Course Booklet

08 - 10 May 2017 De Rode Hoed, Amsterdam, Netherlands

7th EACR-OECI Joint Training Course

Scientific Programme CommitteeRichard Marais (UK), Jorge Reis-Filho (USA),

Giorgio Stanta (Italy), Marc van de Vijver (Netherlands)

Molecular Pathology Approach to Cancer

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Conferences

Day 1 - Monday 08 May 2017

11.30 – 13.30 REGISTRATION Rode Hoed foyer

12.30 – 13.30 WELCOME LUNCH & OPENING OF THE TRADE EXHIBITION Rode Hoed foyer & Oosterhuiszaal

13.30 – 13.45 COURSE WELCOME Oosterhuiszaal ScientificProgrammeCommittee

13.45 – 14.05 Jorge Reis-Filho MemorialSloanKetteringCancerCenter(USA)Q&A: 14.05– 14:15 “Molecularpathology:whybother?” 14.15 – 14.35 Daniel Peeper NKI(Netherlands)Q&A: 14.35 – 14.45 “Whatcanwelearnfromsinglepatients?”

14.45 – 15.15 Serena Nik-Zainal SangerInstitute(UK)Q&A: 15.15 – 15.30 “Massively-parallelsequencing”

15.30 – 16.00 COFFEEBREAK Rode Hoed foyer & Oosterhuiszaal

16.00 – 16.20 Alberto Mantovani Humanitas (Italy) Q&A: 16.20 – 16.30 “Theyin-yangoftumor-associatedmacrophagesandlymphoidcells”

16.30 – 16.50 Fabrice André InstitutGustaveRoussy(France)Q&A: 16.50 – 17.00 “Molecularpathology:anoncologist’sperspective”

17.00 – 18.30 NETWORKINGRECEPTION Rode Hoed foyer & Oosterhuiszaal Ahotbuffetdinnerwillbeservedforallparticipantsandexhibitorstoenjoy.Thetrade exhibitionwillbeopenatthistime,andthereisanopportunitytocontinuenetworking.

Day 2 - Tuesday 09 May 2017

08.30–09.00 Coffeeavailabletopurchasefromthebar

09.00 – 09.20 Giorgio Stanta UniversityofTrieste(Italy)Q&A: 09.20 – 09.30 “Theevolutionofpathology”

09.30 – 09.50 Amaya Viros CRUKManchesterInstitute(UK)Q&A: 09.50 – 10.00 “Themolecularpathologyofmelanomas”

Making it Personal7th EACR-OECI Joint Training Course

Molecular Pathology Approach to Cancer

10.00 – 10.20 David Huntsman UBC/BCCancerAgency(Canada)Q&A: 10.20 – 10.30 “Themolecularpathologyofovariancancer”

10.30 - 11.00 COFFEEBREAK Rode Hoed foyer & Oosterhuiszaal

11.00 – 11.20 Britta Weigelt MemorialSloanKetteringCancerCentre(USA)Q&A: 11.20 – 11.30 “Themolecularpathologyofendometrialcancer”

11.30 – 11.50 Judith Bovee LeidenUniversityMedicalCenter(Netherlands)Q&A: 11.50 – 12.00 “Themolecularpathologyofbonetumours”

12.00 – 12.20 Matt van de Rijn StanfordSchoolofMedicine(USA)Q&A: 12.20 – 12.30 “Themolecularpathologyofsofttissuesarcomas”

12.30 – 13.30 LUNCH & TRADE EXHIBITION Rode Hoed foyer & Oosterhuiszaal

13.30 – 14.00 Marc Ladanyi MemorialSloanKetteringCancerCentre(USA)Q&A: 14.00 – 14.15 “Themolecularpathologyoflungcancer”

14.15 – 14.45 Marc van de Vijver AcademicMedicalCenter,Amsterdam(Netherlands)Q&A: 14.45 – 15.00 “Themolecularpathologyofbreastcancer”

15.00 - 15.30 COFFEEBREAK Rode Hoed foyer & Oosterhuiszaal

15.30 – 16.15 Keynote Lecture - Alberto Mantovani Humanitas(Italy)

Q&A: 16.15 – 16.30 “Immunityandcancer:the(partial)fulfilmentofa100-yearlongdream”

16.30 – 17.30 SATELLITE SYMPOSIUM - ELITE SPONSOR Oosterhuiszaal Followedbytea,coffeeandassortedAmsterdamappetizers

FREE EVENING TO EXPLORE AMSTERDAM

Day 3 - Wednesday 10 May 2017

08.30–09.00 Coffeeavailabletopurchasefromthebar

09.00 – 09.30 Brian Rubin ClevelandClinicandLernerResearchInstitute(USA)Q&A: 09.30 – 09.45 “ThemolecularpathologyofGISTs”

09.45 – 10.05 Pieter Wesseling VUUniversityMedicalCenter(Netherlands)Q&A: 10.05 – 10.15 “Themolecularpathologyofcentralnervoussystemtumours”

10.15 – 10.45 COFFEEBREAK Rode Hoed foyer & Oosterhuiszaal

10.45 – 11.05 Andreas Jung LMUMunich(Germany)Q&A: 11.05 – 11.15 “Themolecularpathologyofcolorectalcancer”

11.15 – 11.35 Marc Ladanyi MemorialSloanKetteringCancerCenter(USA) Q&A: 11.35 – 11.45 “Moleculartestinginclinicalpractice”

11.45 – 12.15 PRESENTATION OF AWARD CERTIFICATES AND COURSE PHOTOGRAPH Oosterhuiszaal

12.15 – 13.00 LUNCH & DEPART Rode Hoed foyer & Oosterhuiszaal

Congratulations to the winners of EACR-ESMO and OECI Meeting Bursaries. Each winner received a full registration free of charge and funds of up to 500 Euros to assist with the cost of travel.

EACR-ESMO and OECI Meeting Bursary Award Winners

EACR-ESMO winnersAshenafi Bulle BELGIUM

Emine Ezel Cilek TURKEY

Selvi Durmus Erim TURKEY

Patricia Gifu FRANCE

Zlatko Marusic CROATIA

Jelena Milovanovic SERBIA

Susanti Susanti UK

Isabel Valença PORTUGAL

Katarina Zeljic SERBIA

OECI winnersVeronika Bentrad UKRAINE

Julija Fadejeva LITHUANIA

Joana Ferreira PORTUGAL

Gizem Calibasi Kocal TURKEY

João Lobo PORTUGAL

Course Evaluation, CME Credits and Certificate of Attendance

Following the close of the course an online survey will be sent requesting participants’ evaluation and feedback on the course. A Certificate of Attendance conveying CME Credits will be available to download and print on completion of the online Evaluation Survey.

The 7h EACR-OECI Joint Training Course: Molecular Pathology Approach to Cancer has been granted 12 European CME credits (ECMEC) by the European Accreditation Council for Continuing Medical Education (EACCME). The EACCME is an institution of the European Union of Medical Specialists (UEMS).

