Susanne K. Kjaer

Long-term effectiveness of the nine-valent human papillomavirus vaccine: Interim results after 12 years of follow-up in Scandinavian women

A pivotal study in women aged 16-26 years demonstrated that the nine-valent human papillomavirus (9vHPV) vaccine was efficacious against high-grade cervical dysplasia related to the HPV types covered by the vaccine. To evaluate whether effectiveness remains above 90% for up to 14 years post-vaccination, a long-term follow-up (LTFU) extension of the study was conducted in Denmark, Norway, and Sweden (

Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

Abstract Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604

Effectiveness of One-Way Text Messaging on Attendance to Follow-Up Cervical Cancer Screening Among Human Papillomavirus–Positive Tanzanian Women (Connected2Care): Parallel-Group Randomized Controlled Trial

Background Rapid human papillomavirus (HPV) DNA testing is an emerging cervical cancer screening strategy in resource-limited countries, yet it requires follow-up of women who test HPV positive. Objective This study aimed to determine if one-way text messages improved attendance to a 14-month follow-up cervical cancer screening among HPV-positive women. Methods This multicenter, parallel-group randomized controlled trial was conducted at 3 hospitals in Tanzania. Eligible participants were aged between 25 and 60 years, had tested positive to a rapid HPV test during a patient-initiated screening, had been informed of their HPV result, and had a private mobile phone with a valid number. Participants were randomly assigned in a 1:1 ratio to the intervention or control group through an incorporated algorithm in the text message system. The intervention group received one-way text messages, and the control group received no text messages. The primary outcome was attendance at a 14-month health provider-initiated follow-up screening. Participants were not blinded, but outcome assessors were. The analysis was based on intention to treat. Results Between August 2015 and July 2017, 4080 women were screened for cervical cancer, of which 705 were included in this trial—358 women were allocated to the intervention group, and 347 women were allocated to the control group. Moreover, 16 women were excluded before the analysis because they developed cervical cancer or died (8 from each group). In the intervention group, 24.0% (84/350) women attended their follow-up screening, and in the control group, 23.8% (80/335) women attended their follow-up screening (risk ratio 1.02, 95% CI 0.79-1.33). Conclusions Attendance to a health provider-initiated follow-up cervical cancer screening among HPV-positive women was strikingly low, and one-way text messages did not improve the attendance rate. Implementation of rapid HPV testing as a primary screening method at the clinic level entails the challenge of ensuring a proper follow-up of women. Trial Registration ClinicalTrials.gov NCT02509702; https://clinicaltrials.gov/ct2/show/NCT02509702. International Registered Report Identifier (IRRID) RR2-10.2196/10.2196/15863

Six‐pattern p53 interpretation in 1293 vulvar squamous cell carcinomas: inter‐pathologist variation and pattern distribution according to p16 status

Aims Vulvar squamous cell carcinoma (VSCC) is classified into human papillomavirus (HPV)‐associated and HPV‐independent types, primarily using p16 immunohistochemistry, with p53 staining playing a complementary role since a subset of HPV‐independent VSCC is driven by TP53 mutations. We aimed to assess the robustness of the six‐pattern p53 classification by evaluating interobserver agreement and mapping pattern distribution in relation to p16 status. Methods We performed p53 immunohistochemistry on 1293 VSCC cases, comprising 832 p16‐negative and 461 p16‐positive cases. Eight pathologists independently evaluated p53, with each case assessed by two pathologists. Expression was classified as wild‐type (scattered or mid‐epithelial) or mutated (basal overexpression, parabasal/diffuse overexpression, absent or cytoplasmic). Interobserver agreement was measured using kappa statistics. Results Overall concordance across the six p53 patterns was 66.7%, increasing to 86.9% when dichotomized as wild‐type versus mutated. In the p16‐negative cases, concordance was 68.8% across all six patterns and 82.6% when dichotomized. Corresponding rates in the p16‐positive cases were 62.9% and 94.6%. Kappa values for pairwise assessments ranged from 0.44 to 0.73 (six‐pattern) and from 0.60 to 0.88 (dichotomized). After resolving discordant cases, 79.9% of p16‐negative cases showed a mutated pattern, and 20.1% were wild type (scattered). Among the p16‐positive cases, 93.1% exhibited a wild‐type pattern. Conclusions Findings support the clinical robustness of the six‐pattern p53 framework, as interobserver agreement was high and most discrepancies were unlikely to impact tumour classification. While p16 proved helpful in p53 interpretation, certain cases remained challenging due to p53 heterogeneity or ambiguous p16/p53 combinations indicating a need for additional molecular testing in such instances.

