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Mitch Dowsett – 1st expert on this subject based on the ideXlab platform
Mechanisms of resistance to Aromatase Inhibitors.The Journal of steroid biochemistry and molecular biology, 2020Co-Authors: Mitch Dowsett, Ian Smith, Lesley-ann Martin, Stephen JohnstonAbstract:
Aromatase Inhibitors are rapidly becoming the first choice for hormonal treatment of steroid receptor positive breast cancer in postmenopausal women. An understanding of the resistance mechanisms to these agents is, therefore, important for the appropriate delivery of treatment to responsive patients and the rational development of new agents targeted at the resistance pathways. De novo resistance appears to be a quantitative rather than qualitative phenomenon with virtually all oestrogen receptor positive tumours showing an anti-proliferative response to the Aromatase inhibitor anastrozole. While the expression of type 1 growth factor receptors reduces response to tamoxifen this appears to have little detrimental effect on response to Aromatase Inhibitors. Studies of acquired resistance in vitro have indicated that acquisition of hypersensitivity to oestrogenic stimulation is a key mechanism that is dependent on enhanced cross-talk of growth factor and oestrogen signaling pathways. Collection of resistant biopsy tissues from patients is important to determine if this mechanism is clinically relevant.
Aromatase Inhibitors versus tamoxifen in early breast cancer patient level meta analysis of the randomised trialsThe Lancet, 2015Co-Authors: Mitch Dowsett, John F Forbes, Matti HakamaAbstract:
Background The optimal ways of using Aromatase Inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain. Methods We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of Aromatase inhibitor versus 5 years of tamoxifen; of 5 years of Aromatase inhibitor versus 2-3 years of tamoxifen then Aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then Aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded Aromatase inhibitor versus tamoxifen first-event rate ratios (RRs). Findings In the comparison of 5 years of Aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured Aromatase Inhibitors significantly during years 0-1 (RR 0.64, 95% CI 0.52-0.78) and 2-4 (RR 0.80, 0.68-0.93), and non-significantly thereafter. 10-year breast cancer mortality was lower with Aromatase Inhibitors than tamoxifen (12.1% vs 14.2%; RR 0.85, 0.75-0.96; 2p=0.009). In the comparison of 5 years of Aromatase inhibitor versus 2-3 years of tamoxifen then Aromatase inhibitor to year 5, recurrence RRs favoured Aromatase Inhibitors significantly during years 0-1 (RR 0.74, 0.62-0.89) but not while both groups received Aromatase Inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of Aromatase Inhibitors than with tamoxifen then Aromatase Inhibitors (RR 0.90, 0.81-0.99; 2p=0.045), though the breast cancer mortality reduction was not significant (RR 0.89, 0.78-1.03; 2p=0.11). In the comparison of 2-3 years of tamoxifen then Aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured Aromatase Inhibitors significantly during years 2-4 (RR 0.56, 0.46-0.67) but not subsequently, and 10-year breast cancer mortality was lower with switching to Aromatase Inhibitors than with remaining on tamoxifen (8.7% vs 10.1%; 2p=0.015). Aggregating all three types of comparison, recurrence RRs favoured Aromatase Inhibitors during periods when treatments differed (RR 0.70, 0.64-0.77), but not significantly thereafter (RR 0.93, 0.86-1.01; 2p=0.08). Breast cancer mortality was reduced both while treatments differed (RR 0.79, 0.67-0.92), and subsequently (RR 0.89, 0.81-0.99), and for all periods combined (RR 0.86, 0.80-0.94; 2p=0.0005). All-cause mortality was also reduced (RR 0.88, 0.82-0.94; 2p=0.0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with Aromatase Inhibitors than tamoxifen (10-year incidence 0.4% vs 1.2%; RR 0.33, 0.21-0.51) but more bone fractures (5-year risk 8.2% vs 5.5%; RR 1.42, 1.28-1.57); non-breast-cancer mortality was similar. Interpretation Aromatase Inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments diff er, but not thereafter. 5 years of an Aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. Copyright (C) Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Open Access article distributed under the terms of CC BY.
meta analysis of breast cancer outcomes in adjuvant trials of Aromatase Inhibitors versus tamoxifenJournal of Clinical Oncology, 2010Co-Authors: Mitch Dowsett, A U Buzdar, M Baum, John F Forbes, Jack Cuzick, Jim Ingle, Alan S Coates, J M Bliss, Marc Buyse, Marco ColleoniAbstract:
Purpose To conduct meta-analyses of randomized trials of Aromatase Inhibitors (AIs) compared with tamoxifen either as initial monotherapy (cohort 1) or after 2 to 3 years of tamoxifen (cohort 2).
Robert F Casper – 2nd expert on this subject based on the ideXlab platform
a historical perspective of Aromatase Inhibitors for ovulation inductionFertility and Sterility, 2012Co-Authors: Robert F Casper, Mohamed F M MitwallyAbstract:
The concept of using Aromatase Inhibitors in place of clomiphene citrate (CC) for ovulation induction was introduced >10 years ago; a brief history of its development is presented. Its worldwide usage for ovulation induction, including as an adjunct for intrauterine insemination and in vitro fertilization has occurred despite the absence of definitive data of superiority to CC. The results of two ongoing potentially definitive multicenter trials of efficacy and safety of letrozole compared with CC are eagerly awaited.
