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PubMed2004

BRCA1 and BRCA2 mutations as prognostic factors in bilateral breast cancer patients.

BACKGROUND: Incidence of primary bilateral breast cancer (BC) is rare and does not exceed 5%. BRCA1/2 mutation carriers diagnosed with breast cancer have a strong life time risk of developing contralateral breast cancer (53% versus 2%). PATIENTS AND METHODS: A group of 108 patients with bilateral breast cancer, who reported at our Cancer Centres from 2000 to 2002, were subjected to genetic testing. Similarities and differences between BRCA1/2 carriers and non-carriers were analysed in terms of family history, pathology of tumour, age of diagnosis, developing contralateral BC and second primary cancer. RESULTS: BRCA1/2 mutations were detected in 32 of 108 patients. Family history of BC was identified in 46.9% of these patients compared with 22.4% of non-carriers (P <0.05). Synchronous BC was diagnosed significantly rarer [4 of 32 (12.5%)] in BRCA1/2 carriers than in the non-carrier group [26 of 76 (34.2%)]. In addition, patients with BRCA mutations were younger when they were diagnosed than non-carriers. BRCA1/2 carriers had a significantly higher incidence of medullary BC (13.6% versus 1.7%) and developed ovarian cancer significantly more frequently than non-carriers (12 of 32 and 1 of 72 patients, respectively). CONCLUSIONS: Patients with bilateral BC having BRCA mutations are significantly younger than non-carriers. They also have a significantly higher family history of BC and an increased risk of developing ovarian cancer. The differences in clinical aspects of BRCA carriers with bilateral BC should be considered in clinical management.

Adult↗

PubMed2003

Venn Mapping: clustering of heterologous microarray data based on the number of co-occurring differentially expressed genes.

MOTIVATION: To evaluate microarray data, clustering is widely used to group biological samples or genes. However, problems arise when comparing heterologous databases. As the clustering algorithm searches for similarities between experiments, it will most likely first separate the data sets, masking relationships that exist between samples from different databases. RESULTS: We developed a program, Venn Mapper, to calculate the statistical significance of the number of co-occurring differentially expressed genes in any of the two experiments. For proof of principle, we analysed a heterologous data set of 170 microarrays including breast and prostate cancer microarray analyses. Significant overlap was found in an unsupervised analysis between metastasized prostate cancer and metastasized breast cancer and BRCA mutated breast cancer. A comparison between single microarray data and the averaged breast and prostate data sets was also evaluated. This analysis suggests that genes expressed higher in stromal cells are also implicated in metastatic prostate cancer and BRCA mutated breast cancer. The Venn Mapper program identifies overlaps between samples from heterologous data sets and directly extracts the genes responsible for the overlap. From this information novel biological hypotheses may be addressed. AVAILABILITY: Venn Mapper is freely available on http://www.erasmusmc.nl/gatcplatform. SUPPLEMENTARY INFORMATION: http://www.erasmusmc.nl/gatcplatform/vennmapper.html.

Algorithms↗

PubMed2000

Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome?

BACKGROUND: Uterine papillary serous carcinoma (UPSC) shares common pathologic, genetic, and clinical features with other serous cancers of müllerian origin. The most common histologic type of ovarian tumor associated with BRCA mutations is papillary serous. Because of these histologic similarities, we postulated that, in some cases, UPSC may be a manifestation of a field defect in BRCA1 carriers, which also includes ovarian carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. METHODS: Fifty-six living patients with UPSC were contacted through their treating physicians and agreed to a family history interview and to provide a blood specimen for BRCA testing. The protein truncation test was used to detect mutations in exons 10 and 11 of BRCA1 and in exon 11 of BRCA2. The presence of four common mutations was assessed by PCR-based specific assays. RESULTS: A high proportion of patients had a past history of breast cancer (11%) or a first-degree relative with breast cancer (29%). Four patients were from families with site-specific hereditary breast cancer. However, there was no clear example of the hereditary breast-ovarian cancer syndrome, and none of the 56 patients was found to carry a BRCA1 or BRCA2 mutation. CONCLUSIONS: BRCA mutations do not appear to predispose to UPSC and this type of cancer does not appear to be a manifestation of the classical hereditary breast-ovarian cancer syndrome. The observed association between UPSC and breast cancer may be due to the presence of mutations in other cancer predisposing genes.

Adult↗

PubMed2004

Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer.

