Cervical Cancer Prevention in the United States—where We've Been and Where We're Going: the American Cancer Society Primary HPV Screening Initiative

Based on the Global Cancer Observatory 2020 estimates, cervical cancer is the fourth most common cancer among women globally, with an estimated 604,000 new cases and 342,000 deaths, the vast majority of which occurred in low-income and middle-income countries.1 In November 2020, the World Health Organization (WHO) launched a global strategy to accelerate the elimination of cervical cancer as a public health problem, underscoring that we have the technical, medical, and policy tools to eliminate this cancer. The key pillars of comprehensive cervical cancer control include primary prevention (human papillomavirus [HPV] vaccination), secondary prevention (screening for and treatment of precancerous lesions), and tertiary prevention (diagnosis and treatment of invasive cervical cancer). The WHO elimination campaign has the following targets, which countries should meet by 2030 in order to be on the path toward achieving the goal of an incidence rate of less than four cases per 100,000 women: 90% of girls fully vaccinated by age 15 years; 70% of women screened with a high-performance test by age 35 years and again by age 45 years; and 90% of women identified with cervical disease (precancer/cancer) receive treatment.2 Vaccination against HPV for adolescent females has been routinely recommended in the United States since 2006. Despite the lack of a school-based vaccination program and modest initial uptake, prevalence of the four-valent HPV vaccine-type infection (types 6, 11, 16, 18) during 2013–2016, compared to the prevaccine era, declined from 11.5% to 1.8% among females aged 14–19 years and from 18.5% to 5.3% among females aged 20–24 years.3, 4 In 2016, because of the vaccine's high immunogenicity, a two-dose schedule was approved, and Gardasil 9 (Merck and Company), a second-generation prophylactic vaccine with the potential to prevent 87% of cervical cancer, became the predominant vaccine distributed in the United States.5 By 2021, adolescent coverage had increased to 76.9% for one or more dose(s) of HPV vaccine, and 61.7% were up to date. Nationally representative data have continued to show increasing impact of the vaccination program in the United States, both in lowering the prevalence of HPV-related cervical lesions and in providing herd immunity.6 Recent datafrom Sweden showed that HPV vaccination was associated with a substantially reduced risk of invasive cervical cancer.7 Exciting advancements are also underway with the development of therapeutic HPV vaccines.8 Although innovations in primary prevention carry significant promise for the upcoming decades, changes in secondary prevention are needed to decrease HPV related cancers in those who are not able to benefit from HPV vaccination.9 The focus of secondary prevention is to detect and treat cervical precancer with approaches that maximize benefits and minimize harms by providing equal management for those at equal risk of high-grade disease. Since the 1960s the Pap test has been instrumental in substantially decreasing the incidence of and mortality from cervical cancer wherever cytology-based, population-wide screening programs were introduced. With increasing understanding of the natural history and causal relationship between HPV and cervical cancer, HPV testing was developed in the early 1990s and was initially included in the 2001 ASCCP management guidelines as a triage test for a cytology interpretation of atypical squamous cells of undetermined significance. Subsequently, several HPV assay platforms have been approved by the US Food and Drug Administration (FDA) and incorporated over the years into both screening and management guidelines.10 HPV screening is proven to have the best tradeoff of benefits and harms.11 The higher sensitivity and negative predictive value of HPV screening supported the safe lengthening of screening intervals in patients at average risk, first to 3 years and then 5 years. Whereas HPV screening is less specific than cytology, it is more reproducible, and the ability to perform risk stratification by genotyping allows for more effective screening triage and surveillance.12 As of early 2023, screening guidelines in the United States allow for three options—primary HPV screening, cotesting (cytology + HPV), and cytology only—with cotesting followed by cytology alone predominantly being used.13, 14 Although primary HPV screening was approved by the FDA in 2014, it has had very limited uptake nationally, estimated at approximately 2%–3%, despite the mounting scientific evidence supporting its implementation.15 The American Cancer Society (ACS) cervical cancer screening guideline released in July 2020 endorsed primary HPV screening beginning at age 25 years as the preferred screening option for average-risk women and individuals with a cervix. The ACS also emphasized that future guideline updates will not include cytology-based screening options.16 As expected, several health care professional organizations expressed concern that the opportunistic cervical cancer screening program in the United States was unprepared to make this transition without addressing challenges at many levels. Responding to the feedback, the ACS launched the Primary HPV Screening Initiative (PHSI) in the fall of 2021 with the goal of addressing concerns and identifying opportunities to support the transition. Close to 100 volunteers representing various stakeholders with interest and expertise in cervical cancer prevention are engaged in this initiative. They are organized into six workgroups, the efforts of which are coordinated by a Steering Committee. The workgroups have been developing tools and recommendations to acknowledge and address challenges and provide resources to support health systems, laboratories, providers, patients, and payors as they make this transition. Provider needs workgroup: Much of the responsibility for transitioning to primary HPV screening falls on clinical care providers, yet they may not have the knowledge, infrastructure, resources, or training to accomplish this easily. By developing an implementation plan and supporting documents, this workgroup will help support providers with the tools they may need to transition their practices away from cotesting and cytology alone to primary HPV screening. Laboratory infrastructure workgroup: Adequate laboratory support is essential to support and conduct FDA-approved primary HPV screening with appropriate triage of HPV-positive patients. Specifically, for specimens that test HPV-positive, laboratories must be able to perform reflex cytology or other FDA-approved triage tests, such as dual staining, on the same clinical specimen. As of 2023, a large percentage of laboratories that offer cotesting either do not have an FDA-approved HPV test platform for primary screening or are not set up to offer this screening option. This group is addressing the logistics and cost of implementing new technology; workflow changes to specimen ordering, testing, and reporting; advocating for changes to