Survival in hereditary breast cancer associated with germline mutations of BRCA2.

PURPOSE: Breast cancer in BRCA1 and BRCA2 gene-mutation carriers may differ from so-called sporadic breast cancer in clinical features and behavior. These potential differences may be of importance for the prevention, screening, and, ultimately, treatment of breast cancer in women with such germline mutations. Thus far, there have been very few studies on the survival of BRCA2-associated breast cancer patients. PATIENTS AND METHODS: We determined the disease-free and overall survival of 28 breast cancer patients from 14 consecutive families with eight different BRCA2 germline mutations. These patients' survival and tumor characteristics were compared with those of a control group of 112 sporadic breast cancer patients matched to them by age and year of diagnosis. RESULTS: The 5-year disease-free survival was 52% for each group (P =.91); the overall survival was 74% for BRCA2 carriers and 75% for sporadic cases (P =.50). At the time of diagnosis, tumors from the BRCA2 carriers were borderline significantly larger in comparison to the tumors in sporadic cases (P =.05), but axillary nodal status was not significantly different in the two groups (node-negativity, 63% v 52. 8%, respectively; P =.34). With respect to steroid receptor status, BRCA2-associated tumors were more likely to be steroid receptor-positive, especially regarding progesterone receptor status (100% v 76.7% positive, respectively; P =.06). Stage-adjusted recurrence and death rates were nonsignificantly better for BRCA2 cases (hazard ratios of 0.84 and 0.59 [P =.61 and P =.19], respectively). In contrast, after 5 years, the rate of metachronous contralateral breast cancer in BRCA2 patients was 12% (v 2% in controls; P =.02). CONCLUSION: Patients with hereditary breast cancer due to BRCA2 have a similar prognosis when compared with age-matched sporadic breast cancer patients. Contrary to our previous observation regarding BRCA1-associated breast cancer, BRCA2 tumors tended to be steroid receptor-positive, instead of steroid receptor-negative.     

Familial breast cancers without mutations in BRCA1 or BRCA2 have low cyclin E and high cyclin D1 in contrast to cancers in BRCA mutation carriers.

PURPOSE: We analyzed the expression of critical cell cycle regulators cyclin E and cyclin D1 in familial breast cancer, focusing on BRCA mutation-negative tumors. Cyclin E expression in tumors of BRCA1 or BRCA2 carriers is higher, and cyclin D1 expression lower, than in sporadic tumors. In familial non-BRCA1/2 tumors, cyclin E and cyclin D1 expression has not been studied. EXPERIMENTAL DESIGN: Cyclin E and cyclin D1 immunohistochemical expression was studied in tissue microarrays consisting of 53 BRCA1, 58 BRCA2, 798 familial non-BRCA1/2, and 439 sporadic breast tumors. RESULTS: In univariate analysis, BRCA1 tumors had significantly more frequently high cyclin E (88%) and low cyclin D1 (84%) expression than sporadic (54% and 49%, respectively) or familial non-BRCA1/2 (38% and 45%, respectively) tumors. BRCA2 tumors had significantly more frequently low cyclin D1 expression (68%) than sporadic or familial non-BRCA1/2 tumors and significantly more frequently high cyclin E expression than familial non-BRCA1/2 tumors. In a logistic regression model, cyclin expression, early age of onset, and estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) status were the independent factors most clearly distinguishing tumors of BRCA1 mutation carriers from other familial breast cancers. High cyclin E and low cyclin D1 expression were also independent predictors of BRCA2 mutation when compared with familial non-BRCA1/2 tumors. Most interestingly, lower frequency of high cyclin E expression independently distinguished familial non-BRCA1/2 tumors also from sporadic ones. CONCLUSIONS: Cyclin E and cyclin D1 expression distinguishes non-BRCA1/2 tumors from both sporadic and BRCA1- and BRCA2-associated tumors and may reflect different predisposition and pathogenesis in these groups.     

Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations.

PURPOSE: Recent laboratory data suggest a role for BRCA1/2 in the cellular response to DNA damage. There is a paucity of clinical data, however, examining the effect of radiotherapy (RT), which causes double-strand breaks, on breast tissue from BRCA1/2 mutation carriers. Thus the goals of this study were to compare rates of radiation-associated complications, in-breast tumor recurrence, and distant relapse in women with BRCA1/2 mutations treated with breast-conserving therapy (BCT) using RT with rates observed in sporadic disease. PATIENTS AND METHODS: Seventy-one women with a BRCA1/2 mutation and stage I or II breast cancer treated with BCT were matched 1:3 with 213 women with sporadic breast cancer. Conditional logistic regression models were used to compare matched cohorts for rates of complications and recurrence. RESULTS: Tumors from women in the genetic cohort were associated with high histologic (P =.0004) and nuclear (P =.009) grade and negative estrogen (P=.0001) and progesterone (P=.002) receptors compared with tumors from the sporadic cohort. Using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity scoring, there were no significant differences in acute or chronic morbidity in skin, subcutaneous tissue, lung, or bone. The 5-year actuarial overall survival, relapse-free survival, and rates of tumor control in the treated breast for the patients in the genetic cohort were 86%, 78%, and 98%, respectively, compared with 91%, 80%, and 96%, respectively, for the sporadic cohort (P = not significant). CONCLUSION: There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years. Although additional follow-up is needed, these data may help in discussing treatment options in the management of early-stage hereditary breast cancer and should provide reassurance regarding the safety of administering RT to carriers of a germline BRCA1/2 mutation.     

Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer

A basal epithelial phenotype is found in not more than 15% of all invasive breast cancers. Microarray studies have shown that this phenotype is associated with breast cancers that express neither estrogen receptor (ER) nor erbB-2 (HER2/neu) (i.e., ER/erbB-2-negative tumors). The ER/erbB-2- negative phenotype is also found in breast cancers occurring in BRCA1 mutation carriers (i.e., BRCA1-related breast cancers). We tested the hypothesis that BRCA1-related breast cancers are more likely than non-BRCA1/ 2-related breast cancer to express a basal epithelial phenotype. Among 292 breast cancer specimens previously analyzed for ER, erbB-2, p53, and germline mutations in BRCA1 and BRCA2, we identified 76 that did not overexpress ER or erbB-2. Of the 72 specimens with sufficient material for testing, 40 expressed stratified epithelial cytokeratin 5 and/or 6 (5/6). In univariate analysis, the expression of cytokeratin 5/6 was statistically significantly associated with BRCA1-related breast cancers (odds ratio = 9.0, 95% confidence interval = 1.9 to 43; P =.002, two-sided Fisher's exact test). Thus, germline BRCA1 mutations appear to be associated with a distinctive breast cancer phenotype.     

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P=0.0003) and BRCA2 (30%; P=0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P=0.0002), progesterone receptor (PR) negative (P=0.004) and were of higher grade (P=0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P=0.0006) and p53 was overabundant (47%; P<0.0000000001) among the difficult-to-treat ER/PR/ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.     

Germline BRCA1/2 mutations and p27(Kip1) protein levels independently predict outcome after breast cancer.

PURPOSE: Decreased levels of the cyclin-dependent kinase inhibitor p27(Kip1) in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27(Kip1) protein levels, and outcome has not been studied. PATIENTS AND METHODS: Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27(Kip1) expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years. RESULTS: Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27(Kip1) expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P =.009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P =.003). Similar results were seen for women whose tumors expressed low levels of p27(Kip1), compared with those with high levels (5-year DDFS, 68% v 93%; P<.0001). In a multivariate analysis, both BRCA1/2 mutation and low p27(Kip1) expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P =.05; and RR, 3.9; 95% CI, 1.4 to 11.1; P =.01, respectively). CONCLUSION: In this study, we showed that BRCA1/2 mutations were associated with low levels of p27(Kip1) in breast cancer. Both BRCA1/2 and p27(Kip1) status were identified as independent prognostic factors.     

