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Research

Research areas

SANCA currently consists of eight sub-studies in three areas.

SANCA currently consists of eight sub-studies in three areas. Sub-studies 1–4 evaluate the feasibility, acceptability, clinical performance and cost-effectiveness of HPV-based anal cancer screening in two high-risk populations. Sub-studies 5–7 evaluate triage strategies for people with a positive anal HPV test, using circulating HPV DNA, host DNA methylation markers, and HPV genotype combined with cycle threshold values. Sub-study 8 assesses whether AI-assisted analysis of endoscopic images can improve detection and classification of anal lesions. Together, the sub-studies are designed to provide the evidence base for a complete anal cancer screening pathway in Sweden.

SANCA is a prospective interventional multicentre study at Karolinska University Hospital, Södersjukhuset (South General Hospital) and Sahlgrenska University Hospital. All sub-studies use the same participants, samples and register linkages, so results can be compared across them. Recruitment started in October 2025 and continues, with follow-up to be continued until 2035. Several sub-studies are first analysed cross-sectionally, and longitudinal analyses follow as follow-up data accumulate. Several sub-studies form the basis of doctoral projects.

In 2024, the International Anal Neoplasia Society (IANS) published consensus guidelines for anal cancer screening in high-risk groups. They propose three screening models: cytology alone, HPV testing alone, or a combination. Anal cytology alone has performed poorly in retrospective studies, and the European Union now recommends against cytology as the primary method in cervical screening. Most of the evidence behind the guidelines comes from men who have sex with men. Whether the proposed models are feasible, acceptable to patients and cost-effective in Swedish healthcare is not known.

The eight SANCA sub-studies in three areas: primary screening, triage of positive anal HPV tests, and AI-assisted endoscopy.

Primary screening

Sub-study 1. Screening women with HIV

Recruiting since October 2025

Background

About 70% of anal cancer cases are diagnosed in women, yet most research on early detection has been done in men who have sex with men. In North America, anal cancer incidence has been stable in men with HIV but is rising in women with HIV, at 11–27 per 100,000 compared with 1.7 per 100,000 in the general population. In women, anal HPV is mainly transmitted from the cervical or external genital area rather than through anal intercourse, and it can persist long after cervical HPV is no longer detectable. Most women with HIV in Sweden are past the age at which HPV vaccination gives the greatest benefit, and vaccination after age 26 has shown no clear protection against anal precancer or cancer. Early detection is therefore the main option.

Read the full design and analysis

Design

Cross-sectional analysis. Women with HIV aged 45 and older attending routine visits at the HIV clinics at Karolinska (about 700 eligible), Södersjukhuset (about 160) and Sahlgrenska (about 190) are invited. About 80% of people with HIV in Sweden were born abroad, and study information is available in the ten most common languages. Each woman takes one anal and one vaginal self-sample (Copan FLOQSwab). Samples are tested with BD Onclarity, which detects 14 oncogenic HPV types and reports HPV16, 18, 31, 45, 51 and 52 individually and the remaining types in three groups. Women with anal oncogenic HPV are referred for high-resolution flexible endoscopy (HR-FEA) at Ersta Hospital in Stockholm or high-resolution anoscopy (HRA) in Gothenburg, with visual inspection, a repeat HPV test, cytology and a sample for DNA methylation. If lesions are seen or cytology shows LSIL or worse, the examination is repeated and lesions are removed with a diathermia snare after local injection of anaesthetic with adrenaline. Cytology is classified according to the Bethesda system and histology as normal, AIN1, AIN2, AIN3 or invasive cancer. Women with vaginal oncogenic HPV are referred for colposcopy according to routine care. Women treated for anal, cervical, vaginal or vulvar precancer are offered HPV vaccination (Gardasil 9). Clinical data come from InfCareHIV and medical records, earlier gynaecological HPV-related lesions from the National Cervical Screening Registry (NKCx), and education, employment, sexual history, smoking and acceptability from a questionnaire. Each woman also gives a blood sample for analysis of circulating HPV DNA. All participants are tested again after 12 months with new anal and vaginal samples and a blood sample. At this second round, referral depends on HPV type and persistence. Women with a new anal infection, or with anal HPV16 that has persisted since the first round, are referred for a new examination including a sample for DNA methylation. Women with a persistent anal infection with another type and a normal examination the year before are tested again after another 12 months. Women with a persistent vaginal infection who are already in follow-up are not referred again, while a new vaginal infection leads to referral for colposcopy.

Outcomes and analysis

The main outcome is the positive predictive value of a positive anal HPV test for histologically confirmed high-grade squamous intraepithelial lesion or worse (HSIL+), with 95% confidence intervals by the Wilson score method. The association between vaginal and anal HPV in the same woman is analysed with the McNemar test for paired samples, with effect sizes as odds ratios. Risk factors for anal HSIL are also studied. About 1,050 women are eligible. Anal oncogenic HPV is expected in 30–45%, and HSIL+ in about 25% of those. About half of women with anal HPV16 are expected to also have vaginal HPV16, and 100 women give 90% power to assess the association between vaginal and anal HPV.

