Multi-gene panel testing for hereditary cancer predisposition in unsolved high-risk breast and ovarian cancer patients.

PURPOSE: Many women with an elevated risk of hereditary breast and ovarian cancer have previously tested negative for pathogenic mutations in BRCA1 and BRCA2. Among them, a subset has hereditary susceptibility to cancer and requires further testing. We sought to identify specific groups who remain at high risk and evaluate whether they should be offered multi-gene panel testing. METHODS: We tested 300 women on a multi-gene panel who were previously enrolled in a long-term study at UCSF. As part of their long-term care, all previously tested negative for mutations in BRCA1 and BRCA2 either by limited or comprehensive sequencing. Additionally, they met one of the following criteria: (i) personal history of bilateral breast cancer, (ii) personal history of breast cancer and a first or second degree relative with ovarian cancer, and (iii) personal history of ovarian, fallopian tube, or peritoneal carcinoma. RESULTS: Across the three groups, 26 women (9%) had a total of 28 pathogenic mutations associated with hereditary cancer susceptibility, and 23 women (8%) had mutations in genes other than BRCA1 and BRCA2. Ashkenazi Jewish and Hispanic women had elevated pathogenic mutation rates. In addition, two women harbored pathogenic mutations in more than one hereditary predisposition gene. CONCLUSIONS: Among women at high risk of breast and ovarian cancer who have previously tested negative for pathogenic BRCA1 and BRCA2 mutations, we identified three groups of women who should be considered for subsequent multi-gene panel testing. The identification of women with multiple pathogenic mutations has important implications for family testing.

Comparing Coordinated Versus Sequential Salpingo-Oophorectomy for BRCA1 and BRCA2 Mutation Carriers With Breast Cancer.

BACKGROUND: Women with breast cancer who carry BRCA1 or BRCA2 mutations must also consider risk-reducing salpingo-oophorectomy (RRSO) and how to coordinate this procedure with their breast surgery. We report the factors associated with coordinated versus sequential surgery and compare the outcomes of each. PATIENTS AND METHODS: Patients in our cancer risk database who had breast cancer and a known deleterious BRCA1/2 mutation before undergoing breast surgery were included. Women who chose concurrent RRSO at the time of breast surgery were compared to those who did not. RESULTS: Sixty-two patients knew their mutation carrier status before undergoing breast cancer surgery. Forty-three patients (69%) opted for coordinated surgeries, and 19 (31%) underwent sequential surgeries at a median follow-up of 4.4 years. Women who underwent coordinated surgery were significantly older than those who chose sequential surgery (median age of 45 vs. 39 years; P = .025). There were no differences in comorbidities between groups. Patients who received neoadjuvant chemotherapy were more likely to undergo coordinated surgery (65% vs. 37%; P = .038). Sequential surgery patients had longer hospital stays (4.79 vs. 3.44 days, P = .01) and longer operating times (8.25 vs. 6.38 hours, P = .006) than patients who elected combined surgery. Postoperative complications were minor and were no more likely in either group (odds ratio, 4.76; 95% confidence interval, 0.56-40.6). CONCLUSION: Coordinating RRSO with breast surgery is associated with receipt of neoadjuvant chemotherapy, longer operating times, and hospital stays without an observed increase in complications. In the absence of risk, surgical options can be personalized.

Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meeting. Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also discussed revisions to genetic testing criteria that take into account ovarian cancer histology and personal history of pancreatic cancer.

Genetic/familial high-risk assessment: breast and ovarian, version 1.2014.

During the past few years, several genetic aberrations that may contribute to increased risks for development of breast and/or ovarian cancers have been identified. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian focus specifically on the assessment of genetic mutations in BRCA1/BRCA2, TP53, and PTEN, and recommend approaches to genetic testing/counseling and management strategies in individuals with these mutations. This portion of the NCCN Guidelines includes recommendations regarding diagnostic criteria and management of patients with Cowden Syndrome/PTEN hamartoma tumor syndrome.

