Cost-effectiveness of primary human papillomavirus triage approaches among vaccinated women in Norway: A model-based analysis.

As Norway considers revising triage approaches following their first adolescent cohort with human papillomavirus (HPV) vaccination entering the cervical cancer screening program, we analyzed the health impact and cost-effectiveness of alternative primary HPV triage approaches for women initiating cervical cancer screening in 2023. We used a multimodeling approach that captured HPV transmission and cervical carcinogenesis to evaluate the health benefits, harms and cost-effectiveness of alternative extended genotyping and age-based triage strategies under five-yearly primary HPV testing (including the status-quo screening strategy in Norway) for women born in 1998 (ie, age 25 in 2023). We examined 35 strategies that varied alternative groupings of high-risk HPV genotypes ("high-risk" genotypes; "medium-risk" genotypes or "intermediate-risk" genotypes), number and types of HPV included in each group, management of HPV-positive women to direct colposcopy or active surveillance, wait time for re-testing and age at which the HPV triage algorithm switched from less to more intensive strategies. Given the range of benchmarks for severity-specific cost-effectiveness thresholds in Norway, we found that the preferred strategy for vaccinated women aged 25 years in 2023 involved an age-based switch from a less to more intensive follow-up algorithm at age 30 or 35 years with HPV-16/18 genotypes in the "high-risk" group. The two potentially cost-effective strategies could reduce the number of colposcopies compared to current guidelines and simultaneously improve health benefits. Using age to guide primary HPV triage, paired with selective HPV genotype and follow-up time for re-testing, could improve both the cervical cancer program effectiveness and efficiency.

Randomized Implementation of a Primary Human Papillomavirus Testing-based Cervical Cancer Screening Protocol for Women 34 to 69 Years in Norway.

BACKGROUND: Cervical cancer screening programs are facing a programmatic shift where screening protocol based on human papillomavirus testing (HPV-Screening protocol) is replacing the liquid-based cytology (LBC-Screening protocol). For safe technology transfer within the nationwide screening programme in Norway, HPV-Screening protocol was implemented randomized to compare the real-world effectiveness of HPV-Screening protocol and LBC-Screening protocol at the first screening round. METHODS: Among 302,295 women ages 34 to 69 years scheduled to attend screening from February 2015 to June 2017, 157,447 attended. A total of 77,207 were randomly allocated to the HPV-Screening protocol and 80,240 were allocated to the LBC-Screening protocol. All women were followed up for 18 months. RESULTS: The HPV-Screening protocol resulted in a relative increase of 60% in the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse [risk ratio (RR) = 1.6, 95% confidence interval (CI) = 1.5-1.7], 40% in CIN grade 3 or worse (RR = 1.4, 95% CI = 1.3-1.6), 40% in cancer (RR = 1.4, 95% CI = 1.0-2.1), and 60% in colposcopy referrals (RR = 1.6, 95% CI = 1.5-1.6) compared with LBC-Screening. The performance of both protocols was age dependent, being more effective in women ages under 50 years. CONCLUSIONS: The HPV-Screening protocol was well accepted by women in Norway and detected more CIN2, CIN3, and cancers compared with the LBC-Screening protocol. IMPACT: A randomized implementation of the HPV-Screening protocol with real-world assessment enabled a gradual, quality assured, and safe technology transition. HPV-based screening protocol may further be improved by using HPV genotyping and age-specific referral algorithms.

A Gene Signature Identifying CIN3 Regression and Cervical Cancer Survival.

The purpose of this study was to establish a gene signature that may predict CIN3 regression and that may aid in selecting patients who may safely refrain from conization. Oncomine mRNA data including 398 immune-related genes from 21 lesions with confirmed regression and 28 with persistent CIN3 were compared. L1000 mRNA data from a cervical cancer cohort was available for validation (n = 239). Transcriptomic analyses identified TDO2 (p = 0.004), CCL5 (p < 0.001), CCL3 (p = 0.04), CD38 (p = 0.02), and PRF1 (p = 0.005) as upregulated, and LCK downregulated (p = 0.01) in CIN3 regression as compared to persistent CIN3 lesions. From these, a gene signature predicting CIN3 regression with a sensitivity of 91% (AUC = 0.85) was established. Transcriptomic analyses revealed proliferation as significantly linked to persistent CIN3. Within the cancer cohort, high regression signature score associated with immune activation by Gene Set enrichment Analyses (GSEA) and immune cell infiltration by histopathological evaluation (p < 0.001). Low signature score was associated with poor survival (p = 0.007) and large tumors (p = 0.01). In conclusion, the proposed six-gene signature predicts CIN regression and favorable cervical cancer prognosis and points to common drivers in precursors and cervical cancer lesions.

