Stage at diagnosis and survival by stage for the leading childhood cancers in Rwanda.

BACKGROUND: The lack of accurate population-based information on childhood cancer stage and survival in low-income countries is a barrier to improving childhood cancer outcomes. METHODS: In this study, data from the Rwanda National Cancer Registry (RNCR) were examined for children aged 0-14 diagnosed in 2013-2017 for the eight most commonly occurring childhood cancers: acute lymphoblastic leukaemia, Hodgkin lymphoma (HL), Burkitt lymphoma (BL), non-Hodgkin lymphoma excluding BL, retinoblastoma, Wilms tumour, osteosarcoma and rhabdomyosarcoma. Utilising the Toronto Childhood Cancer Stage Guidelines Tier 1, the study assigned stage at diagnosis to all, except HL, and conducted active follow-ups to calculate 1-, 3- and 5-year observed and relative survival by cancer type and stage at diagnosis. RESULTS: The cohort comprised 412 children, of whom 49% (n = 202) died within 5 years of diagnosis. Five-year survival ranged from 28% (95% confidence interval [CI]: 12.5%-45.6%) for BL to 68% (CI: 55%-78%) for retinoblastoma. For the cancers for which staging was carried out, it was assigned for 83% patients (n = 301 of 362), with over half (58%) having limited or localised stage at diagnosis. Stage was a strong predictor of survival; for example, 3-year survival was 70% (95% CI: 45.1%-85.3%) and 11.8% (2.0%-31.2%) for limited and advanced non-HL, respectively (p < .001). CONCLUSION: This study is only the second to report on stage distribution and stage-specific survival for childhood cancers in sub-Saharan Africa. It demonstrates the feasibility of the Toronto Stage Guidelines in a low-resource setting, and highlights the value of population-based cancer registries in aiding our understanding of the poor outcomes experienced by this population.

A Proposed Framework and Lexicon for Cancer Prevention.

SUMMARY: Cancer prevention is central to efforts to control the burden of cancer. We propose a new terminology framework to help guide these efforts and promote a key equity principle: "equal care for equal risk."

Increasing power in screening trials by testing control-arm specimens: Application to multicancer detection screening.

BACKGROUND: Cancer screening trials have required large sample-sizes and long time-horizons to demonstrate cancer mortality reductions, the primary goal of cancer screening. We examine assumptions and potential power gains from exploiting information from testing control-arm specimens, which we call the "Intended Effect" (IE) analysis that we explain in detail herein. The IE analysis is particularly suited to tests that can be conducted on stored specimens in the control-arm, such as stored blood for multicancer detection (MCD) tests. METHODS: We simulated hypothetical MCD screening trials to compare power and sample-size for the standard vs IE analysis. Under two assumptions that we detail herein, we projected the IE analysis for 3 existing screening trials (National Lung Screening Trial (NLST), Minnesota Colon Cancer Control Study (MINN-FOBT-A), and Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial-colorectal component (PLCO-CRC)). RESULTS: Compared to the standard analysis for the 3 existing trials, the IE design could have reduced cancer-specific mortality p-values 5-fold (NLST), 33-fold (MINN-FOBT-A), or 14,160-fold (PLCO-CRC), or alternately, reduced sample-size (90% power) by 26% (NLST), 48% (MINN-FOBT-A), or 59% (PLCO-CRC). For potential MCD trial designs requiring 100,000 subjects per-arm to achieve 90% power for multi-cancer mortality for the standard analysis, the IE analysis achieves 90% power for only 37,500-50,000 per arm, depending on assumptions concerning control-arm test-positives. CONCLUSIONS: Testing stored specimens in the control arm of screening trials to conduct the IE analysis could substantially increase power to reduce sample-size or accelerate trials, and provide particularly strong power gains for MCD tests.

NCI Resources for Cancer Immunoprevention Research.