Early detection of high-grade tubal serous carcinoma in women at low risk for hereditary breast and ovarian cancer syndrome by systematic examination of fallopian tubes incidentally removed during benign surgery.

Early detection of sporadic pelvic serous carcinoma remains an elusive goal. In women at high risk for hereditary breast and ovarian cancer syndrome who undergo prophylactic salpingectomy, systematic pathologic examination of the fallopian tubes will detect occult tubal cancer, mostly in the fimbriae, of a minority of women. Such tubal cancers are the putative precursor to advanced-stage pelvic cancer. We hypothesized that early tubal cancer detection can also be accomplished in women at low risk using a similar approach. In this study, we performed complete and systematic examination of the fallopian tubes removed during surgery performed for benign indications. Among 522 women, 4 cases of serous tubal intraepithelial carcinoma (STIC) were identified. Three of these cases would have gone undetected using the current standard of care of sampling only a single random section of the tube. The fourth case was accompanied by occult ovarian carcinoma. The fimbriae contained STIC in 3 of the 4 cases and atypical mucosa in 1 case in which the STIC was in the nonfimbriated portion of the tube. The morphologic and immunohistochemical features (aberrant p53 and MIB-1) of these STICs were similar to those expected in high-risk women. All 4 patients with STIC underwent BRCA1 and BRCA2 gene testing; no germline mutations were identified in any patient. An additional 11 specimens contained atypical mucosal proliferations that fell short of morphologic and immunohistochemical criteria for STIC. Two of these 11 fulfilled criteria for a serous tubal intraepithelial lesion, and the remaining atypical proliferations exhibited normal p53 and MIB-1. For most specimens, the fimbriae could be completely submitted in 1 or 2 cassettes per tube. These results demonstrate that systematic examination of the tubal fimbriae can serve as a form of early detection of sporadic tubal cancer without incurring significant labor or cost. We propose that the tubal fimbriae should be completely examined in all patients undergoing benign surgery even if there are no clinical features to suggest risk for hereditary breast and ovarian cancer syndrome.

Characteristics of individuals with breast cancer rearrangements in BRCA1 and BRCA2.

BACKGROUND: Large rearrangements in BRCA1 and BRCA2 occur in a small percentage (< 1%) of patients tested for hereditary breast (BC) and ovarian cancer. It is unclear what factors predict BRACAnalysis Large Rearrangement Test (BART) positivity. METHODS: Data from 6 centers were included in this analysis. Individuals with negative Comprehensive BRACAnalysis tested for BART were included. RESULTS: From 1300 individuals, 42 (3.2%) were BART positivity. Factors positively associated with BART positivity were Myriad score, first-degree relatives with BC, infiltrating BC with ductal carcinoma in situ, younger age at BC diagnosis, estrogen receptor-negative BC for both the first and second BC, and Latin American/Caribbean ethnicity. Presence of unilateral BC was inversely associated with BART positivity. Several analyses were performed on the variables available to find the model that best predicts for BART positivity. The BART predictive model, including first BC, ovarian cancer, primary maternal ancestry being Latin America/Caribbean, number of first-degree relatives with BC of 1 or more versus 0, and family history of prostate and pancreatic cancer, had good predictive ability with an area under the curve of 0.77. CONCLUSIONS: Several factors are significantly associated with BART positivity. Among them we have found that Latin American/Caribbean ancestry, Myriad score, first degree relatives with BC, younger age at BC diagnosis, estrogen receptor-negative status of BC, and infiltrating ductal carcinoma with ductal carcinoma in situ features are significantly associated with BART positivity. A BART predictive model may help in a clinical setting.

Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome.