Mutations in BRCA1 and BRCA2 that predispose to breast and ovarian cancer are detected in approximately 2.5% of the Ashkenazi Jewish population. To explore whether carriers of Ashkenazi founder mutations in BRCA1 or BRCA2 have an increased risk for colorectal cancer, we screened 586 unselected Ashkenazi Jewish case patients with colorectal cancer for the three common founder mutations in BRCA1 and BRCA2. We identified six carriers (1.02%) among these case patients. After adjusting for age at diagnosis and sex by use of logistic regression analysis, we compared the incidence of carriers in this group of 586 case patients with that of 5012 Ashkenazi Jewish control subjects without a known history of colorectal cancer. The presence of a founder BRCA mutation was not associated with the risk of colorectal cancer (relative risk = 0.50, 95% confidence interval = 0.22 to 1.14). We thus recommend that counseling for colorectal cancer screening and prevention in individuals with BRCA mutations be based on the personal and family history of colorectal cancer or associated syndromic malignancies.

Adult↗

PubMed2005

Hereditary breast and ovarian cancer: review and future perspectives.

Breast cancer (BC) is the most frequent carcinoma in women. The cumulative risk for the disease is 10% up to the age of 80 years. A familial history of BC and ovarian cancer (OC) is a significant risk factor. Some 5-10% of all cases of BC and 25-40% of cases in patients under the age of 35 years have a hereditary origin. BRCA1/BRCA2 mutations are responsible for 3-8% of all cases of BC and 30-40% of familial cases. Ten percent of patients with OC have a genetic predisposition. About 80% of families with a history of OC have BRCA1 mutations, while 15% have BRCA2 mutations. Women at risk can receive counseling from interdisciplinary cancer genetics clinics, while those at high risk can receive genetic testing. Risk calculation programs can define the risks and assist in decision making for genetic testing and clinical options. Clinical options require information on the risks of the disease and its mutation status. Chemoprevention is currently a controversial topic, while the use of oral contraceptives can be regarded as reducing the risk for OC. Prophylactic mastectomy and bilateral ovariectomy are the only options that lead to a demonstrable reduction in risk, but they do, of course, affect the patient's physical integrity. It is not currently known whether intensified early cancer detection is individually beneficial, but this is currently the option that is the least invasive and least burdensome to the patient. Although hereditary BC has different pathological characteristics and the BRCA mutation is an independent negative prognostic factor, there are currently no special treatment guidelines. Without adjuvant hormone therapy or chemotherapy, the overall survival in BRCA mutation carriers is reduced. Chemotherapy regimens involving platinum are particularly beneficial in the treatment of hereditary BC.

BRCA1 Protein↗

PubMed2002

Cross-issue synthesis: potential application to breast cancer, tamoxifen and genetic susceptibility.

BACKGROUND: Cross-design synthesis usually refers to the inclusion in a meta-analysis of studies addressing the same question but using different designs, for example, combining results from randomised trials with those from case-control studies. Here we describe a procedure for combining information from studies addressing different but clinically related questions, referred to, for brevity, as cross-issue synthesis. METHODS: Surveys have measured the oestrogen receptor (ER) status of invasive breast cancer in women with mutations in the BRCA1 or BRCA2 gene. These mutations confer a substantially increased risk of breast cancer. These are also published randomised trials of tamoxifen administered for at least 3 years, either as an adjuvant therapy or for primary prevention, which record whether breast cancer recurred or occured respectively. These studies also give results by ER status. There are biological reasons to suppose that tamoxifen is more effective at preventing ER-positive cancers, and may have little or no effect at preventing ER-negative cancers. Women with BRCA mutations are more likely to develop ER-negative cancers. Combining meta analyses for these two types of studies supplies an estimate of the effectiveness of tamoxifen in preventing breast cancer in women with BRCA mutation. Hierarchical models were developed for this purpose. Estimation was by Markov chain Monte Carlo (MCMC). RESULTS: A range of models were fitted by MCMC. Using these, the effect of tamoxifen on the relative risk of developing breast cancer in women with a mutation in the BRCA1 gene is estimated to be 0.90 95% confidence interval (CI) (0.52, 1.61), and for the BRCA2 gene 0.71 95% CI (0.45, 1.21). DISCUSSION: This procedure can be generalised to combine information from two sets of studies addressing different, but clinically related questions.

