The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium.

BACKGROUND: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers. METHODS: Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. RESULTS: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83). CONCLUSION: Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.

Impact that Timing of Genetic Mutation Diagnosis has on Surgical Decision Making and Outcome for BRCA1/BRCA2 Mutation Carriers with Breast Cancer.

BACKGROUND: Deleterious BRCA mutation carriers with breast cancer are at increased risk for additional breast cancer events. This study evaluated the impact that timing of identification of BRCA+ status has on surgical decision and outcome. METHODS: The authors reviewed all BRCA carriers at their institution whose breast cancer was diagnosed between January 1996 and June 2015. Patient surveys, medical records, and institutional databases were used to collect data. Differences in surgical choice were analyzed using the chi-square test, and rates of subsequent breast cancer events were estimated using the Kaplan-Meier method. RESULTS: The study investigated 173 BRCA carriers with breast cancer (100 BRCA1, 73 BRCA2). Of the women with known BRCA mutation before surgery and unilateral stages 0 to 3 breast cancer (n = 63), 12.7 % underwent lumpectomy, 4.8 % underwent unilateral mastectomy (UM), and 82.5 % underwent bilateral mastectomy (BM). These surgical choices differed significantly (p < 0.0001) from those of patients unaware of their mutation at the time of surgery (n = 93) (51.6 % had lumpectomy, 19.4 % had UM, 29 % had BM). Of the patients with BRCA mutation identified after surgery who underwent lumpectomy or UM, 36 (59 %) of 66 underwent delayed BM. The patients with BRCA+ known before diagnosis presented with significantly lower-stage disease (p = 0.02) at diagnosis (69 % stage 0 or 1) than those whose BRCA mutation was identified after cancer diagnosis (40 % stage 0 or 1). CONCLUSIONS: The study findings showed that BRCA mutation status influences surgical decision. The rates of BM were higher for the patients with BRCA mutation known before surgery. Identification of BRCA mutation after surgery frequently leads to subsequent breast surgery. Genetic testing before surgery is important for patients at elevated risk for BRCA mutation.

Incidence of chronic lymphocytic leukemia and high-count monoclonal B-cell lymphocytosis using the 2008 guidelines.

BACKGROUND: The 1996 National Cancer Institute Working Group (NCI-WG 96) guidelines classified disease in individuals who had a B-cell clone with chronic lymphocytic leukemia (CLL) immunophenotype as CLL if their absolute lymphocyte count was ≥5 × 10(9)/L. The 2008 International Workshop on CLL guidelines (IWCLL 2008) classified disease as CLL if the absolute B-cell count was ≥5 × 10(9)/L or as monoclonal B-cell lymphocytosis (MBL) if the absolute B-cell count was <5 × 10(9)/L. The objective of the current study of Olmsted County, Minnesota, was to assess the effects of these changes on incidence rates and presentation from 2000 to 2010. METHODS: Using diagnostic indices available through the Rochester Epidemiology Project and the Mayo CLL database, the authors identified all patients with newly diagnosed CLL and high-count MBL from 2000 to 2010. Age-specific and sex-specific incidence rates were determined. RESULTS: According to NCI-WG 96 criteria, there were 115 patients with CLL and 8 patients with MBL during the period studied. Using the IWCLL 2008 classification, there were 79 patients with CLL and 40 patients with MBL. Rai stage distribution (low risk, intermediate risk, and high risk) using NCI-WG 96 criteria was 60.9%, 33.9%, and 5.2%, respectively, compared with 43%, 49.4%, and 7.6%, respectively, using IWCLL 2008 criteria. The age-adjusted and sex-adjusted incidence rates (per 100,000) for CLL and MBL were 10.0 and 0.66, respectively, using NCI-WG 96 criteria versus 6.8 and 3.5, respectively, using IWCLL 2008 criteria. The median time to treatment according to NCI-WG 96 criteria was 9.2 years versus 6.5 years with IWCLL 2008 criteria. CONCLUSIONS: Use of the IWCLL 2008 guidelines reduced the incidence of CLL, altered the distribution of initial Rai stage at diagnosis, and shortened the median time to treatment.