX model as a platform for therapeutic decision making that can guide treatment for patients with breast cancer. A prospective clinical trial in TNBC is currently underway. Citation Format: Lisa Stow, Amanda Katz, Hanna Irie, Elisa Port, Justin Stebbing, Daniel Ciznadija, Angela Davies, Keren Paz. Patient-derived xenografts accurately predict patient response in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-31.

Obesity is a known risk factor for breast cancer. We have recently identified that adipokine leptin regulates the expression of a proto-oncogenic enzyme sphingosine kinase 1 (SK1). Signal transducer and activator of transcription 3 (STAT3) has been linked to breast cancer progression and here we investigate the mechanism of leptin-induced STAT3 activation in ER-negative breast cancer. Gene and protein expression in human primary and secondary breast cancer tissues was analysed using quantitative real-time polymerase chain reaction (qRT-PCR) assay and immunofluorescence. Leptin-induced signalling was analysed in human ER-negative breast cancer cells using Western blotting, qRT-PCR and radiolabelling assays. Gene expression and receptor signalling was modified using small interfering RNA and neutralising antibodies. In human ER-negative breast tumours and lymph node metastases, the expression of leptin receptor significantly correlated with SK1. In ER-negative breast cancer cells, SK1 knockdown led to a significant reduction in leptin-induced STAT3 phosphorylation. Knockdown of another known activator of STAT3 signalling, gp130 also resulted in a significant decrease in leptin-induced STAT3 phosphorylation. ELISA assay showed that leptin produces a significant amount of IL-6 in an SK1-dependent manner. IL-6 neutralising antibodies significantly reduced p-STAT3. Immunofluorescent staining of human primary and secondary breast tumours showed significant correlation between SK1 and IL-6 (P < 0.001), SK1 and p-STAT3 (P < 0.01) and IL-6 and p-STAT3 (P < 0.01). Our findings demonstrate that leptin-induced STAT3 is partially cross activated through SK1-mediated IL6 secretion and gp130 activation. Positive correlations in human tissues suggest the potential significance of this pathway in ER-negative breast cancer.

An understanding of epigenetic drivers of tumorigenesis has developed rapidly during the last years. The identification of these changes including DNA methylation and histone modifications in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is a step forward in trying to define underlying biologic processes in this heterogeneous disease. The reversible nature of these changes represents a potential therapeutic target. We present an overview of the current knowledge of epigenetic alterations related to GEP-NETs, focusing on the influence and impact these changes have on pathogenesis and prognosis. The potential role of demethylating agents in the management of this patient population is discussed.

For most of human history there has been no particular importance of establishing the exact time of a person's death, only whether the person is alive or dead. With modern medical advances, however, more precise answers are looked for. For a definition of death to succeed is important that it is a universal definition and that under it, all human beings are correctly identified as alive or dead. This article initially examines the most commonly proposed positions on when a human being dies those of cardiopulmonary death, whole brain death, brainstem death and higher brain death and for each describes scenarios that provide counter-intuitive results. Intuition is used as a benchmark as this is what our patients most commonly use. The second part of the article seeks to establish a more robust definition of death. We argue that death is an event that takes place at a set point in time, when the collection of bodily processes that maintains homoeostasis finally cease. Based upon defining 'human being' as being in possession of human DNA and Olsen's Animalism, the model is applicable to a full lifespan and maintains personal identity throughout the course of life. That this conclusion will interfere with clinical practice concerning organ transplantation is considered, but countered with the argument that there has been a conflation of the normative question of timing of organ retrieval for transplantation with the metaphysical question of what is death.

