Evaluation of yield and experiences of age-related molecular investigation for heritable and nonheritable causes of mismatch repair deficient colorectal cancer to identify Lynch syndrome.

Universal mismatch repair deficiency (dMMR) testing of colorectal cancer (CRC) is promoted as routine diagnostics to prescreen for Lynch syndrome. We evaluated the yield and experience of age-related molecular investigation for heritable and nonheritable causes of dMMR in CRC below age 70 to identify Lynch Syndrome. In a prospective cohort of 3602 newly diagnosed CRCs below age 70 from 19 hospitals, dMMR, MLH1 promoter hypermethylation, germline MMR gene and somatic MMR gene testing was assessed in daily practice. Yield was evaluated using data from the Dutch Pathology Registry (PALGA) and two regional genetic centers. Experiences of clinicians were evaluated through questionnaires. Participating clinicians were overwhelmingly positive about the clinical workflow. Pathologists routinely applied dMMR-testing in 84% CRCs and determined 10% was dMMR, largely due to somatic MLH1 hypermethylation (66%). Of those, 69% with dMMR CRC below age 70 without hypermethylation were referred for genetic testing, of which 55% was due to Lynch syndrome (hereditary) and 43% to somatic biallelic pathogenic MMR (nonhereditary). The prevalence of Lynch syndrome was 18% in CRC < 40, 1.7% in CRC age 40-64 and 0.7% in CRC age 65-69. Age 65-69 represents most cases with dMMR, in which dMMR due to somatic causes (13%) is 20 times more prevalent than Lynch syndrome. In conclusion, up to age 65 routine diagnostics of (non-)heritable causes of dMMR CRCs effectively identifies Lynch syndrome and reduces Lynch-like diagnoses. Above age 64, the effort to detect one Lynch syndrome patient in dMMR CRC is high and germline testing rarely needed.

Breast cancer screening in BRCA1 and BRCA2 mutation carriers after risk reducing salpingo-oophorectomy.

Breast cancer screening is offered to BRCA1 and BRCA2 mutation carriers from the age of 25 years because of their increased risk of breast cancer. As ovarian cancer screening is not effective, risk-reducing salpinghooophorectomy (RRSO) is offered after child bearing age. RRSO before menopause reduces the breast cancer risk as well as breast density. It can be questioned whether after premenopausal RRSO, the intensive breast cancer screening program needs modification. We evaluated the effectiveness of breast cancer screening by clinical breast examination (CBE), mammography, and MRI in a population of 88 BRCA1 and 51 BRCA2 mutation carriers who had RRSO before the age of 52. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each screening modality. During 422 women years, 14 breast cancers were diagnosed; 2 prevalent, 10 screen detected and 2 interval breast cancers (12 in BRCA1 and 2 in BRCA2 mutation carriers). Sensitivity, specificity, PPV, and NPV for the combined screening were 85.7%, 97.6%, 30.0%, and 99.8%, respectively. No tumors were found with CBE, MRI had a sensitivity of 60.0% and mammography of 55.6%. Off all the tumors, 60% were node positive. Effectiveness of CBE and mammography was comparable to earlier findings. MRI screening seemed less effective than earlier findings. After RRSO, the breast cancer risk in BRCA1 and BRCA2 mutation carriers is still high enough to justify intensive breast cancer screening with MRI and mammography.

Universal Tumor DNA BRCA1/2 Testing of Ovarian Cancer: Prescreening PARPi Treatment and Genetic Predisposition.

BACKGROUND: Women with epithelial ovarian cancer (OC) have a higher chance to benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) therapy if their tumor has a somatic or hereditary BRCA1/2 pathogenic variant. Current guidelines advise BRCA1/2 genetic predisposition testing for all OC patients, though this does not detect somatic variants. We assessed the feasibility of a workflow for universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as a prescreen for PARPi treatment and cancer predisposition testing. METHODS: Formalin-fixed paraffin-embedded tissue was obtained from OC patients in seven hospitals immediately after diagnosis or primary surgery. DNA was extracted, and universal tumor BRCA1/2 testing was then performed in a single site. Diagnostic yield, uptake, referral rates for genetic predisposition testing, and experiences of patients and gynecologists were evaluated. RESULTS: Tumor BRCA1/2 testing was performed for 315 (77.6%) of the 406 eligible OC samples, of which 305 (96.8%) were successful. In 51 of these patients, pathogenic variants were detected (16.7%). Most patients (88.2%) went on to have a genetic predisposition test. BRCA1/2 pathogenic variants were shown to be hereditary in 56.8% and somatic in 43.2% of patients. Participating gynecologists and patients were overwhelmingly positive about the workflow. CONCLUSIONS: Universal tumor BRCA1/2 testing in all newly diagnosed OC patients is feasible, effective, and appreciated by patients and gynecologists. Because many variants cannot be detected in DNA from blood, testing tumor DNA as the first step can double the identification rate of patients who stand to benefit most from PARP inhibitors.

Cholesterol profile in women with premature menopause after risk reducing salpingo-oophorectomy.

