BMJ

HPV vaccine: the key to eliminating cervical cancer inequities

Uterine fibroids: NICE recommends new treatment option for moderate to severe symptoms

Latin America is catching up on HPV vaccination and screening

HPV: Cameroon fights back against one of the world’s lowest vaccination rates

Ovarian cancer: Loyalty card data could help identify cases sooner

Calls for cervical screening should treat women like adults

NHS England says it will eliminate cervical cancer by 2040

25 year trends in cancer incidence and mortality among adults aged 35-69 years in the UK, 1993-2018: retrospective secondary analysis

Abstract Objective To examine and interpret trends in UK cancer incidence and mortality for all cancers combined and for the most common cancer sites in adults aged 35-69 years. Design Retrospective secondary data analysis. Data sources Cancer registration data, cancer mortality and national population data from the Office for National Statistics, Public Health Wales, Public Health Scotland, Northern Ireland Cancer Registry, NHS England, and the General Register Office for Northern Ireland. Setting 23 cancer sites were included in the analysis in the UK. Participants Men and women aged 35-69 years diagnosed with or who died from cancer between 1993 to 2018. Main outcome measures Change in cancer incidence and mortality age standardised rates over time. Results The number of cancer cases in this age range rose by 57% for men (from 55 014 cases registered in 1993 to 86 297 in 2018) and by 48% for women (60 187 to 88 970) with age standardised rates showing average annual increases of 0.8% in both sexes. The increase in incidence was predominantly driven by increases in prostate (male) and breast (female) cancers. Without these two sites, all cancer trends in age standardised incidence rates were relatively stable. Trends for a small number of less common cancers showed concerning increases in incidence rates, for example, in melanoma skin, liver, oral, and kidney cancers. The number of cancer deaths decreased over the 25 year period, by 20% in men (from 32 878 to 26 322) and 17% in women (28 516 to 23 719); age standardised mortality rates reduced for all cancers combined by 37% in men (−2.0% per year) and 33% in women (−1.6% per year). The largest decreases in mortality were noted for stomach, mesothelioma, and bladder cancers in men and stomach and cervical cancers and non-Hodgkin lymphoma in women. Most incidence and mortality changes were statistically significant even when the size of change was relatively small. Conclusions Cancer mortality had a substantial reduction during the past 25 years in both men and women aged 35-69 years. This decline is likely a reflection of the successes in cancer prevention (eg, smoking prevention policies and cessation programmes), earlier detection (eg, screening programmes) and improved diagnostic tests, and more effective treatment. By contrast, increased prevalence of non-smoking risk factors are the likely cause of the observed increased incidence for a small number of specific cancers. This analysis also provides a benchmark for the following decade, which will include the impact of covid-19 on cancer incidence and outcomes.

Treatment of epithelial ovarian cancer

ABSTRACTOvarian cancer is the third most common gynecologic malignancy worldwide but accounts for the highest mortality rate among these cancers. A stepwise approach to assessment, diagnosis, and treatment is vital to appropriate management of this disease process. An integrated approach with gynecologic oncologists as well as medical oncologists, pathologists, and radiologists is of paramount importance to improving outcomes. Surgical cytoreduction to R0 is the mainstay of treatment, followed by adjuvant chemotherapy. Genetic testing for gene mutations that affect treatment is the standard of care for all women with epithelial ovarian cancer. Nearly all women will have a recurrence, and the treatment of recurrent ovarian cancer continues to be nuanced and requires extensive review of up to date modalities that balance efficacy with the patient’s quality of life. Maintenance therapy with poly ADP-ribose polymerase inhibitors, bevacizumab, and/or drugs targeting homologous recombination deficiency is becoming more widely used in the treatment of ovarian cancer, and the advancement of immunotherapy is further revolutionizing treatment targets.

Testing menstrual blood for human papillomavirus during cervical cancer screening in China: cross sectional population based study

Abstract Objective To compare the diagnostic accuracy of minipad collected menstrual blood versus clinician collected cervical samples to test for human papillomavirus (HPV) in the detection of cervical intraepithelial neoplasia grade 2/3 or worse (CIN2+/CIN3+). Design Cross sectional population based study. Setting Four urban and three rural communities in Hubei Province, China. Participants 3068 women aged 20-54 years with regular menstrual cycles, enrolled between September 2021 and January 2025. Interventions HPV testing using minipad collected menstrual blood, clinician collected cervical samples, and ThinPrep cytology. Women who tested HPV positive by either collection method or by cytology (atypical squamous cells of undetermined significance or worse) were referred for colposcopy directed biopsy sampling. Main outcome measure Diagnostic accuracy for detecting CIN2+ and CIN3+. Results Among 3068 participants, minipad based HPV testing showed a sensitivity of 94.7% (95% confidence interval 80.9% to 99.1%) for CIN2+ detection, comparable to clinician based HPV testing (92.1%, 77.5% to 97.9%; P=1.00). Although minipad HPV testing showed a lower specificity than clinician HPV testing (89.1%, 88.0% to 90.2% v 90.0%, 88.9% to 91.1%; P=0.001), the negative predictive value matched that of clinician HPV testing (99.9%, 99.7% to 100.0% v 99.9%, 99.7% to 100.0%; P=1.00). Both collection methods had a similar positive predictive value (9.9%, 7.1% to 13.5% v 10.4%, 7.4% to 14.3%; P=0.82) and screening efficiency (10.1 v 9.6 referrals per CIN2+ detected; P=0.82). Conclusions Minipad collected menstrual blood showed comparable diagnostic accuracy to clinician collected cervical samples for HPV testing for detecting CIN2+ and CIN3+. Trial registration ClinicalTrials.gov NCT06082765 .

