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.
CDH1 mutation carriers have a strongly increased risk of developing gastric cancer (GC) and lobular breast cancer (LBC). Clinical data of GC cases and surgical and histological data of prophylactic ...gastrectomies and mastectomies of all 10 Dutch CDH1 mutation families were collected. In vitro functional assays were performed to analyze the nature of the newly found missense mutation c.1748T>G (p.Leu583Arg). Ten different CDH1 mutations were found. Functional assays gave strong arguments for the pathogenic nature of the p.Leu583Arg mutation. The pedigrees comprised 36 GC cases (mean age 40 years, range 20–72 years) and one LBC case. Twenty‐nine/37 carriers alive, aged 18–61 years, underwent prophylactic gastrectomy. Invasive GC‐foci and premalignant abnormalities were detected in 2 and 25 patients, respectively. In four patients GC/signetring cell (SRC) foci were diagnosed at preoperative gastroscopy. Long‐standing presence of SRCs without progression to invasive carcinoma was shown in two others. Multifocal LBC/LCIS was found in the two prophylactic mastectomy specimens. Clefts of lip and/or palate (CL/P) were reported in seven individuals from three families. The age at onset and aggressiveness of GC is highly variable, which has to be included in counseling on planning prophylactic gastrectomies. The incidence of LBC is expected to increase and prophylactic mastectomy needs to be considered. The relationship between CL/P and CDH1 needs further study to inform future parents from hereditary diffuse gastric cancer (HDGC) families adequately.
Non-genetic healthcare professionals can provide pre-test counseling and order germline genetic tests themselves, which is called mainstream genetic testing. In this systematic review, we determined ...whether mainstream genetic testing was feasible in daily practice while maintaining quality of genetic care.
PubMed, Embase, CINAHL, and PsychINFO were searched for articles describing mainstream genetic testing initiatives in cancer care.
Seventeen articles, reporting on 15 studies, met the inclusion criteria. Non-genetic healthcare professionals concluded that mainstream genetic testing was possible within the timeframe of a routine consultation. In 14 studies, non-genetic healthcare professionals completed some form of training about genetics. When referral was coordinated by a genetics team, the majority of patients carrying a pathogenic variant were seen for post-test counseling by genetic healthcare professionals. The number of days between cancer diagnosis and test result disclosure was always lower in the mainstream genetic testing pathway than in the standard genetic testing pathway (e.g., pre-test counseling at genetics department).
Mainstream genetic testing seems feasible in daily practice with no insurmountable barriers. A structured pathway with a training procedure is desirable, as well as a close collaboration between genetics and other clinical departments.
In international guidelines, germline genetic testing is recommended for patients with metastatic prostate cancer. Before undergoing germline genetic testing, these patients should receive pre-test ...counseling. In the standard genetic care pathway, pre-test counseling is provided by a healthcare professional of a genetics department. Because the number of patients with metastatic prostate cancer is large, the capacity in the genetics departments might be insufficient. Therefore, we aim to implement so-called mainstream genetic testing in the Netherlands for patients with metastatic prostate cancer. In a mainstream genetic testing pathway, non-genetic healthcare professionals discuss and order germline genetic testing. In our DISCOVER study, we will assess the experiences among patients and non-genetic healthcare professionals with this new pathway.
A multicenter prospective observational cohort study will be conducted in 15 hospitals, in different regions of the Netherlands. We developed an online training module on genetics in prostate cancer and the counseling of patients. After completion of this module, non-genetic healthcare professionals will provide pre-test counseling and order germline genetic testing in metastatic prostate cancer patients. Both non-genetic healthcare professionals and patients receive three questionnaires. We will determine the experience with mainstream genetic testing, based on satisfaction and acceptability. Patients with a pathogenic germline variant will also be interviewed. We will determine the efficacy of the mainstreaming pathway, based on time investment for non-genetic healthcare professionals and the prevalence of pathogenic germline variants.
This study is intended to be one of the largest studies on mainstream genetic testing in prostate cancer. The results of this study can improve the mainstream genetic testing pathway in patients with prostate cancer.
The study is registered in the WHO's International Clinical Trials Registry Platform (ICTRP) under number NL9617.
: Previous studies have suggested that information offered by sellers of health-related direct-to-consumer genetic tests (DTC-GTs) is often incomplete, unbalanced, or too difficult to understand. The ...extent to which this is the case for sellers accessible to Dutch consumers has not previously been studied.
: The present study aimed to assess the completeness, balance, readability, and findability of informational content on a selection of websites from several health-related DTC-GT sellers accessible to Dutch consumers. An in-depth content analysis was performed based on a recently published checklist outlining key items for policy guidance regarding DTC-GT services.
