Louise Baandrup

Ovarian cancer risk factors in relation to family history

Abstract Background Women with a family history of breast and/or ovarian cancer have an increased ovarian cancer risk. Yet it remains uncertain if common ovarian cancer risk factors—especially those that are modifiable—affect this high-risk population similarly to the general population. Methods Using the Danish and Swedish nationwide registers, we established 2 nested case-control study populations in women with a family history of breast and/or ovarian cancer (2138 ovarian cancers, 85 240 controls) and women without (10 730 ovarian cancers, 429 200 controls). The overall and histology-specific associations were assessed with conditional logistic regression. The country-specific estimates were combined based on a fixed-effect assumption. Results Multiparity, hysterectomy, tubal ligation, salpingectomy, and oral contraceptive (OC) use were associated with a reduced risk of ovarian cancer in women with and without a family history, while endometriosis and menopausal hormone therapy were associated with increased risk. Multiparity and OC use presented protective effects across all histologic subtypes except mucinous ovarian cancer, which was not associated with OC use. Menopausal hormone treatment increased the risk of serous ovarian cancer but decreased the risk of the mucinous and clear cell cancers. Endometriosis was especially related to an increased risk of endometrioid and clear cell ovarian cancer. Conclusion Factors associated with a decreased ovarian cancer risk were similar between women with and without a family history of breast and/or ovarian cancer. Given the higher baseline risk for women with a family history, special attention should be paid to risk factors like endometriosis and nulliparity in this high-risk population.

Prediagnostic use of menopausal hormone therapy and long‐term survival of localized epithelial ovarian cancer: The Extreme study

AbstractUse of menopausal hormone therapy (MHT) prior to an epithelial ovarian cancer (EOC) diagnosis has been suggested to be associated with improved survival. In a recent nationwide cohort study, we found that prediagnostic long‐term MHT use, especially estrogen therapy (ET), was associated with improved long‐term survival in women with nonlocalized EOC. Our aim was to investigate the influence of prediagnostic MHT use on long‐term survival among women with localized EOC in the same nationwide study. Our study cohort comprised all women aged 50 years or older with an EOC diagnosis in Denmark 2000–2014 (n = 2097) identified from the Extreme study. We collected information on usage of systemic ET and estrogen plus progestin therapy (EPT) from the Danish National Prescription Registry. By using pseudo‐values, 5‐ and 10‐year absolute and relative survival probabilities were estimated with 95% confidence intervals (CIs) while adjusting for histology, comorbidity, and income. Relative survival probabilities >1 indicate better survival. The 5‐year absolute survival probabilities were 61% and 56%, respectively, among women who were nonusers and users of prediagnostic MHT, whereas these numbers were 46% and 41%, respectively, regarding 10‐year survival. Use of MHT was not significantly associated with an improved 5‐ or 10‐year survival in women with localized EOC (5‐year relative survival probability = 0.95, 95% CI: 0.89–1.02; 10‐year relative survival probability = 0.92, 95% CI: 0.84–1.02). Similar findings were seen for systemic ET or EPT use. Our findings do not suggest a positive benefit from prediagnostic MHT use on long‐term survival of localized EOC.

Risk of nonovarian cancer in a nationwide‐based study of nearly 5000 women with borderline ovarian tumors in Denmark

AbstractEvidence regarding cancer risk after borderline ovarian tumors (BOTs) is limited. We conducted a nationwide cohort study examining the incidence of nonovarian cancers in women with serous or mucinous BOTs compared with the general female population with up to 41 years of follow‐up. Through the nationwide Pathology Registry, we identified nearly 5000 women with BOTs (2506 serous and 2493 mucinous) in Denmark, 1978 to 2018. We computed standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) as relative risk estimates of specific nonovarian cancers. Compared with general female population rates, women with serous BOTs had increased rates of particularly malignant melanoma (SIR = 1.9; 95% CI: 1.3‐2.6), thyroid cancer (SIR = 3.0; 95% CI: 1.4‐5.4) and myeloid leukemia (SIR = 3.2; 95% CI: 1.5‐5.8), and women with mucinous BOTs had elevated rates of lung cancer (SIR = 1.7; 95% CI: 1.3‐2.1), pancreatic cancer (SIR = 1.9; 95% CI: 1.2‐2.9) and myeloid leukemia (SIR = 2.3; 95% CI: 0.9‐4.7). We found no convincing association with neither breast nor colorectal cancer in women with BOTs. This is the first large nationwide study showing that women with specific types of BOTs have increased risks of several nonovarian cancers, likely due to some shared risk factors or genetic characteristics.

