Karin Kast

Breast Density Changes after Risk-Reducing Salpingo-oophorectomy in Women with a Pathogenic Germline Variant in BRCA1 or BRCA2

Abstract Background: We studied changes in mammographic density (MD) among premenopausal women with a pathogenic germline variant (PGV) in the BRCA1 or BRCA2 gene, comparing those who did and did not undergo risk-reducing salpingo-oophorectomy (RRSO) in the interval between mammograms, accounting for changes in exogenous oral contraceptive or hormone replacement therapy (HRT) use. Methods: From five studies of the International BRCA1/2 Carrier Cohort Study consortium, we included 691 participants who had two or more screening mammograms available, were less than 47 years at the time of RRSO (N = 208), or premenopausal at all mammograms without RRSO (N = 483). MD metrics [percent density (PD), dense area (DA), and non-DA] were quantified using STRATUS. Multivariable linear mixed models assessed changes in MD metrics between groups, adjusting for confounders. Results: The mean PD at first mammogram was 26.8% ± 15.3 (RRSO) and 31.3% ± 18.1 (no RRSO). In a median 1.1 years between mammograms, PD decreased on average by 0.9% [95% confidence interval (CI), −1.6 to −0.2] among women who did not undergo RRSO in the interval between mammograms compared with 5.9% (95% CI, −7.4 to −4.5) among women who underwent RRSO in the interval (adjusted difference, −5.9%; 95% CI, −9.5 to −2.2; P = 0.002). Results were driven primarily by MD changes among BRCA2 PGV carriers. The use of HRT after RRSO attenuated the decline in PD. Conclusions: On average, PD and DA decrease following RRSO in premenopausal carriers, particularly among BRCA2 PGV carriers. HRT formulation affects MD changes. Impact: A decrease in MD may inform the potential protective effect of RRSO against breast cancer.

Phenotype analysis of families with TP53 germline variants at the Center for Familial Breast and Ovarian Cancer, Cologne

AbstractPurposeTumor protein p53 (TP53) pathogenic variant (PV) carriers are identified during genetic testing for hereditary causes of cancer. PVs in TP53 are associated with the Li‐Fraumeni syndrome (LFS), and thus, surveillance and preventive measures are important for TP53 PV carriers. However, the penetrance of TP53 PVs can be low if the Chompret criteria are not fulfilled. In this study, we compared the phenotypic characteristics of families that did and did not fulfill the LFS criteria according to Chompret.MethodsThe German Consortium for Hereditary Breast and Ovarian Cancer (GC‐HBOC) database was used to identify index patients with a likely pathogenic/pathogenic TP53 variant and their family members. The study investigated the type of variant, pedigree, age of onset, number of primary tumors, and histological type of BC.ResultsTP53 PV were present in the index cases of 35 families, 57% (20/35) of which fulfilled the Chompret criteria. The median age of onset at first BC diagnosis was lower in families that fulfilled the Chompret criteria compared to those who did not. Four of all diseased individuals were minors (4%; 4/105) when malignancy was first diagnosed. Sarcomas and brain tumors occurred in 10% (10/105) and in 7% (7/105) of all diseased persons, respectively. BC was the most frequently occurring first tumor (60%; 62/105) and additional malignancy (45%; 20/44) in this cohort. Subsequent malignancies developed in 31% (20/65) of the individuals who fulfilled the Chompret criteria compared with 15% (6/40) of those who did not.ConclusionThe tumor spectrum and age of onset found in this study showed that tumors other than BC had low disease penetrance in TP53 PV carriers identified using the GC‐HBOC criteria for genetic testing.

Oral Contraceptive Use in BRCA1 and BRCA2 Mutation Carriers: Absolute Cancer Risks and Benefits

Abstract Background To help BRCA1 and 2 mutation carriers make informed decisions regarding use of combined-type oral contraceptive preparation (COCP), absolute risk-benefit estimates are needed for COCP-associated cancer. Methods For a hypothetical cohort of 10 000 women, we calculated the increased or decreased cumulative incidence of COCP-associated (breast, ovarian, endometrial) cancer, examining 18 scenarios with differences in duration and timing of COCP use, uptake of prophylactic surgeries, and menopausal hormone therapy. Results COCP use initially increased breast cancer risk and decreased ovarian and endometrial cancer risk long term. For 10 000 BRCA1 mutation carriers, 10 years of COCP use from age 20 to 30 years resulted in 66 additional COCP-associated cancer cases by the age of 35 years, in addition to 625 cases expected for never users. By the age of 70 years such COCP use resulted in 907 fewer cancer cases than the expected 9093 cases in never users. Triple-negative breast cancer estimates resulted in 196 additional COCP-associated cases by age 40 years, in addition to the 1454 expected. For 10 000 BRCA2 mutation carriers using COCP from age 20 to 30 years, 80 excess cancer cases were estimated by age 40 years in addition to 651 expected cases; by the age of 70 years, we calculated 382 fewer cases compared with the 6156 cases expected. The long-term benefit of COCP use diminished after risk-reducing bilateral salpingo-oophorectomy followed by menopausal hormone therapy use. Conclusion Although COCP use in BRCA1 and BRCA2 mutation carriers initially increases breast, ovarian, and endometrial cancer risk, it strongly decreases lifetime cancer risk. Risk-reducing bilateral salpingo-oophorectomy and menopausal hormone therapy use appear to counteract the long-term COCP-benefit.

Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D

Abstract Background The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32–36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44–46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.