Although there is consensus on the cost-effectiveness of a universal approach of screening all colorectal cancer patients for Lynch syndrome (LS) using mismatch-repair (MMR) protein immunohistochemistry (IHC) and/or microsatellite instability (MSI) testing, the question of universal versus selective screening of endometrial cancer patients remains to be resolved. We have prospectively implemented a selective screening algorithm for newly diagnosed endometrial cancer patients, triggered by patient age 50 years or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, and/or presence of MMR-associated tumor morphology. Four-protein MMR IHC and MSI testing were performed if any of the criteria were met. This algorithm excluded screening of older patients without a cancer pedigree and whose tumors lacked MMR morphology. The aim of this study was to retrospectively determine whether these exclusion criteria missed any tumors with abnormal MMR. Among 273 consecutive patients with newly diagnosed endometrial cancers, 181 (66%) lacked criteria for screening. Retrospective MMR IHC confirmed intact MMR in 177 (97.8%) of these 181 unscreened patients, loss of MSH6 in 1 patient (0.5%), and loss of MSH1/PMS2 due to MLH1 promoter hypermethylation in 3 patients (1.7%). In comparison, 41% of patients fulfilling 1 or more criteria for screening had abnormal MMR IHC/MSI, mostly consisting of loss of MLH1/PMS2. MMR morphology contributed to detection of 92% of the abnormal MMR cases while cancer pedigree contributed to detection of the remainder. All of the abnormalities due to MSH2 and PMS2 were detected by the screening algorithm, but 1 of the 4 MSH6 cases was not. The latter finding is consistent with the literature that MSH6 endometrial cancers exhibit a phenotype different than those of the other MMR genes. We conclude that a genotype-specific approach to screening endometrial cancer for LS could consist of universal testing by MSH6 IHC and selective testing by MLH1, PMS2, and MSH2 IHC on the basis of age, cancer pedigree, and MMR morphology. Cost-effectiveness of this hybrid selective strategy deserves further study, particularly in comparison with a universal strategy. Further work to identify phenotypic features of endometrial cancers with methylated MLH1 that would allow them to be excluded from LS screening would also contribute to cost-effectiveness.

Prevalence of BRCA mutations among women with triple-negative breast cancer (TNBC) in a genetic counseling cohort.

BACKGROUND: Revised NCCN guidelines recommend that women ≤60 years with triple-negative breast cancer (TNBC) be referred for consideration of genetic counseling. Small, homogeneous samples have limited evaluation of BRCA mutation prevalence among different ethnicities affected by TNBC subtype. We sought to determine whether the prevalence of BRCA mutations within a TNBC cohort differs by demographic factors. METHODS: We performed a retrospective review of patients with TNBC referred for genetic counseling at two academic Hereditary Cancer Clinics between 2000 and 2012. Demographic data were collected, including age at diagnosis and race/ethnicity. Race was categorized as African American (AA), Ashkenazi Jewish (AJ), Asian, Caucasian, Hispanic, or other. Primary outcome was BRCA mutation status, analyzed by race/ethnicity and age at diagnosis. RESULTS: A total of 469 patients with TNBC who underwent testing for BRCA genetic mutations were identified, of which 450 patients had evaluable BRCA testing results; 139 (30.8 %) had confirmed BRCA1 (n = 106) or BRCA2 (n = 32) mutations. BRCA mutation prevalence differed by ethnicity and race: AA (20.4 %), AJ (50 %), Asian (28.5 %), Caucasian (33.3 %), and Hispanic (20 %). The prevalence of genetic mutations also differed by age at diagnosis: <40 years (43.8 %), 40-49 years (27.4 %), 50-59 years (25.3 %), 60-69 years (12.5 %), and >70 years (16.6 %). CONCLUSIONS: The prevalence of genetic mutations among women with TNBC referred for genetic counseling is high and differs significantly by ethnicity/race and age. This data helps to refine mutation risk estimates among women with TNBC, allowing for more personalized genetic counseling potentially aiding in improved patient decision-making.

Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: experience with a consecutive series of 111 patients using a standardized surgical-pathological protocol.