// Philip Carter 1 , Costi Alifrangis 2 , Biancastella Cereser 1 , Pramodh Chandrasinghe 1, 3 , Lisa Del Bel Belluz 1 , Nina Moderau 1 , Fotini Poyia 1 , Lee S. Schwartzberg 4 , Neha Tabassum 1 , Jinrui Wen 1 , Jonathan Krell 1 and Justin Stebbing 1 1 Department of Surgery and Cancer, Imperial College, London, UK 2 Department of Oncology, University College Hospital, London, UK 3 Department of Surgery, University of Kelaniya, Kelaniya, Sri Lanka 4 West Cancer Center, The University of Tennessee, Memphis, USA Correspondence to: Philip Carter, email: phil.carter@imperial.ac.uk Keywords: tumor profiling; breast cancer; cancer treatment Received: July 29, 2017 Accepted: October 28, 2017 Epub: February 24, 2018 Published: April 03, 2018 ABSTRACT We used data obtained by Caris Life Sciences, to evaluate the benefits of tailoring treatments for a breast carcinoma cohort by using tumor molecular profiles to inform decisions. Data for 92 breast cancer patients from the commercial Caris Molecular Intelligence database was retrospectively divided into two groups, so that the first always followed treatment recommendations, whereas in the second group all patients received at least one drug after profiling that was predicted to lack benefit. The biomarker and drug associations were based on tests including fluorescent in situ hybridization and DNA sequencing, although immunohistochemistry was the main test used. Patients whose drugs matched those recommended according to their tumor profile had an average overall survival of 667 days, compared to 510 days for patients that did not (P=0.0316). In the matched treatment group, 26% of patients were deceased by the last time of monitoring, whereas this was 41% in the unmatched group (P=0.1257). We therefore confirm the ability of tumor molecular profiling to improve survival of breast cancer patients. Immunohistochemistry biomarkers for the androgen, estrogen and progesterone receptors were found to be prognostic for survival.

In Act 1 of the Importance of Being Earnest by Oscar Wilde, Lady Bracknell declares, ‘To lose one parent, Mr Worthing, may be regarded as a misfortune; to lose both looks like carelessness.’

Genes involved in the carcinogenetic mechanisms underlying malignant pleural mesothelioma (MPM) are still poorly characterized. So far, mesothelin (MSLN) has aroused the most interest. It encodes for a membrane glycoprotein, frequently over-expressed in various malignancies such as MPM, and ovarian and pancreatic cancers. It has been proposed as a diagnostic and immunotherapeutic target with promising results. However, an alternative therapeutic approach seems to rise, whereby synthetic molecules, such as antisense oligonucleotides, could be used to inhibit MSLN activity. To date, such a gene-level inhibition has been attempted in two studies only, both on pancreatic and ovarian carcinoma cell lines, with the use of silencing RNA approaches. With regard to MPM, only one cell line (H2373) has been employed to study the effects of MSLN depletion. Indeed, the knowledge on the role of MSLN in MPM needs expanding. Accordingly, we investigated the expression of MSLN in a panel of three MPM cell lines, i.e., NCI-H28, Mero-14, and IstMes2; one non-MPM cell line was used as reference (Met5A). MSLN knock-down experiments on MSLN-overexpressing cells were also performed through silencing RNA (siRNA) to verify whether previous findings could be generalized to a different set of cell cultures. In agreement with previous studies, transient MSLN-silencing caused decreased proliferation rate and reduced invasive capacity and sphere formation in MSLN-overexpressing Mero-14 cells. Moreover, MSLN-siRNA combined with cisplatin, triggered a marked increase in apoptosis and a decrease in proliferation as compared to cells treated with each agent alone, thereby suggesting a sensitizing effect of siRNA towards cisplatin. In summary, our findings confirm that MSLN should be considered a key molecular target for novel gene-based targeted therapies of cancer.

Small mothers against decapentaplegic (SMAD) proteins are a family of signal transduction molecules in transforming growth factor β (TGFβ) ligand pathways that have been found to have a key role in the pathogenesis of inflammatory bowel disease (IBD). Long standing IBD predisposes individuals to colitis-associated colorectal cancer (CAC), an entity that possess unique characteristics compared to hereditary and sporadic cancer. The ligands of the TGFβ super family along with SMADs have also been implicated in several aspects of colorectal cancer formation. SMAD proteins are shown to be involved in a number of potentially carcinogenic mechanisms such as altering gene transcription, controlling stem cell differentiation to causing epigenetic changes. Modulation of these proteins has emerged as a novel therapeutic intervention for IBD although its effect on carcinogenesis remains elusive. This account reviews available evidence linking SMAD proteins to CAC and explores the potential areas for future research in this area.Oncogene advance online publication, 4 September 2017; doi:10.1038/onc.2017.300.