Sub-study 2. Self-collected versus clinician-collected anal HPV samples

Recruiting since October 2025. Inclusion has been extended to the end of 2027.

Background

In cervical screening, self-collected HPV tests detect high-grade lesions as well as clinician-collected tests. For anal samples, recent studies have shown no difference in sample validity between self-collected and clinician-collected swabs, but these studies were mainly done in men who have sex with men. Self-sampling may increase participation by reducing discomfort and examination-related stigma, and would allow testing as part of routine HIV care.

Read the full design and analysis

Design

Cross-sectional analysis of the first 400 women included at Karolinska University Hospital. Each woman is randomized 1:1 to take a self-collected sample first or to have a nurse-collected sample first, and then has the other. Both samples are tested as in sub-study 1. Acceptability and preferred method are measured with a questionnaire based on a theoretical framework of acceptability.

Design of sub-study 2: the first 400 women are randomised 1:1 to sample order.

Outcomes and analysis

Agreement between self-collected and clinician-collected samples from the same woman, measured with Cohen's kappa with 95% confidence intervals. Assuming a true kappa of 0.80, 392 women give 80% power to show agreement with a kappa of at least 0.70 (one-sided alpha 0.025). The effect of sampling order is assessed with a chi-squared test, with effect sizes as odds ratios.

Sub-study 3. Screening transgender and non-binary people with HIV

Inclusion planned from 2027

Background

Transgender women with HIV have anal cancer incidence above 70 per 100,000 at ages 30–44 and above 100 per 100,000 at older ages. Despite specific clinical needs, transgender and non-binary people are often left out of medical research and of the design of screening programmes, which risks reinforcing inequalities in health and healthcare.

Read the full design and analysis

Design

Cross-sectional analysis. Participants are recruited at the same three HIV clinics. Transgender and non-binary people with HIV aged 18 and older are invited, and about 100 participants are expected. Participants take an anal and, where appropriate, a vaginal or neovaginal self-sample. Everyone is referred for HR-FEA or HRA regardless of the HPV result, so findings are available also for those who test negative. People with vaginal or neovaginal oncogenic HPV are referred for colposcopy, and those treated for precancer are offered HPV vaccination. The questionnaire has been adapted together with a reference group of transgender and non-binary people with HIV, and study information is available in the most common languages in this group.

Outcomes and analysis

Feasibility and acceptability, HPV genotypes in anal and neovaginal samples, and cytology findings and biopsy-confirmed lesions. The sub-study is a pilot focused on implementation and is not powered for small effects. Analyses are mainly descriptive and will provide estimates for planning a larger study that also includes transgender and non-binary people without HIV.

Sub-study 4. Cost-effectiveness

Planned for the later part of the study

Background

A screening programme has to be affordable as well as effective. Anal screening uses considerable resources, mainly because many examinations are needed for each precancer found and examination capacity is limited. Whether HPV-based anal screening of women with HIV is cost-effective in Swedish healthcare is not known.

Read the full design and analysis

Design

Decision-analytic modelling study based on the women included in sub-study 1. A Markov model simulates the natural history of anal cancer in women with HIV, with health states and transitions that depend on screening and treatment. The model compares current practice with organised HPV-based screening over a lifetime horizon. Costs include screening, follow-up and treatment, and indirect costs such as loss of productivity.

Outcomes and analysis

The primary outcome is quality-adjusted life years (QALYs). Secondary outcomes are anal cancers prevented through screening and early treatment, HSIL cases detected and treated, and lifetime costs. Incremental cost-effectiveness ratios are expressed as cost per QALY gained and per cancer prevented. Cost-efficiency frontiers, acceptability curves and acceptability frontiers show whether screening is cost-effective across a range of willingness-to-pay thresholds.

Triage of positive anal HPV tests

The negative predictive value of anal HPV testing is very high, but anal HPV is common in people with HIV and most infections never lead to cancer. Additional markers are needed to identify which people with a positive test need further examination, and to avoid unnecessary procedures for those who do not. Sub-studies 5–7 evaluate three triage markers in the same women with a positive anal HPV test, so the markers can be compared and combined.

Sub-study 5. Circulating HPV DNA in blood

Sample collection ongoing

Background

Circulating tumour HPV DNA in plasma is a highly accurate non-invasive marker for HPV-related cancers. In anal cancer, studies have shown a sensitivity of about 90% for both early and advanced disease, with specificity close to 100%. Whether it can be detected at the precancer stage is not known, and the proportion may be close to zero. A blood test would be easy to add to routine HIV care.

Read the full design and analysis

Design

Cross-sectional analysis of all women in sub-study 1 with a positive anal HPV test. Each woman gives a 10 ml blood sample at inclusion and then once a year at follow-up. Circulating HPV DNA is measured with droplet digital PCR at SciLifeLab, Örebro University, using genotype-specific assays chosen according to the HPV types found in the anal sample.

Outcomes and analysis

The proportion of women with circulating HPV DNA among those with a positive anal HPV test, with exact (Clopper-Pearson) 95% confidence intervals, compared with anal cytology results. Because the proportion may be close to zero, 300 women are needed to estimate it with a confidence interval of ±2.5 percentage points.