BACKGROUND: Women carriers of BRCA mutations often have occult malignancy found at the time of risk-reducing bilateral salpingo-oophorectomy (RRSO). We report outcomes in 111 consecutive BRCA-positive women who had RRSO using a rigorous surgical-pathological protocol from 1996 to 2008. METHOD: We identified risk factors associated with finding an occult malignancy at RRSO with outcomes followed for a median of 61 months. RESULTS: A total of 111 BRCA carriers elected RRSO, 10 patients [9.1%] had 14 sites of occult neoplasia. Two patients had invasive serous fallopian tube carcinoma (TSC) only, 1 patient had invasive serous ovarian carcinoma (OSC) only, 5 patients had tubal intraepithelial carcinoma (TIC) only, and 2 patients had multifocal lesions of the ovary (OSC) and TIC. Occult ovarian carcinomas were only detected in BRCA1 patients, and all BRCA2 carcinomas involved only the fallopian tube. The odds of finding occult carcinoma is 4 times greater (odds ratio, 4.3; 95% confidence interval, 1.06-20.7) in women older than 50 than in younger ones (P=0.023). A history of invasive breast cancer was associated with a reduced risk of occult carcinoma (odds ratio, 0.2; 95% confidence interval, 0.05-0.85). In median follow-up of 5 years, recurrence rate after detection of an occult carcinoma was 10% and the risk for primary peritoneal carcinoma was less than 1%. CONCLUSION: A rigorous surgical protocol with meticulous pathologic review at RRSO yielded an overall detection rate of 9.1% for occult gynecological carcinoma in BRCA mutation carriers followed by a multidisciplinary team at a single institution. Primary peritoneal carcinoma after RRSO is rare.

Surveillance of survivors: follow-up after risk-reducing salpingo-oophorectomy in BRCA 1/2 mutation carriers.

OBJECTIVES: To characterize the post-operative care of BRCA1 and BRCA2 mutation carriers who undergo risk-reducing salpingo-oophorectomy (RRSO). METHODS: BRCA1 and BRCA2 mutation carriers from our Cancer Risk Program who elected RRSO were sent questionnaires regarding their post-surgical surveillance and treatment for menopause symptoms, primary peritoneal cancer and bone loss. RESULTS: In 51 mutation carriers who were surveyed a median of 6 years after RRSO, 24 (47%) received dual-energy X-ray absorptiometry (DXA) testing, yearly CA-125 serum testing and yearly pelvic examination. Three women received none of these examinations in follow-up. Respondents reported an average of 3.5 menopausal symptoms (range 0-9). The mean number of menopausal symptoms reported by respondents using HRT was 2.8, compared to 3.9 symptoms reported by women not using HRT (p=0.06). Six of 10 (60%) subjects who reported no history of DXA bone scan, and 10 of 15 (67%) subjects who reported no post-surgical CA-125 serum monitoring noted that their physicians "did not recommend" testing. Two out of six symptomatic women who were younger than 50 (33%) who had no other contraindication to the use of HRT reported their non-use was because their care providers "advised against" HRT use. CONCLUSION: We believe that the lack of post-RRSO health care guidelines has resulted in inconsistent care for this cohort of patients. We proposed that national guidelines be developed to standardize care with the goal of optimizing long term survival in this unique cohort of young cancer previvors.

Correlation of macroscopic and microscopic pathology in risk reducing salpingo-oophorectomy: implications for intraoperative specimen evaluation.

