BRCA Mutation Testing Research Articles

Primary transitional cell carcinoma of the fallopian tube

The fallopian tube is the least common site for origin of malignancy in the female genital tract. Most primary fallopian tube malignancies are adenocarcinomas. Primary transitional cell carcinoma (TCC) of the fallopian tube is an extremely rare tumor with a small number of cases reported in the literature. We present a 67-year-old woman who was found incidentally to have a left adnexal mass on a screening pelvic ultrasound. Subsequently the patient underwent laparoscopic left salpingo-oophorectomy and the specimen was submitted for intraoperative frozen section, which revealed a high-grade carcinoma; therefore, she underwent a laparotomy and total abdominal hysterectomy, right salpingo-oophorectomy and omentectomy. Histopathology revealed high-grade transitional cell carcinoma in the left fallopian tube. Post-surgery she was treated with four cycles of adjuvant chemotherapy with carboplatin and paclitaxel with no complications. Our patient had a family history of malignancy, so genetic testing for BRCA1 and BRCA2 mutations was undertaken and did not reveal any mutation or unclassified variants. Multiplex ligation-dependent probe amplification (MLPA) was normal.

A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes.

BackgroundDetection of mutations by DNA sequencing can be facilitated by scanning methods to identify amplicons which may have mutations. Current scanning methods used for the detection of germline sequence variants are laborious as they require post-PCR manipulation. High resolution melting (HRM) is a cost-effective rapid screening strategy, which readily detects heterozygous variants by melting curve analysis of PCR products. It is well suited to screening genes such as BRCA1 and BRCA2 as germline pathogenic mutations in these genes are always heterozygous.MethodsAssays for the analysis of all coding regions and intron-exon boundaries of BRCA1 and BRCA2 were designed, and optimised. A final set of 94 assays which ran under identical amplification conditions were chosen for BRCA1 (36) and BRCA2 (58). Significant attention was placed on primer design to enable reproducible detection of mutations within the amplicon while minimising unnecessary detection of polymorphisms. Deoxyinosine residues were incorporated into primers that overlay intronic polymorphisms. Multiple 384 well plates were used to facilitate high throughput.Results169 BRCA1 and 239 BRCA2 known sequence variants were used to test the amplicons. We also performed an extensive blinded validation of the protocol with 384 separate patient DNAs. All heterozygous variants were detected with the optimised assays.ConclusionsThis is the first HRM approach to screen the entire coding region of the BRCA1 and BRCA2 genes using one set of reaction conditions in a multi plate 384 well format using specifically designed primers. The parallel screening of a relatively large number of samples enables better detection of sequence variants. HRM has the advantages of decreasing the necessary sequencing by more than 90%. This markedly reduced cost of sequencing will result in BRCA1 and BRCA2 mutation testing becoming accessible to individuals who currently do not undergo mutation testing because of the significant costs involved.

Predictors and prevalence of germ-line BRCA1 and BRCA2 mutations in high-risk patients screened at a community hospital.

e11124 Background: Germline mutations in tumor suppressor genes, BRCA1 and BRCA2, confer high risks of breast and ovarian cancer in affected individuals. Genetic testing for these pathogenic mutations has potentially important health implications for judicious counseling and screening of high risk individuals. Methods: A retrospective analysis was conducted of all the patients seen at the oncology and genetics clinic from 2000 to 2010. A population of over 500 patients was identified, out of whom 310 subjects underwent risk factor assessment and genetic counseling. BRCA testing was performed on 231 of these subjects whereas 79 subjects were not tested secondary to lack of insurance/follow up, or patient/physician preference. Various ethnic groups were identified which included 138 Caucasian, 41 African American, 28 Ashkenazi Jewish, 4 Middle Eastern, 2 Asian and 2 Hispanic subjects. The race/ethnicity of 16 subjects was unknown secondary to lack of documentation. Results: BRCA mutation testing was complet...

Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ.