Cancer prevention and early detection, the first two of the eight primary goals of the National Cancer Plan released in April 2023, are at the forefront of the nation's strategic efforts to reduce cancer incidence and mortality. The Division of Cancer Prevention (DCP) of the NCI is the federal government's principal component devoted to promoting and supporting innovative cancer prevention research. Recent advances in tumor immunology, cancer immunotherapy, and vaccinology strongly suggest that the host immune system can be effectively harnessed to elicit protective immunity against the development of cancer, that is, cancer immunoprevention. Cancer immunoprevention may be most effective if the intervention is given before or early in the carcinogenic process while the immune system remains relatively uncompromised. DCP has increased the emphasis on immunoprevention research in recent years and continues to expand program resources and interagency collaborations designed to facilitate research in the immunoprevention field. These resources support a wide array of basic, translational, and clinical research activities, including discovery, development, and validation of biomarkers for cancer risk assessment and early detection (Early Detection Research Network), elucidation of biological and pathophysiological mechanistic determinants of precancer growth and its control (Translational and Basic Science Research in Early Lesions), spatiotemporal multiomics characterization of precancerous lesions (Human Tumor Atlas Network/Pre-Cancer Atlas), discovery of immunoprevention pathways and immune targets (Cancer Immunoprevention Network), and preclinical and clinical development of novel agents for immunoprevention and interception (Cancer Prevention-Interception Targeted Agent Discovery Program, PREVENT Cancer Preclinical Drug Development Program, and Cancer Prevention Clinical Trials Network).

Round Table Discussion on Optimal Clinical Trial Design in Precursor Multiple Myeloma.

SUMMARY: While the current approach to precursor hematologic conditions is to "watch and wait," this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit-risk assessment.

Advances and challenges in cancer immunoprevention and immune interception.

Invasive cancers typically evade immune surveillance through profound local and systemic immunosuppression, preventing their elimination or control. Targeting immune interventions to prevent or intercept premalignant lesions, before significant immune dysregulation has occurred, may be a more successful strategy. The field of cancer immune interception and prevention is nascent, and the scientific community has been slow to embrace this potentially most rational approach to reducing the global burden of cancer. This may change due to recent promising advances in cancer immunoprevention including the use of vaccines for the prevention of viral cancers, the use of cancer-associated antigen vaccines in the setting of precancers, and the development of cancer-preventative vaccines for high-risk individuals who are healthy but carry cancer-associated heritable genetic mutations. Furthermore, there is increasing recognition of the importance of cancer prevention and interception by national cancer organizations. The National Cancer Institute (NCI) recently released the National Cancer Plan, which includes cancer prevention among the top priorities of the institute. The NCI's Division of Cancer Prevention has been introducing new funding opportunities for scientists with an interest in the field of cancer prevention: The Cancer Prevention-Interception Targeted Agent Discovery Program and The Cancer Immunoprevention Network. Moreover, the Human Tumor Atlas Network is spearheading the development of a precancer atlas to better understand the biology of pre-invasive changes, including the tissue microenvironment and the underlying genetics that drive carcinogenesis. These data will inform the development of novel immunoprevention/immuno-interception strategies. International cancer foundations have also started recognizing immunoprevention and immune interception with the American Association for Cancer Research, Cancer Research UK and the Society for Immunotherapy of Cancer each implementing programming focused on this area. This review will present recent advances, opportunities, and challenges in the emerging field of cancer immune prevention and immune interception.

Cancer screening with multicancer detection tests: A translational science review.

Multicancer detection (MCD) tests use a single, easily obtainable biospecimen, such as blood, to screen for more than one cancer concurrently. MCD tests can potentially be used to improve early cancer detection, including cancers that currently lack effective screening methods. However, these tests have unknown and unquantified benefits and harms. MCD tests differ from conventional cancer screening tests in that the organ responsible for a positive test is unknown, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Among two prospective studies involving greater than 16,000 individuals, MCD tests identified those who had some cancers without currently recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported MCD test sensitivities range from 27% to 95% but differ by organ and are lower for early stage cancers, for which treatment toxicity would be lowest and the potential for cure might be highest. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy to detect different cancers in asymptomatic individuals, whether these tests can detect cancer sufficiently early for effective treatment and mortality reduction, the degree to which these tests may contribute to cancer overdiagnosis and overtreatment, whether MCD tests work equally well across all populations, and the appropriate diagnostic evaluation and follow-up for patients with a positive test.

