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Conferences HPV and Cancer November 12–13, 2010 | Amsterdam www.thelancetconferences.com/hpv-and-cancer Organised by Oncology Committed to eliminating cervical cancer Welcome Message The digene HPV Test Dear Colleague, On behalf of The Lancet Oncology, I would like to welcome you to The Lancet Conference on HPV and Cancer. Together with an internationally renowned Scientific Committee, I have worked to put together an exciting and focused conference programme, which will bring together regional and international experts in the field of HPV and Cancer. Proven detection HPV accounts for 5% of the total global cancer burden. HPV-associated cancers include those of the is the first step! cervix, vagina, vulva, anus, and oropharynx. Although the link between HPV and both cervical and non-cervical cancers has been sufficiently proven, there are many answered questions and challenges surrounding HPV testing, HPV vaccination, and the management of HPV-associated cancers. The aim of this conference is to provide an opportunity for regional and international leaders from the oncology community to address the growing public-health issues associated with HPV and cancer and for delegates to debate the critical issues with thought leaders at the highest level. I would like to express my gratitude to the entire international faculty who have travelled far to participate and bring their expertise to this meeting. I look forward to welcoming you to what I hope will be an interactive, provocative, and productive meeting in Amsterdam. Dr Emma Grainger Deputy Editor, The Lancet Oncology Rely on proven detection with the digene® HPV Test, when used with the Pap: ■■ 100% sensitivity for CIN 3+ ■■ 98% sensitivity for CIN 2+ ■■ Published clinical data covering >870,000 women HPVImageADPhy0510C1US ■■ FDA approved and CE marked Eliminate cervical cancer — www.theHPVtest.com. Cover Photo Credit: Dr Linda Stannard, UCT/Science Photo Library. 03 www.theHPVtest.com Programme Conferences HPV and Cancer Friday, November 12, 2010 Saturday, November 13, 2010 07:30–08:30 Workshop on clinical trial design John A 'Drew' Ridge 9:00–10:40 Parallel session Moderator: Jorma Paavonen 08:50–09:00 Welcome Jim Bonner HPV testing, translational research, and the clinic 9:00–09:50 Opening keynote lecture Moderator: Jim Bonner 09:00 HPV testing in the developing world John Sellors HPV-associated cancers on the rise, a growing problem? Margaret Stanley 09:25 Use of biomarkers in HPV screening programmes Nicolas Wentzensen 09:50–10:20 Coffee break 09:50 Is HPV prognostic, predictive, or both? Lisa Licitra 10:20–12:00 Joint session Moderator: Margaret Stanley 10:15 Therapeutic HPV vaccines Cornelia Trimble HPV vaccines: current issues in HPV-associated cancers 10:40 Session ends 10:20 Cervical cancer screening following prophylactic HPV vaccination Jack Cuzick 9:00–10:40 Parallel session Moderator: Jens Overgaard 10:45 Vaccination for boys: the paediatrician's perspective Hal Jenson Management of mouth and oral-pharyngeal cancers in relation to HPV 11:10 Community-randomised phase 4 HPV vaccination effectiveness trial: baseline characteristics and trial deliverables Matti Lehtinen 09:00 Prevalence, natural history, and transmission of oral HPV in relation to oropharyngeal cancer Gypsyamber Dsouza 11:35 Vaccine development in the developing world John Sellors 09:25 HPV-specific genetic markers in HPV-associated head and neck and cervical cancers Peter Snijders 12:00 Session ends 09:50 Neck dissection in the surgical management of oropharyngeal cancer: controversies and outstanding questions Ian Martin 12:00–13:30 Lunch break 10:15 Evolving treatment paradigms in the management of oropharyngeal cancer Maura Gillison 12:00–12:45 SPONSORED SyMPOSiuM 10:40 Session ends Understanding HPV diseases as preventable: the synergy between basic and human sciences 10:40–11:10 Coffee break 13:30–15:10 Parallel session Moderator: Chris Meijer 11:10–12:25 Joint session Moderator: Joel Palefsky Risk assessment and treatment in cervical cancer Genetics, environment, and lifestyle factors 13:30 Management of women with screen-detected HPV Guglielmo Ronco 11:10 HPV infection in pregnancy: issues in relation to prophylactic and therapeutic strategies Jorma Paavonen 13:55 Risk of high-grade CIN in women with HPV infection: role of persistence and genotyping Nicolas Wentzensen 11:35 Co-morbidity and smoking behaviour in HPV positive and negative HNSCC patients in relation to outcome Jens Overgaard 14:20 Organisation of HPV-based screening Ahti Anttila 12:00 Race and ethnicity in HPV-related oropharyngeal cancer Kevin Cullen 14:45 Age issues in HPV screening Guglielmo Ronco 12:25 Session ends 15:10 Session ends 12:25–14:00 Lunch break 13:30–15:10 Parallel session Moderator: Maura Gillison 14:00–15:15 Parallel session Moderator: Guglielmo Ronco New agents in head and neck cancer Penile and anal cancers: biology and current management 13:30 HPV and incidence trends for head and neck cancer Anil Chaturvedi 14:00 Prevention and treatment approaches to AIN and anal cancer Joel Palefsky 13:55 The new era of targeted agents in head and neck cancer Jim Bonner 14:25 Prophylactic vaccines for anogenital cancer Margaret Stanley 14:20 Side effects of the new targeted agents in head and neck cancer Jean Pierre Armand 14:50 Circumcision for prevention of anogenital and oral cancers? Tim Oliver 14:45 Critical assessment of the role of chemotherapy, surgery, and radiation therapy in HPV-related oropharyngeal Marshall Posner 15:15 Session ends cancer and future clinical trials 14:00–15:15 Parallel session Moderator: Jean Pierre Armand 15:10 Session ends Radiation in HPV-infected head and neck and oral-pharyngeal cancers 15:10–15:40 Tea break 14:00 Radiation in HPV-infected head and neck and oral pharyngeal cancers Pernille Lassen 15:40–17:20 Joint session Moderator: Marshall Posner 14:25 Rationale for radiation dose reduction in HPV-related oropharyngeal cancer Marshall Posner Clinical trial design in relation to HPV-associated disease 14:50 Hypoxia, HPV, and radiotherapy: interactions and implications for outcome Jens Overgaard 15:40 HPV and clinical trial design for head and neck cancer Maura Gillison 15:15 Session ends 16:05 The importance of window of opportunity studies Amanda Psyrri 15:20–16:10 Closing keynote lecture Moderator: Jim Bonner 16:30 Long-term efficacy of HPV vaccination against hard end-points: Cancer registry based follow-up of phase III efficacy trials Jorma Paavonen HPV infection in the HIV-positive host: molecular interactions and clinical implications Joel Palefsky 16:55 Ecological competition of vaccine-type and non-vaccine-type HPVs before and after mass vaccination Matti Lehtinen 16:10–16:20 Closing remarks Jim Bonner 17:20 Session ends 17:20 End of day Programme is correct at time of publication 04 05 Faculty Ahti Anttila Jean-Pierre Armand Finnish Cancer Registry, Helsinki, Finland Institut Claudius Regaud, Toulouse, France Ahti Anttila serves as a cancer epidemiologist and is the Director of Research Jean-Pierre Armand, certified in medical oncology, is General Director of of the Mass Screening Registry of the Finnish Cancer Registry, Helsinki. He the Institut Claudius Regaud, Toulouse. Dr Armand is presently in charge of is also an adjunct professor in epidemiology at the School of Public Health, the construction of a new cancer centre in a European research hub created University of Tampere, Tampere, Finland. His research activities involve on the Toulouse cancer campus. He is an active member of the medical environmental and occupational risk factors and prevention of cancer, and oncology community. Previously Head of Early Clinical New Drugs Programs evaluation of cancer screening programmes. Dr Anttila is an editor of the and Medical Director of Research and Development at the Institut Gustave- current second edition of the EU Guidelines for Quality Assurance in Cervical Roussy, Villejuif, Dr Armand has been involved in phase I–II and phase Cancer Screening and an editor of the supplements to the guidelines on III studies for the treatment of solid tumours. Dr Armand is active in the HPV testing and HPV vaccination, currently being developed in a project European Organization of Research and Treatment of Cancer (EORTC) and coordinated by the International Agency for Research on Cancer. was past chairman of the EORTC protocol review committee. At the EMEA French Agency (AFSSAPS) he is the representative of oncology at the AMM Conflicts of interest Commission, in charge of the approval of anticancer agents. Dr Armand Dr Anttila has disclosed no significant conflicts of interest. has also held the following positions: President of the European Society for Medical Oncology (ESMO); Medical Director of the Federation of European Cancer Societies (FECS); and President of the French Cancer Society (SFC). He is also a member of the international boards of the American Association for Cancer Research (AACR), the scientific committee of the American Society of Clinical Oncology (ASCO) and AACR, the board for clinical trials at Institut National du Cancer (INCa), and is chairman of the president nominating committee of ESMO. He has coauthored more than 300 medical and scientific publications and is a member of the editorial boards of Annals of Oncology, the European Journal of Cancer, Journal of Clinical Oncology, Investigational New Drugs, Anticancer Research, and Clinical Cancer Research. In 2008, he received the Esmo Award for 'European oncologist of the year'. Conflicts of interest Dr Armand has disclosed no significant conflicts of interest. 07 Faculty James A Bonner Anil Chaturvedi Kevin J Cullen Jack Cuzick University of Alabama at Birmingham, Birmingham, Alabama National Cancer Institute, USA University of Maryland Marlene and Stewart Greenebaum Cancer Center, USA Cancer Research UK, London, UK James A Bonner is the Merle M Salter Professor and Chairman for Dr Chaturvedi is an investigator in the infections and immunoepidemiology Jack Cuzick is head of the Centre for Epidemiology, Mathematics and Kevin J Cullen is Director of the University of Maryland Marlene and Stewart the Department of Radiation Oncology at the University of Alabama, branch of the division of cancer epidemiology and genetics, at the National Statistics at Cancer Research UK in London. He is also John Snow professor Greenebaum Cancer Center. Dr Cullen, who specialises in head and neck Birmingham School of Medicine, Birmingham, Alabama. Dr Bonner Cancer Institute. He received his MPH and PhD in epidemiology from Tulane of epidemiology at Wolfson Institute of Preventive Medicine at Queen Mary, cancer, is a professor of medicine at the University of Maryland School is affiliated with University of Alabama Hospitals, and the Veterans University. Dr Chaturvedi's research focuses on the role of infections and University of London. He holds a PhD in mathematics and has previously of Medicine and is head of its programme in oncology. He came to the Administration Hospital. He graduated summa cum laude in chemistry inflammation as a cause of head and neck cancer and lung cancer. His current worked at Oxford University and Columbia University, New York. His current University of Maryland in January, 2004. A graduate of Dartmouth College from Duke University, Durham, North Carolina, and received his medical research on head and neck cancer includes the aetiology and population-level interests are in cancer epidemiology and clinical trials, with special interest and Harvard Medical School, Dr Cullen completed his internship and degree from Wayne State University, Detroit, Michigan. He completed his epidemiology of HPV-associated head and neck cancers. in prevention and screening. He is currently chairman of the International residency at Beth Israel Hospital in Boston and received additional training at radiation oncology training at the University of Michigan Hospital, Ann Breast Cancer Intervention Study (IBIS) steering group, the independent the National Cancer Institute. He served as interim director of the Lombardi Arbor, Michigan. Subsequently, he completed a research fellowship in the statistician for the ATAC trial and is also involved in studies on the use of HPV Conflicts of interest Cancer Center at Georgetown University from October, 2000, to September, Division of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. Dr assays for cervical screening, the use of flexible sigmoidoscopy for colorectal Dr Chaturvedi has declared no significant conflicts of interest. 2002, and was professor of medicine, oncology, and otolaryngology at Bonner was a faculty member at the Mayo Clinic for 8 years prior to moving cancer screening, and markers for the behaviour of early prostate cancer. He is Georgetown University School of Medicine. In 2008, the University of to the University of Alabama at Birmingham (UAB). While at the Mayo Clinic, the statistician for several major breast cancer trials and maintains an active Maryland Greenebaum Cancer Center received NCI Cancer Centre designation. the Mayo Fellows Association named him Teacher of the Year in Radiation interest in developing new statistical methodology, especially in the area of In the same year it was named one of the top 50 cancer centres in America by Oncology in 1994 and 1996, and he was Co-Chair of the Lung Cancer adjustments for non-compliance and cross-over, and multi-arm clinical trials. US News and World Report. Program of the Mayo-North Central Cancer Treatment Group (NCCTG) from He is currently the president of the International Society of Cancer Prevention 1994 to1998. At UAB, he has co-chaired the Experimental Therapeutics and is a fellow of the Academy of Medical Sciences, the Royal Statistical Conflicts of interest section in the cancer center since 1998. Dr. Bonner has had a long research Society, and the Institute of Mathematical Statistics. In 2007, he was chosen Dr Cullen has made the following disclosure: interest in methods of enhancing radiosensitisation, such as combinations of by Thompson Scientific as one of the twelve hottest researchers in all of Research supported in part by a grant from Sanofi Aventis. chemotherapy or targeted therapy with radiotherapy. His current laboratory science. He is the author of more than 400 peer-reviewed papers and has interests are directed at the development of single chain antibodies that published in all the major medical journals. target the epidermal growth factor receptor and can be delivered in a gene therapy approach. He has been the principal investigator of several clinical Conflicts of interest protocols and has published more than 250 manuscripts or abstracts. He is Dr Cuzick has made the following disclosure: a diplomate of the American Board of Radiology and the National Board of Advisory boards: HPV vaccine – Merck, GSK; HPV screening – Qiagen, Medical Examiners. GenProbe, Roche, Abbott. Conflicts of interest Dr Bonner has made the following disclosure: Occasional consulting and honorarium: Bristol-Myers Squibb; ImClone Systems; Oncolytics 08 09 Faculty Gypsyamber D'Souza Maura Gillison Hal B Jenson Pernille Lassen Johns Hopkins Bloomberg School of Public Health, USA Johns Hopkins Medical Institutions, USA Tufts University School of Medicine, USA Aarhus University Hospital, Denmark Dr D'Souza is an epidemiologist whose research focuses on infectious causes Maura Gillison is a head and neck medical oncologist and molecular Dr Jenson specialises in clinical infectious diseases and virology. He has an Dr Lassen has an MD from University of Copenhagen Denmark, and is currently of cancer, primarily human papillomavirus (HPV) infection. She received her epidemiologist recruited at Johns Hopkins. Dr Gillison has made significant MD from George Washington University School of Medicine and completed doing her specialist training in radiation oncology and medical oncology in the PhD in epidemiology from Johns Hopkins in 2006. Additionally, Dr D'Souza research contributions to the fields of tumour virology, cancer biology, and a paediatric residency at Rainbow Babies and Children's Hospital at Case department of oncology at Aarhus University Hospital Denmark. Dr Lassen's has a Master of Science in molecular and cellular biology from the University epidemiology, and was the first to make the association between HPV and Western Reserve University in Cleveland, Ohio, and a fellowship in paediatric research focus is how HPV might affect the outcome for patients with head of Wisconsin-Madison (1999) and a Masters of Public Health in disease oral cancer. In 2009, Dr Gillison presented data at ASCO 2009 showing that infectious diseases at Yale University School of Medicine. He was a visiting and neck cancer treated with primary radiotherapy and, moreover, to what control from the University of Texas-Houston (2002). Dr D'Souza is currently HPV is the most important predictor of clinical response to tumour therapy fellow in molecular biology in 1984 at the Ludwig Institute for Cancer extent response to the specific radiobiological modifications of radiotherapy an Assistant Professor at the Johns Hopkins Bloomberg School of Public status and prognosis for patients with head and neck cancers. As a result of Research in Cambridge, UK. In 2003, he graduated with an MBA from the might depend on the HPV-status of the tumours. She is expected to receive Health. Dr D'Souza's research includes evaluation of etiological heterogeneity these data, the National Cancer Institute has recommended that all clinical University of Texas at Austin. Dr Jenson has been Professor of Pediatrics and her PhD in that research field by June, 2010. among patients with head and neck cancer and the causal role of HPV in trials involving head and neck cancer be stratified by tumour HPV status. Dr Microbiology and Chief of Pediatric Infectious Diseases at the University these cancers. Current research evaluates the natural history of oral HPV, Gillison has published extensively in journals such as The New England Journal of Texas Health Science Center at San Antonio, Texas; Professor and Chair Conflicts of interest transmission between partners, risk factors for persistent infection, and the of Medicine, Journal of The National Cancer Institute, and the Journal of Clinical of the Department of Pediatrics and Director of the Center for Pediatric Dr Lassen has declared no conflicts of interest. effects of HIV-related immunosupression on infection. Dr D'Souza also studies Oncology. Dr Gillison is NCI R01 and R21 funded and holds the newly created Research at Eastern Virginia Medical School and Children's Hospital of The anogenital HPV natural history and cofactors, the benefits of anal Pap testing Jeg Coughlin Chair for Cancer Research in the OSUCCC. King's Daughters in Norfolk, Virginia; and is currently Chief Academic Officer in high-risk men, and cervical Pap testing among HIV-infected women. at Baystate Medical Center, and Professor of Pediatrics and Dean of the Conflicts of interest Western Campus of Tufts University School of Medicine. Dr Jenson is active in Conflicts of interest Dr Gillison has disclosed no conflicts of interest. education and clinical activities in paediatric infectious diseases. His research Dr D'Souza has made the following disclosure: focused on the molecular biology and clinical aspects of infections, especially Received research support from and is a member Epstein-Barr virus and human herpesvirus type 8 and their associated of a scientific advisory board for Merck Inc. cancers. He has authored more than 250 papers, commentaries, and book chapters, and is an associate editor of Infectious Disease Alert and an editor of Nelson Textbook of Pediatrics. Conflicts of interest Dr Jenson has declared no significant conflicts of interest. 