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Rationale: Pancreatic cancer (PC) is considered as one of the deadliest cancers all over the world. Germline and somatic BRCA1/2 mutations have been widely studied in breast and ovarian carcinomas as they have been found to enhance the risk for disease progression. Olaparib, an oral poly(adenosine diphosphate-ribose)polymerase (PARP) inhibitor, has been approved for the treatment strategy of ovarian cancer with any BRCA1/2 mutations. There is a lack of studies which focus on the treatment of other cancer with BRCA-Mutation. Patient concerns: This report describes a patient whose presenting complaints were “Physical examination showed that the pancreas was occupied for one month.” He initially was diagnosed with stage IV PC based on conventional imaging and pathologic assessment. He had a known germline BRCA 2 mutation, which exhibited a good response to PARP inhibitor therapy. Diagnosis: Through the biopsy histopathological examination, imaging examination, and genetic testing, the patient was diagnosed as metastatic PC with BRCA2 mutation. Interventions: He received gemcitabine and albumin-bound paclitaxel chemotherapy from March 15, 2017 to June 30, 2017, and Nivolumab immunotherapy as the maintenance therapy. After serum CA-199 level increased, Olaparib was orally administered from August 17, 2017 to March. After tumor relapsed, he received multiple lines of chemotherapy, including Trametinib Oxaliplatin, S-1, bevacizumab, and irinotecan liposome injection till July 17, 2018. Outcomes: We observed the patient had a good progression-free survival (7.4 months); the lesion of the pancreas was classified as partial disease through Olaparib treatment, which indicated significant shrinkage. But it is difficult to conclude whether such therapy could help prolong the overall survival for such patients. Lessons: The targeted therapy Olaparib showed early signs of potential in treating PC in patients with mutations of the BRCA genes. With emerging therapeutic modalities and next-generation sequencing development, it is increasingly relevant to consider mutation screenings of patients with PC.

e17115 Background: To evaluate the prognosis of BRCA mutation carriers compared to non-carriers and to demonstrate whether BRCA1 and BRCA2 mutation carriers present similar survival patterns among endometrial carcinomas. Methods: This data was from NCI Cancer Genome Atlas endometrial cancer database (TCGA) with pathogenic mutations in BRCA1 (58) or BRCA2 (77) or BRCA1and BRCA2 coexisted mutation (40) and non-mutation (461). We compared clinicopathologic features and prognosis of patients with BRCA1 or BRCA2 or BRCA1and BRCA2 coexisted mutation. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1and BRCA2 as time-varying covariates. Results: We found histologic types of patients with BRCA1 or BRCA2 mutation presented more progressive than non-carriers ( p = 0.029, p= 0.029, respectively). BRCA1 or BRCA2 mutations were detected to be associated with younger patients at diagnosis ( p = 0.036, p = 0.001, respectively). BRCA2 mutation carrier was identified more advanced stage than BRCA non-carriers. Compared to patients with BRCA1 mutation, the body mass index is higher in non-carriers. Before around 100 months survival, BRCA2 mutation carriers had the most favorable overall survival (OS). OS rate of all patients with BRCA1 or BRCA2 mutation was higher than non-carriers. BRCA1 and BRCA2 mutation carriers had similar OS. Around 100 months later, BRCA1 carriers had more favorable OS than patients with BRCA2 mutation, BRCA1 / BRCA2 coexisted mutation and non-carriers ( p < 0.001). Patients with BRCA2 mutation had the most favorable progression-free survival (PFS), following by BRCA1 and BRCA2 coexisted mutation and BRCA2 alteration carriers ( p= 0.011). BRCA non-carriers had the worst PFS and OS all the time. Conclusions: BRCA1 or BRCA2 mutation carriers have favorable overall survival and progression-free survival among patients with endometrial carcinoma. [Table: see text]

5551 Background: In SOLO1 (NCT01844986), maintenance olaparib resulted in a significant improvement in progression-free survival (PFS) for newly diagnosed, BRCA1- and/or BRCA2-mutated, advanced ovarian cancer pts compared with placebo (HR 0.30, 95% CI 0.23–0.41; median not reached vs 13.8 months; Moore et al. N Engl J Med 2018). We investigated PFS in SOLO1 for the subgroups of pts with BRCA1 mutations ( BRCA1m) or BRCA2 mutations ( BRCA2m). Methods: All pts were in clinical complete or partial response to platinum-based chemotherapy and were randomized to maintenance olaparib (300 mg twice daily; tablets) or placebo. After 2 years, pts with no evidence of disease discontinued study treatment, but pts with evidence of disease could continue study treatment. PFS by BRCAm was a predefined analysis. BRCAm were identified by central germline (Myriad or BGI) or local testing; Foundation Medicine testing confirmed tumor BRCAm. Results: Median follow-up for PFS was ~41 months in the olaparib and placebo arms. Of 391 randomized pts, 282 had BRCA1m (72%), 106 had BRCA2m (27%) and three (1%) had both (Table). Two pts in the olaparib arm had somatic BRCAm (one BRCA1m, one BRCA2m); all others had germline BRCAm. At the primary data cut-off, 155 pts in the BRCA1-mutated group (55%), 43 in the BRCA2-mutated group (41%) and none in the BRCA1/2 -mutated group had disease progression. The percentage of BRCA1-mutated pts who received olaparib and were progression-free at 1, 2 and 3 years was 86%, 69% and 53% (vs 52%, 36% and 26% receiving placebo) and for BRCA2-mutated pts was 92%, 85% and 80% (vs 50%, 32% and 29%, respectively). Conclusions: Significant PFS benefit with olaparib versus placebo was demonstrated for all pts, regardless of whether they had BRCA1m or BRCA2m. Statistical tests were not used to compare BRCA1- and BRCA2-mutated pts, but those with BRCA2m appeared to receive greater benefit from maintenance olaparib than those with BRCA1m. Clinical trial information: NCT01844986. [Table: see text]

