HPV genotyping is an important tool for risk stratification of HPV positive women since HPV 16/18 account for approximately 70% of invasive cervical cancers and HPV 16 positive women have a greatly elevated risk of being diagnosed with CIN3+ over the following decade compared to women with other high-risk HPV genotypes.
Extended Genotyping: Informing Risk Stratification and More Personalized Care
Extended Genotyping: Informing Risk Stratification and More Personalized Care
As we move through 2017, Omnia Education would like to look back over 2016 and present to our learners some of the key educational and clinically relevant issues that were addressed, as well as point out those issues that will continue into and through 2017.
The year started out with a look back into 2015 and forward into 2016 to what we at Omnia believed would need to be the key learnings to come from our educational efforts. We observed in early 2016 that when assessing the potential of extended genotyping within primary HPV testing, learners overwhelmingly (91%) indicated application of additional HPV genotypes into their clinical practice would be confusing to them, their staffs, and their patients. And, that they would need to seek guidance from their respective societies, mostly ASCCP and ACOG, for validated algorithm pathways to continue providing a high standard of care to their patients. Further, at this point in time Omnia surveys suggested that upwards of three-quarters of our learners were completely unaware of exactly what tests or assays existed to address extended genotyping in HPV screening; and that 86% were hopeful a computer-based risk assessment tool might eventually become available to them to help in the decision-making process.
During 2016, an eEHCO from Dr. Michelle Khan evaluated the ever-changing paradigms in cervical cancer screening. This report was an assessment of key points provided by Drs. Mark Schiffman and Warner Huh at an Omnia Education CME symposium presented at the ASCCP Conference in New Orleans in April 2016. Dr. Kahn, in describing Dr. Huh’s presentation, focused on data from ATHENA and other trials that provided an evidence base that led to release of Interim Clinical Guidance in 2015 in further support for use of primary high-risk (hr)HPV screening. Also addressed was the question “how will the available screening tests for HPV perform in an increasing population of HPV-vaccinated women,” the answer to which still remains to be determined.
Dr. Kahn next introduced the focus of Dr. Shiffman’s presentation, the possible value of extended high-risk HPV genotyping in cervical cancer screening. This topic, very much in keeping with the self-perceived needs of Omnia’s learners. Dr. Schiffman discussed extended hrHPV genotyping in cervical cancer screening by presenting data from the Kaiser Permanente Northern California Persistence and Progression (PaP) cohort showing the differential risks associated with hrHPV types other than HPV16 and HPV18. The 3-year risk of CIN3+ in women who tested HPV16 positive at baseline was 21.9%, in women who tested HPV18 positive at baseline was 11.5%, and in women who tested positive for HPV33/58, 31, 45, or 52 at baseline was 8.6%, 8.1%, 5.4%, and 5.6%, respectively. This was compared to 3-year risks of 1.5-2.9% for the remaining hrHPV types and 0.08% for women testing hrHPV negative at baseline.
Based on these risks associated with each HPV genotype, Dr. Schiffman proposed risk groups that could potentially be managed accordingly in a clinical setting. This included women at highest risk that could be offered immediate treatment (HPV16 positive), those at high enough risk that they warrant direct referral to colposcopy (HPV18/45/31/52/33/58), those with lower risk but high enough to bring them back for intensified surveillance (HPV51/39/68/35/59/56/66), and those that are low enough risk to return to a regular screening interval.
These findings suggested that using extended genotyping to create risk groups could potentially decrease the number of colposcopies that would otherwise be immediately done in women with hrHPV genotypes that are in the intensified surveillance risk category, and provided to Omnia Education’s learners a glimpse at how extended HPV genotyping could be incorporated into clinical practice. These data are reinforced in an Audio Abstract of Schiffman and colleague’s publication in the International Journal of Cancer that should become available in early 2017. Also becoming available in early 2017 is an Omnia Education CME Journal, authored by Dr. Lee Shuman, focusing on how extended HPV genotyping provides economic value by limiting unnecessary procedures; as well as how such use can lead to more individualized risk stratification for women undergoing cervical cancer screening.