Cervical cancer screening in older women

Young women and anal sex: should we consider rectal PAP smear testing?

HPV screening for cervical cancer is reaching maturity

Endometriosis and uterine fibroids and risk of premature mortality: prospective cohort study

Abstract Objective To prospectively assess the effect of endometriosis and uterine fibroids on the long term risk of premature mortality (younger than 70 years). Design Prospective cohort study Setting The Nurses’ Health Study II, United States (1989-2019). Participants 110 091 women aged 25-42 years in 1989 without a history of hysterectomy before endometriosis or fibroids diagnosis, cardiovascular diseases, or cancer. Main outcome measures Hazard ratios (estimated by Cox proportional hazards models) for total and cause specific premature mortality according to laparoscopically confirmed endometriosis or ultrasound or hysterectomy confirmed uterine fibroids reported in biennial questionnaires. Results 4356 premature deaths were recorded during 2 994 354 person years of follow-up (27.2 years per person), including 1459 from cancer, 304 from cardiovascular diseases, and 90 from respiratory diseases. The crude incidence of all cause premature mortality for women with and without laparoscopically confirmed endometriosis was 2.01 and 1.40 per 1000 person years, respectively. In age adjusted models, laparoscopically confirmed endometriosis was associated with a hazard ratio of 1.19 (95% confidence interval 1.09 to 1.30) for premature death; these models were strengthened after also adjusting for potential confounders including behavioral factors (1.31, 1.20 to 1.44). Cause specific mortality analyses showed that the association was largely driven by mortality from senility and ill-defined diseases (1.80, 1.19 to 2.73), non-malignant respiratory diseases (1.95, 1.11 to 3.41), diseases of the nervous system and sense organs (2.50, 1.40 to 4.44), and malignant neoplasm of gynecological organs (2.76, 1.79 to 4.26). Ultrasound or hysterectomy confirmed uterine fibroids were not associated with all cause premature mortality (1.03, 0.95 to 1.11), but were associated with a greater risk of mortality from malignant neoplasm of gynecological organs (2.32, 1.59 to 3.40) in cause specific mortality analyses. The risk of mortality caused by cardiovascular and respiratory diseases varied according to joint categories of endometriosis and uterine fibroids, with an increased risk of all cause premature mortality among women reporting both endometriosis and uterine fibroids. Conclusion Women with a history of endometriosis and uterine fibroids might have an increased long term risk of premature mortality extending beyond their reproductive lifespan. These conditions were also associated with an increased risk of death due to gynecological cancers. Endometriosis was associated with a greater risk of non-cancer mortality. These findings highlight the importance for primary care providers to consider these gynecological disorders in their assessment of women's health.

Effect of the HPV vaccination programme on incidence of cervical cancer and grade 3 cervical intraepithelial neoplasia by socioeconomic deprivation in England: population based observational study

Abstract Objectives To replicate previous analyses on the effectiveness of the English human papillomavirus (HPV) vaccination programme on incidence of cervical cancer and grade 3 cervical intraepithelial neoplasia (CIN3) using 12 additional months of follow-up, and to investigate effectiveness across levels of socioeconomic deprivation. Design Observational study. Setting England, UK. Participants Women aged 20-64 years resident in England between January 2006 and June 2020 including 29 968 with a diagnosis of cervical cancer and 335 228 with a diagnosis of CIN3. In England, HPV vaccination was introduced nationally in 2008 and was offered routinely to girls aged 12-13 years, with catch-up campaigns during 2008-10 targeting older teenagers aged <19 years. Main outcome measures Incidence of invasive cervical cancer and CIN3. Results In England, 29 968 women aged 20-64 years received a diagnosis of cervical cancer and 335 228 a diagnosis of CIN3 between 1 January 2006 and 30 June 2020. In the birth cohort of women offered vaccination routinely at age 12-13 years, adjusted age standardised incidence rates of cervical cancer and CIN3 in the additional 12 months of follow-up (1 July 2019 to 30 June 2020) were, respectively, 83.9% (95% confidence interval (CI) 63.8% to 92.8%) and 94.3% (92.6% to 95.7%) lower than in the reference cohort of women who were never offered HPV vaccination. By mid-2020, HPV vaccination had prevented an estimated 687 (95% CI 556 to 819) cervical cancers and 23 192 (22 163 to 24 220) CIN3s. The highest rates remained among women living in the most deprived areas, but the HPV vaccination programme had a large effect in all five levels of deprivation. In women offered catch-up vaccination, CIN3 rates decreased more in those from the least deprived areas than from the most deprived areas (reductions of 40.6% v 29.6% and 72.8% v 67.7% for women offered vaccination at age 16-18 and 14-16, respectively). The strong downward gradient in cervical cancer incidence from high to low deprivation in the reference unvaccinated group was no longer present among those offered the vaccine. Conclusions The high effectiveness of the national HPV vaccination programme previously seen in England continued during the additional 12 months of follow-up. HPV vaccination was associated with a substantially reduced incidence of cervical cancer and CIN3 across all five deprivation groups, especially in women offered routine vaccination.

