Tone Bjørge

Differential levels of circulating RNAs prior to endometrial cancer diagnosis

AbstractEndometrial cancer (EC) is one of the most common female cancers and there is currently no routine screening strategy for early detection. An altered abundance of circulating microRNAs (miRNAs) and other RNA classes have the potential as early cancer biomarkers. We analyzed circulating RNA levels using small RNA sequencing, targeting RNAs in the size range of 17–47 nucleotides, in EC patients with samples collected prior to diagnosis compared to cancer‐free controls. The analysis included 316 cases with samples collected 1–11 years prior to EC diagnosis, and 316 matched controls, both from the Janus Serum Bank cohort in Norway. We identified differentially abundant (DA) miRNAs, isomiRs, and small nuclear RNAs between EC cases and controls. The top EC DA miRNAs were miR‐155‐5p, miR‐200b‐3p, miR‐589‐5p, miR‐151a‐5p, miR‐543, miR‐485‐5p, miR‐625‐p, and miR‐671‐3p. miR‐200b‐3p was previously reported to be among one of the top miRNAs with higher abundance in EC cases. We observed 47, 41, and 32 DA miRNAs for EC interacting with BMI, smoking status, and physical activity, respectively, including two miRNAs (miR‐223‐3p and miR‐29b‐3p) interacting with all three factors. The circulating RNAs are altered and show temporal dynamics prior to EC diagnosis. Notably, DA miRNAs for EC had the lowest q‐value 4.39–6.66 years before diagnosis. Enrichment analysis of miRNAs showed that signaling pathways Fc epsilon RI, prolactin, toll‐like receptor, and VEGF had the strongest associations.

Associations of pregnancy‐related factors and birth characteristics with risk of endometrial cancer: A Nordic population‐based case–control study

Many pregnancy‐related factors are associated with reduced endometrial cancer risk. However, it remains unclear whether pregnancy‐related complications (e.g., hypertensive conditions) are associated with risk and whether these associations vary by endometrial cancer subtype. Thus, we evaluated the risk of endometrial cancer, overall and by subtype, in relation to pregnancy‐related factors, pregnancy complications and birth characteristics. Utilizing population‐based register data from four Nordic countries, we conducted a nested case–control analysis of endometrial cancer risk. We included 10,924 endometrial cancer cases and up to 10 matched controls per case. Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models. We further evaluated associations by individual histology (i.e., endometrioid, serous, etc.) or, for rare exposures (e.g., pregnancy complications), by dualistic type (Type I [n = 10,343] and Type II [n = 581]). Preexisting and pregnancy‐related hypertensive conditions were associated with increased endometrial cancer risk (OR [95% CI]: preexisting hypertension 1.88 [1.39–2.55]; gestational hypertension 1.47 [1.33–1.63]; preeclampsia 1.43 [1.30–1.58]), with consistent associations across dualistic type. Increasing number of pregnancies (≥4 vs. 1 birth: 0.64 [0.59–0.69]) and shorter time since last birth (<10 vs. ≥30 years: 0.34 [0.29–0.40]) were associated with reduced endometrial cancer risk, with consistent associations across most subtypes. Our findings support the role for both hormonal exposures and cell clearance as well as immunologic/inflammatory etiologies for endometrial cancer. This research supports studying endometrial hyperplasia, a precursor condition of endometrial cancer, in the context of pregnancy‐related exposures, as this may provide insight into the mechanisms by which pregnancy affects subsequent cancer risk.

Risk of high‐grade cervical lesions in the second round of primary human papillomavirus testing in CervicalScreen Norway: A population‐based cohort study

AbstractAs many countries are transitioning from cytology to human papillomavirus (HPV) testing as the primary cervical cancer screening test, we evaluated the impact of cumulative HPV screening during the implementation of HPV screening in the Norwegian cervical cancer screening programme (CervicalScreen Norway). Data from the second HPV screening round was compared with data from the first round. The second‐round analyses included only women who returned to routine screening 4–6 years following a negative HPV test in the first round. Associations between screening rounds and HPV positivity, cytology results, and follow‐up recommendations were estimated by multinomial logistic regression, and relative risks of cervical intraepithelial neoplasia, grade 3 or worse (CIN3+) by Cox regression. There was a 42% lower risk of being HPV positive in the second screening round compared to the first (age‐adjusted relative risk ratio (aRRR) 0.58, 95% confidence interval (CI) 0.53 to 0.65), and a 70% lower risk of having high‐grade cytology among HPV16 positive women (0.30, 0.12 to 0.78). There was also a 51% reduction in referrals for immediate colposcopy (0.49, 0.39 to 0.62). The overall risk of CIN3+ was 71% lower in the second round compared to the first (age‐adjusted hazard ratio [aHR] 0.29, 95%CI 0.21–0.40), and lower among HPV16 and other high‐risk HPV positive women, but not among HPV18 positives. No cervical cancers were diagnosed in the second round (mean follow‐up 2.4 years). Our findings indicate that HPV test results from previous screening rounds should be considered when designing optimal screening algorithms.