Long‐term survival of nonlocalized epithelial ovarian cancer among women using menopausal hormone therapy prior to diagnosis: The extreme study

AbstractPrediagnostic use of menopausal hormone therapy (MHT) has been suggested to be associated with improved survival of epithelial ovarian cancer (EOC). We investigated the potential long‐term survival benefit of prediagnostic MHT use in women ≥50 years with nonlocalized EOC using the Extreme study including all women in Denmark registered with nonlocalized EOC during 2000 to 2014 (N = 3776). We obtained individual‐level information on prediagnostic use of systemic estrogen therapy (ET) and estrogen plus progestin therapy (EPT) from the National Prescription Registry and estimated absolute and relative 5‐ and 10‐year survival probabilities with 95% confidence intervals (CIs) using pseudo‐values, taking into account histology, comorbidity, income and residual disease. Among women not having used prediagnostic MHT, 5‐ and 10‐year absolute survival probabilities were 19% and 11%, respectively. Compared to MHT nonusers, prediagnostic systemic ET use for 3 to 4 years and ≥ 5 years was associated with 1.43 (95% CI: 1.01‐2.02) and 1.22 (95% CI: 0.96‐1.55) times higher 5‐year survival probabilities, respectively. Ten‐year survival probabilities were also increased but not statistically significantly. Among prediagnostic EPT users, increased 5‐year (1.14, 95% CI: 0.85‐1.53) and 10‐year (1.38, 95% CI: 0.91‐2.08) survival probabilities were observed after use for 3 to 4 years compared to MHT nonuse, whereas EPT use for ≥5 years was not associated with long‐term survival of nonlocalized EOC. Our findings may suggest a better long‐term survival of nonlocalized EOC in women having used long‐term prediagnostic ET. However, the statistical precision of our results did not allow firm conclusions and more studies are needed.

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.

Biopsy‐verified vulvar lichen sclerosus and the risk of non‐vulvar cancer: A nationwide cohort study

AbstractVulvar lichen sclerosus (VLS) is a chronic inflammatory mucocutaneous disease known to be associated with human papillomavirus‐independent vulvar squamous cell carcinoma. Evidence on the association with other types of cancer, however, is sparce. We conducted a large nationwide cohort study examining the incidence of non‐vulvar cancers among women with biopsy‐verified VLS compared with the general female population. By using the nationwide Pathology Registry, we identified all women in Denmark with a biopsy‐verified VLS diagnosis during 1978–2019 (n = 16,921). The cohort was followed up in the Danish Cancer Registry until 2022 for a subsequent non‐vulvar cancer diagnosis. Standardized incidence ratios (SIRs) were computed with 95% confidence intervals (CIs) as relative risk estimates of all specific non‐vulvar cancer sites. Compared with general female population rates, women with biopsy‐verified VLS had decreased rates of several non‐vulvar cancers, including HPV‐related cancers (combined estimate: SIR = 0.5; 95% CI: 0.3–0.7), and lung (SIR = 0.6; 95% CI: 0.5–0.7), liver (SIR = 0.5; 95% CI: 0.2–0.9), and thyroid cancer (SIR = 0.5; 95% CI: 0.3–0.9). The decreased SIRs tended to sustain throughout the follow‐up period following the VLS diagnosis. This large nationwide cohort study shows that women with biopsy‐verified VLS may have a long‐term reduced risk of developing HPV‐related (cervical, vaginal, oropharyngeal, and anal) and smoking‐associated cancers (lung, liver, and cervical) as well as thyroid cancer. Future studies focusing on the mechanisms behind the decreased cancer risk are needed.

