An Update on HPV and Cervical Cancer Prevention

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1 An Update on HPV and Cervical Cancer Prevention Nancy R. Berman MSN, ANP-BC, NCMP, FAANP Adult Nurse Practitioner/Colposcopist Certified Menopause Practitioner (NAMS) Millennium Affiliated Physicians Division of Michigan Healthcare Professionals Farmington Hills, Michigan Clinical Instructor Department of Obstetrics and Gynecology Wayne State University School of Medicine Detroit, Michigan

2 Disclosures Advisory Board: Hologic Advisory Board: LabCorp

3 Objectives At the end of this session, the attendee will: 1. Describe the role of persistent oncogenic HPV in the development of pre-cancer and cancer of the cervix 2. List the current Advisory Committee on Immunization Practice (ACIP) recommendations for appropriate use of 2 or 3 doses of 9vHPV Vaccine 3. Describe the use of HPV testing as co-testing along with the Pap in cervical cancer screening in women 30 and older 4. Describe the use of HPV primary screening in women 25 and older

4 The Burden of HPV Disease

5 High Lifetime Risk of HPV Infection 6.2 million new infections Approximately 20 million people in US currently are infected with HPV By age 50, 80% of sexually active women will have acquired genital HPV infection Most people will never know that they have been infected! Weinstock H. Perspect Sex Reprod Health. 2004; CDC. Self-Study STD Module HPV Infection.

6 HPV and Non-Cervical Cancers HPV 16 Evidence of causal role in cancer of vagina, vulva, penis, anus, oral cavity, oropharynx; limited evidence for carcinogenicity in the larynx HPV 18 Limited evidence of carcinogenicity in vagina, vulva, penis, anus, oral cavity, larynx HPV 6 and 11 Limited evidence of carcinogenicity in vulva, penis, anus, larynx Munoz N. Vaccine IARC. Monographs on the Evaluation of Carcinogenic Risks to Humans

7 Cancers Caused by HPV: U.S. Cancer site Average number of cancers per year probably caused by HPV Male Female Both Sexes Percentage per year Anus 1,400 2,600 4,000 91% Cervix 0 10,400 10,400 91% Oropharynx 7,200 1,800 9,000 72% Penis % Vagina % Vulva 0 2,200 2,200 69% TOTAL 9,300 17,600 26,900 CDC, United States Cancer Statistics (USCS), You Are the Key to HPV Cancer Prevention, CDC

8 HPV and Cervical Cancer Virtually all cervical cancers are associated with persistent infection with high-risk HPV types Data from a variety of studies have confirmed that certain HPV types are associated with cervical cancer: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 Others are probably associated: 26,53, 66, 68,73, 82 Oncogenic HPV is a necessary cause of cervical cancer! IARC. Monographs on the Evaluation of Carcinogenic Risks to Humans. (in press); Munoz N. Vaccine

9 Role of Persistent Infection Persistent infection with high-risk types of HPV is necessary for the progression of high-grade lesions to invasive cancer Average episode lasts 4-20 months <50% of women have same type 1 year later Type 16 has a greater risk of persistence Trottier H. Vaccine

10 Risk Factors for Persistent HPV Infection and/or Neoplastic Progression Smoking HPV type Increasing age Lack of condom use Immunodeficiency (eg, HIV) Possibly OC use Possibly other STIs, such as chlamydia Moscicki A-B. Vaccine. 2006; Moscicki A-B. J Infect Dis. 2004; Hogewoning CJ. Int J Cancer

11 HPV and Cervical Cancer Putting Risk Into Perspective Risk (odds) of cervical cancer with HPV 16 compared with HPV ( ) is 455. Risk of lung cancer in U.S. white male smoker compared with nonsmoker is only 8. Risk of breast cancer with hormone replacement therapy is only 1.8.

12 Natural History of HPV & Cervical Cancer Persistence Normal Cervix Infection Progression Invasion Clearance HPV Infection Regression Pre-cancer Cancer Courtesy of M. Schiffman, National Cancer Institute.