Calendar-period trends in cervical precancer and cancer diagnoses since the introduction of human papillomavirus and cytology co-testing into routine cervical cancer screening at Kaiser Permanente Northern California.

OBJECTIVES: The longer-term impact of introducing human papillomavirus (HPV) testing into routine cervical cancer screening on precancer and cancer rates by histologic type has not been well described. Calendar trends in diagnoses were examined using data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in 2003 for women aged ≥30 years. METHODS: We examined trends in cervical precancer (cervical intraepithelial neoplasia grade 3 [CIN3] and adenocarcinoma in situ [AIS]) and cancer (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]) diagnoses per 1000 screened during 2003-2018. We examined ratios of squamous vs. glandular diagnoses (SCC:ADC and CIN3:AIS). RESULTS: CIN3 and AIS diagnoses increased approximately 2% and 3% annually, respectively (ptrend < 0.001 for both). While SCC diagnoses decreased by 5% per annually (ptrend < 0.001), ADC diagnoses did not change. These patterns were generally observed within each age group (30-39, 40-49, and 50-64 years). ADC diagnoses per 1000 screened did not change even among those who underwent co-testing starting in 2003-2006. SCC:ADC decreased from approximately 2.5:1 in 2003-2006 to 1.3:1 in 2015-2018 while the CIN3:AIS remained relatively constant, ∼10:1. CONCLUSIONS: Since its introduction at KPNC, co-testing increased the detection of CIN3 over time, which likely caused a subsequent reduction of SCC. However, there has been no observed decrease in ADC. One possible explanation for lack of effectiveness against ADC is the underdiagnosis of AIS. Novel strategies to identify and treat women at high risk of ADC need to be developed and clinically validated.

Association of metformin use and cancer incidence: a systematic review and meta-analysis.

BACKGROUND: Metformin is among the most widely used antidiabetics medications because of its minimal toxicity, favorable safety profile, availability, and low cost. In addition to its role in diabetes management, metformin may reduce cancer risk. METHODS: We conducted a comprehensive systematic review and meta-analysis to investigate the association between metformin use and cancer risk, with evaluation by specific cancer type when possible. Applicable studies were identified in PubMed/MEDLINE, Embase, Cochrane Library, Web of Science, and Scopus from inception through March 7, 2023, with metformin use categorized as "ever" or "yes" and a cancer diagnosis as the outcome. Article quality was evaluated using National Heart, Lung, and Blood Institute guidelines, and publication bias was evaluated using the Egger test, Begg test, and funnel plots. Pooled relative risk (RR) estimates were calculated using random-effects models, and sensitivity analysis was completed through leave-one-out cross-validation. RESULTS: We included 166 studies with cancer incidence information in the meta-analysis. Reduced risk for overall cancer was observed in case-control studies (RR = 0.55, 95% confidence interval [CI] = 0.30 to 0.80) and prospective cohort studies (RR = 0.65, 95% CI = 0.37 to 0.93). Metformin use was associated with reduced gastrointestinal (RR = 0.79, 95% CI = 0.73 to 0.85), urologic (RR = 0.88, 95% CI = 0.78 to 0.99), and hematologic (RR = 0.87, 95% CI = 0.75 to 0.99) cancer risk. Statistically significant publication bias was observed within the studies (Egger P < .001). CONCLUSIONS: Metformin may be associated with a decreased risk of many cancer types, but high heterogeneity and risk of publication bias limit confidence in these results. Additional studies in populations without diabetes are needed to better understand the utility of metformin in cancer prevention.

