Reduced mammographic density with use of a gonadotropin-releasing hormone agonist-based chemoprevention regimen in BRCA1 carriers
ABSTRACT Women with a BRCA1 mutation (BRCA1(mut)) need risk reduction options beyond mastectomy and oophorectomy. We evaluated the efficacy, safety, and tolerability of hormonal chemoprevention with a gonadotropin-releasing hormone agonist (GnRHA) with low-dose add-back steroids in BRCA1(mut) carriers.
The 12-month open label clinical trial used the GnRHA deslorelin, ultra-low-dose estradiol (E(2)), and replacement testosterone, administered via daily intranasal spray in premenopausal women with a BRCA1(mut), and intermittent oral medroxyprogesterone acetate. The end points included mammographic percent density, bone mineral density, endometrial hyperplasia, symptom inventory, and quality of life (Medical Outcomes SF-36 survey).
Six of eight BRCA1(mut) women (mean age, 30.3 years; range, 25-36 years) completed the study. Mammographic percent density was significantly reduced at 12 months (median absolute mammographic percent density decrease, 8.3%; P = 0.043), representing a 29.2% median reduction in mammographic percent density. Bone mineral density remained within reference limits for all participants; there were no cases of atypical endometrial hyperplasia and menses resumed within a median of 67 days (range, 35-110 days) after last drug treatment day. The treatment was well tolerated; hypoestrogenic side effects were minimal and transient; and there were no significant changes in quality of life.
The GnRHA deslorelin, with low-dose add-back steroids, was well tolerated and significantly decreased mammographic percent density in BRCA1(mut) carriers. This regimen may reduce breast cancer risk and improve the usefulness of mammographic surveillance by reducing density. This is the first demonstration, to our knowledge, of a direct reduction of mammographic densities in young BRCA1(mut) carriers.
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ABSTRACT: Elevated mammographic density measures are a well-established, relatively strong risk factor for breast cancer development. A systematic review of prospective cohort studies and cross-sectional studies strikingly establishes parallels between the associations of combined postmenopausal estrogen and progestin replacement therapy with, on the one hand, mammo-graphic densities and, on the other hand, breast cancer risk. Other parallel observations were the inverse associations of both mammographic density and breast cancer risk with the selective estrogen receptor modulator tamoxifen, and direct associations with prolactin. Paradoxically, however, high mammographic density has been found associated with higher risks of both estrogen- and progesterone-receptor positive (ER̫/ PR̫) and negative (ER−/PR−) breast cancers, while hormone replacement therapy (HRT) use, but also circulating (blood) levels of androgens, estrogens, and prolactin appear to be associated more specifically to the risk of ER̫ tumors. The effects of aromatase inhibitors and gonadotro-pin-releasing hormone agonists on breast density, as well as on breast cancer risk, still require further investigation. Regarding circulating levels of insulin-like growth factor (IGF)-I or IGFBP-3, studies did not show fully consistent relationships with mammographic density measures and breast cancer risk. In view of these various findings, it is impossible, at present, to propose mammographic density measures as an intermediate risk-related phenotype, integrating the effects of exogenous and/or endogenous hormones on the risk of developing breast cancer.
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ABSTRACT: Study of packet interference is important because interference affects the throughput of a piconet. Motivated by the fact that applications will benefit, in terms of higher available data rate in one direction, by using multiple-slot packets in an asymmetric manner, in this paper, we present an analytical model of packet interference in a cluster of piconets using multiple-slot packets. Also, considering that all the portable devices can have a Bluetooth interface and people are highly mobile these days, it will not be uncommon to find a cluster of piconets of both the 79-hop and the 23-hop types in the same area. We then present an analytical model of interference of multiple-slot packets in a heterogeneous cluster of Bluetooth piconets. By a heterogeneous cluster we mean some piconets are of the 23-hop type and the rest are of 79-hop type. We show how the aggregate throughput in a cluster of piconets degrade under various traffic scenarios, such as 1-slot, 3-slot, and 5-slot packets in symmetric and asymmetric modes in synchronous and asynchronous conditions of master clocks. Our analytic model is based on the idea of probabilistic graphs, where a node denotes a piconet and an edge denotes the probability of interference between two nodes.Communications, 2004 IEEE International Conference on; 07/2004
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ABSTRACT: Information related to the BRCA1 gene has increasingly become a subject for analysis by endocrinologists. For example, it is hard to dismiss the fact that, in BRCA1 mutation carriers, tumors develop predominantly in such estrogen-dependent organs as the mammary glands and ovaries but not in the endometrium. Another characteristic feature is that although BRCA1 mutants and knock-downs are unable to inhibit the transcriptional activity of estrogen receptor-alpha, in BRCA1 mutation carriers breast cancers are often estrogen receptor-negative and originate from the basal rather than the luminal epithelium. The latter, together with other data, suggests that BRCA1-positive breast neoplasms could be considered to be a consequence of the genotoxic variant of hormonal carcinogenesis (that is, associated with DNA damaging rather then with pure hormonal/physiological properties of hormones or their derivatives). Of indisputable significance are the data demonstrating that knocking down of the BRCA1 gene is accompanied by aromatase overexpression and the abolishment of IGF-1 receptor expression suppression, thus increasing both steroid and insulin signaling. Importantly, the endocrine-genotoxic 'liberation' found upon transfer from the wild-type to the mutant BRCA1 provides grounds to regard BRCA1 as a modulator of endocrine-genotoxic switching (predominantly into a direction of DNA-damaging hormone effects) and also to ask whether this is a property of only this or some other tumor suppressor's.Future Oncology 03/2008; 4(1):23-39. DOI:10.2217/147966184.108.40.206 · 2.61 Impact Factor