Articles de revues : « Third-generation aromatase inhibitor »

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Lønning, Per Eystein, et Hans Petter Eikesdal. « Aromatase inhibition 2013 : clinical state of the art and questions that remain to be solved ». Endocrine-Related Cancer 20, n^o 4 (26 avril 2013) : R183—R201. http://dx.doi.org/10.1530/erc-13-0099.

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Following their successful implementation for the treatment of metastatic breast cancer, the ‘third-generation’ aromatase inhibitors (anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancers. These drugs are characterized by potent aromatase inhibition, causing >98% inhibition of estrogen synthesisin vivo. A recent meta-analysis found no difference in anti-tumor efficacy between these three compounds. As of today, aromatase inhibitor monotherapy and sequential treatment using tamoxifen followed by an aromatase inhibitor for a total of 5 years are considered equipotent treatment options. However, current trials are addressing the potential benefit of extending treatment duration beyond 5 years. Regarding side effects, aromatase inhibitors are not found associated with enhanced risk of cardiovascular disease, and enhanced bone loss is prevented by adding bisphosphonates in concert for those at danger of developing osteoporosis. However, arthralgia and carpal tunnel syndrome preclude drug administration among a few patients. While recent findings have questioned the use of aromatase inhibitors among overweight and, in particular, obese patients, this problem seems to focus on premenopausal patients treated with an aromatase inhibitor and an LH-RH analog in concert, questioning the efficacy of LH-RH analogs rather than aromatase inhibitors among overweight patients. Finally, recent findings revealing a benefit from adding the mTOR inhibitor everolimus to endocrine treatment indicate targeted therapy against defined growth factor pathways to be a way forward, by reversing acquired resistance to endocrine therapy.

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Yante, I. Ketut, Desak Gede Agung Suprabawati et Iskandar Ali. « Comparison of Recurrence Rates in Patients with Locally Advanced Breast Cancer after Mastectomy and Received Aromatase Inhibitor Therapy with Steroids and Nonsteroids ». Bioscientia Medicina : Journal of Biomedicine and Translational Research 5, n^o 10 (15 juin 2021) : 945–48. http://dx.doi.org/10.32539/bsm.v5i10.360.

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Introduction. Breast cancer is a problem that is still faced throughout the world. The incidence of cancer in Indonesia is at number 8 in Southeast Asia. The incidence of breast cancer in women is 42.1 per 100,000 population. Aromatase inhibitors are hormonal therapy used in postmenopausal breast cancer with positive ER and/or positive PR. The third generation aromatase inhibitors are divided into 2 categories, namely non-steroidal agents that are reversible and steroid agents that are irreversible. Based on existing studies, there are no consistent research results regarding the incidence of recurrence after aromatase inhibitor therapy, both steroids and non-steroidal. Methods. This study is an analytical observational study with a retrospective cross-sectional design using secondary data from medical records. The research was carried out at the Surgical Clinic of RSUD dr. Soetomo Surabaya on October 1, 2020 until the end with the subject of LABC patients at POSA Surgery RSUD Dr. Soetomo who has undergone mastectomy and radiotherapy and has received adjuvant hormonal aromatase inhibitor therapy for 2 years from January 2018 to January 2020. Results. In the nonsteroidal aromatase inhibitor group, 18 subjects (60%) experienced recurrence and 16 subjects in the steroid aromatase inhibitor group (32%) with an OR of 0.314 (0.12-0.81; p=0.014. Based on the results of multivariate analysis, it was found that the increased risk of recurrence was significantly affected only by the administration of aromatase inhibitor p= 0.052 Conclusion. Women with locally advanced breast cancer after mastectomy who received aromatase inhibitor steroid therapy had a 0.314 times lower risk of recurrence than those who received non-steroidal aromatase inhibitor therapy.

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Yante, I. Ketut, Desak Gede Agung Suprabawati et Iskandar Ali. « Comparison of Recurrence Rates in Patients with Locally Advanced Breast Cancer after Mastectomy and Received Aromatase Inhibitor Therapy with Steroids and Nonsteroids ». Bioscientia Medicina : Journal of Biomedicine and Translational Research 5, n^o 4 (15 juin 2021) : 882–85. http://dx.doi.org/10.32539/bsm.v5i4.360.

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Introduction. Breast cancer is a problem that is still faced throughout the world. The incidence of cancer in Indonesia is at number 8 in Southeast Asia. The incidence of breast cancer in women is 42.1 per 100,000 population. Aromatase inhibitors are hormonal therapy used in postmenopausal breast cancer with positive ER and/or positive PR. The third generation aromatase inhibitors are divided into 2 categories, namely non-steroidal agents that are reversible and steroid agents that are irreversible. Based on existing studies, there are no consistent research results regarding the incidence of recurrence after aromatase inhibitor therapy, both steroids and non-steroidal. Methods. This study is an analytical observational study with a retrospective cross-sectional design using secondary data from medical records. The research was carried out at the Surgical Clinic of RSUD dr. Soetomo Surabaya on October 1, 2020 until the end with the subject of LABC patients at POSA Surgery RSUD Dr. Soetomo who has undergone mastectomy and radiotherapy and has received adjuvant hormonal aromatase inhibitor therapy for 2 years from January 2018 to January 2020. Results. In the nonsteroidal aromatase inhibitor group, 18 subjects (60%) experienced recurrence and 16 subjects in the steroid aromatase inhibitor group (32%) with an OR of 0.314 (0.12-0.81; p=0.014. Based on the results of multivariate analysis, it was found that the increased risk of recurrence was significantly affected only by the administration of aromatase inhibitor p= 0.052 Conclusion. Women with locally advanced breast cancer after mastectomy who received aromatase inhibitor steroid therapy had a 0.314 times lower risk of recurrence than those who received non-steroidal aromatase inhibitor therapy.

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Chowdhury, Simon, et Paul A. Ellis. « Recent advances in the use of aromatase inhibitors for women postmenopausal breast cancer ». British Menopause Society Journal 11, n^o 3 (1 septembre 2005) : 96–102. http://dx.doi.org/10.1258/136218005775544408.

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The aromatase enzyme catalyses the last step in estrogen biosynthesis. There are two classes of third-generation aromatase inhibitors: irreversible steroidal inhibitors (e.g. exemestane) and reversible non-steroidal inhibitors (e.g. anastrozole, letrozole). All three agents have been found to be equivalent or superior to megestrol acetate as second-line therapy for metastatic breast cancer. In the first-line setting, large phase III trials have shown that all three are equivalent or superior to tamoxifen in women with metastatic disease. Several large trials with varying study designs have been launched to analyse their role in the adjuvant setting. The four that have reported found longer average disease-free survival for women who received an aromatase inhibitor than for those who did not. In addition, one trial, MA.17, has shown a survival advantage associated with the use of an aromatase inhibitor in node-positive patients. Guidelines produced by the American Society of Clinical Oncology suggest that adjuvant therapy for postmenopausal women with hormone-receptor-positive breast cancer should include an aromatase inhibitor. However, the long-term consequences of estrogen deprivation in postmenopausal women remain uncertain, particularly with regard to bone and cardiovascular health. The advantages and disadvantages of different hormonal strategies should therefore be carefully considered in each individual case.

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Howell, Anthony. « Anastrozole : A New Gold Standard of Hormonal Treatment for Breast Cancer ? » Women's Health 1, n^o 3 (novembre 2005) : 309–22. http://dx.doi.org/10.2217/17455057.1.3.309.

