Oncology News July/August 2016

Oncology news

Volume 11 Issue 3 • July/August 2016 • www.oncologynews.biz

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Repurposing non-cancer drugs to treat cancer Dysregulation of histone deacetylases in paediatric brain tumours Driver genes in breast cancer: importance, integration & identification Brief view of breast cancer in Iran: cross-road of genetics, cellular and cancer epidemiology

ISSN 1751-4975

FROM THE EDITOR

Spontaneous Regression

T

Denys Wheatley Editor

66

he incidence of reported spontaneous tumour regression over the last two or so years seems quite high. Over many years, several authors have compiled and reviewed as many as 1,000 cases, one study from 1900 to 1987 covering over 400 cases alone [1]. It has been noted that some types of tumour more frequently regress than others, notably some of the neural system. Even melanoma metastases in the brain have spontaneously regressed.

While at the Institute of Cancer Research in London, the director, Sir Alex Haddow, took an interest in this matter. He was informed of any case where transplanted tumours in animals had grown as expected, but then had regressed without being treated (e.g. usually within the control groups). There must have been an underlying hypothesis for which he sought evidence to explain the phenomenon. Since experimental animals are kept under relatively constant conditions, complete regression it is unlikely due to some change in the environment, except that occasional animal picking up an infection. The most obvious hypothesis would be that an animal had an overactive immune system that recognised the tumour and could eventually overwhelm it. Resolution was probably by slow attrition, with tumour cells dying off faster than they proliferated, perhaps under redirection by a change in p53 activity, going to apoptosis rather than re-entering the next cell cycle. A powerful response that elicited massive inflammation would be easily recognised.

It has often been said that tumours are “wounds that do not heal”. My own research in altering the immune status of mice bearing ascites tumours showed that suppressing it allowed the cells to proliferate for longer than in controls, and unexpectedly animals survived longer. When, in contrast, a strong inflammatory reaction was also induced, tumour cells did not proliferate as fast, became highly invasive, and died more quickly than controls. The intensity of the immune response can therefore push tumours one way or the other. One early attempt as a tumour therapy was to inject BCG directly into them, which led to an intense inflammatory reaction and massive necrosis, a treatment starting in the 1970-80s [2] and still used today for non-invasive bladder cancer).

Tumour regression in unexpected (well progressed) cases can be attributed to (but not explained by) changing circumstances in the patient. Operative trauma has been invoked.

Inflammation has been mentioned involved, with cancer cells being more sensitive to hyperthermia than normal cells under these conditions (in fever). Change in diet might influence tumour growth, and marked changes in the hormonal balance in human being might affect tumour growth; pregnancy has occasionally led to tumour regression). Production of inhibitory factors or the lessening of the action of factors that otherwise enhance tumour cell proliferation cannot be excluded. Reduced neovascularisation after a tumour has taken hold might limit growth, but even in such cases it seems odd that a tumour would regress rather than simply maintain its mass.

Regression might be far more common than the 1 in 100,000 cases often quoted. First there are tumours that might have regressed, but were never presented in the first place. The second is the obvious corollary of this, that it is a phenomenon occurring all the time, i.e. we are all producing nidi of transformed cells, but these do not progress to becoming palpable (detectable) tumours. Nevertheless it is thought to occur in breast cancer, but the histological nature of almost all the nodules would not have been investigated [3].

We are left cataloguing cases of spontaneous regression, and have little evidence for any particular hypothesis or more general ideas of what is involved. Unless there are some tumours where this is not such an uncommon event, it is difficult to get a handle on any of the underlying mechanisms, of which there are almost certainly many. Hypotheses are still needed, but we ought to consider what oncologist might suspect as possible explanations in specific cases. Comments to Oncology News would be welcome or send a short article to Cancer Hypotheses (www.cancerhypotheses.org.uk).

REFERENCES 1. Challis GB, Stam HJ. The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncol 1990;29 (5): 545–50. doi:10.3109/02841869009090048.PMID 2206563.

2. Lamm DL, Thor DE, Winters WD, et al. BCG immunotherapy of bladder cancer: inhibition of tumor recurrence and associated immune responses. Cancer. 1981;48(1):82-8.

3. Zhal PH, Mæhlen J, Welch HG. The Natural History of Invasive Breast Cancers Detected by Screening Mammography.

Arch Intern Med 2008;50(21):2311–6.

Volume 11 Issue 3 • July/August 2016

Contents

Volume 11 Number 3 • July/August 2016

66 Editorial 68 Repurposing non-cancer drugs to treat cancer Pan Pantziarka, London, and Gauthier Bouche, Lydie Meheus, Belgium

71 Neuro-oncology – Dysregulation of histone deacetylases in paediatric brain tumours Emily Pinkstone, Portsmouth, UK

76 Breast cancer – Driver genes in breast cancer: importance, integration & identification Nicola Faramarzi and Nadège Presneau, London, UK

80 Breast cancer – Brief view of breast cancer in Iran: cross-road of genetics, cellular and cancer epidemiology Hassan Yousefi and Parvin Mehdipour , Tehran, Iran

84 Conference News Previews and reports from the conference scene.

88 News Update Details of the latest developments and news from the industry and charities.

91 Journal Reviews

www.oncologynews.biz Visit today to: Subscribe for free and read the digital online edition of the magazine Search our extensive online diary of upcoming courses and conferences Access the archive of articles from previous editions of Oncology News

92 Diary Listing of meetings, courses and conferences, both UK and international.

92 Courses & Conferences

Cover image: One of many hats auctioned at the Fenwick charity auction for Brain Tumour Research, see p90 for further details.

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67

FEATURE ARTICLE

Repurposing non-cancer drugs to treat cancer

D Pan Pantziarka, PhD, Scientist, Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium and The George Pantziarka TP53 Trust, London, UK.

Gauthier Bouche, Medical Director, Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium.

Lydie Meheus, PhD, Managing Director, Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium.

Correspondence to: E: anticancer.org.uk@ gmail.com Acknowledgement The authors would like to thank Vikas P. Sukhatme and Vidula Sukhatme for useful discussion of some of the ideas presented in this article.

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rug repurposing, sometimes also referred to as drug repositioning, is a drug development strategy that seeks to reuse licensed drugs for new indications [1,2]. The advantages of repurposing existing well-characterized and widely used drugs are many and obvious, for example the reuse of established pharmacokinetic and toxicology data (including rare adverse events), and low costs (especially for generic medications). This could lead to a significant reduction in the development life-cycle, for example by reducing the need for early-phase clinical trials assessing safety and tolerance.

Examples of successful repurposing are fairly common in medicine. One example is sildenafil (viagra), which was developed for hypertension and angina, but repurposed for erectile dysfunction and then subsequently licensed for pulmonary arterial hypertension.

Another example is methotrexate, one of the first commonly used chemotherapeutics in cancer, now routinely used for severe psoriasis and rheumatoid arthritis. Methotrexate is not the only cancer drug being repurposed for non-oncological conditions; however, examples of non-cancer drugs being repurposed for treating cancer have only a single example, viz. thalidomide. Thalidomide was widely used as a treatment for morning sickness before infamously the association with birth defects was discovered. The drug has subsequently been licensed by the FDA for the treatment of leprosy, and later by the FDA and EMA for the treatment of multiple myeloma.

However, a growing number of clinicians and researchers believe that there are many more agents that can make a positive contribution to cancer treatment. The Repurposing Drugs in Oncology (ReDO) project – is an international collaboration looking specifically at this issue – founded by two not-for-profit foundations – the Anticancer Fund, based in Brussels, and GlobalCures, based in Massachusetts [3]. The project strategy has been to identify approved drugs with the potential to make a clinical difference and bringing them to the attention of clinicians and researchers by summarising and publishing the data in peer-reviewed journals.

In parallel, the parent organisations involved in ReDO have also been collaborating with a range of investigators in different clinical trials to establish the efficacy of some of the drugs they have identified (http://www.anticancerfund.org/ projects/currently-ongoing).

Selecting drug candidates An initial surprise was the high number of potential repurposing candidates; in fact the problem has been to identify the most promising targets rather than simply identifying possible targets. The major criteria used in target selection are: • The drug should be well-known and widely used clinically; • Low toxicity, particularly if it is for long-term use; • There is a relevant putative mechanism of action; • It shows strong evidence of anticancer activity. Human data is valued significantly more highly than in vitro and animal data.

Preclinical data in syngeneic, orthotopic transplantable models or genetically engineered mice is rated more highly than other forms of in vivo models; • There is evidence of anticancer efficacy at standard dosing or at a level that is not associated with significant toxicity; • The drug is not currently being widely pursued as an active agent in oncology.

The last criterion is important as there are a number of candidate drugs currently under intense scrutiny and clinical investigation in oncology, including aspirin, metformin and some statins. ReDO therefore focuses on drugs that have yet to achieve the kind of momentum illustrated by, for example, the Add Aspirin trial (http://www.addaspirintrial.org/).

To date there are published articles on six candidate drugs: mebendazole [4], cimetidine [5], itraconazole [6], nitroglycerin [7], clarithromycin [8] and diclofenac [9] – Table 1 gives details.

Other targets with high potential currently being investigated include the non-selective beta-blocker, propranolol, the anti-malarial, chloroquine, and angiotensin II receptor antagonists (losartan, telmisartan, etc.).

Dirty drugs?

It is apparent from Table 1 that the range of agents with potential for reuse in oncology encompasses an extremely diverse set of drug families. Many different mechanisms of action are at work and only a few of these drugs are directly cytotoxic. Instead many of them have effects on the tumour microenvironment or the immune response, which include: • Disruption of key pathways that mediate resistance to existing treatments, for example, affecting drug efflux or other mechanisms of resistance; Volume 11 Issue 3 • July/August 2016

FEATURE ARTICLE

Table 1 - High-potential drugs for repurposing Drug

Original Indication

Relevant Mechanism of Action

Notes

Mebendazole

Anti-parasitic

Microtubule disruption, Hedgehog pathway inhibition, anti-angiogenic

In vitro, in vivo and some human case studies. P53 independent, also targets XIAP. Currently in trials in glioblastoma.

Cimetidine

Antacid

Cellular proliferation, immunomodulatory, cell adhesion

Evidence that post-operative use reverses immunosuppression. Currently in trial in colorectal cancer.

Itraconazole

Antifungal

Hedgehog pathway inhibition, antiangiogenic, targets cancer stem cells, reverse MDR

Hedgehog a target of interest in multiple cancers. In trials in BCC, prostate and NSCLC.

Nitroglycerin

Vasodilation

Chemo/radio-sensitisation, anti-hypoxic (HIF1-alpha)

HIF1-alpha a target of interest in multiple solid tumours. Current trials in NSCLC.

Clarithromycin

Antibiotic

Autophagy inhibition, anti-angiogenic, immunomodulatory

Most evidence in multiple myeloma and some lymphomas. Currently in trials in MM, lymphoma and NSCLC.

Diclofenac

NSAID

Anti-angiogenic, COX-2/PGE2 inhibitor, immunomodulatory

Pre-clinical and epidemiological data exists, but currently no trials are in progress. The related drug ketorolac in being trialled in breast cancer.

• Inhibition of tumour neoangiogenesis/vascularization; • Stimulation of host immunity and/ or reversal of cancer-associated immunosuppression; • Targeting of oncogenic pathways, for example, Hedgehog signalling; • Disruption of key proliferative pathways, for example, disrupting microtubule dynamics.

Many of these drugs were developed for clinical use at a time when our knowledge of the molecular biology of cancer was far less developed. In contrast to the modern paradigm of drug development – which identifies relevant molecular pathways and then designs specifically targeted agents – many of these older drugs serendipitously have multiple clinically relevant pathways. While once these old drugs were considered ‘dirty drugs’, we can now more usefully classify them as multi-targeted agents.

However, even with these multi-targeted agents, it is unlikely that any single drug will be sufficient to treat cancer. Therefore a key consideration in investigating these repurposed drugs is to consider how it is that they may be used therapeutically.

Typically this means combinations of one or more repurposed drugs with existing therapies. The ReDO papers have explicitly addressed this issue and have identified combination treatments that may be of value in specific clinical settings.

Clinical Trials While there is human data to show an anticancer effect for the candidate drugs, much of this is either retrospective or from small early-phase prospective trials.

Volume 11 Issue 3 • July/August 2016

While the promise of repurposing is that these drugs are relatively cheap, easy to access and potentially easy to adopt clinically, the promise can only be realised if there is convincing evidence of efficacy.

There are numerous clinical trials in progress exploring combinations of repurposed drugs and existing standard of care therapies, including: • Breast cancer (NCT01806259) – Ketorolac 30 mg IV, pre-incisional in patients undergoing curative resection; • NSCLC (NCT01210378) – Transdermal nitroglycerin patch with standard of care (chemo-radiotherapy); • Pediatric optic nerve gliomas (NCT02115074) – Combination of celecoxib and fluvastatin; • Osteosarcoma (NCT02517918) Metronomic cyclophosphamide, methotrexate, zoledronic acid and sirolimus in patients with advanced pre-treated osteosarcoma; • NSCLC – A prospective phase II, randomized multi-centre trial of a bio-modulatory treatment with 3 oral drugs (clarithromycin, pioglitazone and metronomic treosulfan) in patients with NSCLC after platinum failure.

However, there are some cases where the body of evidence in favour of a drug includes high-quality randomised Phase III trials. One of the most striking examples is the classical H2 histamine receptor antagonist, cimetidine. Clinical trials of cimetidine have been carried out in a range of cancers including colorectal, gastric, renal cell carcinoma and melanoma [5].

The results from colorectal cancer are the most extensive; a Cochrane review

concluded that “cimetidine appears to confer a survival benefit when given as an adjunct to curative surgical resection of colorectal cancers” [10]. Cochrane analysis of the 5 cimetidine trials meeting the inclusion criteria, which included 421 patients, yielded a statistically significant improvement in overall survival (HR 0.53; 95% CI 0.32 – 0.87).

Perverse Incentives While the scientific case for repurposing is being made by ReDO and other investigators [11,12], and is now being discussed more widely in the oncological community [13,14], there are significant obstacles in the path to clinical adoption of repurposed drugs.

The first issue is related to the fact that many of the drugs of interest are generics and no longer covered by patent protection. Given the costs associated with running large randomised controlled trials, the lack of patent protection means that pharma companies cannot guarantee a return on their investment should they fund trials. The situation with combination therapies is still more complex, with multiple companies involved the situation requires extended legal negotiations and contracts, all of which require an investment in time and money which cannot be recouped. One upshot of this is that it is often more expensive for institutions to run a trial using cheap generic drugs than it is to run a trial using a significantly more expensive proprietary agent. This leaves many potentially useful treatments languishing as ‘financial orphans’ [15].

The example of cimetidine is 69

FEATURE ARTICLE

instructive in showing that, even with data from multiple Phase III trials, a drug with efficacy may not make it into clinical practice. One factor may be related to the issue of licensing or label extension for a new indication. In normal practice a repurposed drug is typically granted a marketing authorization for a new medical indication by the regulator (the MHRA in the UK). In the absence of a specific license clinicians are often reluctant to prescribe a treatment ‘off-label’, even if evidence of efficacy exists.

Off-label prescribing is not the long-term strategy that ReDO and other researchers are pursuing; an ideal scenario is that the repurposed drug is licensed for its new use. As with trial funding, there are significant direct and indirect costs associated with drug licensing such that generic manufacturers cannot guarantee a return on their investment should they seek a new license or label extension.

Conclusion Drug repurposing holds much potential to deliver new therapies to patients in an accelerated time-frame and at reduced costs compared to de novo drug development.

While there is a renewed level of interest in this strategy, there are significant impediments to progress associated with financial incentives and social policy issues.

Meet the Editorial Team Professor Denys Wheatley is Editor, and is Director of BioMedES. He has strong research ties in Albany, Davis, Auckland, Valencia, Detroit, Budapest, St Petersburg, Heidelberg, Zürich and Hong Kong. He is eager to establish strong interaction with cancer and cell biology teams worldwide, and initiate programmes in the areas in which his expertise lies. His work in cancer research, other scientific fields, with IFCB, and in publishing and scientific communication has led to his receiving awards in recent years.

Dr Richard J Ablin (Associate Editor), is Professor, Pathology, University of Arizona College of Medicine and a Member of the Arizona Cancer Center, Tucson, Arizona. He received the First Award for scientific excellence from The Haakon Ragde Foundation for Advanced Cancer Studies. Dr Ablin discovered prostate-specific antigen (PSA) in 1970. A pioneer of cryosurgery and cryoimmunotherapy, he has extensive experience in cancer research.

Alan Cooper is Assistant Co-Editor – Urology, and is Lead Scientist with the urology research group in Southampton University Hospitals and senior lecturer (albeit with virtually no lecturing burden) in the Department of Biomedical Sciences at Portsmouth University.