Survival of breast cancer patients in BRCA1, BRCA2, and non-BRCA1/2 breast cancer families: a relative survival analysis from Finland.

Reports on the prognosis of familial breast cancer patients have been contradictory. True differences in survival, if they exist, would have important implications for genetic counselling and in treatment of hereditary breast cancer. We assessed the survival rates of 359 familial breast cancer patients (32 patients from BRCA1-positive families, 43 patients from BRCA2-positive families and 284 patients from BRCA1/2-negative breast cancer families) and compared them with those of all other breast cancer patients diagnosed in Finland from 1953 to 1995 (n = 59,517). Cumulative relative survival rates (RSR) were calculated by dividing the observed survival rates by the expected ones. The expected survival rates were derived from the sex, age and calendar year specific life-tables of the general population in Finland. Regression model was used to calculate relative excess risk of death (RR) and to adjust for confounding factors. The overall 5-year RSR of the patients in the BRCA1 families, BRCA2 families, non-BRCA1/2 families and among sporadic cases was 67%, 77%, 86% and 78%, respectively. However, we found no significant differences in the RR adjusted for age, stage and year of diagnosis between the different familial patient groups or the general breast cancer population. In the BRCA1 families the RR tended to be higher [RR 1.30, 95% confidence interval (CI) 0.63--2.70] and in the BRCA2 families lower (RR 0.78, 95% CI 0.39--1.57) than among the general breast cancer patient population. The RR among patients in the non-BRCA1/2 families did not differ from that of the general patient population.     

The Retinoblastoma Gene Undergoes Rearrangements in BRCA1-Deficient Basal-like Breast Cancer

Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we used gene expression profiling to molecularly subtype 577 breast tumors, including 73 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated, and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter methylation but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1-deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1 hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer but rarely in BRCA2 hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings show the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1 status. Cancer Res; 72(16); 4028-36. ?2012 AACR.     

The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families

The frame-shifting mutation 1100delC in the cell-cycle-checkpoint kinase 2 gene (CHEK2) has been reported to be associated with familial breast cancer in families in which mutations in BRCA1 and BRCA2 were excluded. To investigate the role of this variant as a candidate breast cancer susceptibility allele, we determined its prevalence in 237 breast cancer patients and 331 healthy relatives derived from 71 non-BRCA1/BRCA2 multiple-case early onset breast cancer families. Twenty-seven patients (11.4%) were carrying the CHEK2*1100delC variant. At least one carrier was found in 15 of the 71 families (21.1%). There was no evidence of cosegregation between the variant and breast cancer, but carrier patients developed breast cancer earlier than did noncarriers. We studied CHEK2 protein expression in 111, and loss of heterozygosity at CHEK2 in 88 breast tumors from these patients. Twelve of 15 tumors from carriers showed absent protein expression as opposed to 3 of 76 tumors from noncarriers (P < 0.001). CHEK2 loss of heterozygosity was associated with absence of protein expression but not with 1100delC carrier status. Thus, selecting for breast cancer cases with a strong familial background not accounted for by BRCA1 or BRCA2 strongly enriches for carriers of CHEK2*1100delC. Our results support a model in which CHEK2*1100delC interacts with an as yet unknown gene (or genes) to increase breast cancer risk.     

Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors

In approximately 70% of the families with a high frequency of early-onset breast and/or ovarian cancer, BRCA1 or BRCA2 germline mutations cannot be identified with the current screening regime. Therefore, we used data mining to identify a somatic genetic signature to differentiate BRCA1 mutation carriers from non-BRCA1 carriers based on the genetic characteristics of their breast carcinomas. For this purpose, we developed a molecular classifier, which assigns a given tumor to either the BRCA1 or control group based on somatic genetic profiles as revealed by comparative genomic hybridization. This was performed on breast tumors selected from two groups of patients: 28 proven BRCA1 germline mutation carriers; and a control group consisting of 42 breast tumors from patients with unknown BRCA1 or BRCA2 status. We show that BRCA1 breast carcinomas exhibit specific somatic genetic aberrations and can be distinguished from control tumors with an accuracy of 84% (sensitivity of 96% and specificity of 76%). Chromosomal bands used by this classifier include regions on chromosomes 3p, 3q, and 5q. The classifier miss-assigned one patient with a BRCA1 mutation to the non-BRCA1 class. The germline mutation in this patient is a 62bp deletion in the last exon of BRCA1 (5622del62). Possibly, this mutation may give a different phenotypic effect than do mutations in other regions of the gene. Validation on an independent set of BRCA1 and sporadic tumors showed that the BRCA1 classifier correctly identified all 6 BRCA1 tumors and assigned 4 of the 19 control patients to the BRCA1 class. The resulting accuracy on the validation set is 84%.     

Immunohistochemical expression of DNA repair proteins in familial breast cancer differentiate BRCA2-associated tumors.

PURPOSE: Morphologic and immunohistochemical studies of familial breast cancers have identified specific characteristics associated with BRCA1 mutation-associated tumors when compared with BRCA2 and non-BRCA1/2 tumors, but have not identified differences between BRCA2 and non-BRCA1/2 tumors. Because BRCA1 and BRCA2 genes participate in the DNA repair pathway, we have performed an immunohistochemical study with markers related to this pathway to establish the profile of the three groups. MATERIALS AND METHODS: We have studied two tissue microarrays that include 103 familial and 104 sporadic breast tumors, with a panel of DNA repair markers including ATM, CHEK2, RAD51, RAD50, XRCC3, and proliferating cell nuclear antigen. RESULTS: We found more frequent expression of CHEK2 in BRCA1 and BRCA2 tumors than in non-BRCA1/2 and sporadic tumors. We found absence of nuclear expression and presence of cytoplasmic expression of RAD51 in BRCA2 tumors that differentiate them from other familial tumors. We validated these results with a new series of patient cases. The final study with 253 familial patient cases (74 BRCA1, 71 BRCA2, 108 non-BRCA1/2), and 288 sporadic patient cases, has allowed us to confirm our preliminary results. Because BRCA2 tumors present a specific immunohistochemical profile for RAD51 and CHEK2 markers that is different from non-BRCA1/2 tumors, we have built a multivariate model with these markers that distinguish both tumors with an estimated probability of at least 76%. CONCLUSION: Our results suggest that BRCA2 tumors demonstrate more cytoplasmic and less nuclear RAD51 staining, and increased CHEK2 staining. This pattern may distinguish BRCA2 from familial non-BRCA1/2 tumors.     

High risk of contralateral breast carcinoma in women with hereditary/familial non-BRCA1/BRCA2 breast carcinoma

BACKGROUND: The objectives of the current study were to estimate the risk of developing contralateral breast carcinoma (CBC) among women with hereditary/familial non-BRCA1/BRCA2 breast carcinoma and to determine the factors that may predict their risk of CBC. METHODS: The study sample consisted of all families (n = 217 families) that were referred between 1994-2001 to the Clinic of Cancer Genetics at the University Hospital of Ume? for suspected hereditary breast carcinoma. The study included all women in the 217 families who had carcinoma of the breast as their first primary invasive malignancy diagnosed between 1970-2001 in northern Sweden. Exclusion criteria were an estimated lifetime risk < 20%, BRCA1/BRCA2 mutation, noninvasive carcinoma (ductal or lobular carcinoma in situ), and bilateral breast carcinoma. In the final analysis, 204 women were included from 120 families. RESULTS: The cumulative probability of developing CBC among women who had hereditary/familial non-BRCA1/BRCA2 breast carcinoma after 20 years was 27.3% (95% confidence interval, 15.0-37.8) compared with the expected risk (4.9%) among women in northern Sweden who had primary breast carcinoma. A significantly increased risk of CBC was associated with age younger than 50 years at the time of diagnosis of the first primary breast carcinoma (P = 0.006). Adjuvant hormone therapy reduced the risk of CBC (P = 0.036). CONCLUSIONS: Women with hereditary/familial non-BRCA1/BRCA2 breast carcinoma had a high risk of developing CBC. This risk was attenuated further among women who were younger at the time of onset, who had a cumulative probability of developing CBC of nearly 40% after 15 years, which is similar to the estimated risk among BRCA1/BRCA2 mutation carriers. The results of this study emphasized the importance of genetic counseling for these women.     