2019 ASCCP Risk-Based Management Consensus Guidelines: Updates Through 2023.

ABSTRACT: This Research Letter summarizes all updates to the 2019 Guidelines through September 2023, including: endorsement of the 2021 Opportunistic Infections guidelines for HIV+ or immunosuppressed patients; clarification of use of human papillomavirus testing alone for patients undergoing observation for cervical intraepithelial neoplasia 2; revision of unsatisfactory cytology management; clarification that 2012 guidelines should be followed for patients aged 25 years and older screened with cytology only; management of patients for whom colposcopy was recommended but not completed; clarification that after treatment for cervical intraepithelial neoplasia 2+, 3 negative human papillomavirus tests or cotests at 6, 18, and 30 months are recommended before the patient can return to a 3-year testing interval; and clarification of postcolposcopy management of minimally abnormal results.

A novel tailed primer nucleic acid test for detection of HPV 16, 18 and 45 DNA at the point of care.

Cervical cancer is a leading cause of death for women in low-resource settings despite being preventable through human papillomavirus (HPV) vaccination, early detection, and treatment of precancerous lesions. The World Health Organization recommends high-risk HPV (hrHPV) as the preferred cervical cancer screening strategy, which is difficult to implement in low-resource settings due to high costs, reliance on centralized laboratory infrastructure, and long sample-to-answer times. To help meet the need for rapid, low-cost, and decentralized cervical cancer screening, we developed tailed primer isothermal amplification and lateral flow detection assays for HPV16, HPV18, and HPV45 DNA. We translated these assays into a self-contained cartridge to achieve multiplexed detection of three hrHPV genotypes in a disposable cartridge. The developed test achieves clinically relevant limits of detection of 50-500 copies per reaction with extracted genomic DNA from HPV-positive cells. Finally, we performed sample-to-answer testing with direct lysates of HPV-negative and HPV-positive cell lines and demonstrated consistent detection of HPV16, HPV18, and HPV45 with 5000-50,000 cells/mL in < 35 min. With additional optimization to improve cartridge reliability, incorporation of additional hrHPV types, and validation with clinical samples, the assay could serve as a point-of-care HPV DNA test that improves access to cervical cancer screening in low-resource settings.

Estimated US Cancer Deaths Prevented With Increased Use of Lung, Colorectal, Breast, and Cervical Cancer Screening.

Importance: Increased use of recommended screening could help achieve the Cancer Moonshot goal of reducing US cancer deaths. Objective: To estimate the number of cancer deaths that could be prevented with a 10-percentage point increase in the use of US Preventive Services Task Force (USPSTF)-recommended screening. Design, Setting, and Participants: This decision analytical model study is an extension of previous studies conducted for the USPSTF from 2018 to 2023. This study simulated contemporary cohorts of US adults eligible for lung, colorectal, breast, and cervical cancer screening. Exposures: Annual low-dose computed lung tomography among eligible adults aged 50 to 80 years; colonoscopy every 10 years among adults aged 45 to 75 years; biennial mammography among female adults aged 40 to 74 years; and triennial cervical cytology screening among female adults aged 21 to 29 years, followed by human papillomavirus testing every 5 years from ages 30 to 65 years. Main Outcomes and Measures: Estimated number of cancer deaths prevented with a 10-percentage point increase in screening use, assuming screening commences at the USPSTF-recommended starting age and continues throughout the lifetime. Outcomes were presented 2 ways: (1) per 100 000 and (2) among US adults in 2021; and they were expressed among the target population at the age of screening initiation. For lung cancer, estimates were among those who will also meet the smoking eligibility criteria during their lifetime. Harms from increased uptake were also reported. Results: A 10-percentage point increase in screening use at the age that USPSTF recommended screening commences was estimated to prevent 226 lung cancer deaths (range across models within the cancer site, 133-332 deaths), 283 (range, 263-313) colorectal cancer deaths, 82 (range, 61-106) breast cancer deaths, and 81 (1 model; no range available) cervical cancer deaths over the lifetimes of 100 000 persons eligible for screening. These rates corresponded with an estimated 1010 (range, 590-1480) lung cancer deaths prevented, 11 070 (range, 10 280-12 250) colorectal cancer deaths prevented, 1790 (range, 1330-2310) breast cancer deaths prevented, and 1710 (no range available) cervical cancer deaths prevented over the lifetimes of eligible US residents at the recommended age to initiate screening in 2021. Increased uptake was also estimated to generate harms, including 100 000 (range, 45 000-159 000) false-positive lung scans, 6000 (range, 6000-7000) colonoscopy complications, 300 000 (range, 295 000-302 000) false-positive mammograms, and 348 000 (no range available) colposcopies over the lifetime. Conclusions and Relevance: In this decision analytical model study, a 10-percentage point increase in uptake of USPSTF-recommended lung, colorectal, breast, and cervical cancer screening at the recommended starting age was estimated to yield important reductions in cancer deaths. Achieving these reductions is predicated on ensuring equitable access to screening.