OBJECTIVE: A minority of risk-reducing salpingo-oophorectomy (RRSO) specimens from BRCA mutation carriers will contain clinically occult carcinoma that is detectable only using a specialized pathologic evaluation protocol. Although intraoperative detection of cancer may alter immediate surgical management, technical complications impairing pathologic diagnosis may result if fresh tissue dissection and frozen sections are performed on unselected RRSO specimens. We hypothesize that macroscopic specimen findings may predict which RRSO specimens contain cancer and therefore may guide selection of specimens for intraoperative pathologic evaluation. The aim of this study was to correlate the macroscopic and microscopic pathologic findings in RRSO. METHODS: RRSO specimens from 134 women with a BRCA mutation were retrospectively classified by their grossly visible findings (cysts and/or nodules versus grossly unremarkable). Correlation of the gross findings with the microscopic finding of occult tubal and/or ovarian carcinoma was performed by re-examination of all pathology slides. RESULTS: While 46% of RRSO had visible ovarian cysts and 34% had visible tubal/paratubal cysts, no cyst contained cancer on microscopic examination. Carcinoma was detected in 2/22 (9%) visible ovarian nodules and in 2/8 (25%) visible tubal nodules. Conversely, among all 11 RRSO specimens containing cancer, 7 (64%) had no corresponding visible abnormality. CONCLUSION: Frozen section evaluation of a solid nodule may be valuable in patients consented for immediate surgical staging. Otherwise it is best to avoid intraoperative dissection or frozen section of RRSO that are macroscopically normal or contain only cysts; such specimens should remain undissected for immediate formalin-fixation as the first step of the specialized pathology evaluation protocol.

Multistep level sections to detect occult fallopian tube carcinoma in risk-reducing salpingo-oophorectomies from women with BRCA mutations: implications for defining an optimal specimen dissection protocol.

Risk-reducing salpingo-oophorectomy (RRSO) significantly lowers the incidence of ovarian, tubal, peritoneal, and breast cancer in women who carry BRCA1 or BRCA2 germline mutations. A minority of RRSO specimens from these women will contain occult early-stage carcinoma. Most occult cancer is localized in the fallopian tube fimbriae and is as small as 1 mm in size. Pathologic detection is dependent on thoroughness of tissue examination. Recommended protocols to maximize tumor detection emphasize the role of thinly slicing the tubes and ovaries and embedding the entire specimen for microscopic examination. Additional multistep level sections of tubal fimbriae tissue blocks could theoretically increase detection of occult tubal carcinoma but the value of level sections has not been formally evaluated. This study tests the diagnostic utility of multistep level sections in RRSO specimens from 102 women with BRCA germline mutations. The original diagnoses were based on a single section from each block of thinly sliced (2 to 3 mm intervals) tissues of the entire RRSO specimen. Three multistep level sections were retrospectively obtained from each block containing tubal fimbriae. Clinically occult carcinoma ranging in size from 1 to 13 mm was initially detected in 11 of 102 women (5 in tubal fimbriae only, 1 in tubal isthmus only, 2 in fimbriae and ovary, and 3 in ovary only). Diagnoses in the original fimbrial slides and their level sections were concordant in all cases. All tubal cancers were detected in both the original sections and in the multistep level sections. None of the tubal carcinomas that were noninvasive on the original slides showed invasive growth on additional level sections. No tubal carcinoma was identified in the level sections of any case originally classified as benign. Clinical follow-up among women with benign RRSO findings revealed that 2 women subsequently developed peritoneal carcinomatosis at 22 and 62 months postoperatively. Retrospective exhaustive multistep level sectioning of all remaining tubal and ovarian blocks from both these women confirmed the original benign diagnosis in 1 woman but in the other woman, the deepest levels of 1 ovarian block revealed a single 1-mm nodule of cancer at the base of an ovarian surface epithelial invagination. This specimen was one of the first RRSO cases in our experience and on review of the original report, this ovary was not dissected into multiple slices along its short axis but was only bivalved along its long axis. We propose that there does not seem to be any diagnostic value in automatically performing multistep deeper level sections of RRSO specimens if the tissue is sectioned appropriately and if the specimen is sliced at intervals that are no more than 3 mm thick. Guidelines for evaluation of RRSO specimens should emphasize the use of an optimal dissection protocol and the importance of thin tissue slice intervals.

Ovarian pathology in risk-reducing salpingo-oophorectomies from women with BRCA mutations, emphasizing the differential diagnosis of occult primary and metastatic carcinoma.