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

Five breast cancer subtypes have been described in sporadic breast cancer (SBC) using expression arrays: basal-like, ERBB2, normal breast-like, luminal A and B. These molecular subtypes show different genomic aberration patterns (GAPs). Recently, our group described these breast cancer subtypes in 50 non-BRCA1/2 familial tumors using immunohistochemistry assays. We extended this study to the other classes of familial breast cancer (FBC), including 62 tumors (18 BRCA1, 16 BRCA2 and 28 non-BRCA1/2), with the same panel of 25 immunohistochemical (IHC) markers and histological grade obtaining a similar classification. We combined these data with results generated by a 1 Mb BAC array-based CGH study to evaluate the genomic aberrations of each group. We found that BRCA1-related tumors are preferentially basal-like, whereas non-BRCA1/2 familial tumors are mainly luminal A subtype. We described distinct GAPs related to each IHC subtype. Basal tumors had a greater number of gains/losses, while luminal B tumors had more high-level DNA amplifications. Our data are similar to those obtained in SBC studies, highlighting the existence of distinct genetic pathways of tumor evolution, common to both SBC and FBC.     

Are ATM mutations 7271T-->G and IVS10-6T-->G really high-risk breast cancer-susceptibility alleles?

Two mutations of the ATM gene were recently suggested to confer breast cancer risks similar to mutations of BRCA1 or BRCA2. Here, we set out to confirm these findings in 961 families with non-BRCA1/BRCA2 breast cancer from diverse geographical regions. We did not detect the ATM 7271T-->G mutation in any family. The ATM IVS10-6T-->G mutation was detected in eight families, which was similar to its frequency among population-matched control individuals (pooled Mantel-Haenszel odds ratio = 1.60; 95% confidence interval = 0.48 to 5.35; P = 0.44). Bayesian analysis of linkage in the ATM IVS10-6T-->G-positive families showed an overall posterior probability of causality for this mutation of 0.008. We conclude that the ATM IVS10-6T-->G mutation does not confer a significantly elevated breast cancer risk and that ATM 7271T-->G is a rare event in familial breast cancer.     

Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group

The natural history of hereditary and BRCA1- and BRCA2-associated epithelial ovarian cancer may differ from that of sporadic disease. The purpose of this study was to compare the clinical characteristics of BRCA1- and BRCA2-associated hereditary ovarian cancer, hereditary ovarian cancer with no identified BRCA1/2 mutation, and ovarian cancer in population-based controls. BRCA1 and BRCA2 mutation testing was carried out on index cases from 119 families with site-specific epithelial ovarian cancer or breast-ovarian cancer. We estimated overall survival in 151 patients from 57 BRCA1 and BRCA2 mutation families and compared it with that in 119 patients from 62 families in which a BRCA1/2 mutation was not identified. We compared clinical outcome and data on tumor histopathology, grade, and stage. We also compared survival in familial epithelial ovarian cancer, whether or not a mutation was identified, with that of an age-matched set of population control cases. Overall survival at 5 years was 21% (95% confidence interval, 14-28) in cases from BRCA1 mutation families, 25% (8-42) in BRCA2 mutation families, and 19% (12-26) in families with no identified mutation (P = 0.91). Survival in familial ovarian cancer cases as a whole was significantly worse than for population controls (P = 0.005). In the familial cases, we found no differences in histopathological type, grade, or stage according to mutation status. Compared to population control cases, mucinous tumors occurred less frequently in the familial cases (2 versus 12%, P<0.001), and a greater proportion of the familial cases presented with advanced disease (83% stage III/IV versus 56%; P = 0.001). We have shown that survival in familial ovarian cancer cases is worse than that in sporadic cases, whether or not a BRCA1/2 mutation was identified, perhaps reflecting a difference in biology analogous to that observed in breast cancer.     

Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are associated with an increased risk of breast cancer. Whether women with breast cancer who have inherited mutations in these genes have a different outcome after breast conservation therapy than women with "sporadic" cancer is unresolved. Consequently, we compared the outcomes after breast conservation therapy in Ashkenazi women with or without germline mutations in BRCA1 and/or BRCA2 (hereafter called BRCA). METHODS: We studied 305 women of Ashkenazi Jewish descent undergoing breast-conserving treatment for 329 invasive breast cancers. We reviewed their clinical records, retrieved their archival tissue samples, and tested those samples for the founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. Genetic results were linked to clinical data and outcomes by univariate and multivariate analyses. All Pvalues are two-sided. RESULTS: We detected mutations in BRCA genes in 28 of 305 women. Women with BRCA mutations were more likely to be diagnosed with cancer before the age of 50 years (P<.001) and to have lymph node involvement (P =.04). Ipsilateral breast tumor recurrence was more common in women with BRCA mutations, although this did not reach statistical significance (relative risk [RR] = 1.79; 95% confidence interval [CI] = 0.64-5.03). Women with mutations were more likely to develop contralateral breast cancer (RR = 3.50; 95% CI = 1.78-8.74; P =.001). Distant disease-free survival was shorter in women with mutations (66.2% versus 84.3% at 10 years; P =.05), as was breast cancer-specific survival (71.9% versus 87.2% at 10 years; P =.02). Tumor stage and nodal status, but not mutation status, were predictive of distant disease-free and breast cancer-specific survival in multivariate analysis. CONCLUSIONS: Women with BRCA founder mutations are at increased risk for breast cancer-related events after breast conservation. However, mutation status is not an independent predictor of survival and should not influence decisions regarding adjuvant therapy. The increased contralateral breast cancer risk in women heterozygous for BRCA mutations mandates careful surveillance.     

Molecular profile and clinical variables in BRCA1-positive breast cancers. A population-based study

PURPOSE: To evaluate the clinical features of breast cancer patients with genetic susceptibility to this disease and to investigate the contribution of BRCA1 germline mutations to the phenotype of these tumors. PATIENTS AND METHODS: We reviewed the clinical and pathological records of 102 women with suspected inherited susceptibility to breast cancer consecutively seen at the Genetic Oncology Service of Parma, Italy. Sixty-two patients with a high probability of harboring a germline, cancer-predisposing mutation were tested for BRCA1 mutations. Exon 11 was screened using the protein truncation test and detected mutations were confirmed by direct sequencing (DS). All other exons were analyzed by DS. RESULTS: Among the 62 patients with a completed mutation analysis, 48 (77.4%) had wild-type BRCA1, six (9.6%) had variants of unclear significance, eight (13%) had deleterious mutations. BRCA1-associated breast cancers (BABC) were significantly less likely to be diagnosed at stage I than breast cancers in women without mutations (12.5% vs 51%; P = 0.045), more likely to have a high proliferation rate (100% vs 24%, P < 0.001), and more likely to be histological grade 3 (100% vs 14%, P < 0.001), estrogen and progesterone receptor negative (87.5% vs 13%, P < 0.001; 75% vs 23%, P = 0.004), and p53 positive (87.5% vs 30%, P = 0.023). All tumors with BRCA1 mutations were HER-2/neu negative compared with 57% of the non-BRCA1 tumors (P = 0.04). There were no significant differences between BABC and non-BABC in 20-year relapse-free survival, 20-year event-free survival, and 20-year overall survival. CONCLUSION: In this population-based study, BABC seems to present with adverse molecular features when compared with non-BABC, although the prognosis appears to be similar.     