Mr Richard Novell is Assistant Co-Editor – Gastrointestinal Section, and is a Consultant Colorectal Surgeon at the Royal Free Hospital. He was a member of the Court of Examiners of the Royal College of Surgeons for eight years and has been an advisor to NICE, NCEPOD and CORESS, the Confidential Reporting System in Surgery.

Dr Miriam Dwek is Assistant Co-Editor – Breast Cancer, she is a Senior Lecturer in Biochemistry at the Department of Molecular and Applied Biosciences, School of Life Sciences, University of Westminster in London.

References 1. Ashburn TT and Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nature reviews. Drug discovery 2004;3(8):673–83.

2. Langedijk J, Mantel-Teeuwisse AK, Slijkerman DS et al. Drug repositioning and repurposing: terminology and definitions in literature. Drug Discovery Today 2015;20(8):1027–34.

Prof Mohammed RS Keshtgar BSc, FRCSI, FRCS (Gen), PhD is Assistant Co-Editor – Breast Cancer, and is a Professor of Cancer Surgery and Surgical Oncology, Royal Free London Foundation Trust. His main area of interest is minimally invasive approaches in diagnosis and treatment of breast cancer. His research interest is in sentinel node biopsy, intra-operative radiotherapy, quantum dot nanotechnology in breast cancer.

3. Pantziarka P, Bouche G, Meheus L, et al. The Repurposing Drugs in Oncology (ReDO) Project. Ecancermedicalscience 2014;8:442.

4. Pantziarka P, Bouche G, Meheus L, et al. Repurposing Drugs in Oncology (ReDO)-mebendazole as an anti-cancer agent. Ecancermedicalscience 2014;8,443.

5. Pantziarka P, Bouche G, Meheus L, et al. Repurposing drugs in oncology (ReDO)-cimetidine as an anti-cancer agent. Ecancermedicalscience 2014;8:485.

6. Pantziarka P, Sukhatme V, Bouche G, et al. Repurposing Drugs in Oncology (ReDO)-itraconazole as an anti-cancer agent. Ecancermedicalscience 2015;9:521.

7. Sukhatme V, Bouche G, Meheus L, et al. Repurposing Drugs in Oncology (ReDO)-nitroglycerin as an anti-cancer agent. Ecancermedicalscience 2015;9:568.

8. Van Nuffel AM, Sukhatme V, Pantziarka P, et al. Repurposing Drugs in Oncology (ReDO)-clarithromycin as an anti-cancer agent.

Ecancermedicalscience 2015;9:513.

9. Pantziarka P, Sukhatme V, Bouche G, et al. Repurposing Drugs in Oncology (ReDO)-diclofenac as an anti-cancer agent. Ecancermedicalscience 2016;10:610.

10. Deva S and Jameson M. Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer. The Cochrane database of systematic reviews 2012;8(8):CD007814.

11. McCabe B, Liberante F and Mills KI. Repurposing medicinal compounds for blood cancer treatment. Annals of hematology 2015;94(8):1267–76.

12. Mudduluru G, Walther W, Kobelt D, et al. Repositioning of drugs for intervention in tumor progression and metastasis: Old drugs for new targets.

Drug Resistance Updates 2016;26:10–27.

Professor Geoffrey J Pilkington is Assistant Editor Neuro-Oncology, is a Professor of Cellular and Molecular Neuro-oncology at the Institute of Biomedical and Biomolecular Sciences, Portsmouth. His research focuses on the development of models for the study of intrinsic brain tumours, elucidation of their metabolism and mechanisms underlying diffuse local invasive behaviour.

Farrokh Pakzad is Assistant Editor – Skin Cancer, and is currently Consultant Oncoplastic Breast and Melanoma Surgeon at Royal Surrey County Hospital. His main areas of specialist interest are in the management of breast disease, oncoplastic and reconstructive breast surgery and the management of skin cancers, in particular, melanoma.

Farrokh completed his higher surgical training in London, during which he was selected onto the highly competitive National Oncoplastic Fellowship program.

Dr Constantino Carlos Reyes-Aldasoro is Assistant Editor – Image Analysis. He is a Lecturer in Biomedical Image Analysis at the School of Engineering and Mathematical Sciences, City University London. He has developed a unique portfolio of interdisciplinary skills that span from the acquisition of microscopical images to the analysis of biomedical datasets such as magnetic resonance, computed tomography and microscopy to advanced computer programming and website development.

Mriganka De is Assistant Editor – Head & Neck Oncology. Mr De is a Consultant ENT/Head and Neck surgeon at Royal Derby Hospital, Derby. His interest is head and neck cancer with particular focus on management of early laryngeal cancers.

13. Bertolini F, Sukhatme VP and Bouche G. Drug repurposing in oncologypatient and health systems opportunities. Nature reviews. Clinical oncology 2015;1–11.

14. Cazap E. Personalised Cancer Care – A Global Perspective. European Oncology & Haematology 2014;10(02):104.

15. Sukhatme VP, Fang K, Lo A, et al. Financial Orphan Therapies Looking For Adoption, Health Affairs. 2014 [online] Available from: http:// healthaffairs.org/blog/2014/03/06/financial-orphan-therapies-lookingfor-adoption/ (Accessed 27 March 2014).

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International Liaison Committee Mikhail Yu Reutovich, Abdominal Oncology Department, NN Alexandrov National Cancer Center of Belarus, Minsk, Belarus.

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NEURO-ONCOLOGY

Dysregulation of Histone Deacetylases in paediatric brain tumours Emily Pinkstone, BSc, MSc, PhD Student University of Portsmouth, Brain Tumour Research Centre.

Correspondence to: E: emily.pinkstone@ port.ac.uk

T

he World Health Organization (WHO) grades tumours in four stages where grades I and II are benign tumours with a slower proliferation rate, grade III is malignant, with increased proliferation and histological features such as nuclear atypia while grade IV comprise malignant tumours that are highly proliferative with areas of necrosis and carry a very poor prognosis [1]. Paediatric high grade gliomas (pHGG) are a histologically heterogeneous group and distinct from adult gliomas with their unique epigenetic and genetic characteristics. pHGG include diffuse intrinsic pontine gliomas (DIPG) and gliomatosis cerebri which respond poorly to treatment and represent the leading cause of paediatric brain cancer mortality [2]. A 2010 report stated that the incidence of paediatric brain tumours did not change in the 20 years between 1986 and 2006, while in the 10 years before that, the incidence had increased [3].

Defects in chromatin remodelling appear to be central to the pathobiology of pHGG. Chromatin is comprised of nucleosomes, DNA wrapped around an octamer of core histones, compacted together to form a chromosome. The

chromatin structure is unravelled and compacted to allow the transcription of genes as required.

Post-translational modifications are changes in the DNA that affect gene expression without altering the sequence of base pairs, such as acetylation, methylation and phosphorylation, and are controlled through chromatin remodelling enzymes.

Histone Deacetylases Chromatin remodelling enzymes, such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) modify the structure of the chromatin by the addition (HATs) or removal (HDACs) of acetyl groups (depicted in Figure 1) to lysine amino acids present at the N-termini. Addition of acetyl groups decreases binding affinity of the histones to the DNA backbone by neutralising the positive charge of amine groups located on the lysine and arginine amino acids [4,5]. Chromatin is able to relax and expand allowing room for transcription machinery to bind. Removal of acetyl groups increases the positive charge of the histone tails so encouraging binding affinity to the negatively charged phosphate groups on the DNA backbone, causing compression of the chromatin structure [4,5].

Figure 1: Graphical representation of how histone deacetylases (HDACs) and histone acetyltransferases (HATs) effect chromatin structure and consequencely transcription.

TM – transcription machinery

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HDACs are grouped in relation to their structure, cellular localisation and homology with yeast HDAC proteins.

There are 4 zinc dependent groups; I, IIa, IIb and IV with group III containing nicotinamide-adenine-dinucleotise (NAD)-dependent sirtuins. Group I contains HDACs 1, 2, 3 and 8 and are homologous to Rpd3 (reduced potassium dependency 3), a yeast transcriptional regulator, group IIa, containing HDACs 4, 5, 7, 9a and 9b and group IIb containing HDAC6 and 10 are homologous to Hda1 (histone deacetylase 1) in yeast [6]. Group IV contains HDAC11, classed by itself as it is phylogenetically different from groups I and II [6]. Groups I, II and IV share the same enzymatic mechanism of action where the acetyl-lysine amide bond is hydrolysed when a zinc atom binds to the HDAC [6].

HDAC Function in Healthy Cells HDACs are known to be required in many cellular processes on top of transcriptional regulation such as apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism and senescence [7]. HDACs are expressed in the normal functioning brain [8] at differing levels dependent on cell type and function and are critical is learning, memory and neural development.

HDAC Function in Neural Development A 2009 study showed that when HDAC1 and 2 were deleted simultaneously, mice developed tremors associated with myelin deficiency [9]. There was complete loss of both oligodendrocyte precursor cell markers and mature oligodendrocyte markers in the spinal cord and brains of these mice too suggesting HDAC1 and HDAC2 are required for oligodendrogenesis and oligodendrocyte differentiation, yet the loss of HDAC1 and HDAC2 did not impact upon other neural cell types in the developing CNS [9]. However, another study using a similar model showed loss of HDAC1 and HDAC2 caused mice to have smaller brains with a compacted cerebellum [10].

Defects were also found in the cortex, hippocampus and cortical laminar organisation [10]. Significant neuronal abnormalities were also observed and 72

Purkinje cells did not migrate from the nuclei of the cerebellum, preventing normal cerebellar growth [10]. This study suggests HDAC1 and HDAC2 are essential in neural development.

HDAC2 and 3 have been found to bind to genes associated with transcription regulation of differentiation and development in rat brain neural stem cells [11]. HDAC2 and HDAC3 were enriched at promoters of genes, associated with neuronal and oligodendrocyte differentiation [11]. Valproic acid, an HDAC inhibitor, was shown to promote oligodendrocyte differentiation and morphological changes such as formation of myelin plaque-like structures and an increase in oligodendrocyte radius when in combination with a thyroid hormone (T3) [11]. Data showed HDAC2 may be needed for SOX10 gene regulation, required for terminal oligodendrocyte differentiation, in early oligodendrocyte development [11]. HDAC3 has also been reported to repress neuronal genes and differentiation in embryonic neural stem cells [11] showing multiple roles for HDAC’s in neural development.

Class II HDACs have also been shown to be essential in the development of the brain.

HDAC6 was found to play a critical role in dendrite development through interaction with Cdc20 in neuronal centrosomes [12] and HDAC9 was shown to translocate from the nucleus to the cytoplasm with maturation of cortical neurons [13]. When replaced with a mutant HDAC9, total length of dendritic branches was significantly reduced suggesting HDAC9 is required for the proper development of these cells [13]. HDAC10 has been found to interact with the transcription factor Pax3, which is needed for normal neural crest development, among other processes [14].

Oligodendrocyte differentiation depends on HDAC activity to form morphological changes characterised as primary, secondary and tertiary branches [15]. Differentiating progenitors treated with HDAC inhibitors were unable to form branches [15]. Conversely, a 2004 study found that the HDAC inhibitor VPA, promoted neuronal differentiation in foetal neural stem cell cultures [16] showing that potentially HDACs, and consequently HDAC inhibitors, can have both positive and negative effects on neural development dependent on timing and cell type.

Neural Development and Brain Tumours There is increasing evidence that gliomas in childhood could have multiple different cells of origin including neural stem cells, glial progenitor cells, oligodendrocyte progenitor cells and astrocytes [17]. Gliogenesis continues throughout the first year of life [18], precursor cells in the ventral pons peaks in neonates and at around age 6 [19] and myelination continues to early adulthood [20,21,22]. The extent of neural proliferation throughout childhood increases the likelihood of a mutation, and subsequent tumour development, occurring. Aberrant proliferation of pontine-like precursor cells, is caused by dysregulation of neuronal activity during development and these express SOX2, nestin, Olig2 and vimentin [19], also found to be expressed in DIPG, indicating that disruption of neurodevelopmental processes could lead to tumourigenesis.

Epigenetics is crucial in regulating differentiation and thus it’s role in paediatric brain tumour development is indisputable [23].

Dysregulation of HDACs in Childhood Brain Tumours Given the essential and critical roles of HDACs, it is not surprising that dysregulation of these proteins are implicated in tumourigenesis. Inhibitors of HDACs are in clinical trials for treatment of a variety of cancers but since there is rarely a ‘one size fits all’ solution and the consequences of incorrect dosages and compounds could arguably exacerbate the situation.

Significant work is still required to understand what is happening in each tumour so it can be treated accordingly.

HDAC5 and HDAC9 were found to be highly expressed at the mRNA level amongst prognostically unfavourable medulloblastoma patients, whereas HDAC4 and HDAC1 were found to be down-regulated [24]. Patients with high expression of both HDAC5 and HDAC9 had a lower survival probability than those who had high HDAC5 or HDAC9 expression. Patients with low HDAC5 and HDAC9 expression had a significantly higher overall survival probability than either of the other groups [24]. These expression patterns also correlate with molecular Volume 11 Issue 3 • July/August 2016

gliolan® 30 mg/ml powder for oral solution.

Qualitative and quantitative composition: One vial contains 1.17 g of 5 aminolevulinic acid (5-ALA), corresponding to 1.5 g 5 aminolevulinic acid hydrochloride (5 ALA HCl). One ml of reconstituted solution contains 23.4 mg of 5 aminolevulinic acid, corresponding to 30 mg 5 aminolevulinic acid hydrochloride (5 ALA HCl).

Therapeutic indications: gliolan is indicated in adult patients for visualisation of malignant tissue during surgery for malignant glioma (WHO grade III and IV).

Posology and method of administration: This medicinal product should only be used by experienced neurosurgeons conversant with surgery of malignant glioma and in-depth knowledge of functional brain anatomy who have completed a training course in fluorescence-guided surgery. The recommended dose is 20 mg 5 ALA HCl per kilogram body weight.

Contraindications: Hypersensitivity to the active substance or porphyrins; acute or chronic types of porphyria; pregnancy.

Undesirable effects: Adverse reactions observed after the use for fluorescence-guided glioma resection are divided into the following two categories: Immediate reactions occurring after oral administration of the medicinal product before anaesthesia (= active substancespecific side effects); combined effects of 5 ALA, anaesthesia and tumour resection (= procedure-specific side effects).

Substance-specific side effects: Uncommon: Hypotension; nausea, photosensitivity reaction, photodermatosis.

Substance-specific side effects: Uncommon: Hypotension; nausea, photosensitivity reaction, photodermatosis.

Procedure-related side effects: The extent and frequency of procedurerelated neurological side effects depend on the localisation of the brain tumour and the degree of resection of tumour tissue lying in eloquent brain areas. Very common: Anaemia, thrombocytopenia, leukocytosis. Blood bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase or blood amylase increased. Common: Neurological disorders (e.g. hemiparesis, aphasia, convulsions, hemianopsia).

Thromboembolism. Vomiting, nausea. Uncommon: Brain oedema, hypotension. Very rare: Hypesthesia; diarrhoea. One case of moderate chills; one respiratory insufficiency after overdose, which resolved completely.

Legal classification: POM (prescription only medicine).

Price per vial: €980/ £ 950 ex. factory. Marketing authorisation number: EU/1/07/413/001-003.

Marketing authorisation holder: medac GmbH, Theaterstraße 6; D-22880 Wedel.

Date of revision of text: 02/2014. gliolan has been authorised in all countries of the EU as well as in Iceland, Norway, Israel and Taiwan.

Adverse events should be reported.

Reporting forms and information can be found at www.mhra.gov.uk/ yellowcard. Adverse events should also be reported to medac drug safety at: drugsafety@medac.de medac code: medacuk 021/04/2016 Date of Preparation: April 2016

Give her the best chance

fluorescence-guided resection

Gliolan, for the visualisation of malignant tissue during surgery for malignant glioma (WHO grade III and IV) in adult patients.

seeing is the beginning

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subgroups, with lower expression in the WNT and SHH groups and higher expression seen in groups C and D [24].

Therapeutic Potential of HDACs for Childhood Brain Tumours HDAC Inhibitors There are multiple types of HDAC inhibitors (HDACi). They have different structural characteristics and inhibit different HDAC isoforms. Some target just one HDAC, some a whole class of HDACs. HDACis can cause cell cycle arrest, differentiation or apoptosis both in vitro and in vivo [25]. The length of time, concentration and type of inhibitor used affects the number of genes detected with altered transcription [26].