Risk-reducing salpingo-oophorectomy (RRSO) is an effective prophylactic procedure for women with mutations in BRCA1 or BRCA2 genes, both of which confer an increased lifetime risk for ovarian, tubal, peritoneal, and breast cancer. In addition to lowering this risk, RRSO also offers the opportunity to detect occult early-stage fallopian tube or ovarian carcinoma. The differential diagnosis of occult tubal/ovarian cancer includes a spectrum of benign tubal and ovarian alterations and also occult metastatic breast cancer, although only rare cases of the latter have been reported in RRSO. Neoadjuvant breast cancer chemotherapy may contribute to diagnostic difficulty due to treatment-induced cytologic alterations. With the aim of elucidating features which may help with differential diagnosis, this study reports the incidence and pathologic features of benign ovarian alterations, benign ovarian tumors, and occult primary and metastatic malignancies in prophylactic oophorectomies from 108 women with a BRCA mutation and from 35 women with other strong risk factors for hereditary breast/ovarian carcinoma. We direct particular emphasis on morphologic features of primary ovarian lesions that may mimic occult metastatic breast cancer. We also evaluate histologic alterations due to neoadjuvant breast cancer chemotherapy in the ovary and fallopian tube of patients who received such treatment immediately preceding RRSO. Comparison is made to ovarian metastases of breast cancer in our hospital-based population of breast cancer patients, none of whom underwent RRSO. Overall, 69% of RRSO patients had a personal history of breast cancer. Neoadjuvant breast cancer chemotherapy was administered in 15%. Occult primary carcinoma occurred in 7 (6.5%) BRCA patients (5 in fallopian tube, 1 in fallopian tube and ovary, 1 in ovary). Ovarian metastasis of breast cancer occurred in 1 (1%) BRCA patient undergoing RRSO and in up to a similar proportion (0.8%) of the hospital-based population of breast cancer patients. The metastasis in the RRSO patient was clinically occult, unilateral, 0.2 cm, and demonstrated mild atypia without mitoses. Abundant foamy, vacuolated cytoplasm due to neoadjuvant chemotherapy exposure was notable. In contrast, ovarian metastases in the non-RRSO population were all clinically detected, bilateral, large, and exhibited well-developed malignant cytologic features. None of the normal cell types in the ovary or tube demonstrated any cytologic alterations in RRSO patients who received neoadjuvant chemotherapy. The main morphologic mimics of metastasis with superimposed chemotherapy-induced alterations in RRSO were stromal hyperthecosis (n=8), nodular hyperthecosis (n=2), adrenal rests (n=3), hilus cell nodules (n=43), and hilus cell hyperplasia (n=4). Occult primary ovarian carcinoma was reliably distinguished from ovarian metastases of breast cancer by WT-1+, p53+, mammaglobin-, GCDPF-immunoprofile. These results demonstrate that evaluation of RRSO specimens requires awareness of a spectrum of ovarian lesions which may mimic occult primary or metastatic carcinoma; awareness of the masquerading effects of neoadjuvant chemotherapy; and awareness of the potential morphologic differences between occult metastatic breast cancer in RRSO and non-RRSO specimens.

Uptake, time course, and predictors of risk-reducing surgeries in BRCA carriers.

INTRODUCTION AND AIMS: For women who carry BRCA mutations, risk-reducing surgeries are an option to decrease breast and ovarian cancer risk. This study aims to determine the uptake, time course, and predictors of risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) in BRCA carriers. RESULTS: In 272 female carriers, followed for a median of 3.7 years, 23% of those eligible chose RRM, and 51% percent chose RRSO. Among BRCA carriers who chose these procedures, median time to both RRM and RRSO was approximately 4 months after learning of BRCA-positive results. Predictors of RRM were as follows: age below 60 years (hazard ratio 1.8, p=0.04), prior breast cancer (hazard ratio 2.4, p=0.0004), and RRSO (hazard ratio 7.2, p<0.0001). Predictors of RRSO were as follows: age below 60 years (hazard ratio 3.6, p=0.006), prior breast cancer (hazard ratio 1.8, p=0.002), and RRM (hazard ratio 5.4, p<0.0001). CONCLUSIONS: Many women who undergo BRCA testing use these results to make clinical decisions; those who choose risk-reducing surgeries typically do so within months of receiving BRCA-positive results. Predictors of risk-reducing surgery uptake include the following: age below 60 years, prior breast cancer, and utilization of another risk-reducing surgery. Future research directions include examining other preventive and screening options in BRCA carriers as well as studying motivations for choosing or declining risk-reducing surgeries.

