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The Effectiveness of Molecular Assays and Sampling Methods: An Application on HPV Detection in Oropharyngeal and Oral Cavity Cancers Elizabeth A. Kostas-Polston, PhD, APRN, WHNP-BC, FAANP Robert Wood Johnson Foundation Nurse Faculty Scholar Alumnus Assistant Professor, Uniformed Services University of the Health Sciences, Daniel K. Inouye Graduate School of Nursing Assistant Professor, Saint Louis University School of Medicine Department of Otolaryngology, Head & Neck Surgery Women s Health Nurse Practitioner 26 th International Nursing Research Congress, Sigma Theta Tau International July 2015; San Juan, Puerto Rico
Conflict of Interest Disclosure The views expressed are those of the author and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences, the Department of the Defense, or the United States government. No relationship exists between the author and any commercial entity or product mentioned in this presentation which would represent a conflict of interest. No inducements have been made by any commercial entity related to the submission or presentation of this discussion.
Objectives At the completion of this presentation the learner will be able to: 1.Identify precursors and possible warning signs of oropharyngeal (OP) cancer. 2.Describe challenges faced by and the impact on quality of life for individuals diagnosed with quality of life OP cancer. 3.Compare current screening methods used to detect persistent HPV infection and diagnose anogenital vs. non-anogenital HPV-related cancers.
HPV-ASSOCIATED DISEASE & CANCER Epidemiology
Infectious Agents cause 17-20% of Cancer Worldwide: Higher in Developing World Bacterium: H. pylori Virus: HPV Viruses: HBV/HCV Virus: EBV Virus: HHV8 Other agents Stomach Cervix, others Liver Nasopharynx, lymphoma (gastric cancer) Kaposi s sarcoma Several tumor types 0 200,000 400,000 600,000 800,000 Annual number of cases Adapted from de Martel et al, Lancet Oncology 13: 607-15, 2012
Cervical Cancer accounts for >90% of HPVassociated cancer in Developing World Cervix Anus Vulva/vagina Penis HPV cases Total cases Oropharynx 0 100,000 200,000 300,000 400,000 500,000 Annual number of cases ~85% of global cervical cancer occurs in developing world; ~88% of deaths ~1% of women in developing world will die of cervical cancer before they are 75 (Ferlay et al, Int J Cancer, 2015) Adapted from de Martel et al, Lancet Oncol 13: 607-15, 2012; Arbyn et al, Ann Oncol 22:2675-86, 2011
USA: HPV-associated Non-cervical Cancers Affect Both Genders and are as Common as Cervical Cancer HPV16/18 Cervix ~70% Anus Male Female Vulva/vagina Penis HPV cases Total cases >90% Oropharynx 0 2,000 4,000 6,000 8,000 10,000 12,000 Annual number of cases Pap screening has reduced cervical cancer incidence by ~80% No approved screening tests for other HPV-associated cancers Incidence of HPV-positive oropharynx cancer 1988-2004 increased >3-fold MMWR, 2012; Chaturvedi et al, J Clin Oncol, 2011; Gillison, Chaturvedi, and Lowy., 2008
Cervical Cancer is Attributable to Multiple HPV Types; HPV16 Predominates 16 53.5% + 18 70.7% + 45 + 31 + 33 + 52 + 58 + 35 + 59 + 56 + 51 77.4% 80.3% 82.9% 85.2% 87.4% 88.8% 90.1% 91.3% 92.3% 0 20 40 60 80 100 Adapted from Munoz et al, Int J Cancer 111: 278-85, 2004
CERVICAL CANCER SCREENING HPV Testing
Natural History of Cervical CIN1, 2 Cancer HPV Infection CIN2, 3 Average of 10 Years Invasive Cancer Average 6-24 Months HPV Clearance Cox JT. Natural history of HPV. Online CME. www.asccp.org. 2009.