Antineoplastic Agents, Hormonal↗

PubMedDate not supplied

Primary peritoneal serous papillary carcinoma: a new epidemiologic trend? A matched-case comparison with ovarian serous papillary cancer.

The aim of the study was to examine the prevalence of primary peritoneal serous papillary carcinoma (PPSPC) as compared with ovarian serous papillary cancer (OSPC), and to study the clinicopathologic features and the frequency of germline BRCA1 and BRCA2 mutations in patients with PPSPC compared with those with OSPC. The study group included 28 cases of PPSPC. The comparison group included 35 female patients with OSPC, matched for stage, grade, and histologic subtype. All tumors were staged as either IIIB, IIIC or IV according to FIGO criteria. The patient characteristics, family and personal history of malignancies, the prevalence of germline BRCA mutations, clinicopathologic findings, presenting symptoms, pre- and intraoperative findings, and survival were compared in a matched-case retrospective study comparing patients with PPSPC vs. those with OSPC. Statistical analysis was made using Student's t-test, Chi-square, Wilcoxon, Kaplan-Meier and log-rank methods. Women with PPSPC had a significantly earlier menarche (P = 0.037) and a higher number or births (P = 0.03) than women with OSPC. No difference was found with regard to the prevalence of germline BRCA mutations in women with PPSPC compared with women with OSPC (7.1% vs. 25.7%). There was a significant increase (P = 0.02) in the incidence of abdominal distension as reported by PPSPC (64%) vs. OSPC patients (26%). Significantly more women with PPSPC than with OSPC presented with clinical ascites (P = 0.0001) and without palpable pelvic mass (P = 0.000001). On exploratory laparotomy, significantly more women with PPSPC than with OSPC had a minimal disease in the pelvis (P = 0.0087). Three-year survival analysis demonstrated a significantly worse survival rate for the PPSPC group than for the OSPC group (P = 0.017). A significant increase in the prevalence of PPSPC compared with OSPC was observed during the study years (P = 0.00001). We concluded that PPSPC and OSPC might be two distinct cancers, presenting a new epidemiologic trend regarding the increased incidence of PPSPC.

Case-Control Studies↗

PubMed2006

Assessing BRCA carrier probabilities in extended families.

PURPOSE: Carrier prediction models estimate the probability that a person has a BRCA mutation. We evaluated the accuracy of the BOADICEA model and compared its performance with that of other models (BRCAPRO, Myriad I and II, Couch, and Manchester Scoring System). We also studied the effect of extended family information on risk estimation using BOADICEA. METHODS: We compared the area under receiver operating characteristic curves generated from 472 families with one member tested for BRCA mutations. We calculated sensitivity, specificity, and predictive values at an estimated probability of 10% and explored the biases of carrier prediction. RESULTS: BOADICEA performed better than the other models in Ashkenazi Jewish (AJ) families, BRCAPRO performed slightly better in non-AJ families, and Myriad II performed comparably well in both groups. Including extended family information in BOADICEA yielded slightly better performance than did limiting the information to second-degree relatives. Using a 10% cutoff point, BOADICEA and Myriad II were most sensitive in predicting BRCA1/2 mutations in AJ families, and Myriad II was most sensitive in non-AJ families. The Manchester Scoring System was the most sensitive and least specific in a subgroup of non-AJ families. BOADICEA and BRCAPRO tended to underestimate the observed risk at low estimated probabilities and overestimate it at higher probabilities. CONCLUSION: The BOADICEA, BRCAPRO, and Myriad II models performed similarly. Including second-degree relatives slightly improved carrier prediction by BOADICEA. The Myriad II model was the easiest to implement.

Adult↗

PubMed2004

BRCA germline mutations in Jewish women with uterine serous papillary carcinoma.

OBJECTIVE: Our recent study determined the possible effects and incidence of BRCA1 and BRCA2 germline mutations in uterine serous papillary carcinoma (USPC). The purpose of this study was to determine the incidence of these mutations in an enlarged series of USPC. METHODS: We screened DNA from 27 women with USPC for BRCA1 and BRCA2 germline mutations common in the Jewish population (BRCA1-185delAG and 5382 insC,BRCA2-6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity (LOH) at the appropriate loci. RESULTS: Women (20) were of Jewish Ashkenazi origin and seven were non-Ashkenazi. Four of 20 (20%) Ashkenazi women were carriers of germline mutations: three 185delAG mutation and one 5382insC mutation. All carriers had strong family histories of breast-ovarian carcinoma. Seven out of 20 (35%) women had been diagnosed for breast carcinoma before diagnosis of USPC. Family histories of 12 women (60%) showed at least one first-degree relative with breast, ovarian, or colon carcinoma. Loss of heterozygosity analysis found a loss of the wild-type BRCA1 allele in three of the four primary uterine tumors that were examined. CONCLUSIONS: Our findings further support our previous published data suggesting a high incidence of BRCA carriers among USPC Ashkenazi Jewish patients. The loss of heterozygosity in the tumor tissue of carriers coupled with the high frequency of patient and family history of breast and ovarian malignancies suggest that USPC might be part of the manifestation of familial breast-ovarian cancer in Ashkenazi Jewish patients.