13 Why Is the Cervix At Risk Understanding Transformation Zones

14 Transformation Zones and HPV Infection Area where one type of epithelium contacts and gradually replaces another through process of metaplasia Present in cervix, anus, tonsils Areas of HPV-related carcinogenesis Moscicki AB. Vaccine

15 Cervical Transformation Zone Source:

16 HPV Vaccines

Adolescent Vaccination Coverage United States, 2006-2013 MMWR

17 Adolescent Vaccination Coverage United States, MMWR 2014; 63(29); You Are the Key to HPV Cancer Prevention, CDC

18 HPV Vaccine Comparison These Genital warts HPV Types Cause: ~66% of Cervical Cancers ~15% of Cervical Cancers

19 Advisory Committee on Immunization Practice (ACIP) Recommendations Meites E, Kempe A, Markowitz LE. Use of a 2- Dose Schedule for Human Papillomavirus Vaccination Updated Recommendations of the Advisory Committee on Immunization Practice. MMWR Morb Mortal Wkly Rep 2016;65:

20 Current Recommendations: Advisory Committee on Immunization Practice (ACIP) Updated Recommendations of the Advisory Committee on Immunization Practices Routine and catch-up age groups Can be started at age 9 Females through age 26 Males through age 21 who were not adequately vaccinated previous Males age 22 through 26 may be vaccinated The number of recommend doses is based on age at administration of the first dose Before age 15: 2 injections After age 15: 3 injections Meites E, Kempe A, Markowitz LE. Use of a 2- Dose Schedule for Human Papillomavirus Vaccination Updated Recommendations of the Advisory Committee on Immunization Practice. MMWR Morb Mortal Wkly Rep 2016;65:

21 HPV Vaccine Safety

22 VAERS: HPV Vaccine Safety Monitoring Ongoing safety monitoring has shown most reports are nonserious Among the 7.6% of reports coded as serious, most frequently cited possible side effects are headache, nausea, vomiting, and fever Syncope (fainting) continues to be reported following vaccination among adolescents Adherence to a 15-minute observation period after vaccination is encouraged More injection-site reactions expected among those who receive 9vHPV MMWR. 2014;63(RR05);1-30. You Are the Key to HPV Cancer Prevention, CDC

23 #1 Reason That a Parent Doesn t Vaccinate Their Child My Healthcare provider didn t recommend it. I didn t know it was so important. Newitt V, HPV Vaccination, Advance for Nurse Practitioners, July/August, 2015

24 Make a Strong Recommendation Evidence shows that: A health care provider recommendation to get vaccinated, is the single most influential factor in determining whether a parent gets an immunization for their child! Frieden, MD, MPH, CDC Director, Morbidity and Mortality Weekly Report, 7/25/13

25 Cervical Cancer Prevention Pap and HPV Testing

26 Goal of Cervical Cancer Screening Prevent morbidity and mortality from cervical cancer by: Identifying and treating high-grade cervical cancer precursors Avoiding unnecessary and potentially hazardous evaluations and treatment Minimizing costs to healthcare system Increase benefit and decrease harm! Saslow D, et al. CA Cancer J Clin

27 Being rarely or never screened is the major contributing factor to most cervical cancer deaths today.

28 2012 ACS/ASCCP/ASCP Cervical Cancer Screening Guidelines Saslow, Solomon, Lawson, et al. JLGTD, March 14, 2012 (online) Saslow, Solomon, Lawson, et al. CA: A Cancer J for Clinicians, March 14, 2012 (online)

29 Guidelines: Age to Start Cervical Cancer Screening ACS/ASCCP/ASCP, ACOG, USPSTF agree: Start at age 21 regardless of age of sexual debut Moscicki AB, Cox JT. J Low Genit Tract Dis Saslow D. et al. CA Cancer J Clin. 2012; ACOG Committee on Practice Bulletins. Obstet Gynecol. 2012; USPSTF. Moyer VA on behalf of the USPSTF. Ann Intern Med

