Breast cancer after hormone replacement therapy--does prognosis differ in perimenopausal and postmenopausal women?

Hormone replacement therapy (HRT) has been associated with higher incidence of breast cancer in postmenopausal women, but it is unclear if breast cancers developing after HRT use have different prognosis. 1053 women with hormone receptor positive non-metastasized breast cancer were analyzed in a retrospective trial, stratifying by HRT use before diagnosis. Postmenopausal HRT users had significantly more early tumor stages (p<0.001). HRT in postmenopausal patients was associated with longer time to progression (TTP) (HR 0.81, 95%CI 0.55-1.19, p=0.28) and overall survival (OS) (HR 0.68, 95%CI 0.45-1.02, p=0.059). Perimenopausal HRT users showed shorter TTP and OS (HR 1.99, 95%CI 0.57-6.91, p=0.28 and HR 4.59, 95%CI 0.91-23.25, p=0.06 respectively). Higher BMI was significantly associated with poorer prognosis in perimenopausal women only (TTP: HR=1.16; OS: HR=1.31). In this retrospective analysis postmenopausal HRT users seemed to have a better breast cancer prognosis. For perimenopausal HRT users however, a trend towards worse prognosis was found.

[Chemoprevention of breast cancer: a literature review and report on the current status in Germany]. / Medikamentöse Prävention des Mammakarzinoms: eine Ubersicht über die Literatur und den Stand in Deutschland.

The prevention of breast cancer is increasingly of focus in health-politics policies and has gained a valid position in the area of medical intervention. Data from a current meta-analysis of all four randomised Tamoxifen prevention studies illustrate a reduction of 38 % (Odds ratio 0.62; 95 % CI 0.42-0.89) in the incidence of breast cancer. This observation lead to registration of this drug in the USA for the prevention of breast cancer in women with a calculated 5-year risk of > 1.66 %. In addition to Tamoxifen, further substances are currently being tested with the aim of improving the therapeutic index whilst reducing incidence and mortality rates. These are primarily substances which have proven efficacy in the treatment of breast cancer (other antioestrogens, aromatase inhibitors and GnRH-analogues) or those whose mechanism of action predict a preventative effect (retinoids, phytooestrogens, substitution preparations e. g. Tibolone). In Germany, chemoprevention is currently only to be recommended within study protocols, as to date no substance is approved in the indication 'prevention of breast cancer'. A essential contribution to the accrual of valid data is the conduct of breast cancer prevention trials. The participation of women with high risk of breast cancer in Germany is, in contrast to comparable international studies, problematic. Data on the current knowledge and attitude of the female population towards such trials (gathered via a questionnaire of the DACH in 7 000 women) show that only 19.5 % of the women questioned during a consultation with a gynaecologist were aware of the possibility of active chemoprevention. However, 55.3 % stated that they would be prepared to take such a substance, were chemoprevention possible. Studies for both pre- and post-menopausal women with increased risk of breast cancer are currently active in Germany (GISS and IBIS-II of the study group GABG - German Adjuvant Breast cancer Group). An intensive information campaign to raise public awareness of breast cancer risk amongst women and their physicians is planned in conjunction with the IBIS-II study (www.brustkrebsvorbeugen.de). Latest literature recommendations for prevention of breast cancer (Chlebowski et al.) have been assessed.

[Primary and secondary breast cancer prevention. Knowledge, assessment and participation among the female population of Schleswig-Holstein]. / Primäre und sekundäre Brustkrebsprävention. Kenntnisstand, subjektive Beurteilung und Teilnahme einer Stichprobe der weiblichen Bevölkerung Schleswig-Holsteins.

OBJECTIVE: The intention was to find out to what extend women in Schleswig-Holstein were informed about primary and secondary preventive measures concerning breast cancer, how they assess their efficiency and in how far they are willing to take part in them. From June 1999 to April 2000 1 520 women in Schleswig-Holsteins were asked to complete a questionnaire about breast cancer prevention. There was a representative opinion poll of the market research company "Institut für Gesundheitsforschung München (Infratest)". RESULTS: Most of the women (90.6 %) believed in the efficiency of early recognition of breast cancer at the gynaecologist, only 79.3 % of them stated that they took the chance of taking part in the annual examination. According to the doctors Union "Kassenärztliche Vereinigung", only 50.4 % of the female members of health insurance schemes took part in examinations concerning the early recognition of breast cancer in 1999. The degree of knowledge about and participation in preventive measures depend on the age of the women. The gynaecologist was named as the most important source of information and counselling. CONCLUSION: In future the population needs more information and instruction concerning breast cancer preventive measures.

Comparative genomic hybridization detects genetic imbalances in primary ovarian carcinomas as correlated with grade of differentiation.