: The information provided by sellers did not equally cover all aspects relevant to health-related DTC-GT service provision. The provided information was slightly unbalanced, with benefits of health-related DTC-GT usage being overemphasized compared to its risks and limitations. The readability of the provided information was low, on average requiring college education for proper understanding. A findability analysis showed that information concerning all themes is overall relatively evenly distributed across analyzed sellers' websites.
: Information provision by assessed health-related DTC-GT sellers is suboptimal regarding completeness, balance, and readability. To better empower potential consumers to make an informed decision regarding health-related DTC-GT usage, we advocate industry-wide enhancement of information provision.
To successfully implement imaging-based pancreatic cancer (PC) surveillance, understanding the timeline and morphologic features of neoplastic progression is key. We aimed to investigate the ...progression to neoplasia from serial prediagnostic pancreatic imaging tests in high-risk individuals and identify factors associated with successful early detection.
We retrospectively examined the development of pancreatic abnormalities in high-risk individuals who were diagnosed with PC or underwent pancreatic surgery, or both, in 16 international surveillance programs.
Of 2552 high-risk individuals under surveillance, 28 (1%) developed neoplastic progression to PC or high-grade dysplasia during a median follow-up of 29 months after baseline (interquartile range IQR, 40 months). Of these, 13 of 28 (46%) presented with a new lesion (median size, 15 mm; range 7–57 mm), a median of 11 months (IQR, 8; range 3–17 months) after a prior examination, by which time 10 of 13 (77%) had progressed beyond the pancreas. The remaining 15 of 28 (54%) had neoplastic progression in a previously detected lesion (12 originally cystic, 2 indeterminate, 1 solid), and 11 (73%) had PC progressed beyond the pancreas. The 12 patients with cysts had been monitored for 21 months (IQR, 15 months) and had a median growth of 5 mm/y (IQR, 8 mm/y). Successful early detection (as high-grade dysplasia or PC confined to the pancreas) was associated with resection of cystic lesions (vs solid or indeterminate lesions (odds ratio, 5.388; 95% confidence interval, 1.525–19.029) and small lesions (odds ratio, 0.890/mm; 95% confidence interval 0.812–0.976/mm).
In nearly half of high-risk individuals developing high-grade dysplasia or PC, no prior lesions are detected by imaging, yet they present at an advanced stage. Progression can occur before the next scheduled annual examination. More sensitive diagnostic tools or a different management strategy for rapidly growing cysts are needed.
Almost half of pancreatic cancers develop rapidly and without warning signs on scans or endoscopy. The other half grow from earlier visible pancreatic cysts, which are difficult to discern from innocent cysts.
We aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.
From 2006 to 2019, we prospectively enrolled asymptomatic individuals with ...an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.
366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1-32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001).
The diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.
BRCA1/2 mutation carriers have a high lifetime risk of developing breast cancer. Differences in penetrance indicate that this risk may be influenced by lifestyle factors. Because physical activity is ...one of the few modifiable risk factors, it may provide a target to add to breast cancer prevention in this high-risk population. We examined the association between self-reported lifetime sports activity and breast cancer risk in a nationwide retrospective cohort study, including 725 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. We found a nonsignificantly decreased risk for ever engaging in sports activity (HR = 0.84, 95%CI = 0.57–1.24). Among women who had participated in sports, a medium versus low level of intensity and duration (i.e., between 11.0 and 22.7 mean MET hours/week averaged over a lifetime) reduced the risk of breast cancer (HR = 0.59, 95%CI = 0.36–0.95); no dose–response trend was observed. For mean hours/week of sports activity, a nonsignificant trend was observed (HR
low versus never
= 0.93, 95%CI = 0.60–1.43; HR
medium versus never
= 0.81, 95%CI = 0.51–1.29; HR
high versus never
= 0.78, 95%CI = 0.48–1.29;
p
trend overall
= 0.272;
p
trend active women
= 0.487). For number of years of sports activity no significant associations were found. Among women active in sports before age 30, mean MET hours/week showed the strongest inverse association of all activity measures (HR
medium versus low
= 0.60, 95%CI = 0.38–0.96; HR
high versus low
= 0.58, 95%CI = 0.35–0.94;
p
trend
= 0.053). Engaging in sports activity after age 30 was also inversely associated with breast cancer risk (HR = 0.63, 95%CI = 0.44–0.91). Our results indicate that sports activity may reduce the risk of breast cancer in BRCA1/2 mutation carriers.
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.
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