High-Grade Cervical Intraepithelial Neoplasia (CIN) Associates with Increased Proliferation and Attenuated Immune Signaling.

Implementation of high-risk human papilloma virus (HPV) screening and the increasing proportion of HPV vaccinated women in the screening program will reduce the percentage of HPV positive women with oncogenic potential. In search of more specific markers to identify women with high risk of cancer development, we used RNA sequencing to compare the transcriptomic immune-profile of 13 lesions with cervical intraepithelial neoplasia grade 3 (CIN3) or adenocarcinoma in situ (AIS) and 14 normal biopsies from women with detected HPV infections. In CIN3/AIS lesions as compared to normal tissue, 27 differential expressed genes were identified. Transcriptomic analysis revealed significantly higher expression of a number of genes related to proliferation, (CDKN2A, MELK, CDK1, MKI67, CCNB2, BUB1, FOXM1, CDKN3), but significantly lower expression of genes related to a favorable immune response (NCAM1, ARG1, CD160, IL18, CX3CL1). Compared to the RNA sequencing results, good correlation was achieved with relative quantitative PCR analysis for NCAM1 and CDKN2A. Quantification of NCAM1 positive cells with immunohistochemistry showed epithelial reduction of NCAM1 in CIN3/AIS lesions. In conclusion, NCAM1 and CDKN2A are two promising candidates to distinguish whether women are at high risk of developing cervical cancer and in need of frequent follow-up.

Real-world data on cervical cancer risk stratification by cytology and HPV genotype to inform the management of HPV-positive women in routine cervical screening.

BACKGROUND: HPV16/18 detection may improve cervical cancer risk stratification and better guide which HPV-positive women warrant immediate colposcopy/biopsy. We estimated risks of cervical precancer and cancer by HPV genotype and cytology during the implementation phase of primary HPV testing in Norway. METHODS: A total of 3111 women, aged 34-69 years, testing HPV-positive at baseline and undergoing cytology testing from February 2015 to April 2018 had data available for analysis. Risk estimates with 95% confidence intervals (95%CIs) of cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) were estimated for cytology results and HPV genotypes (HPV16, HPV18, and other high-risk HPV). RESULTS: CIN3+ risks were higher for HPV16/18 than other high-risk HPV genotypes. Among women with any cytologic abnormality [atypical squamous cells of undetermined significance or worse], immediate risks were 57.8% (95%CI = 53.0-62.6%) for HPV16, 40.2% (95%CI = 32.3-49.2%) for HPV18, and 31.4% (95%CI = 28.7-34.3%) for other high-risk HPV. Among those with normal cytology, CIN3+ risks were 19.9% (95%CI = 15.0-26.1%) for HPV16 positives, 10.8% (95%CI = 5.6-20.5%) for HPV18 positives, and 5.5% (95%CI = 4.2-7.1%) for other high-risk HPV. CONCLUSIONS: The benefits and harms of managing women based on HPV positivity and cytology results can be better balanced by inclusion of HPV genotyping in screening and choosing more conservative management for other high-risk HPV compared to HPV16/18.

Psychological effect of cervical cancer screening when changing primary screening method from cytology to high-risk human papilloma virus testing.