Incidence and prevalence of drugs used for chronic diseases in survivors of adult‐onset gynaecological cancer – A nationwide cohort study

AbstractObjectivesTo evaluate both incidence and prevalence of drugs used for chronic diseases in survivors of adult‐onset gynaecological cancer.DesignA prospective study.SettingPopulation‐based registries.Population1.76 million women, including 17 500 women with gynaecological cancers.MethodsData from the Cancer Registry of Norway was linked to the Norwegian Prescription Database and other national databases.Main Outcome MeasuresPrevalence ratios (PRs) and hazard ratios (HRs), with 95% confidence intervals (CIs), of dispensed drugs in gynaecological cancer patients (up to 15 years after diagnosis) were estimated by log‐binomial and Cox regression, respectively, with cancer‐free women as reference.ResultsFor gynaecological cancer patients, the incidence of drugs used for pain control was higher than in cancer‐free women, especially the first 5 years after diagnosis, and the prevalence was high at least 10 years after. The prevalence of sex hormones was high in women with gynaecological cancer at least 10 years after diagnosis (cervical and ovarian cancer PR = 23, 95% CI 18–30 and PR = 24, 95% CI 15–38, respectively), but low in cancer‐free women (0.3%). Patients with uterine corpus cancer had a higher prevalence of antidiabetics before and at least 10 years after diagnosis, most pronounced in women diagnosed before age 50 (PR = 10, 95% CI 5.0–21). The prevalence of antidepressants was moderately elevated in women with gynaecological cancers.ConclusionsGynaecological cancer survivors, particularly cervical and ovarian cancer survivors, had an increased long‐term use of drugs for pain control and sex hormones. Survivors of uterine corpus cancer used antidiabetics more often, both before and after diagnosis.

Pregnancy-related risk factors for sex cord-stromal tumours and germ cell tumours in parous women: a registry-based study

Abstract Background Non-epithelial ovarian cancers are divided into sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Whereas parity and other pregnancy-related factors are protective for epithelial ovarian cancer, their associations with SCSTs and GCTs remains unclear. Methods Using data from the medical birth registries from Denmark, Finland, Norway and Sweden, we compared all parous women with a diagnosis of SCSTs (n = 420) or GCTs (n = 345) 1970–2013 with up to 10 parous controls (SCSTs n = 4041; GCTs n = 2942) matched on the cases’ birth year and country. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of associations between pregnancy-related factors and SCSTs and GCTs. Results The risk of SCSTs, but not GCTs, decreased with higher age at last birth [≥40 versus <25 years: OR 0.48 (95% CI 0.23–0.98)]. The risk of SCSTs (but not GCTs) also decreased with shorter time since last birth. Number of births, preterm birth, preeclampsia, and offspring size were not associated with risk of SCSTs or GCTs. Conclusions We found a decreased risk of SCSTs with higher age at last birth and shorter time since last birth. The risk of SCSTs (but not GCTs) may be influenced by the woman’s reproductive history.

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

Abstract 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.

Atypical glandular lesions of the cervix and risk of cervical cancer

AbstractIntroductionCytology screening has been effective in reducing risks for cervical squamous cell carcinoma but less so for adenocarcinoma. We explored the association of atypical glandular cells or absence of glandular cells in cytology, and subsequent histological diagnoses and cancer risk.Material and methodsAll women in Norway with atypical glandular cells of undetermined significance (AGUS), adenocarcinoma in situ (ACIS) and normal/benign cells, but absence of endocervical or metaplastic cells (NC‐NEC) in their first cytology during 1992‐2014 (NC‐NEC; 2005‐2014), recorded in the Cancer Registry of Norway, were included (n = 142 445). Histology diagnoses (stratified by age) within 1 and 3 years after cytology were examined. The Nelson‐Aalen cumulative hazard function for gynecological cancer risk was displayed.ResultsThe majority of AGUS and particularly ACIS were followed with histology within 1 and 3 years. Cervical intraepithelial neoplasia (CIN) lesions were more common in women <35 than in women ≥35 years. Cervical adenocarcinoma followed 13% of ACIS after 1 and 3 years. After ACIS and AGUS, cervical adenocarcinoma was the most frequent cancer subtype. Cumulative risks of cervical adenocarcinoma following ACIS, AGUS and NC‐NEC were 3.5%, 0.9% and 0.05%, respectively, after 22, 22 and 9 years of follow‐up.ConclusionsThere was a high‐risk of glandular malignancies after AGUS and ACIS in cytology. If effective treatment of pre‐cancer and early cancer is available, cytology screening provides some level of prevention of adenocarcinoma. Lack of glandular cells did not entail a higher cancer risk.