Human papillomavirus vaccination and cervical cancer risk

ABSTRACT Persistent human papillomavirus infection is the central cause of cervical cancer, the leading cause of cancer death among women worldwide. Clear evidence from both randomized trials and population based studies shows that vaccination against human papillomavirus reduces the incidence of cervical pre-cancer. These data suggest that the vaccine reduces the incidence of cervical cancer. However, human papillomavirus vaccine coverage is inadequate in all countries, especially in low and middle income countries where disease burden is highest. Supply side strategies to improve coverage include increasing the availability of low cost vaccines, school located delivery, single dose vaccine schedules, and development of vaccines that do not need refrigeration. Demand side strategies include enhancing provider recommendations, correcting misinformation, and public awareness campaigns. The near elimination of cervical cancer is achievable through increased uptake of human papillomavirus vaccination and efforts to increase screening for cervical cancer, especially when enacted to reduce disparities in across the world.

National experience in the first two years of primary human papillomavirus (HPV) cervical screening in an HPV vaccinated population in Australia: observational study

Abstract Objective To review the first two years of the primary human papillomavirus (HPV) cervical screening programme in an HPV vaccinated population. Design Observational study. Setting Australia. Participants 3 745 318 women with a primary HPV test between 1 December 2017 and 31 December 2019; most women aged <40 years had previously been offered vaccination against HPV16 and HPV18. Interventions Primary HPV screening with referral if HPV16 or HPV18 (HPV16/18) positive and triage with liquid based cytology testing (threshold atypical squamous cells-cannot exclude high grade squamous intraepithelial lesion) for women who were positive for high risk HPV types other than 16/18. A 12 month follow-up HPV test was recommended in triaged women with a negative or low grade cytology result, with referral if they tested positive for any high risk HPV type at follow-up. Main outcome measures Proportion of women who had attended for their first HPV screening test, tested positive, and were referred for colposcopy; and short term risk of detecting cervical intraepithelial neoplasia (CIN) grade 2 or worse, CIN grade 3 or worse, or cancer. Results 54.6% (n=3 507 281) of an estimated 6 428 677 eligible women aged 25-69 had undergone their first HPV test by the end of 2019. Among those attending for routine screening, positivity for HPV16/18 and for HPV types not 16/18 was, respectively, 2.0% and 6.6% in women aged 25-69 (n=3 045 844) and 2.2% and 13.3% in highly vaccinated cohorts of women aged 25-34 (n=768 362). Colposcopy referral (ages 25-69 years) was 3.5%, increasing to an estimated 6.2% after accounting for women who had not yet had a 12 month repeat test. Cervical cancer was detected in 0.98% (456/46 330) of women positive for HPV16/18 at baseline, including 0.32% (89/28 003) of women with HPV16/18 and negative cytology. Women with HPV types not 16/18 and negative or low grade cytology at both baseline and 12 months were at low risk of serious disease (3.4% CIN grade 3 or worse; 0.02% cancer; n=20 019) but estimated to account for 62.0% of referrals for this screening algorithm. Conclusions Colposcopy referral thresholds need to consider underlying cancer risk; on this basis, women with HPV16/18 in the first round of HPV screening were found to be at higher risk regardless of cytology result, even in a previously well screened population. Women with HPV types not 16/18 and negative or low grade cytology showed a low risk of serious abnormalities but constitute most referrals and could be managed safely with two rounds of repeat HPV testing rather than one. HPV16/18 driven referrals were low in HPV vaccinated cohorts.