The Mulher Study: cervical cancer screening with primary HPV testing in Mozambique.

OBJECTIVE: To evaluate cervical cancer screening with primary human papillomavirus (HPV) testing in Mozambique, a country with one of the highest burdens of cervical cancer globally. METHODS: Women aged 30-49 years were prospectively enrolled and offered primary HPV testing using either self-collected or provider-collected specimens. Patients who tested positive for HPV underwent visual assessment for treatment using visual inspection with acetic acid to determine eligibility for thermal ablation. If ineligible, they were referred for excision with a loop electrosurgical excision procedure, for cold knife conization, or for cervical biopsy if malignancy was suspected. RESULTS: Between January 2020 and January 2023, 9014 patients underwent cervical cancer screening. Median age was 37 years (range 30-49) and 4122 women (45.7%) were patients living with HIV. Most (n=8792, 97.5%) chose self-collection. The HPV positivity rate was 31.1% overall and 39.5% among patients living with HIV. Of the 2805 HPV-positive patients, 2588 (92.3%) returned for all steps of their diagnostic work-up and treatment, including ablation (n=2383, 92.1%), loop electrosurgical excision procedure (n=169, 6.5%), and cold knife conization (n=5, 0.2%). Thirty-one patients (1.2%) were diagnosed with cancer and referred to gynecologic oncology. CONCLUSION: It is feasible to perform cervical cancer screening with primary HPV testing and follow-up in low-resource settings. Participants preferred self-collection, and the majority of screen-positive patients completed all steps of their diagnostic work-up and treatment. Our findings provide important information for further implementation and scale-up of cervical cancer screening and treatment services as part of the WHO global strategy for the elimination of cervical cancer.

Expanding Cervical Cancer Screening in Mozambique: Challenges Associated With Diagnosing and Treating Cervical Cancer.

PURPOSE: Mozambique has one of the highest burdens of cervical cancer globally. Treatment options are few as most women present with advanced disease, and there are limited trained health professionals and health care resources. The objective of this study was to describe the outcomes of women diagnosed with invasive cancer as part of the Mozambican women undergoing cervical cancer screening with human papillomavirus (HPV) testing in conjunction with family planning services (MULHER) study. MATERIALS AND METHODS: Women age 30-49 years were prospectively enrolled in the MULHER study and offered screening with primary HPV testing followed by treatment of screen-positive women with thermal ablation or excision as appropriate. Women with cervical examination findings suspicious for cancer were referred to one of the three gynecologic oncologists in the country. RESULTS: Between January 2020 and January 2023, 9,014 women underwent cervical cancer screening and 30 women were diagnosed with cervical cancer. In this cohort, four patients (13.3%) had early-stage disease, 18 (60.0%) had locally advanced disease, one (3.3%) had distant metastatic disease, and seven (23.3%) did not have staging information available. Five patients (16.6%) died without receiving oncologic treatment, and seven patients (23.3%) are still awaiting treatment. Of the remaining 18 patients, three (17.6%) underwent surgery and four (23.5%) received radiotherapy. Eleven (36.7%) patients received only chemotherapy. CONCLUSION: As cervical screening programs are implemented in low-resource settings, there will likely be an increase in the number of women diagnosed with invasive cervical cancer. Our results in Mozambique demonstrate the need to increase access to advanced surgery, radiation, and palliative care services.