1512 Background: The frequency of a BRCA mutation among women with ductal carcinoma in situ (DCIS) has not been well described. Consequently, patients with DCIS were not historically considered ideal candidates for genetic testing even in the presence of a family history of breast and ovarian cancer. Therefore, we examined the prevalence of BRCA1/2 mutations in women diagnosed with DCIS. Methods: Patients with DCIS, who were referred for genetic counseling and underwent genetic testing, were included in the study. Patient characteristics were obtained from a prospectively maintained research database. This study was approved by institutional review board. The likelihood of carrying a BRCA mutation was calculated using the BRCAPRO model (Version 5.1). Chi-square analysis was used to determine the difference among mutations carriers vs. non-carriers with DCIS. Results: One hundred and twenty nine patients diagnosed with DCIS underwent genetic testing for BRCA mutations. Twenty-eight percent (37/129) of DCIS patients tested positive for a deleterious BRCA mutation (15 BRCA1, and 22 BRCA2). In addition, 6 were found to have a variant of uncertain significance (VUS). The average age of diagnosis was 46.2 yrs (30-69) in BRCA positive patients and 43.5 yrs (26-65) in BRCA negative patients (p =0.177). Patients who tested positive for the BRCA mutations had significantly more family history of breast and ovarian cancer (p=0.021, p=0.006 (respectively) than those who tested negative; as reflected by the BRCAPro calculation (p ≤0.0001). Fifty seven percent of BRCA positive patients had one breast removed for prophylactic reasons while only 28% BRCA negative patients did (p=0.004). This effect was significantly stronger for patients ≤40 (p=0.007). Conclusions: Patients with DCIS and a family history of breast and/or ovarian cancer have a high rate of BRCA positivity regardless of age. These findings suggest that patients with DCIS are appropriate candidates for genetic testing in the presence of family history and regardless of age even if they do not have invasive cancer.

Genetic Testing for BRCA Mutations Can Save Lives

JAMA Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality Susan M. Domchek, MD; Tara M. Friebel, MPH; Christian F. Singer, MD, MPH; D. Gareth Evans, MD; Henry T. Lynch, MD; Claudine Isaacs, MD; Judy E. Garber, MD, MPH; Susan L. Neuhausen, PhD; Ellen Matloff, MS; Rosalind Eeles, PhD; Gabriella Pichert, MD; Laura Van t’veer, PhD; Nadine Tung, MD; Jeffrey N. Weitzel, MD; Fergus J. Couch, PhD; Wendy S. Rubinstein, MD, PhD; Patricia A. Ganz, MD; Mary B. Daly, MD, PhD; Olufunmilayo I. Olopade, MD; Gail Tomlinson, MD, PhD; Joellen Schildkraut, PhD; Joanne L. Blum, MD, PhD; Timothy R. Rebbeck, PhD Context: Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. Objective: To estimate risk and mortality reduction stratified by mutation and prior cancer status. Design, Setting, and Participants: Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. Main Outcomes Measures: Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. Results: No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer–specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer–specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). Conclusions: Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality. doi:10.1001/jama.2010.1237.

Clinical Management of Hereditary Breast Cancer Syndromes

Over the past 15 years there has been substantial improvement in the understanding of hereditary breast cancer. Germline genetic testing for mutations in BRCA1, BRCA2, PTEN and TP53 allows for the identification of individuals at increased risk for breast, ovarian and other cancers. Advances in screening, prevention and treatment have led to improved clinical management which is best defined for BRCA1 and BRCA2 mutation carriers. The addition of screening techniques such as breast magnetic resonance imaging has been shown to lead to earlier detection. Risk-reducing salpingo-oophorectomy leads to a reduction in the risk of both ovarian cancer and breast cancer and also is associated with an improvement in overall survival. BRCA1/2 mutation status may be applicable to systemic therapy decisions. Preclinical and early clinical research suggests that specific classes of chemotherapy may be more effective in mutation carriers. Finally, PARP inhibitors represent a novel therapeutic strategy that exploits the weaknesses of BRCA1/2-associated malignancies.