30 Cervical Cancer Incidence by Age Group, USCS*, Age Rate per 100, All ages 9.4 *United States Cancer Statistics includes data from CDC s National Program of Cancer Registries and NCI s Surveillance, Epidemiology and End Results Program.Saraiya M et al. Obstet Gynecol 2007;109:

31 Guidelines: Cervical Cancer Screening Interval ACS/ASCCP/ASCP and ACOG Pap testing every 3 years for women ages Preferred for women 30 and older: Cotesting with Pap and HPV test every 5 years Acceptable for women 30 and older: Pap testing alone every 3 years Saslow D. et al. CA Cancer J Clin ACOG. Obstet Gynecol more

32 Guidelines: Cervical Cancer Screening Interval (Continued) USPSTF Pap testing every 3 years for women ages For women ages 30-65, may have Pap test plus HPV test every 5 years to extend screening interval Moyer VA on behalf of the USPSTF. Ann Intern Med

33 Factors Indicating Need for More Frequent Screening HIV infection Immunosuppression DES exposure in utero Previous treatment for CIN 2, CIN 3, or cancer ACOG Practice Bulletin #

34 Guidelines: Age to Stop Cervical Cancer Screening ACS, ASCCP, ASCP, and ACOG Can stop screening in women older than age 65 with no history of CIN2 within the past 20 years and with evidence of adequate negative screening* USPSTF Can stop at age 65 if adequate recent screening with normal Pap tests and are not at high risk for cervical cancer * defined as 3 consecutive normal Pap tests or 2 consecutive negative cotests within preceding 10 years, with the most recent test occurring within the past 5 years. Saslow D. et al. CA Cancer J Clin. 2012; ACOG Committee on Practice Bulletins. Obstet Gynecol ; USPSTF. Moyer VA on behalf of the USPSTF. Ann Intern Med. 2012

35 Guidelines: Screening Post- Hysterectomy ACS/ASCCP/ASCP, ACOG, USPSTF Guidelines Recommend against routine screening if hysterectomy performed for benign disease and no history of high-grade precancer or greater Saslow D. CA Cancer J Clin. 2012; ACOG Committee on Practice Bulletins. Obstet Gynecol. 2012; Moyer VA on behalf of USPSTF. Ann Intern Med

36 HPV Testing

37 Why Test for HPV? Persistent high risk HPV is necessary for the development of cervical cancer An obvious corollary is that the absence of HPV means that the risk of cervical cancer is negligible The negative predictive value for combined HPV Testing and the Pap has been shown to be 99.21% for CIN3. Sherman ME, et al. J Nat Cancer Inst. 2003;95:46-52.

38 HPV Testing for Screening: Stratifies Risk Allows for less frequent testing Identifies women who need increased surveillance Wright TC. Obstet Gynecol Katki HA et al. Lancet Oncol

39 FDA Approved HPV Tests Available Tests HPV Types Detected Identifies HPV Type Hybrid Capture 2 High and low risk panels (request high risk only) Cervista HPV HR High risk No (add on test for 16 and 18) cobas HPV Test High risk Yes for 16 and 18 No APTIMA HPV mrna assay Onclarity High risk High risk No (add on test for 16, 18, and 45) Yes for 16,18, 45 ASCCP. Educate the Educators: HPV and the HPV Vaccines. 2018

40 Screening Interval for Combined Pap and HPV Testing in Women 30 and Older: Co-Testing HPV Result Cytology Recommended Management Negative Negative Cotest in 5 years Negative ASC-US Cotest in 3 years Positive ASC-US Colposcopy Negative LSIL Repeat cotesting in 1 year preferred; colposcopy acceptable Positive Pap > LSIL Colposcopy Any Positive HSIL Negative Colposcopy or immediate loop electrosurgical excision Option 1: Cotest in 12 months Option 2: Reflex to genotyping for HPV 16/18. If positive, colposcopy. If negative, cotest in 12 months Massad LS, et al. J Low Genit Tract Dis Saslow D. CA Cancer J Clin 2012.