Primary & Secondary Prevention Primary Prevention: Vaccination Secondary Prevention: Screening Treatment (tertiary prevention) Normal Pre-cancer Cancer
Cervical Cancer Screening: From Pattern Recognition to Molecular Diagnosis Pap smear screening and other cytology-based methods are based on pattern recognition. They have reduced cervical cancer incidence and mortality (~80% in the USA since 1940 s). 2014: Primary cervical cancer screening by HPV-based testing approved by FDA. HPV-based screening is etiology-based. It is more sensitive and has higher negative predictive value
Declining cervical cancer rates: attributable to decreased squamous cell cancer, but not adenocarcinoma Squamous cell: blacks Squamous cell: whites Adenocarcinoma: whites Adenocarcinoma: blacks Adenosquamous: blacks & whites Adegoke et al, J Womens Health 21:1031-37, 2012
HPV testing can prevent more cervical cancers, especially adenocarcinomas, than cytology *Ratio of incidence with HPV testing vs. incidence with cytology Pooled cervical cancer incidence from 4 randomized controlled trials of cytology (control arm) vs. HPV testing (experimental arm) Ronco et al, Lancet 383: 524-33, 2014
OROPHARYNGEAL SQUAMOUS CELL CARCINOMA (OPSCC) Clinical Presentation
Risk Factors Tobacco use Excessive alcohol use Gender Age Race Human Papillomavirus (HPV)
Warning Signs: Precursors Leukoplakia (white lesion) Erythroplakia (red lesion) Erythroleukoplakia (red-white lesion) **Any white or red lesion that does not resolve itself in two weeks should be reevaluated and considered for biopsy to obtain a definitive diagnosis.
Other Possible Warning Signs A sore, irritation, lump, or thick patch in the mouth, on the lip, or throat A white or red patch in the mouth A feeling that something is caught in your throat Any difficulty chewing or swallowing Any difficulty moving the tongue or jaw Any numbness of the tongue or other parts of the mouth Any swelling of the jaw that causes dentures to fit poorly or become uncomfortable Any pain in one ear with or without hearing loss
TREATMENT & MANAGEMENT Impact/Prevention
Oropharyngeal Squamous Cell Carcinoma (OPSCC) Devastating diagnosis for an individual and their loved ones The treatment is brutal and life altering Facial disfigurement Speech dysfunction Chewing & swallowing difficulties Depression Social Isolation Side effects cause many months/years of physical and mental distress
RESEARCH An Investigation of the Utility of Molecular Assays & Sampling Methods for the Detection of Oropharyngeal HPV Infection
Screening Currently have no FDA approved assay for the detection of HPV infection of the oropharynx.
Purpose To identify a screening test that could be used to test a large group of individuals atrisk for human papillomavirus (HPV) infection of the oropharynx (mouth and tonsils).
Aims 1. To identify differences in the sensitivity, specificity, and positive and negative predictive values across various combinations of biologic samples, analytic methods and collection kits. 2. To investigate how well the various combinations of biologic samples, analytic methods and collection kits predicted the presence of HPV infection in the oropharynx.
Methods Cross-sectional, exploratory pilot study 40 individuals Explored sensitivity and sensitivity of various combinations of biologic samples, and analytic and collection methods Histologic and cytological evaluation Molecular genomic interrogation DNA isolation Third Wave Invader Technology Immunohistochemistry
INCLUSION CRITERIA 18 years of age or older English speaking Primary lesion Sore, irritation, lump, and/or thick, red or white patch noted in their mouth and/or on their tonsils No history of prior chemo radiation therapy
METHODS Sexual History & Social Behavior Questionnaire Demographic & Descriptive Data Saliva, Exfoliated cells, and Biopsy Tissue 1. Gold Standard: Biopsy tissue a. Histology: Routine Evaluation & Diagnosis b. DNA Analysis for HR HPV Status c. p16 IHC Staining for HPV Detection 2. Combinations (Biologic Sample, Collection Container, and Assay a. HPV Positive & Negative Saliva and Exfoliated Cells i. DNA/Saliva Container & Cytology ii. DNA/Saliva Container & Third Wave Invader Chemistry-DNA for HR HPV iii. Non-GYN Liquid Based Container & Saliva & Cytology iv. Non-GYN Liquid Based Container & Saliva & Third Wave Invader Chemistry-DNA for HR HPV
Combination #1: Saliva, Third Wave Invader Technology HR HPV Assay
Combination #1 Table 1: Sensitivity, Specificity, PPV, and NPV. Sensitivity, % (95%CI) 100% (75.9-100) Specificity, % (95% CI) 20% (5.3-48.6) Positive Predictive Value (PPV), (95% CI) 57.1% (37.4-74.9) Negative Predictive Value (NPV), (95%CI) 100% (30.9-100) Kostas-Polston et. al. (2015), unpublished data.