It was only recently that the crystal structure of the interaction between HDAC8 and hydroxamate was solved [27] providing a greater understanding of the mechanism of action of HDAC inhibition. In this case, the hydroxamic acid inhibitor directly interacts with the zinc ion at the base of the catalytic pocket of HDAC8 [26].

Richon et al. (2000) showed increased numbers of cells arresting in G1 phase of the cell cycle with low concentrations of the HDACi, suberoylanilide hydroxamic acid (SAHA), with higher concentrations resulting in cells arresting in both G1 and G2 phase and decreased numbers of cells in S phase [28]. This is thought to be due to the induction of p21, one of the first genes to be switched on under HDAC inhibition, inhibiting cyclin dependent kinases (CDKs) which regulate G1 progression and G1/S, G2/M transitions [29].

Glioblastoma Multiforme Although still not used as a standard mode of treatment, there are case reports of various HDAC inhibitors successfully treating, or managing, childhood brain tumours. In 2004 it was reported that a ten year old with a GBM in the pineal gland showed no evidence of tumour response using the German protocol for malignant gliomas in children (HITGBM-C), which included partial surgical resection, radiotherapy and multiple chemotherapies. After 30 weeks, no response and an array of severe therapy-related side effects, treatment was switched to increasing dosages of 74

Valproic acid (VPA), an HDACi normally used to treat epilepsy in children. After just 14 weeks, the tumour decreased and the child was back in school. Complete remission was seen at 10 months on MRI scans. Unfortunately, the child reduced the dosages due to drowsiness and the tumour relapsed at 16 months from the start of HDACi treatment [30].

Diffuse Intrinsic Pontine Glioma A recent study found twelve out of sixteen DIPG cultures insensitive to traditional chemotherapeutics, demonstrated a concentration dependent decrease in viability and proliferation and increased cell death following treatment with the pan-HDACi, panobinostat [31].

Decreased expression of proliferation associated genes and the oncogene MYC was also observed [31]. Knockdown of HDAC1 or HDAC2 was shown to decrease viability of DIPG cells [31] supporting the notion that inhibition of certain HDACs can be beneficial in the treatment of DIPG. On top of this data, the study showed that the same positive effect happened in a DIPG xenograft mouse model where at just one week there was a significant reduction in tumour growth and treated mice had significantly prolonged survival [31].

Embryonal Brain Tumours Embryonal brain tumours have been shown to have differing levels of sensitivity to HDACis. Proliferation in medulloblastoma cells has been decreased in response to an array of HDACis; Trichostatin A (TSA) and M344 proving most effective [32]. TSA was shown to significantly suppress proliferation in CNS PNET, medulloblastoma, ependymoma, GBM, and mouse neural progenitor cells, with GBM cells being the least responsive [33]. There was increased activation of cleaved caspase 3, a pro-apoptotic protein, and down-regulation of an antiapoptotic protein, Bcl-2, in CNS PNET and medulloblastoma cell lines. At 48 hours of treatment, all cell lines showed a concentration-dependent increase in subG0-G1 phase indicative of apoptosis [31].

Medulloblastoma A 2011 study found that curcumin, derived from the plant Curcuma longa, inhibited HDAC4 and induced medulloblastoma cell death in a time and concentrationdependent manner [25]. Treated cells also

show an increase in caspase-3 cleavage and poly (ADP-ribose)polymerase (PARP) suggestive of apoptosis [25]. However, it is not clear if the increase in cleaved caspase-3 and PARP is related to HDAC4 inhibition.

Another study on medulloblastoma demonstrated TSA decreased viability and induced apoptosis in cell lines. The HDACi up-regulated 714 genes some of which were involved in varying biological pathways such as angiogenesis, apoptosis, Ras, p53 and Wnt signalling cascades [34]. A tumour suppressor gene in medulloblastoma, DKK1, was found to be significantly down-regulated by 80% in cells but increased when treated with TSA [34].

In support of HDACi-induced cell death in medulloblastoma cells, Sonnemann et al. observed a concentration-dependent increase in cell death of medulloblastoma cell lines with three different HDACi compounds [35]. Caspase-3 and -9 activation and a decrease in mitochondrial transmembrane potential suggest these compounds induce apoptosis in these cell [35]. Interestingly, if treated with concomitant ionizing radiation (IR), HDACis lead to cell death at 46-65% compared with 22% with IR alone [35].

The same theory was then tested with chemotherapeutics, which induced cell death in 29% of cells alone and 76% of cells when treated concomitantly with an HDACi [35]. However, this effect was only seen in some combinations of the drugs and the authors attribute this discrepancy to the difference in the mode of action of the cytotoxic agents.

Concomitant Therapy and Clinical Trials Although many HDAC inhibitors have reached clinical trials for various different cancers, unfortunately there are relatively few involving childhood brain tumours.

A phase I trial was, however, conducted with vorinostat in combination with temozolomide for relapsed or refractory primary brain or spinal cord tumours in children [36]. Sixteen of the original nineteen patients were evaluated at the end of the trial, three had stable disease in ependymoma, ganglioglioma and high grade glioma, one patient had a partial response in ependymoma and the rest had progressive disease [36]. No clear relationship was seen between dose and response [36]. This may be due to the Volume 11 Issue 3 • July/August 2016

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different types of tumour enrolled in the trial, as discussed earlier, the same treatment is unlikely to have the same effect across a variety of tumours. It is well known that temozolomide is ineffective in paediatric glioblastoma [37] for instance, but can be beneficial in other tumours and it has been discussed earlier; here how different types of HDACi work differently dependent on the tumour type [25,26].

A clinical trail led by the Pediatric Brain Tumour Consortium (Pediatric Brain Tumour Consortium PBTC-047) in America is now starting a Phase I trial treating children with progressive DIPG with 26 courses of panobinostat over 2 years. With the previous in vitro and in vivo success discussed earlier [31], it is hoped the findings translate into the clinic as expected.

Discussion It is clear there are still huge gaps in our knowledge in the mechanistic roles histone deacetylases play in these tumours and the more we discover, the clearer it is that each tumour has it’s own molecular signature that should be treated in a unique way. Since personalised therapy is still a way off, it is hoped that studies such as the ones discussed here, can enhance our understanding and ability to attack these tumours in novel and more effective ways.

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20. Brody BA, Kinney HC, Kloman AS, Gilles FH. Sequence of central nervous system myelination in human infancy.

I. An autopsy study of myelination. J Neuropathol Exp Neurol. 1987 May;46(3):283-301.

2. Vanan MI, Eisenstat DD. Management of high-grade gliomas in the pediatric patient: Past, present, and future.

Neuro-Oncology Practice. 2014 Nov 14;1(4):145–57.

21. Kinney HC1, Brody BA, Kloman AS, Gilles FH. Sequence of central nervous system myelination in human infancy. II. Patterns of myelination in autopsied infants. J Neuropathol Exp Neurol. 1988 May;47(3):217-34.

3. Smith MA, Seibel NL, Altekruse SF, Ries LAG, Melbert DL, O'Leary M, et al. Outcomes for Children and Adolescents With Cancer: Challenges for the TwentyFirst Century. Journal of Clinical Oncology. 2010 May 18;28(15):2625–34.

4. Barneda-Zahonero B, Parra M. Histone deacetylases and cancer. Molecular Oncology. Elsevier B.V; 2012 Dec 1;6(6):579–89.

5. Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet.

2009 Jan;10(1):32–42.

6. Lucio-Eterovic AKB, Cortez MAA, Valera ET, Motta FJN, Queiroz RGP, Machado HR, et al. Differential expression of 12 histone deacetylase (HDAC) genes in astrocytomas and normal brain tissue: class II and IV are hypoexpressed in glioblastomas. BMC Cancer. BioMed Central; 2008;8(1):243.

7. Li Z, Zhu WG. Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications. Int J Biol Sci. 2014;10(7):757–70.

8. Volmar C-H, Wahlestedt C. Histone deacetylases (HDACs) and brain function. Neuroepigenetics.

2015;1:20–7.

9. Ye F, Chen Y, Hoang T, Montgomery RL, Zhao X-H, Bu H, et al. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction. Nat Neurosci. 2009 Jul;12(7):829–38.

10. Montgomery RL, Hsieh J, Barbosa AC, Richardson JA, Olson EN. Histone deacetylases 1 and 2 control the progression of neural precursors to neurons during brain development. Proc Natl Acad Sci USA. National Acad Sciences; 2009 May 12;106(19):7876–81.

11. Castelo-Branco G, Lilja T, Wallenborg K, Falcão AM, Marques SC, Gracias A, et al. Neural stem cell differentiation is dictated by distinct actions of nuclear receptor corepressors and histone deacetylases. Stem Cell Reports. 2014 Sep;3(3):502–15.

12. Kim AH, Puram SV, Bilimoria PM, Ikeuchi Y, Keough S, Wong M, et al. A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in postmitotic neurons.

Cell. 2009 Jan 23;136(2):322–36.

13. Sugo N, Oshiro H, Takemura M, Kobayashi T, Kohno Y, Uesaka N, et al. Nucleocytoplasmic translocation of HDAC9 regulates gene expression and dendritic growth in developing cortical neurons. Eur J Neurosci. Blackwell Publishing Ltd; 2010 May;31(9):1521–32.

14. Lai I-L, Lin T-P, Yao Y-L, Lin C-Y, Hsieh M-J, Yang W-M. Histone deacetylase 10 relieves repression on the melanogenic program by maintaining the deacetylation status of repressors. J Biol Chem. American Society for Biochemistry and Molecular Biology; 2010 Mar 5;285(10):7187–96.

15. Marin-Husstege M, Muggironi M, Liu A, CasacciaBonnefil P. Histone deacetylase activity is necessary for oligodendrocyte lineage progression. J Neurosci. 2002 Dec 1;22(23):10333–45.

16. Laeng P, Pitts RL, Lemire AL, Drabik CE, Weiner A, Tang H, et al. The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells. J Neurochem. 2004 Oct;91(1):238–51.

17. Zong H, Parada LF, Baker SJ. Cell of origin for malignant gliomas and its implication in therapeutic development.

Cold Spring Harb Perspect Biol. 2015 Jan 29;7(5). pii: a020610. doi: 10.1101/cshperspect.a020610. Review.

18. Roessmann U, Gambetti P. Astrocytes in the developing human brain. An immunohistochemical study. Acta Neuropathol. 1986;70(3-4):308-13

22. Lebel C1, Gee M, Camicioli R, Wieler M, Martin W, Beaulieu C. Diffusion tensor imaging of white matter tract evolution over the lifespan. Neuroimage.

2012 Mar;60(1):340-52. doi: 10.1016/j. neuroimage.2011.11.094. Epub 2011 Dec 8.

23. Baker SJ, Ellison DW, Gutmann DH. Pediatric gliomas as neurodevelopmental disorders. Glia. 2016 Jun;64(6):879-95. doi: 10.1002/glia.22945. Epub 2015 Dec 6. Review.

24. Milde T, Oehme I, Korshunov A, Kopp-Schneider A, Remke M, Northcott P, et al. HDAC5 and HDAC9 in medulloblastoma: novel markers for risk stratification and role in tumor cell growth. Clin Cancer Res. 2010 Jun;16(12):3240–52.

25. Lee SJ, Krauthauser C, Maduskuie V, Fawcett PT, Olson JM, Rajasekaran SA. Curcumin-induced HDAC inhibition and attenuation of medulloblastoma growth in vitro and in vivo. BMC Cancer. 2011;11:144.

26. Xu WS, Parmigiani RB, Marks PA. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene.

2007 Aug;26(37):5541–52.

27. Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ, et al. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure.

2004 Jul;12(7):1325–34.

28. Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. PNAS. National Acad Sciences; 2000 Aug 29;97(18):10014–9.

29. Vidal A, Koff A. Cell-cycle inhibitors: three families united by a common cause. Gene. 2000 Apr 18;247(1-2):1–15.

30. Witt O, Schweigerer L, Driever PH, Wolff J, Pekrun A. Valproic acid treatment of glioblastoma multiforme in a child. Pediatr Blood Cancer. 2004 Aug;43(2):181.

31. Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily MA, et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med. 2015 Jul;21(7):827.

32. Furchert SE, Lanvers-Kaminsky C, Juürgens H, Jung M, Loidl A, Frühwald MC. Inhibitors of histone deacetylases as potential therapeutic tools for high-risk embryonal tumors of the nervous system of childhood. Int J Cancer.

2007 Apr;120(8):1787–94.

33. Rahman R, Osteso-Ibanez T, Hirst RA, Levesley J, Kilday JP, Quinn S, et al. Histone deacetylase inhibition attenuates cell growth with associated telomerase inhibition in high-grade childhood brain tumor cells. 2010 Sep;9(9):2568–81.

34. Vibhakar R, Foltz G, Yoon JG, Field L, Lee H, Ryu GY, et al. Dickkopf-1 is an epigenetically silenced candidate tumor suppressor gene in medulloblastoma. Neuro Oncol.

2007 Apr;9(2):135–44.

35. Sonnemann J, Kumar KS, Heesch S, Müller C, Hartwig C, Maass M, et al. Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells.

Int J Oncol. 2006 Mar;28(3):755–66.

36. Hummel TR, Wagner L, Ahern C, Fouladi M, Reid JM, McGovern RM, et al. A pediatric phase 1 trial of vorinostat and temozolomide in relapsed or refractory primary brain or spinal cord tumors: a Children's Oncology Group phase 1 consortium study. Pediatr Blood Cancer.

2013 Sep;60(9):1452–7.

37. Nicholson HS, Kretschmar CS, Krailo M, Bernstein M, Kadota R, Fort D, et al. Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumours: a report from the children’s oncology group. Cancer. 2007 Oct;110(7):1542-50.

19. Monje M, Mitra SS, Freret ME, Raveh TB, Kim J, Masek M, et al. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc Natl Acad Sci USA. 2011 Mar;108(11):4453–8.

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Driver Genes in Breast Cancer: Importance, Integration & Identification Nicola Faramarzi, MSc, PhD Student Dept. of Biomedical Sciences Faculty of Science and Technology University of Westminster London, UK.

Corresponding author:

Dr Nadège Presneau, PGCertHE, FHEA, PhD, Senior Lecturer in Biomedical Sciences Dept. of Biomedical Sciences Faculty of Science and Technology University of Westminster London, UK E: N.Presneau@ westminster.ac.uk

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I

t is well-known that breast cancer is highly heterogeneous, behaving not as a single disease, but as a collection of tumour subtypes with distinctive aetiologies, origins and genetic signatures [1]. This heterogeneity is mirrored in its complex genomic landscape, and despite advancements in subtype specific therapeutics, many patients have de novo or develop resistance to current therapies due to underlying genetic mutations which require further characterisation.

In the UK, breast cancer is the most common type of cancer, and incidence has increased by approximately 50% since the 1970s. However, due to increasing knowledge of underlying molecular aberrations and the development of subsequent treatments, survival rates have doubled since the 1970s (Figure 1) [2]. On a global scale, approximately 1.68 million women were diagnosed with invasive breast carcinoma worldwide and an estimated 522,000 cases of mortality from the disease in 2012 alone [2].

These statistics demonstrate the need for greater genomic characterisation and research that can be translated to patient-tumour specific molecular diagnosis in the near future.

Until recently, breast cancer was categorised into three subtypes with overlapping clinicopathological parameters – hormone receptor positive (HR+, consisting of estrogen receptors, ER, and progesterone receptors, PR), human epidermal growth factor positive (HER2+) and triple negative breast cancer (TNBC).

Although several types of targeted treatments arose to combat these, such as tamoxifen and trastuzumab for HR+ and HER2+ cancers respectively, these were met with unexpected inefficiency in a large number of patients who were thought to possess the corresponding molecular markers to these treatments [3]. This classification has now been superseded by the ‘intrinsic subtypes’ taxonomy, based more on gene expression and molecular patterns of the tumours [1]. A basic summary of this is shown in Figure 2 [4].

At present, subtypes are diagnosed on the basis of immunohistochemical analysis of a tissue biopsy, or in situ hybridisation to detect single gene amplification [5]. However, it could be argued that this basic diagnosis using a panel of so few histopathological markers is not reflective of many patients’ tumour types and treatment requirements. Hence there is a calling for more

Figure 1: Cancer Research UK statistics illustrating that only 40% of patients survived beyond 10 years in the 1970s compared with 80% of patients today, showing that breast cancer survival beyond 10 years has doubled during this time.

Figure 2: A summary of the intrinsic subtype taxonomy and current molecular markers, adapted from Eroles et al., (2012).

widely available clinical molecular diagnostic approaches to reveal patient specific genetic signatures that can be more efficiently targeted by treatment.