Inefficacité du dépistage des cancers tubo-ovariens dans les situations de risque héréditaire de cancer de l’ovaire ; l’expérience du Centre Oscar-Lambret

As part of a study in the North of France for screening pelvic tumours with plasma proteomic analysis, we included 82 women with hereditary risk of ovarian cancer. We report here the consequences of organized screening with usual tests. CA 125 sampling and a transvaginal pelvic ultrasound by a radiologist were systematically conducted every 6 months. Seventy-two patients were eventually evaluable. Two incident cases of peritoneal carcinomatosis (FIGO IIIB, malignant epithelial serous high-grade tumors) were discovered in two asymptomatic women with a deleterous BRCA1 mutation (2.7%). We did not observe any other primary cancer cases but an ovarian metastasis of a breast cancer. Forty women went off the study: 32 had a prophylactic bilateral salpingo-oophorectomy. Consistent with the literature, biannual screening tests combining CA125 and pelvis ultrasound is ineffective for early detection of a pelvic tumor of tubal or ovarian origin. Testing for BRCA1 or BRCA2 deleterious mutations is then crucial for suspected family syndromes of breast and ovarian cancer. For women carrying a deleterous mutation on BRCA1/2 a salpingo-oophorectomy is the only way, only the time of this surgery is debatable.

Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry

IntroductionSelecting women affected with breast cancer who are most likely to carry a germline mutation in BRCA1 and applying the most appropriate test methodology remains challenging for cancer genetics services. We sought to test the value of selecting women for BRCA1 mutation testing on the basis of family history and/or breast tumour morphology criteria as well as the value of testing for large genomic alterations in BRCA1.MethodsWe studied women participating in the Breast Cancer Family Registry (BCFR), recruited via population-based sampling, who had been diagnosed with breast cancer before the age of 40 years who had a strong family history of breast or ovarian cancer (n = 187) and/or a first primary breast tumour with morphological features consistent with carrying a BRCA1 germline mutation (n = 133; 37 met both criteria). An additional 184 women diagnosed before the age of 40 years who had a strong family history of breast or ovarian cancer and who were not known to carry a germline BRCA1 mutation were selected from among women who had been recruited into the BCFR from clinical genetics services. These 467 women had been screened for BRCA1 germline mutations, and we expanded this testing to include a screen for large genomic BRCA1 alterations using Multiplex Ligation-dependent Probe Amplification.ResultsTwelve large genomic BRCA1 alterations were identified, including 10 (4%) of the 283 women selected from among the population-based sample. In total, 18 (12%), 18 (19%) and 16 (43%) BRCA1 mutations were identified in the population-based groups selected on the basis of family history only (n = 150), the group selected on the basis of tumour morphology only (n = 96) and meeting both criteria (n = 37), respectively.ConclusionsLarge genomic alterations accounted for 19% of all BRCA1 mutations identified. This study emphasises the value of combining information about family history, age at diagnosis and tumour morphology when selecting women for germline BRCA1 mutation testing as well as including a screen for large genomic alterations.

Abstract P2-02-04: MRI Findings and Outcomes in an Underserved Breast Cancer Population Screened with BRCA Testing