10 11 Faculty Matti Lehtinen Lisa Licitra ian C Martin Tim Oliver University of Tampere School of Public Health and Istituto Nazionale Tumori, Milan, Italy National Confidential Enquiry into Patient Outcome and Death, London, UK Barts and The London Medical School, Queen Mary University of London, UK National Institute for Health & Welfare, Finland Lisa Licitra is a medical oncologist, with special expertise in the treatment of Ian C Martin is a consultant maxillofacial surgeon and the clinical director Professor Tim (RTD) Oliver gained his medical degree in 1966 from Cambridge Matti Lehtinen is a professor of public health at the University of Tampere head and neck cancers. She is currently assistant physician in charge of the of head and neck surgery in Sunderland. His main clinical interest is the University, did his research degree with Professor Hilliard Festenstein and Jean School of Public Health, and a research professor at the National Insitute head and neck cancer medical oncology unit at the Istituto Nazionale Tumori surgical management of head and neck cancer, including microvascular Dausset on the biology of histocompatibility antigens in transplantation and for Health and Welfare, Finland. He received his MD in 1983 and PhD in in Milan, Italy. Dr Licitra is a free-contract professor at the State University reconstruction. He is chairman of the British Association of Oral and disease, and was Professor in Medical Oncology at St Barts and The London 1985 from the University of Tampere, where he also received professorship of Milan; a member of the clinical editorial board of the Journal of Clinical Maxillofacial Surgeons, president elect of the British Association of Head Medical School QMUL. He published over 500 papers on immunotherapy and qualifications in virology (1991) and epidemiology (2004). He also received Oncology; Editor of State of the Art Ancology Europe (START), a project of the and Neck Oncologists and clinical coordinator for surgery at the National chemotherapy of Urological and Genital cancer. Since 1995, Professor Oliver awards for best group teacher, best PhD thesis, and assistant professor of Alleanza Contro il Cancro, Ministry of Health, Italy; a reviewer of the PDQ Confidential Enquiry into Patient Outcome and Death. He is vice president of has focused on treatment of early cancer of the prostate and testis as well as the year. In 1994, Dr Lehtinen founded the Nordic Biological Specimen Summaries on head and neck cancers; a board member of the European the Federation of Specialist Surgical Associations and an invited member of trials minimising toxic effects of treatment. He retired from the NHS in 2006, Banks on Cancer Causes and Control (NBSBCCC). He is currently the primary Organization for the Research and Treatment of Cancer (EORTC); and elected Council of the Royal College of Surgeons of England. He also has a medico- but continues to follow up patients recruited to his research trials and pursue investigator for phase III-IV trials in 60 000 adolescents on safety, efficacy, chair of the Head and Neck Cancer Cooperative Group of EORTC. She is also legal interest and a degree in law, and is president elect of the North of his interests in prevention of cancer though his current position as Professor and effectiveness of human papillomavirus (HPV) vaccination, and a co-founder and member of the Italian Group for the Evaluation of Outcomes England Medico-Legal Society. In his spare time Ian is an enthusiastic aviator, Emeritus within the medical school working with the departments of general C. trachomatis/HPV screening trial in 120 000 adolescents. Dr Lehtinen has in Oncology (IGEO), a member of the educational committee of the European and a flying instructor in Newcastle. practice and sports medicine involved in dissecting the differential health been a member of the editorial boards of the Open Vaccine Journal, Sexually Society for Medical Oncology (ESMO), chair of the Head and Neck Faculty benefits of exercise and sunshine in cancer prevention Transmitted Infections and Journal of Clinical Virology. He has published of ESMO, co-founder and member of the European Head and Neck Cancer Conflicts of interest more than 200 original articles and reviews in international peer-reviewed Society, a member of the American Society for Clinical Oncology (ASCO), a Conflicts of interest Mr Ian Martin has declared no conflicts of interest. scientific journals and has written or contributed to over 30 text books. member of the Italian Association for Medical Oncology (AIOM), and honorary Professor Oliver has declared no significant conflicts of interest. member of the European Society for Therapeutic Radiology and Oncology Conflicts of interest (ESTRO). Her main fields of interest are head and neck neoplasms, evidence- Dr Lehtinen has received grants for his HPV vaccination studies from based medicine, clinical methodology in oncology, and quality of life. Dr Licitra Merck & Co. Inc., and GSK Biologicals through his employers. has written five book chapters and approximately 70 scientific articles. Conflicts of interest Dr Licitra has made the following disclosure: Consultant/advisor: BMS, Glaxo, Lilly, Merk-Serono, Amgen Research funding: EISAI, Exelixis, Lilly, Merk-Serono, Amgen Travel expenses to attend medical meetings: Merk Serono. 12 13 Faculty Jorma Paavonen Joel Palefsky Marshall Posner Amanda Psyrri University Hospital, Helsinki, Finland UCSF School of Medicine, USA The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA University of Athens, Greece Jorma Paavonen is a professor of obstetrics and gynaecology at the University Dr Palefsky is a professor of medicine at the UCSF School of Medicine. He Dr Posner is a professor of medicine and the director of the human Dr Amanda Psyrri is an assistant professor of medicine at the University of of Helsinki, and is the physician-in-chief for the department of obstetrics and completed his undergraduate medical training and training in internal monoclonal antibody laboratory in the department of cell and gene therapy Athens in Greece, and an attending physician at Attikon University Hospital. gynaecology at University Hospital, Helsinki, Finland. Professor Paavonen's medicine at McGill University and completed his fellowship in infectious at Mount Sinai School of Medicine. He is also the medical director of the She gained her medical degree from the University of Patras, Greece, and research programmes focus on sexually transmitted diseases (particularly diseases at Stanford University. Dr Palefsky is an internationally recognised clinical trials office for the Tisch Cancer Institute in New York. He is a current completed her medical oncology training at Yale University in 2002. She chlamydial and HPV infections), prevention of preterm birth, HPV vaccination, expert on the molecular biology, treatment, pathogenesis, and natural or past member of the editorial boards of the Journal of Clinical Oncology, joined the faculty of medicine at Yale University as an assistant professor in levonorgestrel-releasing hormone system (LNG-IUS) in the treatment of history of anogenital HPV infections, particularly in the setting of HIV American Journal of Clinical Oncology, Oral Oncology, The Oncologist, the Annals 2003. She is Translational Research Chair of the European Organization for menorrhagia, vulvar pain syndrome, abnormal placentation, and others. infection. He is the director of the world's first clinic devoted to prevention of Oncology, and Head and Neck, and he serves as an ad hoc reviewer for The Research and Treatment of Cancer (EORTC) Head and Neck Cancer Group and Major activities include undergraduate and postgraduate teaching and clinical of anal cancer—the Anal Neoplasia Clinic at the UCSF Cancer Center. He New England Journal of Medicine, Cancer, Journal of Immunology, Clinical Cancer an Associate Editor of the Annals of Oncology. Her research interests include work, both as an obstetrician and a consultant gynaecologist. He is currently has pioneered diagnostic and treatment methods for anal intraepithelial Research, Cancer Research, British Journal of Cancer, and Oncology. Dr Posner has the molecular mechanisms of human papillomavirus-associated head and the principal investigator for the Women's Health research programme and neoplasia (AIN) and has been an advocate for screening and treatment of been a member of several NIH Health review committees. He has published neck carcinogenesis and molecular epidemiology of head and neck cancers. the principal investigator of the global phase 3 and phase 4 HPV vaccination AIN in high-risk populations to prevent anal cancer. He is the chair of the HPV more than 180 peer-reviewed laboratory and clinical studies and multiple Dr Psyrri is also mentor and educator for a large number of trainees. efficacy trials. He is also a member of the Board of the Biomedicum Helsinki Working Group of the AIDS Malignancy Consortium. He is co-chair of the reviews and has been the principal investigator on numerous clinical and Research Institute. Since 1978, Prof Paavonen has authored more than 400 Special Populations Committee for and member of the board of the American translational research trials in head and neck cancer. Dr Posner has reported scientific articles published in peer-reviewed journals (H-Index 48). His most Society for Colposcopy and Cervical Pathology. He is the author of more than on antibody based immunotherapy in pemphigus and HIV, and adoptive recent major publications are on HPV vaccination, Chlamydia-associated 200 publications. immunotherapy in nasopharynx cancer. He holds patents for Human infertility, preterm delivery, and placental abruption. He is or has been the Monoclonal Antibodies to viral and bacterial antigens. associate editor or editorial board member of Sexually Transmitted Diseases, Conflicts of interest Sexually Transmitted Infections, Infectious Diseases in Obstetrics and Gynecology, Dr Palefsky has made the following disclosure: Conflicts of interest and International Journal of STD & AIDS. Research support and advisory board member: Merck and Co. Dr Posner has made the following financial disclosures with pharmaceutical firms and oncology agencies for the past 12 months: Conflicts of interest Honoraria: Sanofi Aventis, Merck Professor Paavonen has made the following disclosure: Clinical research support (no salary): Abraxis, Sanofi Aventis, Astra Zeneca, Receipt of funding from Merck Co. and GlaxoSmithKline Co. through Bristol Myers Squibb, Amgen, NCI, NIAID, Imclone, Novartis, Actogenix the Helsinki University Hospital Research Institute to conduct trials on Consultant: Amgen, Glaxo-Smith-Kline, NCI, BMS, Sanofi Aventis, Oxigene, HPV vaccines. Imclone, Onc-Q-Ity, Biovex, Novartis, Merck, EMD Serono, Member: ASCO, AACR, ASH, AAI, NCCN, RTOG, ESMO Stock: None Significant income from above: None Financial relationship: None 14 15 Faculty John Andrew Ridge Guglielmo Ronco John W Sellors Peter J F Snijders Fox Chase Cancer Center, Pennsylvania, USA Centre for Cancer Prevention, Turin, Italy McMaster University, Canada VU University Medical Center, Amsterdam John Andrew 'Drew' Ridge is Past-President of the American Head and Neck Dr Guglielmo Ronco, an epidemiologist, is responsible for the unit for John is a clinical epidemiologist and Clinical Professor of Family Medicine Peter Snijders is a professor of molecular pathology and head of the Society. At Fox Chase he is chief of the head and neck surgery section, a cervical cancer screening at the Centre for Cancer Prevention in Turin, Italy, at McMaster University after serving for 8 years as Senior Medical Advisor molecular pathology unit in the department of pathology at VU University professor of surgery and developmental therapeutics, and a senior member where he has worked since 1987. From 1990, his main interest has been in of the Reproductive Health Program at PATH in Seattle. At PATH he led a Medical Center, Amsterdam. Since 1988, he has worked on HPV-related in the department of surgical oncology. With PhD thesis work in structural screening for cervical cancer. He has undertaken surveys for the evaluation of public–private partnership project with funding from the Bill & Melinda Gates topics. He was involved in the development of the HPV GP5+/6+ consensus biology and an extensive background in clinical research and trial design, cervical screening at the national and European level and has participated in Foundation and private industry to research and develop new cervical cancer PCR method and was among the first to establish a plausible etiological role he co-directs the Head and Neck Keystone Programme with Erica Golemis the preparation of national and international guidelines for cervical cancer screening tests that are affordable, rapid, and appropriate for public-health of mucosal HPV in tonsillar cancer. He is currently using both in-vitro models and Barbara Burtness. He has been a member of numerous federal advisory screening. Dr Ronco has also studied new methods for cervical screening and programmes in low resource regions. As a result, two new molecular tests, and clinically well-defined patient material to investigate HPV-induced groups, including NCI programme project grant review panels, special related fields. In particular, he is the principal investigator of the NTCC study, one for HPV DNA and another for E6 oncoprotein, are promising. Projects oncogenic progression, in particular the identification and characterisation emphasis panels for the National Institute of Dental and Craniofacial a large (about 100 000 women enrolled), multicentre, randomised trial with the Alliance for Cervical Cancer Prevention and with the HPV Vaccine of genes involved in this process and candidate markers for risk assessment. Research, the NIH/NCI Institutional Review Group SPORE committee, and for the evaluation of new technologies as primary tests for cervical cancer project at PATH have provided him with an understanding of strategies to He is also undertaking clinical trials to test viral and host markers for their head and neck cancer 'think tanks' for the NCI and NIDCR. Ridge has also screening—these include testing for HPV DNA, liquid-based cytology, and prevent cervical cancer. He is an advisor to projects on HPV vaccination in capability to assess the risk of cervical cancer and identify high-grade been a member of several CTEP committees (including Common Data biomarkers for improving the specificity of HPV testing. Canada and female genital schistosomiasis in Africa and a member of the precursor stages during screening. He is (co)author of more than 200 Elements and Surgical Effects). A former ECOG Head and Neck Committee board of Grounds for Health, a non-profit organisation working to prevent international, peer-reviewed articles in his area of expertise. co-chair, he currently serves as co-chair of the Previously Untreated, Locally Conflicts of interest cervical cancer among coffee plantation workers. Advanced Task Force of the NCI Head and Neck Steering Committee. Dr Ronco has made the following disclosure: Conflicts of interest A member of many professional organisations, he has authored more than Participation in internal Scientific Advisory Board (March 2008): Conflicts of interest Professor Snijders has made the following declaration: 100 peer-reviewed articles and book chapters. Gen-Probe (San Diego, CA, USA). Professor Sellors has disclosed no conflicts of interest. Work is funded in part by the Dutch Cancer Society (NKB) and the Netherlands Organization for Health and Development (ZonMW). Conflicts of interest He provided occasional consultation to companies involved in HPV Dr Ridge has disclosed no significant conflicts of interest. diagnostics. He has a relationship with Self-screen. 16 17 Faculty Margaret Stanley Cornelia L Trimble Nicolas Wentzensen University of Cambridge, Cambridge, UK Center for Cervical Disease, Johns Hopkins, Baltimore, USA National Cancer Institute, USA Professor Stanley is Professor of Epithelial Biology in the University of Dr Connie Liu Trimble is a translational researcher whose work focuses on Dr Wentzensen is an investigator for the division of cancer epidemiology Cambridge. She attended the Universities of London, Bristol, and Adelaide, immune therapies for disease caused by human papillomavirus (HPV). At and genetics at the National Cancer Institute (NCI). His area of expertise is is a Fellow of the Academy of Medical Sciences and Honorary Fellow of Johns Hopkins, she has established a multidisciplinary programme—the research on the etiology of gynaecological cancers and biomarker discovery, the Royal College of Obstetricians and Gynaecologists. She has served on Center for Cervical Dysplasia—to provide patient care and education, faculty especially for cervical and ovarian cancer. Dr Wentzensen has worked on several research council committees and was a member of the Biology and and student mentoring, and to support translational research to improve HPV-associated cancers for more than a decade and has focused on the Biotechnology Science Research Council from 2000 to 2003. She is currently the care of patients with HPV. In addition to the design and implementation development of biomarkers for cervical cancer screening from basic research a member of the Spongiform Encephalopathies Advisory Committee that of clinical trials to test immune-based therapies for women with preinvasive to translation in clinical and epidemiological studies. His clinical training and advises the UK government on prion diseases, and in 2004 was awarded the HPV disease, her lab studies the mechanisms of immune-cell recruitment, his experience in running a diagnostic service laboratory for cervical cancer OBE for services to Virology. Her current research focuses on mechanisms of activation, and homoeostasis in the genital mucosa, and mechanisms screening are important assets for conducting epidemiological studies with host defence and the development of vaccines and immunotherapies against of immune evasion by HPV. She is double-boarded in both obstetrics translational impact. Currently, he is the principal investigator for a large human papillomaviruses, the cause of cervix cancer. She has published and gynaecology and in anatomic pathology, with specialty training in cervical cancer biomarker research and discovery effort being undertaken extensively and is at present on the editorial board of Sexually Transmitted gynaecological pathology. at NCI. He recently initiated a new study to analyse the accuracy of cervical Infections, Journal of Clinical Virology, and Reviews in Medical Virology. She is a colposcopy and biopsy in women with abnormal screening results; this council member of the International Papillomavirus Society. Conflicts of interest is currently extended to a world-wide network of studies on colposcopy Dr Trimble has disclosed no conflicts of interest. performance and harmonisation. Apart from his work on cervical cancer, Dr Conflicts of interest Wentzensen is interested in the etiological heterogeneity of ovarian cancer. Professor Stanley has made the following disclosure: Dr Wentzensen earned his MD and a PhD in applied tumour biology from the Consultant/SAB member: Merck Corp, New Jersey, USA; SPMSD, Lyon, France. University of Heidelberg and a Master of Epidemiology from the University Consultant/Phase IV Steering Group Member: GSK Biologicals, Rixensart, Belgium. of Mainz. He joined the National Cancer Institute in 2007. Dr Wentzensen serves as an expert in the Cochrane Gynaecological Cancer Review Group, section 'Prevention of Cervical Cancer', and in the Practice Improvement in Cervical Screening and Management (PICSM) Group that is working on new guidelines for cervical cancer screening incorporating new molecular assays. Conflicts of interest Dr Wentzensen has disclosed no significant conflicts of interest. 