Sub-study 6. DNA methylation markers

Sample collection ongoing

Background

Methylation of host genes is closely linked to anal carcinogenesis. Methylation levels increase from low-grade to high-grade lesions and are highest in anal cancer, which makes methylation a candidate triage marker after a positive anal HPV test.

Read the full design and analysis

Design

Cross-sectional analysis of all women in sub-study 1 with a positive anal HPV test. Anal liquid-based cytology samples are taken at HR-FEA or HRA, and vaginal liquid-based cytology samples are taken from women with vaginal oncogenic HPV. Methylation of host target genes is measured with quantitative multiplex methylation-specific PCR.

Outcomes and analysis

Whether anal methylation markers can be used to triage women with a positive anal HPV test, and whether methylation targets for cervical lesions are related to anal HPV infection in the same women. Methylation levels are compared across anal and cervical histological categories and HPV types.

Sub-study 7. HPV type and cycle threshold values

Sample collection ongoing

Background

Oncogenic HPV types do not carry the same risk. HPV16 causes about 85% of HPV-positive anal cancers. In cervical screening, HPV16 combined with a low cycle threshold (Ct) value, which reflects a high viral load, is linked to a higher risk of high-grade lesions, while non-16/18 types with high Ct values indicate a lower risk. A similar approach could be used to triage positive anal HPV tests, using the same sample and without extra sampling.

Read the full design and analysis

Design

Cross-sectional analysis of all women in sub-study 1 with a positive anal HPV test. Ct values for each positive HPV result, and for beta-globin as a measure of sample quality, are taken from the BD Onclarity assay used in sub-study 1. The sub-study builds on a large population-based evaluation of HPV type and Ct values for risk stratification in cervical screening, led by Jiayao Lei and funded by the Swedish Cancer Society (2024–2027).

Outcomes and analysis

Distribution of HPV and beta-globin Ct values by HPV result and follow-up cytology, and the ability of Ct values to identify HSIL+, measured with the area under the curve and C-index.

AI-assisted risk stratification

Sub-study 8. AI-assisted analysis of endoscopic images

Image collection ongoing

Background

Examination capacity is the main bottleneck for anal screening. HRA requires long training, is time-consuming and is available at few centres, even in high-income countries. Our group has shown that HR-FEA needs less specialised training without loss of visibility, precision or patient comfort. AI support could make assessments more consistent and make the method easier to scale up.

Read the full design and analysis

Design

AI model development and internal validation study, including all participants in sub-studies 1 and 3 in Stockholm. All HR-FEA procedures are recorded on video and stored in a structured format with study ID, date, imaging mode and lesion location. Deep learning models, using convolutional neural networks and transformer-based architectures, are trained on systematically annotated recordings.

Outcomes and analysis

An AI system that can identify and segment anatomical structures in the anal canal, detect and classify lesions, identify non-dysplastic changes, and predict the histopathological diagnosis. Model performance is validated against histopathology.

Future plans

Beyond the current sub-studies SANCA will be expanded to other groups at high risk of anal cancer, including transgender people regardless of HIV status, organ transplant recipients, men who acquired HIV through heterosexual sex, and women with a previous vulvar cancer. The aim is to build the evidence base for a comprehensive national anal cancer screening programme in Sweden, and to inform international guidelines and global efforts to standardise anal cancer screening.

Key references

  1. Clifford GM, Georges D, Shiels MS, et al. A meta-analysis of anal cancer incidence by risk group: toward a unified anal cancer risk scale. Int J Cancer. 2021;148(1):38–47.
  2. Palefsky JM, Lee JY, Jay N, et al. Treatment of anal high-grade squamous intraepithelial lesions to prevent anal cancer. N Engl J Med. 2022;386(24):2273–2282.
  3. Stier EA, Clarke MA, Deshmukh AA, et al. International Anal Neoplasia Society's consensus guidelines for anal cancer screening. Int J Cancer. 2024;154(10):1694–1702.
  4. Lin C, Franceschi S, Clifford GM. Human papillomavirus types from infection to cancer in the anus, according to sex and HIV status: a systematic review and meta-analysis. Lancet Infect Dis. 2018;18(2):198–206.
  5. Borch-Johnsen P, et al. Endoscopic underwater detection and resection of anal squamous intraepithelial lesions. Scand J Gastroenterol. 2024;59(2):232–238.
  6. Lei J, Cuschieri K, Patel H, Lawrence A, Deats K, YouScreen trial team, et al. Human papillomavirus genotype and cycle threshold value from self-samples and risk of high-grade cervical lesions: a post hoc analysis of a modified stepped-wedge implementation feasibility trial. PLoS Med. 2024;21(12):e1004494.
  7. Qvick A, Andersson E, Oldaeus Almerén A, Waenerlund M, Stenmark B, Karlsson C, et al. Sensitive and specific droplet digital PCR assays for circulating tumor HPV DNA: development, validation, and clinical application in HPV-associated cancers. Mol Diagn Ther. 2024;28(6):835–845.