Summary Background CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer. Methods In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I–IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2–8) in conjunction with neoadjuvant docetaxel (75 mg/m 2 on day 1 of cycles 1–4) and FEC (fluorouracil [500 mg/m 2 ], epirubicin [75 mg/m 2 ], and cyclophosphamide [500 mg/m 2 ]; day 1 of cycles 5–8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3–6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was −0·15 to 0·15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting. Findings Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4–53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1–56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (−0·04 [95% CI −0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [ vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%). Interpretation CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer. Funding Celltrion Inc.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Background Advanced pancreatic ductal adenocarcinoma remains a clinical challenge. Only a third of patients receiving FOLFIRINOX combination chemotherapy displays tumour downstaging. Because of their high stability in plasma, especially in extracellular vesicles, microRNAs (miRNAs) hold great promise as a new class of minimally invasive biomarkers. Our aim was to identify differently expressed, blood-based miRNAs to select and monitor patients with advanced pancreatic ductal adenocarcinoma who would benefit from FOLFIRINOX. Methods In this prospective, multicentre study, we enrolled 50 patients with locally advanced or metastatic pancreatic ductal adenocarcinoma receiving FOLFIRINOX. The first cohort of 11 patients was selected according to their short versus long progression-free survival, and miRNA profiling was performed to identify differentially expressed circulating-free miRNAs. Emerging miRNAs, as well as various endogenous control miRNAs, were then validated in extracellular vesicles by RT-PCR in a second cohort of 16 non-progressive patients (ie, those with partial response or stable disease). No further analyses were performed in the other 23 patients, who included progressive patients or those without samples available for exosomes extraction. Findings MiR-29a emerged as a potential biomarker both in the profiling and RT-PCR analyses, in the first and second cohorts, respectively. In particular, it was significantly upregulated (2·36-fold change, p=0·0024) in extracellular vesicles after five cycles of FOLFIRINOX therapy in non-progressive disease. Interestingly, the expression of miR-29a was significantly higher in extracellular vesicles than in circulating free miR-29a (p Interpretation We show that altered levels of miR-29a in plasma extracellular vesicles can anticipate progression of pancreatic ductal adenocarcinoma and guide therapeutic options. Higher miR-29a expression in extracellular vesicles than in circulating free miR-29a suggests an active secretion and warrants further studies on its role in tumour–host interactions. These findings open new opportunities to explore blood-based miRNA profiles and specific miRNA candidates to select patients most likely to respond to FOLFIRINOX. Funding Bennink Foundation, Netherlands; Cancer Center Amsterdam Foundation, Netherlands; AIRC Grant Start Up, Italy; FAS grant, Italy; Action Against Cancer, UK; No Surrender Cancer Trust (in memory of Jason Boas), UK.

Large-scale transcriptome and epigenome analyses have been widely utilized to discover gene alterations implicated in cancer development at the genetic level. However, mapping of signaling dynamics at the protein level is likely to be more insightful and needed to complement massive genomic data. Stable isotope labeling with amino acids in cell culture (SILAC)-based proteomic analysis represents one of the most promising comparative quantitative methods that has been extensively employed in proteomic research. This technology allows for global, robust and confident identification and quantification of signal perturbations important for the progress of human diseases, particularly malignancies. The present review summarizes the latest applications of in vitro and in vivo SILAC-based proteomics in identifying global proteome/phosphoproteome and genome-wide protein-protein interactions that contribute to oncogenesis, highlighting the recent advances in dissecting signaling dynamics in cancer.

In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.

