By Leslie M. Randall, MD, MAS; Mark Stoler, MD, FASCP; and Linda R. Duska, MD, MPH

Originally published in ASCO Daily News; adapted and republished with permission.

In December 2021, we commemorated the 50th anniversary of the National Cancer Act (1971). In his remarks at the signing, President Richard Nixon stated: “As a result of the action, which will come into being as a result of signing this bill, the Congress is totally committed to provide the funds that are necessary, whatever is necessary, for the conquest of cancer.”¹ In the subsequent 50 years, we have greatly improved our ability to “conquer” cervical cancer, through such measures as the development of a vaccine against HPV (the primary etiology of the vast majority of cases of cervical cancer) and the addition of novel targeted therapeutics that have given new hope to women with advanced or recurrent disease. However, even in the presence of novel screening techniques and a very efficacious vaccine, cervical cancer took the lives of an estimated 4,290 women in 2021 in the United States² and continues to be the second leading cause of cancer death in American women age 20 to 39 years.³ Although the overall incidence of cervical cancer has declined, advanced-stage disease and adenocarcinomas are increasing, underscoring the need for targeted efforts to increase HPV vaccination and guideline-based screening.

NCI-Funded Research Led to Significant Advances in Early Detection and Prevention

The elucidation of HPV's etiologic role in more than 95% of cervical cancers, other anogenital cancers, and head and neck cancer is directly attributable to the funding that flowed from the creation of the National Cancer Institute (NCI). This history is the classic paradigm of basic research leading directly to massive benefits for humanity.⁴ The basic tools of molecular biology—DNA extraction, cloning, restriction enzyme digestion patterns, and sequencing—all had to be available to allow Harald zur Hausen, MD, in late-1970s Germany, as well as others in France, Scandinavia, and the United States, to establish the link between HPV and cervical cancer that was first suggested by surgical pathologists and cytopathologists 2 decades earlier.^5-7 The initial observations, based on analysis of tissue pathology, showed that there were two broad classes of HPVs: low-risk, associated with warts; and high-risk, associated with cancer. The ability to detect and genotype tissues with just four probes—HPV types 6 and 11 in 95% of genital warts and HPV types 16 and 18 in approximately 70% of cervical cancers—formed the basis for all eventual clinical HPV tests and elucidated the primary targets of HPV vaccines. Refinement of the same basic technology and the ability to amplify nucleic acids by polymerase chain reaction, together with the analysis of tens of thousands of samples carefully correlated with pathology, established the knowledge base that HPVs are ubiquitous in humans and vertebrates and that more than 200 genotypes are responsible for a substantial disease burden.⁶ These data also established the parameters for all HPV tests, which has led to the establishment of clinically valid HPV testing as the preferred primary screening test for cervical cancer in current guidelines.^8,9

This same science, as well as other NCI-funded research, led to laboratory models for growing infectious papillomavirus, the demonstration that antibodies directed against viral capsid protein could neutralize those infections, and the ability to then synthesize type-specific pseudovirions to use as vaccine antigens. These developments produced the necessary intellectual property in the early 1990s for the development of superbly efficacious prophylactic HPV vaccines that then came on the market in 2006, and whose type spectrum and disease coverage spectrum have expanded, all based on the same fundamental technologies.^10,11 Likewise, the early investigations correlating HPV-associated disease pathogenesis with viral gene expression, in particular the understanding of the critical role of the dysregulation of the proteins E6 and E7 of HPV 16 and other high-risk types in neoplastic development, has led to refinement in clinical HPV tests as well as to the development of therapeutic vaccines in active clinical trials.^7,12

Advances in Treatment Urgently Needed

The significant advances in early detection and prevention led to a decline in cervical cancer incidence, but they have not eliminated deaths from high-risk invasive disease,² where treatment advances remain a priority. This autumn also marks the 50th anniversary of NCI's funding of the cooperative Gynecologic Oncology Group (GOG), which would eventually discover predictors of prognosis, define indications for adjuvant therapy, and set standards of care in all disease settings for cervical cancer.¹³ In early-stage cases, clinicopathologic studies identified two risk groups in patients who had undergone radical hysterectomy: (1) intermediate risk for those with tumors larger than 2 cm, lymphovascular space invasion, and/or deep stromal invasion; and (2) high risk for positive lymph nodes, surgical margins, or parametria.¹⁴ GOG clinical trials reported a 47% reduction in risk of recurrence for patients with intermediate risk disease who were treated with adjuvant pelvic radiation¹⁵ and a 50% reduction for patients at high risk who were treated with chemoradiotherapy.¹⁶ In the locally advanced disease space, where tumors remained localized in the pelvis, GOG collaborated with two additional cooperative groups, the Radiation Oncology Therapy Group and the Southwest Oncology Group, to conduct four additional trials (GOG-85, RTOG-9001, GOG-120, GOG-123) that investigated the addition of weekly radiosensitizing chemotherapy with either cisplatin, 5-FU, hydroxyurea, or their combinations. These studies reported remarkably consistent survival benefits with radiosensitizing chemotherapy, with cisplatin being the best tolerated.^17-20 The findings of these studies prompted a rare NCI Clinical Announcement in 1999 that urged the use of radiosensitizing cisplatin for women with locally advanced disease²¹ and changed the standard of care for the treatment of cervical cancer, a standard that has continued to 2021.