18 19 Speaker Abstracts HPV associated cancers on the rise —a growing problem Margaret Stanley University of Cambridge, Department of Pathology, Cambridge, UK Cervical-cancer screening following prophylactic human papillomavirus vaccination Jack Cuzick Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Viral infections cause at least 15% of human cancers. One of the most important oncogenic viruses is human papillomavirus (HPV); a causal agent Institute of Preventive Medicine, Queen Mary University of London, London, UK in about 5% of all cancers. HPVs are a large group of viruses that infect The recognition that infection with certain types of human papillomavirus both cutaneous and mucosal squamous epithelia and have an exclusively (HPV) is a necessary cause of cervical cancer has opened new fronts intra-epithelial infectious cycle. About 15 mucosal types are high risk or for the prevention of this disease. Primary prevention is now possible cancer-causing HPVs, with HPV type 16 and HPV type 18 the most important. via immunisation with highly efficacious HPV vaccines, and secondary Infection with one of these oncogenic HPVs can cause carcinoma of the cervix prevention has gained impetus with the advent of sensitive HPV DNA testing in women, which is the third most common cancer in women worldwide. to improve traditional cytology-based screening programmes. Although Secondary intervention by screening effectively controls this disease in universal vaccination of teenagers and young women is desirable, cost developed countries, but not in the developing world—which bears 86% of remains a key obstacle. Even with high uptake, a statistically detectable the cervical cancer burden. Projections of population growth indicate that reduction in the burden of cervical cancer via HPV vaccination is unlikely to without primary or secondary intervention such inequality in disease burden be observed for at least 10–15 years. To achieve cost-effective reductions will increase in the coming 3 to 4 decades. in the burden of cervical-cancer prevention, initiatives must consider HPV-associated cancers are not confined to the cervix and HPV infection is screening and immunisation as integrated and organised approaches that implicated in the development of vaginal, vulval, anal, penile, and head and take advantage of HPV testing as primary screening tests, followed by triage neck cancers. Importantly, the incidence of HPV-related cancers in these sites, with cytology. On the basis of preliminary findings from the vaccination particularly anal carcinomas and tonsillar carcinomas, is increasing. trials, as successive cohorts of vaccinated young women reach screening age, reduction in cervical lesions will lead to a decrease in rates of colposcopic referral to about 40–60% of the current case loads in most Western countries. These reductions are likely to translate into initial savings for the health- care system, but the vaccine-induced decrease in cervical lesions might lead to a degradation of performance characteristics of cytology because of a decreased rate of abnormalities. The positive predictive value of cytology will decline in vaccinated women because clinically relevant lesions will become less common. A decline in performance will occur because of a decrease in the signal (squamous abnormalities) to noise (inflammation and reactive atypias) ratio that will have a negative impact due to the subjective and tedious nature of reading and interpreting smears. Another issue is whether screening algorithms can be different for vaccinated versus unvaccinated individuals; this will be particularly important where vaccine coverage is intermediate (30–70%). Knowledge of vaccine status, and registries and other mechanisms are needed if the attendant savings associated with reduced screening are to be realised. 21 Speaker Abstracts Vaccination for boys: Community-randomised phase 4 Vaccine development in Management of women with screen- the paediatrician's perspective vaccination effectiveness trial: baseline the developing world detected human papillomavirus characteristics and trial deliverables Hal B Jenson John Sellors Guglielmo Ronco Tufts University School of Medicine, USA Matti Lehtinen, Dan Apter, Jorma Paavonen McMaster University, Canada Centre for Cancer Prevention, Turin, Italy In studies of boys and young men, the type-specific immunogenicity of University of Tampere, Family Federation Finland, University of Helsinki, Finland The most comprehensive approach to cervical cancer prevention in low- Human papillomavirus (HPV) testing has a lower positive predictive quadrivalent human papillomavirus (HPV) vaccine for HPV types 6, 11, Genital infections with oncogenic human papillomaviruses (HPV) are resource regions would be based on both prophylactic vaccination of girls and value than cytology. Therefore, referring all women infected with HPV to 16, and 18 is 97·4–99·9%, which is non-inferior (and for some segments, common in both men and women. The most important disease associated screening of women at about 35 years of age, since current vaccines provide colposcopy causes many unneeded colposcopies. The most studied approach numerically superior) to the response in girls and young women. Across all with oncogenic HPV infection is cervical cancer—currently the second leading protection against only about 70% of infections causing cervical cancer. is testing women infected with HPV for cytology and immediately referring groups, anti-HPV geometric mean titres peak at 7 months, decline through cause of cancer-related death in women worldwide—but other HPV positive those who show cytological abnormalities to colposcopy. The remaining The WHO position paper on human papillomavirus (HPV) vaccines states: 24 months, and then stabilise through at least 60 months. The prophylactic anogenital cancers and tonsillar cancer occur not infrequently in women and women are retested after 6–18 months and referred to colposcopy only "WHO …recommends that routine HPV vaccination should be included in efficacy of the HPV vaccine in boys and young men 16–26-years of age has men. A prophylactic virus-like particle based on the cervarix vaccine (GSK if HPV infection persists. This approach, denoted as cytological triage, is national immunization programmes, provided that: prevention of cervical been shown in several studies to prevent HPV 6, 11, 16, and 18 related Biologicals, Rixensart), containing HPV16 and 18 L1 proteins, which self- based on the knowledge that only persistent infections are relevant for cancer or other HPV-related diseases, or both, constitutes a public health external genital warts; penile, perineal, or perianal intraepithelial dysplasia assemble to form virus-like particles, formulated with the adjuvant AS04 carcinogenesis. From 35 years of age, the reduction of cervical intraepithelial priority; vaccine introduction is programmatically feasible; sustainable grades 1, 2, or 3; and penile, perineal, and perianal cancer. Efficacy of the has been shown to be highly effective in preventing cervical infections with neoplasia 3 (CIN3) in HPV-screened women versus cytology-screened financing can be secured; and the cost effectiveness of vaccination strategies quadrivalent vaccine for the prevention of genital warts in young men has HPV16 and 18 and associated cervical neoplasia. women at round two was similar in randomised trials that applied cytological in the country or region is considered. HPV vaccines are most efficacious in been shown to be 94·3% (95% CI 63·9–99·9%) in 16–20-year-old men, 85·1% triage and in trials that referred all women to colposcopy, suggesting that Since the protection of adolescent girls before the onset of sexual activity females who are naïve to vaccine-related HPV types; therefore, the primary (33·2–98·4%) in 21–26 year-old men, and 89·4% (69·2–98·1%) in 16–26 protection against cancer is similar. Instead, the positive predictive value of and exposure to oncogenic HPVs is vital, the primary target group for target population should be selected based on data on the age of initiation of year-old men. Clinical efficacy of the quadrivalent vaccine in 9–15 year-old HPV testing with cytological triage is similar to that of cytology, whereas with implementation of national HPV vaccination programmes will be early sexual activity and the feasibility of reaching young adolescent girls through girls and boys is based on supportive immunogenicity bridging data. Cost- direct referral it is markedly less. Infection by HPV type 16 or type 18 has a adolescents. Our phase 4 study was designed as a community-randomised schools, health-care facilities or community-based settings…". effectiveness analyses (cost per quality-adjusted life year) of the quadrivalent higher risk of high-grade CIN than infection with other HPV types. Therefore vaccine confirm less effect and less cost-effectiveness of vaccination in men trial, and will enable assessment of the overall effect (direct effectiveness, Pilot projects addressing issues associated with the introduction of HPV immediate referral to colposcopy, independent of cytology, is suggested by compared with vaccination in women only. Vaccination of men has high indirect effectiveness, or both) of HPV immunisation in a community setting vaccines are being done in low-resource regions of low-income and middle- some experts for women with such infections. One drawback of methods efficacy for prevention of anal intraepithelial neoplasias in men who have sex when early adolescents (12—15 years of age) are targeted for vaccination. income countries, including Uganda, Peru, India, and Vietnam. Cost of that are based on the assessment of persistence of infection is loss to follow with men. The quadrivalent vaccine might be given to boys and men aged 9 Effectiveness will be assessed in the girls once they are 18·5 years of age, vaccines will influence availability in poor settings, and help from the GAVI up. Other biomarkers—such as viral load, E6 and E7 mRNA, and p16-INK4A to 26 year of age to reduce their likelihood of acquiring genital warts, and is who live in communities in which both girls and boys have received HPV16 Alliance and the Pan American Health Organization is anticipated to play overexpression—are under study. A study nested in a randomised trial most effective when given before exposure to HPV through sexual contact. and 18 vaccination (A-arm), or in communities in which girls only have a part to facilitate vaccine purchase by poor countries. Preparation for a showed that triaging women infected with HPV by a single p16-INK4A test Paediatricians must consider vaccine types, immunogenicity, efficacy, cost received HPV16 and 18 vaccination (B-arm) in comparison with girls who vaccination programme should include dissemination and discussion of has 50% higher sensitivity than cytology, while resulting in a similar number effectiveness, public health effects, and impact on public acceptance in live in communities that have received only hepatitis B-vaccination (C-arm). influential messages with girls, parents, health providers, community leaders, of colposcopies. Preliminary data also show that women aged 35 years or formulating recommendations for HPV vaccine for boys and young men. Among unvaccinated adolescents, our trial will also assess the effectiveness religious leaders, teachers, and members of the press. Access to the vaccine older who are infected with HPV, but did not express p16-INK4A, have very of the two HPV16 and 18 vaccination strategies (girls and boys versus girls through the school system has given good coverage, and acceptance by girls low probability of new CIN3. only) in arm A versus B. and their families has been high. Recruitment took place during three school years: 2007–08, 2008–09, and 2009–10, which resulted in equal enrolment of four birth cohorts (born 1992–95) comprising more than 32 000 (40%) early adolescents: 22 000 girls (50% per arm) and 10 000 boys (20–30% per arm) with few adverse effects. Although men are known to play a crucial part in the transmission of oncogenic HPV to women, the effect of vaccination of early adolescent boys has so far only been estimated in modelling studies. Our community- randomised trial will assess the effect of different vaccination strategies in a randomised setting. 22 23 Speaker Abstracts Risk of high-grade cervical intraepithelial Organisation of human papillomavirus Age issues in human papillomavirus HPV and incidence trends for neoplasia in women with human based screening screening head and neck cancer papillomavirus infection—role of persistence and genotyping Ahti Anttila Guglielmo Ronco Anil Chaturvedi Finnish Cancer Registry, Helsinki, Finland Centre for Cancer Prevention, Turin, Italy National Cancer Institute, USA Nicolas Wentzensen Cytological screening for cervical cancer has been used in Western countries In industrialised countries human papillomavirus (HPV) prevalence peaks The causal relationship of HPV infection with a subset of head and neck Division of Cancer Epidemiology and Genetics, National Cancer Institute, since the 1950s and 1960s. Substantial variation in the organisation and at about 20 years of age and subsequently decreases. An increase in clinical cancers could be leading to substantial changes in the population-level Bethesda, MD, USA policy of screening exists; however, this has led to variation in the coverage, sensitivity and loss in specificity versus cytology is high in young people. epidemiology of head and neck cancers. In the USA, incidence rates for head cost-effectiveness, and impact. In the EU, an organised population-based High-grade cervical intraepithelial neoplasia (CIN) occurs very frequently at and neck cancer sites without a causal relationship with HPV infection (oral Carcinogenic human papillomavirus (HPV) infections are the cause of almost cervical screening programme has extended to about a third of the women in short intervals after HPV infection in young women, but its clinical relevance cavity) have significantly declined since 1984, consistent with declining all cervical cancers. HPV type 16 and 18 are identified in about 73% of cancers the potential target population; the rest are either opportunistically screened, is not clear. A randomised trial comparing HPV-based cervical screening with tobacco use. By contrast, incidence rates for HPV-related head and neck cancer worldwide, followed by HPV type 58, 33, 45, 31, and 52. Prospective studies or unscreened. About ten times variation in the cervical-cancer burden exists cytology-based cervical screening separately studied women aged 25–34 sites (oropharynx, including tonsils and base of the tongue) have notably have shown a substantially higher risk of developing cervical intraepithelial between these countries. Countries without any screening have generally the and 35–60 years. In women aged 25–34 years, a substantial increase in the increased during the past two decades, particularly among young males. neoplasia (CIN) grade 3 for infections with HPV type 16 and 18 than for highest burden of cervical cancer. New methods, such as HPV screening, enable detection of CIN3 at the first screening round and decrease at the second Analogous data of increasing incidence for HPV-related head and neck cancer other carcinogenic types. Although most cancers are associated with HPV large-scale benefits and efforts are continuing in order to develop feasible, round was recorded with HPV testing and direct referral of all HPV positives sites are emerging from other parts of the world, including Australia, Canada, infections with single carcinogenic types only, multiple HPV infections affordable, and sustainable cancer screening programmes in these settings. to colposcopy versus cytology. However, no significant difference between Denmark, Finland, Japan, the Netherlands, Sweden, and the UK. The increasing are very common in CIN and complicate HPV type attribution. In a large colposcopy and cytology was identified with HPV testing and cytological incidence for HPV-related head and neck cancer sites in recent calendar periods cross-sectional study, we reported a wide range of potential attribution Screening is a multistep process, however, and European recommendations triage. With both strategies, HPV testing in women below the age of 35 years draws attention to increasing exposure to oral HPV infection among recent of HPV type 16 to CIN3, from 25% in single infections to 75% including all propose solutions for the whole chain, from planning, decision-making, resulted in a three-fold increase of CIN2 detection over the first two screening birth cohorts. Presumably, changes in oral sex behaviours among recent women positive for HPV type 16. HPV infections are very common and most piloting, and gradual rollout, up to monitoring and assessment of the rounds compared with cytology, suggesting relevant over-diagnosis of birth cohorts may have led to an increase in oral HPV exposure, and as a infections regress spontaneously within a few months. Only few infections performance and outcome. From an organisational perspective, extensive regressive CIN2 in young women with HPV testing. Unneeded treatment consequence, increasing incidence rates for HPV-related head and neck cancers. persist over a long period and might develop to CIN3. Thus, testing for efforts are required to introduce changes in health services within and of regressive lesions is a problem because excisional treatment of cervical Consistent with this hypothesis, recent data from Sweden show a three-fold presence and persistence of individual genotypes could offer important outside the programmes, and to enable women to make informed choices. lesions is associated with increased risk of pregnancy-related morbidity. This increase from the 1980s to the 2000s in the proportion of oropharynx cancers additional risk stratification beyond simple high-risk HPV-DNA testing. So far, the integration of HPV tests, mainly in secondary screening, has been problem is particularly relevant at young ages in view of the high probability attributable to HPV infection. These observations underscore the increasing However, implementation of these approaches into screening programmes easier. Introduction of primary HPV screening—with the biggest benefit—is of subsequent pregnancy. A pooled analysis of individual data from burden of HPV-related head and neck cancers worldwide, and highlight the is not trivial. Only few well-validated HPV genotyping assays are available. a slow process. In many countries, a transition from non-population-based randomised trials will be useful in establishing at what age HPV screening need for targeted prevention and treatment strategies. Testing for HPV type persistence requires women to return to follow-up activity to population-based organised cancer screening programmes is should start. In the meantime, routine HPV-based screening should not start testing at appropriate time intervals, and management decisions based essential. This transition has started as an increasing number of countries are too early. With HPV testing there is a potential to stop screening at an earlier on repeat testing require easy access to previous test results. For both HPV planning or piloting primary HPV screening. age than with cytology. However, to date, evidence does not seem sufficient genotyping and testing for type persistence, the gain in risk stratification to recommend a change. needs to be high enough to influence management so that implementation can be justified. 