Family History Of Ovarian Cancer Research Articles

Abstract POSTER-CTRL-1212: The impact of social isolation on ovarian cancer risk and survival

Abstract Introduction: In ovarian cancer mouse models, social isolation has been associated with increased circulating markers of angiogenesis, cell migration, and impaired immune response, as well as increasing tumor burden and aggressiveness. In ovarian cancer patients, social isolation has been associated with increased circulating levels of inflammatory and pro-angiogenic factors. However, social isolation has not been investigated in relation to ovarian cancer risk or survival in humans; we addressed these questions in the Nurses’ Health Study (NHS), a longitudinal cohort of 121,701 US-based nurses. Methods: The Berkman-Syme social network index (BSSNI), a validated measure of social isolation, was assessed every four years in the NHS, starting in 1992. The BSSNI is based on marital status, close friends and relatives, as well as attendance at religious services and other group activities. Women were categorized into four groups: socially isolated, moderately isolated, moderately integrated, and socially integrated. We assessed risk of ovarian cancer associated with the BSSNI and its component parts using Cox proportional hazards models, adjusted for age, duration of oral contraceptive use, family history of ovarian cancer, parity, menopause status, duration of menopausal hormone therapy (by type), and tubal ligation. We further investigated whether the timing of social isolation impacted the results, by evaluating social isolation measured 0-4, 4-8, and 8-12 years prior to cancer diagnosis. In addition, we used Cox proportional hazards models to evaluate whether pre-diagnosis social isolation affected ovarian cancer survival, adjusting as described above plus stage and histology. Results: In follow-up from 1992-2010, we identified 494 epithelial ovarian cancer cases among 53,839 women who completed the BSSNI. In our main analysis, socially isolated women had no increased ovarian cancer risk compared to socially integrated women (relative risk [RR]: 0.93; 95% confidence interval [CI]: 0.65-1.34), although case numbers were small (N=38). However, moderate isolation was associated with increased ovarian cancer risk (RR: 1.27; 95% CI: 1.00-1.61). When we assessed the components of the BSSNI, widowed women were at increased ovarian cancer risk (RR: 1.40; 95% CI: 1.12-1.75) compared to married women; none of the other BSSNI components were associated with ovarian cancer risk. In the analysis evaluating the role of timing of isolation, socially isolated women in the 8-12 years prior to diagnosis had increased ovarian cancer risk compared to socially integrated women (RR: 1.54; 95% CI: 1.02-2.33). Among the 494 ovarian cancer cases in this analysis, 313 women died due to ovarian cancer during follow-up. Neither the BSSNI nor its components were statistically significantly associated with ovarian cancer-specific survival; however, several of the associations were suggestive. For example, social isolation was not associated with survival (RR: 1.13; 95% CI: 0.41-3.13), but moderate isolation was suggestively associated (RR: 1.61; 95% CI: 0.87-3.00). Additionally, being widowed was associated with a 71% increased risk of ovarian cancer death (95% CI: 0.99-2.96). Conclusion: These data add to a growing body of evidence that psychosocial stress is important for ovarian cancer risk and progression. Our data suggest that the timing of social isolation is key, which may have implications for the biology of stress. Future studies should confirm these results and evaluate additional sources of psychosocial stress. Citation Format: Elizabeth M. Poole, Laura Kubzansky, Olivia I. Okereke, Shelley S. Tworoger. The impact of social isolation on ovarian cancer risk and survival [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1212.

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.

The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis. In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.

Abstract 1909: Associations of Vitamin D related polymorphisms with hereditary breast cancer in 1025 subjects undergoing BRCA 1/2 testing