3108 Background: the recent use of PARP inhibitors in clinical practice gives very interesting outcome for ovary tumors with BRCA1 or BRCA2 mutation but also in other tumors with homologous repair deficiency. Nevertheless, no hotspot mutations are present, consequently, more than 85% of observed variants have unknown significance, blocking the use of PARP inhibitor. Methods: Exome analysis was performed on a cohort of 27 patients treated with olaparib. After bioinformatics analyses, variant interpretation was performed by interrogating different databases. For variants of unknown significance (VUS), PROVEAN software and allelic frequency normalized with tumor cellular content were used to classify VUS as potentially benign or potentially deleterious. Results: Among the 27 patients analyzed, 16 harbored already classified variants (3 benign and 13 pathogen variants) and 11 had VUS. The first Progression Free Survival (PFS) analysis showed that benign variants did not respond to olaparib with a median survival of 62 days, whereas pathogenic variants had a median of 109 days. Surprisingly, VUS had a median of 136 days, suggesting that some of them could be classified as potentially deleterious. On the subset of 11 patients with VUS, we applied PROVEAN prediction classifying 5 variants as benign and 6 variants as deleterious, with a median PFS of 54 days and 140 days ( p=0.3235), respectively. With the second prediction, based on variant allelic frequency, we obtained PFS of 73.5 months for benign variants and 210 days for deleterious ones ( p=0.29). By combining both predictions, we classified as benign, VUS predicted benign with both predictions, and as deleterious, VUS predicted as deleterious with at least one prediction. Consequently, we perfectly discriminated benign from deleterious variants with a median PFS of 36 days for predicted benign and 177 days for predicted deleterious ( p=0.0084). From all patients, PFS were significantly different ( p=0.0003) between benign (n=6, 56 days) and deleterious variants (n=21, 140 months). Conclusions: Our work tends to show that VUS of homologous repair genes could be predicted as benign or deleterious, and could increase the number of patients eligible for a treatment by PARP inhibitors. The number of patients needs to be increased in order to validate our prediction algorithm.

Background SOLO1 (NCT01844986) is a randomized, double-blind, phase III trial evaluating the efficacy and safety of the PARP inhibitor, olaparib, as maintenance monotherapy in newly diagnosed advanced OC pts with a BRCAm. A separate pt cohort evaluated the efficacy and safety of olaparib in Chinese pts in this setting. Methods The China cohort of SOLO1 planned to enrol ∼53 newly diagnosed OC pts who had completed first-line platinum-based chemotherapy and were in clinical complete or partial response. This sample size provided around a 90% chance to observe a hazard ratio (HR) of Results All 64 randomized pts received study treatment (olaparib, n = 44; placebo n = 20). Median follow-up was ∼30 months in both arms. Median PFS was not reached in the olaparib arm and was 9.3 months in the placebo arm (Table). Table . 230P PFS events, n Median PFS, months HR (95% CI; P value) Olaparib (n = 44) Placebo (n = 20) Olaparib (n = 44) Placebo (n = 20) Full analysis set (n = 64) PFS, investigator assessed (48.4% maturity) 18 13 NR 9.3 0.46 (0.23, 0.97; 0.0320) PFS, BICR (39.1% maturity) 13 12 NR 9.3 0.39 (0.17, 0.86; 0.0168) CI, confidence interval; NR, not reached. The most common AEs in the olaparib group were nausea (n = 28, 63.6%), anaemia (n = 25, 56.8%) and vomiting (n = 18, 40.9%). Grade ≥3 AEs occurred in 56.8% of olaparib pts vs 30.0% of placebo pts; the most common grade ≥3 AE was anaemia (n = 16, 36.4%). Olaparib dose interruptions, reductions and discontinuations occurred in 56.8%, 27.3% and 6.8% of pts, respectively (vs 30.0%, 10% and 0% of pts in the placebo arm). Conclusions In the China cohort of SOLO1, a clinically relevant improvement in investigator-assessed PFS was observed in newly diagnosed OC pts receiving olaparib maintenance therapy. Olaparib treatment led to a 54% reduction in risk of progression or death vs placebo. The safety results were consistent with the known profile of olaparib in Chinese pts. Clinical trial identification NCT01844986, release date 19 February 2016. Editorial acknowledgement Medical writing assistance was provided by Laura Smart, MChem, from Mudskipper Business Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure J. Liu: Research grant / Funding (institution): AstraZeneca. X. Ma: Full / Part-time employment: AstraZeneca. J. Zhang: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.

e13073 Background: BRCA1 and BRCA2 are tumour suppressor genes.1,2 Functional BRCA proteins regulate cell growth and prevent abnormal cell division that might lead to tumour development. Approximately 17% (Range 3 – 27 %) of ovarian cancer patients worldwide have a BRCA mutation.3 This study aimed to estimate the prevalence of germline BRCA mutations among previously and newly diagnosed ovarian, primary peritoneal or fallopian tube cancer patients in India. Methods: This is a non-interventional, cross-sectional, multicenter, prospective, observational study conducted at 15 sites from different geographical regions across India. The study targets to enroll 240 patients over 6 months. The calculated sample size for this study is 228, assuming 5 % precision and a dropout rate of 10 %. The study enrolled females with new or previous diagnosis of ovarian, primary peritoneal, or fallopian tube cancer. No study medication was administered as a part of study procedure. Results: In the interim analysis performed on the first 100 enrolled patients, 22% of Ovarian, primary peritoneal or fallopian tube cancer patients were found to be BRCA1/BRCA2 mutation positive (CI 0.1433-0.3139). 52% of these enrolled patients were found to have serous histopathology, 23.1% of which were found to be BRCA1/2 positive. The percentage of BRCA1/2 mutation status in patients who had a family history of ovarian or breast cancer was found to be 66.7% and 62.5% respectively. Conclusions: In this study, the prevalence of BRCA1 and BRCA2 mutations among patients with ovarian, primary peritoneal and fallopian tube cancer patients in the first 100 patients enrolled was found to be 22%. References: 1. Vos S, et al. Crit Rev Oncol Hematol. 2018 Jul;127:29-41; 2. Solodskikh SA et al. Mutat Res. 2019 Jan;813:51-57; 3. Alsop K, et al. J Clin Oncol. 2012;30(21):2655-2663.