Cervical cancer in women under 30 years of age in Norway: a population-based cohort study

Abstract Background We compared women with incident cervical cancer under the age of 30 with older women with regard to stage, morphology, screening history and cervical cancer mortality in a population-based cohort study. Methods We included data from the Cancer Registry of Norway. Incidence rates (per 100,000 women-years) were calculated and joinpoint regression was used to analyse trends. The Nelson-Aalen cumulative hazard function for risk of cervical cancer death during a 15-year follow-up was displayed. The hazard ratios (HRs) of cervical cancer mortality with 95% confidence intervals (CIs) were derived from Cox regression models. Results The incidence of cervical cancer in women under the age of 30 has almost tripled since the 1950s, with the steepest increase during 1955–80 (with an annual percentage change (APC) of 7.1% (95%CI 4.4–9.8)) and also an increase after 2004 (3.8% (95%CI -1.3–9.2)). Out of 21,160 women with cervical cancer (1953–2013), 5.3% were younger than 30 years. A lower proportion of younger women were diagnosed at more advanced stages and a slightly higher proportion were diagnosed with adenocarcinoma and adenosquamous carcinoma comparing women above 30 years. The cumulative risk of cervical cancer death was lower for patients under the age of 30. However, the difference between the age groups decreased over time. The overall adjusted HR of cervical cancer mortality was 0.69 (95% CI 0.58–0.82) in women diagnosed under the age of 30 compared to older women. Conclusion There has been an increase in cervical cancer incidence in women under the age of 30. Cervical cancer in younger women was not more advanced at diagnosis compared to older women, and the cervical cancer mortality was lower.

HPV self-sampling among long-term non-attenders to cervical cancer screening in Norway: a pragmatic randomised controlled trial

Abstract Background Cervical cancer screening participation is suboptimal in most settings. We assessed whether human papillomavirus (HPV) self-sampling may increase screening participation among long-term non-attenders in Norway. Methods A pragmatic randomised controlled trial with participation as the primary outcome was initiated in the national cervical screening programme in March 2019. A random sample of 6000 women aged 35–69 years who had not attended screening for at least 10 years were randomised 1:1:1 to receive either (i) a reminder to attend regular screening (control), (ii) an offer to order a self-sampling kit (opt-in) for HPV testing or (iii) a self-sampling kit unsolicited (send-to-all) for HPV testing. Results Total participation was 4.8%, 17.0% and 27.7% among control, opt-in and send-to-all ( P  < 0.0001; participation difference (%) send-to-all vs. control: 22.9 (95%CI: 20.7, 25.2); opt-in vs. control: 12.3 (95%CI: 10.3, 14.2); send-to-all vs. opt-in: 10.7 (95% CI: 8.0, 13.3)). High-risk HPV was detected in 11.5% of self-samples and 9.2% of clinician-collected samples ( P  = 0.40). Most women (92.5%) who returned a positive self-sample attended the clinic for triage testing. Of the 933 women screened, 33 (3.5%) had CIN2 + (1.1%, 3.7%, 3.8% among control, opt-in, and send-to-all, respectively), and 11 (1.2%) had cervical cancer (0%, 1.2%, 1.3% among control, opt-in, send-to-all, respectively). Conclusion Opt-in and send-to-all self-sampling increased screening participation among long-term, higher-risk non-attenders. Clinical trial registration ClinicalTrials.gov NCT03873376.

Self-sampling Among Long-term Non-attenders to Cervical Cancer Screening

The trial will evaluate whether human papillomavirus (HPV) self-sampling may increase cervical cancer screening attendance among under-screened women in Norway, how different ways of offering self-sampling and follow-up may affect attendance, and whether self-sampling may reduce inequities in attendance.