Totally implantable venous access ports are widely used for the administration of chemotherapy in patients with cancer. Although there are several approaches to implantation, here we describe Port-A-Cath(®) (PAC) placement by percutaneous puncture of the subclavian vein with ultrasonographic guidance.Data on our vascular access service were collected prospectively from June 2004. This service included port-a-caths and Hickman lines. Once 1000 consecutive port-a-caths(®) had been reached the study was closed and data analysed for the port-a-caths(®) alone. The left subclavian vein was the preferred site for venous access, with the right subclavian and jugular veins being the alternative choices if the initial approach failed. Patients were followed up in the short-term, and all the procedures were carried out by a single surgeon at each one of two institutions.Venous access by PAC was established in 100 % of the 1,000 cases. Of the 952 patients where the left subclavian vein was chosen for the first attempt of puncture, the success rate of PAC placement was 95 % (n = 904). Pneumothorax occurred in 12 patients (1.2 %), and a wound haematoma occurred in 4 (0.4 %) out of the total 1,000 patients. No infections were recorded during the immediate post-operative period but only in the long-term post-operative use with 8 patients requiring removal of the PAC due to infection following administration of chemotherapy.This is a very large series of PAC placement with an ultrasound-guided approach for left subclavian vein and X-ray confirmation, performed by a single surgeon, demonstrating both the safety and effectiveness of the procedure.

Despite its identification over 100 years ago, new discoveries continue to add to the complexity of the regulation of the endocrine system. Today the nuclear receptors (NRs) that play such a pivotal role in the extensive communication networks of hormones and gene expression remain an area of intense research. By orchestrating core processes, from metabolism to organismal development, the gene expression programs they control are dependent on their cellular context, their own levels, and those of numerous co-regulatory proteins. A previously unknown component of these networks, noncoding RNAs (ncRNAs) are now recognized as potent regulators of NR signaling, influencing receptor and co-factor levels and functions while being reciprocally regulated by the NRs themselves. This review explores the regulation enacted by microRNAs and long ncRNAs on NR function, using representative examples to show the varied roles of ncRNAs, in turn producing significant effects on the NR functional network in health and disease.

Cancer diagnosis, medicine, prevention and care is changing – all for the better. As opposed to the “old days” of luck, trial and error and toxicity, we are now entering a new dawn due to advances in genomics and our understanding of biology. Personalised medicine or PM (aspects of which may also be referred to as precision medicine) is a medical model that proposes the customisation of healthcare – with medical decisions, practices, and/or products being tailored to the individual patient. This talk examines how this has evolved in the field of oncology, to maximise benefits to our patients and minimise toxicity, being able to predict in advance who our therapies will work for.

BACKGROUND The management of brain metastases in patients with germ cell tumors remains controversial. The authors assessed the outcome in this patient group after the introduction of GAMEC chemotherapy (14-day cisplatin, high-dose methotrexate, etoposide, and actinomycin-D with filgrastim support) and cessation of the routine use of cranial irradiation. METHODS Data were recorded prospectively from 39 patients with germ cell tumors and concurrent brain metastases who received treatment before and after the advent of GAMEC after they relapsed on conventional cisplatin-based chemotherapy. Neurosurgery was offered to selected patients. Radiotherapy generally was used only as a salvage therapy after chemotherapy failure. The primary outcome measure was overall survival and was depicted using a Kaplan-Meier plot. RESULTS The 3-year overall survival rates were 38% for the whole cohort, 69% for those who presented with brain metastases at diagnosis (group 1), and 21% and 0% for those who developed metastases after initial chemotherapy (group 2) and while receiving chemotherapy (group 3), respectively. For the whole cohort, the median overall survival was 10.6 months (range, 5.5 months to not evaluable); and, for groups 1, 2, and 3 individually, the overall survival was not yet reached (range, from 7.4 months to not evaluable), 6.2 months (range, 2.1-15.3 months), and 2.7 months (range, from 0.6 months to not evaluable), respectively. The 3-year survival rate for those who received GAMEC chemotherapy was 56% compared with 27% for those who received chemotherapy pre-GAMEC. CONCLUSIONS The prognosis for patients with germ cell tumors and brain metastases seems less bleak than previously thought. It is possible to achieve long-term survival with chemotherapy alone. Cancer 2014;120:1639–1646. © 2014 American Cancer Society.