This cross-sectional study aimed to investigate the effect of premenopausal risk reducing salpingo-oophorectomy (RRSO) on the cholesterol profile of women at increased ovarian cancer risk and to assess possible effects of age at and time since RRSO. We included 207 women who underwent RRSO before menopausal age (52 years) attending the family cancer clinic of an academic hospital and 828 age-matched women from a general population cohort (PREVEND). Participants filled out a questionnaire on socio-demographic characteristics, lifestyle and medical history, had anthropometric measurements and provided blood samples for assessment of serum levels of total cholesterol, HDL-cholesterol and non-HDL-cholesterol. The correlation between RRSO and cholesterol profile was assessed with logistic regression. Furthermore, subgroup analyses were performed to explore a possible effect of age at and time since RRSO. At a median time of 5.9 years (range 2.3-25.2) after surgery, RRSO was associated with low (< 60 mg/dl) HDL-cholesterol (OR 9.74, 95% CI 5.19-18.26) and high (≥ 160 mg/dl) non-HDL-cholesterol (OR 1.85, 95% CI 1.21-2.82) when adjusting for body mass index, hormone therapy, participation on sports and previous chemotherapy. The observed association was not dependent on age or time since RRSO. The RRSO group had less smokers (19.3 vs. 25.8%) and more participation on sports (45.4 vs. 22.0%). Our results suggest that RRSO is associated with a more atherogenic cholesterol profile, despite a lower prevalence of smoking and higher prevalence of participation on sports as compared to controls. This observation can be useful for physicians involved in the counselling and follow-up of women having RRSO.

Elevated Bone Turnover Markers after Risk-Reducing Salpingo-Oophorectomy in Women at Increased Risk for Breast and Ovarian Cancer.

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk in BRCA1/2 mutation carriers. Premenopausal RRSO is hypothesized to increase fracture risk more than natural menopause. Elevated bone turnover markers (BTMs) might predict fracture risk. We investigated BTM levels after RRSO and aimed to identify clinical characteristics associated with elevated BTMs. METHODS: Osteocalcin (OC), procollagen type I N-terminal peptide (PINP) and serum C-telopeptide of type I collagen (sCTx) were measured in 210 women ≥ 2 years after RRSO before age 53. BTM Z-scores were calculated using an existing reference cohort of age-matched women. Clinical characteristics were assessed by questionnaire. RESULTS: BTMs after RRSO were higher than age-matched reference values: median Z-scores OC 0.11, p = 0.003; PINP 0.84, p < 0.001; sCTx 0.53, p < 0.001 (compared to Z = 0). After excluding women with recent fractures or BTM interfering medication, Z-scores increased to 0.34, 1.14 and 0.88, respectively. Z-scores for OC and PINP were inversely correlated to age at RRSO. No correlation was found with fracture incidence or history of breast cancer. CONCLUSIONS: Five years after RRSO, BTMs were higher than age-matched reference values. Since elevated BTMs might predict higher fracture risk, prospective studies are required to evaluate the clinical implications of this finding.

Bone mineral density and fractures after risk-reducing salpingo-oophorectomy in women at increased risk for breast and ovarian cancer.

AIM: Risk-reducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk in BRCA mutation carriers. RRSO is assumed to decrease bone mineral density (BMD) and increase fracture risk more than natural menopause. We aimed to compare BMD and fracture incidence after premenopausal RRSO to general population data and identify risk factors for low BMD and fractures after RRSO. METHODS: In 212 women with RRSO at premenopausal age, BMD was measured by dual energy X-ray absorptiometry. Fractures and risk factors were assessed by self-administered questionnaire. Fracture incidence after RRSO was compared to general practitioner data by using standardised incidence ratios (SIRs). Risk factors for low standardised BMD-scores and fractures were identified by regression analyses. RESULTS: Median age at RRSO was 42years (range 35-65) and duration of follow-up 5years (2-8). Standardised lumbar spine (Z=0.01, p=0.870) and femoral neck BMD (Z=0.15, p=0.019) were not lower than population BMD. Higher age at time of RRSO and use of hormonal replacement therapy were associated with higher, and current smoking with lower standardised BMD-scores. Sixteen women reported 22 fractures. Fracture incidence was not higher than expected from the general population (all fractures: 25-44years: SIR 2.12 [95% confidence interval (CI) 0.85-4.37]; 45-64years: SIR 1.65 [95% CI 0.92-2.72]). CONCLUSION: Five years after RRSO, BMD and fracture incidence were not different than expected from the general population. Based on these data it appears safe not to intensively screen for osteoporosis within five years after RRSO, although prospective research on the long-term effects of RRSO on bone is warranted.

Breast Cancer Incidence After Risk-Reducing Salpingo-Oophorectomy in BRCA1 and BRCA2 Mutation Carriers.

Premenopausal risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers effectively reduces ovarian cancer risk, but also reduces breast cancer risk. Breast cancer risk reductions up to 50% have been reported for both BRCA1 and BRCA2 mutation carriers, but recent prospective studies were not able to reproduce this finding for BRCA1 mutation carriers. Breast cancer incidence after RRSO was assessed in a consecutive series of 104 BRCA1 and 58 BRCA2 mutation carriers. On the basis of data from our own centre, and assuming a 50% risk reduction through RRSO at premenopausal age, we expected to find 8 breast cancers (range 6-10) in this population for the reported screening period (532 women-years). In 162 carriers with a median age of 41 years at RRSO, 13 incident breast cancers were diagnosed. In BRCA1 mutation carriers, 12 incident breast cancers were found compared with 5 (range 3-6) expected and in BRCA2 mutation carriers 1 breast cancer was found compared with 3 (range 2-5) expected. Breast cancer incidence after premenopausal RRSO is still high, especially in BRCA1 mutation carriers. Previously reported breast cancer risk reductions up to 50% were not confirmed. As a consequence, continued intensive screening for breast cancer is warranted in BRCA1 and BRCA2 mutation carriers after RRSO.