Organisation of European Cancer Institutes

www.oeci.euFor membership contact:

oeci@oeci.eu

Developing the Future in

Comprehensive CanCer Care

21-23 June 2017 Brno, Czech Republic

GENERAL ASSEMBLY SCIENTIFIC CONFERENCES

AND RELATED EVENTS

Oncology DaysORGANISATION OF EUROPEAN CANCER INSTITUTES

EUROPEAN ECONOMIC INTEREST GROUPING

3939The OECI is a non-governmental, non-profit Organisation founded in Vienna in 1979 and remodelled in 2005 into OECI-EEIG, a European Economic Interest Grouping, headquartered in Brussels. Today, the OECI counts 78 Member Institutes, which include some of the most prominent European Comprehensive Cancer Centres.The OECI aims to create a critical mass of expertise and competences, contributing to the production and dissemination of knowledge, so as to reduce fragmentation and increase competitiveness. These goals are being achieved by promoting and strengthening the concept of “comprehensiveness”, supporting quality in cancer care also through a well-structured internal organisation. OECI aims to accelerate the production and application of personalised care approaches, and to ensure equal rights to all cancer patients, with the ultimate goal of finding new and better treatments, providing more comprehensive care and improving patient quality of life, through evidence-based medicine. The increasing interest from international organisations, stakeholders & cancer community in the OECI points to the growing importance of a comprehensive cancer network of institutions, where the entire chain of cancer care provision is present.The strong alliance with the European Cancer Patient Coalition – ECPC - provides a coherent picture of today’s cancer patients’ expectations, ranging from: quality of care to information on survivorship and medical nutrition, improvement in the quality of interdisciplinary patient treatment, harmonisation in oncology healthcare practices and patient advocacy capacity to effectively tackle cancer care inequalities in Europe. Giving the crucial role to pathology departments in oncology and in lieu of the expected “influx” of new markers and diagnostics, the OECI acts in close cooperation with the European Association for Cancer Research and the European Society of Pathology, in order to better disseminate the innovation process amongst its members and abroad. The EACR-OECI training course series on “Precision Medicine” and “MolecularPathology Approach to Cancer” in Amsterdam, are just two examples of the OECI efforts to promote the innovation in cancer diagnosis and care.

O

E C

I

E E

I G

ACCREDITATION AND

DESIGNATION

CERTIFYING

COMPREHENSIVE

CANCER CARE

Organisation

of European

Cancer Institutes

Accreditation

and Designation

User Manual V. 2.0

Accreditation

and Designation U

ser Manual V. 2.0

OECI-EEIG Central Office

c/o Fondation Universitaire

11, Rue d’Egmont

B-1000, Brussels, Belgium

Phone: +32 2 512 0146

www.oeci.eu

www.selfassessment.nu

OECI Members A&D certified OECI Members in the A&D process Other OECI Members

7th EACR-OECI Joint Training Course

Molecular Pathology Approach to Cancer

Molecular Pathology Approach to Cancer will provide a discussion of current concepts in molecular pathology, molecular pathology methods

practicing pathologists and oncologists, residents and fellows in pathology and oncology, and molecular biologists with an interest in molecular pathology and precision medicine.

www.eacr.org/conference/molecularpathology2017

Confirmed Speakers

REGISTER NOW

Topics include

Reduced registration rates

for EACR/OECI membersFind out more at www.eacr.org

Fabrice André (France)

Judith Bovee (Netherlands)

David Huntsman (Canada)

Andreas Jung (Germany)

Marc Ladanyi (USA)

Alberto Mantovani (Italy)

Richard Marais (UK)

Serena Nik-Zainal (UK)

Jorge Reis-Filho (USA)

Brian Rubin (USA)

Giorgio Stanta (Italy)

Matt van de Rijn (USA)

Marc van de Vijver (Netherlands)

Britta Weigelt (USA)

Pieter Wesseling (Netherlands)

Amsterdam, Netherlands

Excellent course. Very informative. Very knowledgeable and helpful expert tutors. Great

chance for networking and getting updated.

7th EACR-OECI Joint Training CourseMolecular Pathology Approach to Cancer

Course Speaker Profiles

Listed in programme order

Jorge Reis-Filho (USA)

Daniel Peeper (Netherlands)

Serena Nik-Zainal (UK)

Alberto Mantovani (Italy)

Fabrice André (France)

Giorgio Stanta (Italy)

Marc van de Vijver (Netherlands)

David Huntsman (Canada)

Britta Weigelt (USA)

Judith Bovée (Netherlands)

Matt van de Rijn (USA)

Marc Ladanyi (USA)

Amaya Viros (UK)

Alberto Mantovani (Italy)

Brian Rubin (USA)

Pieter Wesseling (Netherlands)

Andreas Jung (Germany)

Marc Ladanyi (USA)

Molecular pathology: why bother? Jorge Reis-Filho (USA) MD PhD FRCPath, Director of Experimental Pathology, Attending Pathologist, Department of Pathology Affiliate Member, HOPP and cBio, Memorial Sloan Kettering Cancer Center, New York, NY Pathology is at a crossroads. Albeit originally conceived as the science devoted to understanding the mechanisms of disease, in the 20th Century, Pathology came to become a medical specialty primarily devoted to the diagnosis of human illnesses on the basis of histologic analyses of human tissues, and the primary role of the diagnostic surgical pathologist was to guide the surgeon’s hands. The advent of molecular tools for the characterization of human tumors and the emergence of the concept of precision medicine, information above and beyond that offered by histologic analyses of human cancers has become essential. Massively parallel sequencing has allowed for the characterization of the genomes of human cancers at base pair resolution. It is now possible not only to characterize their repertoires of somatic genetic alterations, but also their mutational and rearrangement signatures, which provide important information about the biological processes that shaped the genomes of cancer cells and may inform therapy decision-making. Pathology, given its position at the interface between basic sciences and the delivery of patient care, is central to scientific endeavors devoted to the characterization of human cancers and the identification of diagnostic and predictive biomarkers. In this presentation, the impact of pathology in the design and interpretation of genomics studies and the role of the pathologist in precision medicine multidisciplinary teams will be discussed. What can we learn from single patients? Daniel Peeper (Netherlands) The Peeper laboratory develops and uses function-based genomic approaches to better understand the mechanistic principles of cancer progression, and to identify novel therapeutic targets for achieving more durable clinical responses for cancer patients. We have two main strategies: first, we wish to increase our understanding of how cancer cells originate and function and define their rewired signalling networks. This will expose their weaknesses and allow for the identification of specific and pharmacologically tractable vulnerabilities. Second, we wish to determine how we can manipulate various cell types from the patient’s own immune system to enhance its cytotoxicity towards tumour cells. This approach should uncover new therapeutic targets on immune cells. By focusing on these two main research arms, our objective is to contribute to the development of combinatorial therapies, which simultaneously eliminate the patients’ tumour cells and harness their immune cells. Recent publications:

• Iskit S, Lieftink C, Halonen P, Shahrabi A, Possik PA, Beijersbergen RL, Peeper DS. Integrated in vivo genetic and pharmacologic screening identifies co-inhibition of EGRF and ROCK as a potential treatment regimen for triple-negative breast cancer. Oncotarget. 2016 Jul 12;7(28):42859-42872. doi: 10.18632/oncotarget.10230. PubMed PMID: 27374095; PubMed Central PMCID: PMC5189992.

• Kemper K, Krijgsman O, Kong X, Cornelissen-Steijger P, Shahrabi A, Weeber F, van der Velden DL, Bleijerveld OB, Kuilman T, Kluin RJ, Sun C, Voest EE, Ju YS, Schumacher TN, Altelaar AF, McDermott U, Adams DJ, Blank CU, Haanen JB, Peeper DS. BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts. Cell Rep. 2016 Jun 28;16(1):263-77. doi: 10.1016/j.celrep.2016.05.064. PubMed PMID: 27320919; PubMed Central PMCID: PMC4929150.

• Kemper K, Krijgsman O, Cornelissen-Steijger P, Shahrabi A, Weeber F, Song JY, Kuilman T, Vis DJ, Wessels LF, Voest EE, Schumacher TN, Blank CU, Adams DJ, Haanen JB, Peeper DS. Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts. EMBO Mol Med. 2015 Sep;7(9):1104-18. doi: 10.15252/emmm.201404914. PubMed PMID: 26105199; PubMed Central PMCID: PMC4568946.

• Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, Kong X, Possik PA, Cornelissen-Steijger PD, Geukes Foppen MH, Kemper K, Goding CR, McDermott U, Blank C, Haanen J, Graeber TG, Ribas A, Lo RS, Peeper DS. Low MITF/AXL ratio predicts early resistance to

Speaker profiles

multiple targeted drugs in melanoma. Nat Commun. 2014 Dec 15;5:5712. doi: 10.1038/ncomms6712. PubMed PMID: 25502142; PubMed Central PMCID: PMC4428333.

