Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers.
ABSTRACT Breast cancer penetrance estimates in BRCA1 mutation carriers have varied from 40% to 85%; this heterogeneity has been attributed to variations in risk among different study populations. No study has taken oophorectomy status into account in estimating penetrance. Because prophylactic oophorectomy reduces breast cancer risk by approximately 50%, we hypothesized that population differences in oophorectomy prevalence might significantly influence breast cancer penetrance estimates.
Females from multiple-case breast/ovarian cancer families that segregate deleterious BRCA1 mutations were observed prospectively for breast cancer incidence and oophorectomy.
Within this cohort, 33 cases of breast cancer developed in 98 women with deleterious BRCA1 mutations during follow-up, yielding an estimated cumulative lifetime breast cancer risk of 80%. This estimate increased to 94% when the study participants were censored at the time of oophorectomy. Six of the 33 mutation-positive women who underwent oophorectomy during follow-up developed breast cancer, compared with 27 of 65 mutation carriers with intact ovaries (hazard ratio = 0.38; 95% CI, 0.15 to 0.97). Estimates of absolute breast cancer risk demonstrated that the protective effect of oophorectomy was strongest among women who were premenopausal at the time of surgery. When surgical status was ignored, the strong protective effect of oophorectomy, coupled with the high prevalence of the procedure in these families, led to a significantly lower estimate of the breast cancer penetrance in BRCA1 mutation carriers.
Differing rates of oophorectomy likely represent an underappreciated basis for a portion of the heterogeneity in estimated breast cancer penetrance described in BRCA mutation carriers, particularly mutation carriers from extensively affected, multiple-case families.
- SourceAvailable from: Jerry W Shay
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- "KIF14 is found to be altered in 75 of 825 (9%) of breast cancer cases in The Cancer Genome Atlas, with 40 of 75 (53%) of KIF14 alterations being copy number amplification (cbioportal.org). Because BRCA1 or BRCA2 mutation carriers have 60% to 80% lifetime risk of developing breast cancer  , we hypothesized that early events that drive tumorigenesis may be present before overt cancer is detected. We examined KIF14 expression in 35 benign breast cases, from the Komen "
ABSTRACT: Despite evidence that kinesin family member 14 (KIF14) can serve as a prognostic biomarker in various solid tumors, how it contributes to tumorigenesis remains unclear. We observed that experimental decrease in KIF14 expression increases docetaxel chemosensitivity in estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor 2-negative, "triple-negative" breast cancers (TNBC). To investigate the oncogenic role of KIF14, we used noncancerous human mammary epithelial cells and ectopically expressed KIF14 and found increased proliferative capacity, increased anchorage-independent grown in vitro, and increased resistance to docetaxel but not to doxorubicin, carboplatin, or gemcitabine. Seventeen benign breast biopsies of BRCA1 or BRCA2 mutation carriers showed increased KIF14 mRNA expression by fluorescence in situ hybridization compared to controls with no known mutations in BRCA1 or BRCA2, suggesting increased KIF14 expression as a biomarker of high-risk breast tissue. Evaluation of 34 cases of locally advanced TNBC showed that KIF14 expression significantly correlates with chemotherapy-resistant breast cancer. KIF14 knockdown also correlates with decreased AKT phosphorylation and activity. Live-cell imaging confirmed an insulin-induced temporal colocalization of KIF14 and AKT at the plasma membrane, suggesting a potential role of KIF14 in promoting activation of AKT. An experimental small-molecule inhibitor of KIF14 was then used to evaluate the potential anticancer benefits of downregulating KIF14 activity. Inhibition of KIF14 shows a chemosensitizing effect and correlates with decreasing activation of AKT. Together, these findings show an early and critical role for KIF14 in the tumorigenic potential of TNBC, and therapeutic targeting of KIF14 is feasible and effective for TNBC.Neoplasia (New York, N.Y.) 03/2014; 16(3):247-256.e2. DOI:10.1016/j.neo.2014.03.008 · 5.40 Impact Factor
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- "This article was motivated by a prospective cohort study of hereditary breast and ovarian cancer (HBOC) conducted by the National Cancer Institute (Kramer et al., 2005). In this study, 451 women from 31 families with multiple cases of breast and/or ovarian cancer in multiple generations were followed for up to 30 years. "
ABSTRACT: We develop methods for competing risks analysis when individual event times are correlated within clusters. Clustering arises naturally in clinical genetic studies and other settings. We develop a nonparametric estimator of cumulative incidence, and obtain robust pointwise standard errors that account for within-cluster correlation. We modify the two-sample Gray and Pepe-Mori tests for correlated competing risks data, and propose a simple two-sample test of the difference in cumulative incidence at a landmark time. In simulation studies, our estimators are asymptotically unbiased, and the modified test statistics control the type I error. The power of the respective two-sample tests is differentially sensitive to the degree of correlation; the optimal test depends on the alternative hypothesis of interest and the within-cluster correlation. For purposes of illustration, we apply our methods to a family-based prospective cohort study of hereditary breast/ovarian cancer families. For women with BRCA1 mutations, we estimate the cumulative incidence of breast cancer in the presence of competing mortality from ovarian cancer, accounting for significant within-family correlation.Biometrics 04/2008; 64(1):172-9. DOI:10.1111/j.1541-0420.2007.00868.x · 1.52 Impact Factor
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- "While the specific criteria outlined in Tables 1–4 identify individuals that generally meet these thresholds, there are some patients who do not meet one of the specific criteria listed who may still benefit from genetic risk assessment. Situations which may warrant a lower threshold for genetic risk assessment include: • Families with few female relatives as this may lead to an under-representation of female cancers despite the presence of a predisposing family mutation  ; • Hysterectomy and/or oophorectomy at a young age in multiple family members as this might mask a hereditary gynecologic cancer predisposition ; • Presence of adoption in the lineage. "
ABSTRACT: Women with germline mutations in the cancer susceptibility genes, BRCA1 or BRCA2, associated with Hereditary Breast/Ovarian Cancer syndrome, have up to an 85% lifetime risk of breast cancer and up to a 46% lifetime risk ovarian cancer. Similarly, women with mutations in the DNA mismatch repair genes, MLH1, MSH2 or MSH6, associated with the Lynch/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome, have up to a 40-60% lifetime risk of both endometrial and colorectal cancer as well as a 9-12% lifetime risk of ovarian cancer. Genetic risk assessment enables physicians to provide individualized evaluation of the likelihood of having one of these gynecologic cancer predisposition syndromes, as well the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes. Hereditary cancer risk assessment is a process that includes assessment of risk, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained. This commentary provides guidance on identification of patients who may benefit from hereditary cancer risk assessment for Hereditary Breast/Ovarian Cancer and the Lynch/Hereditary Non-Polyposis Colorectal Cancer syndrome.Gynecologic Oncology 12/2007; 107(2):159-62. DOI:10.1016/j.ygyno.2007.09.031 · 3.69 Impact Factor