From 2015, Norway has implemented high-risk human papilloma virus (hrHPV) testing in primary screening for cervical cancer. Women aged 34-69 years, living in four counties, have been pseudo-randomly assigned (1:1 randomization) to either hrHPV testing every 5 years (followed by cytology if hrHPV is positive), or cytology testing every 3 years (followed by hrHPV testing if low-grade cytology is detected). We compared anxiety and depression scores among participants by screening arm and results. In total, 1,008 women answered a structured questionnaire that included the validated Patient Health Questionnaire-4 (PHQ-4). The Relative Risk Ratio (RRR) of mild vs. normal anxiety and depression scores, and moderate/severe vs. normal anxiety and depression scores, were estimated by multinomial logistic regression with 95% confidence intervals (95% CIs). Compared to women who were screened with cytology, women randomized to hrHPV testing were not more likely to have mild anxiety and depression scores (RRR 0.96, CI 0.70-1.31) nor more likely to have moderate/severe anxiety and depression scores (RRR 1.14, CI 0.65-2.02). Women with five different combinations of abnormal screening test results were not more likely to have mild or moderate/severe vs. normal anxiety and depression scores than women with normal screening results. The likelihood of having abnormal long-term (4-24 months after the screening) anxiety or depression scores among women 34 years and older was not affected by screening method or screening results. The results of our study suggest that a change to hrHPV testing in primary screening would not increase psychological distress among participants.

The legal framework for European cervical cancer screening programmes.

BACKGROUND: A comprehensive legal framework needs to be developed to run the health services and to regulate the information systems required to manage and to ensure the quality of cancer screening programmes. The aim of our study was to document and to compare the status of legal basis for cervical screening registration in European countries. METHODS: An electronic questionnaire including questions on governance, decision-making structures and legal framework was developed. The primary responses were collected by September 2016. RESULTS: We sent the questionnaire to representatives of 35 European countries (28 countries of the EU, with the United Kingdom included as 4 countries; 4 EFTA member countries: Iceland, Liechtenstein, Norway, and Switzerland); responses were collected from 33 countries. The legal framework makes it possible to personally invite individuals in 29 countries (88%). Systematic screening registration in an electronic registry is legally enshrined in 23 countries (70%). Individual linkage of records between screening and cancer registries is allowed in 19 of those countries. Linkage studies involving cancer and screening registries have been conducted in 15 countries. CONCLUSION: Although the majority of EU/EFTA countries have implemented population-based screening, only half of them have successfully performed record linkage studies, which are nevertheless a key recommendation for quality assurance of the entire screening process. The European legislation is open to the possibility of using health data for these purposes; however, member states themselves must recognize the public interest to create a legal basis, which would enable all the necessary functions for high-quality cancer screening programmes.

hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma.

In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in an ex vivo drug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell lines in vitro, and an initial cytotoxic effect was observed in vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients.

Quality assurance of human papillomavirus (HPV) testing in the implementation of HPV primary screening in Norway: an inter-laboratory reproducibility study.

BACKGROUND: Human papillomavirus (HPV) testing as primary screening for cervical cancer is currently being implemented in Norway in a randomized controlled fashion, involving three laboratories. As part of the quality assurance programme of the implementation, an evaluation of the inter-laboratory reproducibility of the HPV test was initiated, to ensure satisfactory HPV test reliability in all three laboratories. METHODS: The HPV test used is the cobas 4800 HPV Test, detecting 14 high-risk types with individual HPV genotype results for HPV16 and HPV18. In addition to the three laboratories involved in the implementation, the Norwegian HPV reference laboratory was included as a fourth comparative laboratory. A stratified sample of 500 cervical liquid based cytology (LBC) samples was used in the evaluation, with an aim towards a high-risk HPV positivity of ~25%. Samples were collected at one laboratory, anonymized, aliquoted, and distributed to the other laboratories. RESULTS: Comparison of the test results of all four laboratories revealed a 95.6% agreement, an 86.3% positive agreement and a kappa value of 0.94 (95% CI 0.92-0.97). For negative cytology specimens, there was a 95.8% overall agreement, a 67.4% positive agreement, and a kappa value of 0.88 (95% CI 0.80-0.93). For abnormal cytology specimens, there was a 95.8% overall agreement, a 95.5% positive agreement, and a kappa value of 0.86 (95% CI 0.71-0.97). CONCLUSIONS: The study showed a high inter-laboratory reproducibility of HPV testing, implying satisfactory user performance and reliability in the laboratories involved in the implementation project. This is important knowledge and we recommend similar studies always to be performed prior to the introduction of new screening routines.