Toward 70% cervical cancer screening coverage: Technical challenges and opportunities to increase access to human papillomavirus (HPV) testing.

The World Health Organization (WHO) has called for the elimination of cervical cancer as a public health problem. Cervical cancer screening through human papillomavirus (HPV) testing is a core component of the strategy for elimination, with a set target of screening 70% of women twice in their lifetimes. In this review, we discuss technical barriers and opportunities to increase HPV screening globally.

A novel human papillomavirus and host DNA methylation score and detection of cervical adenocarcinoma.

BACKGROUND: The widespread introduction of Pap testing in the 1960s was followed by substantial reductions in the incidence of cervical squamous cell cancer (SCC). However, the incidence of cervical adenocarcinoma (ADC) did not decrease, likely because of low Pap test sensitivity for ADC and adenocarcinoma in situ (AIS). This study assessed a novel human papillomavirus (HPV) and host DNA Methylation Score for AIS and ADC screening. METHODS: We measured methylation levels at CpG sites in the L2/L1 open reading frames of HPV16, HPV18, and HPV45-as well as 2 human loci, DCC and HS3ST2. Specifically, we tested exfoliated cervicovaginal cells from women in the HPV Persistence and Progression (PaP) cohort who were positive for 1 of HPV16, 18, or 45, including: 1) 176 with AIS/ADC, 2) 353 with cervical intraepithelial neoplasia-3 (CIN3) or SCC, and 3) controls who either cleared (HPV-Clearers; n = 579) or had persistent HPV16, 18, or 45 infection (HPV-Persisters; n = 292). CpG site-specific methylation percentages were measured using our reported next-generation methods. The Methylation Score was the average methylation percentage across all 35 CpG sites tested. RESULTS: Each individual CpG site had higher methylation percentages in exfoliated cervicovaginal cells collected from patients with AIS/ADC, and as well as those with CIN3/SCC, relative to either control group (weakest P = .004). The Methylation Score for AIS/ADC had a sensitivity of 74% and specificity of 89%. The multivariate odds ratio (OR) between the Methylation Score (4th vs 1st quartile) for AIS/ADC was ORq4-q1 = 49.01 (PBenjamini-Hochberg = 4.64E-12), using HPV-Clearers as controls. CIN3/SCC had similar, albeit weaker, associations with the Methylation Score. CONCLUSIONS: HPV16/18/45-infected women with Methylation Scores in the highest quartile had very high odds of AIS/ADC, suggesting they may warrant careful histologic evaluation of the cervical transition zone (eg, conization or loop electrosurgical excision procedure [LEEP]).

An integrated isothermal nucleic acid amplification test to detect HPV16 and HPV18 DNA in resource-limited settings.

High-risk human papillomavirus (HPV) DNA testing is widely acknowledged as the most sensitive cervical cancer screening method but has limited availability in resource-limited settings, where the burden of cervical cancer is highest. Recently, HPV DNA tests have been developed for use in resource-limited settings, but they remain too costly for widespread use and require instruments that are often limited to centralized laboratories. To help meet the global need for low-cost cervical cancer screening, we developed a prototype, sample-to-answer, point-of-care test for HPV16 and HPV18 DNA. Our test relies on isothermal DNA amplification and lateral flow detection, two technologies that reduce the need for complex instrumentation. We integrated all test components into a low-cost, manufacturable platform, and performance of the integrated test was evaluated with synthetic samples, provider-collected clinical samples in a high-resource setting in the United States, and self-collected clinical samples in a low-resource setting in Mozambique. We demonstrated a clinically relevant limit of detection of 1000 HPV16 or HPV18 DNA copies per test. The test requires six user steps, yields results in 45 min, and can be performed using a benchtop instrument and minicentrifuge by minimally trained personnel. The projected per-test cost is <$5, and the projected instrumentation cost is <$1000. These results show the feasibility of a sample-to-answer, point-of-care HPV DNA test. With the inclusion of other HPV types, this test has the potential to fill a critical gap for decentralized and globally accessible cervical cancer screening.