24 25 Speaker Abstracts The new era of targeted agents Side effects of new targeted drugs Critical assessment of the role of Tumour human papillomavirus status in head and neck cancer in head and neck cancer chemotherapy, surgery, and radiotherapy in as a predictor of survival human papillomavirus-related oropharyngeal James A Bonner Jean-Pierre Armand cancer and future clinical trials Maura Gillison University of Alabama at Birmingham, Birmingham, Alabama Institut Claudius Regaud, Toulouse, France Johns Hopkins Medical Institutions, USA Head and neck cancers are known to have high levels of epidermal growth The most common head and neck cancer is head and neck squamous cell Marshall Posner Tumour human papillomavirus (HPV) status is a strong and independent factor receptor (EGFr) expression. Also, radiation therapy is known to cause carcinoma (HNSCC), which is the sixth most common cause of cancer The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA predictor of survival for patients with head and neck cancer. The relative an increase in EGFr expression. Previous studies revealed that head and neck worldwide. The most extensively studied pathway for targeted treatment in survival for HPV-positive versus HPV-negative patients seems independent Identification of human papillomavirus related oropharyngeal carcinoma cancer patients with high levels of EGFr did poorly, compared with those HNSCC is the epidermal growth factor receptor (EGFR) pathway. Molecular from the therapeutic approach, as long as that approach is within the current (HPVOPC) as a distinct clinical entity in head and neck cancer (HNC) is with low levels, when conventional treatments were employed. Therefore, classification is a very important research area since the traditional clinical- standard of care. Absolute difference in survival between HPV-positive a major advance. The extremes in prognosis identified through human preclinical studies were undertaken and showed radiosensitisation with pathological factors do not provide accurate prognostic information. and HPV-negative patients is consistently 30% or greater at 3–5 years for papillomavirus (HPV) analysis of oropharyngeal carcinoma tumours in clinical the combination of anti-EGFr antibodies and radiation. The combination EGFR family members human epidermal growth factor receptor (HER; or therapeutic approaches that would be considered aggressive (eg, induction trials has created an opportunity and an obligation to examine the biology of an anti-EGFr antibody (cetuximab) and radiation showed promising ERBB1) 1–4, the vascular endothelial growth factors (VEGF) A, B, C, and D, followed by concurrent chemoradiation) or less aggressive (radiation alone). and therapeutic implications of HPVOPC in past, present, and future clinical early clinical results for patients with locoregionally advanced disease. and their receptors VEGFR 1, 2, and 3 AKT. In addition to EGFR pathway, Although clearly a significant prognostic factor the field is struggling with trials. Past studies of multimodality and monotherapy have been reassessed Subsequently, a large international phase 3 study compared the combination important research efforts concentrate on the identification of other the fact that we do not understand to what extent the survival benefit for the by retrospective HPV and p16 immunohistochemistry (as a surrogate for of radiation and cetuximab with standard radiation alone for patients with treatment targets in HNSCC. For each of these targets, new compounds—eg, HPV-positive patient depends on the therapeutic approach. Are we exposing specific HPV testing) among many sites in several trials, and specifically in locoregionally advanced head and neck squamous cell carcinoma. This study monoclonal antibodies and tyrosine kinase inhibitors—have been developed, a young population largely expected to survive cancer to treatment-related the populations at risk with oropharyngeal carcinoma in selected studies. revealed that patients who received cetuximab demonstrated a locoregional some of which are already registered for treatment of head and neck long-term morbidity without true therapeutic benefit? What do we know Several large trials have focused on p16 immunohistochemistry in the control and survival benefit compared with patients treated with radiation cancer—cetuximab. Others are under investigation. These new compounds about treatment response and HPV-status interactions? How should we absence of available HPV-specific data. p16 analysis is not equivalent to alone. At the same time, investigators were exploring the use of cetuximab have shown very different toxic effects compared with existing cytotoxic use this information to determine the optimum treatment approach while HPV positivity and is a heterogeneous prognostic factor. Up to 20% of p16 for patients with metastatic or recurrent head and neck cancer. Cetuximab drugs—eg, cutaneous, cardiovascular, gastrointestinal, and tiredness. These factoring in the effect of treatment on both survival and quality of life? positive tumours are HPV negative. HPV data are retrospectively available in was found to be an effective agent for these patients and recent studies systemic side effects have to be accounted for to apply such long-term three large randomised trials and prospectively in a phase 2 trial; all studies demonstrated that cetuximab in combination with cisplatin enhanced chronic treatments. Combined radiotherapy has very specific local toxic have demographic data that HPVOPC patients are healthier, have a better survival compared with cisplatin alone. Over the past few years, investigators effects compared with cetuximab in head and neck cancer. Reported benefits performance status, and are less prone to secondary environmental cancers have identified a new role for induction chemotherapy in locoregionally of these new compounds are largely superior to the toxic effects; oncologists than environmentally related cancers, and that HPV positive tumours advanced head and neck cancer. Regimens using taxanes in combination should find the best way to manage this fragile balance. respond more completely to treatment. All trials show improved local and with cisplatin have demonstrated significant efficacy for these patients. regional control as the main difference in outcome. Surgical resection alone Additionally, investigators have begun to use anti-EGFr therapies at the also results in an improved outcome in patients with HPVOPC. Current trials time of induction chemotherapy and during radiotherapy. Cetuximab will and treatment algorithms must be re-examined in view of the importance be reviewed as an example of targeted therapy. of stratification or selection for HPV and p16 expression, as well as the effect of smoking behaviour on outcome of treatment for HPVOPC. Trials have been initiated to assess reductions in treatment of patients with HPVOPC. The challenge we face will be the analysis of retrospective studies—wherein surgery, chemoradiotherapy, and sequential therapy all result in very high survival outcomes—to establish the future direction of research and the current standards of care for HPVOPC. Integral to our analysis, we will want to make careful assessments of: patient-selection criteria and trial design and protocol adherence; the short-term outcomes of surgery, chemoradiotherapy, and sequential therapy; and long-term survival, patterns of failure, morbidity, mortality, and overall risk for disease and treatment- related events. 26 27 Speaker Abstracts The importance of 'window Long-term efficacy of human papillomavirus Ecological competition of vaccine and non- Human papillomavirus testing of opportunity' studies vaccination against hard end-points: vaccine type human papillomaviruses before in the developing world cancer-registry-based follow-up of phase 3 and after mass vaccination Amanda Psyrri efficacy trials John Sellors University of Athens, Greece Matti Lehtinen, Marjo Kaasila, Marko McMaster University, Canada The optimal evaluation of HPV- targeted therapies requires the integration Jorma Paavonen, Mohsin Rana, Eero Pukkala Merikukka, Proscovia Namujju, Heljä-Marja A WHO meeting of experts concluded that the use of human papillomavirus of pharmacodynamic assays into early clinical investigations. Phase '0' and Matti Lehtinen Surcel, Johanna Palmroth, Jorma Paavonen (HPV) DNA testing for primary screening will be at least as effective as trials can provide a platform to investigate immune correlates of treatment cytology, and consequently an affordable HPV screening test, which is University of Helsinki, University of Tampere, Finnish Cancer Registry, Universities of Tampere and Oulu; National Institute for Health & Welfare, Oulu; failure in vaccine studies, evaluate biomarkers for drug effects, and provide appropriate for public health programmes in low-resource settings, should be Helsinki, Finland University of Helsinki, Finland pharmacokinetic data. Monitoring HPV vaccine impact on biological achieved. PATH, a non-profit global health organisation has led a project to outcomes is a challenging task and plays an essential part in establishing the While phase 3 studies have shown that vaccination against human Replacement of multivalent vaccine covered serotypes of a microbe by non- develop and then clinically assess two simple, rapid, and portable biochemical benefit of vaccination, monitoring the progress of vaccination programmes, papillomavirus (HPV) types 16 and 18 prevents persistent HPV type16 and vaccine serotypes of the same microbe is abolishing effectiveness of, for tests that are inexpensive, acceptable to women and health-care providers, and yielding data to inform vaccination and disease prevention policies. For 18 infections and most high-risk HPV type positive cervical intraepithelial example, pneumococcal mass vaccination. To understand likelihood of type- safe, accurate, reliable, and appropriate for use in low-resource settings. The this purpose, the US National Cancer Institute has transferred technology neoplasia (CIN) grade 2+ lesions, long-term follow-up of the phase 3 cohorts replacement following vaccination against human papillomavirus (HPV) careHPV test (Qiagen, Gaithersburg, MD) detects oncogenic HPV DNA, and a to Costa Rica, such as state-of-the-art laboratories and a biorepository to is important to prove that HPV type 16 and 18 vaccination prevents cervical types 16 and 18 we studied competition of genital HPV types by assessing strip test (Arbor Vita Corporation, Sunnyvale, CA) detects the E6 oncoprotein support a phase 3 clinical trial evaluating the efficacy of HPV 16/18 vaccine. carcinoma in situ and invasive carcinoma. occurrence of multiple infections caused by the seven most common genital biomarker. The careHPV test performed adequately in a large clinical study. Indeed, the kinetics and phenotype of induced T-cell responses have been HPV types 6, 11, 16, 18, 31, 33, and 45 in fertile-aged Finnish women Although the strip test is still in field testing, the E6 biomarker might allow We used data from the Finnish cancer registry for passive follow up of associated with success or failure of vaccination. For example, HPV16-specific between 1995–2004. Paired first trimester serum samples, from two providers to differentiate between women who are only infected with HPV cluster (age cohort) and individually randomised cohorts of women born in proliferative responses such as cytokine levels and HPV16-specific CD4(+) consecutive pregnancies (mean 2·5 years apart) were retrieved for a random and those who are developing cervical neoplasia. 1984–89 to assess incidence rates of cervical carcinoma in situ and invasive CD25(+)Foxp3(+) T cell population have been correlated with the clinical 3100 subsample of 123 000 women belonging to the Finnish Maternity carcinoma in HPV-vaccinated cohorts in the FUTURE II (Merck &Co. Inc.) In developing countries, there are several challenges to widespread adoption efficacy of therapeutic vaccination. Particularly, a high ratio of HPV16-specific Cohort. 42% had antibodies to at least one HPV type at the baseline. Highly (N=874) and PATRICIA (GSK Biologicals) (N=2404) trials, and a reference of such molecular tests and maximizing their effect on cervical cancer. Before vaccine-prompted effector T cells to HPV16-specific CD4(+)CD25(+)Foxp3(+) significant increases in incidence rate ratios (IRR), indicating an increased cohort (N=7049) from the same communities. After completion of the incorporating a test into national or regional cervical cancer prevention T cells has been shown to predict for clinical success. risk of seroconversion to another HPV type, were consistently noted for trials the cohorts were linked with the Finnish cancer registry using personal strategies, policy makers need evidence that this new test is feasible, cost- HPV33 in both baseline HPV16 and HPV18 antibody-positive women: HPV16 To summarise, 'window of opportunity' studies could identify therapeutic identifiers. A pilot study in 2009 showed that the baseline incidence of CIN3+ effective, and appropriate for their health-system infrastructure and their >16 antibodies— and 33 antibodies (IRR 3·2, 95% CI 2·0–5·2) and HPV18 failures early, and might compress timelines for development of HPV- was 41 per 100000 women years. Assuming that incidence increases as the geographical, cultural, and economic circumstances (compared with other >18 antibodies— and 33 antibodies (3·6, 2·1–5·9); irrespective of the presence targeted approaches. We expect that such trials will become a routine part of cohorts age, the baseline incidence yields 80% power to show 70% vaccine screening approaches). Additionally, private industry needs help navigating of antibodies to other HPV types at baseline, HPV16 antibodies only— >16 early-phase therapeutic vaccine development in the future. efficacy against cervical carcinoma in situ and invasive carcinoma in less than the complexities of product introduction to the public sector of developing and 33 antibodies (2·9, 1·6–5·4) and HPV18 antibodies only— and 33>18 10 years. Because the phase 3 trials included intensive clinical follow-up and countries, which is generally perceived as a high-risk, low-return market. The antibodies (2·5, 1·1–60), but not for the other HPV types. This suggests a health education, which might have modified subsequent risk of cervical results of research on introduction of molecular tests in low-resource regions competitive advantage for HPV33 over other common HPV types before the neoplasia, validation of incidence rates of cervical carcinoma in situ and will be presented. era of HPV mass vaccination. invasive carcinoma in the HPV vaccine cohorts and the reference cohort, not exposed to clinical intervention, will be critical. For such validation, To explore type replacement related to HPV mass vaccination using a comparison of the incidence rates in the FUTURE II and PATRICIA study prophylactic HPV type 16 and 18 virus-like particle vaccine (GSK Biologicals, participants who received placebo or control (hepatitis A) vaccine at the Rixensart), with documented cross-protective efficacy against HPV types 31 baseline, and received no cross-vaccination at the study end, will be made. and 45, we are assessing whether the IRR of non-vaccine high-risk HPV types is significantly different in the HPV type 16 and 18 vaccinated women as Initial results from cancer-registry linkage of the randomised cohorts, which compared with hepatitis A-vaccine recipients. In a sizeable phase 3 trial sub- produced up to 40000 women years of follow-up data for HPV vaccine cohort of initially 4808 16–17 year-old Finnish women, the HPV type 16 and 18 cohorts and reference cohorts, will be reported. vaccine coverage ranged between 1% and 20% by age cohort in the 18 study These findings will be important to establish passive follow up for the site communities. Our study is the first attempt to assess the likelihood of HPV determination of HPV-vaccine efficacy against the hard end-points. type-replacement following HPV mass vaccination in a randomised setting. 28 29 Speaker Abstracts use of biomarkers in human papillomavirus is human-papillomavirus infection Therapeutic human papillomavirus vaccines Prevalence, natural history, and transmission screening programmes prognostic, predictive, or both? of oral human papillomavirus in relation to Cornelia Trimble oropharyngeal cancer Nicolas Wentzensen Lisa Licitra Center for Cervical Disease, Johns Hopkins, Baltimore, USA Division of Cancer Epidemiology and Genetics, National Cancer Institute, Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto nazionale Human-papillomavirus (HPV) associated intraepithelial neoplasias are Gypsyamber D'Souza Bethesda, MD , USA dei Tumori, Via Venezian 1, Milano, Italy lesions that should be susceptible to an HPV-specific T-cell immune response. Johns Hopkins Bloomberg School of Public Health, USA Randomised trials have shown that human papillomavirus (HPV) DNA HPV positivity is recognised to be a biomarker for oropharyngeal cancer. Indeed, a substantial percentage of cervical intraepithelial neoplasias (CIN) Oral human papillomavirus (HPV) infection is recognised as an important testing can be efficiently used in primary cervical cancer screening. Several Biomarkers can be broadly classified as prognostic (associated with disease grade 2 or 3 regress, and findings from clinical trials testing therapeutic cause of head and neck cancer, primarily oropharyngeal cancers. While challenges need to be addressed when restructuring current cytology- outcome) or predictive (associated with tumour response). A prognostic vaccination and also topical imiquimod for vulvar intraepithelial neoplasia the overall incidence of head and neck cancers has declined in the past based screening programmes: first, although HPV DNA testing has very marker is able to separate a certain population according to the outcome (VIN) show that a subset of VIN can also regress. However, immune responses few decades, the incidence rates for oropharyngeal cancers has increased, good sensitivity for detection of cancers and cancer precursors, and its high of interest in the absence of treatment or despite standard non-targeted to HPV antigens required for disease initiation and persistence, measured in especially in men under the age of 60 years. Despite this risk, oral HPV negative predictive value allow extended screening intervals, it cannot treatment. A predictive marker, on the contrary, separates a population the blood, do not reliably predict regression of intraepithelial lesions, either infection has not been well studied, and risk factors for infection and the discriminate between an innocuous transient infection and a prevalent high- according to outcome in response to a targeted treatment. Survival of patients in unvaccinated or vaccinated cohorts. Memory T cells preferentially circulate natural history of these infections are not well understood. grade lesion. A good triage strategy needs to be developed to decide which with HPV-associated head and neck tumours has been analysed in a meta- in the tissue in which they encountered their cognate antigen. Tissue- women with HPV need to undergo further assessment. Second, up to 50% of analysis, which showed a low risk of dying (hazard ratio 0·85) and a low risk resident T cells are antigen-experienced, are predominantly effector memory Initial studies suggest oral HPV prevalence in the general population is low prevalent precancers might be missed using conventional colposcopy-biopsy of recurrence (0·62) in patients with HPV-positive tumours. Different reasons cells, and have a partially activated phenotype. Immediate challenges for (4·5%), with oral HPV type 16, responsible for 95% of HPV-associated head procedures. New clinical algorithms and biomarker discovery and validation of favourable survival outcome have been postulated, which include intact development of therapeutic HPV vaccines include eliciting HPV-specific and neck cancers, prevalent in 1·3% of adults. Oral HPV infection is detected studies need to address these limitations of disease ascertainment. Third, apoptotic machinery in response to radiation and possibly chemotherapy, effector cell responses that are capable of trafficking to and accessing the in 1–2% of children, supporting some non-sexual transmission. Prevalence vaccination against HPV type 16 and 18 greatly reduces the number of cancer absence of field-related secondary cancer, immune-system activation by target tissues; questions that remain to be answered include how T cells increases with age and is higher in women with genital HPV infection and precursors, whereas low grade abnormalities, frequently caused by other viral specific tumour-associated antigens, and effects of radiotherapy or home to the genital tract and head and neck mucosae, how they are retained, individuals infected with HIV than in the general population. The natural types, are less affected. As the signal-to-noise ratio is reduced, identification chemotherapy. In patients with HPV-positive tumours, those able to mount a how they are functionally polarised at the initial antigenic exposure, the history of oral HPV infection is unknown, and whether the well established of new biomarkers with strong discriminatory values is important. Currently, serological immune response against viral E6 or E7 have improved outcomes. degree of elasticity of polarisation of tissue T cells, and how lesion-mediated natural history of cervical HPV is similar for HPV in the oral cavity, which has a several biomarker candidates are being investigated in clinical trials. The most Improved outcome has been reported for patients undergoing primary surgery mechanisms of immune evasion can be identified and circumvented. Clinical distinct immunological environment, is unclear. widely studied markers are HPV mRNA and p16. Recently, several promising for oropharyngeal cancer. Moreover, improved outcome has been reported trials testing immune therapies for HPV disease should incorporate the study Evidence strongly supports the sexual transmission of HPV to the oral region; host gene-methylation markers have been proposed. Biomarker validation for most measures of outcome, including overall survival, progression-free of tissue measures of immunological parameters, and systemic measures of however, because sexual behaviours are colinear (related), establishing which studies need to focus on the effect of biomarkers on risk stratification in the survival, local-regional control, and second primary tumours—except for immune response. behaviours are involved in transmission and the level of risk each might pose study population early on during the assessment process. distant metastases for more than 400 patients with oropharyngeal cancer is difficult. Initial studies suggest that oral HPV can be sexually transmitted undergoing primary concomitant chemoradiation in a randomised phase 3 between couples and that spouses of cervical cancer patients have increased study, which showed that treatment intensification might be useless, especially rates of oropharyngeal cancer. in HPV-positive oropharyngeal tumours. Despite improved outcome, studies reported a trend towards advanced N-stage HPV-positive tumours. This finding confirmed, together with advanced T-stage HPV-positive tumours, possible effects on the risk of distant metastases. HPV-positive tumours showed a statistical improvement of response rates with chemotherapy and organ preservation data, disease-free survival, and improved survival. One study pointed out that response rate to induction chemotherapy is associated with HPV16 gene copies quantified in the single tumour. The same observation was made in p16 tumour staining, which is now recognised as an effective and reliable marker of HPV positivity in head and neck cancer. Indeed, p16 immunohistochemical expression has been strongly correlated with in-situ hybridisation and HPV-gene expression through PCR analysis. Smoking status—categorised as never smoked, past smoker, current smoker, or by packs smoked per year—has been associated with the outcome of patients with HPV-positive oropharyngeal cancer. An inverse correlation between epidermal growth factor receptor (EGFR) expression and smoking exists, suggesting a role of the EGFR pathway in determining prognosis. Association between HPV positivity and tumour response to EGFR inhibitors has not been reported. 