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Tamoxifen has long been the standard endocrine therapy for postmenopausal women with hormone-sensitive breast cancer. However, data now suggest that the third-generation aromatase inhibitors have emerged as superior alternatives for advanced disease. In early disease evaluation of initial adjuvant therapy, data from the Arimidex®, Tamoxifen, Alone and in Combination trial has shown that anastrozole is more effective than tamoxifen with a better risk–benefit profile. This trial provides the most mature data of any aromatase inhibitor study and suggests that anastrozole should be considered the preferred initial adjuvant therapy for postmenopausal women with hormone-responsive early breast cancer. The emergence of aromatase inhibitors as an alternative to tamoxifen for the treatment of breast cancer is challenging the management of the disease and influencing the change of regulatory guidelines.

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Raymond, Lendelle, Nikita Rayani, Grace Polson, Kylie Sikorski, Ailin Lian et Melissa A. VanAlstine-Parris. « Determining the IC50 Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver ». Enzyme Research 2015 (9 novembre 2015) : 1–4. http://dx.doi.org/10.1155/2015/321820.

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Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [11C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [11C]-vorozole is binding to in the liver.

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Fadeeva, Ekaterina P., Alla S. Lisyanskaya, Georgiy M. Manikhas, Ruslan I. Glushakov et Natalia I. Tapilskaya. « Aromatase inhibitors of the third generation in endocrine therapy of breast cancer and endometrial cancer : the successes and failures of the combination therapy ». Reviews on Clinical Pharmacology and Drug Therapy 14, n^o 2 (15 juin 2016) : 47–57. http://dx.doi.org/10.17816/rcf14247-57.

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This review provides the current evidence of clinical studies on the effectiveness of endocrine therapy for breast cancer and endometrial cancer, including endometrial stromal sarcoma, by aromatase inhibitor (AI) III generation. The review presents dates from clinical trials comparing the effectiveness of AI and tamoxifen, as well as dates on combination therapy AI with inhibitors of mTOR pathway (BOLERO-2 trial), an antiestrogen (SWOG S0226, FACT, FIRST trials), an inhibitor of CDK4 / 6 (PALOMA -1 trial) and other drugs.

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de Jong, P. Chr, J. van de Ven, J. W. R. Nortier, I. Maitimu-Smeele, G. H. Denker, J. H. H. Thijssen, P. H. Th J. Slee et M. A. Blankenstein. « Inhibition of breast cancer tissue aromatase activity and estrogen concentrations by the third generation aromatase inhibitor vorozole ». European Journal of Cancer 33 (septembre 1997) : S9. http://dx.doi.org/10.1016/s0959-8049(97)84407-3.

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Goss, Paul E. « Pre-clinical and clinical review of vorozole, a new third generation aromatase inhibitor ». Breast Cancer Research and Treatment 49, S1 (mai 1998) : S59—S65. http://dx.doi.org/10.1023/a:1006052923468.

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Yoshizawa-Ogasawara, Atsuko, Noriyuki Katsumata, Reiko Horikawa, Mari Satoh, Tatsuhiko Urakami et Toshiaki Tanaka. « Third-generation Aromatase Inhibitor Improved Adult Height in a Japanese Boy with Testotoxicosis ». Clinical Pediatric Endocrinology 23, n^o 2 (2014) : 53–58. http://dx.doi.org/10.1297/cpe.23.53.

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Andrikopoulou, Angeliki, Oraianthi Fiste, Michalis Liontos, Meletios-Athanasios Dimopoulos et Flora Zagouri. « Aromatase and CDK4/6 Inhibitor-Induced Musculoskeletal Symptoms : A Systematic Review ». Cancers 13, n^o 3 (26 janvier 2021) : 465. http://dx.doi.org/10.3390/cancers13030465.

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Background: Treatment with aromatase inhibitors (AIs) is fundamental in women with hormone receptor-positive breast cancer in the adjuvant as well as the metastatic setting. Even though it is considered to be a well-tolerated therapy, aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) is the most common adverse event encountered by breast cancer patients. CDK4/6 inhibitors have emerged as a new treatment strategy in metastatic hormone receptor-positive breast cancer. However, the impact of CDK4/6 inhibitors on musculoskeletal symptoms caused by AIs is not well-defined. Objectives: This systematic review aims to identify the frequency of joint symptoms induced by treatment with AIs and CDK4/6 inhibitors in the metastatic setting. Search strategy: Eligible articles were identified by a search of existing literature for the period 2005/01/01–2021/01/01; The algorithm consisted of a predefined combination of the following keywords “breast”, “cancer”, “aromatase inhibitors”, “CDK4/6”, “phase III”. Selection criteria: This study was performed in accordance with PRISMA guidelines. All randomized controlled Phase III trials (RCTs) evaluating the administration of third-generation aromatase inhibitors (AIs) and CDK4/6 inhibitors in postmenopausal women in the metastatic setting were considered eligible for this review. Data collection: Overall, 16 randomized control trials (RCTs) were retrieved, of which nine studies explored the administration of AIs in the metastatic setting and seven studies investigated the combination of CDK4/6 inhibitors and AIs. Arthralgia was reported in 1–47% of patients treated with AIs and 5.8–33.3% of patients treated with CDK4/6 inhibitors. Myalgias occurred in 2–23.7% of patients receiving AIs compared with 4.8–11.9% of patients treated with CDK4/6 inhibitors. The incidence of back pain was 7–32.9% vs. 2.9–8.5% in postmenopausal women with metastatic disease treated with AIs and CDK4/6 inhibitors, respectively. Bone pain was reported in 7–32.9% of postmenopausal women treated with AIs and 2.9–8.5% of women treated with CDK4/6 inhibitors. Conclusions: AI treatment-induced musculoskeletal syndrome is an adverse event affecting over one-third (20–47%) of postmenopausal patients treated with AIs that often leads to treatment discontinuation. Data from RCTs provide evidence that the incidence of musculoskeletal symptoms is relatively decreased upon CDK4/6 inhibitor administration. CDK4/6 inhibitors may provide a protective role against AIMSS development.

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Steele, N., J. Zekri, R. Coleman, R. Leonard, K. Dunn, A. Bowman, I. Manifold, I. Kunkler, O. Purohit et D. Cameron. « Exemestane in metastatic breast cancer : Effective therapy after third-generation non-steroidal aromatase inhibitor failure ». Breast 15, n^o 3 (juin 2006) : 429–35. http://dx.doi.org/10.1016/j.breast.2005.08.032.

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Wang, J., S. Jain, W. Heller, D. Mackie, V. Watson, M. Dweck, R. C. Coombes et C. Palmieri. « Fulvestrant in advanced breast cancer following following failure of tamoxifen and a third generation aromatase inhibitor ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 1073. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.1073.

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1073 Background: Endocrine therapy is a key modality in the management of estrogen receptor positive metastatic breast cancer. Fulvestrant (ICI 182,780) is an estrogen receptor downregulator. It has previously been shown to be as effective as anastrozole in patients who had previously progressed on tamoxifen. Methods: A retrospective study was carried out of metastatic breast cancer patients treated at Charing Cross Hospital between 2002–2005 who had received fulvestrant following treatment failure with tamoxifen and a third generation aromatase inhibitor. All patients were postmenopausal and received fulvestrant 250mg IM every 28 days. Measurable disease was assessed by response evaluation criteria in solid tumors (RECIST). Results: A total of 45 patients were identified with a median age of 60 (range 36 to 90). The ER status was known in 95% (n=43) of patients and was positive in all cases, it was unknown in 2% (n=2). At the time of commencing fulvestrant, 96% (n=43) had metastatic disease and 4% (n=2) locally advanced disease. All patients had received at least 2 lines of prior endocrine therapy (including adjuvant therapy), at time of starting fulvestrant the median number of prior regimens was 3 (range 3–5). Fulvestrant was administered for a median of 4 months (range 1 to 20 months), with 4 patients currently still receiving therapy as of 1 November 2006. Of the 45 patients, 2.2% (n=1) achieved a partial response, while 31% (n=14) achieved stable disease for at least 6 months. Thus, 33.3% (n=15) obtained clinical benefit (defined as PR or SD for at least 6 months). The response rates based on line of therapy will be presented. Of the 45 patients, 41 were evaluable for survival data. The median survival of the remaining patients from the start of fulvestrant therapy was 9 months (range 1 to 48 months). Of the 44 patients, 14% (n=6) remain alive. The treatment was well tolerated and toxicity data will be presented. Conclusions: Fulvestrant is well tolerated and is efficacious as treatment for advanced breast cancer that has failed tamoxifen and a third generation aromatase inhibitors. No significant financial relationships to disclose.