41 Genotyping to Triage Women 30 with Pap-/HPV+ Results Genotyping Positive for 16 or 18 Negative for 16 and 18 Immediate colposcopy Co-testing in 12 months

42 Management of Repeat Testing After HPV +, Cytology - Results HPV Result Cytology Recommended Management Negative Negative Repeat cotesting in 3 years Positive Negative Perform colposcopy Any Pap > ASC-US Perform colposcopy Massad LS, et al. J Low Genit Tract Dis Saslow D. CA Cancer J Clin 2012.

43 Primary HPV Testing for Cervical Cancer Screening Stand-alone HPV test

44 2014 FDA Approval for Primary HPV Testing for Cervical Cancer Screening Rationale More sensitive and reproducible than cytology Assesses current and future risk More cost-effective for large-volume screening May be more useful in women vaccinated against HPV Educate the Educator: ASCCP 2016

45 FDA Approved Tests for Primary HPV Screening (Stand Alone Testing) cobas HPV Test Provides genotyping for HPV 16 and18 concurrently with testing for the presence of 12 other high-risk HPV types Onclarity Test Provides genotyping for HPV 16, 18, 45 and concurrently with testing for the presence of 11 other high risk types

46 Women with HPV16 and HPV18 infections are more likely to develop high-grade disease HPV16+ HPV18+ Other high-risk HPV+ High-risk HPV- 20 Cumulative incidence rate of CIN3 (%) Follow-up time (months) % (11.5, 22.9) 13.6% (3.6, 23.7) 3.0% (1.9, 4.2) 0.8% (0.6, 1.1) Khan MJ, et al. J Natl Cancer Inst 2005; 97:

47 Interim Clinical Guidance Primary hrhpv screening should not be initiated before 25 years of age In Athena, 30% of CIN3+ cases were found in women between 25 and 29 years of age More than half of women from with CIN3+ had normal cytology Primary hrhpv screening can be considered as an alternative to current U.S. cytology alone or cotesting

48 The HPV primary screening algorithm cobas HPV Test other hrhpv+ HPV Cytology HPV16/18+ NILM ASC-US Routine screening Follow-up in 12 months Colposcopy Huh WK, Ault KA, Chelmow D, Davey D, Goulart FA, Garcia FA, Kinney WK, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol 2015:125:

49 Countries Implementing HPV Primary Screening Netherlands: Minister of Health approved HPV primary screening beginning in 2016 Australia: National Health Service adopted screening with HV 16/18 genotyping starting at age 25 y at 5-yr intervals up to age United Kingdom: Evaluating in large national pilot study at 6 National Health Service screening sites including London, Liverpool, and Manchester. Italy: A number of regions have adopted primary screening Educate the Educators: ASCCP 2016

50 USPSTF: Current Draft Guidelines Pap every 3 years age 21 and older HPV testing alone every 5 years starting at age 30 Co-testing with Pap and HPV no longer recommended Draft Recommendation Statement: Cervical Cancer: Screening. U.S. Preventive Services Task Force. October

Cervical Pathology (ASCCP) Guidelines www.

51 Algorithms Are Available! 2012 American Society for Colposcopy and Cervical Pathology (ASCCP) Guidelines Download Algorithms Mobile App: iphone and Android

52 Anal Cancer HPV

53 Anal Cancer Incidence relatively low compared with cervical cancer Incidence is increasing in both men and women by about 2% a year Reason for the increase is not well understood Men who have sex with men (MSM) shown to be one the populations at highest risk Anal receptive intercourse is a risk factor but is not necessary for anal cancer to develop Ferris DG, Cox JT, O Connor DM, Wright VC, Forester J. The anal canal and perianus: HPV-Related Disease. In Modern Colposcopy, Textbook and Atlas, 3 rd ed., 2012, Wolters Kluwer, Lippincott Williams & Wilkins. pg