Abstract Background: Patients with breast cancer and a familial risk and/or BRCA 1 or 2 mutations are at high risk of contralateral breast cancer and ipsilateral recurrence. While MRI screening is recommended for patients with BRCA mutations, and MRI staging for breast cancer is being increasingly used, the outcomes of such testing are not well described, especially in underserved populations. At Los Angeles County Hospital (LAC) for the last 3 years, we have enacted a program of genetic counseling and testing based standard guidelines as well as MRI evaluation of all patients newly diagnosed with breast cancer. LAC serves a population that includes a high number of indigent patients, primarily Hispanic (60%) and Asian (15%). Methods: We undertook a retrospective evaluation of all patients seen at LAC from March 2008 to March 2010 who underwent genetic counseling/testing and MRI as preoperative assessment for histologically documented breast cancer or followup after cancer treatment. IRB approval was obtained to extract data for this analysis. Demographic information along with clinical presentation, MRI and mammography results, additional imaging results, biopsy and surgical procedure and corresponding pathology data were obtained through the review of electronic medical records and clinic charts. Results: A total of 90 patients had both genetic testing and MRI reports available. The median age of all tested patients was 41 years. Ethnicity was 78% Hispanic, 9% Asian, 7% African American, 2% Caucasian and 4% other. BRCA mutation was seen in 20 cases (22%), 12 BRCA-1, 8 BRCA-2, 4 variants of unknown significance, and 66 had no mutation. Breast mass or other symptoms were the mode of detection in 89% of the overall cohort, and 81% in mutation carriers. The index lesion was visible on MRI in 78% and by mammogram in 82% of all patients. Ipsilateral MRI showed 7 abnormal non-index findings in 6 patients (7%); 6 of 7 lesions biopsied showed cancer. In the contralateral breast, 7 abnormalities were noted on MRI, but only 5 were amenable to biopsy as 2 could not be visualized by any means on follow up, and 1 showed cancer. Interestingly, only one of the 13 patients with abnormal findings carried a mutation (BRCA-1) and this patient did not have cancer on contralateral lesion biopsy. Mastectomy was performed in 91% and 78% of patients with and without mutation. Conclusions: Screening, counseling and testing for BRCA mutations is feasible in an underserved population, with a 22% mutation identification rate. MRI detected 5 non-index ipsilateral cancers and one contralateral cancer among 90 patients, with none of the detected cancers among the 20 mutation carriers. While MRI staging may be effective at detecting additional cancers in this underserved and high familial risk population, this appears to be independent of BRCA status. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-02-04.

Abstract P6-03-01: High Percentage of Triple Negative Tumors Present as Palpable Masses

Abstract Introduction: Approximately 15% of newly diagnosed breast cancers are triple negative tumors (TNT; ER-/PR-/HER2-), a subgroup with a particularly poor prognosis. This clinical-pathologic subtype corresponds to, but is not synonymous with basal-like tumors. These cancers are prevalent among African-Americans and BRCA mutation carriers. We hypothesize that TNT are more likely than other breast tumor subtypes to present as a palpable mass or appear between screening examinations. We compared the screening practices and detection modality of women with TNT at our institution. Methods: Between December 2000 to February 2010, 346 women with TNT were identified through the Stanford University Cancer Center tumor registry. Medical records were retrospectively reviewed. Breast imaging screening was compared between women whose cancers presented as a palpable mass versus those which were detected on breast imaging. Patients without prior breast imaging, screening occurring >5 y prior to diagnosis or unknown imaging history were grouped together (UNK). 95% confidence intervals (CT)determined by modified Wald method. Results: Mean age at diagnosis was 53y (range 25 to 97). 82 patients had BRCA mutation testing, of which 41 were positive. 58 women were < 40 y of age; 100 between 40-50 y; and 188 women > 50. 253 were detected on self exam. The rest were found on screening mammography (70), MR imaging (3), non-breast radiologic studies (9); unknown presentation (11). 54 cancers in women < 40 years of age were palpable. Of these, 7% (0.02- 0.18)had screening within 24m(onths), 6% (0.01-0.16)within 2 to 5y(ears) and 87% (0.75-0.94)were UNK. 74 women 40-50y of age with palpable presentations, 36%(0.26-0.48) had screening within 24m, 9%(0.04-0.19) within 2-5y and 54%(0.43-0.65)were UNK. 125 women >50 years of age with palpable presentations, 27%(0.21-0.36) had screening within 24m, 5% (0.02-0.10)within 2-5y and 67%(0.45-0.62) were UNK. Within this group 2 of 4 (<40), 23 of 27 (40-50), and 25 of 34 (>50) had detected masses within 12m of breast imaging. 30 patients carried BRCA mutations. 3 women <40 y had tumor detected on screening; 1 patient had screening at 15m, 2 were UNK. 22 in the 40-50y group were detected on screening; 41% (0.23-0.61)had screening within 24m, and 60%(0.39-0.77) were UNK. 48 women >50y had tumors detected on screening; 50% (0.36-0.64)had screening within 24m,8%(0.03-0.20)within 2-5y, and 42%(0.29-0.56) were ND. In this group, 5 of 9 (40-50), 16 of 24 (>50) had lesions detected within 12m of imaging. 8 patients with image detected tumor carried a BRCA-1 mutation. A total of 249 pts were of screening age and of those 95 were screened within 2 y; yet 65% of those presented with a palpable mass. BREAST IMAGING PRIOR TO DIAGNOSIS, N(%) Conclusion: Our data suggests that regardless of age, TNT present as palpable masses even among those undergoing breast screening. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-03-01.