• Possik PA, Müller J, Gerlach C, Kenski JC, Huang X, Shahrabi A, Krijgsman O, Song JY, Smit MA, Gerritsen B, Lieftink C, Kemper K, Michaut M, Beijersbergen RL, Wessels L, Schumacher TN, Peeper DS. Parallel in vivo and in vitro melanoma RNAi dropout screens reveal synthetic lethality between hypoxia and DNA damage response inhibition. Cell Rep. 2014 Nov 20;9(4):1375-86. doi: 10.1016/j.celrep.2014.10.024. PubMed PMID: 25456132.

• Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov VA, Mackay G, van der Burg SH, Verdegaal EM, Cascante M, Shlomi T, Gottlieb E, Peeper DS. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature. 2013 Jun 6;498(7452):109-12. doi: 10.1038/nature12154. PubMed PMID: 23685455.

Massively-parallel sequencing Serena Nik-Zainal (UK) The recent increase in the speed of sequencing offered by modern sequencing technologies permits an unprecedented degree of exploration of the human genome. No longer are we restricted to PCR-defined fragments of protein-coding exons, we can now investigate all the genetic material in human cells. I explain the principles underlying massively-parallel sequencing giving some insight into the advances as well as the difficulties posed by processing of the enormous datasets generated by modern sequencing experiments. Cancer is the ultimate disorder of the genome, characterised by not just one or two mutations, but hundreds to thousands of acquired mutations that have been accrued through the development of a tumour. Utilising the extraordinary surge in scale as well as the digital nature of massively-parallel sequencing, I explain some of the recent highlights into tumour biology offered by these modern methods: cancer gene discovery, mutation signatures and cancer evolution. Reading: Cancer genomics background http://www.ncbi.nlm.nih.gov/pubmed/19360079 Massively-parallel sequencing http://www.ncbi.nlm.nih.gov/pubmed/18987734 Impact of NGS: reviews http://www.ncbi.nlm.nih.gov/pubmed/24074859 http://www.ncbi.nlm.nih.gov/pubmed/23121054 https://www.ncbi.nlm.nih.gov/pubmed/25468925 Signatures of mutagenesis http://www.ncbi.nlm.nih.gov/pubmed/22608084 http://www.ncbi.nlm.nih.gov/pubmed/23945592 https://www.ncbi.nlm.nih.gov/pubmed/27135926 Cancer evolution http://www.ncbi.nlm.nih.gov/pubmed/22608083 http://www.ncbi.nlm.nih.gov/pubmed/22817890

Speaker profiles

Speaker profiles

The yin-yang of tumour-associated macrophages and lympoid cells Alberto Mantovani (Italy) Humanitas Clinical and Research Center, Humanitas University, Milan, Italy Macrophages are key orchestrators of chronic inflammation. They respond to microenvironmental signals with polarized genetic and functional programmes. M1 and M2 cells represent simplified extremes in a universe of functional states. Available information suggests that some TAM are an M2 population. Polarization of phagocytes sets these cells in a tissue remodelling and repair mode and orchestrate the smouldering and polarized chronic inflammation associated to established neoplasia. Intrinsic metabolic features and orchestration of metabolism are key components of macrophage polarisation and function. Recent studies have begun to address the central issue of the relationship between genetic events causing cancer and activation of protumour, smouldering, non-resolving tumour-promoting inflammation. New vistas have emerged on molecules associated with M2 or M2-like polarization and its orchestration in cancer. Recently, proof-of-principle has been obtained that targeting TAM can be beneficial in human cancer. Moreover, complement has emerged as a key component of tumour-promoting inflammation.

References:

1. Bonavita et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160: 700-714, 2015.

2. Mantovani A, Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med. 2015 Apr 6;212(4):435-445.

3. Mantovani et al. Tumor-associated macrophages as treatment targets in oncology. Nature Rev, Clin. Oncol. 2017 adv. online publication doi: 10.1038/nrclinonc.2016.217

List of relevant publications:

• Mantovani A., Marchesi F., Laghi L., Malesci A., Allavena P. Tumor-associated macrophages as treatment targets in oncology. Nature Rev, Clin. Oncol.; adv. online publication 2017 doi: 10.1038/nrclinonc.2016.217

• Bonavita E, Gentile S, Rubino M, Maina V, Papait R, Kunderfranco P, Greco C, Feruglio F, Molgora M, Laface I, Tartari S, Doni A, Pasqualini F, Barbati E, Basso G, Galdiero MR, Nebuloni M, Roncalli M, Colombo PG, Laghi L, Lambris JD, Jaillon S, Garlanda C, Mantovani A. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160: 700-714, 2015.

• Mantovani A, Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med. 2015 Apr 6;212(4):435-445.

• Mantovani A, Allavena P, Sica A, Balkwill F Cancer-Related Inflammation. Nature 454: 436-444, 2008.

• Mantovani, A., Romero, P., Paluka, AK., Marincola, FM. Tumor immunity: effector response to tumor and the influence of the microenvironment. Lancet 371:771-783, 2008.

• Balkwill F. and Mantovani A. Inflammation and cancer: back to Virchow? Lancet 357: 539-545, 2001.

Molecular pathology: an oncologist's perspective Fabrice André (Italy) References

1. High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial. Massard C, Michiels S, Ferté C, Le Deley MC, Lacroix L, Hollebecque A, Verlingue L, Ileana E, Rosellini S, Ammari S, Ngo-Camus M, Bahleda R, Gazzah A, Varga A, Postel-Vinay S, Loriot Y, Even C, Breuskin I, Auger N, Job B, De Baere T, Deschamps F, Vielh P, Scoazec JY, Lazar V, Richon C, Ribrag V, Deutsch E, Angevin E,

Vassal G, Eggermont A, André F, Soria JC. Cancer Discov. 2017 Apr 1. doi: 10.1158/2159-8290.CD-16-1396. [Epub ahead of print] PMID: 28365644

2. Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis. Lefebvre C, Bachelot T, Filleron T, Pedrero M, Campone M, Soria JC, Massard C, Lévy C, Arnedos M, Lacroix-Triki M, Garrabey J, Boursin Y, Deloger M, Fu Y, Commo F, Scott V, Lacroix L, Dieci MV, Kamal M, Diéras V, Gonçalves A, Ferrerro JM, Romieu G, Vanlemmens L, Mouret Reynier MA, Théry JC, Le Du F, Guiu S, Dalenc F, Clapisson G, Bonnefoi H, Jimenez M, Le Tourneau C, André F. PLoS Med. 2016 Dec 27;13(12):e1002201. doi: 10.1371/journal.pmed.1002201. eCollection 2016 Dec. PMID: 28027327

3. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). André F, Bachelot T, Commo F, Campone M, Arnedos M, Dieras V, Lacroix-Triki M, Lacroix L, Cohen P, Gentien D, Adélaide J, Dalenc F, Goncalves A, Levy C, Ferrero JM, Bonneterre J, Lefeuvre C, Jimenez M, Filleron T, Bonnefoi H. Lancet Oncol. 2014 Mar;15(3):267-74. doi: 10.1016/S1470-2045(13)70611-9. Epub 2014 Feb 7. PMID: 24508104

4. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Le Tourneau C, Delord JP, Gonçalves A, Gavoille C, Dubot C, Isambert N, Campone M, Trédan O, Massiani MA, Mauborgne C, Armanet S, Servant N, Bièche I, Bernard V, Gentien D, Jezequel P, Attignon V, Boyault S, Vincent-Salomon A, Servois V, Sablin MP, Kamal M, Paoletti X; SHIVA investigators. Lancet Oncol. 2015 Oct;16(13):1324-34. doi: 10.1016/S1470-2045(15)00188-6. Epub 2015 Sep 3. PMID: 26342236