Other educational activities offered by Omnia Education in 2016 continued to sharpen the focus on hrHPV screening and extended HPV genotyping, especially as related to potential benefits in clinical practice. Dr. Mark Einstein, in an Audio Abstract, reviewed the article by Cuzik and colleagues in the Journal of Clinical Virology, in which a commercially available test designed to perform individual genotyping of hrHPV in a single assay was evaluated. The platform was validated against other existing assays as was able to group HPV genotypes into clusters that differentially reflected a woman’s relative risk of each grouping with regard to a positive predictive value for CIN2+ disease. A companion article by Joura and colleagues in Cancer Epidemiology, Biomarkers and Prevention supported this effort by demonstrating that many of the relevant HPV genotypes evaluated are represented within the 9-valent HPV vaccine. And, in a separate Audio Abstract, Dr. Tom Wright addressed the value of extended genotyping presented in a study of HPV typing for the management of HPV-positive ASC-US cervical cytologic results, as published by Schiffman and colleagues in Gynecologic Oncology. The article concluded that use of extended genotyping can lead to reduced numbers of women needing to go for immediate colposcopy while still maintaining optimal patient outcomes.
Two other targeted CME activities continued to address extended HPV genotyping in efforts to reinforce their potential value in the clinical setting. The first was an Expert Interview with Dr. Warner Huh on the relationship between use of extended HPV genotyping and the higher sensitivity to detect cervical cancer. The discussion focused on the differential importance of infection with HPV types 16, 18, or 45 and what impact that information might have in the triage setting. The second was a panel discussion between Drs. Tom Wright and Warner Huh on testing algorithms that included extended HPV genotyping. A wide-ranging discussion ensued but focused on the need for a better understanding of what clinical approach should be taken with women presenting with certain HPV genotypes beyond 16 and 18, such as 31, 33 and 51, and what the presence of one or another of these genotypes may mean with regard to next clinical steps.
Finally, let’s not forget the 10 Women’s Annual Health Visit Conferences (WHAV) in which “Updates in Cervical Cancer Screening: An opportunity to reduce unnecessary testing” was presented. These didactic lectures addressed the potential added value of including extended HPV genotyping in cervical cancer screening, as one means to continue improving the outcomes and quality of life of women.
In closing, 2016 was a busy year as Omnia Education sought to address the needs of our learners with regard to cervical cancer screening. Our outlook on 2017 suggests that we will 1) continue to see emergence of new data on extended HPV genotyping, and 2) hopefully gain a clearer perspective on how to put the pieces together and thus help you improve the standard of care you provide to your patients.
Over the last 15 years HPV testing has come to play an increasingly central role in screening women for cervical disease and managing women with abnormal screening results. Expansion of the role of HPV testing has been facilitated by the introduction of HPV tests that can genotype. HPV genotyping is an important tool for risk stratification of HPV positive women since HPV 16/18 account for approximately 70% of invasive cervical cancers and HPV 16 positive women have a greatly elevated risk of being diagnosed with CIN3+ over the following decade compared to women with other high-risk HPV genotypes. The next generation of HPV genotyping assays will provide us with expanded genotyping information beyond HPV 16/18. Expanded genotyping will further improve risk stratification of HPV positive women. Not only will we be able to identify women positive for HPV 16 who have the highest risk for CIN3+, but we will also be able to identify women, who despite being HPV positive, have only a slightly elevated risk for CIN3+ compared to HPV negative women.