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Ligibel, Jennifer A., et Eric P. Winer. « The Aromatase Inhibitors as Adjuvant Therapy for Hormone Receptor-Positive Breast Cancer ». Journal of the National Comprehensive Cancer Network 1, n^o 2 (avril 2003) : 215–21. http://dx.doi.org/10.6004/jnccn.2003.0020.

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Adjuvant hormonal therapy has been shown to decrease the risk of breast cancer recurrence and overall mortality in patients with hormone receptor-positive breast cancer. Tamoxifen has been used in this setting for many years, both in premenopausal and postmenopausal patients. Tamoxifen is not devoid of toxicity, and attempts have been made to develop newer hormonal agents with better efficacy and less toxicity. The aromatase inhibitors have shown equivalent or superior efficacy to tamoxifen in the treatment of metastatic breast cancer, and efforts are underway to determine the role of these agents in early breast cancer. The ATAC trial recently showed that use of the third-generation aromatase inhibitor anastrozole in the adjuvant setting led to a modest improvement in relapse-free survival as compared with tamoxifen. Patients treated with anastrozole were also less likely to develop uterine cancer or experience a thromboembolic event. However, patients treated with anastrozole were more likely than those treated with tamoxifen to suffer a fracture or other musculosketal problem. An ASCO technology assessment panel reviewed the relevant data and issued a consensus statement regarding the use of aromatase inhibitors in the adjuvant setting. In general, the panel favored the continued use of tamoxifen as adjuvant hormonal therapy for most postmenopausal women. Within the next few years, further data from the ATAC trial and from other trials of aromatase inhibitors in the adjuvant setting should be available to guide treatment recommendations for this patient population.

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Miller, W. R., T. J. Anderson, S. White, D. Evans, A. Krause et J. M. Dixon. « Growth factor signalling in clinical breast cancer and its impact on response to conventional therapies : the Edinburgh experience ». Endocrine-Related Cancer 12, Supplement_1 (juillet 2005) : S119—S123. http://dx.doi.org/10.1677/erc.1.00995.

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Neoadjuvant endocrine treatment in which therapy is given while the primary tumour is still in the breast provides a highly useful model system by which to identify mechanisms associated with de novo resistance and signs of early acquired resistance. Most importantly, the model is clinically relevant. It has been confirmed that the absence of tumour oestrogen receptors confers resistance to endocrine therapy. Early changes in tumour cell proliferation following neoadjuvant treatment with the third-generation aromatase inhibitor, letrozole, do not predict accurately for subsequent clinical response. Additionally, changes in proliferation seen at later times can be the consequence of response and may be associated with early resistance. High expression of c-erbB2 does not reduce tumour responses to neoadjuvant treatment with aromatase inhibitors, but is associated with high tumour proliferation before and during treatment. It remains to be determined whether these characteristics confer subsequent resistance to treatment and early relapse in the adjuvant setting.

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Barros-Oliveira, Maria da Conceição, Danylo Rafhael Costa-Silva, Danielle Benigno de Andrade, Umbelina Soares Borges, Cléciton Braga Tavares, Rafael Soares Borges, Janaína de Moraes Silva et Benedito Borges da Silva. « Use of anastrozole in the chemoprevention and treatment of breast cancer : A literature review ». Revista da Associação Médica Brasileira 63, n^o 4 (avril 2017) : 371–78. http://dx.doi.org/10.1590/1806-9282.63.04.371.

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Summary Aromatase inhibitors have emerged as an alternative endocrine therapy for the treatment of hormone sensitive breast cancer in postmenopausal women. The use of third-generation inhibitors represented by exemestane, letrozol and anastrozole is currently indicated. Anastrozole is a nonsteroidal compound and a potent selective inhibitor of the aromatase enzyme. Although a few studies have shown that its pharmacodynamic and pharmacokinetic properties may be affected by interindividual variability, this drug has been recently used in all configurations of breast cancer treatment. In metastatic disease, it is currently considered the first-line treatment for postmenopausal women with estrogen receptor-positive breast tumors. Anastrozole has shown promising results in the adjuvant treatment of early-stage breast cancer in postmenopausal women. It has also achieved interesting results in the chemoprevention of the disease. Therefore, due to the importance of anastrozole both for endocrine treatment and chemoprevention of hormone-sensitive breast cancer in postmenopausal women, we proposed the current literature review in the SciELO and PubMed database of articles published in the last 10 years.

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Goss, Paul E., David Walde, Roland De Coster, Christine Langenaeken et Jan Bruynseels. « Rivizor – A New Third-Generation Aromatase Inhibitor for the Treatment of Advanced Breast Cancer after Tamoxifen Failure ». Oncology 56, n^o 2 (1999) : 114–21. http://dx.doi.org/10.1159/000011951.

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Lefevre, Hervé, Claire Bouvattier, Najiba Lahlou, Catherine Adamsbaum, Pierre Bougnères et Jean-Claude Carel. « Prepubertal gynecomastia in Peutz-Jeghers syndrome : incomplete penetrance in a familial case and management with an aromatase inhibitor ». European Journal of Endocrinology 154, n^o 2 (février 2006) : 221–27. http://dx.doi.org/10.1530/eje.1.02085.

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Background: Peutz-Jeghers syndrome (PJS) is a rare autosomal-dominant disorder characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation and increased predisposition to various neoplasms. Endocrine manifestations in PJS include gynecomastia due to calcified Sertoli cell testicular tumors usually referred to as large-cell calcifying Sertoli cell tumors (LSCT). Objective: To evaluate the value of endocrine markers and aromatase inhibitor treatment in children with PJS and LSCT. Design and setting: Familial cases, followed in a tertiary care center. Patients: Two male siblings aged 7 and 9 years with PJS and LSCT. Intervention: Third generation aromatase inhibitor (anastrozole) in one of the patients. Main outcome measures: Longitudinal measurements of sex-steroids, gonadotropins, Sertoli cell markers and auxological evaluation. Results: The two male siblings with PJS had similar bilateral multifocal testicular calcifications and biochemical evidence of Sertoli cell dysfunction manifested by elevated plasma inhibin-α levels. Only one sibling had gynecomastia. Estradiol levels were normal in both. During treatment with anastrozole, estradiol levels, growth and skeletal maturation, as well as Sertoli cell markers (inhibin B, inhibin-α and anti-Mullerian hormone) decreased. Conclusions: Inhibin-α may be considered as a marker for LSCT in children with PJS, pointing to a specific defect in inhibin regulation in this condition. Moreover, the decrease in Sertoli cell markers during aromatase inhibitor treatment suggests that increased estrogen production is a primary event regulating downstream production of Sertoli cell peptides. Anastrozole is efficient in controlling the clinical features of the disease and should be proposed as an alternative to bilateral orchidectomy, which is often performed in this condition.