Driver genes in cancer There has been great progress in identifying many germ-line mutations, such as BRCA1/2, which now have the ability to detect susceptibility, predict prognosis and dictate patient stratification. However, the success of these genes is dampened by the fact that hereditary mutations are only responsible for up to approximately 5% of all breast cancers. Therefore, Volume 11 Issue 3 • July/August 2016

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Figure 3: An example of a typical workflow for driver gene identification using an integrated and multi-platform data approach.

Bioinformatics analysis can be extremely varied between studies and is dependent on available resources and the expertise of the researcher.

the remaining 95% of breast tumours that develop are instigated by an accumulation of somatic mutations [6].

Somatic mutations occur in all dividing cells due to exogenous (environmental factors such as radiation) or endogenous (faults in DNA replication) mutagens. These types of mutations are acquired and may be classed as a ‘driver’ or ‘passenger’ mutation [7]. Solid tumours can typically contain up to thousands of genetic aberrations and alterations, but only a handful of these are considered driver mutations [8]. Driver mutations provide cells a selective growth advantage (Darwinian evolution) and are considered to be positively selected in cancer cells; these alter critical cellular processes leading to the hallmarks of cancer [9]. In contrast, passenger mutations may arise within the cell, but do not give the cell any growth advantage [10] .

Vogelstein et al., [11] have estimated that an average tumour contains two to eight driver gene mutations. These driver mutations are thought to only provide a small growth advantage to cells, which eventually build up over many years and result in billions of additional cells.

Hence, it follows that the number of these somatic mutations is correlated to age. In this sense, sequential somatic mutations occurring during tumourigenesis can be thought of as an ‘evolutionary clock’ [11].

However, despite the exact number of driver gene mutations required for breast tumour initiation and progression being unknown, Tomasetti C et al have shown that for the development of lung and colon adenocarcinomas, only 3 mutations are Volume 11 Issue 3 • July/August 2016

needed. This has important implications for driver gene identification highlighting that although there is unlikely to be one single gene responsible, there may be only a small handful which can be taken advantage of for therapeutic targeting.

The importance of driver genes Identifying key driver genes in breast cancer, as well as in other cancers, is pivotal in revealing crucial information regarding tumour biology, such as which pathways are disturbed during tumourigenesis. By identifying the genes responsible for driving and altering oncogenic signalling pathways, these can be further explored and may be used to gather information on individual tumours during diagnosis in order to enhance clinical decisions. Additionally these pathway drivers can be potentially targeted, or used to predict and tailor response to therapy [12].

The important implication that driver genes can be targeted for therapeutic development is supported by a study by Rubio-Perez et al. [13] highlighting that of 4000 tumour samples across 28 breast tumour types, only 6% of these were shown to be manageable using currently approved agents [9]. This highlights a need for greater characterisation of driver genes in cancers, particularly for breast cancer patients where current therapies may be ineffective; this is the case for many HER2+ cancers, where nearly half of patients show resistance or inefficiency to trastuzumab [14].

The current genomic landscape of breast cancer It has been established that there are on average approximately 57 somatic mutations per breast cancer [15]. It is important to note that depending on laboratory methods, sample selection and data analysis, many studies identify different sets or signatures of somatic gene mutations [15]. However, there are still a small set of potential driver genes that are recurrently identified across studies, such as TP53, PIK3CA, GATA3 and MAP3KI. Studies have shown that ER-positive tumours have less mutations than ER-negative tumours, which primarily affect PIK3CA. Of all of the intrinsic subtypes, HER2+ has been shown to have the highest mutation rates, with the most frequently mutated gene in HER2+ and the basal-like subtype being TP53 [15].

Gatza et al., [12] used gene expression microarray data and a panel of gene expression signatures to examine patterns of pathway activity to identify specific DNA amplifications and genes within these that represent key drivers. This study identified 8 genes (FGD5, METTL6, CPT1A, DTX3, MRPS23, EIF2S2, EIF6 and SLC2A10) amplified only in patients with proliferative luminal breast cancers, a subtype with few therapeutic options. Liu et al. [16] have also identified candidate driver mutations in the luminal subtype, revealing mutations in BRAF, GNAS, IDH1 and KRAS, by sequencing hotspot regions from cancer related genes.

A comprehensive genomic, 77

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transcriptomic and proteomic analysis integrated with clinical data, by Michaut et al. [17] have confirmed that PI3K pathway mutations and CDH1 inactivating mutations are most frequently altered in invasive lobular breast carcinoma.

Other mutations in ERBB2, MAP3K1, and MAP2K4 were revealed at low frequency.

As can be seen from these studies, there is seldom complete agreement or overlap of identified driver genes across the different breast cancer subtypes; the variety of subtypes also make it difficult to obtain a generalised picture of the driver genes present in breast cancer. This further demonstrates the complexity of breast tumorigenesis and the challenge of identifying true driver genes, necessitating further investigation and characterisation.

This year, new research from a large team of international researchers led by Mike Stratton at the Sanger Institute in Cambridge has identified 93 protein-coding somatic mutations and potential driver genes, as well as 12 base substitution and 6 base rearrangement driver gene signatures [18]. This study analysed 560 breast cancers using whole genome sequencing and comprehensive molecular and bioinformatics analysis. The research is ground-breaking as evidenced by many news outlets reporting the story. It is the largest study that has worked towards identifying the vast majority of somatic mutations in breast cancer, and it has suggested that each breast tumour genome is individual.

Although this leading study has been successful in gaining ‘the bigger picture’ of the mutations driving breast tumour development it is likely that infrequently mutated genes still require classification, and further analysis must aim to develop this list of mutations by investigating the functionality of these genes [18].

Driver gene identification & data integration The advent and progression of sequencing technologies over the past few decades have revealed a vast amount of information regarding breast cancer, and provided researchers with an unprecedented ability to identify genetic alterations driving the oncogenic process.

In the recent past, gene expression and DNA microarrays have steered the way for understanding the heterogeneity of breast oncogenesis, suggesting that the behaviour of an individual’s cancer is based on the tumours’ genetic profile and 78

pattern of gene expression [1]. In addition, the emergence of high-throughput, nextgeneration sequencing (NGS) technology in the past decade has superseded traditional Sanger sequencing, and is evolving rapidly with widespread use across research and clinical laboratories for cancer surveillance, allowing researchers to sequence whole genomes in parallel.

With these technologies being increasingly used for driver gene investigation, a multi-level approach for integrating different types of OMIC data has risen to the forefront of research, with a large number of studies concerned with data-mining from public databases and coupling gene expression with genomic data [19] (Figure 3). An extensive and comprehensive example of a multi-level approach is the use of five data types

by The Cancer Genome Atlas Network [20]. This study uses genomic DNA copy number arrays, exome sequencing, DNA methylation, mRNA arrays, microRNA sequencing and reverse phase protein arrays, and integrated data across these platforms to analyse primary breast cancers. This integrated analysis provided confirmation of previously known somatic mutations, as well as novel subtype associated mutations, GATA3, PIK3CA and MAP3KI in the luminal A subtype [20].

Although smaller studies and research groups are often limited in terms of their resources to perform such large scale and varied analysis, the trend of integrating multiple platforms can still be feasible on a smaller scale, for example by using only two or three platforms, smaller sample sizes, or by data mining from free public databases rather than performing all laboratory analysis in-house.

The few driver gene mutations present in cancers in comparison to passenger mutations makes it difficult to investigate the function of all mutations identified by sequencing. In light of this, bioinformatics analysis tools have been developed to predict the most likely driver genes and mutations, which can therefore be preferentially selected for functional analyses. There are two main approaches used in this instance, which either examine the mutation frequencies or aim to predict the functionality of the mutations [21]. A full description of these approaches are beyond the scope of this review, but are described in full

by Pon and Marra [21]. Alternatively, systematic approaches can reveal groups

of driver genes that are functionally related, or driver genes that are linked by a functional network or significantly enriched signalling pathway (Figure 3) [9].

The challenges of driver gene identification in breast cancer The ongoing research in this field by academic and industrial laboratories worldwide emulate the challenge of driver gene identification. Despite sequencing and array technologies moving at a phenomenal pace, this is not matched by ‘big data’ handling techniques or user-friendly bioinformatics analyses. Furthermore, the number of bioinformatics algorithms, possible analysis pipelines and databases can appear very overwhelming for researchers with little bioinformatics experience.

Aside from technical challenges, there are many factors that cause difficulties in driver gene identification. One important factor to consider is that somatic mutations rarely occur at greater than 10% prevalence, meaning that most driver genes have a much lower incidence and are mutated much more infrequently. This is due to the fact that there is such an enormous and assorted range of somatic mutations occurring in cancer cells, that the frequency of any identified driving mutations can be extremely low, even if they provide cells with a significant growth advantage [8,22]. This can be seen across all breast cancers where only somatic mutations in TP53, PIK3CA and GATA3 appear at >10% incidence [20].

An additional complication is that driver genes can also contain mutations that are not driver mutations [11].

Despite breast tumours originating from the same mammary tissues, the different subtypes can be considered as molecularly different diseases with differing gene expression profiles and therapeutic responses, and it is now accepted that these subtypes do not exhibit identical sets of somatic mutations; it is unlikely that each subtype can be represented by a single driving gene. There is growing evidence suggesting that many primary breast tumours consist of several genetically distinct clones. This inter and intratumour heterogeneity has been demonstrated in approximately twothirds of triple negative breast cancers, particularly in basal-like subtypes, and often means that potential driver somatic mutations are actually only seen in a Volume 11 Issue 3 • July/August 2016

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minority of tumour cells. This can also affect secondary tumours, with the majority of metastatic lesions varying significantly in their driver mutations compared to primary breast tumours.

This presents a challenge to researchers, as driving mutations found in one part of a tumour may not be characteristic of the whole tumour. Although these complex factors pose challenges for driver gene identification in breast cancer, they may be useful for more long term development and implementation of targeted medicine; this would ensure that future therapeutics will be based more upon the molecular biology of individual

tumours [15].

Final thoughts & future directions There is an increasing need for greater characterisation of driver genes in the varying breast cancer subtypes to understand their mechanistic role in tumourigenesis and their respective pathways across the separate subtypes.

These may be used in the future for therapeutic exploration or biomarker discovery, or to develop an extensive catalogue of driver genes for which treatment can be built around and used for tailored and personalised therapy; this aims to address the current inefficacy of

existing breast cancer therapies.

A multi-platform approach for driver gene identification is a highly strategic, prolific and lucrative method for enhancing our knowledge of the molecular basis underpinning breast carcinogenesis, whilst providing attractive potential pharmaceutical targets. However, in order to exploit this information from sequencing studies, the future must focus on addressing the challenges associated with driver gene identification and ‘big data’, and developing more robust and user-friendly bioinformatics pipelines for processing large-scale OMIC data.

References 1. Perou, C and Børresen-Dale A. Systems biology and genomics of breast cancer. Cold Spring Harbor perspectives in biology, 2011;3(2):a003293.

12. Gatza M et al. An integrated genomics approach identifies drivers of proliferation in luminal subtype human breast cancer. Nature genetics 2014; 46(10):1051-9.

2. Cancer Research UK (2015). Breast Cancer Statistics. Available from: http:// publications.cancerresearchuk.org/cancerstats/statsbreast/kfbreast.html [Accessed 14 April 2016].

13. Rubio-Perez C et al. In Silico Prescription of Anticancer Drugs to Cohorts of 28 Tumor Types Reveals Targeting Opportunities. Cancer Cell 2015;27(3):382–96.

3. Rexer, B and Arteaga, C. Optimal targeting of HER2-PI3K signaling in breast cancer: mechanistic insights and clinical implications. Cancer research 2013;73(13):3817– 20.

4. Eroles P et al. Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer treatment reviews 2012;38(6):698–707.

5. Hansen, A and Bedard, P. Clinical application of high-throughput genomic technologies for treatment selection in breast cancer. Breast cancer research 2013;15(5):1-10 6. van der Groep P, van der Wall E and van Diest P. Pathology of hereditary breast cancer. Cellular Oncology 2011;34(2):71–88.

7. Stratton M, Campbell P, and Futreal P. The cancer genome. Nature 2009;458(7239):719-24.

8. Tomasetti C et al. Only three driver gene mutations are required for the development of lung and colorectal cancers. Proceedings of the National Academy of Sciences of the United States of America 2015;112(1):118–23.

9. Gonzalez-Perez A. Circuits of cancer drivers revealed by convergent misregulation of transcription factor targets across tumor types. Genome medicine 2016;8(1):1-12.

10. Greenman C et al. Patterns of somatic mutation in human cancer genomes. Nature 2007;446(7132):153–8.

11. Vogelstein B et al. Cancer genome landscapes. Science 2013;339(6127):1546–58.

14. Esteva F et al. PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. The American journal of pathology 2010;177(4):1647-56.

15. Ng C et al. Breast cancer genomics from microarrays to massively parallel sequencing: paradigms and new insights. Journal of the National Cancer Institute 2015;07(5):djv015–13.

16. Liu S et al. Rapid detection of genetic mutations in individual breast cancer patients by next-generation DNA sequencing. Human genomics 2015;9:2-11.

17. Michaut M et al. Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer. Scientific reports 2016;6:1-13.

18. Nik-Zainal S, et al. Landscape of somatic mutations in 560 breast cancer whole genome sequences. Nature 2016, 1-8.

19. Suo C et al. Integration of somatic mutation, expression and functional data reveals potential driver genes predictive of breast cancer survival. Bioinformatics 2015;31(16):2607–13.

20. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012;490(7418):61–70.

21. Pon J and Marra M. Driver and passenger mutations in cancer. Annual review of pathology 2015;10:25–50.

22. Liu Y and Hu Z. Identification of collaborative driver pathways in breast cancer. BMC genomics 2014;15(1):605-21.

New Journal reviewer for Oncolgy News

Dr Fenella Willis MBBS, FRCP, FRCPath, MD Dr Fenella Willis is a Consultant Haemato-oncologist and Honorary Senior Lecturer at St George’s Hospital, London, UK. She graduated from the Royal Free Hospital School of Medicine in 1993 and completed her specialist training in haematology in South West London in 2004. Her MD involved research into the optimisation of Stem Cell mobilisation.

In her current post she is the clinical lead for the myeloma service and the apheresis service. Her main areas of specialist interest include multiple myeloma and plasma cell disorders and myeloid disorders. She has been the principle investigator on numerous clinical trials and has an active and expanding clinical trial portfolio.

Fenella has joined the Oncology News reviewing panel to review the journal Clinical Lymphoma, Myeloma & Leukemia.

Volume 11 Issue 3 • July/August 2016

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BREAST CANCER

Brief view of breast cancer in Iran: cross-road of genetics, cellular and cancer epidemiology Epidemiology Hassan Yousefi, Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Parvin Mehdipour, Professor, Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Correspondence to: Parvin Mehdipour, E: mehdipor@tums.ac.ir

Iran, located in the Middle part of Asia, has the highest incidence of breast cancer (BC) among women in the region [1]. Among Iranian women, BC is the fifth most common cause of death [2], being ranked first among cancers that are diagnosed [3]. There are several reasons for the high rate of mortality, including metastasis, which is responsible for ~90% of cancer-related mortality [4]. The age of onset of BC in women in Iran is at least one decade less than their western counterparts [5], with the mean age ranging from 47 to 49 years [6]; furthermore, >36% of the tumours occur in women under 40 [7].

Status of BRCA1 and BRCA2 Mutations in IRAN Germline mutations in either BRCA1 or BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancers.

Pietschmann et al. [8] was the first to analyse the complete coding sequences of both genes that concerns the Iranian population.

Two pathogenic mutations in the BRCA2 gene were detected, including a novel deletion c.4415_4418delAGAA, and a previously described insertion c.6033_6034insGT [8]. In one study, which is the first report on the genetic testing of Iranian women, exon-2 of the BRCA1 gene was sequenced in 80 Iranian breast cancer patients and none of the patients showed the 185del AG mutation or any changes in the sequences of this exon. Besides, none of the patients had this mutation [9]. However, the low prevalence of 5382insC or 185delAG in BRCA1 has been reported from a province of Iran and a neighboring country [10].

In the present larger study (>300 patients), cases from 5 southern provinces of Iran were analyzed regarding to 5382insC and 185delAG in BRCA1, and 6174delT in BRCA2. Then data indicated that the mutation was not detected either in patients (250 patients with sporadic breast cancer and 55 familial breast cancer patients), nor in 200 healthy individuals [11]. Table 1 gives the BRCA1/2 gene mutations in the Iranian population.

Family history of malignancies in primary breast cancer patients In order to assess the prognostic value of family history (FH) of malignancies in patients afflicted 80

with breast cancer (BC), Atri et al. [15] examined FH and histopathologic characteristics of 542 Iranian primary BC patients. FH of BC and other malignancies (OM) was positive in 29 and 54% of cases, respectively. The most common OM’s were gastric (67), lung (52) and uterine (47) cancers.