Prognostic impact of p16 and high‐risk HPV DNA in ~1300 patients with vulvar cancer

AbstractThe study aimed to investigate whether vulvar squamous cell carcinoma (VSCC) survival varies by human papillomavirus (HPV) status measured by p16 expression and to determine whether high‐risk HPV (hrHPV) DNA detection adds further prognostic information. Our cohort included 1277 women with histologically verified VSCC (1990–2017) categorized according to p16 and hrHPV DNA. Crude survival was estimated using Kaplan–Meier, and differences in restricted mean survival time were estimated in linear regression models. Analyses were stratified by p16 and p16/hrHPV status and stage, and adjustment included age, calendar year, and comorbidity. Overall analysis showed that 5‐year survival was 67% (95% CI: 63–71%) and 45% (95% CI: 42–48%) in p16‐positive and p16‐negative VSCC, respectively. Overall, detection of hrHPV was associated with a 23% (95% CI: 6–40%) improvement in 5‐year survival in p16‐positive VSCC, whereas hrHPV status did not impact 5‐year survival in p16‐negative VSCC. In adjusted analysis, the survival difference by p16 status increased with increasing stage with a 26% (95% CI: 4–46%) higher 5‐year survival in FIGO IV disease if the tumor was p16‐positive compared to p16‐negative, corresponding to a restricted mean survival time difference of 18 months in favor of p16 positivity. The largest VSCC cohort to date confirms the beneficial prognostic impact of p16 expression regardless of age and comorbidity and with the greatest impact in women with advanced disease. Classification according to p16 was adequate for p16‐negative VSCC, whereas the survival of p16‐positive VSCC was higher if hrHPV testing was also positive.

Use of statins and risk of ovarian cancer: evidence on effect modification by parity, menopause and endometriosis from nationwide nested case-control studies

Previous results on the association between statin use and risk of ovarian cancer (OC) are inconsistent, warranting further investigation. This study aims to examine the association between statin use and risk of OC in a large study population. Based on two nationwide nested case-control studies utilizing data from Danish and Swedish high-quality registries, we identified 11,874 OC cases who were individually matched on age to 474,960 controls using risk-set sampling. Conditional logistic regression was performed separately on the country-specific data to calculate odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) for the association between statin use and risk of OC. Country-specific estimates were combined based on a fixed-effect assumption. Furthermore, we examined potential effect modifications by a priori selected OC risk factors on the association between statin use and OC risk. We found no overall association between statin use and risk of OC (OR = 0.96; 95 % CI: 0.91-1.01); neither with duration nor intensity of use. However, statin use was associated with a decreased risk of OC in subsets of women with endometriosis (OR = 0.70; 95 % CI: 0.53-0.91), and nulliparous women (OR = 0.86; 95 % CI: 0.79-0.93). We found an effect modification of some known ovarian cancer risk factors on the association between statin use and risk of OC. In women with endometriosis, and in nulliparous women, respectively, statin use was associated with a decreased risk of OC, suggesting statins may have potential as a preventive measure.