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Ingle, James N., Vera J. Suman, Kendrith M. Rowland, Deepu Mirchandani, Albert M. Bernath, John K. Camoriano, Paul A. S. Fishkin, Daniel A. Nikcevich et Edith A. Perez. « Fulvestrant in Women With Advanced Breast Cancer After Progression on Prior Aromatase Inhibitor Therapy : North Central Cancer Treatment Group Trial N0032 ». Journal of Clinical Oncology 24, n^o 7 (1 mars 2006) : 1052–56. http://dx.doi.org/10.1200/jco.2005.04.1053.

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Purpose Fulvestrant is an antiestrogen that leads to estrogen receptor degradation and has demonstrated efficacy in breast cancer patients who have had disease recurrence or progression after tamoxifen. This study was designed to examine the efficacy and toxicity of fulvestrant in patients with disease progression on a third-generation aromatase inhibitor (AI). Patients and Methods A one-stage phase II trial was conducted in postmenopausal women with measurable disease by Response Evaluation Criteria in Solid Tumors criteria who experienced disease progression after treatment with a third-generation AI and, at most, one additional hormonal agent. Tumors must have been estrogen receptor and/or progesterone receptor positive. The primary end point was objective response rate, and secondary end points were time to disease progression, survival, duration of response, and toxicity. Results Eighty patients were enrolled, and three were ineligible. Characteristics of the 77 eligible patients included median age of 68 years, performance score of 0 or 1 in 91% of patients, visceral dominant disease in 88% of patients, two prior hormonal treatments in 73% of patients, and prior chemotherapy for metastatic disease in 32% of patients. Eleven patients (14.3%) achieved a partial response, and 16 patients (20.8%) had stable disease for at least 6 months, for a clinical benefit rate of 35%. Antitumor activity seemed to be higher in women with prior treatment with AI alone compared with women whose prior treatment also included tamoxifen. Median time to progression was 3 months, and median survival time was 20.2 months. Fulvestrant was well tolerated. Conclusion Fulvestrant is a well-tolerated treatment and has efficacy against breast cancers that have progressed after therapy with a third-generation AI.

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Ray, Amitabha, et Monica Ficek. « Immunomodulatory effects of anti-estrogenic drugs ». Acta Pharmaceutica 62, n^o 2 (1 juin 2012) : 141–55. http://dx.doi.org/10.2478/v10007-012-0012-3.

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Immunomodulatory effects of anti-estrogenic drugsThere are substantial experimental, epidemiological and clinical evidences that show that breast cancer pathology is influenced by endogenous estrogens. This knowledge is the foundation upon which endocrine deprivation therapy has been developed as a major modality for the management of breast cancer. Tamoxifen, which functions as a competitive partial agonist-inhibitor of estrogen at its receptor, has been widely used for more than three decades for adjuvant endocrine treatment in breast cancer. Currently, other effective drugs for endocrine therapy include raloxifene, different aromatase inhibitors (particularly third-generation agents) and luteinizing hormone-releasing hormone agonists. In recent years, a growing body of evidence suggests that these drugs can also act as immune modulators by altering the function of various leukocytes and the release of different cytokines. Moreover, there is evidence that anti-estrogens may prove to be beneficial in the treatment or prevention of some autoimmune diseases due to their effects on immune function. However, their immunopharmacological aspects in the present state of knowledge are not precisely comprehensible. Only a clear pathophysiological understanding could lead to an efficient strategy for breast cancer prevention and decrease in the mortality due to this disease.

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Amaral, Cristina, Georgina Correia-da-Silva, Cristina Ferreira Almeida, Maria João Valente, Carla Varela, Elisiário Tavares-da-Silva, Anne Marie Vinggaard, Natércia Teixeira et Fernanda M. F. Roleira. « An Exemestane Derivative, Oxymestane-D1, as a New Multi-Target Steroidal Aromatase Inhibitor for Estrogen Receptor-Positive (ER+) Breast Cancer : Effects on Sensitive and Resistant Cell Lines ». Molecules 28, n^o 2 (12 janvier 2023) : 789. http://dx.doi.org/10.3390/molecules28020789.

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Around 70–85% of all breast cancer (BC) cases are estrogen receptor-positive (ER+). The third generation of aromatase inhibitors (AIs) is the first-line treatment option for these tumors. Despite their therapeutic success, they induce several side effects and resistance, which limits their efficacy. Thus, it is crucial to search for novel, safe and more effective anti-cancer molecules. Currently, multi-target drugs are emerging, as they present higher efficacy and lower toxicity in comparison to standard options. Considering this, this work aimed to investigate the anti-cancer properties and the multi-target potential of the compound 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione (Oxy), also designated by Oxymestane-D1, a derivative of Exemestane, which we previously synthesized and demonstrated to be a potent AI. For this purpose, it was studied for its effects on the ER+ BC cell line that overexpresses aromatase, MCF-7aro cells, as well as on the AIs-resistant BC cell line, LTEDaro cells. Oxy reduces cell viability, impairs DNA synthesis and induces apoptosis in MCF-7aro cells. Moreover, its growth-inhibitory properties are inhibited in the presence of ERα, ERβ and AR antagonists, suggesting a mechanism of action dependent on these receptors. In fact, Oxy decreased ERα expression and activation and induced AR overexpression with a pro-death effect. Complementary transactivation assays demonstrated that Oxy presents ER antagonist and AR agonist activities. In addition, Oxy also decreased the viability and caused apoptosis of LTEDaro cells. Therefore, this work highlights the discovery of a new and promising multi-target drug that, besides acting as an AI, appears to also act as an ERα antagonist and AR agonist. Thus, the multi-target action of Oxy may be a therapeutic advantage over the three AIs applied in clinic. Furthermore, this new multi-target compound has the ability to sensitize the AI-resistant BC cells, which represents another advantage over the endocrine therapy used in the clinic, since resistance is a major drawback in the clinic.

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Goss, P. E., E. P. Winer, I. F. Tannock et L. H. Schwartz on behalf of the North Ame. « Randomized Phase III Trial Comparing the New Potent and Selective Third-Generation Aromatase Inhibitor Vorozole With Megestrol Acetate in Postmenopausal Advanced Breast Cancer Patients ». Journal of Clinical Oncology 17, n^o 1 (janvier 1999) : 52. http://dx.doi.org/10.1200/jco.1999.17.1.52.

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PURPOSE: To compare the efficacy and safety of vorozole (VOR) 2.5 mg once daily with that of megestrol acetate (MA) 40 mg four times per day as second-line therapy in postmenopausal women with advanced breast cancer whose disease progressed after tamoxifen treatment. PATIENTS AND METHODS: A total of 452 patients were enrolled onto an open, multicenter, randomized phase III trial comparing VOR to MA for tumor response, safety, and quality of life (as indicated by the Functional Living Index-Cancer score). RESULTS: Vorozole produced a response rate of 9.7%, compared with 6.8% for MA (P = .24). Clinical benefit (complete response + partial response + no change in > 6 months) was demonstrated in 23.5% and 27.2% of patients treated with VOR and MA, respectively (P = .42). Median duration of response was 18.2 months for VOR versus 12.5 months for MA (P = .074). There was no significant difference in time to progression or survival between the treatment groups. Discontinuation of treatment because of adverse events occurred less frequently in the VOR-treated group (3.1% v 6.2%; P = .18). Patients on the VOR arm reported significantly more nausea, hot flushes, arthralgia, upper respiratory tract infection, anorexia, and paresthesia, whereas those treated with MA had significantly more dyspnea, increased appetite, and weight increase. There was no difference between the two treatment groups in Functional Living Index-Cancer scores (total or subscales). However, when analyzed by objective response, patients with complete or partial responses (P = .032) or no change (P = .033) who were receiving VOR had significant improvement in the psychologic well-being subscale, compared with patients given MA. CONCLUSION: Vorozole is well tolerated and as effective as MA in the treatment of postmenopausal advanced breast cancer patients with disease progression after tamoxifen treatment.