The evolution of pathology Giorgio Stanta (Italy) Dept. of Medical Sciences, University of Trieste Today research conducted in patients’ tissues is one of the most important fields of development in oncology. This is especially important for oncology because there are many more actionable mutations in each patient’s cancer than those we are considering for prognosis, diagnosis and treatment. The introduction of new drugs in clinics by regulatory organizations is very slow, and classical trial procedures need very long time to be completed. This is related to the high level of complexity of cancer progression mostly caused by clonal evolution, due to intratumour heterogeneity. Because of this, large tumour molecular categories seem to be insufficient to respond to the very high level of clinical variability. Clinical research presents anyway a high risk of irreproducibility of molecular analysis. The major problems are related to preanalytical conditions of biological samples, standardized analytical methods, and cellular and molecular heterogeneity. To shorten the time to develop a diffused and reproducible clinical research, new types of approaches are designed today, such as N-1 trials. In this case, the single patient can be a specific trial with information collected in different time periods. New clinical research approaches are already being planned by European organizations such as the OECI (Organisation of European Cancer Institutes), which next June will discuss the possibility to effectively perform reproducible clinical research in patients’ biological material, and to activate large networks of N-1 trials in the future. The problems of reproducibility are also tackled with European organizations such as the new SPIDIA4P project for standardization of preanalytical conditions of biological material, and the OECI for the development of standardized analytical procedures, such as liquid biopsies and clinical NGS. In the European Society of Pathology, the tentative drafting of new protocols is being undertaken to overcome heterogeneity with better sampling. The European Infrustructure of Biobanking (BBMRI-ERIC) has recently developed a new expert centre for molecular analyses in clinical tissues (ATMA-EC) to reach higher levels of standardization of molecular analysis. Clinical research is for today’s patients, as an integral part of the clinical activity. This type of research is absolutely necessary for the development of clinical oncology, and presents some new important bioethical considerations.

Speaker profiles

References:

1. http://www.spidia.eu/ 2. https://www.cen.eu/Pages/default.aspx 3. Klement GL, Arkun K, Valik D, Roffidal T, Hashemi A, Klement C, Carmassi P, Rietman E,

Slaby O, Mazanek P, Mudry P, Kovacs G, Kiss C, Norga K, Konstantinov D, André N, Slavc I, van Den Berg H, Kolenova A, Kren L, Tuma J, Skotakova J, Sterba J. Future paradigms for precision oncology. Oncotarget. 2016 Jul 19;7(29):46813-46831.

4. Stanta G, Jahn SW, Bonin S, Hoefler G. Tumour heterogeneity: principles and practical consequences. Virchows Arch. 2016 Oct;469(4):371-84.

The molecular pathology of breast cancer Marc J van de Vijver (Netherlands) MD, PhD, Academic Medical Center, Amsterdam, the Netherlands Breast cancer is presently classified based on tumour diameter, histologic type and grade, lymph node status and estrogen receptor, progesterone receptor and HER2 status. This classification has important implications for the surgical, radiotherapy and systemic treatment of breast cancer patients. A more refined classification should be possible based on genetic alterations and gene expression profiles. Based on histological features, breast cancer is categorized as invasive ductal carcinoma, comprising approximately 70% of all cases; invasive lobular carcinoma, comprising approximately 10% of all cases; and several special and rare types, together comprising 20% of all cases. This histologic classification can be supplemented with categories based on genetic alterations; and categories based on gene expression profiles. Whole genome sequence data will provide the next supplement to a better subclassification of breast cancer, and recently the first such sequence has been presented for an invasive lobular cancer. The genetic alterations identified in breast cancer are amplification of between 10 and 20 oncogenes (or genomic regions with as yet not an identified “driving” oncogenes) and mutations in oncogenes and tumour suppressor genes. Over 1,000 breast carcinomas have been subjected to whole genome sequence analysis or whole exome sequence analysis. From this work it has become clear that there are only three mutations that occur in >10% of breast carcinomas (those in P53, GATA3 and PIK3CA) and also few genes that are amplified in >10% of cases (including HER2, cyclinD1 and CMYC). There are hundreds of mutations that each occur at low frequency in breast cancer. Gene expression profiling has led to the identification of subsets of breast cancer revealed by unsupervised classification termed basal type, ERBB2 like, luminal A, luminal B and normal epithelial like cancers; and supervised classification has revealed good- and poor prognosis subtypes. A growing number of prognostic tests based on gene expression profiling is used clinically. While identification of prognostic gene expression profiles has been successful, it has not been possible yet to identify robust clinically useful predictors of response to systemic treatment. Integration of histologic, genomic and gene expression data of breast carcinomas is leading to an increasingly refined classification that elucidates the initiation and progression of breast cancer at the molecular level; and the identification of novel prognostic and predictive markers that can guide treatment of individual patients. For a review see: Molecular tests as prognostic factors in breast cancer, M.J. van de Vijver, Virchows Arch. 2014 Mar;464(3):283-91

Speaker profiles

The molecular pathology of ovarian cancer David Huntsman (Canada) The three most common types of ovarian cancer, high grade serous, clear cell and endometrioid all arise from cells that are not native to ovary. The clinical and biologic distinctions between these cancers are shaped by both cell of origin (cell context) and genomic features. This talk will focus on how our emerging understanding of histogenesis and genomics is leading to improved diagnostics as well as prevention and management strategies. Along with a review of recent publications our unpublished data on i) potential distinct cells of origin for clear cell and endometrioid carcinomas, ii) mutation and the transformation of endometriosis to ovarian cancer, iii) the fallopian tube and ovarian cancer prevention and iv) the genomic landscape of high grade serous carcinomas will be presented. Among rare ovarian cancers granulosa cell tumours, sertoli leydig tumours and small cell hypercalcemic ovarian cancers are clinically and biologically distinct. In the past few years the key mutations underpinning these mutations have been discovered. This has led to improved diagnostics for granulosa cell tumours and small cell hypercalcemic ovarian cancer. The discovery of pathognomonic mutations has led to the development of model systems and a better understanding of all three cancer types and for small cell ovarian cancers new treatment strategies. Recent publications: Hughes, C. S. et al. Quantitative Profiling of Single Formalin Fixed Tumour Sections: proteomics for translational research. Sci. Rep. 6, 34949; doi: 10.1038/srep34949 (2016). McConechy, M. K. et al. Molecularly Defined Adult Granulosa Cell Tumor of the Ovary: The Clinical Phenotype. JNCI J Natl Cancer Inst, Vol. 108, No. 11: djw134 (2016). Anthony N. Karnezis, Kathleen R. Cho, C. Blake Gilks, Celeste Leigh Pearce and David G. Huntsman. The disparate origins of ovarian cancers: pathogenesis and prevention strategies. Nature Reviews Cancer Vol. 17, 65–74 (2017) doi:10.1038/nrc.2016.113 (2016). The molecular pathology of endometrial cancer Britta Weigelt (USA) The uterine corpus represents the most common site for gynecologic malignancies in the western world. Endometrial cancer comprises a heterogeneous group of tumors with distinct risk factors, histopathological features, and clinical outcome. Genomic studies are continuing to unveil the constellation of genetic alterations in uterine cancer, which have the potential to be used as molecular markers for classification, risk-stratification and therapy decision-making. This presentation will focus on the molecular classification of endometrial carcinomas, including the different types of hypermutated cancers, the advances in the genetic characterization of synchronous endometrial and ovarian cancers as well as of rare subtypes of the disease, including uterine carcinosarcomas. The limitations of the current classification systems and the challenges for the development of a taxonomy for endometrial cancer that accurately reflects its molecular characteristics and clinical behavior will be discussed. Recent publications:

• The Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:67-73.