30 31 Speaker Abstracts Human-papillomavirus-specific genetic Neck dissection in the surgical management Human papillomavirus infection in Racial survival disparity in head and neck markers in human-papillomavirus-associated of oropharyngeal cancer: controversies pregnancy: issues related to prophylactic cancer is attributable to low prevalence head and neck and cervical cancers and outstanding questions and treatment strategies of human papillomavirus in black patients with oropharyngeal cancer—university Peter J F Snijders ian Martin Jorma Paavonen, Matti Lehtinen of Maryland experience. Department of Pathology, VU University Medical Center, Amsterdam, National Confidential Enquiry into Patient Outcome and Death, London, UK University of Helsinki; University of Tampere, Finland The Netherlands Organised mass screening programmes have been effective in reducing cervical This presentation reviews published works to examine the evidence for and In addition to cervical carcinomas, a subset of head and neck squamous cell against the use of neck dissections in the management of oropharyngeal cancer incidence rates. However, screening policies are highly variable, mirrored K J Cullen, S S Patel, L M Schumaker, K Settle, carcinomas (HNSCC), particularly those of the oropharynx, can be attributed squamous cell carcinoma. The primary aim of this review is to establish by highly variable incidence rates. With screening programmes, the disease S iqbal, Tan Ming, S Strome Scott, M Suntha, burden has shifted to cervical intraepithelial neoplasia (CIN). Cervical procedures to high-risk human papillomavirus (HPV), predominantly HPV type 16. whether there is any difference in outcome between treatment strategies in for management of CIN increase the risk for adverse pregnancy outcomes O Goloubeva However, not all HNSCCs with PCR-detectable HPV DNA display E6 and E7 terms of survival and local control or functional outcome and quality of life. mRNA expression. Expression of E6 and E7 mRNA is a sign of a biologically The question of whether HPV status is of value in determining the treatment (APO), ie, preterm birth. Phase 3 studies have shown that vaccination against University of Maryland Marlene and Stewart Greenebaum Cancer Center, USA human papillomavirus (HPV) types 16 and 18 prevents most persistent HPV relevant infection. HPV type 16 DNA positive HNSCCs with E6 and E7 regimen will be addressed. We recently showed that the reported racial survival disparity in head and type 16 and 18 infections and high-risk HPV type related high grade cervical transcripts can be genetically distinguished as a specific subgroup, whereas neck cancer is limited to the site of oropharyngeal cancer and this is due to a There is wide variation in the range of primary sites and stages of disease. intraepithelial neoplasia (CIN2 and 3) lesions. HPV vaccines significantly decrease those without E6 and E7 transcripts have a similar genetic signature as HPV much lower incidence of favourable human papillomavirus (HPV)-positive Most studies are retrospective reports of small unmatched samples, and abnormal cytological findings, colposcopy referrals, colposcopy biopsies, and DNA negative HNSCCs. To detect biologically relevant HPV infections in oropharyngeal cancer in blacks than in whites. followed up over short periods. Bias is often present in case selection. cervical excisional procedures. This has a serious effect on reproductive health, tumour tissue specimens, p16INK4A immunostaining, a highly sensitive but since patients with CIN are generally young. Prophylactic virus like particle With the recent increase in popularity of function sparing chemoradiation, To confirm the difference reported in the prevalence of HPV infection not 100% specific marker for transforming HPV infections, followed by high- HPV vaccines do not contain live virus, but the safety of vaccinating pregnant temporal bias might also occur. Where neck dissection has been used, there between blacks and whites, we did a retrospective analysis of 305 patients risk HPV PCR or in-situ hybridisation assays, seem most promising. women has not been established. Neither of the currently available HPV vaccines is wide variation in the extent of nodal dissection, and no clear definition of with oropharyngeal cancer treated at our institution between 1995 and 2007. To establish whether HPV-associated squamous cell carcinomas arising the selective techniques used. Wide variation also exists in histopathological are recommended for use in pregnancy. Because the main target population Of the 305 patients identified for this study, 176 (58%) were white and 129 from different organs have specific chromosomal alterations in common, methods and reporting, and in the application of adjuvant management of prophylactic HPV vaccination is young women of reproductive age, and to (42%) were black. 253 (83%) patients were men. 238 (78%) of patients had array comparative genome hybridisation profiles of cervical squamous cell strategies and the ordering and timing of adjuvant treatments. minimise the risk of exposure during pregnancy, all clinical trial participants have stage 4 cancers. HPV type 16 status is known for 166 (54%) of 305 patients. been asked to use effective birth control during the vaccination phase, and a carcinomas and HPV (DNA and RNA) positive and negative HNSCCs were Median survival for white patients was 47 months (95% CI 34·8–69·5) versus Taking account of all the limitations of this review, there does appear to be pregnancy test has been done before vaccination. Those with a positive test have compared. Unsupervised hierarchical clustering resulted in one mainly 24 months in blacks (15·0–29·1; p=0·003). Of patients with known HPV evidence for the balance of probability that neck dissections are an effective not been vaccinated. However, many women were or became pregnant during HPV-positive cluster and one mainly HPV-negative cluster. Generally, HPV- status, 49 of 100 white patients were HPV positive, whereas only 11 (17%) of treatment modality, and that the selective neck dissection confers substantial the vaccination phase. We now provide an updated analysis of the pregnancy negative HNSCCs showed more altered regions. Chromosomal gains of 66 black patients were HPV positive (p<0·0001). Median survival for all HPV- benefit over comprehensive neck dissection in terms of functional outcome outcomes for such women enrolled in the phase 3 trials of the two HPV vaccines. 3q24–29 and losses of 11q22.3–25 were common throughout, irrespective of negative patients was 14 months (10·3–27·1), whereas median survival for all without compromising disease control. For active follow up regarding APO, we combined data from five phase 3 trials HPV presence or organ. Loss at 13q21 and gain at 20q were more common HPV-positive patients was 93 months (37–NR; p<0·0001). In a multivariable in HPV-positive squamous cell carcinomas of both organs. Within the group (N=20551) of the quadrivalent HPV type 6, 11, 16, and 18 vaccine (Gardasil, Cox analysis, HPV status had the most substantial effect on survival, but race Merck & Co., Inc, Philadelphia), and two phase 3 trials (N=26130) of the of HPV-positive carcinomas, HNSCCs frequently showed gains of multiple remained an important independent prognostic indicator. bivalent HPV type 16 and 18 vaccine (Cervarix, GSK Biologicals, Rixensart). In regions at 8q, whereas cervical squamous cell carcinomas often showed loss the Gardasil trials, a total of 3620 women became pregnant—1796 women This study confirms, in an independent data set, our findings that the at 17p. The existence of HPV-specific alterations in squamous cell carcinomas in the vaccine arms and 1824 women in the placebo arms. In the Cervarix prevalence of HPV-positive oropharyngeal cancers is much lower in blacks of different anatomical origins, suggests that these alterations are crucial for trials 4710 women became pregnant, and 3599 had intrauterine pregnancies than in whites, and that this difference contributes significantly to overall HPV-mediated carcinogenesis. eligible for analysis—1786 in the vaccine arms and 1813 in the hepatitis A racial survival disparities in head and neck cancer. vaccine (control) arms. For passive follow up regarding APO, we linked the registries of the vaccination trial participants from Finland receiving either Gardasil (N=874) or Cervarix (N=2408) and the Finnish birth registry. The HPV vaccines were generally well tolerated by pregnant women, and no association was found between the vaccines and APO. Active follow up in the clinical trials overall showed no evidence of association between HPV vaccination and risk of miscarriage or other adverse pregnancy outcomes. The pregnancy outcomes in general did not vary between the study arms. Similarly, congenital anomalies detected were evenly distributed between the study arms, and were diverse and consistent with those reported in the general population. The first birth registry linkage results of the passive follow-up of cohorts of the HPV vaccinated and reference cohorts, which produced up to 40 000 women years of follow-up data, will be presented. Systematic reviews and meta-analyses have shown an association between excisional procedures to treat CIN and APO. Thus, counselling and caution in the treatment of young women for cervical abnormalities is recommended, and unnecessary treatment should be avoided. Established pregnancy registries and postmarketing surveillance will provide further long-term data which is critical when millions of young women will be vaccinated against HPV. 32 33 Speaker Abstracts Prevention and treatment approaches to Circumcision, or human papillomavirus Radiotherapy in human papillomavirus Rationale for reduction of radiation anal intraepithelial neoplasia and anal cancer vaccination, or both, in men for prevention infected head and neck and oral dose in human papillomavirus-related of anogenital and oral cancers: possible pharyngeal cancers oropharyngeal cancer Joel Palefsky justification for a future trial of second UCSF School of Medicine, USA generation human papillomavirus vaccines Pernille Lassen Marshall R Posner Like cervical cancer, anal cancer is strongly associated with human Department of Experimental Clinical Oncology, DK-8000 Aarhus C, Denmark The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA papillomavirus (HPV) infection. Anal cancer is preceded by high-grade anal RTD Oliver, L Battery During the past 30 years the incidence of oropharyngeal cancers in the Human papillomavirus related oropharyngeal cancer (HPVOPC) is epidemic intraepithelial neoplasia (HGAIN, AIN 2+). There is no routine AIN screening Western world has increased by five times, and infection with HPV seems in North America and Europe. HPVOPC is a unique disease with a different Institute of Cancer, Barts and The London Medical School, and treatment programme to prevent anal cancer that is similar to the cervical to be the predominant cause for this development. Most patients with prognosis, affecting a different population than previously encountered in Queen Mary University of London, UK intraepithelial neoplasia screening programme to prevent cervical cancer. oropharyngeal cancers are treated with radiotherapy and tumour HPV- head and neck cancer. Patients are young, without significant co-morbidities Treatment of HGAIN is primarily ablative through methods such as infrared Vaccination of boys against human papillomavirus (HPV) will never be positivity is a favourable prognostic factor for radiotherapy outcome. When and risks. Survival at 5 years approaches 70–80% with aggressive treatment. coagulation, and is associated with high recurrence rates. In the long-term, economical in its own right if assessed from the point of view of the health treated with primary radiotherapy alone the 5-year risk of locoregional Improved survival is related to improved local-regional control. Although reduction of anal cancer might therefore be best achieved through prevention economics of cervical cancer. However, if such vaccination prevented other tumour failure in HPV-positive tumours is reduced to a third compared with acute treatment-induced morbidity and mortality are important, the of anal HPV infection and AIN through prophylactic HPV vaccination. cancers, even if only a subset, and were able to alter a surrogate endpoint that of HPV-negative tumours. Likewise, for disease-specific survival and long-term consequences of chemotherapy, surgery, and radiotherapy within less than 5 years of vaccination, the balance of the economical case will In the Merck 020 trial, 598 men who have sex with men (MSM) aged 16–26 overall survival the benefit in favour of HPV-positivity is of similar scale, and are increasingly critical in assessing the ultimate risks and benefits of swing more strongly towards a changing view of vaccination for both sexes. years were randomised to receive quadrivalent HPV (types 6, 11, 16, and 18) the outcome in HPV-positive tumours is substantially improved compared treatment. Late side-effects of chemotherapy are varied and are determined Given the longstanding relationship between circumcision and prevention vaccine or placebo at enrolment, month 2, and month 6. Efficacy analyses with HPV-negative tumours. Thus, tumour HPV status is the strongest by drug selection. Commonly used drugs such as taxanes, platinums, and of cervical cancer, this review examines the geographical incidence and were done in a per-protocol population (seronegative at day 1 and DNA- known independent prognostic factor determining tumour control and fluoropyrimidines have few long-term side-effects and an established record mortality statistics for prostate and cervical cancers and the results from negative from day 1 through month 7 to the relevant vaccine HPV type). survival in single-modality primary radiotherapy of head and neck cancer. from which to extract data. For new compounds and biologics, particularly recent successful randomised trials of circumcision preventing HIV infection. Median follow-up was 2·5 years (post-dose 3). Vaccine efficacy against HPV Response to intensive treatment schedules that combine radiotherapy and when used with other modalities or drugs, late consequences have not had We also consider possible surrogate endpoints in their natural history that types 6, 11, 16, and 18 related AIN in MSM was 77·5% (95% CI 39·6–93.3; chemotherapy is also strongly influenced by tumour HPV status, again with a time to become apparent. Consequences of surgery as monotherapy seem could be assessed in future trials of second generation HPV vaccines. five vaccine cases versus 24 placebo cases). Efficacy against AIN1 was 73% substantial benefit in favour of HPV positivity. Apparently treatment-related to be almost fully vested in the initial encounter. Radiotherapy, with or (16·3–93.4), and efficacy against anal warts was 100% (8·2–100). Efficacy Though deaths from cervical cancer are lower in Saudi Arabia, Israel, and benefits and risks could be used separately on the basis of tumour HPV-status without chemotherapy, is a mainstay of current curative treatment and has against AIN 2+ was 74·9% (8·8–95·4). the USA (0.9, 2.1, 1.7 x 105) compared with Brazil and India (10.9, 15.2 x to secure optimum treatment outcome and to avoid unnecessary treatment- substantial, cumulative, late consequential mortality and morbidity. Late 105), other low circumcising nations—Denmark, Japan, and China (2.5, 2.6, induced morbidity in both HPV-positive and HPV-negative tumours. radiation toxic effects are dose and volume dependent hence a reduction These results show that the quadrivalent HPV vaccine is efficacious in 4.9 x 105)—have lower death rates than high circumcising nations, such as of dose and volume would be expected to reduce late morbidity. Based preventing AIN, including AIN 2+ related to HPV types 6, 11, 16, and 18, Bangladesh and Pakistan (17.9, 12.9 x 105). For prostate cancer, the lowest on results from phase 3 clinical trials, chemoradiotherapy increases local- in MSM naïve to vaccine HPV types at enrolment. HPV vaccination might death rates are in Denmark, Japan, and China (2.5, 5, 1.8 x 105) compared regional control out of proportion to the cost in additional late morbidity. be an important tool for anal cancer prevention in at-risk individuals. with high circumcising nations, such as Saudi Arabia, Israel, and the USA Consideration of radiation as a drug that can be synergistic when combined (5.1, 7.6, 9.7 x 105). India, Bangladesh, and Pakistan (2.5, 1.2, 4 x 105) with other drugs is a key paradigm shift. Reduction of the dose of radiation show similar low death rates from prostate cancer despite differing policies during chemoradiotherapy and administration of additional drugs with on circumcision, whereas Brazil with a low circumcision policy has one of non-overlapping acute and minimal late toxicity to balance radiotherapy the highest death rates (16.3 x 105). A meta-analysis of circumcision and reductions can be tested as a means to increase survival and moderate prostate cancer incidence from five studies (1621 cases and 1499 controls) morbidity. Induction chemotherapy and sequential chemotherapy improve showed an odds ratio of 0.86, whereas three papers comparing Jewish local-regional control compared with radiotherapy. Across phase 3 trials there verses non-Jewish prostate cancer incidence in 2878 Jewish versus 40 768 is improved late mortality and morbidity when induction chemotherapy non-Jewish patients showed an odds ratio of 0.25. Although the WHO/IARC is compared with full dose chemoradiotherapy. We can use the gains in report on vitamin D and cancer failed to show a correlation between a single survival and local-regional control from different components of multimodal spot vitamin D level and later occurrence of prostate cancer, four studies treatment to plan radiotherapy as part of a combined modality treatment— that recruited 1748 cases and 8939 controls found consistently significant with surgery and chemotherapy—and increase or decrease radiotherapy, association between an index of long-term sun exposure and prostate cancer depending on patient and tumour factors, to maximise disease control while risk (OR 3.03, 3.31, 1.41, and 1.24). Pre-existing HPV infection increases minimising late morbidity in HPVOPC. while Muslim cultural background decreases HIV acquisition in the African circumcision trials. Access to sanitation is shown to decrease cervical and penile cancer in Denmark, Brazil, India, and China. These data suggest that by including males in global trials to demonstrate the value of the second generation HPV vaccines, that also sub-randomise the trial subjects to differing policies regarding genital hygiene and that use PSA at the age of 18 years as a surrogate for later prostate cancer occurrence, we could begin to better understand and reduce the differences identified by this analysis. The data could be further enhanced by including questionnaires regarding circumcision status and sun exposure as well as taking blood samples for vitamin D level at enrolment and at 18 years. 