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Anagha, Pooleriveetil Padikkal, et Suchandra Sen. « The Efficacy of Bisphosphonates in Preventing Aromatase Inhibitor Induced Bone Loss for Postmenopausal Women with Early Breast Cancer : A Systematic Review and Meta-Analysis ». Journal of Oncology 2014 (2014) : 1–13. http://dx.doi.org/10.1155/2014/625060.

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Objectives. We aim to determine the efficacy of bisphosphonates in preventing aromatase inhibitor induced bone loss (AIBL) in postmenopausal women with early breast cancer. The secondary objective was to determine the safety of bisphosphonates.Materials and Methods. We searched electronic databases in a time period of 1995 January to 2013 June. Random effects meta-analytical models were used; between study heterogeneity and publication bias was assessed.Results. A total of six eligible studies reported the BMD T score of LS at 12 months and from that 3 trials of Zoledronic acid compared the change in BMD in immediate ZOL versus delayed ZOL done with subgroups like patients with normal BMD at baseline (OR = 5.402, 95% CI = 1.329–21.959,Pvalue = 0.018) and osteopenic BMD at baseline (OR = 4.008, 95% CI = 2.249–7.143,Pvalue = 0.0002). Both had a significant decrease in BMD that favoured the delayed ZOL; 3 trials of risedronate and ibandronate also had a significant decrease in BMD in AIs alone group. Immediate ZOL versus delayed ZOL also showed increased risk of getting an ADR in immediate group.Conclusion. Third generation bisphosphonates has an effect on BMD of patients who are on treatment of AIs in breast cancer. Furthermore, the patients treated with immediate ZOL had a significantly high risk of musculoskeletal ADR’s than patients with delayed ZOL.

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Wilson, Sheridan, et Stephen K. Chia. « Treatment Algorithms for Hormone Receptor-Positive Advanced Breast Cancer : Applying the Results from Recent Clinical Trials into Daily Practice—Insights, Limitations, and Moving Forward ». American Society of Clinical Oncology Educational Book, n^o 33 (mai 2013) : e20-e27. http://dx.doi.org/10.14694/edbook_am.2013.33.e20.

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Hormone receptor–positive (HR+) breast cancer is the most prevalent subtype of breast cancer in both early- and advanced-stage disease. Thus, the treatment of HR+ breast cancer has had the greatest global influence in improving clinical outcomes overall. Although the first-line metastatic breast cancer (MBC) trials comparing a third-generation aromatase inhibitor (AI) to tamoxifen have favored the AI, one of the challenges in translating these findings into clinical practice stems from the influence of prior adjuvant endocrine therapy, particularly the increasing use of adjuvant AIs today, on the choice of endocrine agent in the advanced setting because of the development of acquired resistance. Because the majority of patients enrolled into these studies were either endocrine-treatment naïve or exposed to tamoxifen only, the “real-life” applicability of the evidence is unclear. Because a superior dose of the selective estrogen receptor (ER) downregulator fulvestrant has now been established, its role as first-line therapy is being re-established. We are now starting to see the promise realized with blocking cross-talking growth factor pathways in addition to the ER pathway. The greatest efficacy is seen with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with exemestane and, perhaps to a lesser extent, anti-HER2–directed therapy in combination with an AI. Future gains will likely involve a greater understanding of the redundancy and compensation induced by blocking these pathways, trials involving blocking multiple pathways in addition to hormonal agents, and the molecular interrogation of the individual's tumor in search of predictive biomarkers and “actionable” genomic aberrations.

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Turkistani, Abdullah, et Sharon Marsh. « Pharmacogenomics of third-generation aromatase inhibitors ». Expert Opinion on Pharmacotherapy 13, n^o 9 (17 mai 2012) : 1299–307. http://dx.doi.org/10.1517/14656566.2012.687721.

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LONNING, P. « Pharmacokinetics of third-generation aromatase inhibitors ». Seminars in Oncology 30 (août 2003) : 23–32. http://dx.doi.org/10.1016/s0093-7754(03)00305-1.

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Lytkin, D. V., A. L. Zagayko et T. O. Briukhanova. « The effect of third-generation aromatase inhibitors on aromatase avtivity in visceral adipose tissue ». Regulatory Mechanisms in Biosystems 9, n^o 2 (13 août 2018) : 209–15. http://dx.doi.org/10.15421/021831.

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Pathogenesis and clinical manifestations of metabolic syndrome (and other conditions characterized by the growth of fat mass and decreased adiponectin content) is associated with an imbalance of sex hormones, which develops under the influence of increased aromatase activity in adipose tissue. Drugs of the aromatase inhibitors therapeutic group are able to suppress the course of the aromatase reaction in the central and peripheral organs and tissues. The aim of our study was to establish the relationship between levels of serum adiponectin and adipose tissue aromatase avtivity in Syrian hamsters of different ages and gender with experimental metabolic syndrome and study the effect of aromatase inhibitors on these indicators. Experimental metabolic syndrome in animals was induced by a high-fat and fructose diet. The drugs were administered during the 21-st day in doses of 3.086 (exemestane), 0.309 (letrozole) and 0.126 mg/kg (anastrozole). The aromatase activity of the visceral adipose tissue was determined by the modified kinetic method based on the amount of the reaction product estradiol converted from testosterone. The content of estradiol in adipose tissue homogenate and serum adiponectin levels were measured by the immune enzyme method. The results showed a high inverse correlation between serum adiponectin and adipose tissue aromatase activity in hamsters. Aromatase inhibitors caused a decrease in the adipose tissue aromatase activity and increase in serum adiponectin levels. Letrazol demonstrated the greatest effect, it reduced aromatase activity in adipose tissue by 72–84% and increased serum adiponectin content by 1.6–1.8 times. At the same time, intra-group correlation of the studied parameters was significant. The results show the relationship between adiponectin level and adipose tissue aromatase activity and ability to change these rates by the way of aromatase inhibitors, which may be useful in clinical practice. Third-generation aromatase inhibitors are promising drugs for metabolic syndrome treatment and require further study in clinical trials.

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Sun, Linjia, Xiaoyang Sun, Yu Chen, Binjie Wang et Xiaohui Chen. « Degradation Kinetics Study of Anastrozole in Different Conditions by Reverse-Phase High-Performance Liquid Chromatography and Confirmation of its Major Degradation Product by Ultra-Performance Liquid Chromatography with Tandem Mass Spectrometry ». Current Pharmaceutical Analysis 15, n^o 3 (11 février 2019) : 217–23. http://dx.doi.org/10.2174/1573412914666180406130108.

