©2013 MFMER | slide-1 Mayo Clinic and Alaska: Collaborative Health Care Activities with a Focus in Cancer Steven Alberts, MD MPH Medical Oncology Mayo Clinic - Rochester

©2013 MFMER | slide-2 Disclosures Relevant Financial Relationship(s) None Off Label Usage None

©2013 MFMER | slide-3 Learning Objectives Understanding of the collaborative activities of the Mayo Clinic in Alaska Appreciation of the occurrence of specific cancers in Alaska Native People Recognition of potential areas of collaboration

©2013 MFMER | slide-4 Outline of Presentation Mayo Clinic History and Current Activities Mayo Clinic Cancer Center Cancer in Alaska Native People Mayo Clinic and collaborative activities in Alaska – Focus on cancer

©2013 MFMER | slide-5 Overview of the Mayo Clinic Historical Points of Interest Present Day

©2013 MFMER | slide-6 Founding of the Mayo Clinic

©2013 MFMER | slide-7 Mayo - History 1864: Dr. William Worrall Mayo moves to Rochester to examine new recruits for the Union Army 1883, 1888: Dr. Mayos two sons, William J. and Charles H., join him in practice after finishing medical school

©2013 MFMER | slide-8 Founding of the Mayo Clinic December,1876 Mother Alfred commissioned to establish an academy in Waseca, MN. In 1877 she also established a mission house and day school in Rochester, Minnesota 1883: Tornado strikes Rochester. Mother Alfred Moes, of the Sisters of Saint Francis, proposes to build and staff a hospital if Dr. William Worrall Mayo and his sons will provide medical care. Saint Marys Hospital opens in 1889 with 27 beds

©2013 MFMER | slide-9 Mayo - History 1892: More physicians are invited to join, thus beginning the concept of an integrated group practice. The team approach naturally leads to a division of labor, specialists in different fields working together 1905: Louis Wilson, M.D., develops a rapid way to diagnose surgical specimens (quick-frozen tissue stained with methylene blue), which allows Mayo surgeons to explore, diagnose and repair, all in one operation

©2013 MFMER | slide-10 Mayo - History 1914: Mayo isolates thyroxin, the principal active component of the thyroid gland 1920: Mayo develops a system for grading cancer on a numerical basis that is adopted worldwide and still used today 1934: Edward Kendall, Ph.D., isolates cortisone, a hormone from the suprarenal cortex that will later be used to treat rheumatoid arthritis with dramatic results 1950: Edward Kendall, Ph.D., and Philip Hench, M.D., are awarded the Nobel Prize for the isolation and first clinical use of cortisone

©2013 MFMER | slide-11 Mayo - History 1919: The Mayos turn over the assets of Mayo Clinic to the nonprofit Mayo Properties Association, the forerunner of Mayo Foundation 1915: Doctors come from all over the world to observe and learn, leading to the organization of one of the worlds first formal graduate training programs for physicians, the Mayo School of Graduate Medical Education

©2013 MFMER | slide-12 Mayo - History Early 1900s rapid growth of infrastructure

©2013 MFMER | slide-13 Mayo - History 1939: Will and Charlie Mayo pass away within 2 months of each other

©2013 MFMER | slide-14 Mayo - History Current Era

©2013 MFMER | slide-15 Mayo – Present Day Current Era 2 hospitals Dedicated laboratory and research buildings

©2013 MFMER | slide-16 Mayo – 3 Locations 1986: Mayo Clinic in Jacksonville, FL opens 1987: Mayo Clinic in Scottsdale, AZ opens

©2013 MFMER | slide-17 Education Patient Care Research The best interest of the patient is the only interest to be considered, and in order that the sick may have the benefit of advancing knowledge, union of forces is necessary. (Dr. W. J. Mayo)

©2013 MFMER | slide-18 Mayo Clinic Activities Mayo Clinic is the first and largest integrated, not-for-profit medical group practice in the world Over $8 billion in gross revenues 3,800 physicians and scientists and 50,900 allied health staff 3,600 students, residents, and fellows Over 1 million patients seen each year

©2013 MFMER | slide-19 Mayo Clinic Research Activities New protocols reviewed by the Institutional Review Board 2,513 Active human research studies 8,117 Research publications and review articles in peer-reviewed journals 5,430 Physicians and medical scientists 391 Students 548

©2013 MFMER | slide-20 Mayo Clinic Cancer Center NCI Designated Comprehensive Cancer Center

©2013 MFMER | slide-21 Mayo Clinic Cancer Center 1973: Mayo Clinic Cancer receives NCI designation 2002: Mayo Clinic is the first multicenter clinic to receive comprehensive cancer center designation for its entire cancer program.