34 35 Speaker Abstracts HPV infection in HiV-positive host: molecular interactions and clinical implications Joel Palefsky UCSF School of Medicine, USA The incidence and persistence of anogenital human papillomavirus (HPV) infection and HPV-associated precancerous lesions are increased in HIV- seropositive individuals compared with the general population. Consistent with this, the incidence of HPV-related anal cancer is increased in HIV- seropositive men and women, as is cervical cancer in HIV-seropositive women. However, the incidence of HPV-related cancers in HIV-seropositive individuals has not declined since the introduction of antiretroviral treatment and might instead be increasing as they live longer. Multiple mechanisms might underlie such an increase. The systemic and local immune response to HPV could be affected by HIV-mediated immune attenuation, and local cytokine perturbations might play a part at the tissue level. However, the lack of response to antiretroviral-treatment-associated immune reconstitution suggests that this is not the entire explanation. Direct molecular interactions at the tissue level might occur between HIV and HPV. HIV might upregulate early region HPV gene expression; and HPV and HIV infection might both disrupt tight junctions of mucosal epithelium and facilitate infection with the other viruses. Recent reports show that anogenital HPV infection is associated with increased risk of HIV infection. Clearance of HPV was implicated in HIV acquisition, suggesting that the influx of immune cells associated with HPV clearance might be involved. HPV might therefore cause morbidity and mortality through causation of squamous cell cancers, but also by increasing the risk of HIV infection. If confirmed, HPV vaccination might be useful for reducing the risk of both HIV infection and HPV-associated cancers. 36 37 Poster Abstracts Poster 1 Visual inspection with acetic acid (ViA) and lugols iodine (ViLi) is a feasible screening tool for cervical cancer in rural india Poster 2 Visual inspection with acetic acid (ViA) compared with cytology and HPV DNA testing for cervical cancer screening, experiences at the university of Pavia, italy, B. Balaiah*, R. Lakshmi, D. Meenakshi, to increase screening and treatment at Lacor K. Vinaykumar, M. Kamatchi, S. Vijayakumar, Hospital, Northern uganda et al Tamil Nadu Health Systems Project, India P. Bayo*1, M. Cascella2, M. Roccio2, A. Spinillo2 Background St. Mary's Hospital, Gulu University, Uganda, 1 Available screening methods are cumbersome technically, both from the IRCCS-Fondazione Policlinico San Matteo, University of Pavia, Italy 2 patient's perspective and the infrastructure required. This stimulated the introduction Government of Tamil Nadu to look for an appropriate screening tool for Uganda, like other developing countries, has a high incidence of cervical cervical cancer in a low resource setting. cancer. Lacor hospital is collaborating with the University of Pavia to increase Method screening services in northern Uganda using VIA. Women within the age group 30–60 years were screened using a Objectives combination of Visual Inspection with Acetic acid (VIA) and Lugols Iodine To compare the sensitivity and specificity of VIA to that of cytology and (VILI) in two districts of Tamil Nadu, between February 2007 and January HPV-DNA testing so that it could be used as the cheaper and more feasible 2010. Women who tested positive were evaluated using colposcopy, followed screening method at Lacor Hospital, northern Uganda. by microscopic confirmation. Two strategies: a primary intervention aimed at creating awareness and achieving behavioural change; and a secondary Methods intervention aimed at screening with referral and management, were carried A doctor from Lacor Hospital travelled to the University of Pavia and trained out in all the Primary Health Centers, Government Hospitals, and Medical in colposcopy at department of Obstetrics and Gynecology San Matteo College and Hospital in the intervention districts. Hospital, carrying out VIA, pap smear cytology and HPV DNA tests for the patients attending the colposcopy clinic. The sensitivity and specificity of the Results three screening tests were calculated. A total of 196,559 women in Theni and 291,525 women in Thanjavur were screened using VIA/VILI. Of the 2.59% VIA/VILI positive women in Theni, Results 62.8% underwent colposcopy (98.6% – satisfactory; 1.4% – unsatisfactory), A total of 138 women were examined with VIA, of which 26.8% were and 46.6% had a biopsy. Of the 5.4% VIA/VILI positive women in Thanjavur, positive. 130 (94.2%) had cytology results available and 93 (67.4%) had HPA- 54.5% underwent colposcopy (80.6% – satisfactory, 19.4% – unsatisfactory), DNA test results available. VIA showed an 80% sensitivity in detecting a high 55.8% had a biopsy and 28.7% had ECC. In total, 16.2% in Theni and 21.7% grade lesion compared with 88.9% for cytology and 100% for HPV- DNA in Thanjavur of the biopsy subjected women were confirmed with cervical tests, but it was the most specific (59%) compared to cytology (26.3%) and cancer, of which 31.5% in Theni and 54.9% in Thanjavur were treated. HPV-DNA tests (6.9%). Conclusions Conclusion The pilot proves VIA/VILI as a promising screening tool in low resource VIA has a comparable sensitivity in detecting high grade lesions to that of settings and demonstrates the potential for scale up of the programme in cytology and is even more specific than the cytology and HPV–DNA testing, and all other districts of the State, provided that the appropriate service delivery is therefore, recommended as the sole screening method for Lacor Hospital. strategies are practised for efficient follow up. Keywords Keywords VIA, HPV, cytology, sensitivity Cervical cancer, VIA/VILI, Theni, Thanjavur 39 Poster Abstracts Poster 3 Poster 4 Poster 5 Poster 6 Feasibility and potential application of brush Human papillomavirus prevalence and The effect of social deprivation on exposure Human Papillomavirus (HPV) L1 capsid cytology for detection of oropharyngeal genomic integration in situ and infiltrating to material promoting HPV vaccination: protein and HPV Type 16 as prognostic HPV-infection and HPV-related squamous cervical carcinoma by HiV status evidence from England markers in cervical intraepithelial neoplasia 1 cell carcinoma S. Videla*1, M-P. Cañadas2,3, L. Darwich2,4, C.M. Chivu*1, D.D. Reidpath2 y.S. Choi*, W.D. Kang, S.M. Kim, J.H. Nam, M.A. Broglie*, M. Pawlita, R. Schoenegg, G. Sirera1,5, F. Alameda6, B. Clotet1,5 et al Brunel University, United Kingdom, Monash University, Malaysia 1 2 C.S. Park, H.S. Choi W. Jochum, S.J. Stoeckli 1 Lluita Contra La SIDA Foundation, Spain, 2Retrovirology Laboratory-IrsiCaixa Background Chonnam National University Medical School, Republic of Korea 1 Department of Otorhinolaryngology, Head and Neck Surgery Kantonsspital Foundation, Spain, 3General Lab, Barcelona, Spain, 4Department of Sanitat i In 2008 the health departments of the United Kingdom implemented a introduction St.Gallen, Switzerland, 2Department of Genome Modifications and Carcinogenesis, Anatomia Animal, Autonomous University of Barcelona, Spain, 5HIV Clinical Unit, Human Papilloma Virus (HPV) vaccine campaign in schools to reduce the The aim of the study was to determine whether human papillomavirus (HPV) German Cancer Research Centre (DKFZ), Heidelberg, Germany, 3Institute of Department of Medicine, University Hospital Germans Trias i Pujol, Badalona, incidence of cervical cancer. This campaign, targeting adolescent girls, was L1 capsid protein and the HPV genotype can predict the disease course as Pathology, Kantonsspital St. Gallen, St. Gallen, Switzerland Spain, 6Department of Pathology, Hospital del Mar, Barcelona, Spain supported by the Royal Society for Public Health (RSPH) with educational prognostic markers for cervical intraepithelial neoplasia 1 (CIN1). Background materials for use in school curriculum. Background Methods The prevalence of human papillomavirus (HPV)-related oropharyngeal Human papillomavirus type prevalence, and particularly type HPV-16 in Study design Immunohistochemical staining was performed for HPV L1 capsid protein squamous cell carcinoma (OPSCC) is dramatically increasing. However, little cervical cancers of women with and without human immunodeficiency A cross-sectional study was conducted to examine the relationship between in 101 women who had been confirmed to have CIN1 by histology and HPV is known about the risk factors and the natural course of oropharyngeal HPV virus (HIV-1) infection is a current topic. area deprivation and the take-up of educational materials, related to HPV and high-risk infection by HPV genotyping. The disease course was analyzed infection, as well as its clinical and prognostic significance in OPSCC. This is in Objective cervical cancer and the HPV vaccination, by schools in England. by follow-up histology according to the HPV L1 capsid protein and HPV part due to the lack of adequate sampling methods. The aim of the study was To provide data on the HPV type prevalence and the viral integration Methods genotype over a minimum of 12 months. to validate the diagnostic potential of oropharyngeal brush cytology for the of HPV-16 and HPV-18 in cervical cancer by HIV status. The RSPH contacted 4,624 schools (enrolling girls aged 12–13 years) in Results detection of OPSCC, precancerous lesions and HPV infection. England, offering access to free-of-charge HPV educational materials, Study design CIN1 regressed spontaneously in 60.4% of the women; most cases of Methods Retrospective multicentre descriptive study of a cohort of HIV-positive including professionally developed teaching materials. The relationship regression occurred within 1 year (90.9% of regression cases). HPV L1 Brush samples and corresponding biopsies were taken from the tumor, normal women and a matched cohort of HIV-negative women. between the take-up of the educational materials and the level of social capsid protein-positive patients had a spontaneous regression rate of appearing mucosa around the tumor and distant mucosa in 11 patients with deprivation of the area within which the school was located was analysed 72.7% (48/66) and a rate of persistent disease or progression to higher Patients and Methods using logistic regression, including as covariates geographic location, school OPSCC undergoing panendoscopy. Cytological and histological analyses and grade disease of 27.3% (18/66). HPV L1 capsid protein-negative women Between 1987 and 2008, 31 HIV-infected women diagnosed as in situ or type, and school size. P16 immunostaining were performed using routine methods. Cytological had a regression rate of 37.1% (13/35), and a rate of persistent disease infiltrating cervical squamous cell carcinoma were identified, and 109 HIV- assessment was done according to the Bethesda guidelines. For HPV testing, Results or progression of 62.9% (22/35; p<0.001). HPV16-infected patients had negative subjects were matched by cervical histological diagnosis and age. the L1C1/2 method with sequencing was used. Serum samples were tested for Of the schools invited to receive the educational materials, 1,395 schools a regression rate of 38.6% (17/44) and a rate of persistent disease or HPV detection and typing was performed by multiplex fluorescent PCR and antibodies to the L1, E6 and E7 proteins of HPV types 16 and 18. (30.17%) responded. After controlling for other covariates, schools in the progression of 61.4% (27/44), whereas non-HPV16-infected patients HPV integration by multiplex real-time PCR. Results most deprived areas (the fourth and the fifth quintiles of deprivation) were had a regression rate of 77.2% (44/57) and a rate of persistent disease or Results the least likely (OR=.64, p<.000 and OR=.77, p<.017) to request materials, progression of 22.8% (13/57; p<0.001). Eleven consecutive patients, 4 females and 7 males with a mean age of The most common HPV type in HIV-positive versus HIV-negative women compared with the schools in the least deprived areas (the first quintile). 60 years (range 30–81) have been prospectively enrolled in the study. All Conclusion was: HPV-16 (60% versus 75%, OR:0·5, 95%CI:0.2–1.2), HPV-33 (17% versus brush samples contained sufficient cell material. The samples from the Discussion and Conclusion HPV L1 protein expression is closely related to spontaneous disease 8%, OR:2.4, 95%CI:0.7–7.9), HPV-52 (7% versus 2% OR:3.6, 95%CI:0·5–26·8), distant mucosa revealed neither cytologically nor histologically dysplastic Requests for educational materials supporting the HPV vaccination campaign regression, but HPV16 infection is related to persistent disease or progression HPV-58 (7% versus 5%, OR:1·4, 95%CI:0·2–7.6) and HPV-18 (7% versus 4%; or cancerous changes. In the normal appearing mucosa 3/11 histological were unevenly distributed across England, and the level of social deprivation to high grade lesions in patients with CIN1. OR=0.6, 95%CI:0.3–10.2). Prevalence of multiple HPV infections was 13% in samples showed high grade dysplasia compared to 6/11 cytological was significantly associated with the take-up of materials by schools. At HIV-positive and 17% in HIV-negative women. The integration of HPV-16 Keywords specimen. 9/11 brush samples and 11/11 biopsies from the tumor site least a part of the reason that educational activities are often less effective in was 39% in HIV-positive and 45% in HIV-negative women, and the HPV-18 HPV, L1 capsid protein, CIN, prognostic marker were positive for invasive carcinoma. The sensitivity, specificity, PPV and socially deprived areas is because the level of exposure is less, rather than that integration was 50% in both groups. NPV of brush samples compared to biopsy was 86%, 84%, 80% and 89%, the people are less responsive to these activities. This has specific implications respectively. In 9/11 (82%) patients the tumor was positive for HPV-high risk Conclusion for the delivery of education campaigns targeting HPV and cervical cancer types (8 HPV 16 and 1 HPV 16 and 33). Results of ongoing analyses of HPV- Our data suggest that although HPV-16 seems to be the most prevalent and the HPV vaccination through schools. detection and immuncytochemistry as well as HPV serology will be reported. type in cervical carcinomas in HIV-positive and HIV-negative women, a trend toward a lower prevalence of this type was detected in the HIV- The project Evaluation of HPV education programme of the Royal Society Conclusion of Public Health was funded by the Royal Society of Public Health. positive women. No differences have been observed for HPV-16 and HPV- Based on our preliminary results, brush cytology seems to be a feasible and 18 integration in cervical carcinomas in both groups. These data provide Keywords reliable method to detect pathological cellular changes in the oropharyngeal information about HPV-infection in cervical carcinoma in general and HIV HPV educational materials, area deprivation, school, England mucosa. population in Catalonia (Spain), one of the areas in the world with the lowest Keywords incidence of cervical carcinoma. Brush cytology, HPV, squamous cell carcinoma, oropharynx Keywords Cervical carcinoma, Human Papillomavirus type distribution, HIV-positive women, HPV infection 40 41 Poster Abstracts Poster 7 Poster 8 Poster 9 Poster 10 Acceptance and barriers of human Performance of the APTiMA high-risk CEACAM-1 expression in cervical tissues from Antiviral approaches to treat HPV-related papillomavirus vaccination in Chinese HPV mRNA assay in a referral population patients with recurrence lesion of cervical tumors : The institute Gustave Roussy female university students in comparison with Hybrid Capture 2 intraepithelial neoplasia 2 and 3 grade experience from preclinical data to clinical trials and cytology J.S.y. Chor*, K. Ngai, H. Lam, P.K.S. Chan A. del Toro Arreola*1, S.F. Velasco Ramirez1, E. Deutsch*, M-C. Vozenin The Chinese University of Hong Kong, Hong Kong A. Clad* , J. Weinschenk , J. Rahmsdorf , 1 1 1 A. Quintero Ramos1, S.A. Gutierrez Rubio1, Institut Gustave Roussy, France Purpose F. Schaffrath1, N. Freudenberg1,2 L. Flores Romo2, A. Daneri Navarro1 et al. The knowledge of high risk HPV implication in a significant proportion This study aims to investigate the factors associated with the acceptance Universitaets-Frauenklinik, Freiburg, Germany, 1 1 Universidad de Guadalajara, Departamento de Fisiologia. Guadalajara, Jal, of squamous cell carcinoma of the cervix, anus, head and neck raises the of human papillomavirus (HPV) vaccination in Chinese female university Institute of Pathology, University of Freiburg, Germany 2 Mexico, 2Centro de Investigacion y Estudios Avanzados del Instituto Politecnico question of biologically-driven therapeutic approaches for these tumors(1,2). students Nacional. Mexico, DF, Mexico, 3Clinica de Colposcopia, Hospital General Large-scale anti-HPV vaccination will require at least one or two decades Objective Regional No. 45, Instituto Mexicano del Seguro Social. Guadalajara, Jal, Mexico, before affecting the incidence of HPV-relative cancers. We have developed Methods To evaluate the ability to detect high-risk HPV mRNA and DNA in disease- 4 Universidad de Guadalajara, Salud Publica. Guadalajara, Jal, Mexico, 5Centro de an original approach aiming at sensitizing HPV-related tumors to ionizing This is a case control study using a self-administered questionnaire. Female positive LBC specimens (CIN2+). Estudios Especializados ARG, Instituto para el Fortalecimientos de las Capacidades radiation and chemotherapy using an antiviral agent Cidofovir. Cidofovir university students who had received HPV vaccination in a local vaccination Materials and Methods en Salud. Mexico, Mex, Mexico, 6Servicio de Patologia, OPD Hospital Civil de is a nucleoside analog. Combination of Cidofovir increases radiation campaign were invited to fill in the questionnaires. Controls matched with 424 clinical specimens (collected from patients with abnormal cytology and Guadalajara. Guadalajara, Jal, Mexico sensitivity in vitro and in vivo. Of interest, preclinical findings suggest their major studies were recruited from students who did not receive the controls after treatment) were stored in LBC vials at room temperature for that this radiosensitizing effect is HPV-dependant, suggesting a tumor HPV vaccination at the university. The questionnaires consisted of 5 parts: Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) up to 3 years. All LBC specimens were tested for E6/E7 mRNA of 14 high-risk relative specificity in the clinic. Exposure to Cidofovir indeed correlates with 1) demographics; 2) awareness and perception of HPV and related disease; is involved in several cellular functions such as angiogenesis, proliferation, HPV types in the APTIMA HPV (AHPV, Gen-Probe) and for high-risk HPV a decrease in HPV-related oncoproteins and a restoration of the tumor 3) acceptance and barriers of vaccine in general and HPV vaccine; 4) attitude morphogenesis, apoptosis, intercellular adhesion, tumor suppressor and DNA in the Hybrid Capture 2 (HC2, Qiagen) test. Results were compared to suppressor protein levels p53 and pRB(3). toward vaccination campaign; and 5) sexual and cervical screening practice. invasion promoter. Recently, CEACAM-1 has become the focus of intense cytology and histology. Data were analyzed by chi square and followed by logistic regression. immunological research due to its differential expression in several tumor In addition, exposure to cidofovir is associated with a sharp decline in Results tissues and immune cells. In cases of malignant transformation, a down- metastatic potential, reflecting the inhibitory effects on the cxcr4/SDF1 Results AHPV was positive in 148 out of 150 CIN 3 and 11 out of 12 cervical regulation or loss of CEACAM-1 has been shown in patients with cervical chemotactism as well as a restoration of the p53 inhibition on VEGF. 282 subjects who had been vaccinated against HPV in the campaign carcinoma specimens (sensitivity 98.1% for CIN 3+). The one cervical cancer. Currently, cervical cancer detection is mainly directed to identify completed the questionnaire with a response rate of 69.1%. 