Combination #2: Saliva, Non-GYN, Third Wave Invader Technology HR HPV Assay
Combination #2 Table 1: Sensitivity, Specificity, PPV, and NPV. Sensitivity, % (95%CI) 56.2% (30.5-79.2) Specificity, % (95% CI) 66.7% (38.7-87) Positive Predictive Value (PPV), (95% CI) 64.3% (35.6-86) Negative Predictive Value (NPV), (95%CI) 58.8% (33.4-80.5) Kostas-Polston et. al. (2015), unpublished data.
Combination #3: Oral Scraping, Non- GYN, Cytology
Combination #3 Table 1: Sensitivity, Specificity, PPV, and NPV. Sensitivity, % (95%CI) 31.2% (12.1-58.5) Specificity, % (95% CI) 73.3% (44.8-91) Positive Predictive Value (PPV), (95% CI) 55.5% (22.6-84.6) Negative Predictive Value (NPV), (95%CI) 50% (28.8-71.1) Kostas-Polston et. al. (2015), unpublished data.
Combination #4: Saliva, Tube, Cytology
Combination #4 Table 1: Sensitivity, Specificity, PPV, and NPV. Sensitivity, % (95%CI) 56.2% (30.5-79.2) Specificity, % (95% CI) 66.7% (38.7-87) Positive Predictive Value (PPV), (95% CI) 64.3% (35.6-86) Negative Predictive Value (NPV), (95%CI) 58.8% (33.4-80.5) Kostas-Polston et. al. (2015), unpublished data.
Combination #5: Oral Scraping, Non- GYN, Third Wave Invader Technology HR HPV Assay
Combination #5 Table 1: Sensitivity, Specificity, PPV, and NPV. Sensitivity, % (95%CI) 78.5% (48.8-94.2) Specificity, % (95% CI) 78.5% (48.8-94.2) Positive Predictive Value (PPV), (95% CI) Negative Predictive Value (NPV), (95%CI) 78.5% (48.8-94.2) 78.5% (48.8-94.2) Kostas-Polston et. al. (2015), unpublished data.
Combination #6: Biopsy Tissue and p16 Immunohistochemistry (IHC)
Combination #6 Table 1: Sensitivity, Specificity, PPV, and NPV. Sensitivity, % (95%CI) 87.5% (60.4-97.8) Specificity, % (95% CI) 100% (73.2-100) Positive Predictive Value (PPV), (95% CI) 100% (73.2-100) Negative Predictive Value (NPV), (95%CI) 87.5% (60.4-97.8) Kostas-Polston et. al. (2015), unpublished data.
HPV Status, Lifestyle Habits & Clinical Parameters Gender 1:5 (males : females) 1 AA All OP lesions tumors 16 BOT, 14 Tonsil Average age 53.7 years Marital Status 60% Married 28% Divorced/Separated 82% Ever Smokers Average age of onset 17.8 years Average number of years smoking 26.4 years ETOH 60% Non-drinkers 40% 4 drinks/week
HPV Status, Lifestyle Habits & Clinical Parameters (cont d). First Sexual Activity = 17.4 years Total # of Partners = 14 (Range 1-75) 9% Self-Reported History of STI 9% Self-Reported Partner with History of STI 24% Anal Sex 67% Oral Sex 83% Never Used Condoms 38% No Condoms with Anal Sex 71% Steady Partner
HPV Status, Lifestyle Habits & Clinical Parameters (cont d). 100% OPSCC (histological diagnosis) 50% HPV Positive All but one presented with advanced stage disease/distant metastasis (Tumor Stages III-IVA) p16 (Gold Standard) All but one HR HPV status correlated with p16 status + p16/- HR HPV Third Wave Invader Technology HR HPV Assay
Implications 1. Findings expand understanding of natural history of OP HPV infection. Initial infection clearance vs. persistence carcinogenesis. 2. Establishing the best biological sample type & method, collection kit and laboratory assay may lead to the identification of an accurate, noninvasive test to be used in clinical settings for the purpose of early detection of persistent HPV-related OP infection.
PARTNERING Mentors, Colleagues and Friends
Mark Varvares, M.D. Leonard Grosso, M.D., Ph.D. Ron Walker, M.D. Juan Gonzalez, M.D.
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