Germline BRCA1 mutations increase prostate cancer risk

Background:

Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set.

Methods:

We screened 913 cases aged 36–86 years for germline BRCA1 mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the BRCA1 gene using Sanger sequencing. Multiplex ligation-dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases.

Results:

We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious BRCA1 mutation in this study is 0.45% three of the mutation carriers were affected at age ⩽65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious BRCA1 mutations confer a relative risk of PrCa of ∼3.75-fold, (95% confidence interval 1.02–9.6) translating to a 8.6% cumulative risk by age 65.

Conclusion

This study shows evidence for an increased risk of PrCa in men who harbour germline mutations in BRCA1. This could have a significant impact on possible screening strategies and targeted treatments.     

BRCAPRO 6.0 Model Validation in Male Patients Presenting for BRCA Testing

Background.

BRCAPRO is a risk assessment model to estimate the risk of carrying a BRCA mutation. BRCA mutation carriers are at higher risk of developing breast, ovarian, pancreatic, and prostate cancer. BRCAPRO was developed for women and found to be superior to other risk assessment models. The present study evaluated the validity of BRCAPRO at predicting the risk of male patients carrying a BRCA mutation.

Patients and Methods.

A total of 146 men who presented for genetic counseling and testing from February1997 to September 2011, and their test results were included in the present study. BRCAPRO risk assessment for all patients was calculated using the BRCAPRO clinical CancerGene assessment software.

Results.

The mean age at presentation was 57 years. Of the 146 patients, 48 had breast cancer, 18 had pancreatic cancer, 39 had prostate cancer, 27 had other primary cancers, and 37 had no cancer. Fifty patients (34%) tested positive for a BRCA mutation (22 BRCA1, 27 BRCA2, and 1 BRCA1 and BRCA2). The mean BRCAPRO score for all patients was 24.96%. The BRCAPRO score was significantly higher for patients who tested positive for a BRCA mutation (46.19% vs. 13.9%, p < .01). The area under the receiver operating characteristics curve was 0.83 for all patients for the BRCAPRO score to predict the risk of carrying a BRCA mutation. At a cutoff point of 30.02%, the sensitivity, specificity, positive predictive value, and negative predictive value were 0.74, 0.81, 0.67, and 0.86, respectively.

Conclusion.

BRCAPRO appears to be a valid risk assessment tool for determining the risk of carrying a BRCA mutation in men.

Implications for Practice:

Men carrying genetic mutations in the BRCA gene have a greater risk than the general population of developing certain types of cancer, including breast, pancreatic, and prostate cancer. BRCAPRO is a risk assessment model that predicts the risk of carrying a BRCA mutation. The present study aimed at validating BRCAPRO for use with men seen for genetic counseling, whether affected by cancer or not. The data available for 146 patients revealed that BRCAPRO was effective at identifying patients at risk of BRCA mutation. These findings could help in identifying a subset of high-risk patients who should proceed to genetic testing.     

A prior diagnosis of breast cancer is a risk factor for breast cancer in BRCA1 and BRCA2 carriers

Background

The risk of breast cancer in carriers of BRCA1 and BRCA2 mutations is influenced by factors other than the genetic mutation itself. Modifying factors include a woman’s reproductive history and family history of cancer. Risk factors are more likely to be present in women with breast cancer than in women without breast cancer, and therefore the risk of cancer in the two breasts should not be independent. It is not clear to what extent modifying factors influence the risk of a first primary or a contralateral breast cancer in BRCA carriers.

Methods

We conducted a matched case–control study of breast cancer among 3920 BRCA1 or BRCA2 mutation carriers. We asked whether a past history of breast cancer in the contralateral breast was a risk factor for breast cancer.

Results

After adjustment for age, country of residence, and cancer treatment, a previous cancer of the right breast was found to be a significant risk factor for cancer of the left breast among BRCA1 or BRCA2 carriers (relative risk: 2.1; 95% confidence interval: 1.4 to 3.0; p < 0.0001).