• Murali R, Soslow RA, Weigelt B. Classification of endometrial carcinoma: more than two types. Lancet Oncol 2014;15:e268-78.

Speaker profiles

• Schultheis AM, Ng CK, De Filippo MR, Piscuoglio S, Macedo GS, Gatius S, et al. Massively parallel sequencing-based clonality analysis of synchronous endometrioid endometrial and ovarian carcinomas. J Natl Cancer Inst. 2016;108. pii: djv427.

• Anglesio MS, Wang YK, Maassen M, Horlings HM, Bashashati A, Senz J, et al. Synchronous endometrial and ovarian carcinomas: evidence of clonality. J Natl Cancer Inst. 2016;108. pii: djv428.

• Jones S, Stransky N, McCord CL, Cerami E, Lagowski J, Kelly D, et al. Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes. Nat Commun 2014;5:5006.

• Zhao S, Bellone S, Lopez S, Thakral D, Schwab C, English DP, et al. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition. Proc Natl Acad Sci U S A. 2016;113:12238-43.

• Howitt BE, Sholl LM, Dal Cin P, Jia Y, Yuan L, MacConaill L, et al. Targeted genomic analysis of Müllerian adenosarcoma. J Pathol. 2015;235:37-49.

• Piscuoglio S, Burke KA, Ng CK, Papanastasiou AD, Geyer FC, Macedo GS, et al. Uterine adenosarcomas are mesenchymal neoplasms. J Pathol. 2016;238:381-8.

The molecular pathology of bone tumours Judith Bovée (Netherlands) Professor Judith V.M.G. Bovée is a clinician scientist at the Department of Pathology, LUMC, with a special focus on bone and soft tissue tumours. Her aim is to crosslink patient care (diagnostic pathology of bone and soft tissue tumours) with basic research (elucidating the molecular events underlying sarcoma development and progression) in order to establish improved diagnosis, prognosis and treatment for patients with bone and soft tissue tumours. Bone tumours are considered difficult by most pathologists, as they are rare, have overlapping morphology, need radiological correlation, and the usefullness of immunohistochemistry is limited. Therefore, conventional morphology is still the cornerstone of the diagnosis. Over the past decade, more knowledge has become available on the molecular background of bone tumours. In sarcomas, we recognize three molecular classes of bone tumours. First, tumors with deregulated transcription, which is usually due to a translocation in which the fusion product acts as an aberrant transcription factor, include for instance Ewing sarcoma. Second, deregulated signalling can be caused by specific amplification (e.g. MDM2 in low grade osteosarcoma), specific gene mutation (e.g. GNAS mutation in fibrous dysplasia) or a translocation causing a promotor swab leading to upregulation of a specific gene (e.g. USP6 rearrangement in aneurysmal bone cyst or GRM1 rearrangement in chondromyxoid fibroma). Third, the largest subgroup includes sarcomas with genetic instability and complex karyotypes. These include osteosarcoma and high grade chondrosarcoma. Technical advancements including next generation sequencing have revealed many new genetic alterations in rare bone tumours over the past few years, which helps us to understand their histogenesis, may assist in the differential diagnosis and may provide targets for novel therapeutic strategies. Recent publications:

• Szuhai K, Cleton-Jansen AM, Hogendoorn PCW, Bovée JVMG, Molecular pathology and its diagnostic use in bone tumors., Cancer Genet. 2012 May;205(5):193-204. doi: 10.1016/j.cancergen.2012.04.001.

• Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, Sangiorgi L, Toker B, Liegl-Atzwanger B, San-Julian M, Sciot R, Limaye N, Kindblom LG, Daugaard S, Godfraind C, Boon LM, Vikkula M, Kurek KC, Szuhai K, French PJ, Bovée JVMG, Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet. 2011 Nov 6;43(12):1256-61. doi: 10.1038/ng.1004.

Speaker profiles

• Nord KH, Lilljebjörn H, Vezzi F, Nilsson J, Magnusson L, Tayebwa J, de Jong D, Bovée JVMG, Hogendoorn PCW, Szuhai K., GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma. Nat Genet. 2014 May;46(5):474-7. doi: 10.1038/ng.2927. Epub 2014 Mar 23.

• Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P, Wedge DC, Cooke SL, Gundem G, Davies H, Nik-Zainal S, Martin S, McLaren S, Goody V, Robinson B, Butler A, Teague JW, Halai D, Khatri B, Myklebost O, Baumhoer D, Jundt G, Hamoudi R, Tirabosco R, Amary MF, Futreal PA, Stratton MR, Campbell PJ, Flanagan AM., Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet. 2013 Dec;45(12):1479-82. doi: 10.1038/ng.2814. Epub 2013 Oct 27. Erratum in: Nat Genet. 2014 Mar;46(3):316.

• Mariño-Enríquez A, Bovée JV., Molecular Pathogenesis and Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma. Surg Pathol Clin. 2016 Sep;9(3):457-73.

• van IJzendoorn DG, de Jong D, Romagosa C, Picci P, Benassi MS, Gambarotti M, Daugaard S, van de Sande M, Szuhai K, Bovée JV., Fusion events lead to truncation of FOS in epithelioid hemangioma of bone. Genes Chromosomes Cancer. 2015 Sep;54(9):565-74

The molecular pathology of soft tissue sarcomas Matt van de Rijn (USA) In this talk I will present a molecular approach to the diagnosis of sarcoma. Sarcomas are malignant tumors that originate from connective tissue cells such as muscle cells, fibroblasts and adipocytes. The disease is rare with approximately 11,000 new cases per year in the United States for soft tissue tumors and approximately 3,000 new cases per year for bone sarcomas. Within this group of tumors there are over 50 distinct diagnostic entities. As a result most clinicians only rarely see cases for each subtype leading to unfamiliarity with treatment options but also with diagnostic classifications. Accurate diagnosis is of course a prerequisite for appropriate therapy and this is especially the case when one considers that novel targeted therapies are continuously being developed. The classification of sarcomas has been based on the morphologic recognition of the different appearances of these tumors and has been supported by immunohistochemistry studies in the past decades. More recently it has been recognized that on a molecular level, two broad categories of sarcoma can be identified. One group of sarcomas is characterized by highly complex genetic abnormalities in which to date no specific patterns can be identified. Members of this category include leiomyosarcomas, undifferentiated pleomorphic sarcomas and malignant peripheral nerve sheath tumors. The second group of sarcomas has simple genetic changes that consist of chromosomal translocations, gene amplifications, and oncogenic mutations. Many of these simple genetic changes are actually relevant to the diagnosis of these tumor types as they occur specifically in only one tumor type. In addition they form the basis for much of the targeted therapy approaches that are in practice or are being developed. Specific chromosomal translocations have been identified for more than 40 soft tissue sarcomas and benign soft tissue tumors and this number can be expected to increase. It is not cost effective to maintain a set of individual diagnostic tests (either by RT-PCR or by FISH) for these rare disease in a CLIA-approved manner in diagnostic molecular laboratories. A number of NGS-based approaches have recently been developed that allow for the use of a single test to detect multiple translocations. References:

1. Taylor et al. Advances in sarcoma genomics and new therapeutic targets. Nature Reviews, 2011, 541-557

2. West et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proceedings National Academy of Sciences, 2006, 103: 690-5

3. Tap et al. Structure-guided targeting of the CSF1 receptor in tenosynovial giant cell tumor. New England Journal of Medicine, 2015, 373:428-37