Aromatase Inhibitors: potential reproductive implications.Journal of Minimally Invasive Gynecology, 2009Co-Authors: Mohamed A. Bedaiwy, Noha A. Mousa, Robert F CasperAbstract:
MEDLINE, EMBASE, Scopus, and Web of Science databases literature search from inception to March 2009 was performed to identify published clinical trials and cohort, observational, and in vitro studies that evaluated the use of Aromatase Inhibitors in reproductive medicine for indications other than ovulation induction. Aromatase Inhibitors are currently being investigated for breast cancer prevention in women at high risk. Aromatase Inhibitors may be used for treatment of symptomatic myomas and endometriosis as an alternative to surgical intervention. Current evidence does not support the routine use of Aromatase Inhibitors for these conditions without prospective controlled trials. Aromatase inhibitor cotreatment can be used to prevent the initial estrogen flare effect of gonadotropin-releasing hormone agonist treatment to offer flexibility in initiating this therapy.
Aromatase Inhibitors in ovarian stimulation.The Journal of Steroid Biochemistry and Molecular Biology, 2007Co-Authors: Robert F CasperAbstract:
The selective estrogen receptor modulator, clomiphene citrate (CC), has been the principal drug used for induction of ovulation in women with polycystic ovarian syndrome (PCOS). CC is associated with adverse side effects and low pregnancy rates attributed to long-lasting estrogen receptor depletion. Anastrozole and letrozole are potent, non-steroidal, reversible Aromatase Inhibitors, developed for postmenopausal breast cancer therapy. We hypothesized that Aromatase Inhibitors could mimic the action of CC in reducing estrogen negative feedback on follicle stimulating hormone (FSH) secretion, without depleting estrogen receptors. In a series of preliminary studies, we reported the success of Aromatase inhibition in inducing ovulation in anovulatory women with PCOS. Moreover, we showed that concomitant use of Aromatase Inhibitors resulted in a significant reduction of the FSH dose needed for controlled ovarian hyperstimulation. We suggest that Aromatase Inhibitors act through an increase in endogenous gonadotropin secretion as well as through increased intraovarian androgen levels that may increase ovarian FSH receptors. Recently, we demonstrated the safety of Aromatase Inhibitors in pregnancy outcome studies examining spontaneous pregnancy loss, multiple pregnancy rates and congenital anomalies compared to a control group of infertility patients treated with CC.
Paul E Goss – 3rd expert on this subject based on the ideXlab platform
effects of steroidal and nonsteroidal Aromatase Inhibitors on markers of bone turnover in healthy postmenopausal womenBreast Cancer Research, 2007Co-Authors: Paul E Goss, Peyman Hadji, Milayna Subar, Paula Abreu, Torben Thomsen, Jose BankebochitaAbstract:
In contrast to nonsteroidal Aromatase Inhibitors, the steroidal Aromatase inactivator exemestane does not have detrimental effects on bone in animal models. This study was designed to compare the effects of exemestane with the nonsteroidal Aromatase Inhibitors anastrozole and letrozole on serum and urine levels of biomarkers of bone turnover in healthy postmenopausal women.
Prevention of Breast Cancer Using SERMs and Aromatase InhibitorsJournal of Mammary Gland Biology and Neoplasia, 2003Co-Authors: Kathrin Strasser-weippl, Paul E GossAbstract:
Breast cancer is one of the most common cancers of women in the Western world. Despite modest achievements in the treatment of this disease, there is a substantial unmet medical need to reduce the occurrence of new breast cancers. In several prospective, placebo-controlled trials, the antiestrogen tamoxifen has been shown to reduce the incidence of both invasive cancer and preinvasive breast lesions. Meanwhile, numerous other selective estrogen receptor modulators (SERMs) are being developed and trials comparing tamoxifen to these agents are ongoing. The goal of these studies is not only to show superior chemopreventive efficacy of the newer SERMs, but also an improved side-effect profile. The proof-of-principle demonstrated with tamoxifen suggests that strategies inhibiting estrogen are a logical way forward in breast cancer prevention. Aromatase Inhibitors, which antagonize estrogen by blocking its synthesis from androgens, offer an alternative way of preventing the effects of estrogen and its metabolites on the breast. In this paper, the available data on SERMs including tamoxifen and raloxifene in breast cancer prevention and the data pointing to the efficacy of Aromatase Inhibitors in this setting are outlined.
Aromatase Inhibitors in the treatment and prevention of breast cancerJournal of Clinical Oncology, 2001Co-Authors: Paul E Goss, Kathrin StrasserAbstract:
PURPOSE: The purpose of this article is to provide an overview of the current clinical status and possible future applications of Aromatase Inhibitors in breast cancer. METHODS: A review of the literature on the third-generation Aromatase Inhibitors was conducted. Some data that have been presented but not published are included. In addition, the designs of ongoing trials with Aromatase Inhibitors are outlined and the implications of possible results discussed. RESULTS: All of the third-generation oral Aromatase Inhibitors—letrozole, anastrozole, and vorozole (nonsteroidal, type II) and exemestane (steroidal, type I)—have now been tested in phase III trials as second-line treatment of postmenopausal hormone-dependent breast cancer. They have shown clear superiority compared with the conventional therapies and are therefore considered established second-line hormonal agents. Currently, they are being tested as first-line therapy in the metastatic, adjuvant, and neoadjuvant settings. Preliminary results sug…