Conclusions

In a woman with a BRCA1 or BRCA2 mutation who is diagnosed with breast cancer, the risk of cancer in the contralateral breast depends on the first diagnosis. That observation supports the hypothesis that there are important genetic or non-genetic modifiers of cancer risk in BRCA carriers. Discovering risk modifiers might lead to greater personalization of risk assessment and management recommendations for BRCA-positive patients.     

Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers

Purpose:

The objective of this study was to estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers; and measure the extent to which host, family history, and cancer treatment-related factors modify the risk.

Patients and methods:

Patients were 810 women, with stage I or II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up.

Results:

Overall, 149 subjects (18.4%) developed a contralateral breast cancer. The 15-year actuarial risk of contralateral breast cancer was 36.1% for women with a BRCA1 mutation and was 28.5% for women with a BRCA2 mutation. Women younger than 50 years of age at the time of breast cancer diagnosis were significantly more likely to develop a contralateral breast cancer at 15 years, compared with those older than 50 years (37.6 vs 16.8% P=0.003). Women aged <50 years with two or more first-degree relatives with early-onset breast cancer were at high risk of contralateral breast cancer, compared with women with fewer, or no first-degree relatives with breast cancer (50 vs 36% P=0.005). The risk of contralateral breast cancer was reduced with oophorectomy (RR 0.47; 95% CI 0.30–0.76; P=0.002).

Conclusion:

The risk of contralateral breast cancer risk in BRCA mutation carriers declines with the age of diagnosis and increases with the number of first-degree relatives affected with breast cancer. Oophorectomy reduces the risk of contralateral breast cancer in young women with a BRCA mutation.     

Associations between BRCA Mutations in High-Risk Breast Cancer Patients and Familial Cancers Other than Breast or Ovary

Purpose

We investigated the relationship between BRCA mutations and the distribution of familial cancers other than breast or ovary in high-risk breast cancer patients.

Methods

Patients with breast cancer who had at least one of the following risk factors were enrolled: reported family history of breast or ovarian cancer; 40 years of age or younger age at diagnosis; bilateral breast cancer; or male gender. Genetic testing for BRCA mutation and questionnaires about personal and family histories of malignancies were performed.

Results

Among the 238 eligible patients, 49 (20.6%) patients had BRCA1/2 mutations, which were more frequent in patients with multiple risk factors (p<0.0001). There were 271 members of 156 (65.5%) families who had histories of other primary cancer. The distribution of the families was 119 (63.0%) and 37 (75.5%) in the BRCA-negative and positive group, respectively (p=0.0996). Multiple familial cancers occurred in 70 families, which were significantly more frequent in BRCA-positive families (p=0.0034). By ordinal logistic regression, the occurrence of multiple familial cancers was associated with BRCA mutations (p=0.0045), not with other risk factors. The most common site of disease was the stomach, which is the most common in nationwide. And the proportional incidence of pancreatic cancer (6.8%) was significantly higher than that of nationwide cancer statistics (2.4%, p=0.0137).

Conclusion

BRCA mutations in high-risk breast cancer patients were associated with multiple risk factors and multiple family members with other primary cancers. Genetic counseling based on accurate information should be provided to families with BRCA mutation carriers.     

Characteristics of BRCA1/2 Mutation-Positive Breast Cancers in Korea: A Comparison Study Based on Multicenter Data and the Korean Breast Cancer Registry

Purpose

Mutations in BRCA genes are the main cause of hereditary breast cancer in Korea. The aim of this study was to investigate the characteristics of breast cancers involving BRCA1 (BRCA1 group) and BRCA2 (BRCA2 group) mutations.

Methods

We retrospectively reviewed the medical records of patients with BRCA1 (BRCA1 group) or BRCA2 (BRCA2 group) mutation positive breast cancer from multiple centers and compared the data to that of the Korean Breast Cancer Society registry (registry group).