280 matched We also found that Cidofovir can also exert synergistic cell killing in carcinoma specimen missed by AHPV contained exclusively HPV 53, a type and treat CIN2-3. The rate of recurrence for CIN2-3 after treatment ranges controls completed the same questionnaire. Comparing the two groups, combination with antiEGFR targeted agents. Preliminary data of the first considered low-risk and not included in AHPV assay. HC2 was positive in 146 between 5% and 20%. We consider it important to measure the expression we have found that safety concerns, particularly because this was a new clinical trial combining Cidofovir to chemoradiation in the setting of HPV out of 150 CIN 3 and 10 out of 12 cervical carcinoma specimens (sensitivity of this molecule in patients with recurrence lesions and believe it could be a product was the main barrier to acceptance of this vaccine. Peer group was positive cervical cancer will be presented as well the strategy implemented to 96.3% for CIN 3+). One of the two cervical carcinoma specimens missed prognostic marker of recurrence and progression to cancer. the most influential factor in the student's decision. We found that there was treat metastatic HPV related tumors using antiEGFR combined to cidofovir . by HC2 contained HPV18, the other was HPV DNA negative in the Linear no association in the cervical screening practice and sexual behaviour with This study was intended to assess the CEACAM-1 expression in cervical Array HPV Genotyping test. Both specimens were positive in the AHPV References vaccination acceptance. Neither their family income nor whether they came tissue and peripheral blood from patients with or without CIN2-3 recurrence assay, indicating high risk HPV mRNA expression. AHPV had a significantly 1 Vozenin,M-C., Deutsch, E. et al. What Have We Learned From Human from overseas or mainland China were independent associating factors. after treatment. Inclusion of women at cohort was made at the moment (p<0.0001) higher specificity (75.0%) compared to the HC2 assay (61.0%) for Papillomavirus-Positive Tumors? Trying to Connect Data About Biomarkers Conclusion of CIN2-3 diagnosis. Our study cohort enrolled 69 patients diagnosed by Among Human Papillomavirus-Related Squamous Cell Carcinomas. J. Clin. the detection of CIN 2+. Vaccine acceptance is the crucial element in the success of a population histophatological criteria as CIN2-3. The patients were treated by Loop Oncol. 2010 Conclusions Electrosurgical Excision Procedure and were monitored at 6 and 12 months. vaccination programme. Health promotion and education can be targeted 2 Vozenin,M-C. Deutsch, E. et al. Unravelling the biology of human AHPV and HC2 test were both more sensitive and the AHPV assay also CEACAM-1 in cervical lesions was determinate by immunohistochemistry to increase the vaccination uptake. Moreover, our study clarified the papillomavirus (HPV) related tumours to enhance their radiosensitivity. more specific than cytology. The only four patients with positive AHPV and and in peripheral blood by flow cytometry. misconception that HPV vaccination is associated with sexual behaviour Cancer Treat Rev. 2010. negative HC2 and cytology results after treatment showed recurrence of and cervical screening practice. At this time we did not find significant differences in CEACAM-1 expression 3 Abdulkarim et al. Antiviral agent Cidofovirrestores p53 function and CIN2+ (with the identical HPV type) at follow-up testing after more than one from patients with and without post-treatment recurrence; however, enhances the radiosensitivity in HPV-associated cancers. Oncogene. 2002 Trial registration year. The AHPV assay appears to be a very sensitive and specific test of cure. our results show a high expression of CEACAM-1 in tissues of patients 4 Amine, Bourhis, Deutsch, Vozenin-Brotons. Novel anti-metastatic action of N/A Keywords without recurrent lesion and a decrease in the expression of CEACAM-1 in cidofovir mediated by inhibition of E6/E7, CXCR4 and Rho/ROCK signaling in Funding High-risk HPV, HPV mRNA, comparison, HPV DNA HPV tumor cells. PLoS One. 2009 patients with recurrent lesion. These data suggests that this decrease in the No external funding CEACAM-1 expression could be associated with a phenotype compatible with Keywords Keywords a greater degree of malignant transformation; however, to evaluate with HPV, radiosensitization, Cidofovir, clinical trial HPV vaccination, Chinese, acceptance more confidence the role of this molecule it will be necessary to increase the patient cohort and examine more women with recurrence lesions. Keywords Cervical cancer, cervical intaepithelial neoplasia, CEACAM-1, recurrence lesion 42 43 Poster Abstracts Poster 11 Poster 12 Poster 13 Poster 14 Neutralization of closely-related non-vaccine Markers of HPV infection in HPV vaccinated Role of transcription factor AP-1 in Low integrated status of Human HPV genotypes by HPV vaccine sera Czech women esophageal squamous cell carcinoma: Papillomavirus in combination with low viral Alterations in activity and expression during load is associated with poor radiotherapy E. Draper*1, S. L. Bissett1, D. Edwards2, E. Hamsikova*, V. Ludvikova, J. Smahelova, Human Papillomavirus infection outcome in uterine cervical cancer G. Munslow2, K. Soldan1, S. Beddows1 M. Salakova, J. Stasikova, R. Tachezy Health Protection Agency, United Kingdom, 2NHS Bolton, United Kingdom 1 Institute of Hematology and Blood Transfusion, Czech Republic S. Hussain*1, A. C. Bharti2, i. Salam3, J-y. Kim*1, J-W. Roh2, J-A. Lee1, H-J. Shin1 Background Purpose M. A. Bhat4, M. M. Mir5, S. Hedau5 et al. 1 Research Institute and Hospital, National Cancer Center, Korea, Republic of, As the majority of cervical cancers are associated with HPV genotypes Currently two prophylactic HPV vaccines are commercially available to 1 Division of Molecular Oncology, Institute of Cytology & Preventive Oncology 2 Department of Obstetrics and Gynecology, Dongguk University Ilsan Hospital, from two distinct Alpha-Papillomavirus clades (A7: HPV18, 39, 45, 59, prevent HPV16/18 infection and associated lesions. It has been shown that (ICMR), I–7, Sector-39, Noida, India, India, 2Department of Clinical Biochemistry, College of Medicine, Dongguk University, Republic of Korea 68 and A9: HPV16, 31, 33, 35, 52, 58), the extent to which the current vaccination of females incidentally or persistently infected with vaccinal HPV Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, Purpose HPV16/18 vaccines will protect against related genotypes is an important types is less effective or ineffective. The aim of the study was to assess the India, India, 3Department of Cardiovascular and Thoracic Surgery, Sher-I-Kashmir To examine the physical status of human papillomavirus in locally advanced unresolved issue. Few published data are available on the frequency or titer proportion of sexually active women who were at risk of reduced vaccine Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India, India, cervical cancer and its effect on radiotherapy outcome. of neutralizing antibodies against closely-related non-vaccine types, for efficacy and compare the strength of antibody response elicited by particular 4 Department of Immunology and Molecular Medicine Sher-I-Kashmir Institute of example HPV31 and HPV45. vaccines one year after the third dose. Patients and Methods Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India, India, 5Department Patients were treated by radiotherapy±cisplatin concurrent chemotherapy Objectives Methods of Biosciences, Jamia Millia Islamai; New Delhi, India, India, 6Dr. B.R. Ambedkar between 2003 and 2006. The physical status of the human papillomavirus To determine the frequency and titer of cross-neutralizing (HPV31 and Altogether 222 women (16–49 years, mean 23.4 years) were enrolled. Before Research Centre for Biomedical Research (ACBR), University of Delhi (North (HPV) gene was examined in cervical tumours from 111 radiotherapy patients HPV45) antibodies in sera from individuals immunized with CervarixTM the first vaccine dose and one year after the third dose, a sample for HPV DNA Campus), Delhi, India, India and was compared with the viral load measured by Hybrid Capture II (HCII). within the UK National HPV Immunization Programme. detection and typing and blood for anti-HPV antibodies assessment were Background To quantitatively estimate integrated viral genes in individual tumours, taken. HPV DNA detection and typing was done by PCR and RLB/sequencing, Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer- real-time polymerase chain reaction was performed for HPV type-specific Methods sera were tested for presence of antibodies to VLPs derived from HPV6, 11, related deaths in the Jammu and Kashmir (J&K) region of India. A substantial E6 and E2. The amount of integrated viral gene was calculated by equation Blood samples were collected from 13–14 year old girls (n=70), after a median 16, 18. proportion of esophageal carcinoma is associated with infection of high-risk of E6-E2/E6 and was grouped into two using cut-off value of 0.5. Four of 5.9 months (IQR 5.7–6.0) from receiving their third dose of CervarixTM vaccine. Neutralization assays were performed using L1L2 pseudoviruses Results HPV type 16 and HPV18, the oncogenic expression of which is controlled by combinational groups were made using the E6-E2/E6 and HPV viral load representing HPV16, 18, 31, 45 and the control BPV1. HPV DNA prevalence in the whole cohort (38.7%) was age dependent. host cell transcription factor Activator Protein-1 (AP-1). We have therefore value using the median value (E6-E2/E6≤0.5/low viral load (Group 1), E6-E2/ Vaccinal types were found in 13.1% of females, not present in women over investigated the role of DNA binding and expression pattern of AP-1 in E6≤0.5/high viral load (Group 2), E6-E2/E6>0.5/low viral load (Group 3), and Findings 30 years. Overall 23.4% of women were anti-HR VLP seropositive, in women esophageal cancer with or without HPV infection. E6-E2/E6>0.5/high viral load (Group 4)). Disease-free survival was compared Cross-neutralizing antibodies against HPV31 (76% of sera, 95% CI 64– above 30 years the positivity was as high as 59%. Incident infection (HPV Methods between the designated groups. 85%) and HPV45 (20%, 95% CI 11–31%) were evident among this group of DNA+/Ab–) with vaccinal HPV types was observed in 5.0% and persistent Seventy five histopathologically-confirmed esophageal cancer and an equal Results vaccinees. The low prevalence of these HPV types in the population and the infection (HPV DNA+/Ab+) in 7.2%. About 19% women cleared the HPV16/18 number of corresponding adjacent normal tissue biopsies from Kashmir were There was a considerable variation in the physical status of HPV in cervical ages within the study cohort, suggest these responses are due to vaccination. infection. Geometric mean titer of HPV16/18 antibodies was available for analyzed for HPV infection, DNA binding activity and expression of AP-1 cancer. The presence of a high proportion of integrated physical status Cross-neutralization titers against HPV31 and HPV45 were substantially 71/35 women vaccinated by Silgard/Cervarix. For both antigens antibody family of proteins by PCR, gel shift assay and immunoblotting respectively. tends to be associated with superior treatment outcome. There were 18 lower than for vaccine types (GeoMean for HPV31 of 0.96% [95%CI, 0.48– levels were higher after Cervarix application. Group 1, 33 Group 2, 36 Group 3, and Group 4 patients. Univariate Cox 1.92%] the HPV16 titer; for HPV45 of 0.39% [95%CI, 0.19–0.80%] the HPV18 Results titer). Conclusions A high DNA binding activity and elevated expression of AP-1 proteins were analysis showed physical status, histologic grade, metastatic lymph node, Our study has shown that at least about 60% of women enrolled have already observed in esophageal cancer, which differed between HPV positive (19%) tumor size, and clinical stage as significant factors for poor prognosis. On interpretation encountered the HPV infection. HPV vaccination might have reduced efficacy and HPV negative (81%) carcinomas. While JunB, c-Fos and Fra-1 were the multivariate analysis, Group 1 (low viral load and low integrated status) Here we show that neutralizing antibody responses against closely-related, in more than 10% of vaccinated women who were positive for HPV16/18 major contributors to AP-1 binding activity in HPV negative cases, Fra-1 was showed significantly inferior disease-free survival (DFS) compared with the non-vaccine types are relatively common, but the antibody titers are DNA at the first dose of vaccine application. completely absent in HPV16 positive cancers. Comparison of AP-1 family Groups 2,3,4 (HR of group 2,3,4=0.13, 0.16, 0.17, p=0.003, 0.006, and 0.009, very low (≤1% of type-specific titer). Studies have shown that HPV16/18 proteins demonstrated high expression of JunD and c-Fos in HPV positive respectively). Other prognostic factors included poorly differentiated grade neutralizing titers in genital secretions are much lower than those found in Funding tumors, but interestingly, Fra-1 expression was extremely low or nil in these (p=0.02) and advanced stage (p=0.009). the periphery. It is unclear, therefore, whether these low levels of HPV31/45 IGA MZ CR # NS10656-3; GAAV CR # IAA500960903 antibodies would be sufficient to protect against infection in the absence of tumor tissues. Conclusion Keywords other immune mechanisms. Their utility as surrogate markers of protection Conclusion Cervical cancer with a lower amount of integrated HPV virus and low HPV HPV vaccine, HPV DNA, HPV antibody remains to be determined. Differential AP-1 binding activity and expression of its specific proteins viral load is associated with inferior disease-free survival. Our result suggests between HPV-positive and HPV-negative cases indicate that AP-1 may play strong host factors in the prognosis of uterine cervical cancer treated Keywords an important role during HPV induced esophageal carcinogenesis. primarily by radiotherapy. Antibodies, cross-neutralisation, vaccine Keywords Keywords Activator Protein-1 (AP-1), Human Papilloma Virus (HPV), esophageal cancer, Cervical cancer, viral load, physical status, radiotherapy Kashmir 44 45 Poster Abstracts Poster 15 Poster 16 Poster 17 Poster 18 Detection of Human Papillomavirus DNA improving cervical cancer screening by HPV Second primary cancers after an index head Treatment of anal neoplasia – A long-term in breast cancers testing of vaginal specimens self-collected at and neck cancer: subsite-specific trends in the outcome study home: the MARCH randomized controlled trial era of HPV-associated oropharyngeal cancer L. Lorenzon*1, M. Bononi2, M. R. Torrisi1, M. Nathan*1, N. Hickey1, N. Singh2, M. Sheaff2 A. Ciardi2, D. French1, A. Frega1 A.T. Lorincz*1, E. Lazcano-Ponce2, L.G.T. Morris*1, A.G. Sikora2, P.N. Vila2, Homerton University Hospital NHS Foundation Trust, United Kingdom, 1 1 Sant'Andrea Hospital, II faculty of medicine and Surgery, University of Rome A. Cruz-Valdez2, J. Salmeron3, P. uribe4, R.B. Hayes3, i. Ganly1 Barts and the London NHS Trust, United Kingdom 2 " La Sapienza", Italy, 2Policlinico Umberto I, I Faculty of Medicine and Surgery, M. Hernandez Avila5 et al. Memorial Sloan-Kettering Cancer Center, United States, 2Mount Sinai School of 1 Background University of Rome "La Sapienza", Italy Medicine, United States, 3New York University School of Medicine, United States Currently there are no guidelines for the treatment of high-grade anal 1 Wolfson Institute of Preventive Medicine, Queen Mary University of London, Background intraepithelial neoplasia (AIN 2/3). Barts and The London School of Medicine, London, United Kingdom, 2Centro Background Several studies reported the detection of the HPV within breast cancer tissues de Investigación en Salud Poblacional. Instituto Nacional de Salud Pública, Patients with head and neck squamous cell carcinoma (HNSCC) are at Aim in the past, with an ample range of positivities. Cuernavaca, Morelos, Mexico, 3Unidad de Investigación Epidemiológica y en significantly elevated risk of second primary malignancies (SPM), most To identify the benefits, if any, of treatment of AIN 2/3. 31 breast cancers and 12 controls were investigated for the presence of HPVs Servicios de Salud, Instituto Mexicano del Seguro Social, Cuernavaca, Morelos, commonly within the head and neck, lung and esophagus (HNLE). Our Methods DNA; secondary aims were a) to detect the HPV DNA in metastatic nodes; Mexico, 4Centro Nacional de Equidad y Género, Secretaría de Salud, México, D.F., objectives were to identify subsite-specific differences in SPM risk and Analysis of treatment and follow-up data of AIN 2/3 in a specialist unit in the UK. b) to investigate positive patients for a possible cervical HPV co-infection; Mexico, 5Subsecretaria de Prevención y Control de Enfermedades, Secretaría de distribution, and to describe trends in risk over the past three decades, both Salud, México, D.F, Mexico Results and c) to evaluate the E6 and E7 mRNA expression in HPVs positive breast before and during the era of HPV-associated oropharyngeal SCC. Eighty four patients with intra-anal (77) or external (7) disease underwent cancer tissues. Exclusion criteria: past breast/cervical cancers, neo-adjuvant The Mexican Appraisal of Routine Cytology versus vaginal HPV screening Methods treatment and had regular follow-up for more than 36 months. 87% were treatments. (MARCH) for detecting cervical intraepithelial neoplasia grades 2, 3 or cancer Population-based cohort study of 75,087 patients with HNSCC in the SEER men and 82% were men who have sex with men (MSM). 61% were HIV Methods (CIN 2+) in underserved women. program. Excess SPM risk was quantified using standardized incidence ratios positive. 3 patients had other immune defects. 33.3% had AIN3 while 66.7% Cancers: 29 ductal and 2 lobular cancers, mean age 57 years, range 35–78. Methods (SIR), excess absolute risk (EAR) per 10,000 person-years at risk (PYR), and had AIN2. 87% received laser ablative treatment, while the rest had excision Controls: 10 fibroadenomas and 2 papillomas, mean age 27 years, range A population-based randomized controlled trial (RCT) of 22,866 mostly rural number needed to follow. Trends in SPM risk were analyzed using joinpoint or topical imiquimod treatment. The median follow-up was 60 months 25–35. women aged 25 to 65 years in central Mexico. Randomization was to: 1) self- log-linear regression. (mean 65; range 36–169). All recurrent disease was treated, after biopsy for HPV genotyping was performed after DNA extraction from paraffin- collection of vaginal specimens at home to determine high risk (HR) HPV status Results histology verification. Histology of repeat biopsies in 64 patients after initial embedded surgical specimens (cancers, controls and nodes) or from by the Hybrid Capture 2 test (the HPV arm; n=9,202), and 2) routine cervical In HNSCC patients, the SIR of second primary solid tumor was 2.2 (95%CI treatment revealed 11 cases of AIN3, 14 cases of AIN2 and 26 cases of AIN1 cytological cervical samples. cytology smears collected at primary healthcare centres (the cytology arm; 2.1–2.2), representing an EAR of 167.7 cancers per 10,000 PYR. Lung cancers (total 88 biopsies; 39% AIN 2/3). In total there were 72 further treatment n=13,664). Positive tests were referred to colposcopy and biopsy as required. were the most common, followed by head and neck and esophagus. The attempts in these 64 patients during follow-up (laser 65, imiquimod 5 and After RNA extraction, stored frozen HPV positive cancer tissues were further excision 2). None of the treated patients developed invasive anal squamous An intention to screen analysis was conducted in Stata 10.1 adjusting for non- risk of SPMs was highest for hypopharyngeal SCC (SIR=3.5, EAR=307.1 per investigated for E6 and E7 mRNA expression. carcinoma (anal cancer) or treatment related complications. compliance and contamination, weighting rates according to the age structure 10,000 PYR), and lowest for laryngeal SCC (SIR=1.9, EAR=147.8 per 10,000 Results and level of social deprivation using proportional fixation criteria. PYR). Prior to the 1990s, oropharyngeal cancers carried the second highest Discussion HPV DNA was detected in 9 cancers (29%), HPV 16 the most frequent. All risk of SPM, after hypopharyngeal cancers. Since 1991, SPM risk has fallen Currently available follow-up studies of high-grade AIN (AIN 2/3) show a Results controls resulted negative for HPV (p 0.04). significantly among patients with oropharyngeal SCC (annual percentage progression rate of 9–14% to anal cancer, over a 60 month period, despite The prevalence of HPV was 9.6% (95% CI 8.5–12.1), and the cytology Among 9 HPV positive breast cancer patients, 6 patients resulted co-infected abnormal rate was 0.43% (95% CI: 0.23–0.71). HPV testing identified change in EAR = -4.6%, p=0.03). Oropharyngeal cancers now carry the lowest some intervention. In our cohort no one developed anal cancer (p<0.05). at the cervix, sharing at least one the HPV types. 