For metastatic and recurrent disease, GOG discovered that, contrary to prevalent opinion, cervical cancer was indeed a chemosensitive disease. Two active phase II queues, the 127-series for cytotoxic regimens and the 227-series for biologic and targeted therapies, revealed activity for platinum, taxanes, topotecan, gemcitabine, and bevacizumab. The GOG-204 protocol ultimately investigated multiple platinum-containing doublets for frontline treatment in the phase III setting, declaring cisplatin plus paclitaxel as the most active combination.²² In 2013, GOG-240 subsequently reported the first shift toward biologic-targeted therapy when an overall-survival advantage was seen with the addition of the antiangiogenic drug bevacizumab to the standard chemotherapy backbone.²³ Despite further work with cytotoxic regimens, the standard of care has not changed since these pivotal trials were completed.

Cervical cancer drug development is currently focused on molecular targets and is dominated by immunotherapy. The NCI was the first to show proof of concept for cellular immunotherapy with complete tumor regression in two patients with recurrent cervical cancer after a single infusion of HPV-16-reactive tumor-infiltrating lymphocytes (TILs).²⁴ These two responses brought the HPV-driven biology of cervical cancer back full circle and initiated an explosion of interest in immunotherapy. Cellular therapies, although exciting, are associated with challenges in delivery, including the need for a resectable tumor from which to extract TILs, time to expand the TIL population in vitro, and the need for lymphodepletion and administration of interleukin-2 at the time of TIL administration.²⁵

There is also significant enthusiasm for the study of immune checkpoint inhibitors (ICIs) as single agents, in combination with standard therapy, or in combination with other immune active agents. Development of these agents has been rapid, requiring partnership with industry and with former U.S. clinical trial groups to expedite trials, and further driven by the U.S. Food and Drug Administration Safety Innovation Act (FDASIA) of 2012, which allows accelerated approvals based on surrogate endpoints.²⁶ Pembrolizumab was the first and, to date, only ICI to receive an accelerated approval in 2018 for the second- and third-line treatment of PD-L1+ tumors,²⁷ based on an objective response rate that was low (14.3%) but which was associated with a long duration of response, with the median duration of response not being reached in the cohort.²⁸ Two subsequent, large, phase III trials of ICI therapy have reported, meeting their primary endpoints of OS at early interim analyses.^29,30 KEYNOTE-826, the confirmatory trial for pembrolizumab, will likely move ICI into the first-line chemotherapy space. Additional U.S. Food and Drug Administration innovations, such as breakthrough and fast-track designations, are also driving this wave of development, now extended to cellular and noncellular immunotherapy combinations and even earlier lines of therapy.

The Road Ahead: Addressing HPV Vaccine Hesitancy and Racial Disparities in Care

Although the advances that began in 1971 have brought us far, we can and must do better, as evidenced by several sobering U.S. statistics. It is clear that cervical cancer disproportionately affects women of racial and ethnic minorities, socioeconomically disadvantaged groups, and those residing in rural or underserved areas³¹; Black women have the worst 5-year relative survival by race.³¹ Vaccine uptake was estimated at only 21.5% among adults age 18 to 26 years in 2018 and at 54.2% in adolescents age 13 to 17 years in 2019.^32,33 Screening rates fell by 82% during the COVID-19 pandemic, but quickly rebounded by targeting high-risk women and implementing home self-testing in one health system³⁴; yet the United States continues to not follow the science of implementing HPV primary screening.

Globally, cervical cancer is more prevalent in the developing world and in areas where HIV is endemic.³⁵ In 2020, the World Health Organization launched the Cervical Cancer Elimination Initiative, targeting a global annual incidence rate of less than 4 per 100,000 women-years by reaching 90% HPV vaccination uptake, 70% high-performance HPV testing, and effective treatment of 90% of invasive and preinvasive cases by 2030. We have the tools to achieve this goal, but the promise of the conquest of cervical cancer will require us to fully, innovatively, and equitably commit to its eradication.

Dr. Randall is the Dianne Harris Wright Professor and Director of Gynecologic Oncology in the Department of Obstetrics and Gynecology and Massey Cancer Center at VCU Health. She is also the Cervical Cancer Clinical Trials Lead for the GOG Partners side of the GOG Foundation. Disclosure.

Dr. Stoler is a professor (emeritus) of pathology and clinical obstetrics and gynecology at the University of Virginia Health. Disclosure.

Dr. Duska is the Lawrence Penniston Family Endowed Professor of Women's Oncology Research in the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, and the Vice-Chair for Research for the Department of Obstetrics and Gynecology, University of Virginia School of Medicine. She serves as editor-in-chief of ASCO Connection. Disclosure.

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