Results

The patients of the BRCA1 group were diagnosed at a younger age (median age, 37 years) and had tumors of higher histological (61.3% with histological grade 3) and nuclear (37.5% with nuclear grade 3) grade than those of the registry group. In addition, the frequency of ductal carcinoma in situ in the BRCA1 group was lower (3.7%) than in the registry group, and the BRCA1 group were more likely to be triple-negative breast cancer (61.3%). Patients in the BRCA2 group were also younger at diagnosis (mean age, 41 years) and were more likely to have involvement of the axillary node than the registry group (45.5% vs. 33.5%, p=0.002). The BRCA1 and BRCA2 groups did not show a correlation between tumor size and axillary node involvement.

Conclusion

We report the characteristics of BRCA mutation positive breast cancer patients in the Korean population through multicenter data and nation-wide breast cancer registry study. However, BRCA-mutated breast cancers appear highly complex, and further research on their molecular basis is needed in Korea.     

Long-term results of screening with magnetic resonance imaging in women with BRCA mutations

Background:

The addition of breast magnetic resonance imaging (MRI) to screening mammography for women with BRCA mutations significantly increases sensitivity, but there is little data on clinical outcomes. We report screening performance, cancer stage, distant recurrence rate, and breast cancer-specific mortality in our screening study.

Methods:

From 1997 to 2009, 496 women aged 25 to 65 years with a known BRCA1/2 mutation, of whom 380 had no previous cancer history, were enrolled in a prospective screening trial that included annual MRI and mammography.

Results:

In 1847 screening rounds, 57 cancers were identified (53 screen-detected, 1 interval, and 3 incidental at prophylactic mastectomy), of which 37 (65%) were invasive. Sensitivity of MRI vs mammography was 86% vs 19% over the entire study period (P<0.0001), but was 74% vs 35% from 1997 to 2002 (P=0.02) and 94% vs 9% from 2003 to 2009 (P<0.0001), respectively. The relative sensitivities of MRI and mammography did not differ by mutation, age, or invasive vs non-invasive disease. Of the incident cancers, 97% were Stage 0 or 1. Of 28 previously unaffected women diagnosed with invasive cancer, 1 BRCA1 mutation carrier died following relapse of a 3 cm, node-positive breast cancer diagnosed on her first screen at age 48 (annual breast cancer mortality rate=0.5%). Three patients died of other causes. None of the 24 survivors has had a distant recurrence at a median follow-up of 8.4 years since diagnosis.

Conclusion:

Magnetic resonance imaging surveillance of women with BRCA1/2 mutations will detect the majority of breast cancers at a very early stage. The absence of distant recurrences of incident cancers to date is encouraging. However, longer follow-up is needed to confirm the safety of breast surveillance.     

The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study

Introduction

While it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations.

Methods

A retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status.

Results

The cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95%CI, 37.6% to 50.6%) for patients from BRCA1 positive families, 33.5% (95%CI, 22.4% to 44.7%) for patients from BRCA2 positive families and 17.2% (95%CI, 14.5% to 19.9%) for patients from families that tested negative for BRCA1/2 mutations. Younger age at first breast cancer was associated with a higher risk of contralateral breast cancer. For women who had their first breast cancer before the age of 40 years, the cumulative risk of contralateral breast cancer after 25 years was 55.1% for BRCA1, 38.4% for BRCA2, and 28.4% for patients from BRCA1/2 negative families. If the first breast cancer was diagnosed at the age of 50 or later, 25-year cumulative risks were 21.6% for BRCA1, 15.5% for BRCA2, and 12.9% for BRCA1/2 negative families.

Conclusions

Contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations is similar to the risk in patients with sporadic breast cancer. Thus, the mutation status should guide decision making for contralateral mastectomy.     