Abstract Background: Vitamin D plays an important role in many normal body functions, including regulation of cell growth, bone formation, inflammation, neuromuscular and immune function. Lower serum levels of 25-hydroxyvitamin D, an index of vitamin D status, are associated with greater risk of cancer. Genetic variants in vitamin D related genes have been linked to breast cancer (BC) risk. These include the vitamin D receptor (VDR) and the GC gene that encodes for the vitamin D binding protein. Aims: To determinate the frequency of 5 single nucleotide polymorphisms (SNPs) of VDR and GC in a large cohort of subjects candidate to BRCA 1/2 genetic testing and to assess any interaction between vitamin D and BRCA pathways on disease outcome. Methods: From 2002 to 2012 blood samples from 1025 subjects with family history of ovarian cancer (OC) or BC were collected after informed consent was signed during the genetic counseling. DNA was extracted from whole EDTA treated blood and Allelic Discrimination (Applied Biosystems’ Taqman assays) of VDR (BsmI, FokI, TaqI, ApaI) and GC SNPs is ongoing. Results: At last follow-up in February 2014 our cohort included 272 unaffected subjects (117 BRCA carriers, 37 WT and 118 true negative) and 753 affected subjects (276 BRCA1/2 carriers, 469 WT and 1 true negative subjects). Amongst BC patients (N = 675), 221 were BRCA carriers, 446 WT, and 8 true negative. Those affected ofBC and OC (N = 27), included 23 BRCA carriers and 4 WT, while OC patients (N = 51) included 32 BRCA carriers and 19 WT. Here we present the preliminary data obtained for VDR and GC SNPs in 833 and 710 subjects, respectively. None of the genotypes deviated from the Hardy-Weinberg equilibrium. At the AACR meeting the genotyping of all subjects will be completed. Conclusions: Our results of vitamin D genotyping will be correlated with BC tumor molecular subtype in affected subjects, and any association with BRCA mutation and outcome will be assessed. The study was funded by IEO Foundation and AVON. Description of vitamin D genetic polymorphisms and their frequenciesSNPsType of polymorphismMinor Allele Frequency (MAF)MAF HapMapHWE Pvalue(1df chi-square test)rs 1544410; VDR BsmITransition C/TT: 0.420.440.50rs2228570; VDR FokITransition A/GA: 0.360.410.72rs731236; VDR TaqITransition A/GC: 0.410.440.52rs7975232; VDR ApaITransversion A/CG: 0.430.430.91rs22282679; GCTransversion G/TG: 0.280.260.52 Citation Format: Valentina Aristarco, Harriet Johansson, Debora Macis, Aliana Guerrieri Gonzaga, Sara Gandini, Davide Serrano, Irene Feroce, Monica Barile, Antonella Puccio, Lorenzo Brocca, Bernardo Bonanni. Associations of Vitamin D related polymorphisms with hereditary breast cancer in 1025 subjects undergoing BRCA 1/2 testing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1909. doi:10.1158/1538-7445.AM2015-1909

African Americans and Hispanics Remain at Lower Risk of Ovarian Cancer Than Non-Hispanic Whites after Considering Nongenetic Risk Factors and Oophorectomy Rates.

Risk factors for invasive epithelial ovarian cancer (IEOC) among Hispanics and African Americans are understudied despite notable differences in incidence relative to non-Hispanic whites. We used multivariate logistic regression to examine parity, oral contraceptive use, tubal ligation, endometriosis, family history of ovarian cancer, and talc use and risk of IEOC among Hispanics (308 cases and 380 controls), African Americans (128 cases and 143 controls), and non-Hispanic whites (1,265 cases and 1,868 controls) using four case-control studies we conducted in Los Angeles County. We expressed each of these factors in the form of increasing risk and calculated population attributable risk percentage (PAR%) estimates for the six risk factors separately and jointly in the three groups. The risk associations with these six well-accepted factors were comparable in the three groups. The significant racial/ethnic differences in the prevalence of these factors and differences in their oophorectomy rates explained 31% of the lower incidence in African Americans compared with non-Hispanic whites, but only 13% of the lower incidence in Hispanics. The PAR%s ranged from 27.5% to 31.0% for no tubal ligation, 15.9% to 22.2% for not using oral contraceptives, and 12.2% to 15.1% for using talc in the three groups. All six risk factors are comparably important in the three groups. Differences in the prevalence of these factors and their oophorectomy rates explained approximately one third of the difference in incidence between African Americans and non-Hispanic whites. Devising strategies to lessen the burden of IEOC will be applicable to all three racial/ethnic groups.

