Emerging Challenges in Primary Care. Cervical Cancer Screening: Appropriate Use of Pap & HPV Testing

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1 Emerging Challenges in Primary Care Cervical Cancer Screening: Appropriate Use of Pap & HPV Testing

2 Faculty Nancy R. Berman, MSN, ANP-BC, NCMP, FAANP Adult Nurse Practitioner Certified Menopause Practitioner Millennium Affiliated Physicians Division of Michigan Healthcare Professionals Farmington Hills, MI

3 Disclosures Nancy R. Berman, MSN, ANP-BC, NCMP, FAANP serves as an advisory board committee member and speaker for Hologic (Self), Bayer (Spouse). Additionally, her spouse serves as a speaker for Smith and Nephew.

4 Learning Objectives 1. Describe the role of persistent oncogenic HPV in the development of pre-cancer and cancer of the cervix. 2. Describe the use of HPV testing as co-testing along with the Pap in cervical cancer screening in women 30 and older. 3. Describe the use of HPV primary screening in women 25 and older. 4. Describe 3 important messages that clinicians will teach women regarding HPV infection.

5 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

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

7 Who are the Rarely and Never Screened? Descriptions Minorities Low SES* Foreign born Living in the US < 10 years No usual source of health care Where are the data? US Census NCHS Cervical cancer mortality BRFSS µ NHIS** * Socio-economic status National Center for Health Statistics, CDC µ Behavioral Risk Factor Surveillance System, CDC ** National Health Interview Survey, CDC

8 What s to Know, What s New and What s Changed HPV Natural History

9 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, including: 26, 53, 66, 68, 73, 82 IARC. Monographs on the Evaluation of Carcinogenic Risks to Humans.; Munoz N. Vaccine

10 HPV Impact: Cervical Cancer In the US (2014 estimate): 12,340 cases per year 4,030 deaths per year Worldwide (2008 estimate): 530,000 cases per year 275,000 deaths per year 85% of deaths occur in developing countries Cervical cancer screening: costs $3.4 billion annually American Cancer Society. Cancer Facts and Figures. 2012; GLOBOCAN 2008 (IARC). Insinga RP. AJOG

11 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

12 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 Weinstock H. Perspect Sex Reprod Health. 2004; CDC. Self-Study STD Module HPV Infection.

13 Role of Persistent Infection Persistent infection with high-risk types of HPV is necessary for the progression of high-grade lesions to invasive cancer Trottier H. Vaccine more

14 Role of Persistent Infection (Continued) 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

15 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. Educate the Educator: ASCCP 2016

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

17 Risk Factors for HPV Infection Sexual Activity Multiple Partners Younger age at sexual debut Lack of condom use Ley C. J Natl Cancer Inst. 1991; Winer RL. N Engl J Med. 2006; Ho GYF. N Engl J Med

18 Condom Use and HPV Prevention Rate of HPV infection per 100 patient-years at risk Winer RL. N Engl J Med

19 HPV Vaccination Before HPV exposure Boys and girls age 11 to 12 Catchup vaccination to age 26 Garland SM. N Engl J Med. 2007; Winer RL. J Infect Dis. 2005; CDC 2013; CDC 2014.

20 What s to Know, What s New and What s Changed Secondary Prevention Identifying and treating high-grade precancerous lesions

21 Current Approach to Cervical Cancer Prevention Requires four separate but linked components: HPV vaccination Screening Cytology with or without HPV testing Stand alone HPV testing: HPV Primary Screening Evaluation of screen-positive women using colposcopy and cervical biopsy Treatment of women with biopsy-confirmed highgrade cervical cancer precursors Wright T. Obst Gynecol 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:

22 Potential Harms From Cervical Cancer Screening Anxiety from an abnormal test that the patient might fear to be a sign of cancer Stigma from diagnosis of a ubiquitous sexually transmitted infection (HPV) Time and patient expense related to screening and management Pain and injury from the procedures and treatment Increased risk of premature delivery and pregnancy loss Einstein, M, Cox, J.T., Cervical Disease, OBG Management, Vol.25, May 2013

23 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)

24 Age to Start Cervical Cancer Screening Factors to consider HPV infections are common in young women Cervical cancer is rare in adolescents/young women Evaluation of minor cytological abnormalities: Is expensive Causes anxiety Can lead to unnecessary treatments ACOG Committee on Gynecologic Practice. Obstet Gynecol

25 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

26 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:

27 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

28 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

29 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 #

30 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

31 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

32 Interval Extension and Well Woman Visit Pap is only one part of the annual well woman exam Unteach women about annual cervical screening Individualized: age, prior screening, HPV status Pap only part of visit, and not every year The annual exam should include Screening, evaluation, counseling, immunizations per age, risk factors Cervical Cytology Screening. ACOG Practice Bulletin No American College of Obstetricians and Gynecologists. Obstet Gynecol 2009; 114:

33 July 1, 2014

34 June 30, 2014

35 HPV Testing

36 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.