Contribution of BRCA1 germ-line mutations to breast cancer in Greece: a hospital-based study of 987 unselected breast cancer cases

Background:

In most Western populations, 5–10% of all breast cancer cases can be attributed to major genetic factors such as predisposing mutations in BRCA1 and BRCA2, with early-onset cases generally considered as an indicator of genetic susceptibility. Specific BRCA1 and BRCA2 mutations or different mutation frequencies have been identified in specific populations and ethnic groups. Previous studies in Greek breast and/or ovarian cancer patients with family history have shown that four specific BRCA1 mutations, c.5266dupC, G1738R, and two large genomic rearrangements involving deletions of exons 20 and 24, have a prominent function in the population''s BRCA1 and BRCA2 mutation spectrum.

Methods:

To estimate the frequency of the above mutations in unselected Greek breast cancer women, we screened 987 unselected cases independently of their family history, collected from major Greek hospitals.RESULTS: Of the 987 patients, 26 (2.6%) were found to carry one of the above mutations in the BRCA1 gene: 13 carried the c.5266dupC mutation (1.3%), 6 carried the exon 24 deletion (0.6%), 3 carried the exon 20 deletion (0.3%), and 4 carried the G1738R mutation (0.4%). Among 140 patients with early-onset breast cancer (<40 years), 14 carried one of the four mutations (10.0%).

Conclusion:

These results suggest that a low-cost genetic screening for only the four prominent BRCA1 mutations may be advisable to all early-onset breast cancer patients of Greek origin.     

Association between BRCA Mutation Status,Pathological Findings,and Magnetic Resonance Imaging Features in Patients with Breast Cancer at Risk for the Mutation

Purpose

We investigated the relationship between BRCA mutations, pathological findings, and magnetic resonance imaging (MRI) features in patients with breast cancer at risk for the mutation.

Methods

Genetic testing for BRCA mutations was performed in 275 breast cancer patients with at least one risk factor for the mutation. Using the breast imaging reporting and data system MR lexicon, morphological and kinetic features were reviewed on MRI scans of 230 tumors in 209 patients. The relationship between BRCA mutations, pathologic findings, and MRI data was examined, and disease recurrence was estimated.

Results

BRCA mutations were detected in 48 patients (23.0%), of which 21 (10.0%) were in BRCA1, and 25 (12.0%) in BRCA2. Additionally, two patients (1.0%) had mutations in both genes. Cancers in patients with BRCA1 mutations more frequently showed a higher nuclear grade (p=0.0041), and triple-negative (TN) phenotype (p<0.0001). On MRI scans, the cancers were seen as mass-type in 182 out of 230 lesions (79.1%), and nonmass type in 48 cases (20.9%). Among the features indentified by MRI, rim enhancement was significantly associated with molecular subtypes based on immunohistochemistry (p<0.0001), and nuclear grade (p=0.0387) in multiple logistic regression analysis. Rim enhancement on MRI, along with advanced pathologic N stage, was associated with increased disease recurrence (p=0.0023) based on multivariate analysis. However, the proportion of mass and nonmass tumors, and the distribution of morphological shape, margin, internal enhancement, and kinetic features assessed by MRI were not different according to BRCA mutation status.

Conclusion

BRCA1 mutations were associated with aggressive pathological characteristics, and the TN phenotype. Rim enhancement was frequently seen on MRI scans of high-grade cancers and in the TN phenotype. And it was a significant predictor of disease recurrence. However, a direct association with BRCA mutations was not observed.     

Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study

Background:

The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes.

Methods:

We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person–years at risk by the appropriate age-, sex- and country-specific incidence rates from the five countries.

Results:

Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54–1.40, P=0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30–1.81, P=0.7). The SIR for colon cancer was 3.81 (95% CI 1.77–7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33–1.00) for women aged 50 years and above.

Conclusion:

The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.     

Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy

Introduction

BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2-mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy.

Methods

Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-like^CGH status, others as non-BCRA-like^CGH. Stage-III patients (n = 249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE₉₀C) chemotherapy.