Transitional cell metaplasia of fallopian tube fimbriae: a potential mimic of early tubal carcinoma in risk reduction salpingo-oophorectomies from women With BRCA mutations.

Germline mutations in the hereditary breast/ovary carcinoma genes BRCA1 or BRCA2 confer increased lifetime risk for ovarian, fallopian tube, and primary peritoneal carcinoma. This risk can be minimized by prophylactic surgery. Risk-reducing salpingo-oophorectomy (RRSO) provides 2 potential benefits: long-term cancer risk reduction and immediate detection of occult early carcinoma, which frequently arises in the tubal fimbriae. Recognition of occult early tubal carcinoma is challenging because it is often microscopic in size and can be confined to the fimbrial epithelium without invasion. Transitional cell metaplasia is a benign epithelial alteration that is a common finding in the serosa of the tube but is underrecognized in the tubal fimbriae, where it may mimic tubal intraepithelial carcinoma. The aim of this study was to define the incidence, morphology, immunophenotype, and distribution of transitional cell metaplasia of the fimbriae in RRSO specimens from 96 women with BRCA germline mutations and to compare these features to those of tubal intraepithelial carcinoma in this cohort. RRSO specimens from an additional 30 women at increased risk for ovarian cancer based on strong family history were also studied, along with RRSO from 1 patient with Lynch syndrome, and 1 patient with PTEN mutation. Transitional cell metaplasia of the fimbriae was present in 26% of all RRSO specimens. It was commonly multifocal (67%), with involvement of the tip, edges, or base of the fimbrial plicae. Average size of a metaplastic focus was 1.3 mm (range: 0.1 to 10 mm). None of the metaplastic foci expressed p53 by immunohistochemistry nor was there increased staining for the proliferation marker MIB-1. Occult early carcinoma was detected in 6/128 RRSO specimens. Median tumor size was 2.7 mm (range: 1 to 11 mm). All expressed p53 and showed markedly increased MIB-1 staining. The key criteria distinguishing transitional cell metaplasia from tubal intraepithelial carcinoma were uniform cell size and shape, normal nucleus:cytoplasm ratios, lack of nuclear atypia, presence of nuclear grooves, lack of mitoses, and absence of p53 expression or increased staining for MIB-1. No particular clinical variables (BRCA 1 vs. BRCA 2 mutation, parity, personal history of breast cancer, prior abdomino-pelvic surgery, or intraoperative findings) or benign pathologic alterations in the RRSO specimens were associated with the presence of transitional cell metaplasia of the fimbriae. None of the patients with this finding developed peritoneal carcinoma during follow-up ranging from 1 month to 9 years. This study demonstrates that transitional cell metaplasia of the fimbriae is a common benign finding in RRSO specimens that should not be confused with the much less common finding of tubal intraepithelial carcinoma.

Prevalence and characteristics of pancreatic cancer in families with BRCA1 and BRCA2 mutations.