37 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

38 HPV Detection with FDA-Approved Tests Four tests are currently FDA approved and commercially available in the US One is approved for primary, stand-alone screening more

39 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 High risk No (add on test for 16, 18, and 45) ASCCP. Educate the Educators: HPV and the HPV Vaccines

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 What s to Know, What s New and What s Changed Primary HPV Testing for Cervical Cancer Screening

45 FDA approves first human papillomavirus test for primary cervical cancer screening The U.S. Food and Drug Administration today approved the first FDA-approved HPV DNA test for women 25 and older that can be used alone to help a health care professional assess the need for a woman to undergo additional diagnostic testing for cervical cancer. The test also can provide information about the patient s risk for developing cervical cancer in the future.

46 FDA Approved Test for Primary HPV Screening (Stand Alone Testing) Roche cobas HPV Test Provides genotyping for HPV types 16 and 18 concurrently with testing for the presence of 12 other high-risk HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, & 68) Has an internal control for specimen adequacy Currently: this is the only test that is FDA approved for primary HPV testing!

47 Why HPV Primary Screening? Co-testing (Pap and HPV testing) is only marginally better than HPV testing alone!

48 Issues to Consider With Cytology Highly subjective test: substantial inter- and intralaboratory variability and limited reproducibility Misses quite a few cervical cancers Unable to identify those women who are at future risk of developing cervical cancer precursors Unclear how cytology will perform as HPV vaccine uptake rates increase in the US

49 Performance of Cervical Cytology Sensitivity for >CIN2 Author Year Number Method Sensitivity 95% CI Petry ,466 Conv 44% (30-58%) Coste ,080 Conv 65% (50-80%) Taylor ,114 LBC 71% (58-81%) Ronco ,760 LBC 74% (62-84%) Mayrand ,153 Conv 57% (34-78%) 2012 US Preventative Task Force Review

50 Importance of Genotyping for HPV 16 &18 Over two thirds of cervical cancers in the United States are caused by HPV 16 &18 Other individual high-risk HPV genotypes are associated with far fewer cancers Persistent HPV 16 infection confers a very high risk for CIN 3+, as shown in multiple long-term studies Educate the Educators, ASCCP 2016

51 Predictive Value of HPV Genotyping National Cancer Institute-Kaiser Northwest Study 20,817 women with satisfactory cytology at enrollment ( ) Archived samples tested with PCR for HPV Follow-up with cytology, standard workup for abnormal findings Case-control design (women with/without CIN) Women followed for up to 15 y (median = 10.5 y) Educate the Educators, ASCCP 2016

52 Predictive Value of HPV Genotyping 15-y risk of CIN 3+ in Kaiser Northwest cohort Educate the Educator: ASCCP 2016

53 What Study Led to FDA Approval for Primary HPV Testing? ATHENA Addressing the Need for Advanced HPV Diagnostics

54 ATHENA: Addressing the Need for Advanced HPV Diagnostics Prospective, multicenter, US-based study of 47,208 women aged 21 and older Recruited at time of routine screening 2.6% had been vaccinated against HPV Screened by liquid based cytology and HPV test

55 ATHENA Designed to assess the medical utility of pooled high-risk HPV DNA in addition to genotyping for HPV 16 and 18 in 3 populations Women 21 and older with a cytologic finding of ASC-US Women 30 and older with normal cytology Women aged 25 and older in the overall screening population with any cytologic finding

56 Variability of Cervical Cytology Cytology for the ATHENA study Educate the Educator: ASCCP 2016

57 Absolute Risk of CIN in Cytology- Women Women 30 years, Athena Study Wright TC, Stoler MH, Behrens CM, 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): Educate the Educator ASCCP 2016

58 Proportion of CIN3 by Age Group Athena Trial: Why Start Primary Screening at Age 25 Wright TC, Stoler MH, Behrens CM, 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): Educate the Educator ASCCP 2016

59 Primary High Risk Human Papillomavirus Testing for Cervical Cancer Screening Interim Clinical Guidance 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:

60 Interim Clinical Guidance Published Obstetrics & Gynecology, February 2015 Rationale: A negative hrhpv test provides grater reassurance of low CIN3+ risk than a negative cytology result Because of equivalent or superior effectiveness, primary hrhpv screening can be considered as an alternative to current U.S> cytology-based cervical cancer screening methods. Cytology alone and cotesting remain the screening options specifically recommended in major guidelines 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:

61 Interim Clinical Guidance Based on limited data: Triage of hrhpv positive women using a combination of genotyping for HPV 16 and 18 And reflex cytology for women positive for the 12 other hrhpv genotypes appears to be a reasonable approach to managing hrhpv-positive women 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:

62 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:

63 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

64 Interim Clinical Guidance Rescreening after a negative primary hrhpv screen should occur NO SOONER than every 3 years 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:

65 Interim Clinical Guidance Primary hrhpv screening can be considered as an alternative to current U.S. cytology alone or cotesting HPV 16/18 genotyping and reflex cytology for women positive for the other 12 types: achieves a reasonable balance of disease detection with the number of screening tests and colposcopies required to achieve that detection 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:

66 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

67 HPV Primary Screening New ACOG Guidelines Recommends following the SGO/ASCCP guidelines if HPV primary screening is used Additional recommendations: Stop screening women at 65 y who have a history of negative findings. Do not use HPV testing to screen women who have had a hysterectomy. Follow-up with cotesting at 12 months if HPV+ and cytology-negative and HPV 16/18 negative. Use only the FDA approved test. Educate the Educators: ASCCP 2016

68 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

69 Case Study Your 42-year old patient with no previous HPV screening was screened by you, using HPV testing alone. The patient is HPV (+) for HPV 16 and the panel of 12 other types How do you interpret this result? What is the next step in her management? Does she need a reflex to a Pap?

70 Case Study You are a colposcopist and bring her in for immediate colposcopy or refer her out for colposcopy. The colposcopy is adequate, as the squamocolumnar junction is seen 360 degrees around. There are no lesions to biopsy and an ECC is performed, which is reported as negative. What will you do next? How will you determine what you do next?

71 Guidelines Are Meant to Increase Benefits and Decrease Harms! Complicated? HELP IS AVAILABLE!

2012 American Society for Colposcopy and Cervical Pathology

72 The Patient is Out of Primary Screening Guidance and Into Management of Abnormal Screening Test Guidelines! 2012 American Society for Colposcopy and Cervical Pathology (ASCCP) Guidelines Download Algorithms Mobile App: iphone and Android

73 Case Study According to the consensus guidelines for managing abnormal cervical cancer screening tests and cancer precursors. 1. Women 25 to 65: Algorithm: Management of Women with No Lesion or Biopsy-confirmed Cervical Intraepithelial Neoplasia Grade 1 (CIN1) Preceded by Lesser Abnormalities FOLLOWUP WITHOUT TREATMENT Lesser Abnormalities Includes HPV 16+ or 18+ The management is cotesting in 12 months 1. Massad LS, et al updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):

74 Case Study The patient is cotested in 12 months. The results are NILM/HPV 16+. What will you do next? Massad LS, et al updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):

75 Case Study The patient will return to colposcopy. At the 12 month follow-up: if the Pap is ASC-US or HPV (+): Colposcopy is indicated. Massad LS, et al updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121(4):

76 Cervical Cancer Screening Options for 2017 Attributes Cytology Cotesting HPV Primary Interval 3 years 5 years 3 years Age to start 21 years 30 years 25 years Complexity High Highest Low Level of Protection Moderate High High* Referrals to Colposcopy Lowest Higher Higher *Greater than cotesting if done q3 years vs q5 years for cotesting Wright, TC, Omnia, Webinar, 12/15

77 What s to Know, What s New and What s Changed HPV Counseling

78 Counseling Women with HPV Remind your patient that: Most women 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. more

79 Counseling Women with HPV (Continued) Most women who have HPV do not develop abnormal cells or cancer. Women who have HPV in their cells a long time are at greater risk for developing abnormal cells or cancer.

80 Messaging Educate women when they are being screened, about the role of HPV infection in cervical cancer You need an HPV test to determine if you have the virus Your son or daughter may be vaccinated to be protected from being infected by the types in the vaccine

Utilize Written Materials Helpful in supporting patient

available in additional languages including Spanish

Cancer Society American Society for Colposcopy and

81 Utilize Written Materials Helpful in supporting patient education Patients can use for later reference Many are available in additional languages including Spanish Unbranded materials: Center for Disease Control American Cancer Society American Society for Colposcopy and Cervical Pathology Association of Reproductive Health Professionals

82 Summary The 2012 Guidelines for cervical cancer prevention More benefit with least harm (over screening) 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 clinicians been more important!

83 Summary HPV Testing in Primary Screening Interim Guidance has been published Are you ready? Will you perform stand alone HPV testing as primary screening?

84 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!

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9/19/17. Emerging Challenges in Primary Care: Cervical Cancer Screening: Appropriate Use of Pap & HPV Testing. Faculty.

9/19/17. Emerging Challenges in Primary Care: Cervical Cancer Screening: Appropriate Use of Pap & HPV Testing. Faculty. Emerging Challenges in Primary Care: 2017 Cervical Cancer Screening: Appropriate Use of Pap & HPV Testing Faculty Nancy R. Berman, MSN, ANP-BC, NCMP, FAANP Adult Nurse Practitioner Certified Menopause