Ever since Harold zur Hausen’s laboratory first identified HPV 16 DNA in an invasive cervical cancer in 1983, investigators have been trying to utilize the association between HPV and cervical neoplasia to improve clinical care. The first commercial HPV test was called ViraPap®. This test was FDA cleared in 1989 and detected only a limited number of HPV genotypes. ViraPap® detected 7 HPV genotypes including 2 low-risk genotypes (HPV 6 and 11) and 5 high-risk genotypes including HPV 16 and 18. When this test was first introduced it was unclear what the clinical benefit was of knowing a woman’s HPV status and some doctors called ViraPap® “a test waiting for a purpose” whereas others said “it is at best a waste of money”.1 However, as the test began to be used by some clinicians as an adjunct to either cytology or colposcopy, the benefits of knowing a woman’s HPV status quickly became apparent. HPV positive women were found to have a greatly increased risk of biopsy-confirmed CIN compared to HPV negative women.2
In the mid-1990s, a more advanced HPV test called Hybrid Capture® was developed for routine clinical use. This newer test identified 9 high-risk HPV genotypes as a pooled mixture and did not detect low-risk genotypes which are only occasionally found in women with CIN 2+. Because of the change in the HPV genotypes that were tested for, the Hybrid Capture® had both improved sensitivity and improved specificity for biopsy-confirmed CIN 2,3 compared to the original ViraPap® test.3,4 Hybrid Capture® was widely used in a clinical trials around the world and many of these trials showed significant clinical benefit in specific subgroups of women, especially those with ASCUS cytology results. Subsequently the Hybrid Capture® test was modified to expand its detection to 12 high-risk HPV genotypes that were still reported as a pooled result, e.g. positive or negative for any of the 12 genotypes. Based on the results of the large NCI-sponsored ALTS trial, the 2001 ASCCP Consensus Guidelines considered reflex HPV testing with Hybrid Capture® as an option for managing women with ASCUS and within several years, most women in the U.S. with ASCUS were undergoing reflex HPV testing (Figure 1).5,6 By 2003 there was sufficient clinical trials data to support the FDA approval of Hybrid Capture® for cotesting together with cytology in women 30 years and older. Interim Guidance from the ASCCP recommended that cytology negative HPV positive women should simply be followed up with a repeat cotest in 12 months (Figure 2).7,8 The rationale for this recommendation was that HPV positive's cytology negative women had a relatively low risk for high-grade cervical neoplasia (CIN2+) and did not require immediate colposcopy. The advantage of this approach was that approximately half of the HPV positive women would spontaneously become HPV negative during the 12 months of follow-up and do not require colposcopy. Women who were persistently HPV positive have a high enough risk for high-grade cervical neoplasia (CIN2+) that colposcopy is warranted.
After cotesting was FDA approved, many clinicians were hesitant to adopt the approach. In part this was due to concerns about counseling HPV positive women as to when and how they acquired their infection. Lack of an effective triage that would allow HPV positive women at greatest risk of having an undiagnosed CIN 2+ to be referred for immediate colposcopy also made some clinicians hesitant to adopt cotesting. This changed in 2009 when the FDA-approved 2 newer HPV tests that were capable of identifying women infected with HPV 16 and HPV 18. These two HPV genotypes account for over 70% of invasive cervical cancers globally and over half of CIN 3 lesions in the U.S. Based on the results of several large clinical trials, the ASCCP recommended that women with HPV 16/18 who are negative by cytology be referred to colposcopy, whereas women positive for the “other” HPV genotypes are followed-up in 12 months (Figure 3). The availability of partial genotyping assays caused cotesting to rapidly expand in the U.S. and today the majority of women 30 years and older are cotested. Genotyping for HPV 16/18 also makes HPV primary screening, e.g. screening with HPV alone, more attractive because women at greatest risk for CIN 2+ can be identified and referred for colposcopy (Figure 4). HPV primary screening is now FDA-approved for use in the U.S. using the cobas® HPV test, and has been adopted for the national screening programs in Netherlands, U.K, Sweden, Australia, Turkey, and specific regions of Italy.