54 Anal Cancer History of HPV associated lesions at genital sites other than the anus are associated with anal cancer Immunosuppression is an important risk factor for anal cancer Solid organ transplant recipients of heart, kidney and lungs HIV- associated immunosuppression Anal cancer is associated with high-risk types of HPV (16 and 18 are identified in about 80%) Ferris DG, Cox JT, O Connor DM, Wright VC, Forester J. The anal canal and perianus: HPV-Related Disease. In Modern Colposcopy, Textbook and Atlas, 3 rd ed., 2012, Wolters Kluwer, Lippincott Williams & Wilkins, pg

55 Anal Cancer Screening Anal screening Cytologic screening High resolution anoscopy (HRA) HRA directed biopsy Treatment of high grade anal intraepithelial neoplasia (HGAIN) aims to prevent invasive anal squamous cell cancer Ferris DG, Cox JT, O Connor DM, Wright VC, Forester J. The anal canal and perianus: HPV-Related Disease. In Modern Colposcopy, Textbook and Atlas, 3 rd ed., 2012, Wolters Kluwer, Lippincott Williams & Wilkins, pg

56 Current Status of Screening Recommendations Routine anal cytology screening is NOT recommended by CDC, USPSTF, ACS, or ISDA National Guidelines Clearinghouse has no guidelines for anal cytology screening However New York State Department of Health now recommends anal cytology for HIV-infected individuals who: 1) are MSM, 2) have had genital warts or 3) have had CIN New York State Dept of Health.

57 Head and Neck Cancer HPV

58 Incidence in United States Women Men Total Oral cavity and pharynx 11,710 28,540 40,250 Larynx 2,520 9,840 12,360 Total 14,230 38,380 52,610 American Cancer Society. Facts & Figures

59 HPV as a Risk Factor Incidence of HPV-positive oropharyngeal cancers increased by 225% from 1998 to 2004 (0.8 per 100,000 to 2.6 per 100,000) Incidence of HPV-negative cancers declined by 50% (2.0 per 100,000 to 1.0 per 100,000) If trends continue, incidence of HPV-positive oropharyngeal cancers will be greater than incidence of cervical cancers by Chaturvedi AK. J Clin Oncol

60 Differences HPV positive HPV negative Site Tonsil, base of tongue Various sites Age Younger Older Risk Sexual behavior Tobacco, alcohol Incidence Increasing Decreasing Survival Better Worse Vidal L. Hematol Oncol Clin N Am

61 Survival probability: HPV-negative vs. HPV-positive tumors Only HPV-positive oropharyngeal cancer patients showed significantly better survival when compared with all head and neck patients Best survival from oropharyngeal cancer: HPV-positive with no history of smoking Worst survival from oropharyngeal cancer: HPV-negative with a history of smoking Sethi S. Int J Cancer Inst

62 Oropharyngeal Cancer Located in middle of the throat: base of the tongue, tonsils, soft palate, walls of the pharynx. No precursor lesions or biomarkers Data does not support the role of saliva tests Often presents as lymphadenopathy with the cancer deep in the tonsillar crypts Oral HPV or cancer in monogamous couples: no current recommendation to change behavior Oral Presentation: D Souza, G., ASCCP Annual Meeting. April 20, 2018.

63 United States Preventive Services Task Force Guidelines The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for oral cancer in asymptomatic adults. Release Date: November 2013 Final Update Summary: Oral Cancer: Screening. U.S. Preventive Services Task Force. September

64 American Cancer Society Guidelines the cancer-related check-up should include examination for cancers of the thyroid, testicles, ovaries, lymph nodes, oral cavity, and skin, as well as health counseling... Smith RA. CA Cancer J Clin

65 Counseling Patients with HPV Remind your patient that: Most people will have HPV at some point. There is no way of knowing how long HPV has been present. Having HPV is not a sign of infidelity or promiscuity. Most women who have HPV do not develop abnormal cells or cancer. Most HPV infections will go away on their own in a relatively short time.