Due to its aggressive and late presentation, there is an urgent need for novel and reliable biomarkers for the diagnosis and prognostication of pancreatic ductal adenocarcinoma (PDAC). MiRNAs have been extensively profiled in PDAC tissues, biopsies, blood samples and other biofluids and their expression levels compared to normal and chronic pancreatitis (CP) specimens in order to identify the most relevant candidates. Consolidation of these activities has not been attempted until now. The evaluated meta-review by Ma et al. helps to define the use of miRNAs as biomarkers for detecting this tumor-type and predicting survival outcomes in PDAC. Based on frequency and consistency between microarray studies, they identified a miRNA meta-signature for recognising PDAC: upregulation of miR-21, 23a, 31, 100, 143, 155, and 221; with downregulation of miR-148a, 217 and 375. Furthermore, they validated high miR-21, high miR-31 and low miR-375 tumoural expression as independently prognostic for poor overall-survival (OS; n = 70).

Background & Aims There has not been a broad analysis of the combined effects of altered activities of microRNAs (miRNAs) in pancreatic ductal adenocarcinoma (PDAC) cells, and it is unclear how these might affect tumor progression or patient outcomes. Methods We combined data from miRNA and messenger RNA (mRNA) expression profiles and bioinformatic analyses to identify an miRNA−mRNA regulatory network in PDAC cell lines (PANC-1 and MIA PaCa-2) and in PDAC samples from patients. We used this information to identify miRNAs that contribute most to tumorigenesis. Results We identified 3 miRNAs (MIR21, MIR23A, and MIR27A) that acted as cooperative repressors of a network of tumor suppressor genes that included PDCD4, BTG2, and NEDD4L. Inhibition of MIR21, MIR23A, and MIR27A had synergistic effects in reducing proliferation of PDAC cells in culture and growth of xenograft tumors in mice. The level of inhibition was greater than that of inhibition of MIR21 alone. In 91 PDAC samples from patients, high levels of a combination of MIR21, MIR23A, and MIR27A were associated with shorter survival times after surgical resection. Conclusions In an integrated data analysis, we identified functional miRNA−mRNA interactions that contribute to growth of PDACs. These findings indicate that miRNAs act together to promote tumor progression; therapeutic strategies might require inhibition of several miRNAs.

Prostate cancer is the most common non-cutaneous cancer in North American and European men and the second leading cause of male cancer-related death [1]. The lifetime probability of developing prostate cancer in the UK is 14% [1] and in 2010 there were there were 40,975 new cases, accounting for 10,721 deaths [2]. Prostate cancer is associated with many risk factors, including age, family history, ethnicity, diet, and weight and although it is estimated that not more than 5% of all prostate cancer cases are hereditary, family history is appropriately considered a relevant risk factor. Many genetic changes have been associated with prostate cancer, including mutations in P53, P21, and P73 and tumour suppressor genes [3].

Harmonious interactions between radiation, medical, interventional and surgical oncologists, as well as other members of multidisciplinary teams, are essential for the optimization of patient care in oncology. This multidisciplinary approach is particularly important in the current landscape, in which standard-of-care approaches to cancer treatment are evolving towards highly targeted treatments, precise image guidance and personalized cancer therapy. Herein, we highlight the importance of multidisciplinarity and interdisciplinarity at all levels of clinical oncology training. Potential deficits in the current career development pathways and suggested strategies to broaden clinical training and research are presented, with specific emphasis on the merits of trainee involvement in functional multidisciplinary teams. Finally, the importance of training in multidisciplinary research is discussed, with the expectation that this awareness will yield the most fertile ground for future discoveries. Our key message is for cancer professionals to fulfil their duty in ensuring that trainees appreciate the importance of multidisciplinary research and practice.

Introduction: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. Recently, different experimental approaches, such as RNA Sequencing, crosslinking immunoprecipitation (CLIP) methods and its variations, together with computational approaches have been developed to elucidate the miRNA-mRNA targetome. Areas covered: This report focuses on comparing the different experimental and computational approaches, describing their advantages and disadvantages and providing several examples of preclinical (in vitro and in vivo) and clinical studies that have identified miRNA target genes in various tumour types, including breast, ovary, colorectal and pancreas. Expert commentary: The combination of CLIP methods with bioinformatic analyses is essential to better predict miRNA-mRNA interactions and associate their specific pathways within the extensive regulatory network. Nevertheless, further studies are needed to overcome the difficulties these methods have, in order to find a gold standard method that identifies, without any bias, the regulatory association between miRNAs and their target mRNAs.

TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell-cell junctions' pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis.

Background: Amongst the various risk factors for breast cancer (BC), the molecular basis which may explain the correlation between age at first full-term and breast cancer risks is still understudied. Epidemiology studies indicate that an early first full-term pregnancy (before 25 years of age) confers a significant level of protection towards the development of post-menopausal BC compared to the risk in nulliparous or late-parous women. On the other hand, any pregnancy relates to a higher risk in developing cancer during or within one year of pregnancy (pregnancy-associated breast cancer, PABC). Thus, the relation between age of pregnancy and breast cancer risk may be too difficult to explain using only epidemiology data. Aims of the study: With our research study, we aim to study a cohort of 60 normal breast samples of nulliparous and age-matched early- and late-parous women collected from Komen Tissue Bank, University of Indiana, and to create for the first time a mathematical model of cell clone expansion in the normal breast growth. This will allow us to determine how the rates of both cancer drivers, passenger mutations and genetic variations are affected by pregnancy. We then aim to translate this in cancer tissues, and to determine how the rate of the same mutations in both pregnancy and non pregnancy-associated cancers (post-menopausal). At the same time, we intend to create a mouse model which will be used to further validate our model, where driver mutations will be induced in the mammary epithelium of pregnant mice of different ages. This will allow us to test our model of growth of a mutated clone in a pregnancy environment, and to determine what are the molecular changes in the pregnant mammary gland which can trigger a different BC risk in the early-parous cohort. Results: To examine the mutational landscape in the normal parous and nulliparous women, we extracted DNA from laser-capture microdissected epithelium and the stroma, the latter of which will be used to eliminate germ line mutations. We are currently analysing the results from Whole Genome Sequencing at 30x 100pe on a MGISEQ2000 platform on a first set of samples (two nulliparous samples and two age-matched parous samples from both early and late pregnancy). Our procedure for processing and analysis of this data follows the Broad Institute's “GATK Best Practice Guidelines” for use of next generation sequencing (NGS) data. Based on the collected data, we plan to continue with targeted sequencing or whole genome sequencing on the remaining samples. Conclusions: Our study will provide novel information on which areas of the genome are mostly mutated or altered in the normal breast, and will indicate how mutated cells, including mutations in driver genes for breast cancer, and genetic alterations change in the contest of pregnancy. With the mathematical model of clone growth/extinction, we intend to explain how different ages of pregnancy can significantly alter the clone composition in the normal breast and result in a different probability of developing breast cancer. Citation Format: Cereser B, Tabassum N, Carter P, Del Bel Belluz L, Stebbing J. Study of the mutational landscape of normal and pregnant breast to predict pregnancy-associated breast cancer risk [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-04-06.

TAM (Tyro3-Axl-Mer) receptor tyrosine kinases and Met are implicated in several hallmarks of cancer progression including sustained angiogenesis, enhanced motility, tissue invasion and acquisition of metastatic potential through the upregulation of epithelial-to-mesenchymal transition. Increasing evidence has confirmed Axl and Met as emerging central drivers of adaptive resistance to targeted therapies across a wide variety of cancers. In this issue of Oncogene, Zhou et al. describe the mechanisms linking Axl and Met activation to acquired resistance to sunitinib in renal cell carcinoma (RCC), providing a pre-clinical rationale for the development of Axl and Met inhibitors including cabozantinib in anti-angiogenic resistant RCC.