The above discussion on how HPV testing came to be adopted in the U.S. is informative because it clearly shows that improvements in the tests used to detect HPV have driven improvements in clinical care. The current generation of HPV tests is sensitive enough that HPV negative women do not require rescreening for three years and women negative by both HPV and cytology, do not need rescreening for five years.9,10 Although there is some dissention in the screening community as to exactly how long we should extend the screening interval, not having to be screened yearly is clearly less burdensome to women and also provides economic benefits.11 Moreover, the introduction of genotyping tests for HPV 16/18 provides some level of risk stratification since HPV 16/18 positive women who are at greatest risk for CIN 2+ are immediately identified and can be referred to colposcopy. Risk stratification and more personalized care are considered by many to be the future of medicine and it is likely that the next generation of HPV tests that will provide extended genotyping beyond HPV 16/18 will provide an opportunity for improved risk stratification. These extended genotyping tests are currently in large clinical trials both in the U.S. and other countries.
The rationale for extended genotyping HPV tests comes from large epidemiologic studies that have been carried out around the world for the last decade. Although 13 HPV genotypes are classified by the International Agency for Research on Cancer (IARC) as being oncogenic, the proportion of invasive cervical cancers associated with these 13 genotypes varies considerably. Several years ago Xavier Bosch and his coworkers in Barcelona used a sensitive HPV genotyping method to test over 8,000 invasive cervical cancers (Figure 5).12 Globally, HPV 16 was by far the most common HPV genotype in invasive cervical cancer. HPV 16 was identified in 61% of the cervical cancers. HPV 18 was identified in 10%, HPV 45 in 6%, HPV 31 and 33 were each identified in 4% of cancers. However, some genotypes formally classified as “high-risk” such as 51, 56, and 68 were uncommon. This indicates that there is wide variation in the risk associated with the different “high-risk” HPV genotypes. Prospective follow-up studies both from the U. S. and Europe also have found wide variation in the risk of developing CIN 3+ for the different “high-risk” HPV genotypes. In one of the largest of these studies from Denmark, 33,288 women 14-90 yrs of age with normal cytology had samples that were genotyped using a sensitive PCR assay.13 The cohort was then followed in the nationwide pathology register for up to 11.5 years. In women 30 years and older at enrollment, the eight-year absolute risk of CIN3+ was 21.8% if HPV 16 was identified at baseline. The eight-year risk if they had HPV 18, HPV 31, HPV 33, or other high-risk HPV genotypes were 12.8%, 11.3%, 12.9%, and 3.9%, respectively (Figure 6). No cases of CIN3+ were detected in women positive for HPV 35 alone or HPV 66 alone. The proportion developing CIN3+ was slightly higher when HPV 16 was found alone (23.3%) compared to when it occurred in conjunction with other HPV genotypes (17.2%). A similar pattern of risk stratification was seen in women under the age of 30. When looking at glandular lesions, both adenocarcinoma in situ and adenocarcinoma was highest in women with single HPV 18 infections (6.6%). A study of similar design was carried out by the NCI among 20,000 women enrolled in Kaiser Permanente Portland OR.14 This study had somewhat less follow-up than the Danish study. The medium length of follow-up for women under 30 years with negative cytology was 4.6 years, but this increased to 10.7 years for women 30 years and older. Among women 30 years and older, the highest absolute risk of CIN3+ was found in HPV 16 positive women (14.5%) (Table 1). HPV 16 was also the most common genotype. HPV 31 had the second highest risk (12.5%) followed by HPV 18 (10.7%). HPV 45, 52, and 58 had absolute risks lower then HPV 18 and considerably higher than that of many of the other “high-risk” HPV genotypes. There were few cases of CIN3+ in women with HPV 56, 68 and no cases in women with HPV 39, 59, 66. HPV 39, 56, 59, 66 and 68 accounted for approximately half of all women positive for a high-risk HPV genotype. Both the Danish and the U.S. study suggest that extended genotyping assays could provide clinically useful risk stratification of HPV positive women and reduce the number of relatively low-risk women being referred for colposcopy.