©2013 MFMER | slide-22 Mayo Clinic Cancer Center NCI Recognized Programs Cancer Prevention and Control Cell Biology Developmental Therapeutics Gastrointestinal Cancers Genetic Epidemiology and Risk Assessment Gene and Virus Therapy Hematologic Malignancies Immunology and Immunotherapy Neuro-Oncology Womens Cancers

©2013 MFMER | slide-23 Mayo Clinic Cancer Center Over the last 10 years MCCC activities supporting translational research and clinical trials have included, 6 P50 SPORE grants, U10 NCCTG Chairs grant, N01 Phase II contract, U10 CCOP Research Base grants, U01 Phase I grant, Chemoprevention Network (CPN) contract, Multiple R01 and R21 grants, as well as, numerous foundation grants

©2013 MFMER | slide-24 Mayo Clinic Cancer Center Clinical Research – Clinical Trials Program 242 studies open to accrual and 419 studies closed to accrual but still actively collecting data Approximately 1,500 patients enrolled to clinical treatment trials each year

©2013 MFMER | slide-25 CP Mayo Clinic Cancer Center (MCCC) Cancer - major component of Mayos clinical practice New cancer diagnoses each year - 16,000+ Approximately 20,000 cancer patients receive treatment each year at Mayo Cancer - 1/3 of Mayos total research portfolio Cancer Care and Research Care occurs primarily in the Department of Oncology, Department of Radiation Oncology, and Division of Hematology, and Department of Surgery Research in the Cancer Center

©2013 MFMER | slide-26 CP Cancer Center Accomplishments Publications Over 7,000 publications during the last 5 year period Increase in high impact publications Clinical journals (e.g., JAMA, NEJM, J Clin Oncol) Scientific journals (e.g., Science, Nature, Cell) Research funding Increase in overall peer-reviewed funding ( ) $77.6 million to $145 million Increase in NCI funding ( ) $56.3 million to $106 million Total Funding > $200 Million

©2013 MFMER | slide-27 Alaska and Mayo Clinic Connection Mayo ClinicAlaska Native People

©2013 MFMER | slide-28 Mayo Clinic Activities in Alaska Adult and Pediatric Cardiac Clinics, ­0 Teams of Mayo Cardiac physicians traveled to Alaska on an annual basis to conduct pediatric and adult cardiac clinics, including assessment of surgical candidates for referral to the Mayo Clinic The cardiac and surgery clinics were first coordinated by the Alaska Territorial Office and then the State of Alaska, with the assistance of handicapped and crippled children programs The clinics continued until Alaska medical facilities were able to provide the needed surgical services in- state

©2013 MFMER | slide-29 North American Nasopharyngeal Cancer (NPC) Study, ANMC researchers collaborated with Mayo Clinic, Rochester, MN staff (ENT, pathology, microbiology, immunology, etc.) on a national study of etiology of NPC including the relationship of the cancer to the Epstein-Barr virus

©2013 MFMER | slide-30 Design of Radiology Department for the New Alaska Native Medical Center ANMC Chief Radiologist John Midthun consulted with Mayo Clinic Radiologist Bernie King for the design and implementation of the PACS digital imaging system at the new Alaska Native Medical Center which opened 1996

©2013 MFMER | slide-31 Yukon-Kuskokwim Health Corporation: "Promoting Community Wellness", 1999 Thomas Kottke, MD, Mayo Clinic Cardiovascular Disease Specialist, traveled to Bethel to provide support and training of Community Health Aides/ Practitioners (CHA/Ps) at a regional conference encouraging community level wellness initiatives

©2013 MFMER | slide-32 Cancer in Alaska Native People

©2013 MFMER | slide-33 Cancer in Alaska Native People

©2013 MFMER | slide-34 Alaska Native Tumor Registry Population-based registry Includes information on AN people living in Alaska at the time of diagnosis of cancer from 1969 to the present Contributes to the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program since 1999 Anne Lanier, MD MPH Janet Kelly, MS MPH

©2013 MFMER | slide-35 Causes of Death in Alaska Native People Mortality data for years ; Source: NCHS; Alaska Native Tumor Registry, 2010

©2013 MFMER | slide-36 Cancer-related Mortality (Cancer in Alaska Native People Year Report.