66 Summary HPV Vaccine is a cancer prevention vaccine Your recommendation is the most significant factor in whether age appropriate young men and women are vaccinated HPV vaccination is underutilized in the U.S.

67 Summary The 2012 Guidelines for cervical cancer prevention Identifies low risk women (HPV and Pap negative) and reassures them about safety of longer screening interval Identifies truly at-risk women with persistent HPV Follow them diligently FDA approval of HPV testing as a primary screen, April 2014 Never has education of patients and practitioners been more important!

68 Summary Majority of cervical cancer in U.S. occurs in women who have not been screened or infrequently screened Improving access to screening for these women will have a great impact on the prevention of cervical cancer!

69 References 1. Saslow D, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. J Low Genit Tract Dis. 2012;16(3): Walboomers JM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1): Huh WK, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol. 2015;125(2): Massad LS, et al updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4): Hamborsky J KA, Wolfe S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13 th ed. Washington, DC: Public Health Foundation; Ho GY, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338(7): Ho GY, et al. Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia. J Nat Cancer Inst. 1995;87(18):

70 References 8. Moscicki AB, et al. Chapter 5: Updating the natural history of HPV and anogenital cancer. Vaccine. 2006;24(Suppl 3):S3/ Schiffman M, Kjaer SK. Chapter 2: Natural history of anogenital human papillomavirus infection and neoplasia. J Natl Cancer Inst Monogr. 2003(31): Jemal A, et al. Annual Report to the Nation on the Status of Cancer, , featuring the burden and trends in human papillomavirus(hpv)-associated cancers and HPV vaccination coverage levels. J Nat Cancer Inst. 2013;105(3): Wright TC Jr., et al. Interlaboratory variation in the performance of liquid-based cytology: insights from the ATHENA trial. Int J Cancer. 2014;134(8): Ciavattini A, et al. Loop electrosurgical excision procedure and risk of miscarriage. Fertil Steril. 2015;103(4): Jin G, et al. Pregnancy outcome following loop electrosurgical excision procedure (LEEP) a systematic review and meta-analysis. Arch Gyn Obstet. 2014;289(1): Ronco G, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383(9916): Wright TC Jr., et al. Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with highrisk HPV+ cytology-negative results. Am J Clin Pathol. 2011;136(4): Ronco G, et al. HPV16 and HPV18 genotyping in cervical cancer screening. Lancet Oncol. 2011;12(9):

71 References 19. Wright TC, et al. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136(2): Wright TC, Jr., et al. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46.e41-46.e Cox JT, et al. Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing, and genotyping for HPV 16/18: results from the ATHENA HPV study. Am J Obstet Gynecol. 2013;208(3):184 e e Stoler MH, et al. Point-Counterpoint: Cervical Cancer Screening Should Be Done by Primary Human Papillomavirus Testing with Genotyping and Reflex Cytology for Women over the Age of 25 Years. J Clin Microbiol. 2015;53(9): Blatt AJ, et al. Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices. Cancer Cytopathol. 2015;123(5): Gage JC, et al. Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. J Nat Cancer Inst. 2014;106(8). 25. Qaseem A, et al. Screening pelvic examination in adult women: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2014;161(1): Practice Bulletin No. 157: Cervical Cancer Screening and Prevention. Obstetrics and gynecology. 2016;127(1):e1-e20.

Disclosures. Objectives (Continued) Objectives. Goal of Cervical Cancer Screening. An Update on HPV and Cervical Cancer Prevention

Disclosures. Objectives (Continued) Objectives. Goal of Cervical Cancer Screening. An Update on HPV and Cervical Cancer Prevention An Update on HPV and Cervical Cancer Prevention Disclosures Consultant and Speaker: Hologic Advisory Board: LabCorp Nancy R. Berman MSN, ANP-BC, NCMP, FAANP Adult Nurse Practitioner/Colposcopist Certified