Results

Among patients with BRCA-like^CGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE₉₀C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-like^CGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P = 0.004). Half of all BRCA-like^CGH tumors were ER-positive.

Conclusions

Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-like^CGH patients) and those without benefit (non-BRCA-like^CGH patients).     

BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years

Background:

Triple-negative (TN) tumours are the predominant breast cancer subtype in BRCA1 mutation carriers. Recently, it was proposed that all individuals below 50 years of age with TN breast cancer should be offered BRCA testing. We have evaluated the BRCA1 mutation frequency and the implications for clinical practice of undertaking genetic testing in women with TN breast cancer.

Methods:

We undertook BRCA1 mutation analysis in 308 individuals with TN breast cancer, 159 individuals from unselected series of breast cancer and 149 individuals from series ascertained on the basis of young age and/or family history.

Results:

BRCA1 mutations were present in 45 out of 308 individuals. Individuals with TN cancer <50 years had >10% likelihood of carrying a BRCA1 mutation in both the unselected (11 out of 58, 19%) and selected (26 out of 111, 23%) series. However, over a third would not have been offered testing using existing criteria. We estimate that testing all individuals with TN breast cancer <50 years would generate an extra 1200 tests annually in England.

Conclusion:

Women with TN breast cancer diagnosed below 50 years have >10% likelihood of carrying a BRCA1 mutation and are therefore eligible for testing in most centres. However, implementation may place short-term logistical and financial burdens on genetic services.     

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Background:

In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.

Methods:

We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.

Results:

We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers.

Conclusion:

This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.     

The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers

Background:

Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation.

Methods:

We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases.

Results:

Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03–5.31, P=0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36–7.03, P=0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family.

Conclusion:

The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies.     

An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions

Background.

BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA-associated cancers have been shown to have greater sensitivity to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA-associated PAC have not been reported.

Methods.

Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center.

Results.

Fifteen patients, five male, with a BRCA1 (n = 4) or BRCA2 (n = 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum-based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response.

Conclusion.

BRCA mutation–associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC.     

Triple-negative breast cancer and PTEN (phosphatase and tensin homologue)loss are predictors of BRCA1 germline mutations in women with early-onset and familial breast cancer,but not in women with isolated late-onset breast cancer

Introduction

Given that breast cancers in germline BRCA1 carriers are predominantly estrogen-negative and triple-negative, it has been suggested that women diagnosed with triple-negative breast cancer (TNBC) younger than 50 years should be offered BRCA1 testing, regardless of family cancer characteristics. However, the predictive value of triple-negative breast cancer, when taken in the context of personal and family cancer characteristics, is unknown. The aim of this study was to determine whether TNBC is a predictor of germline BRCA1 mutations, in the context of multiple predictive factors.

Methods

Germline mutations in BRCA1 and BRCA2 were analyzed by Sanger sequencing and multiple ligation-dependent probe amplification (MLPA) analysis in 431 women from the Malaysian Breast Cancer Genetic Study, including 110 women with TNBC. Logistic regression was used to identify and to estimate the predictive strength of major determinants. Estrogen receptor (ER) and phosphatase and tensin homologue (PTEN) status were assessed and included in a modified Manchester scoring method.

Results

Our study in an Asian series of TNBC patients demonstrated that 27 (24.5%) of 110 patients have germline mutations in BRCA1 (23 of 110) and BRCA2 (four of 110). We found that among women diagnosed with breast cancer aged 36 to 50 years but with no family history of breast or ovarian cancer, the prevalence of BRCA1 and BRCA2 mutations was similar in TNBC (8.5%) and non-TNBC patients (6.7%). By contrast, in women diagnosed with breast cancer, younger than 35 years, with no family history of these cancers, and in women with a family history of breast cancer, the prevalence of mutations was higher in TNBC compared with non-TNBC (28.0% and 9.9%; P = 0.045; and 42.1% and 14.2%; P < 0.0001, respectively]. Finally, we found that incorporation of estrogen-receptor and TNBC status improves the sensitivity of the Manchester Scoring method (42.9% to 64.3%), and furthermore, incorporation of PTEN status further improves sensitivity (42.9% to 85.7%).