Altogether this study indicates the possibility of a correlation between FH of BC and OM, and histopathologic characteristics of the proband’s tumours, which would put forward FH as a prognostic factor rather than a simple risk factor in BC.

1 - An interphase FISH analysis in invasive ductal breast carcinoma among Iranian women Genetic markers both at single gene and chromosomal level can be important in improving the diagnosis and prognosis of breast cancer patients. Behjati et al. [16] investigated the copy number of chromosome 1 and 8 by interphase fluorescence in situ hybridisation (FISH) as a prognostic parameter in 50 Iranian women aged 35 to 64 years who had sporadic invasive ductal breast carcinoma. Aneusomy for these chromosomes occurred in all 50 patients to different extents [16].

2 - Expression analysis of MiR-21, MiR-205, and MiR-342 in breast cancer in Iran Savad et al. [17] analysed the expression of miR-21, miR-205, and miR-342 in 59 patients with breast cancer. Samples were divided into 3 groups according to their immunohistochemistry (IHC) classification: (ER+ and/or PR+; group I); (HER2+; group II); (ER- / PR- / HER2- ; group III).

They found that miR-21 expression was similar in all three groups. Both miR-205 and miR-342 expression were significantly downregulated in group III. Both miR-205 and miR-342 expression was significantly downregulated in group III, from which they concluded that miR-21 does not discriminate between different breast cancer groups. In contrast, miR-205 and miR-342 may be used as potential biomarkers for diagnosis of triple-negative breast cancer [17].

3 - A meta-analysis on concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization Volume 11 Issue 3 • July/August 2016

BREAST CANCER

BRCA1 Mutation

BRCA1 Nucleotide

Coding

Amino acid

Mutation

Nucleotide

Coding

Amino acid Glu1735

A>G

g.4987-92

GAA>GAG

C>T

g.5075-53

ATT>CTT

c.44

Ileu15Leu

G>A

g.5152+66

CCC>CCA

c.74

Pro25

G>T

g.421

ATC>GTC

c.76

Ile26Val

C>T

g.1286

IVS2-1G>C

c.80

No change

TCT>ACT

c.550

Ser177Thr

p.Asp693Asn

TTG>CTG

c.2311

Leu771

c.2212

Leu871Pro

Tyr 987X c.2077

G>A C>T

c.2082

p.Asp693Asn

CTG>CCG

T>C

c.2311

p.Leu771Leu

CCA>CGA

c.2814

Pro938Arg

C>T

c.2612

p.Pro871Leu

GAA>GGA

c.3111

Glu1038Gly

A>G

c.3113

p.Glu1038Gly

AGC>AAC

c.3119

Ser1040Asn

G>A

c.3119

p.Ser1040Asn

GGT>AGT

c.3419

Gly1140Ser Ser1436

A>G

c.3548

p.Lys1183Arg

TCT>TCC

c.4301

T>C

c.4308

p.Ser1436Ser

AGT>GGT

c.4837

Ser1613Gly

A>G

c.4837

p.Ser1613Gly

GGA>GAA

c.5213

Gly1738Glu

T>A

c.2286

p.Arg762Ser

Refs (8,13,14,15)

TGT>AGT

939

c.822

p.Cys274Ser

BRCA2

ACT>ACA

1118

c.999

p.Thr333Thr

Mutation

GCT>GCC

1085

c.966

p.Ala322Ala

G>A

c.9485-1

GGA>GGT

1088

c.969

p.Gly323Gly

T>C

g.8755–66

GGG>CGG

942

c.825

p.Gly275Arg

T>C

g.7806–14

INS C

1088

c.969

p.Gly323Stop

C>T

g.7435+53

AGT>CGT

909

c.792

p.Ser264Arg

A>G

c.7242

p.Ser2414Ser

CAG>CGG

1186

c.1068

p.Gln356Arg

A>C

c.5529

p.Ala1843Ala

AAG>A-G

1135

c.1017

p.Lys340Stop

T>C

c.3807

p.Val1269Val

GAG>CAG

p.Glu23Gln

G>A

c.3516

p.Ser1172Ser

TTA>TGA

Leu3Stop codon

A>G

c.3396

p.Lys1132Lys

CGC>TGC

Arg7Cys

A>G

c.2971

p.Asn991Asp

IVS2+9G>C

No change

T>C

c.2229

p.His743His

IVS1-20G>A

No change

A>G

c.1365

p.Ser455Ser

IVS1-8A>G

No change

A>C

c.1114

p.Asn372His

IVS2+24A>G

No change

A>C

c.865

p.Asn289His

ACG>AGG

Thr77Arg

IVS6-70 T>G

No change

IVS5-8A>G

No change

GAA>GGA

Glu1391Gly

IVS7+83(-TT)

No change

CTT>TTT

c.4771

Leu1522Phe

AAA>TAA

Lys581Stop codon

GTG>GTC

c.6494

Val2171

AAC>CAC

Asn1403His

CTA>CTG

c.4770

Leu1521

TTA>TGA

Leu1418S.Co

Refs (8,15)

(FISH) to detect HER2 gene overexpression in breast cancer Bahreini et al. [18] designed a metaanalysis to evaluate the concordance and discordance between immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) in detecting HER2 alteration in human breast cancer. They identified 172 citations, for which our inclusion criteria were met Volume 11 Issue 3 • July/August 2016

by 18 articles, representing 6,629 cases.

The overall concordance and discordance rate between IHC staining with score 0/1+ and FISH for detection failure of HER2 expression was 96 and 4%, respectively. This showed that the overall proportion of FISHpositive and -negative rate for IHC score 2+ in the detection of HER2 expression was 36 and 64%, respectively, and 91 and 9% for 3+ IHC scores.

Nucleotide

Coding

Amino acid

4 - Expression of hTR and hTERT in human breast cancer: correlation with clinicopathological parameters Telomerase has been associated in some studies with negative prognostic indicators.

Hosseini-Asl et al. [19] tried to detect any association between telomerase sub-units, including hTERT and hTR, and prognostic 81

BREAST CANCER

indicators, such as tumour size and grade, nodal status and patient’s age. Data from tumour samples from 46 patients with primary invasive breast cancer and 3 patients with benign tumours were collected. RT-PCR analysis was used for the detection of hTR, hTERT and PGM1 (as a housekeeping) gene expression. hTR and hTERT were expressed in 31 (67.4%) and 38 (82.6%) samples, respectively.

There was a significant association between hTR gene expression and younger age at diagnosis (p=0.019) compared with patients ≤40 years. None of the benign tumours expressed hTR gene. However, the expression of hTERT gene was detected in two samples. There was no significant association between hTR and hTERT expression and tumour grade, stage and nodal status.

5 - BRCA1 alternative splicing in breast tumorogenesis The BRCA1 gene has almost 11 alternate spliced variants that have been mentioned as susceptibility factors for initiation and progression of breast cancer. Vosoughi et al. [20] analysed the expression of BRCA1 by qualitative and quantitative RT-PCR assays among 27 samples from patients with primary breast cancer. The variants Δ2, Δ11b, and Δ14 were detected; they also found that the BRCA1 gene was expressed in 85.2% of the tumours. The distribution of Δ2, Δ11b, and Δ14 variants were 91.3%, 73.9%, and 78.3%, respectively. These findings regarding the variants emphasise the importance of BRCA1 alternative splicing for breast tumorogenesis.

We have investigated the association of Ki67 labeling index, cyclin E and CDC25A expression, with clinical followup data in breast carcinomas [21]. Flow cytometry was used to detect gene amplification of cyclins in 44 tumour tissue with invasive breast carcinomas, Cyclin E or CDC25A were upregulated in 34% of the tumours. Both CDC25A and cyclin E protein expression were correlated with Ki67 expression (p<0.001). These findings suggest a possible prognostic value for CDC25A as a cell cycle marker and may imply a characteristic of high-risk breast cancer patients.

Hosseini-As et al. [22] used TRAP assay to detect telomerase activity, and at the same time conducted RT-PCR on DNase treated and DNase untreated RNA samples for primary invasive breast

82

cancer from 50 patients. They found that 72% of RNA samples were contaminated with DNA and application of DNase could decrease the expression of hTR to a level that had a significant association (p<0.001) with telomerase activity.

Thus with this strategy, hTR expression could be used instead of TRAP assay for telomerase activity evaluation.

By using a novel Evolutionary Models and Periodic Charts in p- and q-Individual Chromosomes of Auxiliary Lymph Node and Buccal Cells and mining the subtelomeric signal profiling of individual chromosomes’ arms, we have suggested that it could be translated to a personalised developmental insight in buccal cells and auxiliary lymph node of breast neoplasm’s cells by Novel Periodic Chart [23].

Atri et al. [24] sought a possible association between early onset of BC and familial clustering in Iran, but found no significant association between having a FH of BC and developing early-onset disease (OR 0.55, CI 95% 0.277–1.091).

In fact, and contrary to what was expected, the early onset BC cases in our population tended to be associated with a negative FH of the disease in comparison with the non-early-onset cases (p=0.083).

Risk Factors The majority of information about the etiology of breast cancer is typically derived from the investigations performed in developed countries, while, Iran is a country with different ethnic and cultural groups facing relatively rapid demographic and life style changes.

For example, the average number of childbirths per woman dropped from over 7 in the early 1980s to 1.7 in 2007.

Such demographic changes can affect the pattern of breast cancer and thus investigating breast cancer in Iran may provide some unique information on breast cancer aetiology.

Thus, Sepandi et al. [25] undertook a large study based on the results of breast cancer screening program of 11,850 women between 2004 and 2012 referred to the Shahid Motahhari breast clinic affiliated to Shiraz University of Medical Sciences to assess some risk factors of breast cancer in Iran. This study showed that family history of breast cancer, occupation, education level, parity, menopausal status, age at menarche, and age at the first pregnancy were related to the risk of breast cancer.

Accordingly, employed women were at a higher risk of breast cancer compared to the housewives. This might be due either to socioeconomic status or exposure to stress or occupational carcinogens.

In agreement with Population-Based research conducted in Iran [26] literacy was a protective factor for breast cancer.

Consistent with other studies [27], our results show that an early age at menarche is associated with a higher risk of breast cancer. This association can be related to longer exposure to endogenous oestrogens [28]. However, a younger age at first pregnancy seems to be a protective factor in the risk of developing breast cancer. This might be due to the higher degree of terminal differentiation of mammary epithelial cells at the first birth, which allows the epithelium to metabolise carcinogens and repair DNA destructions more efficiently [29].

The results show a strong relationship between age at the first pregnancy and risk of breast cancer, and the women who had experienced their first pregnancy after 35 years were at a higher risk of breast cancer compared to those experiencing pregnancy at <15 years of age [25].

The Iranian population is one of the youngest populations in the world that will face ageing in the following decades.

Therefore, although the incidence rate of breast cancer is increasing in young women, it will increase even more in future.

Complementary insights Mutation detection is considered as a fundamental aim in cancer research, but, in order to unmask the functional complexity, a comprehensive strategy is required. So the following items may be considered either for research and/or diagnosis: 1. Basic design relies on the pedigreebased exploring.

2. Focusing on Tumour Biology is a leading paradigm in cancer research, notably in diagnosis and therapy.

3. A personalised approach will provide cancer patients the more appropriate prognostic, predictive and preventive strategies.

In conclusion, a bridging system in cancer research and managements relies on multi-disciplinary and exploratory research with translatable capacity. Such a task will be achievable by considering pedigree-based and personalised insight.

Volume 11 Issue 3 • July/August 2016

BREAST CANCER

References 1. Moore MA, Eser S, Igisinov N, et al. Cancer epidemiology and control in NorthWestern and Central Asia-past, present and future. Pancreas 2010;4(4.2):0.7-1.9.

2. Khadivi R, Harrirchi I, Akbari ME. Ten year breast cancer screening and follow up in 52200 women in Shahre-Kord, Iran (1997-2006). Iranian Journal of Cancer Prevention. 2012;1(2):73-7.

3. Mousavi SM, Gouya MM, Ramazani R, et al. Cancer incidence and mortality in Iran. Annals of Oncology 2009;20(3):556-63.

4. Tayyeb B, Mehdipour P. Pathogenesis of Breast Cancer Metastasis to Brain: a Comprehensive Approach to the Signaling Network. Molecular neurobiology.

2014:1-9.

5. Harirchi I, Ebrahimi M, Zamani N, et al. Breast cancer in Iran: a review of 903 case records. Public health 2000;114(2):143-5.

6. Harirchi I, Karbakhsh M, Kashefi A, et al. Breast cancer in Iran: results of a multi-center study. Asian pacific journal of cancer prevention 2004;5(1):24-7.

7. Mousavi SM, Mohaghegghi MA, Mousavi-Jerrahi A, et al. Burden of breast cancer in Iran: a study of the Tehran population based cancer registry. Asian Pacific Journal of Cancer Prevention 2006;7(4):571.

8. Pietschmann A, Mehdipour P, Atri M, et al. Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families. Journal of cancer research and clinical oncology. 2005;131(8):552-8.

BioMedES Ltd

Producing the very best definitive versions of your biomedical reports and papers www.biomedes.co.uk Why not contact us at: BioMedES Ltd Leggat House, Keithhall, Inverurie, AB51 0LX, UK. T: +44-1467-6702809, F: +44-1467-629123, E: info@biomedes.co.uk

9. Ghaderi A, Talei A, Farjadian S, et al. Germline BRCA1 mutations in Iranian women with breast cancer. Cancer letters 2001;165(1):87-94.

10. Mehdipour P, Hosseini-Asl S, Savabi-E A, et al. Low frequency of 185delAG founder mutation of BRCA1 gene in Iranian breast cancer patients. J Cancer Molecules. 2006;2:123-7.

11. Karimaghaee N, Talei A-R, Banani SJ. Analysis of BRCA1 and BRCA2 mutations in southern Iranian Breast cancer patients. Archives of Iranian medicine 2009;12(6):584-7.

12. Karami F, Mehdipour P. A Comprehensive Focus on Global Spectrum of BRCA1 and BRCA2 Mutations in Breast Cancer. BioMed research international 2013;2013.

Never heard of us?

Not surprising, since our operations are mostly “behind the scenes”. But we may be able to help you with your publication problems, from technical notes to e-books.

13. Sadr‐Nabavi A, Dastpak M, Homaei‐Shandiz F, et al. Analysis of novel mutations in BRCA1 in Iranian families with breast cancer. Hereditas 2014;151(2-3):38-42.

14. Keshavarzi F, Javadi GR, Zeinali S. BRCA1 and BRCA2 germline mutations in 85 Iranian breast cancer patients. Familial cancer 2012;11(1):57-67.

15. Atri M, Mehdipour P, Javidroozi M, et al. Linking histopathology and family history in breast cancer. Asian Pacific J Cancer Prev. 2002;3:33-9.

16. Behjati F, Atri M, Najmabadi H, et al. Prognostic value of chromosome 1 and 8 copy number in invasive ductal breast carcinoma among Iranian women: an interphase FISH analysis. Pathology & Oncology Research 2005;11(3):157-63.

17. Savad S, Mehdipour P, Miryounesi M, et al. Expression analysis of MiR-21, MiR-205, and MiR-342 in breast cancer in Iran. Asian Pacific Journal of Cancer Prevention 2012;13:873-7.

18. Bahreini F, Soltanian AR, Mehdipour P. A meta-analysis on concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) to detect HER2 gene overexpression in breast cancer. Breast Cancer 2014:1-11.

What does BioMedES do?

• BioMedES reworks sound scientific papers, technical reports, and other (biomedical) documents, putting them into the most idiomatic English and passes the most stringent peer review and quality control assessments

19. Hosseini-Asl S, Atri M, Modarressi MH, et al. The expression of hTR and hTERT in human breast cancer: correlation with clinico-pathological parameters.

International Seminars in Surgical Oncology; 2006: BioMed Central Ltd. 20. Vosoughi E, Faghani N, Mehdipour P, et al. BRCA1 alternative splicing in breast tumorogenesis. Annals of Biological Research 2013; 4(4):139-43.

• It copy edits for a number of big biomedical publishing houses

21. Mehdipour P, Pirouzpanah S, Sarafnejad A, et al. Prognostic implication of CDC25A and cyclin E expression on primary breast cancer patients. Cell biology international 2009;33(10):1050-6.

• It provides the Secretariat for an international organisation for cell biology (www.ifcbiol.org) and an enterprise company

22. Hosseini-Asl S, Modarressi MH, Atri M, et al. The association between telomerase activity and expression of its RNA component (hTR) in breast cancer patients: the importance of DNase treatment. Journal of carcinogenesis 2006;5(1):17.

23. Mehdipour P, Javan F, Atri M. Novel evolutionary models and periodic charts in p-and q-individual chromosomes of auxiliary lymph node and buccal cells. Disease markers 2013;35(6):833-45.