Second cancers in 475 000 women with early invasive breast cancer diagnosed in England during 1993-2016: population based observational cohort study

Abstract Objective To describe long term risks of second non-breast primary cancers and contralateral breast cancers among women with early invasive breast cancer after primary surgery. Design Population based observational cohort study. Setting Routinely collected data from the National Cancer Registration and Analysis Service for England. Participants All 476 373 women with breast cancer as their first invasive (index) cancer registered in England from January 1993 to December 2016 with follow-up until October 2021. Main outcome measures Rates and cumulative risks of subsequent primary cancers, compared with those occurring in the general population; associations with characteristics of patients, index tumours, and adjuvant treatments. Results Although 64 747 women developed a second primary cancer, the absolute excess risks compared with risks in the general population were small. By 20 years, 13.6% (95% confidence interval 13.5% to 13.7%) of women had developed a non-breast cancer, 2.1% (2.0% to 2.3%) more than expected in the general population, and 5.6% (5.5% to 5.6%) had developed a contralateral breast cancer, 3.1% (3.0% to 3.2%) more than expected. The absolute excess risk of contralateral breast cancer was greater in younger than in older women. Among specific types of non-breast cancer, the largest 20 year absolute excess risks were for uterine and lung cancers. Although for cancers of the uterus, soft tissue, bones and joints, and salivary glands, as well as acute leukaemias, standardised incidence ratios exceeded those of the general population by a factor of at least 1.5, absolute excess risks at 20 years were <1% for every individual non-breast cancer type. When patients were categorised according to adjuvant treatment, radiotherapy was associated with increased contralateral breast and lung cancer, endocrine therapy with increased uterine cancer (but reduced contralateral breast cancer), and chemotherapy with increased acute leukaemia. These were consistent with effects reported in randomised trials, but positive associations for soft tissue, head and neck, ovarian, and stomach cancers were also identified, and these have not previously been observed in trials. This suggested that approximately 2% of all the 64 747 second cancers and 7% of the 15 813 excess second cancers in the cohort may be attributable to adjuvant therapies. Conclusions The risk of a second primary cancer in women treated for early invasive breast cancer is slightly higher than for women in the general population. Contralateral breast cancer accounts for around 60% of the overall increase, with higher risks in younger women. The risk associated with adjuvant therapies is small.

Association of bilateral salpingo-oophorectomy with all cause and cause specific mortality: population based cohort study

Abstract Objectives To determine if bilateral salpingo-oophorectomy, compared with ovarian conservation, is associated with all cause or cause specific death in women undergoing hysterectomy for non-malignant disease, and to determine how this association varies with age at surgery. Design Population based cohort study. Setting Ontario, Canada from 1 January 1996 to 31 December 2015, and follow-up to 31 December 2017. Participants 200 549 women (aged 30-70 years) undergoing non-malignant hysterectomy, stratified into premenopausal (<45 years), menopausal transition (45-49 years), early menopausal (50-54 years), and late menopausal (≥55 years) groups according to age at surgery; median follow-up was 12 years (interquartile range 7-17). Exposures Bilateral salpingo-oophorectomy versus ovarian conservation. Main outcomes measures The primary outcome was all cause death. Secondary outcomes were non-cancer and cancer death. Within each age group, overlap propensity score weighted survival models were used to examine the association between bilateral salpingo-oophorectomy and mortality outcomes, while adjusting for demographic characteristics, gynaecological conditions, and comorbidities. To account for comparisons in four age groups, P<0.0125 was considered statistically significant. Results Bilateral salpingo-oophorectomy was performed in 19%, 41%, 69%, and 81% of women aged <45, 45-49, 50-54, and ≥55 years, respectively. The procedure was associated with increased rates of all cause death in women aged <45 years (hazard ratio 1.31, 95% confidence interval 1.18 to 1.45, P<0.001; number needed to harm 71 at 20 years) and 45-49 years (1.16, 1.04 to 1.30, P=0.007; 152 at 20 years), but not in women aged 50-54 years (0.83, 0.72 to 0.97, P=0.018) or ≥55 years (0.92, 0.82 to 1.03, P=0.16). Findings in women aged <50 years were driven largely by increased non-cancer death. In secondary analyses identifying a possible change in the association between bilateral salpingo-oophorectomy and all cause death with advancing age at surgery, the hazard ratio gradually decreased during the menopausal transition and remained around 1 at all ages thereafter. Conclusion In this observational study, bilateral salpingo-oophorectomy at non-malignant hysterectomy appeared to be associated with increased all cause mortality in women aged <50 years, but not in those aged ≥50 years. While caution is warranted when considering bilateral salpingo-oophorectomy in premenopausal women without indication, this strategy for ovarian cancer risk reduction does not appear to be detrimental to survival in postmenopausal women.