Aged↗

PubMed2002

[Tamoxifen and breast cancer].

Tamoxifen is a selective estrogen receptor modulator (SERM) with pro- and anti-estrogenic properties. Currently it is the most widely used agent for first line treatment against hormone sensitive metastatic breast cancer and the only approved hormonal agent for adjuvant treatment of organ confined breast cancer. Furthermore, its uses have been extended for the treatment of intraductal breast carcinoma patients. In such settings the most worrisome side effect of tamoxifen is its ability to increase the rates of uterine cancers. It has been claimed that most of these cancers are found at an early stage because of vaginal bleeding. Moreover, it has been shown that for most women transvaginal ultrasound is an ineffective screening method for the early detection of uterine carcinomas. It is important, however, to notice that long term tamoxifen treatment can cause metastatic uterine cancer--not only carcinomas but also sarcomas (mainly malignant mixed mesodermal tumors. It should be noted that, at least for the special population of BRCA mutation carriers, transvaginal ultrasound can increase our ability for the earlier discovery of ovarian cancer. Thus, we believe that there is still a place for the use of transvaginal ultrasound in special populations. This is specifically for long term tamoxifen users (more than the usually recommended five years), women with a higher chance of having uterine carcinomas (namely very high body weight, strong family history) and women with a high index of suspicion as carriers of a BRCA mutation. Until new second generation SERMs and aromatase inhibitors are shown to possess better anti-cancer abilities than tamoxifen, this drug will remain in wide use, however, we must not overlook its possible rare side effects.

Antineoplastic Agents, Hormonal↗

PubMed2000

Physicians' attitudes towards mammography and prophylactic surgery for hereditary breast/ovarian cancer risk and subsequently published guidelines.

After a BRCA mutation has been identified in the context of hereditary breast/ovarian cancer (HBOC), mammographic screening and prophylactic surgery are two of the main options available to those responsible for the clinical management of healthy women. The aim of this study was to describe the attitudes of specialists towards the clinical management of women with an HBOC risk: this information was collected prior to the publication of the recent French guidelines. A random national sample of 1169 French surgeons, gynaecologists and obstetricians was surveyed using a mailed questionnaire, to which 700 of these physicians (60%) responded. When dealing with a BRCA mutated woman, 88.6% of the respondents said they would recommend mammographic screening, but only 27.1% would recommend that it should be carried out annually from the age of 30 years onwards, as recommended in the French guidelines; 10.9% would find it acceptable to propose prophylactic mastectomy from the age of 30 years, and 22.9% would find it acceptable to propose prophylactic oophorectomy from the age of 35 years. The specialists who agreed with recommending breast/ovarian cancer genetic testing also had more positive attitudes towards prophylactic mastectomy (adj OR = 3.4, 95% CI = 1.4-8.2), as did those who had previously recommended prophylactic mastectomy when gene testing was not yet available (adj OR = 2.06, 95% CI = 1.23-3.44). The respondents' attitudes towards prophylactic oophorectomy and mastectomy were significantly associated (adj OR = 3.9; 95% CI = 2.3-6.5). Previous recommendation of prophylactic mastectomy was associated (P < 0.01) with a higher level of knowledge of breast/ovarian cancer genetics and with medical practice in this field. French physicians' attitudes towards mammographic screening and prophylactic surgery were not in complete agreement with the subsequently published French guidelines, the impact of which has now to be considered. Constantly evolving knowledge about the efficacy of preventive intervention will give practitioners new elements to integrate into their counselling.

Attitude of Health Personnel↗

PubMed1999

Ovarian dysplasia in prophylactic oophorectomy specimens: cytogenetic and morphometric correlations.