24. Atri M, Jafarimojarrad E, Javidroozi M, et al. Lack of association between early onset of breast cancer and numbers of affected relatives in an Iranian population.

Familial cancer 2003;2(2):117-8.

25. Sepandi M, Akrami M, Tabatabaee H, et al. Breast Cancer Risk Factors in Women Participating in a Breast Screening Program: a Study on 11,850 Iranian Females. Asian Pacific Journal of Cancer Prevention 2014;15(19):8499-502.

26. Harirchi I, Azary S, Montazeri A, et al. Literacy and breast cancer prevention: a population-based study from Iran. Asian Pac J Cancer Prev 2012;13:3927-30.

27. Naieni KH, Ardalan A, Mahmoodi M, et al. Risk factors of breast cancer in north of Iran: a case-control in Mazandaran Province. Asian Pacific Journal of Cancer Prevention 2007;8(3):395.

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28. Peeters P, Verbeek A, Krol A, et al. Age at menarche and breast cancer risk in nulliparous women. Breast cancer research and treatment 1995;33(1):55-61.

29. Russo J, Moral R, Balogh GA, et al. The protective role of pregnancy in breast cancer. Breast Cancer Res 2005;7(3):131-42.

Volume 11 Issue 3 • July/August 2016

83

CONFERENCE NEWS Are you organising an annual meeting or conference which you would like to tell our readers about?

Or would you like to write a report on a meeting or conference of particular interest?

If so, contact Patricia McDonnell at Oncology News on T/F: +44 (0)288 289 7023, E: patricia@oncologynews.biz

2nd John Fitzpatrick Irish Prostate Cancer Conference Date: 21-22 April 2016. Venue: Dublin, Ireland. Report by: Emma Leacy, Claire Tonry and Stephen R Pennington (UCD Conway Institute, University College Dublin, Ireland).

T

he second annual John Fitzpatrick Irish Prostate Cancer Conference, previewed in the Jan/Feb 2016 issue of Oncology News, took place at the Aviva Stadium on the 21st & 22nd of April 2016 (weblink). Leading Irish, UK, European and International healthcare professionals came together to hear and discuss the latest developments in prostate cancer research. The programme consitisted of 5 integrated lecture sessions and two panel discussions. As befitting of the stature and international reputation of urologist Professor John Fitzpatrick and the esteem in which he was held the programme contained leading edge presentations from those at the forefront of Prostate Cancer Research nationally in Ireland and internationally.

The Conference also provided the opportunity (on the second day) for Dr Rob O’Connor, Director of Research at The Irish Cancer Society, and Dr Chris Sweeney, Dana-Farber Cancer Institute, Boston, to announce the award of the first Professor John Fitzpatrick Fellowship to Dr Emma Allott (pictured below).

Dr Allot will investigate the role of cholesterol metabolism in prostate cancer in this the first research initiative that forms part of a Boston-Ireland prostate cancer collaboration. It was fitting that members of Prof Fitzpatrick’s family were present during the brief award

Dr Emma Allott

84

ceremony in which Dr O’Connor made an impassioned plea for research to remain at the foundation of all prostate cancer efforts.

The Conference began with a Diagnostics-themed first session and a comprehensive and authoritative overview of “Smarter Prostate Cancer Screening and Detection” by Stacy Loeb (NYU, New York). Citing NCCN guidelines for biopsy indications Dr Loeb remarked that ‘combinations of multiple markers can improve their predictive value’. Loeb finished her talk with a heartfelt photo slideshow tribute to her close friend John Fitzpatrick.

In the following presentation internationally trained pathologist and research Stephen Finn (Trinity College Dublin, Dublin) introduced the role of obseity and metabolic syndrome in prostate cancer and described recent excercise intervention research studies that are underway and noted that more rigorous exercise regimes are on the way for participants of the forthcoming Movember GAP5 exercise intervention study. Next, Jelle Barentsz (Radboud University Nijmegen Medical Center, Nijmegen), in the first of his talks at the conference discussed the use of multi-parametric MRI in prostate cancer detection. Since 2005 he has seen a 14-fold increase in mpMRI referals at his clinic and noted that education and training are key for radiologists to avoid missing lower grade cancers.

Jeremy Clark (University of East Anglia, Norwich) opened the Emerging Biomarkers session by introducing the use

of RNA probes for detecting biomarkers in tissue and more recently in urine, the latter which formed part of the now completed Movember GAP1 biomarker programme. Sue Slovin (MSKCC, New York) reviewed immune and autoimmune biomarkers and stressed the need to maximise currently available agents to justify their utility. This proved to be a suitable introduction for Emmanuel Antonarakis (Johns Hopkins Sidney Kimmel, Comprehensive Cancer Center, Baltimore) to discuss androgen receptor variants as treatment selection markers.

His research into the AR-V7 splice has shown that CRPC patients are resistant to hormone therapy with enzalutamide and abiraterone. Alternative therapies need to be utilized for these patients, and rapid detection of these biomarker variants is crucial.

The first panel discussion was chaired

by Joe O’Sullivan (Queen’s University Belfast) and featured an all-star multidisciplinary team of 2 surgeons, 2 medical oncologists, and 1 radiation oncologist. The first case study, which O’Sullivan had dubbed “the easy one”, caused considerable debate among

Volume 11 Issue 3 • July/August 2016

CONFERENCE NEWS

the group. By the 3rd case study the team were in agreement about the need to correct MRI setup disparities across centres and to thoroughly discuss the pros and cons of each treatment choice with their patients. As Chris Sweeney noted early on in the vibrant, entertaining and educational discussion, there is convincing evidence that patients do better when they are involved in the treatment decision making process.

Day 2 of the conference began with Session 3 on Trials & Outcomes. David Galvin (Mater Misericordiae University Hospital, Dublin) introduced IPCOR (Irish Prostate Cancer Outcomes Research) and its patient-centered approach to collecting data using mobile and web apps as part of its strategy to provide hospitals and policy makers with the information reporting needed to inform future healthcare decisions that affect prostate cancer care in Ireland. Next up was radiation oncologist John Armstrong (John Armstrong, St. Luke’s Hospital, Dublin).

John described the beginnings and growth of ICORG – the All Ireland Clinical Oncology Research Group – which he (Radiation Oncologist) and Prof John Crown (Molecular Oncologist) founded in 1996. His excellent presentation ended with an emphasis on the need for teamwork and a Monty Pythonesque tribute to the substantial achievements of ICORG. Asking “What has ICORG ever done for us?” he noted that ICORG led trials and the work of ICPORG investigators have been instrumental in many improvements in Prostate Cancer treatment in Ireland including 3D scans and intensity-modulated radiation therapy becoming routine in clinical practice in the country. Paul Cathcart (Guy’s and St. Thomas’, London) in his description of the impressive UK National Prostate Cancer Audit noted that it had highlighted the disparities between cancer care in different locations around the UK and this was further emphasised by John Kelly (University College London, London) who graphically revealed how age adjusted mortality improves in prostate cancer surgery as you travel West to East along one of London’s main Underground Lines – one year per Underground Station. John described their advanced Quality Assurance efforts for systematic training, development and monitoring of urologists performing robotic surgery and their progress in achieving reduced geographic variations in patient outcomes.

Session 4, a Multidisciplinary Plenary Session, began with Chris Sweeney comparing the hetergeneous nature of prostate cancer to “50 Shades of Grey”. In his lively and detailed presentation he described advances in chemo-hormonal therapy and the hugely impactful CHAARTED trial he coordinated. Michael Blute (Massachusetts General Hospital, Boston) continued on from Loeb’s Day 1 discussion on biomarkers and focused attention on the impact of PSA screening. Blute described how he is cautious about the “all or nothing” approach to the use of PSA as screening tool and the impact the USPTF recommendations on PSA screening are having on the stage at which men are now diagnosed with and present for treatment in the US. The presentations moved from screening to translational research with David Waugh (Queen’s University Belfast) speaking about the use of inflammatory signals as targets for treatment describing the role of IL-8 in PTEN-deficient patients as an example. In the next presentation Gerard Morton (Sunnybrook Health Sciences Centre, Toronto) used an analogy of a bear in the water (and a photograph of a personal kayak-based real life encounter with the same!) to introduce the need to sometimes Volume 11 Issue 3 • July/August 2016

change direction and the considered the question of whether brachytherapy should become the preferred treatment for localized prostate cancer. Gerard highlighted its superior outcome when used alone in patients with low-risk disease compared with external beam radiation therapy.

Robert Nadler (Northwestern University Feinberg School of Medicine, Chicago) began the 5th and closing session on ‘ Trends in Management’ by noting the popular opinion that high volume equates to high skill and how some argue that trainee urologists need to perform multiples of thousands of biopsies a year and greater than 10’s of radical biopsies a day to become proficient.

He also discussed, with Blute, the relative merits of robot assisted versus open prostatectamy methods and urged surgeons to utilize the Rocco Stitch to improve urinary incontinence. Peter Hoskin (Mount Vernon Cancer Centre, Middlesex) joked that other speakers had already given most of his presentation but he was still able to deliver an attention grabbing and compelling presentation that included discussion on the use of the cyberknife and high dose radiation. In the second of his presentations, Jalle Berentz introduced new imaging techniques and demonstrated their role through various case studies. Finally, self-proclaimed survivorship physician John Mulhall (MSKCC, New York), closed the session by lamenting the lack of evidence provided by commercial enterprises promoting therapies for erectile dysfunction (ED) and the difficulties that the placebo effect has on evidence-based assessment of any ED therapies.

The closing panel discussion was chaired by Paul Sweeney (Mercy University Hospital, Cork) and in a series of case studies the assembled panel of experts (Emmanuel Antonarkis, Paul Cathcart, Peter Hoskin, Stacy Loeb and Thomas Lynch (St. James’s Hospital, Dublin)) insisted on learning more about each individual patient’s condition before making ‘hasty’ decisions about the best treatment options. The differences in opinions about treatment decisions from these key opinion leaders could be seen as highlighting the need for further collaboration among multidisciplinary teams when making treatment decisions and for new improved decision making tools. One thing everyone agreed on was the need for a patient focussed approach to information sharing and treatment discussion. An appropriate conclusion to this second John Fiitzpatrick Prostate Cancer Conference. The dates of the 3rd John Fiitzpatrick Prostate Cancer Conference will be announced on the conference website and in Oncology News.

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CONFERENCE NEWS

HemOnc Today Melanoma and Cutaneous Malignancies Annual Meeting Date: 18-19 March 2016. Venue: New York, USA. Report by: Janet Fricker, Medical Journalist.

Intralesional therapy combined with checkpoint inhibitors here to stay in melanoma In melanoma intralesional therapy, whether monotherapy or in combination with checkpoint inhibitors, is clearly here to stay, concluded a debate at the HemOnc today Melanoma and Cutaneous Malignancies Annual Meeting, March 18-19, New York.

Speaking for the motion ‘Intralesional Monotherapy is here to stay,’ Merrick Ross (MD Anderson Cancer Center) described how intralesional therapy is used for stage IIIb/c regionally metastatic in-transit disease with or without nodal disease; stage MIa (distant skin, soft tissue and nodal metastases); and Stage MIa with low volume visceral disease. The dual treatment goals, he explained, are locally ablative therapy for local disease control and induction of systemic host immune anti-tumour activity. Ross provided an overview of the three main intralesional therapies: • T-VEC [talimogene laherarepvec, OncoVEX GM-CSF]: a herpes simplex virus type 1. Phase 3 trial completed, already licensed.

• PV-10: a 10% solution of the dye Rose Bengal. Phase 2 trial completed, phase 3 trial ongoing.

• Coxsackie A21 virus [Cavatak, viralytics]: a naturally occurring ‘common cold’ intracellular adhesion molecules 1(ICAM1) targeted RNA virus. Phase 2 trial completed.

Each agent, Ross said, can selectively invade and lyse tumour cells. “You start with ablation of the tumour which would express tumour derived antigens, then when the tumour is destroyed, you prime dendritic cells to express activated T cells that proliferate and migrate to distant tumours,” he said.

For the remainder of his presentation Ross focused on T-VEC and PV-10, the agents for which he has greatest clinical experience.

In the phase 2 PV-10 study, involving 80 patients, a complete response rate of 24% was achieved in both injected lesions and uninjected ‘bystander lesions’, with a disease control rate (DCR) of 71% for 86

Merrick Ross

Robert Andtbacka

injected lesions and 55% for bystander lesions. To get a good bystander response patients need to have a good local response demonstrated by the CR and PR bystander response being 67% for those with strong local responses compared to 5% for those with a negative local responses (P<0.0001).

In the phase 3 OPTiM trial, 436 patients with injectable, unresectable stage IIIB-IV melanoma were randomized 2:1 to TVEC intralesional injections (n=295) or GM-CSF (n=141). Results showed a durable response rate (objective response lasting for at least six months) was achieved in 16.3% of T-VEC patients versus 2.1% of GM-CSF patients (P<0.0001). The objective overall response was 26.4% for T-VEC versus 5.7% for GM-CSF. The risk of developing visceral or bone metastasis was reduced by 59% for T-VEC patients compared with GM-CSF controls. “This suggests some sort of systemic immune response has developed preventing visceral metastases,” said Ross.

At 12 months 73.7% of the T-VEC patients survived versus 69.4% of the GM-CSF patients, indicating survival trends favouring T-VEC. Summarising the data, Ross said, studies in stage 3B/C melanoma patients show response rates are higher for intralesional therapies than approved systemic immunotherapies. Furthermore, grade 3-4 adverse events were lower for intralesional therapies. But adding checkpoint inhibitors, cautioned Ross, would change the toxicity profile. “I have never seen a pituitary gland disappear or a colon rupture with intralesional therapies, side effects seen with some checkpoint blocking agents.”

Speaking against the motion, Robert Andtbacka, (University of Utah) made a

case for combining intralesional therapies with checkpoint inhibitors. Response rates with combinations, Andtbacka argued, are better than with either agent alone and combination treatment does not add toxicity.

In the Checkmate 067 trial of nivolumab plus ipilimumab, the best change from baseline in target lesion volume was 51.9% for the combination, versus -34.5% for nivolumab alone and +5.9% for ipilimumab alone. That 40% of combination treatment patients experienced grade 3-4 adverse event was of concern.

But recent trials combining intralesional therapies with checkpoint inhibitors reveal enhanced immune responses and no increases in toxicity. Notably, a phase 1b trial of ipilimumab plus TVEC (involving 18 patients) showed no new safety signals or dose limiting toxicities. The DCR was 72%, with durable responses in 44% and complete regression of uninjected non-visceral and visceral lesions in 39%.

The ongoing phase 3 MASTERKEY-265 study, comparing T-VEC plus pembrolizumab to placebo plus pembrolizumab, with plans to recruit 660 patients, it is hoped will provide definitive answers about outcomes and side effects. “Where checkpoint inhibitors don’t work this can be due to the lack of lymphocytes. Intralesional therapies can boost checkpoint inhibitors through enhancing levels of lymphocytes,” said Antbacka.

Planned trials exploring other combinations include a phase 2 of pembrolizumab + IL-12 electroporation, a phase Ib trial of pembrolizumab +CVA21, and a phase trial of pembrolizumab +-PV-10.

Sanjiv Agarwala, the meeting’s chairman (St. Luke’s Cancer Center) said, “We have to realize intralesional therapy is not going anywhere, it’s here to stay. It’s a new paradigm for potential combinations, and perhaps in the future the ultimate melanoma regimen is going to be an intralesional therapy with a systemic, checkpoint inhibitor.

Monotherapy also is applicable to specific patients.”

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CONFERENCE NEWS

Childhood Cancer 2016: A scientific and educational meeting showcasing state-of-the-art translational science in childhood cancer Date: 5-7 September 2016. Venue: London, UK. Report by: Katie Martin, Research Development Manager, Children with Cancer UK.

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very year in the UK, around 1,600 children and more than 2,000 teenagers and young adults are diagnosed with cancer.

Increases in the survival rates for children with cancer are a major success story, overall five-year survival has doubled over the last 50 years to more than 80%.

This success has been particularly marked in leukaemia, the most common of the childhood cancers, where survival has increased from below 10% in the 1960s to almost 90% today.

But much remains to be done. Even amongst the leukaemias, there are forms that continue to have a poor outlook. Some childhood cancers simply have no effective treatment and care is palliative from the outset. New treatments are desperately needed to save these young patients.

For those who are successfully treated, life is forever changed. Treatment is gruelling and survival is achieved through the use of intensive treatment regimes that may include surgery, radiotherapy and chemotherapy. All this can leave survivors facing serious longterm and late treatment-related effects. We are only just beginning to fully understand the true extent of these effects but with an estimated 35,000 survivors of childhood cancer alive in the UK alone, it undoubtedly represents a huge burden of morbidity.