The role of BRCA mutation testing in determining breast cancer therapy

Landmark discoveries in the field of breast cancer research include the identification of germline BRCA mutations as a cause of hereditary disease, and the use of gene-expression profiling to identify distinct subtypes of breast cancer. These findings, coupled with the availability of rapid germline testing, make it possible to identify a BRCA mutation carrier contemporaneous with a diagnosis of breast cancer. For the first time, testing for a germline mutation that predisposes to cancer has the potential to influence the immediate surgical, radiotherapeutic, and drug treatment choices of an individual with a new diagnosis of breast cancer. In this Review, we examine the implications of moving germline BRCA mutation testing from highly specialized family cancer clinics to mainstream settings.

BRCA mutations in the management of breast cancer: the state of the art

Genetic testing for BRCA1 and BRCA2 mutations is gaining acceptance in clinical oncology worldwide and may help target unaffected high-risk women for prevention and for close surveillance. Annual screening with MRI seems to be an effective surveillance strategy, but the long term follow-up of women with small MRI-detected breast cancers is necessary to establish its ultimate value. Women with cancer and a BRCA mutation may benefit from tailored treatments, such as cisplatin or olaparib. The treatment goals for a woman with a BRCA-associated breast cancer should be to prevent recurrence of the initial cancer and to prevent second primary breast and ovarian cancers. Mutations in BRCA1 and BRCA2 are presented throughout the world and it is important that the benefits of genetic testing and of targeted therapies be extended to women who live outside of North America and Western Europe.

Expanding the Criteria for BRCA Mutation Testing in Breast Cancer Survivors

Every year approximately 25% of women diagnosed with breast cancer are younger than 50 years of age, and almost 10% of them have a BRCA mutation. Not all potential carriers are identified by existing criteria for BRCA testing. We estimated the costs and benefits of different BRCA testing criteria for women with breast cancer younger than 50 years. We developed a Markov Monte Carlo simulation to compare six criteria for BRCA mutation testing: (1) no testing (reference); (2) medullary breast cancer in patients younger than 50 years; (3) any breast cancer in patients younger than 40 years; (4) triple negative (TN) breast cancer in patients younger than 40 years; (5) TN breast cancer in patients younger than 50 years; (6) any breast cancer in patients younger than 50 years. Net health benefits were life expectancy and quality-adjusted life expectancy, and primary outcome was the incremental cost-effectiveness ratio (ICER). The model estimated the number of new breast and ovarian cancer cases. BRCA mutation testing for all women with breast cancer who were younger than 50 years could prevent the highest number of breast and ovarian cancer cases, but with unfavorable ICERs. Testing women with TN breast cancers who were younger than 50 years was cost-effective with an ICER of $8,027 per year of life gained ($9,084 per quality-adjusted life-year), and could reduce subsequent breast and ovarian cancer risks by 23% and 41%, respectively, compared with the reference strategy. Testing women with TN breast cancers who were younger than 50 years for BRCA mutations is a cost-effective strategy and should be adopted into current guidelines for genetic testing.