Epidemiology, Pathology and Histochemistry Features in Women with Breast Cancer

Background: Breast cancer is the most frequent malignancy among women and is the leading cause of death through middle-aged women. Despite the high frequency of breast cancer among Iranian women, the epidemiological characteristics of breast cancer among Iranian patients are yet unknown. Herein, we investigate epidemiology, pathology and histochemistry features in women with breast cancer in Iran. Materials and Methods: Between of 2002 to 2012, 546 patients with breast cancer, who were referred to Rasool-Akram Hospital, Tehran, Iran were studied. They were surveyed for age, size of tumor, family history of disease, laterality, type of pathology, grade, stage, tumor markers and metastasis. Results: The mean age of patients at diagnosis was 46.8±11 years. Size of tumor in 113 patients (20.7%) was 0.1-2 cm, 349 patients (63.9%) between 2.1-5 cm and 84 patients (15.4%) >5 cm. Forty-seven patients (8.6%), 382 patients (70%) and 117 patients (21.4%) had grade I, grade II and grade III, respectively. 185 patients (33.9%) had metastasis (35 patients at diagnosis and 150 patients in time of treatment) to other organs. 538 patients (98.5%) didn’t have family history of ovarian cancer and also 501 patients (91.8%) didn’t have family history of breast cancer. Conclusions: The mean age at diagnosis of BC in Iran is around 46 to 49 years. Tumor size in our study is lower than many studies. The organ as site of the most metastases was the lung in our patients, while in other studies it is the bone.

A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects

BackgroundAlthough BRCA1 and BRCA2 mutations account for only ∼27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1,...

Abstract P4-12-16: Teasing out the PALB2 phenotype

Abstract Background: Biallelic mutations in PALB2 (Partner and Localizer of BRCA2) are known to cause Fanconi Anemia Type N. Multiple reports have demonstrated an increased risk for cancer in individuals heterozygous for PALB2 mutations. For example, a recent study by Antoniou et al reported a 33-58% lifetime risk for breast cancer in PALB2 mutation carriers, with 30% of carriers reporting triple negative breast cancer (TNBC). Other studies have suggested associations between PALB2 heterozygosity and pancreatic cancer, ovarian cancer, male breast cancer, and prostate cancer as well. We aimed to better define PALB2 phenotypes by assessing clinical history of TNBC, pancreatic, ovarian, and prostate cancers amongst PALB2 mutation carriers identified via multigene panel testing. Methods: We reviewed clinical histories of 11,007 individuals who underwent PALB2 sequence and deletion/duplication analysis as part of a multigene hereditary cancer panel. Descriptive statistics were utilized for clinical histories of PALB2 carriers, and chi square analysis was used to compare clinical histories of PALB2 mutation carriers to mutation-negative controls. Individuals with mutations in other cancer susceptibility genes were excluded from analysis. Results: A total of 98 PALB2 mutation carriers identified among 9610 individuals were included in our analysis. The majority of mutation carriers were Caucasian (80%) and female (92.8%). All identified mutations were truncating (nonsense, frameshift, or gross deletions). No pathogenic missense mutations were identified in this cohort. 77.6% (n=76) of mutation carriers had breast cancer, diagnosed at a mean age of 48. Hormone receptor status was available for 48 mutation carriers and 2469 controls. 37.5% (18/48) of breast cancers in mutation carriers were reported as triple negative, compared to 17.1% (423/2469) of breast cancers in controls (OR: 2.9 ; p= 0.0002). 7.8% (n= 8) of PALB2 mutation carriers had ovarian cancer. There was no significant difference in the incidence of ovarian cancer between PALB2 mutation carriers and controls (OR: 0.65 ; p= 0.25). Additionally, mutation carriers were significantly less likely to have a family history of ovarian cancer than controls (OR: 0.5; p= 0.02). 5.9% (n=6) of mutation carriers had pancreatic cancer, diagnosed at a mean age of 57.8, compared to 61 for controls. PALB2 mutation carriers were 1.3 times more likely to have personal and/or family history of pancreatic cancer, although this was not statistically significant (p= 0.22). Similarly, PALB2 mutation carriers were 1.5 times more likely to have a family history of prostate cancer, although this was not statistically significant (p= 0.09). Conclusions: Our data supports existing literature associating PALB2 mutations with TNBC. We did not observe significant associations between PALB2 carrier status and a clinical history of pancreatic, prostate, or ovarian cancers. However, this data should be interpreted with caution, as it is possible that unidentified genetic factors contributed to the clinical history of cancer in our mutation-negative controls. Investigation of PALB2-associated cancer risks in an unselected prospective cohort would help to further elucidate the PALB2 phenotype. Citation Format: Emily K Dalton, Rachel McFarland, Holly Laduca, Shuwei Li, Chia-Ling Gau. Teasing out the PALB2 phenotype [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-16.