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Background: Drug stability is essential in the process of drug production, storage, appliance, and so on. Some drugs’ degradation products may even have a toxic side effect, which can result in safety risks and economic losses. Therefore, it is very imperative to develop a suitable stability indicating an analytical method for anastrozole which could be used for stability testing, routine and in-process quality control analysis or other further studies. Methods: A reverse-phase high-performance liquid chromatography method was developed and validated for the degradation kinetics study of anastrozole, a selective non-steroid third-generation aromatase inhibitor, which would provide a basis for further studies on anastrozole. The degradation product was confirmed by ultra-performance liquid chromatography with tandem mass spectrometry. Results: Results showed that the degradation behavior of anastrozole followed first-order kinetics in different temperatures, pH values and oxidation conditions. It was suggested that the degradation behavior of anastrozole was pH-dependent and it’s more stable at lower pH values. Conclusion: A high performance liquid chromatography method was established and used to determine the residual concentration of anastrozole in this study. It was found that the degradation behavior of anastrozole followed first-order kinetics at different temperatures, pH values and oxidation conditions. According to the results, the degradation of anastrozole was found to be pH-dependent and it is more unstable in alkaline conditions. The information of degradation kinetics will be useful for understanding the chemical stability of anastrozole and provide a reference for the further preparation research and clinical therapy of anastrozole.

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Papadimitriou, Dimitrios T., Eleni Dermitzaki, Kleanthis Kleanthous, Anastasios Papadimitriou et George Mastorakos. « Exaggerated Premature Adrenarche in Boys : Comparative Study of a Therapeutic Intervention With the Aromatase Inhibitor Anastrozole Versus Morning Low Dose Hydrocortisone ». Journal of the Endocrine Society 5, Supplement_1 (1 mai 2021) : A666—A667. http://dx.doi.org/10.1210/jendso/bvab048.1360.

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Abstract Background: In boys, idiopathic premature adrenarche (IPA) is defined as the appearance of pubic or axillary hair/odor before the age of 9 yrs, not due to pathology of the adrenal glands. Exaggerated Adrenarche (EXAD), occurring in 10-15% of children with IPA, is characterized by an elevated >10 DHEA/Δ4 ratio (theoretically indicating reduced 3-β-HSD activity) and accelerated bone age (BA) maturation, continuously increasing the projecting distance from the target height (TH) curve, beyond the one observed in the pattern of Constitutional Advancement of Growth (CAG), eventually leading to short stature (SS). It is traditionally successfully treated with a morning (6-8 am) low dose of hydrocortisone (8 mg/m2) in order to reduce the androgens produced and delay BA progression, similarly to the standard treatment of non-classical (late-onset) CAH. Third generation aromatase inhibitors (AI) have been shown to delay BA by inhibiting the peripheral aromatization of androgens and are being widely used off-label to treat short SS in boys. Aims: To evaluate the effectiveness of the AI anastrozole in delaying BA in boys with EXAD. Methods: 39 boys with advanced BA and a predicted adult height (PAH) <170cm and > -1SDS from TH) were included. Group-A (n=28) received anastrozole 1mg x 1 p.o. and group-B (n=11) low dose (8 mg/m2) hydrocortisone at 6-8 am for at least 3 yrs. All measurements were made on the same height meter by the same examiner. The two groups did not differ in terms of age at intervention onset: 8.6 in group A vs 8.74 yrs in group B, TH: 175.7 vs 175.7 cm, PAH: 168.4 vs 167.8 cm and BA advancement: +2.3 yrs in group A vs +2.4 yrs in group B. A 6-month follow-up included clinical examination, BA assessment, and laboratory tests (general blood, lipid chart, LH, FSH, TESTO, E2, E1, and complete calcium metabolism). Lumbar spine DEXA scan and X-Ray was performed on an annual basis. Results: Both groups had a statistically significant gain in PAH after 3yrs of treatment: Group A +10.3 cm (1.53 SD), p<0.001, and group B +7.1 cm (1.06 SD), p=0.007. Thus, group A exceeded their TH by +3cm (0.45 SDS) and group B reached -0.8cm (-0.11 SDS) from their TH, p=0.03. The reduction of BA advancement was statistically significant in both groups (p<0.05), with superiority of the anastrozole-treated group: at 3yrs in group A BA advancement was +0.48 yrs, and at group B +1.24 yrs (p<0.001). No clinical adverse events or abnormal tests were noted in any of the groups. Bone density and vertebral morphology was not affected within or between groups. Conclusions: Aromatase Inhibitors may have a place in managing exaggerated adrenarche in boys, showing superiority to traditional low-dose hydrocortisone in improving predicted adult height and delaying bone age maturation, but notably by overcoming quality of life and compliance issues associated with hydrocortisone therapy (mandatory 6-8 am).

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Lønning, Per Eystein, et Jürgen Geisler. « Indications and limitations of third-generation aromatase inhibitors ». Expert Opinion on Investigational Drugs 17, n^o 5 (30 avril 2008) : 723–39. http://dx.doi.org/10.1517/13543784.17.5.723.

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McCloskey, Eugene. « Effects of third-generation aromatase inhibitors on bone ». European Journal of Cancer 42, n^o 8 (mai 2006) : 1044–51. http://dx.doi.org/10.1016/j.ejca.2005.10.028.

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Lenz, A. M., D. Shulman, E. A. Eugster, S. Rahhal, J. S. Fuqua, O. H. Pescovitz et K. A. Lewis. « Bicalutamide and Third-Generation Aromatase Inhibitors in Testotoxicosis ». PEDIATRICS 126, n^o 3 (16 août 2010) : e728-e733. http://dx.doi.org/10.1542/peds.2010-0596.

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Chia, Stephen, William Gradishar, Louis Mauriac, Jose Bines, Frederic Amant, Miriam Federico, Luis Fein et al. « Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone Receptor–Positive, Advanced Breast Cancer : Results From EFECT ». Journal of Clinical Oncology 26, n^o 10 (1 avril 2008) : 1664–70. http://dx.doi.org/10.1200/jco.2007.13.5822.

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Purpose The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor–positive (HR+) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. Materials and Methods Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. Results A total of 693 women were randomly assigned to fulvestrant (n = 351) or exemestane (n = 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups (hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). The overall response rate (7.4% v 6.7%; P = .736) and clinical benefit rate (32.2% v 31.5%; P = .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. Conclusion Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI.

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Lonninq, P. E. « Are there any difference between third-generation aromatase inhibitors ? » European Journal of Cancer Supplements 6, n^o 7 (avril 2008) : 52. http://dx.doi.org/10.1016/s1359-6349(08)70326-4.

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Goss, Paul E., et Kathrin Strasser. « Aromatase Inhibitors in the Treatment and Prevention of Breast Cancer ». Journal of Clinical Oncology 19, n^o 3 (1 février 2001) : 881–94. http://dx.doi.org/10.1200/jco.2001.19.3.881.

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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 suggest that the inhibitors might displace tamoxifen as first-line treatment, but further studies are needed to determine this. CONCLUSION: The role of aromatase inhibitors in premenopausal breast cancer and in combination with chemotherapy and other anticancer treatments are areas of future exploration. The ongoing adjuvant trials will provide important data on the long-term safety of aromatase inhibitors, which will help to determine their suitability for use as chemopreventives in healthy women at risk of developing breast cancer.

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Ratre, Pooja, Keerti Mishra, Amit Dubey, Amber Vyas, Akhlesh Jain et Suresh Thareja. « Aromatase Inhibitors for the Treatment of Breast Cancer : A Journey from the Scratch ». Anti-Cancer Agents in Medicinal Chemistry 20, n^o 17 (12 novembre 2020) : 1994–2004. http://dx.doi.org/10.2174/1871520620666200627204105.