A growing body of research describes cancers other than breast and ovarian in families with BRCA1/2 mutations, but the prevalence and characteristics of pancreatic cancer in these families has not been well described. This study was designed to: (1) estimate the prevalence of pancreatic cancer in BRCA1/2 positive families; (2) ascertain age of onset and gender distribution of pancreatic cancer in this cohort; and (3) compare age and gender characteristics of pancreatic cancer in BRCA1/2 positive families with those of the general population. Within the UCSF Cancer Risk Program cohort, 24/219 (11.0%) BRCA1 and 17/156 (10.9%) BRCA2 families had at least 1 individual with pancreatic cancer. In the 24 BRCA1 families, median age of diagnosis was 59 (range 45-80) in males, and 68 (range 38-87) in females (male:female ratio = 2.00). In the 17 BRCA2 families, median age of diagnosis was 67 (range 39-78) in males and 59 (range 46-81) in females (male:female ratio = 1.11). The SEER database, which describes cancer characteristics in a representative sample of the US population, reports a median age of 70 in males and 74 in females (male:female ratio = 0.96) over the same time period. Additionally, mean ages of diagnosis of pancreatic cancer in BRCA1/2 families differ significantly from the SEER mean (P = 0.0014 for BRCA1 and P = 0.011 for BRCA2 by unpaired t-test). Our findings suggest that families with early onset pancreatic cancer and features of hereditary breast and ovarian cancer should be considered for BRCA1/2 testing.

Performance of BRCA1/2 mutation prediction models in Asian Americans.

PURPOSE: There are established differences in breast cancer epidemiology between Asian and white individuals, but little is known about hereditary breast cancer in Asian populations. Although increasing numbers of Asian individuals are clinically tested for BRCA1/2 mutations, it is not known whether computer models that predict mutations work accurately in Asian individuals. We compared the performance in Asian and white individuals of two widely used BRCA1/2 mutation prediction models, BRCAPRO and Myriad II. PATIENTS AND METHODS: We evaluated BRCAPRO and Myriad II in 200 Asian individuals and a matched control group of 200 white individuals who were tested for BRCA1/2 mutations at four cancer genetics clinics, by comparing numbers of observed versus predicted mutation carriers and by evaluating area under the receiver operating characteristic curve (AUC) for each model. RESULTS: BRCAPRO and Myriad II accurately predicted the number of white BRCA1/2 mutation carriers (25 observed v 24 predicted by BRCAPRO; 25 predicted by Myriad II, P > or = .69), but underpredicted Asian carriers by two-fold (49 observed v 25 predicted by BRCAPRO; 26 predicted by Myriad II; P < or = 3 x 10(-7)). For BRCAPRO, this racial difference reflects substantial underprediction of Asian BRCA2 mutation carriers (26 observed v 4 predicted; P = 1 x 10(-30)); for Myriad II, separate mutation predictions were not available. For both models, AUCs were nonsignificantly lower in Asian than white individuals, suggesting less accurate discrimination between Asian carriers and noncarriers. CONCLUSION: Both BRCAPRO and Myriad II underestimated the proportion of BRCA1/2 mutation carriers, and discriminated carriers from noncarriers less well, in Asian compared with white individuals.

Development and pilot evaluation of novel genetic educational materials designed for an underserved patient population.

Genetic counseling for BRCA1 and BRCA2 mutations involves teaching about hereditary cancer, genetics and risk, subjects that are difficult to grasp and are routinely misunderstood. Supported by a grant from the Avon Foundation, the UCSF Cancer Risk Program started the first genetic testing and counseling service for a population of traditionally underserved women of varied ethnic and social backgrounds at the San Francisco General Hospital (SFGH). Informed by educational theory and clinical experience, we devised and piloted two simplified explanations of heredity and genetic risk, with the aim of uncovering how to best communicate genetics and risk to this underserved population. A "conventional" version comprised pictures of genes, pedigrees, and quantitative representations of risk. A "colloquial" pictorial version used an analogy of the "information book" of genes, family stories and vignettes, and visual representations of risk, without using scientific words such as genes or chromosomes. A verbal narrative accompanied each picture. We presented these modules to four focus groups of five to eight women recruited from the SFGH Family Practice Clinic. Overall, women preferred a picture-based approach and commented that additional text would have been distracting. The majority of women preferred the colloquial version because it was easier to understand and better conveyed a sense of comfort and hope. We conclude that simplicity, analogies, and familiarity support comprehension while vignettes, family stories, and photos of real people provide comfort and hope. These elements may promote understanding of complex scientific topics in healthcare, particularly when communicating with patients who come from disadvantaged backgrounds.