Population distribution of lifetime risk of ovarian cancer in the United States.

In U.S. women, lifetime risk of ovarian cancer is 1.37%, but some women are at a substantially lower or higher risk than this average. We have characterized the distribution of lifetime risk in the general population. Published data on the relative risks and their variances for five well-accepted risk and protective factors for ovarian cancer, oral contraceptive use, parity, tubal ligation, endometriosis, and first-degree family history of ovarian cancer in conjunction with a genetic risk score using genome-wide significant common, low penetrance variants were used. The joint distribution of these factors (i.e., risk/protective factor profiles) was derived using control data from four U.S. population-based studies, providing a broad representation of women in the United States. A total of 214 combinations of risk/protective factors were observed, and the lifetime risk estimates ranged from 0.35% [95% confidence interval (CI), 0.29-0.42] to 8.78% (95% CI, 7.10-10.9). Among women with lifetime risk ranging from 4% to 9%, 73% had no family history of ovarian cancer; most of these women had a self-reported history of endometriosis. Profiles including the known modifiable protective factors of oral contraceptive use and tubal ligation were associated with a lower lifetime risk of ovarian cancer. Oral contraceptive use and tubal ligation were essentially absent among the women at 4% to 9% lifetime risk. This work demonstrates that there are women in the general population who have a much higher than average lifetime risk of ovarian cancer. Preventive strategies are available. Should effective screening become available, higher than average risk women can be identified.

Serous tubal intraepithelial carcinoma: an incidental finding at the time of prophylactic bilateral salpingo-oophorectomy.

Background. Serous tubal intraepithelial carcinoma (STIC) is a precursor lesion for high-grade pelvic serous carcinoma. The incidence of STIC is estimated to occur in 0.6% to 6% of women who are BRCA positive or have a strong family history of breast or ovarian cancer. Case. A 56-year-old woman underwent robotic-assisted sacrocolpopexy, rectocele repair, and concurrent bilateral salpingo-oophorectomy for recurrent stage 3 pelvic organ prolapse and reported family history of ovarian cancer. Histopathologic examination of her left fallopian tube revealed STIC. Conclusion. We report this rare occurrence of STIC in a patient undergoing surgery primarily for pelvic organ prolapse and having a family history of ovarian cancer. Possible management options include observation with annual physical exam and CA-125, surgical staging, or empiric chemotherapy. However, due to the lack of consensus regarding management options, referral to a gynecologic oncologist is recommended.

Predictors that Influence Election of Contralateral Prophylactic Mastectomy among Women with Ductal Carcinoma in Situ who are BRCA-Negative.

The authors retrospectively examined the contralateral prophylactic mastectomy (CPM) rate among 100 women with ductal carcinoma in situ who are BRCA negative. Of 100 women with ductal carcinoma in situ, 31 elected contralateral prophylactic mastectomy (CPM). Factors associated with increased likelihood of undergoing contralateral prophylactic mastectomy (CPM) among this cohort were: family history of ovarian cancer, marital status, reconstruction, mastectomy of the affected breast, and tamoxifen use.

Commentary on 'Performance of ultrasound as a second line test to serum CA125 in ovarian cancer screening'.

Commentary on 'Performance of ultrasound as a second line test to serum CA125 in ovarian cancer screening'.

