The Role of Aromatase Enzyme in Hormone Related Diseases and Plant- Based Aromatase Inhibitors as Therapeutic Regimens.

Medicinal plants have a long history of use as food and remedy in traditional and modern societies. They have been used as herbal drugs and sources of novel bioactive compounds. They provide a wide array of chemical compounds, many of which can not be synthesized via current synthesis methods. Natural products may provide aromatase inhibitory activity through various pathways and may act clinically effective for treating pathologies associated with excessive aromatase secretion, including breast, ovarian, and endometrial cancers, endometriosis, uterine fibroid, benign prostatic hyperplasia (BPH), prostate cancer, infertility, and gynecomastia. Recent studies have shown that natural products with aromatase inhibitory activity can also be good options against secondary recurrence of breast cancer by exhibiting chemopreventive effects. Therefore, screening for new plant-based aromatase inhibitors may provide novel leads for drug discovery and development, particularly with increased clinical efficacy and decreased side effects.

Cáncer de mama en el varón: revisión de la literatura y aportación de nuestra casuística / No disponible

Objetivos: Revisar los perfiles inmunohistoquímicos, aspectos genéticos y hormonales ligados a la expresión de tumores, factores pronósticos y tratamientos hormonales como inhibidores de la aromatasa en el cáncer de mama en el varón. Así mismo aportar nuestra casuística. Métodos: Se realizó una búsqueda bibliográfica utilizando las palabras clave cáncer de mama, varón, clasificación molecular e inmunohistoquímica en los repertorios bibliográficos de Pubmed y Tripdatabase entre los años 2001-2011. Así mismo hemos realizado un estudio retrospectivo de los varones que han sido diagnosticados e intervenidos quirúrgicamente por cáncer de mama en nuestro hospital en los últimos 15 años. Conclusiones: La clasificación según los marcadores inmunohistoquímicos del cáncer de mama permitiría distinguir aquellos con mejor y peor pronóstico, siendo el más favorable el tipo luminal A y sienta las bases del tratamiento tanto neo como adyuvante(AU)

Objectives: To review the immunohistochemical profiles, genetic and hormonal aspects linked to the expression of tumors, prognosis factors and hormonal treatments, like aromatase inhibitor, in male breast cancer. Also, to report our casuistry. Methods: A bibliographic review using the keywords breast cancer, male, molecular and immunohistochemical classification was carried out on PubMed and Tripdatabase between 2001 and 2010. Also, we made a retrospective study of male patients with breast cancer diagnosed and treated in our hospital within the last 15 years. Conclusions: The classification of breast cancer in male patients according to immunohistochemical markers would permit to distinguish between tumors with good or bad prognosis, being the luminal A type the most favourable, and assess the basis of neodjuvant and adjuvant treatment(AU)

Carcinoma de células fusiformes tipo “fibromatosis-like”: una variante inusual de carcinoma metaplásico de mama asociado a carcinoma ductal / No disponible

El carcinoma de células fusiformes tipo fibromatosis-like esuna variante del carcinoma metaplásico, que ha sido reconocidorecientemente como una entidad distinta e independiente del restode los tumores metaplásicos, que recuerda a la fibromatosis yse caracteriza por ser un tumor de bajo grado, con mejor pronósticoy tendencia a la recidiva local. Presentamos un caso de unapaciente de 71 años con un carcinoma tipo fibromatosis-likeasociado a un carcinoma ductal de la mama. La histología revelóun tumor de células fusiformes simulando una fibromatosis, dondese puede identificar un componente epitelial en forma de carcinomaductal o intraductal en continuidad con el componente deaspecto fusiforme. Inmunohistoquímicamente presentó positividadfocal para marcadores epiteliales y mioepiteliales como citoqueratinasy expresión de marcadores mesenquimales como vimentina.El diagnóstico exacto puede presentar dificultad tantoradiológica como anatomopatológica y plantea el diagnóstico diferencialcon lesiones benignas como fibromatosis, fascitis nodularo malignas como sarcomas. El comportamiento y pronósticono ha sido del todo aclarado aunque se ha visto que es un tumorque se caracteriza por un alto riesgo de recidiva, bajo potencialpara metastatizar en ganglios linfáticos regionales pero con capacidadpara producir metástasis a distancia y por tanto, debería sertratado en consecuencia(AU)

