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PubMed2002

Medical counselling in the clinical management of BRCA mutation.

Among medical activities, the choice of an intervention is less and less the primacy of experts over persons, whom under the current dominant model of autonomy are the ones in charge of the decision. However, counselling is ethically relevant and acceptable provided that three conditions are fulfilled: 1. Besides information, patient asks for advice; 2. Advice is not given in an authoritative way, with strong incitement or directiveness; 3. It should be explicitly expressed that, if the patient doesn't follow the physician's advice, this will by no means prevent treatment nor the continuation of their relationship. Within an utilitarian perspective, a decision is something like a balance of facts and values. Therefore, the main (insurmountable?) difficulty lays in the assessment of patient's values. Counselling is all the more difficult and should be cautiously delivered as the situation at stake is assumed to exhibit a huge range of inter-individual values. Physicians should have deep respect for genuine individual values and/or cultural factors. The aim of clinical management is to increase life expectancy, taking into account quality of life and dignity of the person. Deliberative, iterative process seems to be a good way to reach a fair decision. While counselling the patient, the physician has to know for whom (or what) (s)he is acting. Indeed it is not always easy to distinguish among the interest of the patient, of its relatives, of the community of patients or even the interest of science or... self-interest.

Counseling↗
PubMed2002

Evaluating breast cancer risk: available models to assess individual breast cancer risk and probability to be a BRCA mutation carrier.

Several models have been generated to estimate breast cancer risk and to predict the probability to identify a BRCA1 or BRCA2 germ line mutation. Each model, based on a slightly different study design and purpose, takes into account a definite number of relevant parameters and ultimately pertains to a specific cohort of women or population. Aim of this work is to underline validity and limits of available tools and their appropriate use in the daily practice.

Adult↗
PubMed2002

Perspectives in the clinical management of BRCA mutations carriers.

The recent identification of the breast cancer-associated genes BRCA1 and BRCA2 is changing the clinical care provided to women at high-risk of breast cancer. We briefly review what is currently known about the clinical management of individuals who bear (or are suspected of bearing) genes mutations and which are the prevention strategies that would reduce the incidence and mortality of breast cancer in this subset of women.

Breast Neoplasms↗
PubMedDate not supplied

Deletions on chromosome 4 in sporadic and BRCA mutated tumors and association with pathological variables.

BACKGROUND: Chromosomal aberrations in breast tumors from BRCA1 and BRCA2 germ-line mutation carriers are considerably more frequent than what is seen in sporadic breast tumors. According to Comparative Genomic Hybridisation analysis (CGH), deletions on chromosome 4 are one of the most frequent events in BRCA1-associated tumors, suggesting inactivation of specific tumor suppressor genes. MATERIALS AND METHODS: In the present study, 16 microsatellite markers covering chromosome 4 were used to map loss of heterozygosity (LOH) in tumors from BRCA1 (n=41) as well as in tumors from BRCA2 (n=66) mutation carriers and in tumors from unselected cases of breast cancer (n =68). RESULTS: The frequency of LOH in these groups ranged from 16-73% in BRCA1-associated tumors, 13-42% in BRCA2-associated tumors and 8-33% in unselected tumors. LOH was significantly more frequent in BRCA1-associated tumors as compared to BRCA2-associated tumors and unselected tumors, and particularly high (over 70%) at 4q35.2. Pathological variables that were found significantly associated (p< or =0.05) with LOH at specific markers were: high percentage of cells in S-phase, negative estrogen receptor status, young age at diagnosis and large tumors. Deletion mapping indicates the existence of seven non-overlapping regions at chromosome 4, which were identified in all three groups of tumors. Three of these seven regions, 4p16.3-p16.1, 4q27-q32.1 and 4q35.1-4qter, have not been reported in breast cancer previously. CONCLUSION: The results manifest the frequent alterations of chromosome 4 in BRCA1-associated breast tumors and indicate the location of several genes of potential importance in breast cancer development.

Breast Neoplasms↗
PubMed2001

Loss of heterozygosity on chromosome 13q12-q14, BRCA-2 mutations and lack of BRCA-2 promoter hypermethylation in sporadic epithelial ovarian tumors.