Predictors that influence contralateral prophylactic mastectomy election among women with ductal carcinoma in situ who tested negative for a BRCA mutation.

42 Background: Patients with ductal carcinoma in situ (DCIS) are at increased risk for developing contralateral breast cancer (CBC). Consequently, more women with DCIS are electing to undergo contralateral prophylactic mastectomy (CPM). We previously reported a 27% CPM rate among patients with DCIS who were evaluated for BRCA genetic testing (positive, negative, not tested). In this specific cohort, we further evaluated factors associated with CPM in patients with DCIS who tested negative for a BRCA mutation. Specifically, we aimed to identify differences within BRCA-negative patients who underwent CPM and those who did not. Methods: This retrospective study from a prospective registry included 100 women with DCIS referred for genetic counseling between 2003 and 2011. Patient characteristics included: age, marital and educational status, tumor markers, nuclear grade, family history of breast cancer (BC) and ovarian cancer (OC), race, Ashkenazi Jewish ancestry, and BRCA results. Univariate and multivariate logistic regression analyses were used to determine predictive factors associated with CPM election. Results: Of 100 BRCA-negative patients, 31 (31%) underwent CPM. Univariate analysis revealed patients who had a first-degree relative with OC were more likely to elect CPM that those who did not (p = 0.0278). Patients who had a family history of OC (53.3%) were more likely to choose CPM than those with no family history (p = 0.0425). Married patients were more likely to elect CPM than those who were not married (p = 0.0235). In multivariate analysis, married patients were more likely to elect CPM than those who were not married (OR = 4.367; 95% CI, 1.198-15.924; p = 0.0255). Conclusions: The CPM rate among patients with DCIS who tested negative for a BRCA mutation is high. Factors associated with increased rate of CPM among this group include a family history of OC and being married. Further studies are needed to evaluate patients' perceptions of CBC risk and their role in the likelihood of CPM choice.

Risk‐reducing surgery for women at high risk of epithelial ovarian cancer

Key content The lifetime risk of ovarian cancer in the general population is 1.4% but women with hereditary ovarian cancer syndromes have a lifetime probability as high as 25–60% for developing epithelial ovarian cancer. Screening has not been found to be associated with a statistically significant reduction in mortality from ovarian cancer and cannot be routinely recommended even for women at high risk. Serum CA125 levels are only elevated in 50–60% of stage I ovarian cancers and interval cancers may develop between screening visits. Studies show a 4–20% risk of finding an occult malignancy at the time of risk‐reducing bilateral salpingo‐oophorectomy. Studies support the efficacy of risk‐reducing bilateral salpingo‐oophorectomy in significantly reducing the risk of gynaecological and breast cancer in women who carry BRCA1 or BRCA2 mutations. Women undergoing risk‐reduction bilateral salpingo‐oophorectomy should be counselled about the effects of early menopause and the available management options including hormone replacement therapy. Learning objectives To be able to identify those women at increased risk of ovarian cancer. To be able to appropriately counsel those at high risk of ovarian cancer regarding modifiable risk factors, screening and the role of risk‐reducing surgery, including prophylactic bilateral salpingo‐oophorectomy and its alternatives such as tubal ligation and salpingectomy. To understand the limitations of current screening modalities for the reduction of ovarian cancer risk. Ethical issues Ethical concerns exist pertaining to the performance of screening modalities, which have not been found to significantly reduce mortality from ovarian cancer and can cause harm in terms of psychological and surgical morbidity from false‐positive results. For those with a positive family history of ovarian cancer but no genetic cancer syndrome, the discussion to perform risk‐reducing surgery should be balanced against the risk of surgical morbidity and early menopause. Individual patient risk factors must be considered in the decision‐making process.

A multi-institutional study on the association between BRCA1/BRCA2 mutational status and triple-negative breast cancer in familial breast cancer patients.