Fibromatosis-like spindle cell carcinoma of the breast is avariant of metaplastic carcinoma that has recently been recognizedas a different entity because of its resemblance to fibromatosisand similar propensity for local recurrence. We presenta case of 71- year-old lady with a fibromatosis-like carcinomaassociated with ductal carcinoma of the breast. Finalhistology revealed a tumor with predominant spindle cells in acollagenous background, simulating a fibromatosis. Inmunohistochemistryshowed focal positivity of ephithelial and myoephitelialmarkers as citokeratins and expression of mesenchymalmarker as vimentin in the tumor. This tumor can posediagnostic difficulty radiologic as histopathology and the differentialdiagnosis includes both benign and malignant spindlecell breast lesions as a fibromatosis, nodule fascitis or sarcomas.The behaviour and prognosis have not been well clarifiedalthough there seems to have high risk of local recurrence, lowpotential to metastasize to regional lymph nodes and potentialfor distant metastasis and should be treated accordingly(AU)

Quimioprevenção do câncer de mama / Current status of breast cancer chemoprevention

Quimioprevenção é definida como o uso de agentes químicos naturais ou sintéticos para reverter, suprimir ou prevenir a progressão carcinogênica para carcinoma invasor. Os fármacos que agem como agentes quimiopreventivos contra o câncer de mama são divididos em dois grupos principais: os que previnem cânceres de mama receptor de estrogênio (RE) positivos, como os moduladores seletivos do receptor de estrogênio (SERM), inibidores de aromatase, agonistas de GnRH e fitoestrogênios; e os fármacos que previnem os cânceres RE-negativos, como os inibidores da ciclooxigenase-2 (COX-2), retinóides, as estatinas, os inibidores do receptor tirosina quinase, o anticorpo monoclonal contra HER-2 e os inbidores da telomerase. Resultados do estudo conduzido pelo NSABP que comparou o tamoxifeno com o raloxifeno (STAR), avaliando a eficácia na redução de risco, assim como a toxicidade desses dois SERMs em uma população similar e de alto risco para câncer de mama, demonstrou que o raloxifeno é tão efetivo quanto o tamoxifeno na redução de risco de câncer de mama invasor (p=0,83) e apresentou menor risco de eventos tromboembólicos e catarata; todavia, exibiu maior risco de carcinoma não invasor, porém sem significância estatística. Baseado nos dados promissores que revelaram diminuição de risco de câncer de mama contralateral em estudos de adjuvância, alguns inibidores de aromatase, incluindo o letrozol, anastrazol e exemestane, estão sendo incorporados em investigações para avaliar sua eficácia como agentes preventivos de alto risco em mulheres. Os inibidores de COX-2 demonstraram sua eficácia na prevenção do câncer de mama em estudos caso-controle e coorte, sendo necessários estudos aleatórios para atestar sua eficácia. O resultado positivo de alguns ensaios clínicos na prevenção do câncer de mama em populações de alto risco sugere que a quimioprevenção é uma estratégia racional e atraente.

Chemoprevention is defined as the use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenic progression of invasive cancer. Drugs that act as chemoprevention agents for breast cancer are divided into two major groups: drugs that prevent Estrogen Receptor (ER) - positive breast cancers [selective estrogen receptor modulators (SERM), aromatase inhibitors GnKH agonists and phytoestrogens] and drugs that prevent ER - negative breast cancers [cyclooxygenase-2 (COX-2) inhibitors, retinoids, statins, receptor tyrosine, kinase inhibitors, monoclonal antibody against HER-2 and telomerase inhibitors]. Results from the NSABP Study of Tamoxifen and Raloxifene (STAR), which compared the risk-reducing efficacy as well as toxicity of these two SERMs in a similar high-risk for breast cancer population, showed that Raloxifene is as effective as Tamoxifen in reducing the risk of non-invasive breast cancer (p=.83). It has a statistically significant lower risk of thromboembolic events and cataracts, however a non- statistically significant higher risk of noninvasive breast cancer. Based on promising data involving reduction of contralateral breast cancer risk in adjuvant studies, several aromatase inhibitors, including letrozole, anastrozole and exemestane, are being included in trials to evaluate their efficacy in breast cancer prevention in both case-control and cohort studies As such randomized studies to confirm this efficacy are needed. Positive results of several recent clinical trials for preventing breast cancer in high-risk populations suggest that chemoprevention is a rational and attractive strategy.

[Current status of breast cancer chemoprevention]. / Quimioprevenção do câncer de mama.