The combined finding of HPV 16, 18, or 45 and cytologic Atypical Glandular Cells (AGC) indicates a greatly elevated risk of in situ and invasive cervical adenocarcinoma.

BACKGROUND: Cervical screening has not effectively controlled cervical adenocarcinoma (AC). Human papillomavirus (HPV) testing is recommended for cervical screening but the optimal management of HPV-positive individuals to prevent AC remains a question. Cytology and HPV typing are two triage options to predict the risk of AC. We combined two potential biomarkers (atypical glandular cell, AGC, cytology and HPV-types 16, 18, or 45) to assess their joint effect on detecting AC. METHODS: Kaiser Permanente Northern California (KPNC) used triennial co-testing with cytology and HPV testing (positive/negative) for routine cervical screening between 2003 and 2020. HPV typing of a sample of residual HPV test specimens was performed on a separate cohort selected from KPNC (Persistence and Progression, PaP, cohort). We compared risk of prevalent and incident histologic AC/AIS (adenocarcinoma in situ) associated with preceding combinations of cytologic results and HPV typing. Risk of squamous cell cancer (SCC)/cervical intraepithelial neoplasia grade 3 (CIN3) (SCC/CIN3) was also included for comparison. RESULTS: Among HPV-positive individuals in PaP cohort, 99% of prevalent AC and 96% of AIS were linked to HPV-types 16, 18, or 45 (denoted HPV 16/18/45). Although rare (0.09% of screening population), the concurrent detection of HPV 16/18/45 with AGC cytology predicted a highly elevated relative risk of underlying histologic AC/AIS; the absolute risk of diagnosing AC/AIS was 12% and odds ratio (OR) was 1341 (95%CI:495-3630) compared to patients with other high-risk HPV types and normal cytology. Cumulatively (allowing non-concurrent results), approximately one-third of the AC/AIS cases ever had HPV 16/18/45 and AGC cytology (OR = 1785; 95%CI:872-3656). AGC was not as strongly associated with SCC/CIN3. CONCLUSION: Detection of HPV 16/18/45 positivity elevates risk of adenocarcinoma, particularly if AGC cytology is also found.

Impact of HPV testing in opportunistic cervical screening: Support for primary HPV screening in the United States.

Human papillomavirus (HPV) testing for cervical screening increases diagnosis of precancer and reduces the incidence of cervical cancer more than cytology alone. However, real-world evidence from diverse practice settings is lacking for the United States (U.S.) to support clinician adoption of primary HPV screening. Using a population-based registry, which captures all cervical cytology (with or without HPV testing) and all cervical biopsies, we conducted a real-world evidence study of screening in women aged 30 to 64 years across the entire state of New Mexico. Negative cytology was used to distinguish cotests from reflex HPV tests. A total of 264 198 cervical screening tests (with exclusions based on clinical history) were recorded as the first screening test between 2014 and 2017. Diagnoses of cervical intraepithelial neoplasia grades 2 or 3 or greater (CIN2+, CIN3+) from 2014 to 2019 were the main outcomes. Of cytology-negative screens, 165 595 (67.1%) were cotests and 4.8% of these led to biopsy within 2 years vs 3.2% in the cytology-only group. Among cytology-negative, HPV tested women, 347 of 398 (87.2%) CIN2+ cases were diagnosed in HPV-positive women, as were 147 of 164 (89.6%) CIN3+ cases. Only 29/921 (3.2%) CIN3+ and 67/1964 (3.4%) CIN2+ cases were diagnosed in HPV-negative, cytology-positive women with biopsies. Under U.S. opportunistic screening, across a diversity of health care delivery practices, and in a population suffering multiple disparities, we show adding HPV testing to cytology substantially increased the yield of CIN2+ and CIN3+. CIN3+ was rarely diagnosed in HPV-negative women with abnormal cytology, supporting U.S. primary HPV-only screening.