Speaker profiles

The molecular pathology of lung cancer Marc Ladanyi (USA) Tumor genetic testing is now standard of care for patients with non-small cell lung cancer. Lung adenocarcinomas, which account for approximately 50% of lung cancers, are molecularly sub-classified and their therapy dictated by the presence of distinct molecular alterations including EGFR mutations and ALK or ROS1 fusions that confer sensitivity to selective kinase inhibitors. Additional alterations such as BRAF V600E, RET fusions, and ERBB2 amplifications are found in smaller subsets of patients, but when present may also predict for response to targeted inhibitors. In other patients, defined oncogenic drivers such as KRAS mutations are detected for which preclinical studies have nominated targeted approaches, but the clinical utility of such therapies has yet to be established. As a result of advances in DNA sequencing, the prospective molecular analysis of tumors for mutations in hundreds of cancer-associated genes is now feasible using multiplexed assays that use as input small quantities of formalin fixed paraffin embedded tissue. Through an institution-wide initiative in clinical cancer genomics initiated in 2014, we have implemented large scale genomic profiling for targetable cancer drivers and other cancer-relevant alterations in all patients with advanced solid cancers. Over 15,000 patients have been profiled using the MSK-IMPACT capture-based, targeted DNAseq assay. Subsets of patients have also been studied for oncogenic fusions by targeted RNAseq or for germline cancer predisposition alleles. An overview of our experience will be presented. Recent publications:

• Jordan EJ, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discovery (in press)

• Paik PK, Drilon A, Yu H, Rekhtman N, Ginsberg MS, Borsu L, Schultz N, Berger MF, Rudin CM, Ladanyi M. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5:842–849.

• Hyman DM, Solit DB, Arcila ME, Cheng DT, Sabbatini P, Baselga J, Berger MF, Ladanyi M. Precision medicine at Memorial Sloan Kettering Cancer Center: clinical next-generation sequencing enabling next-generation targeted therapy trials. Drug Discov Today. 2015 Dec;20(12):1422-8.

• Cheng DT, et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. J Mol Diagn. 2015 May;17(3):251-64.

• Arcila ME, Drilon A, Sylvester BE, Lovly CM, Borsu L, Reva B, Kris MG, Solit DB, Ladanyi M. MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking. Clin Cancer Res. 2015 Apr 15;21(8):1935-43.

The molecular pathology of melanomas Amaya Viros (UK) Ultraviolet radiation (UVR) is the only environmental carcinogen driving cutaneous melanoma. UVR contributes to malignant progression through direct DNA damage and by inducing an inflammatory response. There is a great variability in the number of mutations detected by massively parallel DNA sequencing in different melanoma samples. The specific contribution of UVR to distinct melanoma subtypes is unknown. Mouse models of melanoma driven by the more relevant melanoma oncogenes can help dissect the exact contribution of the environment to distinct molecularly defined melanoma subtypes. References:

1. Bald T, et al Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature. 2014 Mar 6;507(7490):109-13.

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Speaker abstractsSpeaker profiles

2. Viros A et al. Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53. Nature. 2014 Jul 24;511(7510):478-82.

3. Zaidi, M.R., et al., Interferon-gamma links ultraviolet radiation to melanomagenesis in mice. Nature, 2011. 469(7331): p. 548-53.

4. Dhomen, N., et al., Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell, 2009. 15(4): p. 294-303.

Keynote Award Lecture Immunity and cancer: the (partial) fulfilment of a 100-year long dream Alberto Mantovani (Italy) Humanitas Clinical and Research Center; Humanitas University, Rozzano (Milan), Italy

Paul Erhlich is a founding father of modern Medicine and Immunology with his amazing foresight of antibodies. He and other founding fathers were observing the tools of immunology, such as antiserum therapy developed by Kitasano and Behring here in Germany, changing the course of dreadful diseases such as difteria. They dreamed of using the tools of immunity to fight cancer. Thus, generations of physicians and scientists have dreamed of using the power of our immune system to fight cancer, prompted by the key contribution that vaccinology and immunology have given to double our life expectancy in less than a century. Efforts along this line lead to what I would consider no more than proof of principle clinical evidence, a lot of frustration and widespread skepticism among oncologists. In the last 16 years we have witnessed a change in the accepted paradigm of the essence of cancer, crystallized once more by Hanahan and Weinberg in a review in Cell in 2011. The new version of the paradigm includes the microenvironment, the ecological niche, as a key component of cancer. In brief, development of a clinically observed tumor is associated with the recruitment of “corrupted policemen”, macrophages, and other white blood cells, which help cancer to progress. Concomitantly, the directors of the adaptive immunity orchestra, the T cells, are put to sleep; they are like a “Ferrari” with many brakes on. The brakes we call “checkpoints”, and the “corrupted policemen” help holding the brakes on.

The change in paradigm together with progress in identifying the cells and molecules involved in immunity have led to a revolution in the fight against cancer. We use antibodies, cytokines and anti-cytokine molecules to treat patients and to protect them from toxicity; we release brakes called checkpoints; we are learning how to stop corrupted policemen and how to reeducate and increase in number and arm the army of our soldiers.

References:

1. Mantovani A., Marchesi F., Laghi L., Malesci A., Allavena P. Tumor-associated macrophages as treatment targets in oncology. Nature Rev, Clin. Oncol.; adv. online publication 2017 doi: 10.1038/nrclinonc.2016.217

2. Bonavita E, Gentile S, Rubino M, Maina V, Papait R, Kunderfranco P, Greco C, Feruglio F, Molgora M, Laface I, Tartari S, Doni A, Pasqualini F, Barbati E, Basso G, Galdiero MR, Nebuloni M, Roncalli M, Colombo PG, Laghi L, Lambris JD, Jaillon S, Garlanda C, Mantovani A. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160: 700-714, 2015.

3. Mantovani A, Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med. 2015 Apr 6;212(4):435-445.

4. Mantovani A, Allavena P, Sica A, Balkwill F Cancer-Related Inflammation. Nature 454: 436-444, 2008.

5. Mantovani, A., Romero, P., Paluka, AK., Marincola, FM. Tumor immunity: effector response to tumor and the influence of the microenvironment. Lancet 371:771-783, 2008.

6. Balkwill F. and Mantovani A. Inflammation and cancer: back to Virchow? Lancet 357: 539-545, 2001.

Speaker profiles

The molecular pathology of GISTs Brian Rubin (USA) This lecture will focus on more recent developments related to gastrointestinal stromal tumor. (GIST). GISTs were originally thought to harbor either KIT or platelet-derived growth factor receptor A (PDGFRA) mutations only, which are targeted by KIT and PDFRA inhibitors such as imatinib mesylate therapeutically. However, more recent discoveries have highlighted additional, less common oncogenic driver mutations including NF1, BRAF and succinate dehydrogenase (SDH) mutations, and gene fusions. Some of these newly discovered mutations are germline mutations which further complicate GIST patient management. Genotyping GISTs has become more important since not all genotypes respond equally to FDA-approved tyrosine kinase inhibitors. Because it is apparent that GIST is comprised of a family of related cancers driven by different oncogenic mechanisms, GIST has become a paradigm for personalized cancer therapy. Recent developments in GIST immunohistochemistry (IHC) demonstrate how IHC can be used to diagnose GIST and screen for specific GIST mutations. DOG1 is particularly useful in the diagnosis of KIT IHC negative GIST including those GISTs with PDGFRA mutations, which can also potentially be identified by PDGFRA immunohistochemistry. SDHB immunohistochemistry is useful in characterizing GISTs with SDHA-D mutations while SDHA immunohistochemistry is able to identify SDHA mutant GISTs. Finally, allele-specific BRAF V600E antibodies are useful in identifying BRAF V600E-mutated GIST. References: 1. Rubin BP. GIST and EGIST. In: Enzinger and Weiss’s Soft Tissue Tumors / John R. Goldblum,

Andrew L. Folpe, Sharon W. Weiss. – 6th Ed. Philadelphia: Elsevier Saunders. 2014. p. 569-590. 2. Rubin BP, Heinrich MC. Genotyping and immunohistochemistry of gastrointestinal

stromal tumors: An update. Semin Diagn Pathol. 201515:S0740-2570. 3. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function

mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577-80. 4. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA

activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708-10. 5. Gill AJ. Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. Pathology.

