Furthermore, it is clear that the incidence of estrogen receptor (ER)-negative cancers is not reduced with preventive tamoxifen therapy and that some ER-positive precancerous lesions might be resistant to tamoxifen [1]

ubatubasat | Posted on January 5, 2023 |

Furthermore, it is clear that the incidence of estrogen receptor (ER)-negative cancers is not reduced with preventive tamoxifen therapy and that some ER-positive precancerous lesions might be resistant to tamoxifen [1]. Drug development Important priorities for breast cancer prevention are to develop a variety of new prevention agents that have fewer side effects or a different side effect profile from that of tamoxifen, that are compatible with hormone replacement therapy (HRT), and that are effective in ER-negative as well as in tamoxifen-resistant ER-positive precancerous tissue. To develop new drugs in a short period and at reasonable cost, more efficient clinical testing models are being developed for phase I and II prevention trials. and to assess the response in phase II prevention trials. If validated, morphological and molecular markers could eventually replace cancer incidence as an indicator of efficacy in future phase III trials. or invasive cancer, it is not clear what groups of women receive enough benefit to offset the potential side effects. These side SN 2 effects include increased risk of menstrual abnormalities and bone loss in young pre-menopausal women, and increased risk of hot flashes, sexual dysfunction, cataracts, uterine cancer, and thromboembolic phenomena in perimenopausal and post-menopausal women [1,2,3]. Concerns about the risk:benefit ratio, particularly in women over 50, have led to the recommendation that this group not receive tamoxifen unless their short-term risk approaches 1% per year for women with a uterus and 0.5% per year for women without a uterus [4]. In the USA, many women are not given the option of simultaneous tamoxifen and hormone replacement for fear of increasing thromboembolic risk [1,5]. Furthermore, it is clear that the incidence of estrogen receptor (ER)-negative cancers SN 2 is not reduced with preventive tamoxifen therapy and that some ER-positive precancerous lesions might be resistant to tamoxifen [1]. Drug development Important priorities for breast cancer prevention are to develop a variety of new prevention agents that have fewer side effects or a different side SN 2 effect profile from that of tamoxifen, that are compatible with hormone replacement therapy (HRT), and that are effective in ER-negative as well as in tamoxifen-resistant ER-positive precancerous tissue. To develop new drugs in a short period and at reasonable cost, more efficient clinical testing models are being developed for phase I and II prevention trials. These models use potentially reversible morphological and molecular biomarkers that will enhance short-term risk prediction, that will improve the probability of response by matching the biomarker profile in precancerous tissue to agents in the appropriate drug class, and that will be used to assess response in a preliminary fashion before a cancer incidence trial [6]. Biomarkers Several potentially reversible biomarkers have been associated with increased cancer risk, including mammographic breast density, insulin growth factor-1 and its binding protein, serum estrogen and testosterone levels, and intraepithelial neoplasia (IEN) [7,8,9,10,11,12,13]. IEN is probably the risk biomarker most closely related to the underlying neoplastic process [11]. IEN can be functionally defined as a condition with morphological, molecular and genetic abnormalities as well as an increased risk for breast cancer. Using this definition, breast IEN can be viewed as beginning with simple hyperplasia and extending through atypical hyperplasia and carcinoma. Molecular alterations noted in at least a subset of IEN that clamor for targeted intervention include the following: (1) aberrant methylation and histone deacetylation of the promoter region of many tumor suppressor genes [14,15,16]; (2) increased growth factor and growth factor receptor expression/activation, resulting in increased mitogen-activated kinase activity; (3) increased cyclooxygenase-2 (COX-2) expression, tissue polyamines, angiogenesis and protease activity [17,18,19,20,21]; (4) overexpressed ER and hypersensitive ER variants [22,23]; and (5) increased aromatase and sulfatase activities, which result in increased breast estrogen levels [24,25]. Potential agents Histone deacetylase inhibitors combined with demethylating agents are promising as a means of rehabilitating silenced tumor suppressor genes in ER-negative or ER-positive precancerous tissue [26,27]. Inhibitors of activated tyrosine kinase, COX-2, metalloproteases, and polyamine synthesis should also have activity in ER-negative as well as ER-positive tamoxifen-resistant precancerous tissue. These types of agents might be used in premenopausal women or postmenopausal women taking HRT without altering the menstrual cycle or inducing hot flashes [17,28]. The same can be said