NANOG is the human ortholog of the mouse Nanog gene1 and is a member of the homeobox family of DNA binding transcription factors.2 NANOG plays an important role in the maintenance of pluripotency and self-renewal of human embryonic stem cells.3 ,4 Chambers et al 3 were the first researchers who identified this transcription factor and named it according to the mythological Celtic land of the ever young, Tir na nOg. Their study was focussed on comparing expressed sequence tag (ESC) libraries between mouse ESCs and various somatic tissues. They also detected this gene in the mouse embryonic carcinoma cells. NANOG is a transcription factor that forms part of a complex regulatory network and its function is based on regulating cell death, proliferation and determining cell fate.5 It is known that NANOG is expressed in cancer stem cells (CSCs) and ESCs.5 Indeed, CSCs have the potential to regulate self-renewal and differentiation within a tumour, triggering tumourigenesis, and NANOG promotes the long-term proliferative potential of these cells.6 Additionally, various studies have suggested that NANOG protein is highly expressed in cancerous tissues, whereas in normal adult tissues, its expression is much lower.5 This short review highlights several aspects of the structure, expression and function of the NANOG gene, including also its role in tumourigenesis and various types of cancers, cancer prognosis and anticancer therapies. Both the human and murine Nanog gene are located in the short arm of chromosome 12 (12p13), a ‘hotspot’ region frequently exposed to duplications and amplifications in human tumours derived from the germ line, particularly in male germ cell tumours.2 ,7 The human and the mouse Nanog gene encode for a protein of 305 amino acids.2 ,5 ,8 Surprisingly, when comparing the 60 amino acids in …

Sphingosine kinase 1 (SK1) plays an important role in estrogen-dependent breast tumorigenesis, but its regulation is poorly understood. A subset of microRNAs (miRNA, miR) is regulated by estrogen and contributes to cellular proliferation and cancer progression. Here, we describe that miR-515-5p is transcriptionally repressed by estrogen receptor α (ERα) and functions as a tumor suppressor in breast cancer. Its downregulation enhances cell proliferation and estrogen-dependent SK1 activity, mediated by a reduction of miR-515-5p posttranscriptional repression. Enforced expression of miR-515-5p in breast cancer cells causes a reduction in SK1 activity, reduced cell proliferation, and the induction of caspase-dependent apoptosis. Conversely, opposing effects occur with miR-515-5p inhibition and by SK1 silencing. Notably, we show that estradiol (E2) treatment downregulates miR-515-5p levels, whereas the antiestrogen tamoxifen causes a decrease in SK1, which is rescued by silencing miR-515-5p. Analysis of chromatin immunoprecipitation sequencing (ChIP-Seq) data reveals that miR-515-5p suppression is mediated by a direct interaction of ERα within its promoter. RNA-sequencing (RNA-Seq) analysis of breast cancer cells after overexpressing miR-515-5p indicates that it partly modulates cell proliferation by regulating the Wnt pathway. The clinical implications of this novel regulatory system are shown as miR-515-5p is significantly downregulated in ER-positive (n = 146) compared with ER-negative (n = 98) breast cancers. Overall, we identify a new link between ERα, miR-515-5p, proliferation, and apoptosis in breast cancer tumorigenesis. Cancer Res; 73(19); 5936–48. ©2013 AACR.

Background: Understanding their experiences of diagnosis is integral to improving the quality of care for women living with advanced/metastatic breast cancer. Methods: A survey, initiated in March 2011, was conducted in two stages. First, the views of 47 breast cancer-related patient groups in eight European countries were sought on standards of breast cancer care and unmet needs of patients. Findings were used to develop a patient-centric survey to capture personal experiences of advanced breast cancer to determine insights into the ‘trade-off' between extending overall survival and side effects associated with its treatment. The second online survey was open to women with locally advanced or metastatic breast cancer, or their carers, and responders were recruited through local patient groups. Data were collected via anonymous local language questionnaires. Results: The online stage II survey received a total of 230 responses from 17 European countries: 94% of respondents had locally advanced or metastatic breast cancer and 6% were adult carers. Although the overall experience of care was generally good/excellent (77%), gaps were still perceived in terms of treatment choice and information provision. Treatment choice for patients was felt to be lacking by 32% of responders. In addition, 68% of those who responded would have liked more information about future medical treatments and research, with 57% wishing to receive this information from their oncologist. Two-thirds (66%) of women with advanced breast cancer, or their carers, believed life-extending treatment to be important so that they can spend more time with family and friends, and 67% said that the treatment was worthwhile, despite potential associated side effects. Conclusion: These findings show a continuing need to provide women with advanced breast cancer with better information and emphasise the importance that these patients often place on prolonging survival.