Ovarian cancer: NICE recommends expanding availability of genetic testing

Untreated cervical intraepithelial neoplasia grade 2 and subsequent risk of cervical cancer: population based cohort study

Abstract Objective To describe the long term risk of cervical cancer in women with untreated (that is, undergoing active surveillance) or immediately treated cervical intraepithelial neoplasia grade 2 (CIN2). Design Nationwide population based historical cohort study. Setting Danish healthcare registries. Participants Women with CIN2 diagnosed in 1998-2020 and aged 18-40 years at diagnosis, who had either active surveillance or immediate treatment with large loop excision of the transformation zone (LLETZ). Women with a previous record of CIN2 or worse or LLETZ were excluded. Main outcome measure A Weibull survival model for interval censored time-to-event data was used to estimate the cumulative risk of cervical cancer. Inverse probability treatment weighting was used to adjust estimates for age, index cytology, calendar year, and region of residence. Results The cohort included 27 524 women with CIN2, of whom 12 483 (45%) had active surveillance and 15 041 (55%) had immediate LLETZ. During follow-up, 104 cases of cervical cancer were identified—56 (54%) in the active surveillance group and 48 (46%) in the LLETZ group. The cumulative risk of cervical cancer was comparable across the two groups during the active surveillance period of two years. Thereafter, the risk increased in the active surveillance group, reaching 2.65% (95% confidence interval 2.07% to 3.23%) after 20 years, whereas it remained stable in the LLETZ group at 0.76% (0.58% to 0.95%). Conclusions Undergoing active surveillance for CIN2, thereby leaving the lesion untreated, was associated with increased long term risk of cervical cancer compared with immediate LLETZ. These findings show the importance of continued follow-up of women having active surveillance.

Short term complications of conisation and long term effects on fertility related outcomes in Denmark: register based nationwide cohort study

Abstract Objective To report on complications of conisation and its effects on fertility and stenosis. Design Register based nationwide cohort study on routinely collected data using several linked databases. Setting Primary and secondary care in Denmark, 2006-18. Population The conisation cohort comprised 48 048 conisations on women aged 23-65 who had undergone conisation within 120 days of a cervical biopsy. The biopsy cohort comprised 48 048 biopsies on women who had undergone a cervical biopsy but not conisation who were matched by age and time of procedure. Women were excluded from the conisation cohort before long term outcome analyses if they had undergone hysterectomy, resection of the uterus, or had cervical cancer or any long term outcomes within the 10 years before their conisation. Main outcome measures Bleeding, infection, and gynaecological operations within 30 days of conisation (stratified by age, year of conisation, and number of previous conisations) and long term risk of fertility treatment, fertility consultation, stenosis, cervical dilatation, infertility diagnoses, and death at any point after conisation. Long term outcomes were followed up until death, emigration, diagnosis of cervical cancer, hysterectomy or resection of uterus, or the end of 2018. Long term outcomes were analysed with incidence rate ratios from Cox regression models. Results Bleeding, infection, and gynaecological operations were registered for 2.81% (n=1351), 0.48% (n=231), and 3.95% (n=1897) of all conisations within 30 days of the procedure, respectively. Women in the conisation cohort had increased risk of stenosis (incidence rate ratio 14.81, 95% confidence interval 7.55 to 29.05, 0.41% v 0.03% (n=176 v 12)) and cervical dilatation (2.68, 2.41 to 2.97, 4.01% v 1.58% (n=1735 v 668)) compared with women in the biopsy cohort. No significant differences were observed for the other outcomes when adjusting for baseline covariates (such as age and region of residence). Cervical suturing after bleeding was associated with a substantial increase in the risk of stenosis and cervical dilatation. Conclusion This study found higher rates of complications within 30 days of conisation than previous studies with comparable outcome definitions, and a substantially increased risk of stenosis and cervical dilatation for women who had cervical suturing to treat bleeding after conisation. However, these results were based on few events in a small subgroup, and are therefore associated with major uncertainty. This study supports previous findings that conisation does not generally increase rates of infertility treatment or infertility diagnoses.

How can China achieve WHO’s 2030 targets for eliminating cervical cancer?

Eliminating cervical cancer as a global public health problem requires equitable action

Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation

AbstractObjectiveTo determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population.DesignRetrospective, population based diagnostic evaluation.Participants49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project.Main outcome measuresGenotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in theBRCA1andBRCA2genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data.ResultsOverall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in theBRCA1andBRCA2genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03).ConclusionsSNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.

Personal use of permanent hair dyes and cancer risk and mortality in US women: prospective cohort study