BACKGROUND: In the current study the authors attempted to evaluate genetic alterations in a large set of primary ovarian carcinomas and to compare the genetic findings with clinical parameters such as grade of tumor differentiation. This strategy was applied to identify chromosomal regions containing genes associated with tumor progression. METHODS: Genetic imbalances were assessed in 106 primary ovarian carcinomas using comparative genomic hybridization (CGH). CGH was applied because it is a powerful tool with which to screen the entire genome of a tumor for genetic changes by highlighting regions of altered DNA sequence copy numbers (deletions and amplifications). Multivariate statistical standard procedures were used to determine an association between tumor grading and genetic alterations. RESULTS: One hundred three carcinomas showed aberrant CGH profiles. The most frequent alterations were amplifications of 8q, 1q, 20q, 3q, and 19p, which occurred in 69-53% of tumors, and underrepresentations of 13q, 4q, and 18q, which occurred in 54-50% of tumors. Undifferentiated ovarian carcinomas (World Health Organization Grade 3) were found to be correlated significantly with underrepresentation of 11p and 13q as well as with overrepresentation of 8q and 7p (P = 0.001, 0.001, 0.01, and 0.027, respectively). However, 12p underrepresentation and 18p overrepresentation were significantly more frequent in well and moderately differentiated tumors (P = 0.01 and 0.004, respectively). To facilitate the interpretation and clinical application of the results of the current study, the significant aberrations were translated into a score system. This score system can be used easily for the prediction of an undifferentiated phenotype with a specificity and sensitivity of 79% and 86%, respectively. CONCLUSIONS: The current study data show that primary ovarian carcinomas are based on consistent genetic alterations that most likely are important for the development of this tumor entity. The correlation between certain aberrations and undifferentiated carcinomas may help to discriminate between primary and secondary genetic events and may indicate the location of those genes involved in cellular functions associated with tumor progression and the development of anaplastic and aggressive phenotypes.

Ten novel BRCA1 and BRCA2 mutations in breast and/or ovarian cancer families from northern Germany.

Germline mutations in the BRCA1 and BRCA2 gene account for the majority of high-risk breast/ovarian cancer families. We have screened such families from Northern Germany by using DHPLC analysis and subsequent direct sequencing techniques. In ten families we identified six novel BRCA1 and 4 novel BRCA2 mutations comprising four frame shift mutations, one nonsense and one splice site mutation in the BRCA1 gene as well as three frameshift mutations and one nonsense mutation in the BRCA2 gene. Our analysis contributes to the further characterisation of the mutational spectrum of BRCA1 and BRCA2.

A highly sensitive, fast, and economical technique for mutation analysis in hereditary breast and ovarian cancers.

Mutation analysis of complex genes without hotspots for sequence variations, such as BRCA1, is time-consuming and expensive. Of all currently available methods, direct sequencing has the highest sensitivity, but also the highest costs. Other techniques, such as SSCP, DGGE, and PTT, are more economical but, depending on the experience of the investigator, have at best a sensitivity of 90%. We investigated in a prospective study the feasibility and accuracy of the DHPLC technique. We present the application of the DHPLC protocol for BRCA1 mutation detection on a HPLC device from Bio-Tek Kontron Instruments (Neufahrn, Germany). DNA from 46 women with hereditary breast and ovarian cancer undergoing genetic testing for BRCA1 mutations were tested. Of 1,518 amplicons analyzed by DHPLC, corresponding to 33 fragments spanning the entire BRCA1 gene, 626 were also directly sequenced. The comparison demonstrated that DHPLC detected all alterations found by direct sequencing. No false-positive signals were seen in cases of homozygous sequences. Further, no false-negative results were ever obtained in women with mutations or polymorphisms, or both. In cases of known genetic variations, the nature of the alterations could be predicted by DHPLC. We also compared different separation matrices. Up to about 500 injections, no significant differences in sensitivity could be observed between poly(styrene divinylbenzene) and end-capped silica based columns. However, after more than 500 injections, the resolution of hetero- from homoduplex deteriorated rapidly on silica columns.

A comparison of BRCA1 mutation analysis by direct sequencing, SSCP and DHPLC.

The most sensitive screening technique for genes that predispose patients for particular cancers is direct sequencing. However, sequencing of complex genes is technically demanding, costly and time-consuming. We have tested alternate screening techniques to find a fast sensitive method for detecting alterations of DNA in the large BRCA1 gene prior to sequencing. Sequencing of this gene is particularly arduous because it lacks clearly defined mutation sites. The single-strand conformation polymorphism (SSCP) technique is one of the most frequently used pre-screening methods but its sensitivity and efficiency is not completely satisfying. We have compared the SSCP assay with a newly developed technique called denaturing high performance liquid chromatography (DHPLC) to screen the BRCAl gene. We studied 23 patients at high risk for early onset breast and ovarian cancer and four controls. In these patients, a total of 113 fragments with sequence variations in the BRCA1 gene could be identified. The DHPLC technique resolved 100% of the DNA alterations that were observed in cycle sequencing. In contrast, mutation analysis by SSCP accounted for 94% of the detected variations. In addition, DHPLC screening allowed us to discriminate between different alterations in a single fragment, because of the characteristic elution profiles of the DNA molecules. Polymorphisms that were present in our samples could be predicted by means of DHPLC testing independently of sequence analysis. We conclude that DHPLC is a highly potent screening method for genetic analyses. It is highly sensitive, efficient and economical and can be automated.