The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction model that is used to compute probabilities of carrying mutations in the high-risk breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, and to estimate the future risks of developing breast or ovarian cancer. In this paper, we describe updates to the BOADICEA model that extend its capabilities, make it easier to use in a clinical setting and yield more accurate predictions. We describe: (1) updates to the statistical model to include cancer incidences from multiple populations; (2) updates to the distributions of tumour pathology characteristics using new data on BRCA1 and BRCA2 mutation carriers and women with breast cancer from the general population; (3) improvements to the computational efficiency of the algorithm so that risk calculations now run substantially faster; and (4) updates to the model’s web interface to accommodate these new features and to make it easier to use in a clinical setting. We present results derived using the updated model, and demonstrate that the changes have a significant impact on risk predictions. All updates have been implemented in a new version of the BOADICEA web interface that is now available for general use: http://ccge.medschl.cam.ac.uk/boadicea/ .

Supplementary Tables S1–S3 and figures S1 and S2 can be found at: http://carcin.oxfordjournals.org/.-- et al., BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germline mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with eleven 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 (WCL), 20 (ECL) and 6 families (SoS). Mutation age was estimated with the DMLE software in a range of 45-68 and 45-71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G>A, were located in a double-hairpin loop structure (c.2794-c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923-bp fragment of BRCA2 and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G>A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin-loop of c.2808_2811del, and one affected the same position (c.2808A>G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG and BRCA2-c.5946delT and c.8537delAG, are concentrated in hairpin-loops suggesting that these structures may represent mutational hotspots., Instituto de Salud Carlos III (PI10/2910 to E.A.V., ISCIIIRETIC: RD06/0020/1051 and PI10/01422 to L.F.); Junta de Castilla y León, Consejería de Educación (CSI004A10-2 to E.A.V.); Consejería de Sanidad (BIO39/VA27/10 to E.A.V.); Cancer Prevention Program of the Regional Government of Castilla y León; The European Social Fund and Consejería de Educación de la Junta de Castilla y León under the P.O. Castilla y León 2007–13 to A.A.; Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute, Government of Catalonia (2009SGR290 to L.F.); Spanish Association Against Cancer (to L.F.).

Breast reconstruction is an option for women with BRCA1 or BRCA2 mutations who elect to undergo prophylactic mastectomy to prevent breast cancer. We report on the uptake of breast reconstruction after prophylactic mastectomy in women with BRCA mutations from eight countries.Women with a BRCA1 or BRCA2 mutation were questioned regarding their cancer preventive practices. Information was recorded on prophylactic mastectomy and breast reconstruction.A total of 1,635 women with a BRCA1 or BRCA2 mutation who elected to undergo prophylactic mastectomy from eight countries were included. A total of 1,137 women (69.5%) had breast reconstruction after prophylactic mastectomy. A total of 58.7% of women over the age of 45 years at the time of prophylactic mastectomy had breast reconstruction compared to 77.6% of women 35 years of age or younger [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.26-0.50, p0.001]. In addition, 62.9% of women with a breast cancer diagnosis (contralateral prophylactic mastectomy) had breast reconstruction after prophylactic mastectomy compared to 79.7% of women without a previous breast cancer diagnosis (OR 0.48, 95% CI 0.38-0.61, p0.001). A total of 66.9% of women from Canada had breast reconstruction after mastectomy compared to 71.9% of American women (OR 0.75, 95% CI 0.59-0.96, p = 0.02).The majority of women elect for breast reconstruction after prophylactic mastectomy. However, younger women and those without a previous diagnosis of breast cancer are more likely to have breast reconstruction than older women or those with a previous diagnosis of cancer.

The frequency of BRCA1 and BRCA2 mutations is higher in Israel than in almost all other countries. One strategy to reduce the burden of hereditary breast and ovarian cancers is to offer genetic testing followed by risk-reducing surgery (mastectomy and salpingo-oophorectomy) for mutation carriers. The extent to which Israeli women who carry mutations undergo these surgeries is not well characterized. Israeli women who are BRCA1 or BRCA2 mutation carriers and followed at a single high-risk clinic were asked to complete a questionnaire detailing their clinical histories at the time of genetic results disclosure and a follow-up questionnaire was completed 18 or more months thereafter. A total of 205 mutation carriers completed the questionnaires. Of 170 women with no cancer history, 84 (49%) had a risk-reducing bilateral salpingo-oophorectomy and 22 (13%) had a risk-reducing mastectomy. Five of 35 (14.3%) women with breast cancer opted for contralateral mastectomy. Approximately one half of Israeli women with a BRCA1 or BRCA2 mutation opt for risk-reducing oophorectomy, but the rate of risk-reducing mastectomy is only 13%.

The main indication of prophylactic mastectomy pertains to BRCA1 or BRCA2 mutation carriers. Prophylactic mastectomy includes the simple method and the subcutaneous method. Both methods can be followed by breast plastic reconstruction either at the same time or later. This review examines key issues regarding prophylactic mastectomy: the selection of patients, its effectiveness, its limitations, convergence/divergence in existing guidelines, and future perspectives.