AbstractObjectiveTo evaluate the associations between personal use of permanent hair dyes and cancer risk and mortality.DesignProspective cohort study.Setting and participants117 200 women enrolled in the Nurses’ Health Study, an ongoing prospective cohort study of female nurses in the United States. The women were free of cancer at baseline, reported information on personal use of permanent hair dyes, and were followed for 36 years.ExposureStatus, duration, frequency, and integral use (cumulative dose calculated from duration and frequency) of permanent hair dyes. Age at first use and time since first use of permanent hair dyes.Main outcome measuresAssociations of personal use of permanent hair dyes with risk of overall cancer and specific cancers, and cancer related death. Age and multivariable adjusted hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazard models.ResultsEver users of permanent hair dyes had no significant increases in risk of solid cancers (n=20 805, excluding non-melanoma skin cancers; hazard ratio 0.98, 95% confidence interval 0.96 to 1.01) or hematopoietic cancers overall (n=1807; 1.00, 0.91 to 1.10) compared with non-users. Additionally, ever users did not have an increased risk of most specific cancers (cutaneous squamous cell carcinoma, bladder cancer, melanoma, estrogen receptor positive breast cancer, progesterone receptor positive breast cancer, hormone receptor positive breast cancer, brain cancer, colorectal cancer, kidney cancer, lung cancer, and most of the major subclasses and histological subtypes of hematopoietic cancer) or cancer related death (n=4860; 0.96, 0.91 to 1.02). Basal cell carcinoma risk was slightly increased for ever users (n=22 560; 1.05, 1.02 to 1.08). Cumulative dose was positively associated with risk of estrogen receptor negative breast cancer, progesterone receptor negative breast cancer, hormone receptor negative breast cancer, and ovarian cancer. An increased risk of Hodgkin lymphoma was observed only for women with naturally dark hair (based on 70 women, 24 with dark hair), and a higher risk of basal cell carcinoma was observed for women with naturally light hair.ConclusionNo positive association was found between personal use of permanent hair dye and risk of most cancers and cancer related mortality. The increased risk of basal cell carcinoma, breast cancer (estrogen receptor negative, progesterone receptor negative, hormone receptor negative) and ovarian cancer, and the mixed findings in analyses stratified by natural hair color warrant further investigation.

Breast and ovarian surgery reduces cancer risk in women at high risk

The study Marcinkute R, Woodward ER, Gandhi A, et al. Uptake and efficacy of bilateral risk reducing surgery in unaffected female BRCA1 and BRCA2 carriers. J Med Genet 2021;0:1-8. To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/earlier-decisions-breast-ovarian-surgery-reduce-risk-cancer/

Endometriosis link with ovarian cancer … and other research

Ovarian cancer: identifying and managing familial and genetic risk—summary of new NICE guidance

Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study

Abstract Objective To evaluate the association between human papillomavirus (HPV) vaccination and serious adverse events in adolescent girls in South Korea. Design Cohort study. Setting A large linked database created by linking the Korea Immunization Registry Information System and the National Health Information Database, between January 2017 and December 2019. Participants 441 399 girls aged 11-14 years who had been vaccinated in 2017: 382 020 had been vaccinated against HPV and 59 379 had not been vaccinated against HPV. Main outcome measures Outcomes were 33 serious adverse events, including endocrine, gastrointestinal, cardiovascular, musculoskeletal, haematological, dermatological, and neurological diseases. A cohort design was used for the primary analysis and a self-controlled risk interval design for the secondary analysis; both analyses used a risk period of one year after HPV vaccination for each outcome. Incidence rate and adjusted rate ratios were estimated using Poisson regression in the primary analysis, comparing the HPV vaccinated group with the HPV unvaccinated group, and adjusted relative risks were estimated using conditional logistic regression in the secondary analysis. Results Among the 33 predefined serious adverse events, no associations were found with HPV vaccination in the cohort analysis, including Hashimoto’s thyroiditis (incidence rate per 100 000 person years: 52.7 v 36.3 for the vaccinated and unvaccinated groups; adjusted rate ratio 1.24, 95% confidence interval 0.78 to 1.94) and rheumatoid arthritis (incidence rate per 100 000 person years: 168.1 v 145.4 for the vaccinated and unvaccinated groups; 0.99, 0.79 to 1.25), with the exception of an increased risk observed for migraine (incidence rate per 100 000 person years: 1235.0 v 920.9 for the vaccinated and unvaccinated groups; 1.11, 1.02 to 1.22). Secondary analysis using self-controlled risk intervals confirmed no associations between HPV vaccination and serious adverse events, including migraine (adjusted relative risk 0.67, 95% confidence interval 0.58 to 0.78). Results were robust to varying follow-up periods and for vaccine subtypes. Conclusions In this nationwide cohort study, with more than 500 000 doses of HPV vaccines, no evidence was found to support an association between HPV vaccination and serious adverse events using both cohort analysis and self-controlled risk interval analysis. Inconsistent findings for migraine should be interpreted with caution considering its pathophysiology and the population of interest.

Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis

Objective To explore the efficacy of human papillomavirus (HPV) vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment. Design Systematic review and meta-analysis Data sources PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov were screened from inception to 31 March 2021. Review methods Studies reporting on the risk of HPV infection and recurrence of disease related to HPV infection after local surgical treatment of preinvasive genital disease in individuals who were vaccinated were included. The primary outcome measure was risk of recurrence of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) after local surgical treatment, with follow-up as reported by individual studies. Secondary outcome measures were risk of HPV infection or other lesions related to HPV infection. Independent and in duplicate data extraction and quality assessment were performed with ROBINS-I and RoB-2 tools for observational studies and randomised controlled trials, respectively. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was implemented for the primary outcome. Observational studies and randomised controlled trials were analysed separately from post hoc analyses of randomised controlled trials. Pooled risk ratios and 95% confidence intervals were calculated with a random effects meta-analysis model. The restricted maximum likelihood was used as an estimator for heterogeneity, and the Hartung-Knapp-Sidik-Jonkman method was used to derive confidence intervals. Results 22 articles met the inclusion criteria of the review; 18 of these studies also reported data from a non-vaccinated group and were included in the meta-analyses (12 observational studies, two randomised controlled trials, and four post hoc analyses of randomised controlled trials). The risk of recurrence of CIN2+ was reduced in individuals who were vaccinated compared with those who were not vaccinated (11 studies, 19 909 participants; risk ratio 0.43, 95% confidence interval 0.30 to 0.60; I 2 =58%, τ 2 =0.14, median follow-up 36 months, interquartile range 24-43.5). The effect estimate was even stronger when the risk of recurrence of CIN2+ was assessed for disease related to HPV subtypes HPV16 or HPV18 (six studies, 1879 participants; risk ratio 0.26, 95% confidence interval 0.16 to 0.43; I 2 =0%, τ 2 =0). Confidence in the meta-analysis for CIN2+ overall and CIN2+ related to HPV16 or HPV18, assessed by GRADE, ranged from very low to moderate, probably because of publication bias and inconsistency in the studies included in the meta-analysis. The risk of recurrence of CIN3 was also reduced in patients who were vaccinated but uncertainty was large (three studies, 17 757 participants; 0.28, 0.01 to 6.37; I 2 =71%, τ 2 =1.23). Evidence of benefit was lacking for recurrence of vulvar, vaginal, and anal intraepithelial neoplasia, genital warts, and persistent and incident HPV infections, although the number of studies and participants in each outcome was low. Conclusion HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision. GRADE assessment for the quality of evidence indicated that the data were inconclusive. Large scale, high quality randomised controlled trials are required to establish the level of effectiveness and cost of HPV vaccination in women undergoing treatment for diseases related to HPV infection. Systematic review registration PROSPERO CRD42021237350.

Advances in the management of endometrial cancer

ABSTRACT Endometrial cancer is now the most lethal gynecologic malignancy, with incidence rates rising globally. Treatment strategies have historically been focused on a combination of surgery, radiation, and/or chemotherapy based primarily on histology and extent of tumor. Advances in the evaluation and treatment of endometrial cancers are occurring at a rapid pace, with a new focus on genomic profiling and targeted therapies. Surgical removal of the tumor remains the mainstay of therapy, but adjuvant treatments are a shifting paradigm. In the realm of gynecologic malignancies, endometrial cancer leads in the evolution of precision medicine. The ability to analyze patients, tumors, and therapy has increased over the past 10 years. Gaps in knowledge about racial and ethnic disparities, as well as pre-invasive disease prevention, are closing. This review describes the advances in endometrial cancer with a focus on people at risk, molecular classification, and modern therapeutic strategies.

Extension of cervical screening intervals with primary human papillomavirus testing: observational study of English screening pilot data

Abstract Objectives To provide updated evidence about the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and cervical cancer after a negative human papillomavirus (HPV) test in primary cervical screening, by age group and test assay. Design Observational study. Setting Real world data from the English HPV screening pilot’s first and second rounds (2013-16, follow-up to end of 2019). Participants 1 341 584 women. Interventions Cervical screening with HPV testing or liquid based cytological testing (cytology or smear tests). Women screened with cytology were referred to colposcopy after high grade cytological abnormalities or after borderline or low grade abnormalities combined with a positive HPV triage test. Women screened with HPV testing who were positive were referred at baseline if their cytology triage test showed at least borderline abnormalities or after a retest (early recall) at 12 and 24 months if they had persistent abnormalities. Main outcome measures Detection of CIN3+ and cervical cancer after a negative HPV test. Results For women younger than 50 years, second round detection of CIN3+ in this study was significantly lower after a negative HPV screen in the first round than after cytology testing (1.21/1000 v 4.52/1000 women screened, adjusted odds ratio 0.26, 95% confidence interval 0.23 to 0.30), as was the risk of interval cervical cancer (1.31/100 000 v 2.90/100 000 woman years, adjusted hazard ratio 0.44, 0.23 to 0.84). Risk of an incident CIN3+ detected at the second screening round in the pilot five years after a negative HPV test was even lower in women older than 50 years, than in three years in women younger than 50 years (0.57/1000 v 1.21/1000 women screened, adjusted odds ratio 0.46, 0.27 to 0.79). Women with negative HPV tests at early recall after a positive HPV screening test without cytological abnormalities had a higher detection rate of CIN3+ at the second routine recall than women who initially tested HPV negative (5.39/1000 v 1.21/1000 women screened, adjusted odds ratio 3.27, 95% confidence interval 2.21 to 4.84). Detection after a negative result on a clinically validated APTIMA mRNA HPV test was similar to that after clinically validated cobas and RealTime DNA tests (for CIN3+ at the second round 1.32/1000 v 1.14/1000 women screened, adjusted odds ratio 1.05, 0.73 to 1.50). Conclusions These data support an extension of the screening intervals, regardless of the test assay used: to five years after a negative HPV test in women aged 25-49 years, and even longer for women aged 50 years and older. The screening interval for HPV positive women who have negative HPV tests at early recall should be kept at three years.