BACKGROUND: Ovarian dysplasia, a potential precursor to ovarian carcinoma, has been described in ovarian tissue obtained by prophylactic oophorectomy and also adjacent to ovarian carcinoma. Women with a family history of ovarian carcinoma, especially those of Jewish Ashkenazi descent, often test positive for BRCA mutant genes. Prophylactically removed ovaries, generally described as normal on macroscopic examination, can exhibit a "preneoplastic phenotype" and unsuspected neoplasm. METHODS: Histologic slides of ovarian tissue from 54 Ashkenazi Jewish women were reviewed. All had a family history of ovarian carcinoma and all were tested for BRCA mutations. Forty-four women tested positive. Thirty-one women underwent prophylactic oophorectomy and 23 underwent oophorectomy for ovarian carcinoma. Normal, dysplastic, and ovarian carcinoma epithelial cells were analyzed morphometrically combining nuclear area measurements with chromatin texture assessment using a novel method based on the computation of autocorrelation coefficients and a derived parameter (Beta). Discriminant analysis between classificatory algorithms was used to obtain results. RESULTS: Ovarian dysplasia was identified in 77.6% of the prophylactic oophorectomy specimens. An unsuspected ovarian carcinoma was diagnosed in one prophylactic oophorectomy specimen. Of 10 women who underwent prophylactic oophorectomy and were negative for BRCA mutations, three had ovarian dysplasia. The average nuclear measurements of the dysplastic cells were similar to those published previously. The new autocorrelation-based method evaluating nuclear texture, as revealed by tridimensional surface plots, demonstrated high discriminatory potential. Discriminant analysis based on nuclear area and nuclear texture information resulted in the correct classification of nearly all the cases in the three diagnostic categories. CONCLUSIONS: Ovaries removed by prophylactic oophorectomy examined in their entirety often reveal ovarian dysplasia and occasionally ovarian carcinoma. The new morphometric method used was highly discriminatory in the evaluation of nuclear texture. Ovarian dysplasia in women with risk factors for ovarian carcinoma is significant in early ovarian carcinogenesis.

Adult↗

PubMedDate not supplied

Primary and metastatic ovarian cancer in patients with prior breast carcinoma. Pre-operative markers and treatment results.

BACKGROUND: The pre-operative diagnosis of primary and metastatic malignant ovarian tumors in patients treated for breast cancer is difficult. The objective of this study was to analyze and compare the characteristics and outcome of women with a history of breast cancer in order to identify pre-operative markers useful in differential diagnosis and the role of surgery in their management. MATERIALS AND METHODS: The medical records of 36 patients with a history of breast cancer, who had been operated on either for primary or metastatic cancer between 1987 and 2003, were reviewed retrospectively. RESULTS: Twenty-seven patients had been diagnosed with primary epithelial ovarian cancer (POC) and nine had metastatic disease (MOC), resulting in a 3:1 ratio. The median age of breast and ovarian cancer diagnosis was 45 and 56 years, respectively, and the median interval was 8 years. The serum CA 125 level was elevated in the majority of cases, in 70% of the POC group and 56% of the MOC, but the median level was higher, though not statistically significant, in the former. Serum CA 15-3 levels were elevated >100 U/ml in 89% of patients with MOC (p = 0.0002). BrCA mutation risk, as calculated with the BRCAPRO software program, was 41.8% and 9% in primary and metastatic tumors, respectively (p=0.0477). Ovarian spread was not the only site of metastatic breast cancer in 55.5% of the MOC group, compared to 11% of the POC patients Disease was disseminated in the abdominal cavity at the time of diagnosis in both groups, however, 78% of patients had unilateral tumors in the POC group and bilateral disease in the MOC (p=0.0133). Cytoreduction to less than 2 cm tumor diameter was feasible in 67% of primary and 44% of metastatic neoplasms. In the follow-up period (12-204 months), the median survival was 10 months for patients with metastatic disease, compared to 33 months for those with primary tumors (p<0.05). CONCLUSION: Small bilateral ovarian enlargements and minor serum elevation of CA 125 titers in patients with initial Stage IV breast cancer, suffering from multiple metastatic disease, are likely to illustrate MOC. Unilateral ovarian mass and high serum levels of CA 125 in apparently disease-free patients with a positive family history and high prevelance of BRCA mutations are suggestive of primary tumors. Optimal cytoreduction was feasible in both groups, but survival was longer in patients with primary tumors (p<0.05).

Adult↗

PubMed2004