To prospectively assess the efficacy of bilateral risk-reducing mastectomy (BRRM) when compared with surveillance on breast cancer (BC) risk and mortality in healthy BRCA1 and BRCA2 mutation carriers.Five hundred and seventy healthy female mutation carriers (405 BRCA1, 165 BRCA2) were selected from the institutional Family Cancer Clinic database. Eventually, 156 BRCA1 and 56 BRCA2 mutation carriers underwent BRRM. The effect of BRRM versus surveillance was estimated using Cox models.During 2037 person-years of observation (PYO), 57 BC cases occurred in the surveillance group versus zero cases during 1379 PYO in the BRRM group (incidence rates, 28 and 0 per 1000 PYO, respectively). In the surveillance group, four women died of BC, while one woman in the BRRM group presented with metastatic BC 3.5 years after BRRM (no primary BC), and died afterward, yielding a HR of 0.29 (95% CI 0.02-2.61) for BC-specific mortality.In healthy BRCA1/2 mutation carriers, BRRM when compared with surveillance reduces BC risk substantially, while longer follow-up is warranted to confirm survival benefits.

Worldwide, more than one million women are diagnosed with breast cancer every year, making it the most common female malignancy in the developed world. Germline mutations in BRCA1 and BRCA2 genes are estimated to increase the risk for developing breast cancer by up to 87%. From a clinical point of view, identification of BRCA1 and BRCA2 mutation carriers offers an opportunity to early identify or prevent the development of malignancy; therefore the ability to determine which women are more likely to carry BRCA1 or BRCA2 mutations is of great importance. The available diagnostic tests for mutation analysis of BRCA1 and BRCA2 are time- and labor-intensive, expensive, and do not allow the identification of all the functional mutations. We utilized the Fluorescent lifetime (FLT) imaging microscopy method which allows recognizing different cell populations, in order to distinguish between lymphocytes from BRCA1 and BRCA2 mutation carriers and non-carrier women by using easily obtainable lymphocyte cells from peripheral blood. Our results demonstrate that cells originated from BRCA2-mutation carriers have significantly lower FLT values compared with BRCA1 mutation carriers and control cells. This simple, inexpensive and sensitive method may be utilized in the future to detect BRCA2 mutation carriers, particularly those bearing unknown functional mutations.

Patients with HER2-positive breast cancer and brain metastases have limited treatment options, and, as a result of their poor performance status and worse prognosis, they are underrepresented in clinical trials. Not surprisingly, these patients may not be fit enough to receive any active treatment and are offered supportive therapy. BRCA2 mutations are reported to be rarely associated with HER2-overexpressing advanced breast cancer and even more rarely with brain metastases at diagnosis. We report on a BRCA2-positive breast cancer patient with metastatic disease in multiple sites, including the brain, and poor performance status who exhibited an extraordinary clinical and imaging response to the novel anti-HER2 therapy pertuzumab after multiple lines of therapy including anti-HER2 targeting. To our knowledge, the clinicopathologic and therapeutic characteristics of this patient point to a unique case and an urgent need for further investigation of pertuzumab in patients with brain metastases.

Background Gastric cancer (GC) is part of the spectrum of diseases linked to BRCA1 and BRCA2 mutations that increase the risk of breast and ovarian cancer. Data suggesting an increased risk of developing GC among BRCA1 and BRCA2 mutation carriers are based almost exclusively on indirect studies. The objective was to assess in a direct study whether there is a relationship between GC and selected recurrent BRCA1 and BRCA2 mutations in the Polish population. Methods Three hundred seventeen GC patients (193 males and 124 females; mean age 59.5 ± 12.8 y) diagnosed at the Department of Gastroenterology at the Pomeranian Medical University were included in this retrospective study. All patients were genotyped for 3 BRCA1 Polish founder mutations (5382insC, C61G and 4153delA) as well as for 9 known recurrent mutations in BRCA1 and BRCA2 genes. Genotyping was performed using allele-specific oligonucleotide polymerase chain reaction (ASA-PCR) for 4153delA and 5382insC, restriction fragment length polymorphism (PCR-RFLP) for C61G and TaqMan real-time PCR for 185delAG, 3819del5, 3875del4, 5370C > T, 886delGT, 4075delGT, 5467insT, 6174delT and 8138del5. Results Among tested mutations one founder BRCA1 mutation 5382insC was detected in two of 317 (0.63 %) GC cases. A comparison of frequency of detected BRCA1 founder mutations in GC patients to previously described 4570 Polish controls (0.63 % vs. 0.48 %) failed to indicate an increased risk of GC in the mutation carriers (OR = 1.3; 95 % CI 0.3-5.6, p = 0.71). A comparison of frequency of GC male cases and male controls (1.0 % vs. 0.43 %,OR = 1.5; 95 % CI 0.3-6.4, p = 0.61) allowed to formulate the same conclusion that there is no increased risk for GC for males. None of the 9 recurrent BRCA1 and BRCA2 mutations has been detected in tested GC patients. Conclusion The current study indicates that founder BRCA1 mutations reported in Polish breast/ovarian cancer patients do not contribute to increased GC risk. The nine tested recurrent BRCA1 and BRCA2 mutations were not detected in GC patients which may suggests that they are rare in GC patients in the Polish population. Further analyses, including sequencing of entire sequences of BRCA1 and BRCA2 genes, are necessary to ultimately determine the role of these two genes in GC in Poland.