RASSF1A polymorphism A133S is associated with early onset breast cancer in BRCA1/2 mutation carriers

The tumor suppressor gene RASSF1A regulates cell cycle progression, apoptosis, and microtubule stability and is inactivated by promoter methylation in approximately 50% of breast cancers. It has been shown previously that the polymorphism A133S in RASSF1A reduces its ability to regulate cell cycle progression and this polymorphism is associated with an increased risk of breast cancer. We analyzed the frequency of RASSF1A A133S in 190 Caucasian women without breast cancer and 653 patients with breast cancer including 138 BRCA1 and BRCA2 (BRCA1/2) mutation carriers, 395 non-BRCA1/2 mutations carriers, and 120 untested for BRCA1/2 mutations. Patients with breast cancer had a higher frequency of A133S than the controls [P = 0.017; odds ratios (OR), 1.71; 95% confidence intervals (95% CI), 1.10-2.66]. There is also a higher frequency of A133S in patients with higher familial breast cancer risk (P = 0.029; OR, 1.76; 95% CI, 1.06-2.92) and patients carrying BRCA1/2 mutations (P = 0.037, OR, 1.82; 95% CI, 1.04-3.18). Importantly, we found that the co-occurrence of a BRCA1 or BRCA2 mutation and A133S in RASSF1A was associated with earlier onset of breast cancer compared with those individuals with either a BRCA1/2 mutation or the A133S polymorphism alone (36.0 versus 42.0 years old, P = 0.002). Our data suggest that the presence of the RASSF1A A133S polymorphism is associated with breast cancer pathogenesis in general and modifies breast cancer age of onset in BRCA1/2 mutations carriers. Our results warrant a large-scale study to examine the effect of the A133S polymorphism in the development of breast and other types of cancers.     

中国BRCA1/2突变阳性和突变阴性乳腺癌病理学特征的比较性研究

背景与目的：BRCA1和BRCA2是两个最主要的遗传性乳腺癌相关基因,本研究旨在发现中国BRCA1/2突变阳性乳腺癌的病理学特征。方法：本研究入组了2012—2016年间287例接受过BRCA1/2基因突变检测的乳腺癌,对其中BRCA1/2突变阳性和突变阴性患者的组织病理学和免疫组织化学检测结果进行了比较性研究。结果：在287例乳腺癌中,66例为BRCA1突变阳性,47例为BRCA2突变阳性,174例为BRCA1/2突变阴性。BRCA1突变的乳腺癌表现为更高的组织学分级（P＜0.001）,更高比例的三阴性乳腺癌（72.7%,P＜0.001）。BRCA1突变阳性和BRCA2突变阳性的乳腺癌中人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）的阳性表达率较BRCA1/2突变阴性的乳腺癌更低（P＜0.001）。BRCA1突变阳性乳腺癌基底标志物细胞角蛋白5/6（cytokeratin 5/6,CK5/6）和表皮生长因子受体（epidermal growth factor receptor,EGFR）的阳性率为50%,明显高于其他两组（P＜0.001）,雄激素受体（androgen receptor,AR）的阳性率也更低（P＜0.05）。结论：中国BRCA1突变阳性乳腺癌更多为三阴性乳腺癌,具有CK5/6和EGFR的阳性率更高等特点,并且BRCA1和BRCA2突变阳性乳腺癌中HER2受体阳性率也更低。