Children with Cancer UK is one of the UK’s

leading funders of research into childhood cancer. We support a broad range of research aiming to advance understanding of childhood cancers and promote the development of more effective, less damaging treatments. We are currently funding more than 50 distinct research projects at centres around the UK. At Childhood Cancer 2016 we will address three themes over three days: precision medicine, immunotherapy and causation.

Speakers will provide a state of the art update as to how new developments in translational science are being harnessed to further improve survival and quality of survival for children suffering from cancer before turning attention to the question of causation on the final day.

The event is designed to bring together clinicians and scientists from different disciplines within paediatric oncology to exchange knowledge and ideas. Each day combines an outstanding line-up of plenary speakers with free communication and panel debates.

Preview

On the first day, Josef Vormoor (Newcastle University) and David Walker (University of Nottingham) are in the chair to consider precision medicine and the extent to which it is a reality for children with cancer in 2016.

Plenary lectures will be delivered by Stefan Pfister (German Cancer Research Centre), Anthony Moorman (Newcastle University), Richard Gilbertson (Cambridge University) and Darren Hargrave (Great Ormond Street).

Persis Amrolia and John Anderson (Great Ormond Street) are in the chair for day two, focused on immunotherapy and childhood cancer. They will be joined by world-leading immunotherapy experts Nai-Kong Cheung (Memorial Sloan Kettering), Stephan Grupp (Children’s Hospital of Philadelphia), Daniel Lee (US National Cancer Institute) and Martin Pule (UCL Cancer Institute).

And on day three, Denis Henshaw (University of Bristol) and Chris Portier (US Environmental Defense Fund) will take the chair to consider what we know about influenceable causes of childhood cancer, joined on the podium by Soterios Kyrtopoulos (National Hellenic Research Foundation), Tariq Enver (UCL Cancer Institute) and Kurt Straif (IARC).

For further information, please visit www.childhoodcancer2016.org.uk

BASO~ACS @ NCRI 2016 Date: 6-9 November 2016. Venue: Liverpool, UK.

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he conference venue is the award winning Liverpool Convention Centre set on a delightful waterfront. The NCRI Cancer Conference provides a forum for researchers from different disciplines to exchange knowledge and ideas and BASO~ACS is joining forces with the NCRI to increase the surgical research profile in the UK. The Conference programme showcases the best in basic science, clinical trials, qualitative research, dataset analysis and cancer surgery.

The aim of this collaboration is to provide a unique environment for interdisciplinary learning and the cross fertilisation of ideas by bringing together delegates from all cancer Volume 11 Issue 3 • July/August 2016

Preview

research disciplines.

The programme will be a hybrid of a standard BASO meeting with educational sessions focused purely on surgical technical issues on day 1 followed on by strong surgical track running through the rest of the conference.

There will be surgical plenaries, prize sessions, BASO~ACS Awards presentations, workshops and networking. Our Key Speakers include: • Professor Robert Grimer, Pioneer of paediatric bone sarcoma surgery.

• Professor Margaret Stanley, OBE, Expert on the role of HPV in cancer causation & its prevention.

• Professor Cheng-Har Yip, President Breast Surgery International, Malaysia .

• Professor David Jayne, Expert in the field of surgical robotics for abdominal disorders.

• Professor Rob Bristow, Expert in the Radiobilogy of Prostate Cancer

Trainees Meeting will be hosted on 6th November.

We look forward to welcoming you to the UK’s largest Cancer Conference.

Visit www.BASO.org.uk for further details.

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NEWS UPDATE Latest developments on products and services from the industry. To have your news included contact Patricia McDonnell at Oncology News on T/F: +44 (0)288 289 7023, E: patricia@oncologynews.biz

Varian Medical Systems starts equipment installation at new Proton Therapy Centre in Netherlands Varian Medical Systems have delivered the cyclotron for the new multi-room HollandPTC in Delft, which will be equipped with the Varian ProBeam® proton therapy system.

The cyclotron, a particle accelerator which accelerates protons to two thirds of the speed of light for clinical use, is a core piece of equipment of the ProBeam® system.

The delivery marks the start of equipment installation, a key milestone for each new proton therapy centre.

HollandPTC is part of Medical Delta, the medical-technological collaboration of the universities and university medical centres of Leiden, Delft and Rotterdam. Due for completion in 2017, the center will feature

Updated NICE quality standard recommends Oncotype DX® in earlystage breast cancer

NICE has published its latest quality standard, recommending the use of Genomic Health’s Oncotype DX test in eligible patients with early-stage breast cancer.

The new standard states that people with ER-positive, HER2-negative and lymph nodenegative early breast cancer who are at intermediate risk of distant recurrence should be offered gene expression profiling with Oncotype DX. The test provides information about the genetic makeup of a tumour and predicts whether a patient is likely to benefit from chemotherapy. This can help avoid unnecessary chemotherapy and the associated harmful side-effects and costs.

The NICE quality standard has been updated to reflect changes in the national priorities for improvements in breast cancer care since the original standard’s publication in 2011. Genomic expression profiling is one of six statements that require attention of commissioners, health care professionals and service providers to help drive more widespread and consistent adoption in order to improve the quality of care.

To read the full NICE press release visit https:// www.nice.org.uk/news/press-and-media/ updated-nice-quality-standard-identifies-areasfor-breast-cancer-improvement For further information about Oncotype DX call Genomic Health on 020 3031 8087.

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research room.

“Delivery of the cyclotron is the next major milestone in bringing this advanced cancer-fighting technology to patients in the Netherlands,” said Dr Moataz Karmalawy, general manager of Varian’s Particle Therapy division. “As well as offering pencil-beam scanning, the most advanced form of proton therapy, HollandPTC will be a key research site feeding into a national program to study and improve the efficacy of protons.”

two proton therapy treatment rooms with full rotational gantries, one for fixed-beam eye treatments, as well as a dedicated

For further information contact: Neil Madle, Varian Medical Systems T: +44 7786 526068 E: neil.madle@varian.com W: www.varian.com

Provectus Biopharmaceuticals Announces Abstract Available Online of Trials in Progress; Abstract for Poster Presentation at ASCO Annual Meeting Presentation took place June 4, 2016, ASCO Meeting Runs June 3-7, 2016, Chicago, Illinois Provectus Biopharmaceuticals, Inc have announced the availability online of an abstract titled “Intralesional rose bengal for treatment of melanoma” which was presented as a poster at the annual meeting of the American Society of Clinical Oncology (“ASCO”) in Chicago June 3-7, 2016.

To see this abstract, visit: http://abstracts.asco.org/176/AbstView_176_171580.html.

The poster for the abstract, ID: TPS9600, was presented on June 4, 2016, running from 1:00-4:30.

For further information visit: www.pvct.com

ePrescribing for Paediatric Oncology CIS Oncology today announces a surge of activity in the deployments of its Paediatric ChemoCare solution. ChemoCare, already known as the system of choice for adult chemotherapy ePrescribing in 130+ UK hospitals, has recently been selected by three Paediatric Cancer Specialist Treatment Centres (PTC) to rollout network and single hospital solutions of ChemoCare.

Birmingham Children’s Hospital has extended the functionality of its current Paediatric ChemoCare implementation to enable the Paediatric Oncology Shared Care Units (POSCUs) in the West Midlands Children’s Cancer Network to prescribe chemotherapy using the same database so there is a single paediatric oncology prescription record for children receiving treatment in more than one hospital in the same network. Oxford Children’s Hospital (part of Oxford University Hospitals NHS

Foundation Trust) and Noah’s Ark Children’s Hospital for Wales (part of Cardiff & Vale University Health Board) have also opted for the ChemoCare solution to support its Oncology services for children and young people.

CIS Oncology’s Paediatric ChemoCare is successfully used to prescribe chemotherapy in 70% of Paediatric Cancer Specialist Treatment Centres (PTC) across the UK. It is one of the few products capable of supporting this complex field of medicine, supporting users as they prescribe and administer the complex protocols used within Paediatric Oncology.

Follow us on @CISoncology to keep up to speed with all our latest developments or visit www.cis-healthcare.com

Volume 11 Issue 3 • July/August 2016

NEWS UPDATE

Presentation slides now available from the Melanoma Immunotherapy Regional Meeting in Dubrovnik, Croatia Dr Sanjiv Agarwala (Professor of Medicine, Temple University; Chief of Oncology and Hematology, St Luke’s Cancer Center in Bethlehem, PA) has presented at the Melanoma Immunotherapy Regional Meeting in Dubrovnik, Croatia. In the presentation, titled “The Changing Paradigm in Immunooncology: The Past vs. the Future in the Treatment of Melanoma”, Dr Agarwala gave a thorough overview of recent advances in

the treatment of melanoma and discussed promising clinical trials.

Slides from Dr Agarwala’s presentation are now available from the Provectus website at http://www.pvct.com/presentation/DubrovnikMelanoma-2016-05.pdf For further information visit: www.pvct.com

Varian extending advanced cancer care in Turkey Cancer patients in Turkey will gain access to advanced radiotherapy treatments with news that Varian Medical Systems has been selected to supply multiple treatment machines to public and private hospitals in the country. To date this year, Varian has booked orders for more than 20 medical linear accelerators from Turkish hospitals. The new systems will be delivered over the next 18 months.

In March, Varian was selected to equip hospitals in the cities of Mersin and Ankara with multiple modern Varian linear accelerators, including two TrueBeam™ systems and the country’s first VitalBeam device. These machines are for sites that are the first radiotherapy schemes within the Integrated Healthcare Campus Project tendered by the Turkish ministry of health under a PPP (Public Private Partnership) program and will be supplied to the main contractor, DIA Holding.

“We have selected Varian radiotherapy systems for our Mersin and Ankara

Bilkent integrated health campus projects because of their operational capability, clinical excellence and versatility,” said Murad Bayar, of DIA Holding. “Due to the complexity and size of these campus projects, which are among healthcare PPP initiatives in Turkey, we wanted to work with the best.”

For further information contact: Neil Madle, Varian Medical Systems, T: +44 7786 526068 E: neil.madle@varian.com W: www.varian.com

Myriad Genetics strengthen UK team – David Spackman, new General Manager David Spackman has taken over as General Manager, Myriad Genetics, UK and Ireland. The UK team will focus upon the private sector to offer more treatment options for women diagnosed with certain types of breast cancer, whilst also offering considerable savings to insurers in safely avoiding unnecessary invasive treatments. Myriad will later look to expand into the public sector.

“The UK presents an exciting opportunity for Myriad Genetics’ range of hereditary cancer and other disease state genetic panels. There is growing awareness of the benefits of understanding genetic predispositions to certain types of cancers. Such information can be used to make informed decisions concerning risk reducing surgery to avoid

Volume 11 Issue 3 • July/August 2016

cancer and in making treatment decisions for those diagnosed with cancer,”” said Spackman.

Spackman has considerable experience in the National Institute of Health Research and the Area Health Science Networks and Diagnostic Evidence Consortia to generate clinical and health economic evidence to support submissions to NICE. Until recently Spackman was General Manager and Commercial Country Lead (UK, IRL and NL) of Thermo Fisher Diagnostics, Clinical Diagnostics Division.

Powerful imaging technology aids research to transform clinical pathways

The TOHETI programme is undertaking innovative research in order to discover how imaging technology can be used more proactively and effectively.

The Transforming Outcomes and Health Economics Through Imaging (TOHETI) programme is looking to change the way medical imaging works by undertaking a range of pioneering research. The research aims to streamline diagnostic pathways in order to enhance patient care whilst contributing to a more cost-effective health service. A recently installed SOMATOM® Force CT system will aid the research, in addition to two further CT and two 3T-MRI scanners from Siemens Healthineers which are set to go live later this year across Guy’s and St Thomas’. The £13.3m TOHETI programme has been funded by Guy’s and St Thomas‘ Charity and Guy’s and St Thomas‘ NHS Foundation Trust.

Nyree Griffin, Consultant Gastrointestinal Radiologist, Guy’s and St Thomas’ NHS Foundation Trust, explains, “Through this TOHETI programme we are carrying out a 1-year study, where CT colonography will be offered as a first line, non-invasive alternative investigation for patients who are at low to medium risk of colorectal cancer. A health economic analysis will be performed, comparing the outcomes of this new CT colonography pathway with the traditional optical colonoscopy pathway. It is hoped that the results of this study will facilitate discussions on a revised colon cancer pathway in our Trust, which should be more cost effective, result in reduced waiting times in endoscopy, increased access to CT colonography, and improved patient experience” Further information is available on the Internet at http://www.healthcare.siemens.com/

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NEWS UPDATE

Fenwick charity auction success for Brain Tumour Research Fenwick of Bond Street has partnered with charity Brain Tumour Research to celebrate the iconic store’s 125th anniversary this year. In collaboration with some of the UK’s most established hat designers, they hosted a millinery exhibition and online auction, with all proceeds going to Brain Tumour Research. The auction of 13 bespoke hats, one for each decade that the store has been trading, plus an Ascot Royal Enclosure Experience came to a close in a flurry of bidding on 2nd June.

The charity, known for its annual ‘Wear A Hat Day ‘campaign each March, was also supported by Fenwick of Bond Street customers donating a discretionary £1 on every transaction in the store and in two in-store restaurants during the exhibition.

Fenwick also incorporated text codes for

charity donations in their anniversary window displays.

Philip Treacy OBE, a patron of Brain Tumour Research, provided the hat representing the present decade, while Stephen Jones OBE, created a piece to reflect the 1940s. Both milliners have previously designed exclusive brooches to support ‘Wear A Hat Day’, as have fellow couture milliners featured in the exhibition, Rachel TrevorMorgan and Vivien Sheriff.

Philip Treacy said:“I am delighted to have created a bespoke piece for Fenwick and I wish them a happy 125th birthday. To know it will be auctioned to raise money for Brain Tumour Research is a wonderful bonus, as they are a charity close to my heart.”

For further information visit: www.braintumourresearch.org

Varian selected to provide planning software for new UK Proton Therapy Centre Varian Medical Systems has been selected by The Christie NHS Foundation Trust to provide Eclipse treatment planning software for the proton center currently under construction at the Manchester hospital. Varian is already supplying treatment equipment for the two UK national proton centers being constructed at The Christie and at University College Hospital in London.

“We selected Varian as the proton treatment planning software provider because of the technical excellence and strong connectivity of its systems, together with the fact that Varian is a well-established and reliable supplier of cancer treatment equipment and software,” said Matthew Clarke, The Christie’s lead physicist for proton treatment planning. “The ability of the Eclipse system to enable robust optimisation of treatment plans as well as truly adaptive planning based on images taken during the treatment were instrumental in our decision.”

Steve Laws, Varian’s VP of software sales in EMEIA, said, “Varian is proud to have

IANO President's Prize 2016 In 2016 the IANO will be awarding it's 4th President's Prize to one successful applicant following submission of a research project. This year's prize will be presented at the IANO session during the European Oncology Nurses Society Conference on the 17th & 18th October 2016 at the Aviva Stadium, Dublin. The prize will be a clinical placement in Memorial Sloan Ketttering Cancer Centre (MSKCC) in New York, USA for one week which will be funded by an educational grant from Bayer.

Memorial Sloan Kettering is the world's oldest and largest private cancer centre which has devoted more than a century to patient care as well as innovative research, making significant contributions to new and better therapies for the treatment of cancer. This award will be an excellent opportunity for the successful candidate to work alongside a multidisciplinary oncology team within their chosen speciality area, in a world renowned centre of excellence.

Abstract submission deadline: Friday 16th Sept 2016 Supported by an unrestricted Educational Grant from Bayer

been selected to provide advanced treatment planning software for this major new facility. This decision recognises our longterm commitment to the proton therapy market and our ability to offer a level of compatibility and technical excellence that no other oncology software provider can match.”

The judging panel will be independent of Bayer

For further information contact: Neil Madle, Varian Medical Systems T: +44 7786 526068 E: neil.madle@varian.com W: www.varian.com

To have your event or news featured in the magazine contact Patricia McDonnell – E: patricia@oncologynews.biz

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Volume 11 Issue 3 • July/August 2016

JOURNAL REVIEWS

Journal of Lymphoma, Myeloma and Leukaemia May 2016 Evaluating the Impact of a Switch to Nilotinib on Imatinib-Related Chronic Low-Grade Adverse Events in Patients with CML-CP: The Enrich Study Cortes JE, Lipton JH, Miller CB et al, Clin Lymphoma Myeloma Leuk.