Purpose To compare breast cancer prognosis in BRCA1 and BRCA2 mutation carriers with that in patients with sporadic disease. Patients and Methods An international population-based cohort study was conducted in Canada, the United States, and Australia of 3,220 women with incident breast cancer diagnosed between 1995 and 2000 and observed prospectively. Ninety-three had BRCA1 mutations; 71, BRCA2 mutations; one, both mutations; 1,550, sporadic breast cancer; and 1,505, familial breast cancer (without known BRCA1 or BRCA2 mutation). Distant recurrence and death were analyzed. Results Mean age at diagnosis was 45.3 years; mean follow-up was 7.9 years. Risks of distant recurrence and death did not differ significantly between BRCA1 mutation carriers and those with sporadic disease in univariable and multivariable analyses. Risk of distant recurrence was higher for BRCA2 mutation carriers compared with those with sporadic disease in univariable analysis (hazard ratio [HR], 1.63; 95% CI, 1.02 to 2.60; P = .04). Risk of death was also higher in BRCA2 carriers in univariable analysis (HR, 1.81; 95% CI, 1.15 to 2.86; P = .01). After adjustment for age, tumor stage and grade, nodal status, hormone receptors, and year of diagnosis, no differences were observed for distant recurrence (HR, 1.00; 95% CI, 0.62 to 1.61; P = 1.00) or death (HR, 1.12; 95% CI, 0.70 to 1.79; P = .64). Conclusion Outcomes of BRCA1 mutation carriers were similar to those of patients with sporadic breast cancer. Worse outcomes in BRCA2 mutation carriers in univariable analysis seem to reflect the presence of more adverse tumor characteristics in these carriers. Similar outcomes were identified in BRCA2 carriers and those with sporadic disease in multivariable analyses.

The aim of this study is to delineate more clearly the prevalence of HER2+ breast cancer in women with germline BRCA1/2 mutations. For this purpose, we analysed primary mutation screens on women with breast cancer with unequivocal HER2 amplification and assessed the proportion of BRCA1 and BRCA2 breast cancers that were HER2+ comparing this with the existing literature. The results are that 1063 primary BRCA screens had confirmed tumour HER2 status. If HER2+ only 2.5 % (4/156) and 3.2 % (5/156) of women had a BRCA1 or BRCA2 mutation identified respectively; compared to 27.7 % (115/415) and 8.2 % (34/415) with triple negative tumours. Only 2.1 % (4/195) women with BRCA1-related breast cancer had HER2 amplified breast cancers rising to 6.8 % (n = 12, p = 0.04) in BRCA2. These rates are in keeping with most of the existing literature except a recent large multicenter report which documented higher rates but with no control group. The study concluded that true HER2-amplified breast cancers are rare amongst BRCA1 mutation carriers and are less common in BRCA2 than background rates.

Background: Germ-line mutations in the tumor suppressor gene BRCA2 (breast cancer 2, early onset) predispose carriers mostly to breast cancer, and BRCA2 mutation carriers also face a 2-fold increase in the risk of developing diabetes.Hyperglycemia, the hallmark of diabetes, is a major risk factor for endothelial dysfunction leading to vascular complications. The relationship linking role of BRCA2 in the development of diabetes and endothelial dysfunction remains mainly unexplored. Methods: To elucidate the role of BRCA2 in diabetes and endothelial apoptosis/dysfunction in vitro, we silenced BRCA2 in human umbilical vein endothelial cells (ECs) and evaluated the markers of EC function and apoptosis following hyperglycemia. Results: We first confirmed the basal expression of BRCA2 in ECs at transcript and protein levels by qPCR and immunoblotting, respectively. Interestingly, hyperglycemia significantly induced BRCA2 expression after 48 hours of treatment. We then silenced BRCA2 in ECs and confirmed successful silencing at transcript and protein levels. Hyperglycemia significantly increased the reactive oxygen species (ROS) production in the BRCA2-deficient ECs in comparison to control ECs. Increased ROS production was associated with exacerbated DNA-damage in BRCA2-silenced ECs as evidenced by increased expression and activation of DNA double-stranded breaks (DSBs) marker H2A.X and reduced RAD51-foci formation, an essential regulator of DSB repair. Increased DSBs were associated with significantly increased activation of p53. Elevated levels of DNA-damage and activated-p53 were further associated with significantly increased hyperglycemia-induced apoptosis in BRCA2-silenced ECs as measured by immunoblotting for cleaved-caspase-3, Bax and by TUNEL-staining.Key indices of endothelial function, including tube formation and NO production, were significantly reduced following hyperglycemia-treatment in BRCA2-deficient ECs. Conclusion: Our data for the first time, show an entirely novel role of BRCA2 as a regulator of endothelium in the setting of hyperglycemia, and provide important clues regarding the potential susceptibility of BRCA2 mutation carriers to hyperglycemia-induced cardiovascular complications.

This abstract was withdrawn by the authors.

Background: BRCA2 carriers typically develop luminal B-type breast cancers. Their exact sensitivity to conventional chemotherapy remains unclear. Promising drugs such as parp inhibitors are currently being developed in this indication. We attempted to evaluate pathological response rates of BRCA2 carriers in current the routine setting. Patients and methods: we screened our database of all patients seen at our genetic clinic over the past 15 years who were completely tested for BRCA1 and BRCA2 mutation and had received primary anthracyclines/taxanes-based chemotherapy (6-8 cycles) for invasive breast cancer as primary care. The pathological responses of pts who tested positive for BRCA2 were compared to those of BRCA1 and BRCA2-negative patients who had been diagnosed with luminal breast cancer (ER-positive, Her2-negative). Results: Among 155 BRCA2-carriers and 503 wild-type patients, 24 BRCA2 pts and 58 pts with luminal B-type breast cancer have received primary standard anthracyclin/taxane-based chemotherapy. Median age was 38 for both populations. Median tumor size was 45 and 40 mm respectively among carriers and WT pts. 60% of BRCA2 and 100% of WT luminal B pts had ER-positive disease. A pathological complete response occurred in 18% of BRCA2 carriers and of 39% of luminal B Wt-pts. 65% of BRCA2 and 51% of WT-pts pts remained node-positive. Conclusion: Deleterious germline mutations of BRCA2 are associated with a low probability of complete pathological response and a high risk of axillary invasion after conventional primary chemotherapy. Alternative treatments are highly expected. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-16.