Triple-negative breast cancer (TNBC) accounts for 12-24% of all breast cancers. Here, we studied 221 familial breast and/or ovarian cancer patients from 37 hospitals using a comprehensive approach to identify large genomic rearrangements (LGRs) as well as sequence variants, and investigated the association between BRCA1/2 mutational status and TNBC. We performed direct sequencing or mutation scanning followed by direct sequencing. Then, 143 BRCA1/2 mutation-negative patients were screened for LGRs. In this study, the prevalence of BRCA1/2 mutations was high (36.9%). The prevalence of BRCA1 mutations was similar to that of BRCA2 mutations: 49.4 versus 50.6%, respectively. TNBC was diagnosed in 35.2% of BRCA1/2 mutation carriers and 57.1% of BRCA1 mutation carriers. Conversely, two-thirds of TNBC patients carried BRCA1/2 mutation(s), and about half were BRCA1 mutation carriers. When stratified by the mutated gene, TNBC prevalence in BRCA1 mutation carriers was significantly lower when there was a family history of ovarian cancer. Our multinomial logistic regression model demonstrated that no single factor was sufficient, and at least two factors, such as a patient with family history of both breast cancer and ovarian cancer or a patient diagnosed at a relatively young age (<40years) with a TNBC phenotype, are necessary to indicate BRCA1/2 genetic testing in this population. Our results suggest that TNBC is a strong predictor for the presence of a BRCA1 mutation in this population, but additional risk factors should also be evaluated to ascertain a 10% or higher prior probability of BRCA1/2 mutation testing.

Predictors that influence contralateral prophylactic mastectomy election among women with ductal carcinoma in situ who were evaluated for BRCA genetic testing.

Patients with ductal carcinoma in situ (DCIS) are at increased risk for developing contralateral breast cancer (CBC). Consequently, more women with DCIS are electing to undergo contralateral prophylactic mastectomy (CPM). We evaluated factors associated with CPM in patients with DCIS who underwent genetic counseling for BRCA testing. This retrospective study involved 165 women with DCIS referred for genetic counseling between 2003 and 2011. Patient characteristicswere age, marital and educational status, tumor markers, nuclear grade, family history of breast cancer (BC) and ovarian cancer (OC), race, Ashkenazi Jewish ancestry, and BRCA results. Univariate and multivariate logistic regression analyses were used to determine predictive factors associated with CPM election. Of 165 patients, 44 (27%) underwent CPM. Patients <45years of age were more likely to elect CPM (p=0.0098). A BRCA+ mutation was found in 17 patients (10.3%), and BRCA+ women were more likely to elect CPM than BRCA or untested women (p=0.0001). Patients who had a family history of OC (57.7%) were more likely to choose CPM than those with no family history (p=0.0004). Younger age, BRCA+, and an OC family history remained significant in the multivariate model (p<0.008). The CPM rate among patients with DCIS who undergo genetic counseling is high. Factors associated with increased likelihood of CPM among this group were age, BRCA+, and a family history of OC. Further studies are needed to evaluate patients' perceptions of CBC risk and their role in the likelihood of CPM choice.

Obstetrician-gynecologists’ opinions on elective bilateral oophorectomy at the time of hysterectomy in the United States

This study aims to assess obstetrician-gynecologists' opinions on elective bilateral oophorectomy (BO) at the time of hysterectomy in the United States and to describe factors that influence their views. In April 2012, an anonymous survey was mailed twice to practicing obstetrician-gynecologists, randomly selected from a list produced by the American Medical Association, in an effort to assess their opinions regarding elective BO at the time of hysterectomy. The effects of gynecologists' various characteristics on their opinions were also evaluated. Of 1,002 mailed surveys, 443 (44%) were returned completed. Of the respondents, 59% were male and 79% were white. The largest age group was 51 to 55 years (20%), and the mean time since completion of residency was 23 years. In women with an average risk of ovarian cancer, the proportions of physicians who favored elective BO were as follows: women younger than 51 years, 32%; women aged 51 to 65 years, 62%; women older than 65 years, 6%. These recommendations were not influenced by the physicians' age, sex, training, or geographic region. If a hysterectomy candidate was younger than 51 years and had a personal history of breast or ovarian cancer and a family history of ovarian cancer, these proportions were increased to 77% and 64%, respectively. Other factors that influenced the respondents' recommendations were the women's personal history of cardiovascular disease (21%), osteoporosis (23%), and sexual dysfunction (23%). One third of obstetrician-gynecologists continue to recommend elective BO for hysterectomy candidates younger than 51 years. The majority recommend elective BO for women aged 51 to 65 years. Their demographic characteristics do not influence their opinions.