©2013 MFMER | slide-37 Cancer Death Rates by Gender Cancer remains the leading cause of death among Alaska Native people. The all cancer mortality rate has exceeded the US white cancer mortality rate for more than 30 years. There have not been any significant declines. The leading cause of cancer death is lung cancer; where the mortality rate is 40% higher in Alaska Native people than US whites (Cancer in Alaska Native People Year Report.

©2013 MFMER | slide-38 Alaska Native Cancer Sites which are Higher than US White Rates, * All are significantly different from US Rates

©2013 MFMER | slide-39 Alaska Native Cancer Sites which are Lower than US White Rates, * All rates are significantly different from US Rates

©2013 MFMER | slide-40 Cancer Incidence in Indian Health Service Areas,

©2013 MFMER | slide-41 Cancer Incidence Rates in AI/AN by IHS Region in Contract Health Service Delivery Area Counties, *NHW= non-Hispanic Whites from all CHSDA counties; source: Wiggins, et al., 2008 All sites, men

©2013 MFMER | slide-42 All Sites Cancer Incidence Rates in AI/AN by IHS Region in Contract Health Service Delivery Area Counties, *NHW= non-Hispanic Whites from all CHSDA counties; source: Wiggins, et al., 2008 All sites, women

©2013 MFMER | slide-43 Mayo Clinic and Alaska Interactions

©2013 MFMER | slide-44 Colorectal Cancer Incidence in AI/AN People

©2013 MFMER | slide-45 Colon Cancer – Risk Factors Defined Risk Factors Diet: Consumption of animal fat, meat, and protein and a concomitant decreased consumption of fiber Tobacco: 1.4-fold increase risk of death from colorectal cancer in smokers compared to non- smokers (Int J Cancer 124: , 2009) Hereditary Factors: Accounts for approximately 15% of colorectal cancer across populations

©2013 MFMER | slide-46 Colon Cancer – Molecular Changes (Gastroenterology 143: , 2012)

©2013 MFMER | slide-47 Assessing Molecular Changes in Alaska Native People with Colorectal Cancer CRC from 329 Alaska Native people (165 Eskimo, 111 Indians, and 53 Aleut) evaluated for defective DNA mismatch repair (MMR), testing tumors for altered protein expression (hMLH1, hMSH2, and hMSH6) and for the presence of microsatellite instability (MSI) Findings 46 (14%) showed both MSI and altered protein expression; 42 (91%) with a loss of hMLH1, 3 (7%) hMSH2, and 1 (2%) hMLH1/hMSH6. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2344–50)

©2013 MFMER | slide-48 Assessing Molecular Changes in Alaska Native People with Colorectal Cancer Findings Continued Tumors with loss of hMLH1 further evaluated for hMLH1 promoter hypermethylation and for the BRAF-V600E mutation (23 of 27) tested positive for the V600E alteration Conclusion CRC with defective MMR among the Eskimo sample fit the typical profile for hMLH1-related cancer associated with sporadic CRC, whereas the pattern in the Aleut and Indian suggests the possibility that germ line hMLH1 mutations may be present

©2013 MFMER | slide-49 Patterns of Care Study MenWomen AK NativeUS WhiteAK NativeUS White Localized41.1%40.3%39.4%38.6% Regional34.6%35.8%35.9%37.2% Distant20.7%18.5%21.2%17.8% Unstaged3.7%5.4%3.5%6.4% Care provided to AN people with colorectal cancer consistent with national guidelines Appropriate incorporation of molecular markers

©2013 MFMER | slide-50 Screening and Prevention Colorectal cancer is a potentially preventable cancer Importance of screening Reducing risk factors Chemoprevention

©2013 MFMER | slide-51 Screening Development of colorectal cancer Opportunity for early detection (Source: NIH Transformative R01 Program)

©2013 MFMER | slide-52

©2013 MFMER | slide-53 Based on tumor exfoliation Whole colonocytes Proteins Metabolites RNA DNA Nearly 100% discrimination of CRC and adenomas from normal mucosa Highly sensitive assay technique, QuARTS (quantitative allele-specific real-time target and signal amplification)

©2013 MFMER | slide-54 Stool DNA Identified 85% of patients with CRC and 54% of patients with adenomas 1 cm with 90% specificity (aggregate 87% detection rate for CRC stages IIII). Detection rates increased with adenoma size: 54% 1 cm, 63% >1 cm, 77% >2 cm, 86% >3 cm, and 92% >4 cm (P <.0001). Based on receiver operating characteristic analysis, the rate of CRC detection was slightly greater for the training than the test set (P =.04), whereas the rate of adenoma detection was comparable between sets. Sensitivities for detection of CRC and adenoma did not differ with lesion site (Gastroenterology Feb; 142(2): ) Training Set Test Set

©2013 MFMER | slide-55 Colon Cancer in Alaska Native People (Cancer in Alaska Native People Year Report.