Background In view of the increased risk of developing breast (BC) cancer, BRCA mutation carriers are offered intensive surveillance or risk reducing mastectomy (RRM) and/or salpingo-ovariectomy (RRSO). It is insufficiently clear how to counsel mutation carriers who have been treated for OC, and it may be questioned whether RRM is indicated. It is possible that BC risk, both of primary (PBC) and contralateral BC (CBC), may be modified by the treatment given for OC mostly including surgery and platinum-based chemotherapy. Further, the BC risk has to be weighted against the risk of death after OC. So far, there are no data available on the PBC or CBC risk after OC in BRCA mutation carriers. Patients and Methods From the database of the institutional Family Cancer Clinic (FCC), we selected BRCA-associated OC patients either without (n= 79, at risk of PBC) or with a history of unilateral BC (n=37, at risk of CBC). Controls were BRCA mutation carriers without OC, either without (n=351) or with a history of unilateral BC (n=294). Follow-up started at OC diagnosis, and for controls at date of first visit at the FCC or the 35th birthday. Exclusion criteria were: other malignancy besides epithelial OC or BC, inadequate follow-up data, bilateral breast cancer or mastectomy. Data analyses were performed using t- and chi-squared tests, and Kaplan-Meier survival method with death prior to BC as competing risk event. Results Only six OC patients (5.1%) did not receive chemotherapy as part of primary therapy for OC, five at risk of PBC and one at risk of CBC. Chemotherapy schedules were mainly platinum-based (92%). RRSO was performed in 45% of the controls. The risks of PBC at 2, 5, and 10 years in BRCA-associated OC patients were 3%, 6% and 11%, respectively, versus 6%, 16% and 28% in unaffected BRCA mutation carriers (p=0.03). The mortality rate at those time points in the OC group was 13%, 33% and 61%, respectively, versus 1%, 2% and 2% in unaffected mutation carriers (p In patients with a history of unilateral BC, the risks of CBC at 2, 5, and 10 years in OC patients were 0%, 7% and 7%, respectively, versus 6%, 16% and 34% in the BC patients without OC (p=0.06). The mortality rate at similar time points was 19%, 34%, and 55%, respectively, in the OC group versus 4%, 11%, and 21% for the non-OC patients (p Conclusions The risk of developing a PBC or CBC was much lower in BRCA mutation carriers with a history of OC than in mutation carriers without OC. Also, since the 10-year mortality rate after ovarian cancer was 55–60% and the risk of developing a PBC or CBC at the highest was 11% over the same time period, our data suggest that intensive breast cancer surveillance strategies for the BRCA-associated ovarian cancer group might be reconsidered, while risk reducing mastectomy is not indicated unless in specific cases requiring careful consideration in a multisciplinary setting. Further studies in larger groups are warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-04.

There is evidence that tamoxifen treatment ofBRCA1andBRCA2carriers for prior breast cancer increases risk of endometrioid subtype endometrial cancer (EC), and suggestive evidence thatBRCA1andBRCA2mutation carriers may be predisposed to EC in the absence of tamoxifen exposure. We assessed the association of EC withBRCA1orBRCA2mutation status in Australasian breast-ovarian families. Report of at least one case of EC was significantly greater inBRCA1-positive families (35/218 (16%); p = .03) and non-significantly greater inBRCA2-positive families (23/189 (12%); p = .6), compared to high-risk breast cancer families without aBRCA1/2mutation (86/796 (11%)). EC was the first/concurrent cancer for 41% of EC cases with multiple cancer diagnoses fromBRCA1/2families, and early onset for most of these diagnoses. Mutation status was imputed for ungeno-typed individuals from 57BRCA1/2pedigrees reporting EC using BRCAPRO. Effects of genotype on EC diagnosis age, and interaction with tamoxifen therapy, were assessed using Cox proportional hazards regression analysis. EC risk was non-significantly marginally greater forBRCA1carriers (hazard ratio = 1.25, 95%CI = 0.65–2.41), andBRCA2carriers (HR = 1.12, 95%CI = 0.51–2.45), compared to non-carrier family members. Tamoxifen therapy was highly significantly associated with EC (HR = 6.68, 95%CI = 3.12–15.15; p = 1.7 x 10-6) inBRCA1/2families, with no evidence for interaction between tamoxifen therapy andBRCA1/2genotype. Our family-based study supports a 7-fold increase in EC risk with tamoxifen exposure for female family members fromBRCA1/2families. Early onset EC in carriers without tamoxifen use suggests that further study is required to assess association of modest EC risk withBRCA1/2mutation status alone.

Alcohol consumption increases the risk of breast cancer among women in the general population, but its effect on women who carry a BRCA gene mutation is unclear. We conducted a case-control study of 1925 matched pairs of predominantly premenopausal women who carry a BRCA1 or a BRCA2 mutation. Information on current alcohol consumption was obtained from a questionnaire administered during the course of genetic counselling or at the time of enrollment. A modest inverse association between breast cancer and reported current alcohol consumption was observed among women with a BRCA1 mutation (OR = 0.82, 95% CI 0.70-0.96), but not among women with a BRCA2 mutation (OR = 1.00; 95% CI 0.71-1.41). Compared to non-drinkers, exclusive consumption of wine was associated with a significant reduction in the risk of breast cancer among BRCA1 carriers (p-trend = 0.01). Alcohol consumption does not appear to increase breast cancer risk in women carrying a BRCA gene mutation.