BACKGROUND: BRCA-1 and BRCA-2 are tumor suppressor genes in familial breast-ovarian carcinoma syndrome. BRCA-1 is also a tumor suppressor gene in sporadic ovarian carcinomas. However, the role of BRCA-2 in sporadic ovarian tumors remains unclear. METHODS: DNA from 52 patients with clinically apparent sporadic ovarian tumors was extracted from blood and from fresh-frozen tumor tissue and normal tissue (10 benign, 7 borderline, and 35 malignant). Loss of heterozygosity (LOH) was analyzed in six microsatellite loci on chromosome 13q. BRCA-2 mutations were detected by single-strand conformation polymorphism analysis and the protein truncation test. BRCA-2 promoter methylation was evaluated by methylation specific polymerase chain reaction analysis. RESULTS: LOH on chromosome 13q12-q14 was identified in 16 tumors (30.8%): Fifteen of these tumors were carcinomas (15 of 35 tumors; 42.8%) and one was a borderline tumor. LOH was frequent in carcinomas with serous differentiation (12 of 16 tumors; 75%). LOH on chromosome 13q12-q14 coexisted with LOH on chromosome 17q in 10 carcinomas. BRCA-2 methylation was not detected in any tumor. BRCA-2 mutations were found in three tumors (one somatic nonsense and two germline frameshift). BRCA-2 fulfilled the two hits for a tumor suppressor gene in these three tumors; in one of them, a BRCA-1 tumor suppressor role had been demonstrated previously. CONCLUSIONS: The results suggest that BRCA-1 and BRCA-2 may act synergically in sporadic ovarian carcinomas with serous differentiation. The demonstration of BRCA-2 germline mutations in patients with ovarian carcinoma with LOH on chromosome 13q12-q14 and lack of a remarkable family history of cancer suggest that the proportion of ovarian carcinomas that result from hereditary predisposition may be higher than previously estimated.

BRCA2 Protein↗
PubMed2007

The distal fallopian tube: a new model for pelvic serous carcinogenesis.

PURPOSE OF REVIEW: Research over the past 50 years has yielded little concrete information on the source of pelvic serous cancer in women, creating a knowledge gap that has adversely influenced our ability to identify, remove or prevent the earliest stages of the most lethal form of ovarian cancer. RECENT FINDINGS: The distal fallopian tube is emerging as an established source of many early serous carcinomas in women with BRCA mutations (BRCA+). Protocols examining the fimbrial (SEE-FIM) end have revealed a noninvasive but potentially lethal form of tubal carcinoma, designated tubal intraepithelial carcinoma. Tubal intraepithelial carcinoma is present in many women with presumed ovarian or peritoneal serous cancer. A candidate precursor to tubal intraepithelial carcinoma, entitled the 'p53 signature', suggests that molecular events associated with serous cancer (p53 mutations) may be detected in benign mucosa. SUMMARY: A fully characterized precursor lesion is a first and necessary step to pelvic serous cancer prevention. The emerging data offer compelling evidence for a model of 'fimbrial-ovarian' serous neoplasia, and call attention to the distal fallopian tube as an important source for this disease, the study of which could clarify pathways to cancer in both organs and generate novel strategies for cancer prevention.

Adenocarcinoma, Mucinous↗
PubMed2006

Advances in the recognition of tubal intraepithelial carcinoma: applications to cancer screening and the pathogenesis of ovarian cancer.

Prophylactic salpingo-oophorectomies from women with BRCA mutations (BRCA+) have identified the tube as a frequent site of early pelvic serous carcinoma (tubal intraepithelial carcinoma [TIC]). These observations have implications for both the early recognition of pelvic serous carcinoma in susceptible women and determining the ultimate site of origin for pelvic serous carcinomas. Moreover, the unique pathology of TIC has shifted attention from the more exuberant proliferations mentioned in prior studies to a spectrum of neoplastic atypias that can be morphologically subtle. This review addresses a multitude of epithelial changes; benign, malignant, and an intriguing third group, which we term "p53 signatures," is found in benign, nonciliated epithelium and stain intensely positive for p53. Understanding all 3 is important for the proper management of women undergoing prophylactic salpingo-oophorectomy and possibly formulating an integrated model for the pathogenesis of serous carcinoma in the reproductive tract. A protocol for sectioning and extensively examining the fimbriated end (SEE-FIM), and its rationale, is described.

Biomarkers, Tumor↗
PubMed2006

The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome.