©2013 MFMER | slide-56

©2013 MFMER | slide-57 Rates of tobacco use are higher in AN people. Recent Behavioral Risk Factor Surveillance System (BRFSS) survey the rate of smoking in AN people is 45% compared to 21% in non-Native Alaskans

©2013 MFMER | slide-58 Yukon-Kuskokwim Neonatal Tobacco Exposure Pilot project, 1998 Mayo Nicotine Dependence Center Director Richard Hurt, MD and staff and YKHC program director Caroline Renner, MPH, collaborated on a pilot study to assess the impact of exposure of newborn infants to spit tobacco used by mothers during pregnancy and delivery.

©2013 MFMER | slide-59 Iqmik: high pH of the punk fungus ash (pH 10.9) allows almost 100% of the nicotine to be in the freebase form Y-K Delta Alaska Native people are introduced to Iqmik at a very young age as it is frequently given to infants and children Substantial nicotine in neonates without exposure to the gaseous phase constituents of tobacco smoke Neurobehavioral effects of nicotine withdrawal observed in neonates born to Alaska Native women who use Iqmik and other forms of tobacco during pregnancy (Journal of Maternal-Fetal and Neonatal Medicine 17(4): 281–289, 2005)

©2013 MFMER | slide Start of Mayo, ANTHC, YKHC collaboration Meeting with AN leadership Needs Identified Focus groups conducted Key informant interviews Community priorities Study on nicotine exposure in pregnant women and newborns Adolescent focus groups Adolescent prevalence study Chemical assessment of ash Pregnant women prevalence study R21 grant to develop behavioral intervention for pregnant women NIDA and OWHR funded Community led youth tobacco cessation retreat R21 grant to evaluate efficacy of youth tobacco cessation retreat NIDA funded R01 level project to develop a biomarker feedback intervention for pregnant women NCI U54

©2013 MFMER | slide-61 Pregnant Women Pilot intervention with pregnant women indicated low rate of participation and success New interventions being developed and piloted (Journal of Cancer Education 27(Suppl 1): S86-90, 2012) Youth Focus Group - Motivators to quit tobacco Perceived adverse health effects of tobacco, Improved self-image and appearance, Potential to be a future role model as a nontobacco user for family and friends. Findings being used to develop tobacco cessation programs for Alaska Native youth (Health education & behavior 36: , 2009)

©2013 MFMER | slide-62 Breast Cancer

©2013 MFMER | slide-63 Breast Cancer Risk Factors Risk factors: Age: menarche, first birth, menopause Parity Family history of breast cancer Hormone replacement therapy Lactation Hysterectomy Prior breast biopsy Smoking status Ethnic group Breast Density

©2013 MFMER | slide-64 Mammogram density has also not been studied in Alaska Native women The breast tissue parenchymal pattern as depicted on a mammogram is a factor that is influenced by hormonal breast cancer risk factors such as age at first birth, parity, menopause, and HRT3 Density is a strong independent indicator of breast cancer risk

©2013 MFMER | slide-65 Retrospective review of a sample of all sequential screening mammography examinations that were performed at the Alaska Native Medical Center between January and August of 1998 (n: 662 women) Aleut and Indian women were less likely to have high-density mammograms than were Eskimo women (P ). No significant differences were found between ethnic group for conventional breast cancer risk factors

©2013 MFMER | slide-66 (Mayo Clinic Proceedings 88(1): 68-73, 2013) Pilot study to provide telemedicine-based consultations for women at high risk for breast cancer Now service offered by Mayo Breast Clinic

©2013 MFMER | slide-67 Other Current Activities Annual Cancer Conference at ANMC (1998 – Present) Native American Programs at Mayo Clinic Native C.I.R.C.L.E. (Cancer Information Resource Center for Learning and Education): serves as a national resource for information and educational materials specifically targeting the American Indian/Alaska Native (AI/AN) population. Native WEB (Women Enjoying the Benefit) focuses on increasing cervical and breast cancer screening. Spirit of Eagles is a multi-faceted national AI/AN cancer initiative developed with the support of the NCI Leadership Initiative on Cancer and the current NCI Community Network Program.

©2013 MFMER | slide-68