Abstract P5-13-03: Factors associated with prophylactic mastectomy among BRCA-positive patients with no personal history of breast cancer

Abstract Background: The rate of prophylactic mastectomy (PM) has recently increased1. A deleterious mutation in the BRCA1 or BRCA 2 genes is among the major reasons why patients pursue PM 2, 3. Women with BRCA1 or BRCA2 gene mutations have up to an 87% risk to develop an invasive breast cancer (BC), and up to 45% risk for ovarian cancer (OC)2, 3. Most studies evaluating predictors of PM in BRCA mutation carriers are performed among women with breast cancer; however, accurate predictors for PM among unaffected BRCA mutation carriers are less defined. In a single institution study we aimed to evaluate predictors of PM among BRCA carriers with no personal history of breast cancer. Method: One hundred seventy seven women with no personal history of BC, who tested positive for a BRCA1 or BRCA 2 germline mutation, were included in the study. Patients’ characteristics were obtained from a prospectively maintained research database under an IRB approved protocol at UT MD Anderson Cancer Center. Univariate analyses using chi-square and logistic regression analysis were used to determine predictive factors associated with PM. The patient characteristics examined included age, martial and educational status, bilateral salphingo-oophorectomy (BSO), family history of 1st and 2nd degree relatives with breast (BC) and ovarian cancer (OC), race, and BRCA genetic test result. Results: Out of the 177 BRCA1 and BRCA 2 positive patients, 51 (29%) elected for PM. The average age for the cohort was 44 years (range 23-91). The majority were Caucasian (81%), and married (72%) with a college degree (64%). One hundred sixty-four (92%) patients had 1st and 2nd degree relatives with BC, 93 (53%) had 1st and 2nd degree relatives with OC, and 85 (48%) had undergone BSO. A logistic regression model was run to identify factors associated with undergoing PM, including family history of OC, family history of BC, BSO and age. Patients with a family history of OC were 2.5 times more likely than those without to have had a PM (p = 0.0125), and patients who had a BSO were 0.137 times less likely to have had a PM (p &amp;lt;.0001). Only 12 patients did not have a family history of BC and none of those patients had a PM, so an Odds Ratio could not be calculated. However, it was determined through the Fisher's exact test that patients with a family history of BC were more likely to undergo a PM (p = 0.0198). Conclusion: The rate of PM in our cohort was slightly lower than expected. Factors associated with PM included a family history of BC and OC. Interestingly, having had a BSO was associated with lower likelihood of undergoing PM (menopausal status will be further evaluated); possibly due to the knowledge that BSO reduces breast cancer risk. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-03.

Prevalence and differentiation of hereditary breast and ovarian cancers in Japan

We assembled needed data on the prevalence and characteristics of BRCA1/2 in Japan. Our study of BRCA1/2 collected data at eight institutions in Japan on 320 individuals with a strong family history of breast cancer, according to the NCCN guidelines, by the end of March 2012. Among 260 proband cases, 46 (17.7%) were positive for BRCA1, and 35 (13.5%) were BRCA2-positive. Therefore, the total pathological mutation rate was 30.7%. Pathology data after breast surgery were obtained from 37 cases of BRCA1 mutation, 23 (62.2%) of which were triple negative (TN). On the other hand, 29 cases (82.9%) of BRCA2 mutations were Luminal type. The most prevalent BRCA1 mutation site was L63X, found in 10 families. L63X was reported previously by studies in Japan, and it may be a founder mutation. We found two cases of large deletion detected by multiplex ligation-dependent probe amplification. One was an entire deletion of exon 20 and the lacked exons 1-9. TN with a family history of ovarian cancer was 11/20 (55%). TN under 40-year-old(y.o.) 15/23 (65.2%) and TN with one or more breast cancers in family history 17/32 (53.1%) showed higher incidences of BRCA1 mutation. Hereditary breast and ovarian cancer (HBOC) may have nearly the same prevalence in Japan as in the US or Europe. If TN cases are taken into account, the ratio of BRCA1 is higher. L63X may be one of the founder mutations in Japan. A nationwide database of HBOC is important to develop risk models for BRCA1/2 carriers in Japan.

