AbstractObjectiveTo investigate the incidence and characteristics of breast cancer in transgender people in the Netherlands compared with the general Dutch population.DesignRetrospective, nationwide ...cohort study.SettingSpecialised tertiary gender clinic in Amsterdam, the Netherlands.Participants2260 adult trans women (male sex assigned at birth, female gender identity) and 1229 adult trans men (female sex assigned at birth, male gender identity) who received gender affirming hormone treatment.Main outcome measuresIncidence and characteristics (eg, histology, hormone receptor status) of breast cancer in transgender people.ResultsThe total person time in this cohort was 33 991 years for trans women and 14 883 years for trans men. In the 2260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7-37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5).ConclusionsThis study showed an increased risk of breast cancer in trans women compared with cisgender men, and a lower risk in trans men compared with cisgender women. In trans women, the risk of breast cancer increased during a relatively short duration of hormone treatment and the characteristics of the breast cancer resembled a more female pattern. These results suggest that breast cancer screening guidelines for cisgender people are sufficient for transgender people using hormone treatment.
Objective
To examine the effect of a premenopausal risk‐reducing salpingo‐oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years ...after RRSO.
Design
A cross‐sectional study with prospective follow‐up, nested in a nationwide cohort.
Setting
Multicentre in the Netherlands.
Population or Sample
641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n = 436) or a postmenopausal RRSO ≥ age 54 (n = 205). All participants were older than 55 years at recruitment.
Methods
Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression.
Main Outcome Measures
The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO.
Results
After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests compared with women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio OR 1.8, 95% confidence interval 95% CI 1.1–3.1) and multitasking (OR 1.9, 95% CI 1.1–3.4) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60–70 years).
Conclusions
Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition.
Background
In healthy
BRCA1/2
mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over ...BC surveillance has been reported yet.
Methods
In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for
BRCA1
and
BRCA2
mutation carriers.
Results
During a mean follow-up of 10.3 years, 722 out of 1712
BRCA1
(42%) and 406 out of 1145
BRCA2
(35%) mutation carriers underwent BRRM. For
BRCA1
mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20–0.90) for overall mortality and 0.06 (95% CI 0.01–0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For
BRCA2
mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15–1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM.
Conclusion
BRRM was associated with lower mortality than surveillance for
BRCA1
mutation carriers, but for
BRCA2
mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type.
Objective
To study the impact of premenopausal risk‐reducing salpingo‐oophorectomy (RRSO), compared with postmenopausal RRSO, on urinary incontinence (UI) ≥10 years later.
Design
Cross‐sectional ...study, nested in a nationwide cohort.
Setting
Multicentre in the Netherlands.
Population
750 women (68% BRCA1/2 pathogenic variant carriers) who underwent either premenopausal RRSO (≤45 years, n = 496) or postmenopausal RRSO (≥54 years, n = 254). All participants were ≥55 years at the time of the study.
Methods
Urinary incontinence was assessed by the urinary distress inventory‐6 (UDI‐6); a score ≥33.3 indicated symptomatic UI. The incontinence impact questionnaire short form (IIQ‐SF) was used to assess the impact on women's health‐related quality of life (HR‐QoL). Differences between groups were analysed using regression analyses adjusting for current age and other confounders.
Main outcome measures
Differences in UDI‐6 scores and IIQ‐SF scores between women with a premenopausal and a postmenopausal RRSO.
Results
Women in the premenopausal RRSO group had slightly higher UDI‐6 scores compared with women in the postmenopausal RRSO group (P = 0.053), and their risk of symptomatic UI was non‐significantly increased (odds ratio OR 2.1, 95% confidence interval 95% CI 0.93–4.78). A premenopausal RRSO was associated with a higher risk of stress UI (OR 3.5, 95% CI 1.2–10.0) but not with urge UI. The proportions of women with a significant impact of UI on HR‐QoL were similar in the premenopausal and postmenopausal RRSO groups (10.4% and 13.0%, respectively; P = 0.46).
Conclusions
More than 15 years after premenopausal RRSO, there were no significant differences in overall symptomatic UI between women with a premenopausal and those with a postmenopausal RRSO.