Abstract IA3-3: Genetic testing for breast and ovarian cancer: From risk assessment to therapeutic targeting

Abstract Germline genetic variation can be used in a number of ways to improve the care of patients. First, such information can be used to predict the development of disease. Knowledge of risk can lead to targeted preventative strategies. Finally, understanding the genetic etiology for the development of an individual's cancer has the potential to lead to targeted drug development. Inherited BRCA1 and BRCA2 mutations are a model for this paradigm. Since these genes were identified in 1994 and 1995, much work has been done to establish mutation-associated cancer risks and potential management strategies. Deleterious mutations in both genes are associated with a high risk of breast and ovarian cancer, as well as lower risks of other tumor types. Risk-reducing salpingo-oophorectomy significantly reduces the risk of breast and ovarian cancer in mutation carriers and work is ongoing to establish the optimal timing of this procedure as well as the potential for hormone replacement therapy. Women with BRCA1 or BRCA2 mutations require increased breast screening with the addition of breast MRI at the minimum. Prophylactic mastectomy is a valid option. More recently attention has turned to the impact of the biological basis of disease in BRCA1/2 mutation carriers with breast and ovarian cancer on decisions regarding systemic therapy. Due to the role of BRCA1 and BRCA2 proteins in cellular functions such as homologous DNA repair, an enhanced sensitivity to platinum agents and reduced sensitivity to spindle poisons has been postulated and supported by in vitro studies and early clinical data. An additional pathway to target that has been recently identified is poly(ADP-ribose) polymerase (PARP). PARP is a key enzyme in the base-excision repair pathway. In vitro, PARP inhibitors given to BRCA1 or BRCA2 deficient cell lines have led to cell death through synthetic lethality. Early clinical trials have demonstrated efficacy for PARP inhibitors in BRCA1 and BRCA2 mutation carriers with advanced breast and ovarian cancer, with objective response rates in heavily pretreated patients of greater than 40%. Genetic testing for BRCA1 and BRCA2 mutations can be seen as a model for translating the biology of a disease into risk assessment, prevention and treatment, thus demonstrating the potential for inherited genetics to directly impact the care of patients. Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA3-3.

Accrual Strategies for Cancer Genetics Research: Blurred Boundaries

and BRCA2 founder mutations in an unselected group of Ashkenazi Jewish women, with an astounding 2,000 women enrolled within 14 days of an article appearing in one of Canada’s most respected newspapers. Given the overwhelming interest among the target population, one might ask exactly what information prompted such an overwhelming response. The article in question was published on the front page of the Toronto Globe and Mail (Saturday May 24, 2008) with a large-font headline reading: “Cancer test a genetic crystal ball for Jewish women.” 2 The first line in the piece stated: “For the first time in Canada, Jewish women will be offered the chance to alter their genetic destiny by taking a test…” a patently untrue and sensationalistic statement, given that presymptomatic BRCA1 and BRCA2 mutation testing, including Ashkenazi Jewish founder mutations, have been available for many years through medical genetics services nationwide. The concept of altering genetic destiny remains a potentially very desirable goal for those at real or perceived risk but is highly problematic in the clinical setting as any involved with the provision of genetic and oncologic care can easily attest. The goal of the test was “to prevent cancer” as elucidated by one of the investigators in the article. Two rabbis were quoted, the first commenting that “The rate of the gene is so high, it will be one of the tests that is normally done,” equatingBRCA1 and-2 testing to screening for Tay-Sachs, a culturally specific heritable disease. The other stated that genetic testing was a no-brainer imputing Halacha (Jewish law) that “insists that one is obligated to take care of oneself” as rationale for testing. Risks of taking the test are described as “primarily psychological, such as depression and stress, or unpredicted implications for obtaining life or critical care insurance.” Although the authors note a number of limitations to their work, the ethical implications are not mentioned. How sensationalistic is a headline allowed to be in order to generate accrual to a research study? How appropriate is it to imbibe the research with culturally and religiously significant implications directly aimed at the ethnic group under investigation? How justified is it to minimize the potential emotional angst and psychological turmoil that genetic testing can engender for subjects and their families? What degree of overstatement can be accepted when describing bothBRCA mutation incidence as well as the evidence of benefit from testing, when approaching a susceptible population for research purposes? With the goal of the research summarized as “to prevent cancer,” along with supporting patient vignettes, religious calls to action, and minimization of the clinical, psychological and emotional dilemmas faced by all those undergoing genetic testing, who could resist making the call to enroll in the study? Although the potential benefits of presymptomatic BRCA1 and -2 mutation detection can be significant, the clinical, ethical, and emotional dilemmas surrounding genetic testing for hereditary cancer syndromes can be even more so. The recent American Society of Clinical Oncology policy statement update regarding genetic and genomic testing for cancer susceptibility 3 elucidates evolving concerns regarding direct-to-consumer genetic testing, which have relevance for both industry and academia.

