Dedicated clinics have been established for the early diagnosis and treatment of women at risk for inherited breast cancer, but the effects of such interventions are currently unproven. This second report on prospectively diagnosed inherited breast cancer from the European collaborating centres supports the previous conclusions and adds information on genetic heterogeneity and the effect of oophorectomy. Of 249 patients, 20% had carcinoma in situ (CIS), 54% had infiltrating cancer without spread (CaN0) and 26% had cancer with spread (CaN؉). Five-year survival was 100% for CIS, 94% for CaN0 and 72% for CaN؉ (p ؍ 0.007). Thirty-six patients had BRCA1 mutations, and 8 had BRCA2 mutations. Presence of BRCA1 mutation was associated with infiltrating cancer, high grade and lack of oestrogen receptor (p < 0.05 for all 3 characteristics). For BRCA1 mutation carriers, 5-year survival was 63% vs. 91% for noncarriers (p ؍ 0.04). For CaN0 patients, mutation carriers had 75% 5-year disease-free survival vs. 96% for noncarriers (p ؍ 0.01). Twenty-one of the mutation carriers had undergone prophylactic oophorectomy, prior to or within 6 months of diagnosis in 13 cases. All but 1 relapse occurred in the 15 who had kept their ovaries, (p < 0.01); no relapse occurred in those who had removed the ovaries within 6 months (p ؍ 0.04) Contralateral cancer was more frequently observed in mutation noncarriers, but this finding did not reach statistical significance. Our findings support the concept that BRCA1 cancer is biologically different from other inherited breast cancers. While current screening protocols appear satisfactory for the majority of women at risk of familial breast cancer, this may not be the case for BRCA1 mutation carriers. The observed effect of oophorectomy was striking.
Women with a family history of breast cancer are commonly offered regular clinical or mammographic surveillance from age 30. Data on the efficacy of such programmes are limited. Clinical, pathological and outcome data were recorded on all breast and ovarian cancers diagnosed within familial breast cancer surveillance programmes at collaborating centers in Norway and the UK up to the end of 2005. These have been analyzed according to the mutation status of the affected women (BRCA11ve, BRCA21ve or mutation-negative). Breast cancer was diagnosed in 442 patients subsequently followed for a total of 2095 years. Eightynine (20%) had BRCA1 mutations, 35 (8%) BRCA2 mutations and in 318 (72%) no mutation could be detected (''mut neg''). Fiveyear survival in BRCA1 was 73% compared to 96% in BRCA2 and 92% in mut neg (p 5 0.000). Among BRCA1 mutation-carriers, 5-year survival was 67% for cases diagnosed as carcinoma in situ, 84% for node-negative invasive cancers and 58% for those with nodal involvement (p > 0.05). For BRCA2 mutation-carriers the corresponding figures were 100, 100 and 90% (p > 0.05), while for mut neg women they were 100, 97 and 71% (p 5 0.03). Regular surveillance in women at increased familial risk of breast cancer is associated with a good outcome if they carry BRCA2 mutations or no detectable mutation. Carriers of BRCA1 mutations fare significantly worse, even when their tumors are diagnosed at an apparently early stage. The differences in outcome associated with different genetic causes of disease were associated with demonstrated differences in tumor biology. The findings demonstrate the outcome for genetically different breast cancers detected within a programme for early diagnosis and treatment, which is relevant to genetic counseling when women at risk have to chose between the options for preventing death from inherited breast cancer. ' 2007 Wiley-Liss, Inc.
Protocols for activity aiming at early diagnosis and treatment of inherited breast or breast-ovarian cancer have been reported. Available reports on outcome of such programmes are considered here. It is concluded that the ongoing activities should continue with minor modifications. Direct evidence of a survival benefit from breast and ovarian screening is not yet available. On the basis of expert opinion and preliminary results from intervention programmes indicating good detection rates for early breast cancers and 5-year survival concordant with early diagnosis, we propose that women at high risk for inherited breast cancer be offered genetic counselling, education in ‘breast awareness’ and annual mammography and clinical expert examination from around 30 years of age. Mammography every second year may be sufficient from 60 years on. BRCA1 mutation carriers may benefit from more frequent examinations and cancer risk may be reduced by oophorectomy before 40–50 years of age. We strongly advocate that all activities should be organized as multicentre studies subjected to continuous evaluation to measure the effects of the interventions on long-term mortality, to match management options more precisely to individual risks and to prepare the ground for studies on chemoprevention.