Uncertainty is increasingly discussed during genetic counseling due to innovative techniques, e.g., multigene panel testing. Discussions about uncertainty may impact counselees variably, depending on ...counselors' communication styles. Ideally, the discussion of uncertainty enables counselees to cope with uncertainty and make well-informed decisions about testing. We examined the impact of how counselors convey uncertainty and address counselees' uncertainty, and explored the role of individual characteristics. Therefore, a randomized controlled experiment using videos was conducted. Former counselees (N = 224) viewed one video depicting a genetic consultation about multigene panel testing. The extent of counselors' communication of uncertainty (comprehensive vs. the essence) and their response to counselees' uncertainty expressions (providing information vs. providing space for emotions vs. normalizing and counterbalancing uncertainty) were systematically manipulated. Individual characteristics, e.g., uncertainty tolerance, were assessed, as well as outcome variables (primary outcomes: feelings of uncertainty and information recall). No effects were found on primary outcomes. Participants were most satisfied when the essence was communicated, combined with providing information or providing space responses (p = 0.002). Comprehensive information resulted in less perceived steering toward testing (p = 0.005). Participants with lower uncertainty tolerance or higher trait anxiety were less confident about their understanding when receiving comprehensive information (p = 0.025). Participants seeking information experienced less uncertainty (p = 0.003), and trusted their counselor more (p = 0.028), when the counselor used information providing responses. In sum, the impact of discussing uncertainty primarily depends on individual characteristics. Practical guidelines should address how to tailor the discussion of uncertainty.
Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS
) ...relative to standard gene testing in non-
Dutch BC families.
We included 3918 BC cases from 3492 Dutch non-
BC families and 3474 Dutch population controls. The association of the standardised PRS
with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS
. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in
,
and
was known.
The family history-adjusted PRS
was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS
in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS
had the largest impact for
and
.
Our results support the application of the PRS
in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.
We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each ...of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10⁻⁷) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10⁻⁵; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10⁻¹⁰). Genotype accounted for ~9% of the population-attributable risk of ASD.
We performed a systematic literature review of recommended 'major' and 'possible' clinical risk markers for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). We searched the Medline, ...Embase and Cochrane databases for articles published between 1971 and 2007. We included English language reports on HCM patients containing follow-up data on the endpoint (sudden) cardiac death using survival analysis. Analysis was undertaken using the quality of reporting of meta-analyses (QUORUM) statement checklist. The quality was checked using a quality assessment form from the Cochrane Collaboration. Thirty studies met inclusion criteria and passed quality assessment. The use of the six major risk factors (previous cardiac arrest or sustained ventricular tachycardia, non-sustained ventricular tachycardia, extreme left ventricular hypertrophy, unexplained syncope, abnormal blood pressure response, and family history of sudden death) in risk stratification for SCD as recommended by international guidelines was supported by the literature. In addition, left ventricular outflow tract obstruction seems associated with a higher risk of SCD. Our systematic review provides sound evidence for the use of the six major risk factors for SCD in the risk stratification of HCM patients. Left ventricular outflow tract obstruction could be included in the overall risk profile of patients with a marked left ventricular outflow gradient under basal conditions.
The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic ...diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers.
The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility.
Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46-1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39-1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60-2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk.
No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers.
There is an underuse of genetic testing in breast cancer patients with a lower level of education, limited health literacy or a migrant background. We aimed to study the effect of a health literacy ...training program for surgical oncologists and specialized nurses on disparities in referral to genetic testing.
We conducted a multicenter study in a quasi-experimental pre-post (intervention) design. The intervention consisted of an online module and a group training for surgical oncologists and specialized nurses in three regions in the Netherlands. Six months pre- and 12 months post intervention, clinical geneticists completed a checklist with socio-demographic characteristics including the level of health literacy of each referred patient. We conducted univariate and logistic regression analysis to evaluate the effect of the training program on disparities in referral to genetic testing.
In total, 3179 checklists were completed, of which 1695 were from hospital referrals. No significant differences were found in educational level, level of health literacy and migrant background of patients referred for genetic testing by healthcare professionals working in trained hospitals before (n = 795) and after (n = 409) the intervention. The mean age of patients referred by healthcare professionals from trained hospitals was significantly lower after the intervention (52.0 vs. 49.8, P = 0.003).
The results of our study suggest that the health literacy training program did not decrease disparities in referral to genetic testing. Future research in a more controlled design is needed to better understand how socio-demographic factors influence referral to breast cancer genetic testing and what other factors might contribute.
•Study on the effect of a health literacy training on access to breast cancer genetic testing.•Background characteristics of breast cancer patients pre- and post-intervention are compared.•Mean age of patients referred by trained hospitals was significantly lower after intervention.•The health literacy training did not decrease disparities in referral to genetic testing.
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