The BRCAPRO 5.0 model is a useful tool in genetic counseling and clinical management of male breast cancer cases

No study has evaluated the performance of BRCA1/2 mutations prediction models in male breast cancer (MBC) series. Although rare, MBC deserves attention because male and female breast cancers share many characteristics, including the involvement of genetic predisposition factors such as BRCA1/BRCA2 mutations. Indeed, the occurrence of MBC is a commonly used criterion to select families for BRCA mutation testing. We evaluated the performance and clinical effectiveness of four different predictive models in a population-based series of 102 Italian MBC patients characterized for BRCA1/2 mutations. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for each risk model at the 10% threshold. The area under the ROC (AUC) curves and its corresponding asymptotic 95% CIs were calculated as a measure of the accuracy. In our study, the BRCAPRO version 5.0 had the highest combination of sensitivity, specificity, NPV and PPV for the combined probability and for the discrimination of BRCA2 mutations. In individuals with negative breast-ovarian cancer family history, BRCAPRO 5.0 reached a high discriminatory capacity (AUC=0.92) in predicting BRCA2 mutations and showed values of sensitivity, specificity, NPV and PPV of 0.5, 0.98, 0.97 and 0.67, respectively, for the combined probability. BRCAPRO version 5.0 can be particularly useful in dealing with non-familial MBC, a circumstance that often represents a challenging situation in genetic counseling.

Safety and Efficacy of Perforator Flap Breast Reconstruction With Combined Intraabdominal Procedures

Genetic testing for BRCA mutations has led to greater needs for breast reconstruction and prophylactic gynecologic procedures. A retrospective review of all perforator flap breast reconstructions was performed over 5 years. A total of 316 flaps were performed on 232 patients. Nineteen patients had an intraabdominal procedure at the time of their breast reconstruction, including 8 unilateral and 11 bilateral reconstructions (22 flaps). The concomitant procedures incurred an additional mean operative time of 61 minutes. One arterial thrombosis occurred leading to a single flap failure (1/30, 3.3%). No significant differences were noted in complication rates between the combined group and those who did not have a simultaneous procedure (anastomotic complications 3.3% vs. 7.7%; failure rate 3.3% vs. 3.1%; abdominal wound 10.5% vs. 15%; fat necrosis 10% vs. 12.2%). The coordinated effort allowing simultaneous intraabdominal procedures and perforator flap breast reconstruction affords effective reconstruction for those requiring additional procedures without an increase in postoperative complication rates.

Effect of Genetic Counseling and Testing for BRCA1 and BRCA2 Mutations in African American Women: A Randomized Trial

Background: Limited empirical data are available on the effects of genetic counseling and testing among African American women. Objective: To evaluate the effects of genetic counseling and testing in African American women based on different levels of exposure: (a) women who were randomized to culturally tailored (CTGC) and standard genetic counseling (SGC) to women who declined randomization (non-randomized group), (b) participants and non-participants in genetic counseling, and (c) BRCA1 and BRCA2 (BRCA1/2) test result acceptors and decliners. Design: Randomized trial of genetic counseling conducted from February 2003 to November 2006. Measures: We evaluated changes in perceived risk of developing breast cancer and cancer worry. Results: Women randomized to CTGC and SGC did not differ in terms of changes in risk perception and cancer worry compared to decliners. However, counseling participants had a significantly greater likelihood of reporting reductions in perceived risk compared to non-participants (p = 0.03). Test result acceptors also had a significantly greater likelihood of reporting decreases in cancer worry (p = 0.03). However, having a cancer history (p = 0.03) and a BRCA1/2 prior probability (p = 0.04) were associated with increases in cancer worry. Conclusions: Although CTGC did not lead to significant improvements in perceived risk or psychological functioning, African American women may benefit from genetic counseling and testing. Continued efforts should be made to increase access to genetic counseling and testing among African American women at increased risk for hereditary disease. But, follow-up support may be needed for women who have a personal history of cancer and those with a greater prior probability of having a BRCA1/2 mutation.