Conclusions

We found that TNBC is an important criterion for highlighting women who may benefit from genetic testing, but that this may be most useful for women with early-onset breast cancer (35 years or younger) or with a family history of cancers. Furthermore, addition of TNBC and PTEN status improves the sensitivity of the Manchester scoring method and may be particularly important in the Asian context, where risk-assessment models underestimate the number of mutation carriers.     

Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age: individual patient data meta-analysis

Background:

We investigated the additional contribution of mammography to screening accuracy in BRCA1/2 mutation carriers screened with MRI at different ages using individual patient data from six high-risk screening trials.

Methods:

Sensitivity and specificity of MRI, mammography and the combination of these tests were compared stratified for BRCA mutation and age using generalised linear mixed models with random effect for studies. Number of screens needed (NSN) for additional mammography-only detected cancer was estimated.

Results:

In BRCA1/2 mutation carriers of all ages (BRCA1=1219 and BRCA2=732), adding mammography to MRI did not significantly increase screening sensitivity (increased by 3.9% in BRCA1 and 12.6% in BRCA2 mutation carriers, P>0.05). However, in women with BRCA2 mutation younger than 40 years, one-third of breast cancers were detected by mammography only. Number of screens needed for mammography to detect one breast cancer not detected by MRI was much higher for BRCA1 compared with BRCA2 mutation carriers at initial and repeat screening.

Conclusions:

Additional screening sensitivity from mammography above that from MRI is limited in BRCA1 mutation carriers, whereas mammography contributes to screening sensitivity in BRCA2 mutation carriers, especially those ⩽40 years. The evidence from our work highlights that a differential screening schedule by BRCA status is worth considering.     

Morphological predictors of BRCA1 germline mutations in young women with breast cancer

Background:

Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data.

Methods:

We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation.

Results:

The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6–47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7–25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3–5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83–0.90).

Conclusion:

Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.     

High prevalence of deleterious <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> germline mutations in arab breast and ovarian cancer patients

Purpose

The BRCA1 and BRCA2 (BRCA) genes are heavily involved in mammalian cell DNA repair processes. Germline pathogenic mutations in BRCA increase the lifetime risk of developing breast and/or ovarian cancer in women. In the Arabian Peninsula, most breast and ovarian cancers are diagnosed as early-onset cases, some of which may be due to germline variants in BRCA genes. To identify the BRCA germline mutation frequency and spectrum in the Arab breast and ovarian cancers, we have sequenced the protein-coding exons of these genes.

Methods

All BRCA coding exons were sequenced using genomic DNA isolated from lymphocytes in 173 Arab breast and ovarian cancer patients by a massively parallel sequencing technology and verified by Sanger sequencing.

Results

We identified a total of 17 distinct pathogenic mutations, of which four were novel, in 28 patients; nine out of 108 breast (8.3%) and 19 out of 65 ovarian cancer (29.2%) patients. Thirteen of the 17 mutations were detected in BRCA1 and four mutations were found in BRCA2 gene. Four pathogenic BRCA1 mutations (c.1140dupG, c.4136_4137delCT, c.5095C>T, and c.5530delC) accounted for 54% of all the mutations detected in our patient cohort. Additionally, we identified a likely pathogenic BRCA1 missense variant in two of 108 breast (1.9%) and a BRCA2 missense variant in one of 65 ovarian cancer (1.5%) patients.

Conclusions

The overall frequencies of the BRCA germline mutations were 10.2% in breast and 30.7% in ovarian cancer patients. These data shed new light into the prevalence of BRCA mutations in the Arab women population.