existing federal and laboratory accreditation requirements related to cytology-based screening; working on the development and/or modification of quality-assurance practices; and supporting the impact of the transition on the current workforce engaged in cytology-based screening. Information technology/electronic health record workgroup: Health information technology plays an important role in how providers and laboratories address the logistics of primary HPV screening implementation, from ordering to reporting of results. This group is navigating considerations for electronic health record systems and laboratory information systems that include understanding the importance of structured data to facilitate the inclusion of screening and management guideline clinical decision support, results tracking, and preventive care tracking tools. Insurance coverage/payors workgroup: To successfully provide coverage for a different screening method, ensuring the establishment of billing codes to support primary HPV screening starting at age 25 years is essential. In addition, insurance plans across the country will need to include primary HPV screening as a covered service. Access, coverage, and reimbursement are core issues that this workgroup is addressing. Moving from cytology alone: Screening with cytology alone is still used by an estimated 20% of providers, many of whom serve patients in lower resource and safety-net settings.17 Serving these vulnerable populations at high risk of cervical cancer who have limited screening options is essential if we are to provide equitable access to high-quality, primary HPV screening in a way that will impact cervical cancer disparities. A component of such a strategy has to be laying the groundwork for HPV self-sampling when this technology becomes FDA-approved. Patient perceptions: This group includes patient advocates who are developing communication and educational materials explaining the HPV test, the positive implications of transitioning to primary HPV screening, and the lack of harm when moving away from screening with cytology alone and/or cotesting. They will also help with the PHSI's coordination with organizations on cohesive messaging to overcome resistance to the recommendations. The ACS PHSI is an important step forward in addressing barriers, identifying opportunities, and providing resources to stakeholders as the United States transitions to adoption of large-scale primary HPV screening. Ensuring equitable access and affordability of HPV screening to low-resource settings and to patients at higher risk of cervical precancer/cancer is a key consideration of the effort. There are several ongoing endeavors to disseminate information from the PHSI workgroups, such as commentaries, practical publications, presentations at the meetings of various professional organizations, access to an ACS website with resources, and more.15, 18 The PHSI is also leading the way in developing many synergistic relationships for the newly formed ACS National Roundtable on Cervical Cancer.19 The management of patients with abnormal test results has also undergone a major paradigm shift in which follow-up is now based on the risk of developing precancer/cancer.20 The 2019 ASCCP risk-based management consensus guidelines use a combination of current results and past history, with recommendations for increased surveillance, colposcopy, or treatment in patients who are at higher risk for cervical high-grade disease or cancer, while minimizing procedures for patients at lower risk. In these guidelines, HPV-based screening forms the basis of risk assessment. The risk estimates that trigger management actions are called clinical action thresholds and were defined by a consensus group that included stakeholders from 20 professional societies, federal organizations, and patient advocacy groups. Based on data from trials and clinical laboratory cotesting, 9%–11% of patients are expected to test positive for high-risk HPV, and, irrespective of genotyping data, all positive primary HPV screening tests should have additional reflex triage because the findings may inform the management decision. In this era of precision medicine, the risk-based approach personalizes care for patients. Clinical decision support for providers is available through mobile and web-based applications, and a personalized risk-assessment tool that provides risk-based management recommendations in lay language is available for patients in English and Spanish.21 These guidelines will be regularly updated through an Enduring Guidelines process to keep pace with approval of new technologies and changes in population characteristics. The National Cancer Institute is continuing to generate risk estimates for new technologies and other screening and management questions, and the previously generated clinical action thresholds are used to guide recommendations. Because the risk framework can be applied to different situations, new algorithms are no longer needed for each test. This makes for a more timely and flexible process compared with developing interim guidance and organizing consensus conferences to update guidelines. An Enduring Guidelines working group reviews the new evidence from population-based and other studies as well as from any newly approved tests and develops draft recommendations for consensus group review and subsequent approval for incorporation into risk estimates.22 Despite the opportunistic screening program in the United States, cervical cancer comprises 0.7% of new cancers; however, cancer health care disparities are still at play. Greater than 50% of cervical cancers occur in those who have never been screened or have not been screened in the past 5 years.23, 24 Self-collection of vaginal samples for primary HPV screening may be a successful strategy to reach under-screened populations and is under consideration for approval by the FDA at the time of this writing. Also awaited are the updated US Preventive Services Task Force cervical cancer screening guidelines, which will be important for coordination across organizations and subsequent coverage and reimbursement policies. Needless to say, cervical cancer prevention has seen much advancement and, with continued efforts toward making vaccination, screening, and management more readily accessible and equitable, its future elimination is certainly within reach. Steering Committee and Laboratory Infrastructure Workgroup members of the American Cancer Society's Primary HPV Screening Initiative provided input to support the development of this commentary. Special thanks to Levi S. Downs Jr, MD; Eduardo L. Franco, MPH, DrPH, PhD(Hon); Francisco García, MD. MPH; Akiva P. Novetsky, MD, MS; Rebecca B, Perkins, MD; Robert A. Smith, PhD; Debbie Saslow, PhD; and Jane Gerndt, MPH, for their review of this article. Ritu Nayar, MD is a member of the Steering committee and Chair of the Laboratory Infrastructure Workgroup for the ACS Primary HPV Screening Initiative. She is a co-author of the 2019 ASCCP risk-base and management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors and a member of the Enduring Guidelines Working Group.