2012;44:285-92. 6. Gasparotto D, Rossi S, Polano M, Tamborini E, et al.. Quadruple-Negative GIST Is a Sentinel for

Unrecognized Neurofibromatosis Type 1 Syndrome. Clin Cancer Res. 2017; 23:273-282. PubMed PMID: 27390349.

7. Shi E, Chmielecki J, Tang CM, Wang K, et al. FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. J Transl Med. 2016;14:339. PubMed PMID: 27974047; PubMed Central PMCID: PMC5157084.

8. Gramza AW, Corless CL, Heinrich MC. Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors. Clin Cancer Res. 2009;15:7510-7518.

9. Agarwal R, Robson M. Inherited predisposition to gastrointestinal stromal tumor. Hematol Oncol Clin North Am. 2009;23:1-13.

10. Haller F, Moskalev EA, Faucz FR, Barthelmess S, Wiemann S, Bieg M, et al. Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocr Relat Cancer. 2014;21:567-77.

The molecular pathology of central nervous system tumours Pieter Wesseling (Netherlands) Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands Department of Pathology, Princess Máxima Center for Pediatric Oncology, Utrecht, and University

Medical Center Utrecht, The Netherlands Correspondence to: Pieter Wesseling, MD, PhD, Dept. of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; or email: p.wesseling@vumc.nl

The World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) provides an international standard for the diagnosis of these neoplasms and serves as an important guide for use in the design of studies monitoring response to therapy and clinical outcome. In May 2016, an update of the 4th edition of the WHO CNS Tumour Classification was officially released1. This revised WHO Classification represents a paradigm shift as, for the first time, the definition of multiple CNS tumour entities is now partly based on particular genotypic characteristics. The most substantial changes in the WHO 2016 Classification concern gliomas and embryonal tumors2. According to the 2016 classification, most diffuse gliomas are diagnosed based on presence/absence of IDH mutation and 1p/19q codeletion. Medulloblastomas, the most frequent 'embryonal' CNS tumours in children, are now ideally classified based on molecular characteristics as well (WNT-activated; SHH-activated & TP53-wildtype; SHH-activated & TP53-mutant; non-WNT/non-SHH). Additional examples of (pediatric) CNS tumours that are molecularly defined are atypical teratoid/rhabdoid tumour (AT/RT; typically carrying a SMARCB1 or, much less frequently, a SMARCA4 mutation), a particular subtype of ependymoma (RELA fusion-positive), and diffuse midline glioma (H3 K27M-mutant). Incorporation of these molecular markers in the definition of CNS tumours not only allows for a much more precise and reproducible diagnosis of gliomas and embryonal neoplasms, but also carries important prognostic and/or predictive meaning. The lecture will cover 'what's new' in the WHO 2016 Classification with a focus on the most relevant molecular markers for the diagnosis of CNS tumours and on tools that can be used to assess these markers in daily clinical practice. References:

1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Ellison DW, Figarella-Branger D, Perry A, Reifenberger G, Deimling A von. WHO Classification of Tumours of the Central Nervous System. IARC Press, Lyon 2016

2. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131: 803-20

The molecular pathology of colorectal cancer Andreas Jung (Germany)

Institute for Pathology of the University of Munich, Thalkirchnerstrasse 36, D-80337 Munich, Germany, andreas.jung@lmu.de

Colorectal Cancer (CRC) is one of the world leading causes for cancer related death although CRCs are one of the best studied cancer types.1 From a tumorgenetic point of view CRCs can be subdivided at least into three different diseases: rectal cancer and microsatellites stable (MSS) and high grade microsatellite instable (MSI-H) colonic cancers (CC)2. MSS and MSI-H CC have a complete different biology. MSS-CC follow the multistep carcinogenesis model developed mostly by Bert Vogelstein’s lab. This type of CC is characterized by an activation of the Wnt-signaling pathway mostly be initiating mutations in the tumorsuppressor-gene APC (adenomatous polyposis coli). 1 The activity of the Wnt-pathway can be enhanced by activation of the RAS/ RAF/ MAPK 3 or PIK3CA/ AKT/ mTOR 4 signaling pathways. In contrast MSI-H CC are related to the serrated route proposed by Jeremy Jass 5 which is related to oncogene induced senescence (OIS) initiated in many cases by tumorgenetic activation of the oncogene BRAF6 which is followed by a transcriptional activation of DNA-Methyl-Transferases (DNMT) 7 what results in the CpG island methylator phenotype (CIMP). These tumors are characterized by deficient DNA-repair as the MLH1 (Mut L homologue)- or O6MGMT (Methyl-Guanosine-Methyl-Transferase)-genes are inactivated due to methylation 6. Thereby, the loss of MLH1 expression is causative for the MSI-H phenotype. Both MSS- and MSI-H types of cancer differ significantly from each other with respect to their clinical outcome. Expectedly, tumorgenetic mutations in the RAS- (KRAS [Kirstin rat sarcoma], NRAS [neuronal RAS])- as well as BRAF (RAS associated factor, B-type)-genes and status of microsatellite stability became important biomarkers for both prognosis as well as predicting response for targeted therapies aiming for the EGFR (epidermal growth factor receptor). Thus, the analysis of these three markers, RAS, BRAF and MSI-H/MSS, are strongly recommended by the ESMO guidelines 8. When using targeted anti-EGFR directed monoclonal antibodies cetuximab or panitumumab in combination with chemotherapy like FOLFIRI 9 or FOLFOX 10,11 which has been

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approved for the therapy of metastatic CRC (mCRC) by the European Medicines Agency (EMA) tumors will develop in most if not all of cases resistance to this therapy which is accompanied by tumorgenetic mutations in genes reactivating the RAS/ RAF/ MAPK pathway 12,13. For several of these mutations targeted therapeutics are available which might be used for selected patients in an off-label setting 14 not only for mCRCs. Thus, a functional testing of actionable mutations by next-generation sequencing using appropriate gene-specific panels can be the basis for such an approach resulting in a molecular tumor board. One of the major goals in this setting is the clever interpretation of results15.

References:

1. Kinzler, K. W. Cell 87, 159-170., (1996). 2. The Cancer Genome Atlas. Nature 487, 330-337, (2012). 3. Lemieux, E. Oncogene 34, 4914-4927, (2015). 4. Ormanns, S. BMC Cancer 14, 624, (2014). 5. Jass, J. R. Histopathology 50, 113-130, (2007). 6. Rad, R. Cancer Cell 24, 15-29, (2013). 7. Carragher, L. A. EMBO Mol Med 2, 458-471, (2010). 8. Van Cutsem, E. Ann Oncol 27, 1386-1422, (2016). 9. Heinemann, V. Lancet Oncol 15, 1065-1075, (2014). 10. Bokemeyer, C. J Clin Oncol 27, 663-671, (2009). 11. Douillard, J.-Y. New Engl J Med 369, 1023, (2013). 12. Bertotti, A. Nature 526, 263-267, (2015). 13. Misale, S. Science translational medicine 6, 224ra226, (2014). 14. Sartore-Bianchi, A. Lancet Oncol 17, 738-746, (2016).