Chemoprevention is defined as the use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenic progression of invasive cancer. Drugs that act as chemoprevention agents for breast cancer are divided into two major groups: drugs that prevent Estrogen Receptor (ER)-positive breast cancers [selective estrogen receptor modulators (SERM), aromatase inhibitors GnKH agonists and phytoestrogens] and drugs that prevent ER-negative breast cancers [cyclooxygenase-2 (COX-2) inhibitors, retinoids, statins, receptor tyrosine, kinase inhibitors, monoclonal antibody against HER-2 and telomerase inhibitors]. Results from the NSABP Study of Tamoxifen and Raloxifene (STAR), which compared the risk-reducing efficacy as well as toxicity of these two SERMs in a similar high-risk for breast cancer population, showed that Raloxifene is as effective as Tamoxifen in reducing the risk of non-invasive breast cancer (p=.83). It has a statistically significant lower risk of thromboembolic events and cataracts, however a non- statistically significant higher risk of noninvasive breast cancer. Based on promising data involving reduction of contralateral breast cancer risk in adjuvant studies, several aromatase inhibitors, including letrozole, anastrozole and exemestane, are being included in trials to evaluate their efficacy in breast cancer prevention in both case-control and cohort studies As such randomized studies to confirm this efficacy are needed. Positive results of several recent clinical trials for preventing breast cancer in high-risk populations suggest that chemoprevention is a rational and attractive strategy.

Aromatase inhibition for the treatment of idiopathic hypogonadotropic hypogonadism in men with premature ejaculation.

BACKGROUND: Idiopathic hypogonadotropic hypogonadism (IHH) has been observed to occur in men with premature ejaculation (PE). Common IHH therapies include testosterone replacement, which increases testosterone levels but suppresses gonadotropin release; and gonadotropin-releasing hormone supplementation, which restores gonadotropin levels but is impractical for chronic use. Hormonal imbalances associated with IHH/PE are thought to be related to hyperactivity of the cytochrome P-450 enzyme aromatase. METHODS: Ten male patients with a diagnosis of IHH/PE were treated with the aromatase inhibitor anastrazole (1 mg/d orally). Levels of free and total testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin, and estradiol were determined at baseline and after 2 weeks of therapy. RESULTS: After 2 weeks of therapy with anastrazole, levels of testosterone, luteinizing hormone, and estradiol had returned to normal. No effect was noted on premature ejaculation. CONCLUSION: These results suggest that aromatase inhibition with anastrazole may provide a practical and efficacious alternative for the treatment of IHH but is not effective in preventing premature ejaculation.

The current status of aromatase inhibitors in the management of breast cancer.

The third generation of specific AIs have made a very exciting contribution to the management of hormone responsive breast cancer. We can now state with confidence that their role in advanced breast cancer has overtaken that of tamoxifen, which should be relegated to a second-line treatment. Indeed, as a recent publication confirmed that first-line anastrozole followed by tamoxifen is an effective treatment sequence, this sequence may be considered the best choice for treating patients with hormone receptor-positive ABC. As far as the primary disease is concerned, the ATAC data certainly suggest that there is an alternative to tamoxifen in selected postmenopausal women with hormone receptor-positive disease. With more mature follow-up the study might even show that after a passage of nearly 20 years tamoxifen has lost its lead position in the adjuvant stakes as well.

Complete estrogen blockade for the treatment of metastatic and early stage breast cancer.

Complete estrogen blockade has long been sought as a more effective means of controlling breast cancer compared with single agent endocrine therapy. This approach may be accomplished through the use of agents which reduce estrogen production combined with agents that prevent the activity of estrogen at the cellular level. For prostate cancer, another hormonally responsive malignancy, this approach has not been successful at improving survival compared with that achieved with single agent therapy. Preclinical information is contradictory for many promising combinations and may not reflect the true nature of in vivo interaction between agents. For premenopausal patients with metastatic breast cancer, the combination of a luteinising hormone-releasing hormone (LHRH) agonist and tamoxifen is clearly effective, but whether the combination is more effective than either single agent is still controversial. Similar response rates and overall survival were reported with goserelin or goserelin plus tamoxifen by Jonat et al. in 1 randomised, prospective study, but the addition of tamoxifen improved time to progression. A second trial comparing buserelin plus tamoxifen with either single agent reported superior efficacy in terms of response rates, disease-free survival and overall survival with combination therapy. A meta-analysis of 4 randomised trials making similar comparisons, demonstrated significant improvement in median overall survival, progression-free survival, response rate, and duration of response with the combination of a LHRH agonist (goserelin or buserelin) and tamoxifen in premenopausal breast cancer patients with metastatic disease. For postmenopausal women with metastatic breast cancer, the addition of an aromatase inhibitor to tamoxifen has yet to be prospectively compared to single agent therapy. Use of endocrine combinations in the treatment of early stage breast cancer is under investigation. Preliminary results of some of the ongoing adjuvant therapy trials indicate that the combination of a LHRH agonist and tamoxifen may have similar efficacy to cyclophosphamide, methotrexate, and fluorouracil chemotherapy in premenopausal women with estrogen receptor-positive tumour. Addition of LHRH agonist therapy in premenopausal patients with estrogen receptor-positive tumour who had maintained the ovarian function following chemotherapy [cyclophosphamide, doxorubicin (adriamycin), fluorouracil, and tamoxifen], also led to a reduction in the risk of recurrence. These studies have identified a sub-population of patients who may benefit from the addition of combination endocrine therapy. Overall, the issue is quite complex and the data from many ongoing trials are still awaited with anticipation to further delineate the role of complete estrogen deprivation in this disease.