Recently, researchers from the NCI tested 2,079 archived samples from women with ASCUS from Kaiser Permanente Northern California using the next generation BD Onclarity™ HPV assay.15 This extended genotyping assay identifies HPV 16, 18, 31, 45, 51, and 52 individually and HPV 33/58 as a paired channel result.16 Combined these 8 genotypes account for 91% of invasive cervical cancers.12 The other high-risk HPV genotypes are reported as various pooled mixtures. The median length of follow-up in this study among women without CIN2+ was 3.6 years. The overall 3-year cumulative risk of CIN3+ for HPV positive women with ASCUS was 5.2% which is similar to what has been observed in other U.S. cross-sectional studies. 17-19 As would be expected, HPV 16 was the most prevalent high-risk genotype in women with ASCUS and women with HPV 16 had the greatest 3-year risk of CIN3+ (16.0%) (Table 2). Women positive for HPV 18, 31, and 33/58 also had a substantial risk of CIN3+ (at least 7%). However, women positive for HPV 35/39/68 and HPV 56/59/66 had relatively low 3-year cumulative risk of CIN3+ (less than 2%). This is the same level of risk as observed in women with ASCUS who were Hybrid Capture® positive but HPV negative with the Onclarity™ assay. The authors of the study discussed the possibility of using extended genotyping assays to further stratify HPV positive women with ASCUS into a group requiring immediate colposcopy, e.g. those with HPV 16, 18, 31, and 33/58, and a group that could be followed-up with repeat testing in 12 months, e.g. those with HPV 35/39/68 and 56/59/66. This would reduce the number of women with ASCUS referred for immediate colposcopies by approximately 40% (Table 3).
Beginning with the 2001 ASCCP Consensus Guidelines, a central tenant of management guidelines has been that women with a similar risk of having CIN3+ should be managed similarly.6,20,21 We have just four different management options for women with abnormal screening results. Women can have extended interval screening, repeat screening at a short interval, be referred to colposcopy, or undergo a LEEP. Based on the most recent ASCCP management guidelines we can identify approximate risk cutoffs for each of these options (Table 3). Thus, as summated in Table 3, women with a risk of CIN3+ of less than 1% are considered appropriate for extended interval screening (cotesting at 3-5 years). Women with a risk of 1-4% are followed expectantly and undergo repeat cotesting in 6-12 months. Women with a risk of CIN3+ of greater than 4% are generally referred to colposcopy and those with a risk of 30% or greater are given the option of undergoing a LEEP. Using these risk cut-offs, the NCI Kaiser study indicates that women with ASCUS who have either HPV35/39/68 or HPV 56/59/66 are suitable for expectant management as opposed to being referred for immediate colposcopy. Moreover, women with ASCUS who have HPV 45 or 52 are on the borderline between repeat contesting in 6-12 months and requiring immediate colposcopy. This type of approach to risk stratification using extended genotyping assays is expected to reduce the number of women requiring colposcopy while assuring that those with the greatest risk of CIN3+ get an immediate workup.
The introduction of expanded genotyping assays is expected to facilitate better risk stratification and more personalized care for HPV positive women. Expanded genotyping assays are already available in many countries and it is hoped that they will become available in the U.S. within the next several years. While we are awaiting regulatory approval of such assays in the U.S., large clinical trials are underway that will let us determine the best way to incorporate expanded genotyping into clinical guidelines.
- Rubin R. Can a new test aid Pap smear in predicting cancer? Dallas Morning News 1989;May 17, 1989.
- Cox TJ, Schiffman MH, Winzelberg AJ, Patterson JM. An evaluation of human papillomavirus testing as part of referral to colposcopy clinics. Obstetrics and Gynecology 1992;80:389-95.
- Ferris DG, Wright TC, Jr., Litaker MS, et al. Triage of women with ASCUS and LSIL on Pap smear reports: management by repeat Pap smear, HPV DNA testing, or colposcopy? J Fam Pract 1998;46:125-34.
- Wright TC, Jr., Lorincz A, Ferris DG, et al. Reflex human papillomavirus deoxyribonucleic acid testing in women with abnormal Papanicolaou smears. Am J Obstet Gynecol 1998;178:962-6.
- Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003;188:1383-92.
- Wright TC, Jr., Cox JT, Massad LS, Twiggs LB, Wilkinson EJ. 2001 consensus guidelines for the management of women with cervical cytological abnormalities. Journal of American Medical Association 2002;287:2120-9.
- Wright TC, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. New England Journal of Medicine 2003;348:489-90.
- Wright TC, Jr., Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004;103:304-9.
- Saslow D, Solomon D, Lawson HW, 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. Am J Clin Pathol 2012;137:516-42.
- Huh WK, Ault KA, Chelmow D, et al. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Gynecologic oncology 2015;136:178-82.
- Kinney W, Wright TC, Dinkelspiel HE, DeFrancesco M, Thomas Cox J, Huh W. Increased cervical cancer risk associated with screening at longer intervals. Obstet Gynecol 2015;125:311-5.
- de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010;11:1048-56.
- Thomsen LT, Frederiksen K, Munk C, Junge J, Iftner T, Kjaer SK. Long-term risk of cervical intraepithelial neoplasia grade 3 or worse according to high-risk human papillomavirus genotype and semi-quantitative viral load among 33,288 women with normal cervical cytology. Int J Cancer 2015;137:193-203.
- Schiffman M, Glass AG, Wentzensen N, et al. A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study. Cancer Epidemiol Biomarkers Prev 2011;20:1398-409.
- Schiffman M, Vaughan LM, Raine-Bennett TR, et al. A study of HPV typing for the management of HPV-positive ASC-US cervical cytologic results. Gynecologic oncology 2015;138:573-8.
- Wright TC, Jr., Stoler MH, Agreda PM, et al. Clinical performance of the BD Onclarity HPV assay using an adjudicated cohort of BD SurePath liquid-based cytology specimens. Am J Clin Pathol 2014;142:43-50.
- Stoler MH, Wright TC, Jr., Cuzick J, et al. APTIMA HPV assay performance in women with atypical squamous cells of undetermined significance cytology results. Am J Obstet Gynecol 2013;208:144 e1-8.
- Stoler MH, Wright TC, Jr., Sharma A, Apple R, Gutekunst K, Wright TL. High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. Am J Clin Pathol 2011;135:468-75.
- Stoler MH, Wright TC, Jr., Sharma A, et al. The interplay of age stratification and HPV testing on the predictive value of ASC-US cytology. Results from the ATHENA HPV study. Am J Clin Pathol 2012;137:295-303.
- Wright TC, Jr., Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006 consensus guidelines for the management of women with abnormal cervical screening tests. J Low Genit Tract Dis 2007;11:201-22.
- Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol 2013;121:829-46.
- Guest: Thomas C. Wright, Jr., MD
Available credits: 0.50
Disclosure of Conflicts of Interest:
In accordance with the ACCME Standards for Commercial Support, The Omnia-Prova Education Collaborative (TOPEC) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. TOPEC resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs.
Thomas C. Wright, Jr., MD
Professor Emeritus of Pathology and Cell Biology
New York, New York
Dr. Wright has disclosed that he is a consultant for Roche Molecular Systems, and Ventana and is on the speakers’ bureau for BD Diagnostics and Cepheid.
• Sean T. Barrett has nothing to disclose.
• Kenneth Brown has nothing to disclose.
• Barry A. Fiedel, PhD has nothing to disclose.
• Kia K. Gray, MPH has nothing to disclose.
- Differentiate when it is appropriate to integrate co-testing and primary HPV testing or chose one over the other when managing HPV+ women
- Decide which high-risk genotypes are important for management
- Determine which algorithms to use and how to incorporate genotyping into cervical cancer screening
- Identify cases where expanded genotyping could potentially be used
This activity is designed to meet the educational needs of obstetricians, gynecologists, primary care physicians, nurse practitioners, physician assistants, and certified nurse-midwives.
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