2016 May;16(5):286-96.

Background: Many patients treated with imatinib experience treatment related adverse events which can have a significant impact on quality of life and adherence to treatment which in turn can influence patient outcomes. The aim of the ENRICH (Exploring Nilotinib to Reduce Imatinib Related Chronic Adverse Events) study was to evaluate the effect of switching patients with imatinib associated toxicities to nilotinib.

Methods: In this phase II study, the effect of switching patients with imatinib related chronic low grade non-haematological adverse events to nilotinib was evaluated in 52 patients across 15 centres between December 2009 and August 2012. The primary end point was overall improvement in imatinib adverse events (AEs) at the end of cycle 3, after the switch to nilotinib (decrease of 1 toxicity grade or 50% improvement in symptoms). The secondary end point included time to and duration of complete cytogenetic response (CCyR) and major molecular response (MMR) during the 12 month study follow up. Quality of life (QOL) and the MD Anderson symptom inventory CML (MDASI-CML) module score were assessed at baseline and 5 additional time points over a 12 month period.

Results: At end of cycle 3, after switching to nilotinib, 84.6% of patients experienced an overall improvement in their imatinib related AEs and 62.9% of patients experience a complete resolution of their symptoms.

After switching to nilotinib, new AEs developed in 98.1% of patients. The majority for these were grade 1 or 2 non-haematologic AEs. The most common AEs were headache, fatigue, rash and pruritus. More serious AEs were reported in a minority of patients and 8 patients (15.4%) discontinued treatment because of AEs. At baseline, before switching to nilotinib, 7 patients (13.5%) did not have a CCyR. All these patients achieved a CCyR by end of month 6. Of these 7 patients, the median time to achieve CCyR was 1.9 months and the median duration of CCyR was 282 days. At baseline, 18 patients (34.6%) did not have a MMR (BCR-ABL1 < 0.1% on the international scale). By end of cycle 3, 11 patients (61.1%) achieved an MMR and 15 patients (83.3%) achieved a MMR at any time point during the study. The median time to achieve MMR was 2.8 cycles. No patient with an MMR at screening lost it during the study. Throughout the study, QOL improvements relative to baseline were seen in most evaluable patients. Improvement in MDASI-CML scores relative to baseline were seen throughout the study Conclusion: The ENRICH study showed that switching from imatinib to nilotinib led to improvements in imatinib-related AEs in most patients. Nilotinib therapy resulted in improved disease control, as evidenced by maintenance and/or achievement of CCyR and MMR in most patients. Observed improvements in QOL and MDASI-CML scores demonstrated the impact of AEs on QOL. Low-grade haematological and non-haematological AEs negatively affect QOL in patients with CML receiving long-term TKI therapy and these need to be taken into consideration when assessing patients response and compliance to treatment.

experience chronic low grade toxicities. Patients may not complain about these side effects but there is good evidence that low grade toxicities may increase the risk of poor compliance which in turn is linked to sub-optimal disease control. Long term outcome is linked to good disease control.

In the International randomized study of interferon versus STI571 (IRIS study), 4.9% of patients discontinued first line imatinib due to AEs in the first 5 years of follow up. The risk of AEs was increased in patients on the higher doses of imatinib. This study was however conducted before the availability of second generation tyrosine kinase inhibitors (TKIs). At that time alternative treatment options were limited (stem cell transplant or interferon-α plus chemotherapy) and often had a suboptimal response.

As a result of this patients and clinicians were often more willing to accept low grade toxicities.

The initial registration studies for Nilotinib were conducted before second-generation TKIs were approved. Patients recruited into these studies either grade 3/4 toxicities or were patients with sub-optimal CCyR and MMR responses who had not responded to higher dose imatinib (600mg or 800mg). In these patients the rationale behind a switch to an alternative therapy such as nilotinib was clear. The ENRICH study focused on a different cohort of patients. These patients had low grade AEs due to imatinib, a problem that can be easily overlooked in clinical practice but can have a significant impact on compliance and overall response to treatment.

The ENRICH study confirms that for patients with low grade toxicities, nilotinib offers a viable alternative with improvement in many AEs, overall improved rates of CCyR and MMR and improved QOL. It offers a tolerable and effective treatment in majority of patients but clinicians need to be mindful that a minority may experience different AEs. In the Nilotinib phase 2 trial reported by Kantarjian in Blood (2007), in CP-CML patients who had failed imatinib, biochemical disturbances such as grade 3-4 elevation of lipase or grade 3-4 hyperglycaemia were seen in 18% and 12% of patients respectively. It is important for clinicians who are considering switching to a second generation TKIs to consider the potential impact of other known AEs. In the case of Nilotinib, clinicians may need to consider the impact of biochemical changes such as elevations of lipids and glucose especially in patients with other cardiovascular risk factors.– FW

PANEL OF JOURNAL REVIEWERS Mr Mriganka De, FRCS (ORL-HNS), Consultant ENT Head & Neck/ Thyroid Surgeon, Derby Royal Hospital, UK. Mr Tasadooq Hussain, BA(Edu.) (MD) MRCS, Clinical Research Fellow Breast Surgery at Castle Hill Hospital, Hull and Eat Yorkshire Hospitals NHS, UK. Richard Novell, MChir FRCS, Consultant Coloproctologist, The Royal Free Hospital, London, UK. Xinchao Pan, Postdoctoral Fellow, Department of Internal Medicine, Division of Nephrology in UT Southwestern Medical Center, Dallas, TX , USA. Dr Ankit Rao, ST5 in Medical Oncology, West Midlands Deanery, Birmignham, UK. Dr Sunil Upadhyay, Consultant Clinical Oncologist, Queen’s Centre for Oncology, Castle Hill Hospital, Hull, UK. Dr Fenella Willis, MBBS, FRCP, FRCPath, MD, Consultant Haemato-oncologist and Honorary Senior Lecturer, St George’s Hospital, London, UK.

Reviewer’s comments: Many patients with chronic phase CML

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EVENTS DIARY To have your event listed in the Oncology News diary, E: patricia@oncologynews.biz by August 4th 2016.

2016 July NEW 7th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone and other Musculoskeletal Diseases 2-5 July 2016; Oxford, UK W: www.molpharmworkshop.org Beatson International Cancer Conference 3-6 July 2016; Glasgow, UK W: www.beatson.gla.ac.uk/conf Liverpool Hands-on Transoral Laser Microsurgery for Head & Neck Cancer course 4-5 July 2016; Liverpool, UK E: shonagh.nugent@aintree.nhs.uk Targeted Treatments of Haematological Cancers 5 July 2016; London, UK E: conferenceteam@rmh.nhs.uk T: +44 (0)20 7808 2921 W: www.royalmarsden.nhs.uk/ studydays

NEW London and South East regional Introduction to Lymphoma study day 7 July 2016; London, UK W: www.lymphomas.org.uk/shop/ conferences-and-events/london-andsouth-east-regional-introductionlymphoma-study-day

Oncoplastic Breast Surgery and ADM Reconstruction 7-9 July 2016; London, UK E: PA-surgicaloncology@kcl.ac.uk T: +44 (0)207 188 6380 The Christie Advanced Radiotherapy Summer School 11-14 July 2016; Manchester; UK E: education.events@christie.nhs.uk T: +44 (0)161 918 7409 Trachaeostomy Study Day 18 July 2016; London, UK E: conferenceteam@rmh.nhs.uk T: +44 (0)20 7808 2921 W: www.royalmarsden.nhs.uk/ studydays

NEW Lymphoma Management Course 18-19 July 2016; Oxford, UK W: www.lymphomas.org.uk/ health-professionals/ education-and-training-health -professionals/ lymphoma-management-course BACR & ECMC Joint Meeting, Therapeutic interventions for cancer prevention – the way forward 18-19 July 2016; Bristol, UK http://bacr.org.uk/events/30 UK Breast Cancer Research Symposium 2016 22–23 July 2016; London, UK www.breastcancerconference.org

1st London Minimally Invasive Head and Neck Surgery Symposium Friday 14th October 2016 The Royal College of Surgeons of England 35-43 Lincoln’s Inn Fields, London, WC2A 3PE

Oropharyngeal cancer - Evolution and evidence for primary surgical treatment This symposium aims to provide the latest evidence on the rationale, techniques (TORS and TOLM), outcomes and clinical trials for minimally invasive surgery, in the treatment of oropharyngeal cancer.

It is intended for all members of the head and neck cancer multidisciplinary team.

Symposium Organisers

Registration Fee

Mr Enyi Ofo, London Mr Dae Kim, London

Consultants Trainees Allied health professionals

Faculty Ms Fiona Charman, London Dr Mererid Evans, Cardiff Professor Kevin Harrington, London Professor Katherine Hutcheson, USA Mr Nicholas Hyde, London Mr Jean-Pierre Jeannon, London Professor Terry Jones, Liverpool Professor Suren Krishnan, Australia Professor Vin Paleri, Newcastle Dr Jo Patterson, Newcastle Barrister Daniel Sokol, London Dr Selvam Thavaraj, London Mr Stuart Winter, Oxford

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£150.00 £100.00 £75.00

For further details please contact the events team: Tel: +44 (0) 114 225 9143/9035 Email: academia.bbmuk@bbraun.com Web: www.aesculap-academia.co.uk

August IASLC 7th Latin American Conference on Lung Cancer 25-27 August 2016; Panama City, Florida, USA W: www.iaslc.org Managing Complex Lymphoedema (Level 4 and M) 29 August 2016; Glasgow, UK Margaret Sneddon T: +44 (0)141 330 2072 E: lymph@glasgow.ac.uk

September Future horizons in lung cancer 1 September 2016; London, UK W: www.rsm.ac.uk Medicine Management Study Day 6 September 2016; London, UK E: conferenceteam@rmh.nhs.uk T: +44 (0)20 7808 2921 W: www.royalmarsden.nhs.uk/ studydays

NEW Childhood Cancer 2015 6-7 September 2016; London, UK http://childhoodcancer2016.org.uk Introduction to Cancer Biology and Personalised Cancer Treatments 6-7 September 2016; Manchester; UK E: education.events@christie.nhs.uk T: +44 (0)161 918 7409 7th European Congress of Head & Neck Oncology 7-10 September 2016; Budapest, Hungary W: http://echno2016.org

NEW 16th International Conference on Progress in Vaccination Against Cancer (PIVAC-16) 12-14 September 2016; Winchester, UK W: www.eacr.org 23rd Congress of the European Association for Crano Maxillo-Facial Surgery 13-16 September 2016; London, UK W: www.eacmfscongress.org Royal College of Radiologists Annual Scientific Meeting 2016 14 September 2016; London, UK W: www.rcr.ac.uk/asm Myeloma Academy Roadshows – doctors 14 September 2016; Birmingham, UK E: academy@myeloma.org.uk T: +44 (0)131 557 3332 W: myeloma-academy.org.uk

NEW Medicine & me: Living with Lymphoma 15 September 2016; London, UK W: www.lymphomas.org.uk/ how-we-can-support-you/ patient-and-carer-events

Myeloma Academy Roadshows – nurses 15 September 2016; Birmingham, UK E: academy@myeloma.org.uk T: +44 (0)131 557 3332 W: myeloma-academy.org.uk Targeted Treatments of Paediatric Cancers 15 September 2016; London, UK E: conferenceteam@rmh.nhs.uk T: +44 (0)20 7808 2921 W: www.royalmarsden.nhs.uk/ studydays Lymphoedema: Core Skills and Knowledge (Level 3) 16 September 2016; Glasgow, UK Margaret Sneddon T: +44(0)141 330 2072 E: lymph@glasgow.ac.uk

NEW Breast cancer in the young, the pregnant and with family history 16 September 2016; London, UK W: www.rsm.ac.uk NEW Active Immune Therapy of Cancer – Emerging Strategies 20 September 2016; London, UK W: www.smi-online.co.uk/ pharmaceuticals NEW Cancer Vaccines & Combination Therapies 20 September 2016; London, UK W: www.smi-online.co.uk/ pharmaceuticals NEW Applied therapeutics for palliative medicine: An intensive update for consultants, other senior doctors and senior clinicians 20 September 2016; London, UK W: www.rsm.ac.uk NEW Proton Therapy Congress 20-21 September 2016; London, UK http://protontherapycongress.com Cancer in low and middle income countries: A call for a global fund the evidence 21 September 2016; London, UK W: www.rsm.ac.uk

NEW Cancer Vaccines 21-22 September 2016; London, UK W: www.smi-online.co.uk/ pharmaceuticals NEW SBNS Autumn Meeting 21-23 September 2016; Stoke, UK W: www.sbns.org.uk Volume 11 Issue 3 • July/August 2016

BTOG 2017 15th Annual BTOG Conference 2017 Wednesday 25th - Friday 27th January 2017 Dublin Poster submission: Opens 1st August 2016 - Closes 1st October 2016 Registration and hotel booking: Opens 1st September 2016 BTOG is a multi-disciplinary group for professionals involved with thoracic malignancies. BTOG aims to improve the care of patients with thoracic malignancies through multidisciplinary education, developing and advising on guidelines for patient care and facilitating and nurturing clinical trial ideas into full protocols.

BTOG Chair: Dr Sanjay Popat Secretariat: British Thoracic Oncology Group (BTOG) Glenfield Hospital, Leicester LE3 9QP England Tel: + 44 116 250 2811 Website: www.btog.org

Email: dawn.mckinley@uhl-tr.nhs.uk Twitter @BTOGORG

11-13 December 2016

RAI Amsterdam, The Netherlands

th

European Multidisciplinary Colorectal Cancer Congress

ANNUAL SCIENTIFIC MEETING 2016

Wednesday 14 September 2016, The Barbican, London

The oncology lecture stream, which features as part of the RCR’s ASM, will provide an update on planning and delivering state of the art radiotherapy for pelvic malignancies (lower gastrointestinal, genitourinary and gynaecological), issues of normal tissue tolerance, pelvic retreatment and managing the side effects of pelvic radiotherapy.

The President’s Lecture will be delivered by Professor Hedvig Hricak from Memorial Sloan-Kettering Cancer Centre, USA, speaking on Oncologic imaging in clinical decision making – the next frontier. The programme also welcomes Professor Søren Bentzen of the University of Maryland, USA, speaking on Normal tissue tolerance.

The ASM will feature an industry exhibition, College AGM and lunchtime symposium delivered by Professor David Larson, Stanford University, California, USA on CT Radiation dose optimisation and process control, which is an ideal opportunity for attendees to network with colleagues from around the world.

The 2016 meeting App will feature the full programme, biographies of plenary speakers, allows delegates to create personalised schedules and make notes on sessions during the meeting. Look out for exciting new features including learning points and references and poster abstracts. This will be available to download free from the Google Play or Apple App store by searching RCR ASM.

www.EMCCC2016.org

Attendance at the meeting will earn delegates 6 RCR CPD credits.

For details of the programme, venue, and accommodation and to book a place, please visit: www.rcr.ac.uk/asm

Topics include:

6 – 9 November 2016 BT Convention Centre Liverpool, UK

Join us at the

2016 NCRI Cancer Conference The UK’s Largest Cancer Research meeting

• Science journalism • Radiobiology and prostate cancer • Immunotherapy • APOBECs and relevance to cancer • Phase III trials • Surgical oncology … And many more

Confirmed speakers include: • Kat Arney

Freelance science writer and science broadcaster, London, UK

• Rob Bristow,

University of Toronto, Canada

• David Currow,

Flinders University, Australia

Standard registration opens on 1 July 2016

Late breaking submission opens on 1 August 2016

• Lieping Chen,

Yale School of Medicine, USA

• Iain Hagan,

Cancer Research UK Manchester Institute, UK

• Reuben Harris,

University of Minnesota, USA

• Mark Krasnow,

Stanford University, USA

• Charles Rudin,

Memorial Sloan Kettering Cancer Center, USA

• Alex Snyder

Memorial Sloan Kettering Cancer Center, USA

• Jennifer Wargo,

MD Anderson Cancer Center, USA

conference.ncri.org.uk 06. 2016 - Oncology news - 180mm x 130mm - LANDSCAPE.indd 1

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@NCRI #NCRI2016 6/21/2016 9:48:24 AM

Volume 11 Issue 3 • July/August 2016

48th Congress of the International Society of Paediatric Oncology The Convention Centre

REGISTER TODAY Early Registration Deadline: July 19, 2016 Registration Deadline: September 27, 2016

siop2016.kenes.com

Volume 11 Issue 3 â&#x20AC;˘ July/August 2016

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ESMO 2016 COPENHAGEN DENMARK 7-11 OCTOBER 2016

2017

ESMO 2018 MUNICH GERMANY 19-23 OCTOBER 2018

ESMO BECOMES ANNUAL! Mark your calendar for the upcoming ESMO Congresses.

2016

ESMO 2017 MADRID SPAIN 8-12 SEPTEMBER 2017 IN PARTNERSHIP WITH EACR

2018