[Current status and prospectives of aromatase inhibitors in the treatment of advanced breast cancer]. / Stato attuale e prospettive nel trattamento del carcinoma mammario avanzato con gli inibitori dell'aromatasi.

Endocrine therapy represents one of the most effective instruments for the palliative and adjuvant treatment of breast cancer, in particular in postmenopausal patients. While tamoxifen still forms the treatment of choice during the adjuvant phase and the first-line treatment during the metastatic phase, aromatase inhibitors undoubtedly represent the treatment of choice for patients who do not respond to antiestrogen treatment. These drugs represent a heterogeneous family of compounds able to provide more or less selective inhibition of aromatases by forming an irreversible bond with the catalytic site of the enzymatic complex (type I inhibitors) or using a competitive mechanism (type II inhibitors). Among the type I drugs, 4-hydroxyandrostenedione and hexamestane are those that probably attract greatest clinical interest. These drugs can significantly reduce the circulating levels of estrone and estradiol, and have been shown to be active in 20% of patients pretreated with tamoxifen. Moreover, hexamestane was also effective in patients pretreated with type II inhibitors, of which the parent drug is aminoglutethimide. This drug is still used in the second and third-line treatment of breast cancer but, since it causes collateral effects in a substantial percentage of patients, above all when used at higher doses in combination with hydrocortisone, it will soon be replaced by second and third generation inhibitors, like letrozole, fadrozole, vorozole and anastrozole. These drugs have been shown to be significantly more active than aminoglutethimide, both in vitro and in vivo, and above all more selective. In particular, even at high doses anastrozole has not been found to interfere with steroidogenesis at a corticoadrenal level. Moreover, anastrozole has been shown to be very active even at relatively modest doses given in a single daily dose. Two recent controlled studies, including a total of over 600 patients, recently demonstrated that, if used in second line in patients who no longer responded to adjuvant or palliative tamoxifen therapy, anastrozole is just as effective but probably better tolerated than megestrol acetate. Studies are now in progress or are currently being launched to evaluate the possible value of anastrozole and other third generation inhibitors both as first-line treatment and as adjuvant treatment as an alternative or in combination with tamoxifen.

[Hormone therapy of metastasizing breast carcinoma]. / Hormontherapie des metastasierenden Mammakarzinoms.

In patients with metastatic breast cancer, cure is almost always an exception, irrespective of the therapy given. Thus the preservation of the quality of life or palliation in case of symptoms must be the principal goal. Only a small group of patients with their tumour showing a highly aggressive behaviour should be considered for primary chemotherapy. Aggressive tumour growth is then characterized by negative hormonal receptors, short disease-free interval and predominant visceral tumour growth. For all other patients there is not enough advantage to justify the clearly higher toxicity of a primary chemotherapy. This majority of patients with metastatic breast cancer can profit to a higher degree from hormonal treatment. Irrespective of the type of the hormonal therapy, the response rate is positively correlated with postmenopausal status, high hormonal receptor expression, al long disease-free interval, no previous adjuvant therapy and higher age. Advantages and problems of the various forms of hormonal manipulations are discussed. The recommended sequence of therapy represents only a handrail that needs to be adjusted carefully, according to the individual situation, the needs and expectations of the patient and in due knowledge of the toxicity of each hormonal substance. Combinations of different hormonal agents do not yield an additional benefit and should therefore be dropped for a sequential approach.