A proportion of adenocarcinomas in prophylactic adnexectomies (bilateral salpingo-oophorectomies [BSOs]) from women with BRCA mutations (BRCA positive) occur in the fallopian tube. We analyzed a consecutive series of BSOs from BRCA-positive women following an index case of fimbrial serous carcinoma. To determine if the fimbria is a preferred site of origin, we followed a protocol for Sectioning and Extensively Examining the FIMbria (SEE-FIM). Immunostaining for p53 and Ki-67 was also performed. Thirteen BRCA-positive women (cases) and 13 women undergoing BSOs for other disorders (controls) were studied. Tubal carcinoma was detected in 4 cases at the initial histologic evaluation and in no controls. A fifth carcinoma was discovered following further sectioning of the fimbriae. Three were BRCA2 positive and two BRCA1 positive. Three were in the fimbria, one in both the fimbria and proximal tube, and one involved the ampulla. Four were serous carcinomas, four were confined to the tube, and three were noninvasive (intraepithelial). No ovarian carcinomas were identified. All tumors were Ki-67 positive (>75% of cell nuclei), and excluding one endometrioid carcinoma, p53 positive (>75% cell nuclei); p53 positivity in the absence of elevated Ki-67 did not correlate with morphologic neoplasia. The fimbria was the most common location for early serous carcinoma in this series of BRCA-positive women. Protocols that extensively examine the fimbria (SEE-FIM) will maximize the detection of early tubal epithelial carcinoma in patients at risk for ovarian cancer. Investigative strategies targeting the fimbriated end of the fallopian tube should further define its role in the pathogenesis of familial and sporadic ovarian serous carcinomas.

Adenocarcinoma↗
PubMed2001

BRCA-1 and BRCA-2 mutations as prognostic factors in clinical practice and genetic counselling.

Women in general have a 10% risk of developing breast cancer and a 2-3% chance of ovarian cancer in their life-times. Mutations in BRCA-1 and BRCA-2 are present in only a small portion (5-10%) of all breast cancers. Carriers of mutations in these genes have a greater risk of cancer, especially before menopause in the case of BRCA-1 carriers. In addition, their risk of contralateral breast cancer is significantly higher than for the general population (4.2-53% vs. 2%). The grade of contralateral tumours in these patients is more aggressive. BRCA-2 hereditary breast cancer seems more heterogeneous than the BRCA-1 phenotype, and not clearly different from sporadic forms. However, since 20-30% of carriers of BRCA mutations never develop breast or ovarian cancer, there must be other 'risk modifiers'. Survival is better for carriers of hereditary ovarian cancer. Patients with these mutations are referred for genetic counselling, a complex process which includes: an informative dialogue between the proband and the geneticist, drawing up a family history, informed consent, evaluation of risk, genetic testing and possible involvement of healthy family members.

BRCA1 Protein↗
PubMed2006

Evaluation of models to predict BRCA germline mutations.

The selection of candidates for BRCA germline mutation testing is an important clinical issue yet it remains a significant challenge. A number of risk prediction models have been developed to assist in pretest counselling. We have evaluated the performance and the inter-rater reliability of four of these models (BRCAPRO, Manchester, Penn and the Myriad-Frank). The four risk assessment models were applied to 380 pedigrees of families who had undergone BRCA1/2 mutation analysis. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operator characteristic (ROC) curve were calculated for each model. Using a greater than 10% probability threshold, the likelihood that a BRCA test result was positive in a mutation carrier compared to the likelihood that the same result would be expected in an individual without a BRCA mutation was 2.10 (95% confidence interval (CI) 1.66-2.67) for Penn, 1.74 (95% CI 1.48-2.04) for Myriad, 1.35 (95% CI 1.19-1.53) for Manchester and 1.68 (95% CI 1.39-2.03) for BRCAPRO. Application of these models, therefore, did not rule in BRCA mutation carrier status. Similar trends were observed for separate BRCA1/2 performance measures except BRCA2 assessment in the Penn model where the positive likelihood ratio was 5.93. The area under the ROC curve for each model was close to 0.75. In conclusion, the four models had very little impact on the pre-test probability of disease; there were significant clinical barriers to using some models and risk estimates varied between experts. Use of models for predicting BRCA mutation status is not currently justified for populations such as that evaluated in the current study.

Area Under Curve↗