Diagnostic tests for ovarian cancer in premenopausal women with non-specific symptoms (ROCkeTS): prospective, multicentre, cohort study

Abstract Objective To investigate the accuracy of risk prediction models and scores for diagnosing ovarian cancer in premenopausal women presenting to secondary care with symptoms and abnormal test results. Design Prospective cohort study. Setting Secondary care in 23 hospitals in the UK between June 2015 and March 2023. Participants Premenopausal women presenting with non-specific symptoms, and raised serum levels of cancer antigen 125 or abnormal imaging results, were prospectively recruited, predominantly referred through the NHS urgent suspected cancer pathway from primary care. A head-to-head comparison of the accuracy of the six risk prediction models and scores was conducted using donated blood and ultrasound scans performed by NHS staff trained in the use of International Ovarian Tumour Analysis (IOTA) imaging terminology. The index tests used were Risk of Malignancy Index 1 (with pre-stated thresholds of 200, 250), Risk of Malignancy Algorithm (7.4%, 11.4%, 12.5%, 13.1%), IOTA Assessment of Different Neoplasias in the adnEXa (ADNEX) (3%, 10%), IOTA simple rules risk model (3%, 10%), IOTA simple rules, and cancer antigen 125 (CA 125, 87 IU/mL). Participants were classified as having primary invasive ovarian cancer versus having benign or normal pathology according to the reference standard determined from surgical specimens or biopsies by histology or cytology, if undertaken, or else at 12 month follow-up. After June 2018, because of covid restrictions and concerns about sample size, recruitment was restricted to only women undergoing surgery within three months of presentation to clinic (in whom ovarian cancer was more likely). Main outcome measures Diagnostic accuracy at predicting primary invasive ovarian cancer versus benign or normal histology, assessed by analysing the sensitivity, specificity, C index, area under receiver operating characteristic curve, positive and negative predictive values, and calibration plots in participants with conclusive reference standard results and available index test data. Results 88 of 1211 premenopausal women received diagnoses of primary ovarian cancer: 49 of 857 women in the pre-June 2018 cohort (prevalence of 5.7%) and 39 of 354 women in the post-June 2018 cohort (11.0%). For the diagnosis of primary ovarian cancer (n=799 women, after exclusion of 58 other diagnoses), Risk of Malignancy Index 1 at the 250 threshold had a sensitivity of 42.6% (95% confidence interval (CI) 28.3 to 57.8; specificity 96.5%, 94.7 to 97.8). Compared with Risk of Malignancy Index 1 at the 250 threshold, CA 125 and all other tests had higher sensitivity (CA 125 at 87 IU/mL threshold: 55.1%, 40.2 to 69.3, P=0.06; Risk of Malignancy Algorithm at 11.4% threshold: 79.2%, 65.0 to 89.5, P<0.001; IOTA ADNEX at 10% threshold: 89.1%, 76.4 to 96.4, P<0.001; IOTA simple rules risk at 10% threshold: 83.0%, 69.2 to 92.4, P<0.001; IOTA simple rules: 75.0%, 56.6 to 88.5, P=0.01) and lower specificity (CA 125 at 87 IU/mL threshold: 89.0%, 86.5 to 91.2, P<0.001; Risk of Malignancy Algorithm at 11.4% threshold: 73.1%, 69.6 to 76.3, P<0.001; IOTA ADNEX at 10% threshold: 75.1%, 71.4 to 78.6, P<0.001; IOTA simple rules risk at 10% threshold: 76.0%, 72.4 to 79.3, P<0.001; IOTA simple rules: 95.2%, 93.0 to 96.9, P=0.06). Results for IOTA simple rules were inconclusive in 120 of 799 participants. Analysis of the complete cohort (n=1211), including the 354 premenopausal women with a higher likelihood of developing ovarian cancer, yielded similar results. Conclusions Compared to Risk of Malignancy Index 1 at 250 threshold—the test currently used in NHS secondary care to triage women to tertiary care—most tests improve sensitivity but reduce specificity. Ultrasound triage with the IOTA ADNEX model at 10% in secondary care demonstrated the highest sensitivity gain, with a comparable decline in specificity to other comparator tests. Ultrasound with the IOTA ADNEX model at 10% should be considered the new standard of care test for triaging premenopausal women in secondary care. Implementation should incorporate staff training and quality assurance. Trial registration ISRCTN17160843 .

Should women with Lynch syndrome be offered gynaecological cancer surveillance?