Germline BRCA2 mutations in female carriers confer a cumulative breast cancer risk at age 70 years of 49% (95% CI: 40–57%), an ovarian cancer risk of 18% (95% CI: 13–23%), and a moderate increased risk of pancreatic cancer (Chen and Parmigiani, 2007). Although the available evidence is not sufficient to decisively conclude that the clinical outcome of women with BRCA1/2-associated breast cancer differs significantly from those of women with sporadic tumours, BRCA1-associated breast cancer often manifests adverse outcome features. Establishment of pre-clinical models, which accurately reflect the genetic and phenotypic features of primary tumours, and their response to treatment, is an important step in identifying novel therapeutic targets and testing new treatment modalities. New strategies may take advantage of the specific DNA repair defects inherent in BRCA-deficient cells, such as the defect in homologous recombination. In fact, most of the insights into the functions of the BRCA2 protein have included key insights from studies of mice by the use of gene targeting and from studies of altered mouse embryonic cells (Evers and Jonkers, 2006). BRCA2 has a key role in DNA double-strand break repair and cell-cycle control. BRCA2-related defects are associated with chromosomal abnormalities, a hallmark of the genomic instability that could foster tumourigenesis. Moreover, BRCA2 participates in the regulation of mitosis and cytokinesis that contribute to numerical chromosomal stability. Although conventional, non-conditional, mouse mutants might be used to model familial forms of cancer, they do not mimic sporadic tumourigenesis because the initiating mutation is present in all cells of the body, including those that constitute the tumour microenvironment. Moreover, embryonic lethality and development of non-epithelial tumours are another important limitation of genetically mutated Brca2 mice. Some murine Brca2 mutant mammary tumour models develop mammary tumours with histopathological features that are significantly different to their human counterparts. Although some studies report a strikingly similar histopathology in BRCA1 null breast tumours from mice and humans (Dennis, 1999; Xu et al, 1999), their relevance to the human situation remains to be demonstrated. The most used human BRCA2-mutated model is the CAPAN1 pancreatic cell line that is mainly used to understand drug resistance in BRCA1/2 mutation carrier, as well as in defining functionally important domains within BRCA2 (Edwards et al, 2008). To date, only one BRCA2-mutated breast cancer xenografts (MX1) is available, (Donawho et al, 2007) but its characterisation has not been described in detail. Genetic testing to identify BRCA1/2 mutations is widely available and commonly employed. As a result, increasing numbers of women are aware that they are mutation carriers at the time of their cancer diagnosis. Unfortunately, current knowledge is not sufficient to mandate specific local or systemic treatments that are tailored to BRCA1/2 mutation carriers. In fact, the available studies examining the issue of whether BRCA1/2-associated breast cancer should be treated differently from sporadically occurring, non-familial disease are almost exclusively retrospective and limited by small size and various ascertainment biases. Recently, inhibitors of the DNA repair proteins, poly(ADP-ribose) polymerase 1 and 2 (PARP1/2), have been shown to be selectively cytotoxic to tumour cells with BRCA1 or BRCA2 deficiency. Preclinical data, including that generated with a limited array of tumour cell line xenografts, suggest that PARP inhibitors can act as single agents to selectively kill cancers with BRCA1 or BRCA2 mutations, and phase I clinical trial results confirm that PARP inhibitors have some single-agent activity in cancers with BRCA1/2 mutations (Fong et al, 2009). However, little is known about the long-term effects of these drugs and it seems likely that some tumours may have de novo resistance or acquired resistance (Ashworth, 2008). Thus, definitive answers remain elusive, and preclinical evaluation of new targeted therapy is limited by the lack of suitable preclinical models (Robson, 2007a). Here, we report the establishment and characterisation of a novel xenograft, human breast cancer xenograft (HBCx-17) established from a breast cancer in a woman carrying a BRCA2 germline mutation. We show that this xenograft accurately reflects the genetic and the phenotypic features of the primary tumour, thus providing a new model to test new therapies for BRCA2-mutated patients.

e13528Background: Facing an increased lifetime risk of breast and ovarian cancer, unaffected BRCA1 and BRCA2 mutation carriers receive genetic counseling regarding National Comprehensive Cancer Net...

Purpose Li-Fraumeni syndrome (LFS) is a hereditary cancer syndrome, characterized by a high risk of developing cancer at various sites and ages. To date, limited clinical benefits of genetic testing for LFS have been demonstrated, and there are concerns about the potential adverse psychosocial impact of genetic testing for LFS. In this study, we evaluated the uptake of genetic testing and the psychosocial impact of undergoing or not undergoing a genetic test for LFS. Patients and Methods In total, 18 families with a p53 germline mutation in the Netherlands were identified. Eligible family members were invited to complete a self-report questionnaire assessing motives for undergoing or not undergoing genetic testing, LFS-related distress and worries, and health-related quality of life. Results Uptake of presymptomatic testing was 55% (65 of 119). Of the total group, 23% reported clinically relevant levels of LFS-related distress. Carriers were not significantly more distressed than noncarriers or than those with a 50% risk who did not undergo genetic testing. Those with a lack of social support were more prone to report clinically relevant levels of distress (odds ratio, 1.3; 95% CI, 1.0 to 1.5). Conclusion Although preventive and treatment options for LFS are limited, more than half of the family members from known LFS families choose to undergo presymptomatic testing. An unfavorable genetic test result, in general, does not cause adverse psychological effects. Nonetheless, it is important to note that a substantial proportion of individuals, irrespective of their carrier status, exhibit clinically relevant levels of distress which warrant psychological support.