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Background: Estrogens are essential for the growth of breast cancer in the case of premenopausal as well as in postmenopausal women. However, most of the breast cancer incidences are reported in postmenopausal women and the concurrent risk surges with an increase in age. Since the enzyme aromatase catalyses essential steps in estrogen biosynthesis, Aromatase Inhibitors (AIs) are effective targeted therapy in patients with Estrogen Receptor positive (ER+) breast cancer. AIs are more effective than Selective Estrogen Receptor Modulators (SERMs) because they block both the genomic and nongenomic activities of ER. Till date, first, second and third-generation AIs have been approved by the FDA. The third-generation AIs, viz. Letrozole, Anastrozole, Exemestane, are currently used in the standard treatment for postmenopausal breast cancer. Methods: Data were collected from Medline, PubMed, Google Scholar, Science Direct through searching of keywords: ‘aromatase’, ‘aromatase inhibitors’, ‘breast cancer’, ‘steroidal aromatase inhibitors’, ‘non-steroidal inhibitors’ and ‘generations of aromatase inhibitors’. Results: In the current scenario of breast cancer chemotherapy, AIs are the most widely used agents which reveal optimum efficacy along with the least side effects. Keeping in view the prominence of AIs in breast cancer therapy, this review covered the detailed description of aromatase including its role in the biosynthesis of estrogen, biochemistry, gene expression, 3D-structure, and information of reported AIs along with their role in breast cancer treatment. Conclusion: AIs are the mainstream solution of the ER+ breast cancer treatment regimen with the continuous improvement of human understanding of the importance of a healthy life of women suffering from breast cancer.

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L√∏nning, P. E. « Aromatase inhibitors in breast cancer. » Endocrine-related cancer 11, n^o 2 (juin 2004) : 179–89. http://dx.doi.org/10.1677/erc.0.0110179.

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The development of aromatase inhibitors for breast cancer therapy is a result of successful translational research exploring the biochemical effects of different compounds in vivo. Studies assessing plasma oestrogen levels as well as in vivo aromatase inhibition have revealed a consistent difference with respect to biochemical efficacy between the third generation compounds (anastrozole, letrozole and exemestane) and the previous, first and second generation drugs, corresponding to the improved clinical effects of these compounds as outlined in large phase III studies. Thus, endocrine evaluation has been found to be a valid surrogate parameter for clinical efficacy. Moreover, the results from these studies have added important biological information to our understanding of endocrine regulation of breast cancer. Based on the clinical results so far, aromatase inhibitors are believed to play a key role in future adjuvant therapy of postmenopausal breast cancer patients and potentially also for breast cancer prevention. Interesting findings such as the lack of cross-resistance between steroidal and non-steroidal compounds should be further explored, as this may add additional information to our understanding of breast cancer biology.

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Nabholtz, Jean-Marc A., et David M. Reese. « Third-generation aromatase inhibitors in the treatment of advanced breast cancer ». Breast Cancer 8, n^o 4 (octobre 2001) : 305–9. http://dx.doi.org/10.1007/bf02967529.

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Rieber, Alyssa G., et Richard L. Theriault. « Aromatase Inhibitors in Postmenopausal Breast Cancer Patients ». Journal of the National Comprehensive Cancer Network 3, n^o 3 (mai 2005) : 309–14. http://dx.doi.org/10.6004/jnccn.2005.0018.

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Aromatase inhibitors (AIs) have greatly enriched the treatment of hormone receptor-positive breast cancer in postmenopausal patients. Before the introduction of the well-tolerated third-generation AIs, tamoxifen was the mainstay of endocrine therapy for hormone receptor-positive breast cancer. Many clinical trials have shown the superiority of AIs compared with tamoxifen in adjuvant breast cancer treatment, as well as their benefit in metastatic breast cancer. NCCN guidelines recommendations for their use are based on the evidence provided by these clinical trials. This discussion reviews the evidence supporting the current guidelines for use of AI therapy in the treatment of hormone receptor-positive postmenopausal breast cancer patients.

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Rocha-Cadman, Xiomara, Mary Jane Massie et Katherine Du Hamel. « Aromatase inhibitors and mood disturbances ». Palliative and Supportive Care 10, n^o 3 (8 juin 2012) : 225–27. http://dx.doi.org/10.1017/s1478951512000636.

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AbstractWe describe the case of a 56-year old woman with no prior psychiatric history who was diagnosed with hormone receptor positive early-stage breast cancer and who developed severe mood changes after administration of anastrozole, which resolved after discontinuation of treatment. Aromatase inhibitors (AIs) are the preferred hormonal approach for postmenopausal women with estrogen hormone sensitive breast cancer. The third-generation agents (anastrozole, letrozole, and exemestane) have been shown to be more effective and safer than the selective estrogen receptor modulators tamoxifen and raloxifen. Treatment strategies with these agents include the use of an AI as an upfront strategy for 5 years, as a sequential approach after 2–3 years of tamoxifen, or as extended use after the classical 5 years of tamoxifen. The side effects of AIs, as compared with selective estrogen receptor modulators, are different, reflecting the specific mechanism of action of these drugs. AIs are well tolerated and cause a lower incidence of gynecological symptoms (vaginal bleeding, discharge, and endometrial neoplasia), venous thromboembolic events, and hot flashes compared with tamoxifen. However, the use of AIs have been associated with loss of bone density, arthralgia, myalgia, a negative effect on lipid metabolism, and cardiovascular risk (Tomao et al., 2011). Mood disturbances, somnolence, anxiety, fatigue, hot flashes, and memory impairment have been reported among patients receiving anastrozole as adjuvant therapy.

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MORALES, L., D. TIMMERMAN, P. NEVEN et R. PARIDAENS. « Endometrial safety of third generation aromatase inhibitors versus tamoxifen in breast cancer patients ». International Journal of Gynecological Cancer 16, s2 (septembre 2006) : 515–17. http://dx.doi.org/10.1111/j.1525-1438.2006.00684.x.

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Garuti, Giancarlo, Fulvia Cellani, Giovanna Centinaio, Giuseppe Montanari, Giulio Nalli et Massimo Luerti. « Prospective endometrial assessment of breast cancer patients treated with third generation aromatase inhibitors ». Gynecologic Oncology 103, n^o 2 (novembre 2006) : 599–603. http://dx.doi.org/10.1016/j.ygyno.2006.04.004.

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Augusto, Tiago, Cristina Amaral, Natércia Teixeira et Georgina Correia-da-Silva. « The involvement of autophagy in the acquired resistance to third-generation aromatase inhibitors ». Free Radical Biology and Medicine 120 (mai 2018) : S118. http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.388.

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Simsa, Peter, Attila Mihalyi, Cleophas M. Kyama, Jason M. Mwenda, Vilmos Fülöp et Thomas M. D'Hooghe. « Selective Estrogen-Receptor Modulators and Aromatase Inhibitors : Promising New Medical Therapies for Endometriosis ? » Women's Health 3, n^o 5 (septembre 2007) : 617–28. http://dx.doi.org/10.2217/17455057.3.5.617.

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Endometriosis is an estrogen-dependent disease and estrogen-related pathways are imbalanced in women with endometriosis. One of the key enzymes in estrogen synthesis is aromatase. Inhibiting this pathway at several points is a promising idea for the treatment of endometriosis. The third generation of aromatase inhibitors is becoming more potent in efficacy, with fewer side effects than previous generations, but cotreatment with other hormones is needed to inhibit ovarian stimulation. Other components that promote estrogen synthesis such as COX-2 can also be potentially targeted. Selective estrogen-receptor modulators could also be interesting in view of their tissue-specific effect. However, all these new drugs are still in an early phase of development. At present, it is too early to conclude that aromatase inhibitors, COX-2 inhibitors or selective estrogen-receptor modulators really present any added value compared with the existing drugs that can be used to achieve hormonal suppression in the medical treatment of endometriosis.