Clinical Outcome of Isolated Serous Tubal Intraepithelial Carcinomas (STIC)

Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women with BRCA mutation due to increased risk of pelvic serous carcinoma. Serous tubal intraepithelial carcinoma (STIC) is a pathologic finding of unknown clinical significance. This study evaluates the clinical outcome of patients with isolated STIC. We retrospectively reviewed the medical records of consecutive patients with a germline BRCA1/2 mutation or a high-risk personal or family history of ovarian cancer who underwent RRSO between January 2006 and June 2011. All patients had peritoneal washings collected. All surgical specimens were assessed using the sectioning and extensively examining the fimbria protocol, with immunohistochemistry when indicated. p53 signature lesions and secretory cell outgrowths were excluded. Of 593 patients who underwent RRSO, isolated STIC was diagnosed in 12 patients (2%). Five patients (42%) were BRCA1 positive, 5 patients (42%) were BRCA2 positive, and 2 patients (17%) had high-risk family history. Preoperatively, all patients with STIC had normal CA-125 levels and/or pelvic imaging results. Seven patients underwent hysterectomy and omentectomy, 6 patients (46%) had pelvic node dissections, and 5 patients (39%) had para-aortic node dissections. With the exception of positive peritoneal washings in 1 patient, no invasive or metastatic disease was identified. No patient received adjuvant chemotherapy. At median follow-up of 28 months (range, 16-44 months), no recurrences have been identified. Among the cases of isolated STIC after RRSO reported in the literature, the yield of surgical staging is low, and short-term clinical outcomes are favorable. Peritoneal washings are the most common site of disease spread. Individualized management is warranted until additional data become available.

Adiposity post prophylactic oophorectomy in young women at high risk for breast and ovarian cancer.

1572 Background: Bilateral prophylactic salpingo-oophorectomy (BPSO) is the current standard of care for BRCA1/2 mutation carriers and women with a strong family history of ovarian cancer. We have previously demonstrated an association between early oophorectomy, adiposity and mortality in the general population. Methods: A cross sectional study was conducted between November 2009 and January 2013 in 87 women with a family history of breast and ovarian cancer and/or BRCA1/2 mutation to identify the effect of early BPSO on multiple health outcomes. Twenty-two women who underwent BPSO within 1 to 5 years of enrollment while premenopausal and not on hormone therapy were compared to 44 premenopausal women with intact ovaries and the same age distribution and 21 postmenopausal women with intact ovaries and not on hormone therapy. Multiple anthropometric measures were taken and % body fat assessed by DEXA scan. Linear regression was used to estimate differences in these measures between the three groups. Results: The mean ages were 47, 47, and 54 years in the BPSO, premenopausal and postmenopausal groups respectively. Parity, alcohol intake, smoking and race did not significantly differ between groups. Fewer BPSO women had ever used oral contraceptives (OCP) compared to the premenopausal group (p =0.05). The BPSO group had lower mean physical activity (p = 0.05) compared to the two other groups. BMI was increased in the BPSO group but was not statistically different across groups. However, mean waist and abdominal circumference and trunk % body fat were significantly higher among women who underwent BPSO compared to both groups. In multivariate analyses adjusting for age, physical activity, and OCP use, the average waist circumference was 7.92 cm (95% CI 1.46, 14.37) higher and 8.98 cm (95% CI 0.40, 17.46) higher in the BPSO group compared to the postmenopausal and premenopausal groups, respectively. A similar pattern was seen for abdominal circumference. Association with % body fat were not statistically significant. Conclusions: This pilot study suggests that increased central adiposity, is a sequelae of BPSO in young women. Longitudinal studies are needed to confirm results and evaluate the efficacy of interventions.