Integrins containing the beta(3) subunit are key players in tumor growth and metastasis. A functional Leu33Pro polymorphism (rs5918) in the beta(3) subunit of the integrin gene (ITGB3) has previously been suggested to act as a modifier of ovarian cancer risk in Polish BRCA1 mutation carriers. To investigate the association further, we genotyped 9,998 BRCA1 and 5,544 BRCA2 mutation carriers from 34 studies from the Consortium of Investigators of Modifiers of BRCA1/2 for the ITGB3 Leu33Pro polymorphism. Data were analysed within a Cox-proportional hazards framework using a retrospective likelihood approach. There was marginal evidence that the ITGB3 polymorphism was associated with an increased risk of ovarian cancer for BRCA1 mutation carriers (per-allele Hazard Ratio (HR) 1.11, 95% CI 1.00-1.23, p-trend 0.05). However, when the original Polish study was excluded from the analysis, the polymorphism was no longer significantly associated with ovarian cancer risk (HR 1.07, 95% CI 0.96-1.19, p-trend 0.25). There was no evidence of an association with ovarian cancer risk for BRCA2 mutation carriers (HR 1.09, 95% CI 0.89-1.32). The polymorphism was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers. The ITGB3 Leu33Pro polymorphism does not modify breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

Objective The aim of the study is to explore the reliability of the high resolution melting (HRM) analysis for the identification of BRCA1/BRCA2 mutation carriers among the family members of index patient (IP) and for distinguishing the presence of two or more genetic variants within the same amplicon. Design and methods We studied 27 different BRCA1/BRCA2 pathogenic mutations detected in 35 families with 194 subjects. HRM was performed in the LightCycler 480 (Roche). Results HRM method detected 110 BRCA1/BRCA2 mutations among the 192 relatives studied (57%). No false negative results were observed in any of the family members and all of them were in agreement with sequencing analysis, therefore the method might help to avoid unnecessary sequencing of wild type (WT) genotypes. The HRM method also allows the detection of other alterations that we initially had not searched (three unclassified variants and several polymorphisms). Furthermore, HRM has also been capable of distinguishing the presence of two or more genetic variants in the same amplicon of the same sample. Conclusions HRM is a rapid, sensitive, specific, cost-effective and reliable screening method that in less than 2 h allows the easy identification of BRCA1 and BRCA2 genetic variations and also avoids the unnecessary sequencing of WT genotypes. Furthermore the method is also capable of detecting new genetic variants and allows the simultaneous detection of the presence of more than one genetic variant.

We present a case of dramatic response of poor prognosis cancer in a lady with a germline mutation in the BRCA2 gene who was exposed to platinum containing chemotherapy. She is cancer-free 10 years' later. Such cases provide clinical scenarios for the basis of trials of platinum-like agents in individuals with BRCA mutations who develop cancer.

The close functional relationship between p53 and the breast cancer susceptibility genes BRCA1 and BRCA2 has promoted the investigation of various polymorphisms in the p53 gene as possible risk modifiers in BRCA1/2 mutation carriers. Specifically, two polymorphisms in p53, c.97-147ins16bp and p.Arg72Pro have been analysed as putative breast cancer susceptibility variants, and it has been recently reported that a p53 haplotype combining the absence of the 16-bp insertion and the presence of proline at codon 72 (No Ins-72Pro) was associated with an earlier age at the onset of the first primary tumour in BRCA2 mutation carriers in the Spanish population. In this study, we have evaluated this association in a series of 2932 BRCA1/2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.

In this study 759 breast cancer patients, including 9 BRCA1 and 98 BRCA2 mutation carriers, and 653 mutation-negative unaffected controls were genotyped for the AURKA 91T → A polymorphism. Individuals homozygous for the 91A allele were found to be at increased risk of breast cancer compared to 91T homozygotes (OR = 1.87; 95% CI = 1.09–3.21). This association was strengthened when cases carrying BRCA mutations were excluded (OR = 2.00; 95% CI = 1.15–3.47). BRCA carrier cases differed from sporadic cases and their allele distribution was very similar to controls. These results show a statistically significant increased risk of sporadic breast cancer for individuals that are homozygous for the 91A allele but no effect in carriers of BRCA mutations. This may throw light on previously conflicting results.

Potential interaction of Aurora-A amplification and BRCA2 mutation was examined in breast tumours from BRCA2 999del5 mutation carriers (n = 20) and non-carriers (n = 41). Aurora-A amplification studied by FISH was significantly more common in breast tumours from BRCA2 mutation carriers (p = 0.0005). Extensive Aurora-A amplification was also detected on metaphase chromosomes in three breast epithelial cell lines with the same BRCA2 mutation. In addition, significant association was found between Aurora-A amplification and TP53 mutations in non-BRCA2 mutation carrier tumours (p = 0.007). These results suggest that breast tumours with mutations in BRCA2 or TP53 could be promising candidates for Aurora-A targeted treatment.

Ten years after the identification of the breast and ovarian cancer predisposition genes, BRCA1 and BRCA2, an emerging literature has explored the efficacy of strategies for primary as well as secondary prevention of breast and ovarian cancer in BRCA1 and BRCA2 mutations carriers. The integration of magnetic resonance imaging for breast cancer screening in BRCA carriers has achieved a higher sensibility of the screening, and an early detection of breast cancer. However, we don't have yet enough level of evidence that magnetic resonance imaging could reduce mortality in BRCA carriers. Because of the limitations of screening for ovarian cancer, bilateral prophylactic salpingo-oophorectomy has been established as one of the most effective strategies to prevent ovarian cancer in BRCA1 and BRCA2 mutation carriers. This strategy also has a favorable effect on the reduction of risk of breast cancer if is performed before the age of 50. The management of this patients must be individualized and multidisciplinary.