Current approaches and challenges to cervical cancer prevention in the United States
A digest of cervical cancer screening options and new tools and innovations that may help reduce cervical cancer rates—along with equitable preventive care and increased HPV vaccination rates
p16/Ki-67 dual-stain cytology
An additional tool for triaging HPV-positive patients is the p16/Ki-67 dual stain test (CINtec Plus Cytology; Roche), which was FDA approved in March 2020. A tumor suppressor protein, p16 is found to be overexpressed by HPV oncogenic activity, and Ki-67 is a marker of cellular proliferation. Coexpression of p16 and Ki-67 indicates a loss of cell cycle regulation and is a hallmark of neoplastic transformation. When positive, this test is supportive of active HPV infection and of a high-grade lesion. While the dual stain test is not yet formally incorporated into triage algorithms by national guidelines, it has demonstrated efficacy in detecting CIN 3+
In the IMPACT trial, nearly 5,000 HPV-positive patients underwent p16/Ki-67 dual stain testing compared with cytology and HPV genotyping.25 The sensitivity of dual stain for CIN 3+ was 91.9% (95% CI, 86.1%–95.4%) in HPV 16/18–positive and 86.0% (95% CI, 77.5%–91.6%) in the 12 other genotypes. Using dual stain testing alone to triage HPV-positive results showed significantly higher sensitivity but lower specificity than using cytology alone to triage HPV-positive results. Importantly, triage with dual stain testing alone would have referred significantly fewer women to colposcopy than HPV 16/18 genotyping with cytology triage for the 12 other genotypes (48.6% vs 56.0%; P< .0001).
Self-sampling methods: An approach for potentially improving access to screening
One technology that may help bridge gaps in access to cervical cancer screening is self-collected HPV testing, which would preclude the need for a clinician-performed pelvic exam. At present, no self-sampling method is approved by the FDA. However, many studies have examined the efficacy and safety of various self-sampling kits.26
One randomized controlled trial in the Netherlands compared sensitivity and specificity of CIN 2+ detection in patient-collected versus clinician-collected swabs.27 After a median follow-up of 20 months, the sensitivity and specificity of HPV testing did not differ between the patient-collected and the clinician-collected groups (specificity 100%; 95% CI, 0.91–1.08; sensitivity 96%; 95% CI, 0.90–1.03).27 This analysis did not include patients who did not return their self-collected sample, which leaves the question of whether self-sampling may exacerbate issues with patients who are lost to follow-up.
In a study performed in the United States, 16,590 patients who were overdue for cervical cancer screening were randomly assigned to usual care reminders (annual mailed reminders and phone calls from clinics) or to the addition of a mailed HPV self-sampling test kit.28 While the study did not demonstrate significant difference in the detection of overall CIN 2+ between the 2 groups, screening uptake was higher in the self-sampling kit group than in the usual care reminders group (RR, 1.51; 95% CI, 1.43–1.60), and the number of abnormal screens that warranted colposcopy referral was similar between the 2 groups (36.4% vs 36.8%).28 In qualitative interviews of the participants of this trial, patients who were sent at-home self-sampling kits found that the convenience of at-home testing lowered barriers to scheduling an in-office appointment.29 The hope is that self-sampling methods will expand access of cervical cancer screening to vulnerable populations that face significant barriers to having an in-office pelvic exam.
It is important to note that self-collection and self-sample testing requires multidisciplinary systems for processing results and assuring necessary patient follow-up. Implementing and disseminating such a program has been well tested only in developed countries27,30 with universal health care systems or within an integrated care delivery system. Bringing such technology broadly to the United States and less developed countries will require continued commitment to increasing laboratory capacity, a central electronic health record or system for monitoring results, educational materials for clinicians and patients, and expanding insurance reimbursement for such testing.
HPV vaccination rates must increase
While we continue to investigate which screening methods will most improve our secondary prevention of cervical cancer, our path to increasing primary prevention of cervical cancer is clear: We must increase rates of HPV vaccination. The 9-valent HPV vaccine is FDA approved for use in all patients aged 9 to 45 years.
The American College of Obstetricians and Gynecologists and other organizations recommend HPV vaccination between the ages of 9 and 13, and a “catch-up period” from ages 13 to 26 in which patients previously not vaccinated should receive the vaccine.31 Initiation of the vaccine course earlier (ages 9–10) compared with later (ages 11–12) is correlated with higher overall completion rates by age 15 and has been suggested to be associated with a stronger immune response.32
A study from Sweden found that HPV vaccination before age 17 was most strongly correlated with the lowest rates of cervical cancer, although vaccination between ages 17 and 30 still significantly decreased the risk of cervical cancer compared with those who were unvaccinated.33
Overall HPV vaccination rates in the United States continue to improve, with 58.6%34 of US adolescents having completed vaccination in 2020. However, these rates still are significantly lower than those in many other developed countries, including Australia, which had a complete vaccination rate of 80.5% in 2020.35 Continued disparities in vaccination rates could be contributing to the rise in cervical cancer among certain groups, such as American Indian and Alaska Native populations.5
Work—and innovations—must continue
In conclusion, the incidence of cervical cancer in the United States continues to decrease, although at disparate rates among marginalized populations. To ensure that we are working toward eliminating cervical cancer for all patients, we must continue efforts to eliminate disparities in health access. Continued innovations, including primary HPV testing and self-collection samples, may contribute to lowering barriers to all patients being able to access the preventative care they need. ●