Frandsen et al. respond to “A note on variable adjustments”

Abstract In response to M. Naylor’s valuable critique of our study “Polycystic Ovary Syndrome and Endometrial Cancer Risk: Results from a Nationwide Cohort Study,” we recognize the merit in the suggested areas. We recognize that including information on hormone therapy may have added to the understanding of the relationship between polycystic ovary syndrome (PCOS) and endometrial cancer risk. We further acknowledge the importance of the frequency of gynecological visits, which we have treated as a mediator rather than a confounder, given its role in reflecting PCOS severity and management. This approach, however, may introduce surveillance bias by influencing early cancer detection rates. Although the Danish health care system is fully subsidized, our exclusive use of hospital records may miss some PCOS cases managed in primary or specialized care settings outside the hospital, potentially leading to underestimation of the true association. Incorporating these variables in future studies could enhance analytical scope, though it would involve complex methodologies. We appreciate the comprehensive feedback, which underscores the necessity for further studies to elucidate the links between PCOS and endometrial cancer. These insights will inform future research and advance understanding in this area.

Polycystic ovary syndrome and endometrial cancer risk: results from a nationwide cohort study

Abstract Most previous studies found an elevated risk of endometrial cancer among women with polycystic ovary syndrome (PCOS). However, these had highly varying methods for ascertainment of PCOS diagnoses and limitations such as few exposed women and short follow-up. In this cohort study, we investigated the association between PCOS and endometrial cancer among women born in Denmark between January 1, 1940, and December 31, 1993 (n = 1 719 121). Data in this study, including PCOS and endometrial cancer diagnoses and covariates, were derived from nationwide registers. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% CIs. A total of 7862 endometrial cancer cases were identified during 23.7 years of follow-up (IQR, 37.7-61.9). We found an increased risk of endometrial cancer among women with PCOS compared with women without PCOS (HR = 3.02; 95% CI, 2.03-4.49). The risk was increased for premenopausal women (HR = 5.82; 95% CI, 3.64-9.30), whereas no marked association was seen for postmenopausal women. However, for postmenopausal women, results were limited by few cases and young age at the end of follow-up. Mounting evidence of an increased risk for endometrial cancer among women with PCOS reinforces the need for prevention and early detection. This article is part of a Special Collection on Gynecological Cancers.

Risk of Epithelial Ovarian Tumors among Women Diagnosed with Hypothyroidism and Hyperthyroidism: Findings from a Large Nationwide Cohort Study

Abstract Background: Prior research on the association between thyroid disease, ovarian cancer, and borderline ovarian tumors has been inconsistent. This nationwide cohort study investigated the risk of epithelial ovarian cancer and borderline ovarian tumors among 1,058,745 Danish women born between January 1, 1960, and December 31, 1997, and were followed until December 31, 2022, in relation to hypothyroidism and hyperthyroidism. Methods: Data on thyroid diagnoses, ovarian tumors, covariates, migration, and vital status were retrieved from Danish national registers. Hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer and borderline ovarian tumors overall and for histologic subtypes were estimated using adjusted Cox proportional hazard models. A landmark analysis assessed ovarian tumor risk at age 60 years by thyroid disease status before age 40 years. Results: Over a median of 18.4 years of follow-up, 49,015 women developed hypothyroidism, 26,950 hyperthyroidism, 905 ovarian cancer, and 1,111 borderline ovarian tumors. No association was found between hypothyroidism and ovarian cancer (HR, 1.10; CI, 0.78–1.55) or borderline tumors (HR, 0.88; CI, 0.60–1.29). Hyperthyroidism was associated with increased rates of serous ovarian cancer (HR, 1.62; CI, 1–2.63) and borderline ovarian tumors (HR, 1.78; CI, 1.26–2.52), especially in postmenopausal and premenopausal women, respectively. However, absolute risk differences at age 60 years were small and not statistically significant. Conclusions: Hyperthyroidism may increase the rate of epithelial ovarian tumors, though clinical significance remains unclear, warranting further research. Impact: These findings indicate that hyperthyroidism may modestly influence epithelial ovarian tumor risk, underscoring the need to clarify shared biological mechanisms between thyroid and ovarian function.

Use of SMSs to Improve Attendance to Cervical Cancer Follow-up Screening

This study evaluates the effect of the SMS intervention 'Connected2Care' on the attendance rate to cervical cancer screening follow-up appointments.