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Damodaran, Senthil, Paul V. Plourde, Halle C. F. Moore, Ian Churchill Anderson et David Jay Portman. « Open-label, phase 2, multicenter study of lasofoxifene (LAS) combined with abemaciclib (Abema) for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and an ESR1 mutation after progression on prior therapies. » Journal of Clinical Oncology 40, n^o 16_suppl (1 juin 2022) : 1022. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.1022.

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1022 Background: Resistance to endocrine therapy can develop when treating estrogen receptor positive (ER+), metastatic breast cancer (mBC). Treatment with aromatase inhibitors can lead to acquired mutations in the estrogen receptor 1 ( ESR1), which can constitutively activate the ER, leading to endocrine resistance and worse disease prognosis. Treatment options for mBC patients with an ESR1 mutation are limited. Further, data suggest that patients could derive clinical benefit from Abema after progression on prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). LAS, a third-generation selective estrogen receptor modulator, as monotherapy or combined with a CDK4/6i, was shown to have superior efficacy over fulvestrant (FVT) in preclinical breast cancer models expressing ESR1 mutations. Based on these results, a phase 2 clinical trial of LAS combined with Abema was initiated in mBC patients with ESR1 mutations. Methods: ELAINE 2 is an open-label, phase 2, multicenter trial evaluating the safety and efficacy of LAS combined with the CDK4/6i, Abema. Study participants were pre- and postmenopausal women with ER+/HER2- mBC with acquired ESR1 mutation (identified by ctDNA testing), whose disease had progressed on one or two lines of hormonal therapy for metastatic disease with or without a CDK4/6i (including Abema). Patients took oral LAS 5 mg/day and Abema 150 mg BID. Treatment continued until evidence of disease progression, death, unacceptable toxicity, or withdrawal from the study. The primary endpoint was safety, and secondary endpoints were progression free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Results: 29 patients were enrolled at 16 US sites (Oct 2020 to June 2021). Mean age was 58.3 y (35-79 y); 86% were Caucasian. Most had progressed with at least 2 previous hormonal treatments (80%). All except 1 patient received a prior CDK4/6i and 72% had received prior FVT; 48% had chemotherapy in the metastatic setting. Four patients discontinued the trial due to adverse events (AEs, n = 2), consent withdrawal (n = 1), or investigator withdrawal (n = 1). No deaths occurred during the study and few Grade 3/4 AEs were observed. Most common AEs were diarrhea, nausea, and leukopenia. Five patients had an Abema dose reduction from 150 mg to 100 mg BID. To date, 11 patients have progressed and 14 continue treatment. The censored median PFS was 13.9 mos (95% CI, 8.0‒NE), the ORR 33.3% (95% CI, 16.3‒56.3) with 6 confirmed partial responses, and the CBR 62.1% (95% CI, 44.0‒77.3). Conclusions: LAS combined with Abema in the ELAINE 2 trial was well tolerated and demonstrated robust and meaningful efficacy in women with ER+/HER2- mBC and an ESR1 mutation who had progressed on previous CDK4/6i therapies. Clinical trial information: NCT04432454.

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Bonte, J. « Third generation aromatase inhibitors and inactivators in the treatment and prevention of breast cancer ». European Journal of Cancer 36 (septembre 2000) : 114. http://dx.doi.org/10.1016/s0959-8049(00)00269-0.

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Borne, J. « Second and third generation aromatase inhibitors in the treatment and chemoprevention of breast cancer ». International Journal of Gynecology & ; Obstetrics 70 (2000) : A10. http://dx.doi.org/10.1016/s0020-7292(00)81965-7.

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Khan, Qamar J., Anne P. O'Dea et Priyanka Sharma. « Musculoskeletal Adverse Events Associated with Adjuvant Aromatase Inhibitors ». Journal of Oncology 2010 (2010) : 1–8. http://dx.doi.org/10.1155/2010/654348.

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Musculoskeletal symptoms including arthralgia and myalgia occur frequently in aging women, particularly during the transition to menopause, when plasma estrogens precipitously decline. In postmenopausal women (PMW) with breast cancer, third-generation aromatase inhibitors (AIs) as adjuvant hormonal therapy have proven to be more effective, and to have a more predictable side effect profile, than tamoxifen. However, AIs further reduce plasma estrogens in PMW, exacerbating musculoskeletal symptoms. Clinical trial data have shown significantly higher incidences of arthralgia and myalgia with AIs compared with women on tamoxifen or placebo. Symptoms may be severe enough to significantly affect quality of life; musculoskeletal symptoms are a frequent reason for discontinuing therapy. In many cases, symptoms can be effectively managed with oral analgesics or other strategies. Early recognition and effective management of musculoskeletal symptoms can help maximize treatment compliance, enabling patients to derive optimal benefit from therapy in terms of preventing recurrence.

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Augusto, Tiago Vieira, Georgina Correia-da-Silva, Cecília M. P. Rodrigues, Natércia Teixeira et Cristina Amaral. « Acquired resistance to aromatase inhibitors : where we stand ! » Endocrine-Related Cancer 25, n^o 5 (mai 2018) : R283—R301. http://dx.doi.org/10.1530/erc-17-0425.

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Aromatase inhibitors (AIs) are one of the principal therapeutic approaches for estrogen receptor-positive (ER+) breast cancer in postmenopausal women. They block estrogen biosynthesis through aromatase inhibition, thus preventing tumour progression. Besides the therapeutic success of the third-generation AIs, acquired resistance may develop, leading to tumour relapse. This resistance is thought to be the result of a change in the behaviour of ER in these breast cancer cells, presumably by PI3K/AKT pathway enhancement along with alterations in other signalling pathways. Nevertheless, biological mechanisms, such as apoptosis, autophagy, cell cycle modulation and activation of androgen receptor (AR), are also implicated in acquired resistance. Moreover, clinical evidence demonstrated that there is a lack of cross-resistance among AIs, although the reason is not fully understood. Thus, there is a demand to understand the mechanisms involved in endocrine resistance to each AI, since the search for new strategies to surpass breast cancer acquired resistance is of major concern.

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Van Asten, Kathleen, Patrick Neven, Anneleen Lintermans, Hans Wildiers et Robert Paridaens. « Aromatase inhibitors in the breast cancer clinic : focus on exemestane ». Endocrine-Related Cancer 21, n^o 1 (février 2014) : R31—R49. http://dx.doi.org/10.1530/erc-13-0269.

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Breast cancer is the most prevalent type of cancer in women and responsible for significant female cancer-related mortality worldwide. In the Western world, over 80% of breast cancers are hormone-receptor positive for which endocrine therapy is administered. The main anti-estrogen treatments in use consist of selective estrogen-receptor modulators, such as tamoxifen, and third-generation aromatase inhibitors (AIs), such as exemestane, letrozole, and anastrozole. In this review, the focus will lie on exemestane, its clinical use, and its side-effect profile. Exemestane is the only third-generation steroidal AI. Its efficacy as a first-line treatment in metastatic breast cancer has been demonstrated. Therefore, exemestane could be considered a valid first-line therapeutic option, but it also can be used in second-line or further situations. Exemestane is mostly used as part of sequential adjuvant treatment following tamoxifen, but in this setting it is also active in monotherapy. Furthermore, this AI has been studied in the neoadjuvant setting as presurgical treatment, and even as chemoprevention in high-risk healthy postmenopausal women. It may reverse side effects of tamoxifen, such as endometrial changes and thromboembolic disease but may also cause some inconvenient side effects itself. Additionally, there is a lack of total cross-resistance between exemestane and nonsteroidal AIs as far as their anti-tumoral efficacy is concerned; moreover the two classes of AIs display a nontotal overlapping toxicity profile. Taking together, exemestane can be considered as a useful treatment option at all stages of breast cancer.

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