Aortic dissections (AD) are characterized by the separation of the artery into two sheets, possibly due to fragility of the vessel wall. A mucoid histological pattern, imparted to the tissues mainly by hyaluronan and proteoglycans, can be seen in "cysts" and, in chronic cases, in a band of repair tissue. We studied the localization of hyaluronan, versican, decorin and biglycan in situ in aortas of 21 patients with recent AD, 8 with chronic AD and in 15 control cases. None of these substances was increased in the areas of mucoid "cysts" that possibly contain anomalous material. Similar distributions were seen in normal and dissected aortas: versican and hyaluronan were more prominent in the external half of the medial layer where the dissection usually occurs. Since these molecules play a role in resistance to compression, disorders not detected by our method may be involved in aortic dissection. Hyaluronan was seen adjacent to fibrin at the dissection tear, probably as an early wound repair phenomenon. Biglycan, hyaluronan and mostly versican are seen during advanced repairing. The mucoid deposits may represent various compounds which reflect different disorders in vascular biology.
BACKGROUND: Surveillance programmes for women at increased genetic risk of breast cancer are being established worldwide but little is known of their efficacy in early detection of cancers and hence reduction in mortality.METHODS: Data were contributed from seven centres participating in the EU Demonstration Programme on Clinical Services for Familial Breast Cancer. All breast tumours (n = 161) detected prospectively, from the time of enrolment of women in a screening programme, were recorded. Analysis took account of age at diagnosis, whether tumours were screen-detected or not, their pathological stage and outcome by Kaplan—Meier survival plots.RESULTS: Mean age at diagnosis was 48.6 years. Overall, 75% of tumours were detected in the course of planned examinations. For women under age 50 at diagnosis, this figure was 68%. Eighteen percent were mammographically negative, (23% in patients under age 50). At first (“prevalence”) round and at follow-up screening, 16% and 22% of tumours respectively were carcinoma in situ (CIS) while 27% and 22% respectively had evidence of nodal or distant spread (CaN+). Comparison of screen-detected and other tumours showed that the latter were more frequently mammogram-negative and CaN+. Overall five-year survival was 89% and five-year event-free survival 86%. Five-year event-free survival was 100% for CIS, 88% for invasive cancer without nodal or distant spread and 67% for CaN+.CONCLUSIONS: The majority of cancers arising in women at increased genetic risk of breast cancer can be detected by planned screening, even in those under age 50. Surveillance should include regular expert clinical examination and teaching of “breast awareness” as well as mammography. Attention to the logistics of screening programmes may improve still further the proportion of tumours that are screen-detected. The trend towards earlier pathological stage in tumours detected during follow-up rounds and the preliminary findings on survival analysis suggest that this approach will prove to be of long-term benefit for breast cancer families.
Up to 40% of referrals from primary care to 'breast cancer family clinics' prove to be of women whose assessed risk falls below the guidelines' threshold for management in secondary or tertiary care, despite recommendations that they should be screened out at primary care level. A randomised trial, involving 87 such women referred to the Tayside Familial Breast Cancer Service compared two ways of communicating risk information, letter or personal interview. Both were found to be acceptable to referred women and to their family doctors, although the former expressed a slight preference for interview. Only four women returned to their family doctors with continuing concerns about breast cancer. Nevertheless, understanding of information provided by either route was unsatisfactory, with apparent confusion about both absolute and relative risks of breast cancer. Substantial minorities appear to believe that they are at no increased risk at all, or even below the population level of risk, while others remain convinced that their personal risk has been underestimated. Family history record forms, completed by the referred women, preferably with the assistance of relatives, are crucial to full assessment of familial risk but one quarter of women referred to the Tayside Familial Breast Cancer Service currently do not complete and return these forms ahead of their clinic appointment. Further collaboration between primary care and the Breast Cancer Family Service is required to improve provision for concerned women whose risks fall below the threshold for special surveillance and to maximise effective use of the family history record form.
Analysis of activity was undertaken in an established regional clinic providing risk assessment, counselling, screening and management for women with a family history of breast or ovarian cancer. The objectives were to determine: (1) how closely the route and pattern of referrals matched official guidelines (2) whether the previously recorded socio-economic imbalance among clinic clientele persisted and (3) the economic and practical consequences of committing resources to verification and extension of reported family histories. The findings were: (1) after some years of operation, the proportion of referrals direct from primary care had increased from less than 50% to over 75%, with a concomitant slight decrease in overall referral rate; (2) the socio-economic distribution of patients referred had become less selective and (3) extension and verification of reported family histories led to a redistribution of risk categories, increasing the proportion of referrals judged to be in the "low risk" category, from 25% (based on referral letter alone) to 41% (at the end of the process). The costs associated with this approach are offset by the savings generated and it allows specialised counselling and screening services to be targeted more efficiently.
Scottish women at increased risk of breast cancer have scope for protective changes in lifestyle and support a risk-reduction trial. The needs of younger women and of those with daughters should be addressed in its design.
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