of monoterpenes [29] and sulindac sulfone [30], which may act primarily to induce apoptosis [31]. Several compounds such as difluoromethylornithine (an inhibitor of polyamine synthesis) and perillyl alcohol (a monoterpene) are already in phase I-II prevention testing, and trials for others such as celecoxib, a COX-2 inhibitor, and ZD1839, a tyrosine kinase inhibitor, are in the.In the USA, many women are not given the option of simultaneous tamoxifen and hormone replacement for fear of increasing thromboembolic risk [1,5]. molecular markers could eventually replace cancer incidence as an indicator of efficacy in future phase III trials. or invasive cancer, it is not clear what groups of women receive enough benefit to offset the potential side effects. These side effects include increased risk of menstrual abnormalities and bone loss in young pre-menopausal women, and increased risk of hot flashes, sexual dysfunction, cataracts, uterine cancer, and thromboembolic phenomena in perimenopausal and post-menopausal women [1,2,3]. Concerns about the risk:benefit ratio, particularly in women over 50, have led to the recommendation that this group not receive tamoxifen unless their short-term risk approaches 1% per year for women with a uterus and 0.5% per year for women without a uterus [4]. In the USA, many women are not given the option of simultaneous tamoxifen and hormone replacement for fear of increasing thromboembolic risk [1,5]. Furthermore, it is clear that the incidence of estrogen receptor (ER)-negative cancers is not reduced with preventive tamoxifen therapy and that some ER-positive precancerous lesions might be resistant to tamoxifen [1]. Drug development Important priorities for breast cancer prevention are to develop a variety of new prevention agents that have fewer side effects or a different side effect profile from that of tamoxifen, that are compatible with hormone replacement therapy (HRT), and that are effective in ER-negative as well as in tamoxifen-resistant ER-positive precancerous tissue. To develop new drugs in a short period and at reasonable cost, more efficient clinical testing models are being developed for phase I and II prevention trials. These models use potentially reversible morphological and molecular biomarkers that will enhance short-term risk prediction, that will improve the probability of response by matching the biomarker profile in precancerous tissue to agents in the appropriate drug class, and that’ll be used to assess response in a preliminary fashion before a malignancy incidence trial [6]. Biomarkers Several potentially reversible biomarkers have been associated with improved tumor risk, including mammographic breast density, insulin growth factor-1 and its binding protein, serum estrogen and testosterone levels, and intraepithelial neoplasia (IEN) [7,8,9,10,11,12,13]. IEN is probably the risk biomarker most closely related to the underlying neoplastic process [11]. IEN can be functionally defined as a disorder with morphological, molecular and genetic abnormalities as well as an increased risk for breast cancer. By using this definition, breast IEN can be viewed as beginning with simple hyperplasia and extending through atypical hyperplasia and carcinoma. Molecular alterations mentioned in at least a subset of IEN that clamor for targeted treatment include the following: (1) aberrant methylation and histone deacetylation of the promoter region of many tumor suppressor genes [14,15,16]; (2) improved growth element and growth element receptor manifestation/activation, resulting in improved mitogen-activated kinase activity; (3) improved cyclooxygenase-2 (COX-2) manifestation, cells polyamines, angiogenesis and protease activity [17,18,19,20,21]; (4) overexpressed ER and hypersensitive ER variants [22,23]; and (5) improved aromatase and sulfatase activities, which result in improved breast estrogen levels [24,25]. Potential providers Histone deacetylase inhibitors combined with demethylating providers are promising as Mmp15 a means of rehabilitating silenced tumor suppressor genes in ER-negative or ER-positive precancerous cells [26,27]. Inhibitors of triggered tyrosine kinase, COX-2, metalloproteases, and polyamine synthesis should also possess SN 2 activity in ER-negative as well as ER-positive tamoxifen-resistant precancerous cells. These types of providers might be used in premenopausal ladies or postmenopausal ladies taking HRT without altering the menstrual cycle or inducing sizzling flashes [17,28]. The same can be said of monoterpenes [29] and sulindac sulfone [30], which may act primarily to induce apoptosis [31]. Several compounds such as difluoromethylornithine (an inhibitor of polyamine synthesis) and perillyl alcohol (a monoterpene) are already in phase I-II prevention screening, and tests for others such as celecoxib, a COX-2 inhibitor, and ZD1839, a tyrosine kinase inhibitor, are in the active planning stage [32,33,34,35]. New selective estrogen receptor modulators (SERMs) that maintain breast antagonist and bone agonist activity but lack uterine agonist.