Early onset HER2-positive breast cancer is associated with germline TP53 mutations.

BACKGROUND: Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li-Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited. METHODS: We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls). RESULTS: Patients who tested positive for germlineTP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls (P = .0001). Among patients with a mutation, 70% had estrogen receptor- and/or progesterone receptor-positive tumors, compared with 68% in the control group (P = .87). After adjusting for age at breast cancer diagnosis, having a HER2-positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6-18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91-0.99). CONCLUSIONS: This study suggests an association between germline TP53 mutations and early onset HER2-positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2-targeted therapies, and elucidate some of the molecular pathways involved in breast cancer.

Obstetrics/gynecology residents' knowledge of hereditary breast and ovarian cancer and Lynch syndrome.

Although there have been many studies regarding physicians' knowledge of hereditary cancer syndromes, very little information exists regarding medical residents' knowledge of hereditary cancer syndromes. Obstetrics/gynecology residents completed a test which evaluated their knowledge of hereditary breast and ovarian cancer and Lynch syndrome. Areas of relative deficit were identified. Residents indicated a desire and need for more education regarding this topic. Cancer genetics education programs should place more emphasis on the areas in which residents' appeared to be deficient in order to aid future physicians in the identification of high-risk individuals.

Clinicopathologic characteristics of breast cancer in BRCA-carriers and non-carriers in women 35 years of age or less.

PURPOSE: Breast cancer diagnosed in women 35 years of age or less accounts for <2% of all breast cancer cases. Clinical and pathologic characteristics of early onset breast cancer are not well defined in BRCA mutation carriers and non-carriers. METHODS: 194 women diagnosed with breast cancer at 35 years of age or less who had BRCA1/2 mutation testing were included in the study. Logistic regression models were fit to determine the associations between clinical variables and BRCA status. RESULTS: Thirty-two (17%) and 12 (6%) patients had BRCA1 and BRCA2 mutations, respectively. BRCA1-carriers had a higher likelihood of a positive family history (FH) of breast and/or ovarian cancer (P = 0.001), or first-degree relatives diagnosed with breast cancer at <50 years old (P = 0.001) compared to non-carriers. BRCA2-carriers were more likely to have a FH of male breast cancer compared to noncarriers (P = 0.02). Among BRCA2-carriers, the age at first full-term pregnancy was younger in ER-negative cases compared with ERpositive cases (19.5 vs. 28.5 years old; P = 0.01). BRCA1-carriers with a later age at menarche were more likely to have a later stage at diagnosis (P = 0.04). Non-carriers with a lower BMI were more likely to have lymph node involvement (P = 0.03). CONCLUSIONS: Several associations were identified between reproductive risk factors or BMI and disease characteristics. Further characterization may result in a better understanding of the trends in young onset breast cancer in BRCA-carriers and non-carriers.

Knowledge, attitudes, and clinical experience of physicians regarding preimplantation genetic diagnosis for hereditary cancer predisposition syndromes.

Approximately 5-10% of cancers are caused by an inherited predisposition. Individuals affected by hereditary cancer are often concerned about transmitting a predisposition to cancer to their children. Preimplantation genetic diagnosis (PGD) is a technology that allows embryos without a deleterious mutation associated with a hereditary cancer syndrome to be identified and implanted. The aim of this study is to assess the knowledge, attitudes, and clinical experience of physicians regarding PGD for hereditary cancer predisposition syndromes. Hereditary Breast and Ovarian Cancer (HBOC) and Familial Adenomatous Polyposis (FAP) are two hereditary cancer syndromes highlighted in this present study. A survey assessing physicians' attitudes, knowledge, and clinical practice was completed by a total of 373 gynecologic oncologists (GYN ONCs) and obstetrics and gynecologists (OB/GYNs). Physicians had a limited knowledge of PGD for hereditary cancer; however, physicians reported PGD was an appropriate option for patients with either HBOC or FAP. Although GYN ONCs were more likely to care for patients with hereditary cancer (P < 0.001), they were less likely than OB/GYNs to refer their patients to a PGD specialist (P = 0.004). While 80% of GYN ONCs and 91% of OB/GYNs would refer patients to a PGD specialist, clinical experience indicates that only 29% actually referred their patients. Since 68% of physicians had incorrect or limited knowledge of PGD for hereditary cancer, there is a need for additional education.

Accuracy of the BRCAPRO model among women with bilateral breast cancer.

BACKGROUND: The likelihood of identifying a BRCA mutation was often calculated using the BRCAPRO model. A previous study suggested that this model may overestimate the chance of detecting a BRCA mutation among women diagnosed with bilateral breast cancer. Studies also suggested that few patients with bilateral breast cancer whose age at first diagnosis is >40 years were mutation carriers. The objectives of this study were to determine the accuracy of the BRCAPRO model among women with bilateral breast cancer and to determine whether their mutation status was dependent on their age at first diagnosis. METHODS: A retrospective chart review was performed. Women who were diagnosed with bilateral or unilateral breast cancer and who had undergone comprehensive BRCA1 and BRCA2 genetic testing at M. D. Anderson Cancer Center between 1997 and 2006 were included in the study. RESULTS: For individuals with pre-test carrier probabilities >31%, the proportion of positive tests was significantly lower than predicted by the BRCAPRO model (P < .05). In addition, the carrier rate of BRCA mutations was significantly higher (P = .002, Fisher exact test) in women with bilateral breast cancer whose age at first diagnosis was 40 years. CONCLUSIONS: The BRCAPRO model was overestimating the relative contribution bilateral breast cancer had on the likelihood of detecting a BRCA1 or BRCA2 mutation. Bilateral breast cancer did not appear to be a good indicator of mutation status, particularly for women whose age at first diagnosis is >40 years.

BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model.

PURPOSE: The BRCAPRO model, used to predict a family's likelihood of carrying a BRCA1 or BRCA2 mutation, was designed using mutation frequencies of white and Ashkenazi Jewish populations, and may not be applicable to other populations. BRCAPRO was recently validated in African Americans, although has yet to be examined in Hispanics. This retrospective study reports the mutation frequency and spectrum of BRCA1 and BRCA2 mutations in a Hispanic population and evaluates the BRCAPRO model in Hispanics. PATIENTS AND METHODS: A descriptive analysis of mutation frequency and spectrum was performed for Hispanic patients who underwent BRCA1 and BRCA2 genetic testing at a single institution. For comparative analysis of the BRCAPRO risk model, Hispanic patients who underwent comprehensive analysis were compared with white controls using area under the receiver operating characteristic curves (AUROC). RESULTS: Fourteen Hispanic individuals who underwent comprehensive analysis were identified to carry a mutation in BRCA1 or BRCA2 (17.9%; 95% CI, 10.2% to 28.3%) and seven individuals had a variant of uncertain significance (9.0%; 95% CI, 12.0% to 30.8%). A total of eight different mutations and three variants were observed within the entire Hispanic population. When evaluating the performance of the BRCAPRO model, the AUROC for Hispanics was 0.774 (95% CI, 0.63 to 0.90), compared with the AUROC of 0.770 (95% CI, 0.65 to 0.89) for whites. CONCLUSION: Deleterious BRCA1 and BRCA2 mutations occur at considerable frequency within the Hispanic population, many of which have been identified previously in other ethnic populations. The BRCAPRO model appears to perform equally well in Hispanics as in whites.