114.6/10,000 (95% CI 93.2–136.0) CIN 2+ versus 38.95/10,000 (95% CI risk of SPM of any head and neck subsite. Recurrent disease was limited in volume and repeated treatment was 26.42–51.47) by cytology, a 2.94-fold (95% CI 2.86–3.03) greater relative Conclusions acceptable. Moreover, there was no sequel to treatment. We now need Just 1 out of 8 patients with metastatic nodes was tested positive for HPV sensitivity. Similarly HPV detected 3.98-fold more invasive cancers than Since the early 1990s, the risk of second cancer after oropharyngeal SCC has prospective large scale studies to verify this outcome and modelling studies infection, the others resulted negative. cytology. The positive predictive value (PPV) of HPV testing for CIN 2+ was fallen dramatically. This trend has occurred contemporaneously with the rise are needed to establish cost-benefit analysis of treatment. A search for the E6 and E7 mRNAs expression was conducted in 5 patients. 12.3% (95% CI 10.2–14.5) and for cytology was 62.7% (95% CI 50.4–75.0). of oncogenic HPV-associated oropharyngeal cancer. It is likely that the risk of Keywords The analysis failed in detecting the expressions in all the patients. second primary cancer is substantially lower in HPV+ versus HPV- head and Conclusions Anal cancer, high-grade anal neoplasia, treatment of AIN 2/3, cancer prevention Discussion Self-collection of vaginal specimens at home for HR-HPV DNA detection was neck cancer. These findings may have implications for current interest in de- The rate of HPV infection within breast cancer patients was significant if highly sensitive for identifying CIN 2+ with an acceptable PPV and was readily escalation of systemic therapy in HPV-associated HNSCC. compared with controls, however since positive cancers did not express the established and maintained. Despite a lower PPV we favour frontline HPV Figures viral mRNAs, its role in oncogenesis remains unclear. testing for low resource settings because such women will be screened at Excess absolute risk (EAR) of second primary malignancy (SPM) in solid 2/3 of the patients who tested positive for HPV at the breast site shared at most a few times in their lives and the high sensitivity of a single HPV screen tumor sites and the head and neck, lung and esophagus (HNLE) over time, least one of the HPV types at the cervical site, however the mechanism of is of paramount importance. by subsite of index head and neck cancer (OC: oral cavity, OP: oropharynx, transmission (mechanical/systemic spreading) remains unclear. Funding L:larynx, HP:hypopharynx) Keywords The Health Ministry and Public Health Institute of Mexico, and QIAGEN Keywords HPV, breast cancer Corp. provided funding; sponsor entities had no role in study design, data Second primary cancer, second primary malignancy, oropharynx, HPV collection, analyses, or interpretations. Keywords HPV, cervical cancer, RCT, cervical cytology 46 47 Poster Abstracts Poster 19 Poster 20 Poster 21 Poster 22 Concordance between paired cervical and Differential gene expression and HPV The impact of HPV-status on survival in Molecular variants of Human Papillomavirus urine samples in HPV-DNA detection and HPV in penile carcinoma patients treated with radiochemotherapy for Type 16 (HPV-16) and 18 (HPV-18) in italy genotyping advanced inoperable oropharyngeal cancer P. Rahal*1, M.T.O. Mota1, E. Babeto1, E. Tanzi*1, E.R. Frati1, S. Bianchi1, A. Zappa1, G. Orlando*1, S. Bianchi2, F. Mazza1, M. Fasolo1, M.F. Calmon1, J.L. Bonilha2, R.V.D. Silvestre3 et al. R. Semrau*1, H. Duerbaum2, S. Temming1, F. Mazza2, G. Orlando2 A. Amendola2, E. Tanzi2 et al. 1 Laboratory of Genomics Studies, São Paulo State University, Brazil, 2Department C. Huebbers3, J. P. Klussmann4, S. F. Preuss2 Università di Milano,Dip Sanità Pubblica-Microbiologia-Virologia, Italy, 1 1 STD Unit Infect Dis II; L Sacco University Hosp, Italy, Dipartimento di Sanità 2 of Pathology, College of Medicine, FAMERP, Brazil, 3Papillomavirus and Respiratory 1 Department of Radiation Oncology, University of Cologne, Germany, Department 2 L Sacco University Hospital, STD Unit Infectious Diseases II, Milan, Italy 2 Pubblica-Microbiologia-Virologia, Università di Milano, Italy Virus Laboratory, Institute Evandro Chagas/SVS/MS, Brazil, 4Department of of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Cologne, Background Pathology, Antonio Prudente Foundation, Brazil, 5Department of Pathology, State Germany, 3Jean-Uhrmacher Institute, University of Cologne, Germany, Background The prophylactic HPV vaccine protects against HPV-16 and HPV-18, two University of Campinas, Brazil 4 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Low adhesion rates to cervical cancer screening programs based on cervical high-risk HPV genotypes that are the cause of about 70% of cervical cancer Penile cancer (PC) is an invasive epithelium tumor, representing more than of Giessen, Germany worldwide. This vaccine has been prepared using the L1 protein since its samples collection limits the efficacy of this strategy; less invasive and effective sampling could be helpful for the screening of high risk or low 10% of the malignancies in men in some developing countries, mainly in Background immunodominant epitopes elicit high-titre neutralizing antibodies. Intratypic adherent women such as adolescent/young women, immigrants, women in Brazil. Studies on the aetiopathogenesis of this cancer have focused on its HPV-status is an independent prognostic indicator of survival in variants of L1 gene of HPV-16 and HPV-18 have been described. The present developing countries. association with HPV. Patients with PC without treatment usually die within oropharyngeal squamous cell carcinoma (OSCC). It is reported that HPV- study aims to evaluate the genetic diversity of HPV-16 and HPV-18 L1 gene. 2 years following diagnosis, because of uncontrollable loco regional disease or positive OSCC show better response to radiochemotherapy (RCT) than HPV- Agreement between HPV infection/genotyping on cervical and urine paired Methods from distant metastasis. negative OSCC. Our patients are primarily treated with surgery. Definitive RCT samples to define the efficacy of a preventive strategy based on an easier-to- 26 HPV-16 and 5 HPV-18 positive cervical samples obtained from Italian The aim of this study is to evaluate the possible role of HPV in the is therefore solely used for advanced inoperable tumor stages. The influence women were analyzed in their L1 coding gene sequences (HPV-16: 1,498 bp, collect sample is evaluated in this study. development of PC and the use of the RaSH technique to analyze gene of HPV status on survival in this subgroup of patients was studied. nt. 5,603–7,101; HPV-18: 1,489 bp, nt. 5,613–7,101). Phylogenetic analysis Methods expression in normal tissues and penile tumors. HPV detection was carried of the amino acid sequences was conducted by Neighbor-Joining method Patients and Methods Paired cervical and urine samples were collected in the same day from 107 out by PCR with generic primers GP5+/GP6+, and HPV typing was done by and Amino Poisson correction model, using MEGA package (version 4.1.). We included patients with inoperable OSCC treated with RCT at our women attending STD Unit, L Sacco Hospital (Italy). Multiplex-PCR on the direct sequencing. RaSH methodology identified differentially expressed A bootstrap analysis (n=1,000) was performed. institution. The patients received either 69.2Gy with concomitant boost HPV-L1 gene for viral genome and RFLP (Restriction Fragment Length genes, generating subtractive cDNA libraries. (ccb) technique or 70Gy conventionally fractionated (cf). Concurrent Results Polymorphism) technique using 3 restriction enzymes (RsaI, HaeIII, DdeIII, The presence of HPV was analyzed in 58 samples of patients with PC chemotherapy was administered weekly (paclitaxel 40mg/m2, carboplatin Most (25/26, 96.1%) sequences belonged to the HPV-16 European prototype Recombinant Enzyme, BioLabs inc, New England) for HPV genotyping and a high prevalence (85.12%) of HPV was observed. Of the 16 samples AUC1) for 6 weeks. We analyzed tumor specimens for presence of HPV-DNA. lineage (similarity range: 99.4–99.7%), and one to the non-European lineage were used. sequenced, HPV-16 was found in 14 (87.5%) samples, HPV-11 in 1 (6.3%) and Furthermore, p16 expression was evaluated as a surrogate marker for HPV (similarity: 99.6%). Eighteen amino acid variations were observed in the study Agreement between tests was assessed using Kappa statistic (k). Fisher's HPV-35 in 1 (6.3%). The RaSH subtractive libraries identified the presence of associated tumors. Overall survival and the disease-free survival rates were sequences. Six (33%) of these mutations fell into the immunodominant loop: exact test was performed to test difference between paired proportions. 57 genes differentially expressed between both samples; 30 in tumor samples calculated using the Kaplan-Meier method. three in FG loop, two in DE loop, and one in BC loop. One HPV-18 sequence Results and 27 in the normal tissue. The genes PBEF1, ANX1, RPL6 and KIAA1033 Results belonged to the HPV-18 African lineage (similarity: 99.8%) and presented the The prevalence of HPV infection was 65.4% and 62.6%, respectively in were over-expressed in the tumors. On the other hand, the gene p16 was We included data of 60 patients with stage IV disease. 36.7 % were HPV variation from valine to histidine in position 384. The other HPV-18 sequences cytobrush and urine samples (concordance rate and 95%CI: 97.2%; 91.4– over-expressed in normal tissue. Finally, the expression of the selected genes positive and 63.3% HPV negative. 51 patients (85%) received ccb and 9 fell into the European lineage (similarity range: 99.5–100%) and presented four 99.3). High concordance rates were observed also for single or multiple was confirmed by qRT-PCR. Only ANX1 was validated with over-expression in patients (15%) cf radiotherapy. Mean follow up was 22.4 months. The 3-year mutations, one of them into FG immunodominant loop. infections (k 93.7; 81.8–98.4), for infection from HR or LR types (k 89.1; 80% of all samples. disease free survival was 42.9% for p16-positive patients and 13.5% for p16- Conclusions 75.6–95.9), and for single genotypes: HPV-16 – k 95.7 (87.2–98.9); HPV-18 – The results obtained are capable of revealing differences in the patterns negative patients (p=0.007). The 3-year overall survival was 37.3% for all These data indicate the presence of amino acid changes in HPV-16 and k 100 (93.5–100); HPV-6 – k 94.3 (85.3–98.1); HPV-11 – k 97.1 (89.1–99.5); of gene expression between normal and tumor tissues. Moreover, a high patients and did not significantly differ between HPV positive and negative HPV-18 L1 partial sequences. The biological role of these mutations is still HPV-53 – k 95.7 (87.2–98.9); HPV-56 – k 97.1 (89.1–99.5). prevalence of HPV was observed, suggesting an important role of this virus patients. unknown. Particular attention may be addressed to assessing whether HPV The sensitivity of this method for HPV-DNA, any HR-HPVs, HPV-16 and HPV- in penile carcinogenesis. Such information will contribute to develop a Conclusion intratypic variants correlate with the clinical outcome of the disease and with 18 were 96%, 91%, 80% and 100% respectively. Negative predicting values possible marker for penis tumor diagnostic and prognostic, improving the The HPV-status influences the disease free survival in patients with advanced, clinical implications for the long-term use of an L1-virus-like particle-based over 95% were observed for HPV-16, -18, -6, -11, -53, -56. development of directed therapies against this new putative marker. inoperable tumor stages. However, the overall survival in this subgroup of prophylactic vaccine. Conclusion Keywords OSCC patients seems not to be correlated with the HPV-status. Comorbidity Keywords Urine-based assay for detection of HPV-DNA and HPV genotyping could be Penile cancer, gene expression, HPV, RaSH in this subgroup of patients with inoperable tumor stages seems to have HPV-16 variants, HPV-18 variants, L1 gene suitable for a wider and effective screening approach based on the molecular stronger influence on overall survival then the potential prognostic impact of diagnosis of high-risk HPV infections for the high concordance rate observed HPV-status. with results obtained on cervical samples. Keywords Keywords Radiochemotherapy, advanced head and neck cancer, inoperable, prognosis Molecular screening, cervical samples, urine samples, tests agreement 48 49 Poster Abstracts Acknowledgments Poster 23 Gold Sponsor Anal cancer incidence trends in uS and uK: age-period-cohort analysis A.G. Renehan*1, J. Bohlius2, K.M. Clough-Gorr2, N. Low2, M. Zwahlen2, M. Egger2 1 The Christie NHS Foundation Trust, School of Cancer and Enabling Sciences, University of Manchester, United Kingdom, 2Institute for Social and Preventive Medicine, University of Bern, Switzerland Background HPV is implicated in the development of anal carcinoma. Incidence rates of anal cancer are increasing in many populations. To better understand the basis to these trends, we analysed incidence trends in US and UK populations using age-period-cohort (APC) models. Methods Using the Surveillance Epidemiology and End Results (SEER: whites, 1973 to 2006) and the Office of National Statistics (ONS; 1971 to 2007) registries, we estimated world standardized incidence rates (SIRs) using direct Bronze Sponsor Exhibitors methods; constructed separately period and birth cohort descriptive curves; and examined combined effects of age, period and cohort using iterative reweighted least squares regression modelling with unconstraint internal estimation methods (IEM). Results In total 26,494 (SEER: 8,970; ONS: 17,524) cases were recorded. Incidence rates increased three-fold in both the US and UK registries. By 2006, rates were higher in the US for men compared with women [standardized incidence rate (SIR) = 1.65 (95% CI: 1.45, 1.85) v 1.45 (1.27, 1.63)], but higher among women in the UK [SIR = 0.74 (0.65, 0.83) v 0.94 (0.85, 1.04)]. The APC analysis revealed a significant period effect (P < 0.0001) for US and UK population in both genders, but differences in cohort effects. Specifically, for the US population, there was a bimodal birth cohort effect with increases in effect after the birth year 1945, particularly for men. Conclusions APC modelling of anal cancer rates for the US and UK revealed common period effects since the early 1970s consistent with a common environment influence, such as increasing HPV or HIV prevalence. There were contrasting patterns in birth cohort effects generating hypotheses that modes of HPV The Lancet HPV and Cancer Conference 2010 acknowledges the support of transmission and/or processes of anal cancer development differ between populations, implying that screening and early detection programmes need to be population-specific. Keywords Incidence of anal cancer, Time trends, Birth cohort, Age effect 50 E CAN YW D DA O TO MO RE New indication Up to 45 for women years old Gardasil is a vaccine for use from the age of 9 years for the prevention of: Premalignant genital lesions (cervical, vulvar and vaginal) and cervical cancer causally related to certain oncogenic Human Papillomavirus (HPV) types External genital warts (condyloma acuminata) causally related to specific HPV types The decision to vaccinate each individual woman should take into account her risk CO00636 for previous HPV exposure and her potential benefit from vaccination. Abridged Prescribing Information for use in the European Area GARDASIL® (Human Papillomavirus medical treatment should always be available in case of rare anaphylactic reactions. Syncope (fainting) Vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed)). Refer to Summary of Product Characteristics for may follow any vaccination, especially in adolescents and young adults. Vaccinees should be carefully full product information. Presentation: Gardasil is supplied as a single dose pre-filled syringe containing observed for approximately 15 minutes after administration of Gardasil. As with any vaccine, vaccination 0.5 ml of suspension. Active ingredients: Each dose contains L1 protein of HPV type 6 (20 µg), type with Gardasil may not result in protection in all vaccine recipients. Gardasil will only protect against diseases 11 (40 µg), type 16 (40 µg) and type 18 (20 µg), adsorbed on amorphous aluminium hydroxyphosphate that are caused by HPV types 6, 11, 16 and 18 and to a limited extent against diseases caused by certain sulphate adjuvant. Indications: Gardasil is a vaccine for use from the age of 9 years for the prevention related HPV types. Gardasil has not been shown to have therapeutic effect. Vaccination is not a substitute of premalignant genital lesions (cervical, vulvar and vaginal), and cervical cancer and external genital for routine cervical screening. There are no data on the use of Gardasil in individuals with impaired immune warts (condyloma acuminata) causally related to certain oncogenic Human Papillomavirus (HPV) types 6, responsiveness. The vaccine should be given with caution to individuals with thrombocytopaenia or any 11, 16 and 18); and external genital warts (condyloma acuminata) causally related to specific HPV types. coagulation disorder because bleeding may occur following an intramuscular administration in these The indication is based on the demonstration of efficacy of Gardasil in adult females 16 to 26 years of age individuals. Interaction: Administration at the same time as hepatitis B vaccine did not interfere with the and on the demonstration of immunogenicity of Gardasil in 9- to 15-year old children and adolescents. immune response to the HPV types. Gardasil may be concomitantly administered with a combined booster Protective efficacy has not been evaluated in males. The use of Gardasil should be in accordance with vaccine containing diphtheria (d) and tetanus (T) with either pertussis [acellular, component] (ap) and/or official recommendations. Dosage and administration: The primary vaccination series consists of 3 poliomyelitis [inactivated] (IPV) (dTap-IPV vaccines) with no significant interference with antibody response separate 0.5ml doses administered according to the following schedule: 0, 2, 6 months. If an alternate to any of the components of either vaccine. Use of hormonal contraceptives did not appear to affect the schedule is necessary the second dose should be administered at least one month after the first and the immune response to Gardasil. Pregnancy and lactation: There is insufficient data to recommend the use third dose at least three months after the second. All three doses should be given within a 1 year period. The of Gardasil during pregnancy. Gardasil can be given to breastfeeding women. Undesirable effects: Very need for a booster dose has not been established. Paediatric population: there is no experience with the use common: pyrexia and at the injection site, erythema, pain and swelling. Common: bruising and pruritus of Gardasil in children below 9 years of age. The vaccine should be administered by intramuscular injection. at the injection site, pain in extremity. For a complete list of undesirable effects, including post-marketing It is recommended that individuals who receive a first dose of Gardasil complete the 3-dose vaccination undesirable effects, please refer to the Summary of Product Characteristics. Marketing authorisation course with Gardasil. Contraindications: Hypersensitivity to any component holder: Sanofi Pasteur MSD SNC, 8 rue Jonas Salk, F-69007, Lyon, France of the vaccine. Hypersensitivity after previous administration of Gardasil. Acute ® Registered trademark Date of last review: August 2010 Marketing severe febrile illness. Warnings and precautions: The decision to vaccinate an authorisation number: EU/1/06/357 Date of MA Approval: 20 individual woman should take into account her risk for previous HPV exposure September 2006 and her potential benefit from vaccination. As with all vaccines, appropriate
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