Biopsy‐verified vulvar lichen sclerosus: Incidence trends 1997–2022 and increased risk of vulvar squamous precancer and squamous cell carcinoma

AbstractPopulation‐based data on the epidemiology of vulvar lichen sclerosus (LS) are sparse and only few prospective studies have investigated the malignant potential of the disease. We used the nationwide Danish Pathology Registry to first assess the incidence of biopsy‐verified vulvar LS in the period 1997–2022 and second to examine the incidence of vulvar high‐grade squamous precancer and squamous cell carcinoma (SCC) in women with biopsy‐verified vulvar LS (1978–2019) compared with that expected in the general female population. For the latter aim, we computed standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). During our study period, the age‐standardized incidence rate of vulvar LS increased from 5.0 (1997–1998) to 35.7 (2021–2022) per 100,000 person‐years. Compared with the general female population, women with biopsy‐verified vulvar LS had significantly increased rates of vulvar high‐grade squamous precancer (SIR = 8.5; 95% CI: 7.2–10.0) and SCC (SIR = 16.2; 95% CI: 14.2–18.4). The SIRs of vulvar high‐grade squamous precancer and SCC did not vary substantially according to length of follow‐up. This nationwide and population‐based study shows a 7‐fold increase in the incidence of biopsy‐verified vulvar LS since 1997. Data also show that women with biopsy‐verified vulvar LS have 8.5 and 16 times higher than expected incidence of vulvar high‐grade squamous precancer and SCC, respectively. The substantially increased incidence of vulvar high‐grade squamous precancer and SCC following LS is important in relation to the clinical management and follow‐up of LS patients.

PD‐L1 expression in vulvar cancer: a systematic review and meta‐analysis

Programmed cell death ligand‐1 (PD‐L1) expression in cancer may predict clinical response to immunotherapeutic treatment with PD‐1/PD‐L1 inhibitors. Within the vulvar cancer field, PD‐L1 expression has only been assessed by a few studies. We conducted a meta‐analysis to examine the prevalence of PD‐L1 positivity in vulvar cancer. PubMed, Embase, and Cochrane were searched for articles reporting on PD‐L1 expression in vulvar cancer. Study selection and data extraction were performed independently by two authors. We extracted data on PD‐L1 prevalence in vulvar cancer according to combined positive score (CPS) and tumour proportion score (TPS). Cutoff values for positivity were ≥1 or ≥10 for CPS and ≥1% and ≥5% for TPS. Random‐effects models were used to estimate pooled PD‐L1 prevalence, with 95% confidence intervals (CIs). Tests of between‐study heterogeneity were evaluated by the I2 statistics. Sources of heterogeneity were explored by subgroup analyses and meta‐regression. In total, 19 studies were included. Pooled PD‐L1 prevalence in vulvar cancer was 83.4% (95% CI: 70.8–91.3; I2 = 80.0) and 53.9% (95% CI: 37.4–69.6; I2 = 93.0) according to CPS and TPS, respectively. Based on TPS, human papillomavirus (HPV)‐associated vulvar squamous cell carcinomas (SCC) showed a lower PD‐L1 prevalence (39.9%; 95% CI: 13.3–74.2) compared with HPV‐independent SCC (62.6%; 95% CI: 33.7–84.6), but meta‐regression showed no significant variation in PD‐L1 prevalence by HPV status. PD‐L1 prevalence was similar in advanced (44.9%; 95% CI: 29.8–61.1) and localized vulvar cancer (56.7%; 95% CI: 18.9–76.7). In conclusion, PD‐L1 expression in vulvar cancer is frequent but between‐study heterogeneity was high. Based on a subgroup of heterogenous studies, we found no strong variation in PD‐L1 prevalence according to HPV status and stage.

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.