Molecular testing in clinical practice Marc Ladanyi (USA) Tumor genetic testing is now standard of care for patients with non-small cell lung cancer. Lung adenocarcinomas, which account for approximately 50% of lung cancers, are molecularly sub-classified and their therapy dictated by the presence of distinct molecular alterations including EGFR mutations and ALK or ROS1 fusions that confer sensitivity to selective kinase inhibitors. Additional alterations such as BRAF V600E, RET fusions, and ERBB2 amplifications are found in smaller subsets of patients, but when present may also predict for response to targeted inhibitors. In other patients, defined oncogenic drivers such as KRAS mutations are detected for which preclinical studies have nominated targeted approaches, but the clinical utility of such therapies has yet to be established. As a result of advances in DNA sequencing, the prospective molecular analysis of tumors for mutations in hundreds of cancer-associated genes is now feasible using multiplexed assays that use as input small quantities of formalin fixed paraffin embedded tissue. Through an institution-wide initiative in clinical cancer genomics initiated in 2014, we have implemented large scale genomic profiling for targetable cancer drivers and other cancer-relevant alterations in all patients with advanced solid cancers. Over 15,000 patients have been profiled using the MSK-IMPACT capture-based, targeted DNAseq assay. Subsets of patients have also been studied for oncogenic fusions by targeted RNAseq or for germline cancer predisposition alleles. An overview of our experience will be presented. Recent publications:

• Jordan EJ, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discovery (in press)

• Paik PK, Drilon A, Yu H, Rekhtman N, Ginsberg MS, Borsu L, Schultz N, Berger MF, Rudin CM, Ladanyi M. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5:842–849.

• Hyman DM, Solit DB, Arcila ME, Cheng DT, Sabbatini P, Baselga J, Berger MF, Ladanyi M. Precision medicine at Memorial Sloan Kettering Cancer Center: clinical next-generation

Speaker profiles

Speaker profiles

sequencing enabling next-generation targeted therapy trials. Drug Discov Today. 2015 Dec;20(12):1422-8.

• Cheng DT, et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology. J Mol Diagn. 2015 May;17(3):251-64.

• Arcila ME, Drilon A, Sylvester BE, Lovly CM, Borsu L, Reva B, Kris MG, Solit DB, Ladanyi M. MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking. Clin Cancer Res. 2015 Apr 15;21(8):1935-43.

MADRID2017 esmocongress.org

Integrating science into oncology for a better patient outcome

ESMO 2017

MADRID SPAIN 8-12 SEPTEMBER 2017

IMPORTANT DEADLINES

10 May 2017 Abstract submission

7 June 2017 Early registration

19 July 2017 Late-breaking abstracts

9 August 2017 Late registration

Organiser Partner

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M

Y

CM

MY

CY

CMY

K

SILICON_DEParraryNxT_ADV_210x297_soggCHOOSE_PURITY_11112016.pdf 1 11/11/16 14:09

2nd Special Conference

EACRAACR

SIC24-27 JUNE2017

FLORENCE

ITALY

The Challenges of Optimising Immuno and Targeted Therapies

From Cancer Biology to the Clinic

Why participate?The conference will present the latest achievements in multidisciplinary research in targeted therapies and immunotherapies

Continuing Medical Education (CME) credits available

Basic, translational and clinical scientists

Physicians, practising medical, surgical and radiation oncologists

Experts involved in development of new therapeutics

Who should attend?

Challenges to the development of precision medicine approaches and drug resistance, and the ongoing efforts to better stratify patients for targeted therapy

Role of the microbiome and other microenvironmental factors in influencing therapy response

Utility of recent technical advances

The programme will include:

Regular rate registration deadline: 22 May 2017

For more information, visit www.ecco-org.eu/EAS2017

Conference Secretariat:c/o ECCO - the European CanCer Organisation+32 (0) 2 775 02 01EAS2017@ecco-org.euwww.ecco-org.eu/EAS2017

#EAS17

EUROPEAN UNION OF MEDICAL SPECIALISTSThe European Accreditat ion Council for

Continuing Medical Educat ion EACCME®I n s t i t u t i o n o f t h e U E M S a i s b l

RUE DE L NDUSTRIE, 24 T +32 2 649 51 64BE- 1040 BRUSSELS F +32 2 640 37 30www.eaccme.eu accreditation@uems.eu

UEMSaisbl Union Européenne des Médecins Spécialistes -1040 BruxellesIBAN BE28 0001 3283 3820 BIC (SWIFT) BPOTBEB1 VAT n° BE 0469.067.848

Conflict of Interest Disclosure Form

(to be completed by scientific/organising committee members)

NAME Richard Marais

Cancer Research UK Manchester Institute

In accordance with criterion 24 of document U

relationship, must be provided to the EACCME® upon submission of the application. Decla rations also must be

made readily available, either in printed form, with the programme of the LEE, or on the website of the

organiser of the LEE. Declarations must include whether any fee, honorarium or arrangement for re-

imbursement of expenses in relation to the LEE has been provided.

DISCLOSURE

I have no potential conflict of interest to report

I have the following potential conflict(s) of interest to report

Type of affiliation / financial interest Name of commercial company

Receipt of grants/research supports:

Receipt of honoraria or consultation fees: Pfizer

Stock shareholder:

Spouse/partner:

Other support (please specify): Institute of Cancer Research Rewards to

Inventors Scheme

Signature: Date: 07/11/2016

EUROPEAN UNION OF MEDICAL SPECIALISTSThe European Accreditat ion Council for

Continuing Medical Education – EACCME®I n s t i t u t i o n o f t h e U E M S a i s b l

RUE DE L’INDUSTRIE, 24 T +32 2 649 51 64BE- 1040 BRUSSELS F +32 2 640 37 30www.eaccme.eu accreditation@uems.eu

UEMSaisbl – Union Européenne des Médecins Spécialistes Rue de l’Industrie 24, BE-1040 BruxellesIBAN BE28 0001 3283 3820 BIC (SWIFT) BPOTBEB1 VAT n° BE 0469.067.848

Conflict of Interest Disclosure Form

(to be completed by scientific/organising committee members)

NAME : Marc J. van de Vijver

AFFILIATION: Academic Medical Center, Department of Pathology, Amsterdam

In accordance with criterion 24 of document UEMS 2012/30 “Accreditation of Live Educational Events by the

EACCME”, all declarations of potential or actual conflicts of interest, whether due to a financial or other

relationship, must be provided to the EACCME® upon submission of the application. Declarations also must be

made readily available, either in printed form, with the programme of the LEE, or on the website of the

organiser of the LEE. Declarations must include whether any fee, honorarium or arrangement for re-

imbursement of expenses in relation to the LEE has been provided.

DISCLOSURE

I have no potential conflict of interest to report

I have the following potential conflict(s) of interest to report

Type of affiliation / financial interest Name of commercial company

Receipt of grants/research supports: Seno Medical Instruments, Inc

Hoffmann La Roche Ltd

Receipt of honoraria or consultation fees: Member Pathology Advisory Board Hoffmann

La Roche Ltd

Member Pathology Advisory Board Merck,

Sharp and Dohme

Member Advisory Board Genomic Health

Co-inventor 70-gene prognosis profile in breast

cancer

Signature: Date: 5 December 2016

Tuesday 09 May 2017 16.30 – 17.30Oliver Stephan, Menarini Silicon Biosystems“Copy Number Aberration profiling on pure DEPArray (TM) digitally sorted tumour cells from FFPE and CTC: the new frontier of tumour stratification”

Satellite Symposia

We are pleased to announce that Menarini Silicon Biosystems will not only be exhibiting at the course but also inviting participants to join a Satellite Symposium. This gives participants the opportunity to take part in an additional scientific session.

The Satellite Symposium will be followed by tea, coffee and assorted Amsterdam appetizers courtesy of Menarini Silicon Biosystems.

EACR Sustaining MembersThe European Association for Cancer Research gratefully acknowledges the companies that support the Association as Sustaining Members. Through Sustaining Membership, companies offer ongoing support to the EACR and provide the means for the Association to develop important initiatives. The EACR Conference Series is an important example of this.

The organisers wish to express their appreciation for the significant support provided by sponsors at the 7th EACR-OECI Joint Training Course on Molecular Pathology Approach to Cancer. Their interest and enthusiasm for the course has enabled the organisers to provide an impressive scientific programme.

Elite Sponsor

SponsorsExhibitors