Screening for BRCA1 Mutations in Patients with Triple Negative Breast Cancer and Basal Phenotype.

Abstract Introduction: Most models estimating risk of carrying germline BRCA mutations are based on family history and age of cancer onset. Additional histologic criteria may be useful to identify patients at risk for harboring BRCA1 mutations. BRCA1 positive breast tumors are significantly more often estrogen receptor, progesterone receptor, and erbB-2 (HER2-neu) negative (“triple negative” (TN)) and are strongly associated with a basal phenotype confirmed by DNA microarray. Basal-like tumors express cytokeratins 5,6, and 14 or 17 by immunohistochemistry (IHC). It is unknown whether testing for BRCA1 mutations in TN basal-like breast cancer patients will identify additional carriers of mutations in this gene.Methods: A retrospective evaluation of patients with triple negative breast cancer seen at Cooper Cancer Center between 2004 and 2006 was performed after IRB approval. IHC was performed to identify the subset of basal-like breast cancers.Results: A total of 89 women were identified as diagnosed with TN breast cancer, while 53 had pathology available for review. 21 patients were identified as basal phenotype, whereas 32 were non-basal. Of the 21 patients who had basal-phenotype tumors, six underwent genetic testing and 3 were found to have a deleterious BRCA1 mutation. Of 32 non-basal patients, 9 patients underwent genetic testing and 2 were found to have a deleterious BRCA1 mutation. There was no difference between basal subtype and BRCA1 postivity [Fisher's Exact Test p=0.32]. Of note, 1of 5 (20%) patients with basal phenotype had no family history but tested positive for BRCA1 mutation and would have been missed by relying on conventional methods.Conclusion: Although there is a trend towards a higher percentage of TN breast cancer patients with basal subtype having BRCA 1 mutations (50 vs 22%), this was not found to be statistically significant (Fisher's exact p=0.32). However, this dataset is limited by a small sample size. Only 40% of TN breast cancer patients had a basal phenotype by IHC in this study, while other studies have shown 70- to 85% rate. Ongoing evaluation of patients with basal-like subtype and triple negative tumors should continue to investigate this relationship, especially in light of newer therapeutics that may impact this population. This data also suggests that patients with basal phenotype and triple negative disease should be considered for referral for genetic testing even in the absence of family history. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4075.

Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2

Genetic testing for BRCA1 and BRCA2 mutations in family members of individuals with known deleterious mutations can distinguish between patients at high risk of disease and those who are not. Some studies have suggested that individuals testing negative for known familial mutations (true negatives), may still have a higher risk of breast cancer (BC) than the general population. We have examined a prospectively followed cohort of true negative women in the US. Subjects were close relatives of known BRCA1 and BRCA2 mutation carriers who had undergone genetic testing, were negative for the known familial mutation, and were unaffected at the time of genetic testing. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated using SEER incidence rates. Among 375 true negatives, two invasive and two in situ BC and no ovarian cancers were diagnosed with mean follow up of 4.9 years (total of 1,962 person years).Four invasive BC were expected, whereas two were observed, for an age-adjusted SIR of 0.52 (95% CI 0.13-2.09). We observed more cases of in situ BC (n = 2) than were expected (n = 0.9; SIR = 2.30; 95% CI 0.57-9.19).There were no cases of ovarian cancer observed; 0.4 case was expected. In this prospective study of women who were unaffected at the time of genetic testing and who were negative for the known familial mutation in BRCA1/2, no excess risk of invasive BC was observed. Our data suggest that such women in the US should adhere to population based guidelines for breast cancer screening.