Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs).

Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed

The Efficacy of Neoadjuvant Androgen Deprivation Therapy as a Prostate Volume Reduction before Brachytherapy for Clinically Localized Prostate Cancer

From September 2003 to December 2005, 188 patients who visited our hospital and allied institutions for the purpose of prostate brachytherapy were administrated hormonal therapy for volume reductions before brachytherapy. The pretreatment and posttreatment of prostate volume using a transrectal ultrasound volumetric study and the types and duration of hormonal therapy were analyzed. We administered 91 patients with Luteinizing hormone-releasing hormone (LH-RH) agonist, 49 patients with anti-androgen (bicaltamide/flutamide), and 48 patients with maximum androgen blockade (MAB). The duration of the hormonal therapy was 1-3 months for 49 patients, 4-6 months for 59 patients, 7-9 months for 40 patients, 10-12 months for 32 patients, and over 13 months for 8 patients. Before the initiation of hormonal therapy, the mean prostate volume was 35.12 ml (11.04-78.71 ml), and the average of prostate volume before and after hormonal therapy was 36.79 ml and 24.79 ml, respectively (a 32.4% reduction). The prostate volume reduction rate was 32.0% for the LH-RH agonist only, 18.1% for the anti-androgen only and 41.2% for the MAB. No statistically significant difference was observed for the duration of hormonal therapy between 3 groups. A three-month course of the neoadjuvant LH-RH agonist indicated a sufficient volume reduction effectiveness for a large prostate volume.</p

Hormonal therapy for cancer

Hormone therapy is an effective and non-toxic therapy for oestrogen and progesterone receptor-positive breast cancer and prostate cancer. Serum levels of oestradiol and testosterone are controlled by the hypothalamic–pituitary–gonadal pathway. Oestradiol is produced in premenopausal women from the ovaries and in postmenopausal women by peripheral conversion of adrenal androgens by aromatase. In premenopausal women with breast cancer and men with prostate cancer, treatment is primarily achieved by castration. In postmenopausal women selective oestrogen receptor modulators (e.g. tamoxifen) or aromatase inhibitors are used. Hormone therapy can be used to reduce the size of the primary cancer prior to radical surgery or radiotherapy or to reduce the risk of recurrence. Hormone therapy is highly effective in patients with locally advanced or metastatic disease, with a high response rate. Most patients eventually relapse with ‘castrate-refractory’ disease, for which increasing numbers of active agents are entering clinical practice

Breast Cancer Risk in Relation to the Interval Between Menopause and Starting Hormone Therapy

Background: Although breast cancer risk is greater in users of estrogen-progestin than estrogen-only formulations of menopausal hormonal therapy, reports on their effects have been somewhat inconsistent. We investigated whether the timing of these therapies affected breast cancer incidence. Methods: A total of 1 129 025 postmenopausal UK women provided prospective information on hormonal therapy use and other factors relevant for breast cancer risk. We used Cox regression to estimate adjusted relative risks (RRs) of breast cancer in hormonal therapy users vs never users and calculated standardized incidence rates. All statistical tests were two-sided. Results: During 4.05 million woman-years of follow-up, 15 759 incident breast cancers occurred, with 7107 in current users of hormonal therapy. Breast cancer incidence was increased in current users of hormonal therapy, returning to that of never users a few years after use had ceased. The relative risks for breast cancer in current users were greater if hormonal therapy was begun before or soon after menopause than after a longer gap (Pheterogeneity <. 001, for both estrogen-only and estrogen-progestin formulations). Among current users of estrogen-only formulations, there was little or no increase in risk if use began 5 years or more after menopause (RR = 1.05, 95% confidence interval [CI] = 0.89 to 1.24), but risk was statistically significantly increased if use began before or less than 5 years after menopause (RR = 1.43, 95% CI = 1.35 to 1.51). A similar pattern was observed among current users of estrogen-progestin formulations (RR = 1.53, 95% CI = 1.38 to 1.70, and RR = 2.04, 95% CI = 1.95 to 2.14, respectively). At 50-59 years of age, annual standardized incidence rates for breast cancer were 0.30% (95% CI = 0.29% to 0.31%) among never users of hormone therapy and 0.43% (95% CI = 0.42% to 0.45%) and 0.61% (95% CI = 0.59% to 0.64%), respectively, among current users of estrogen-only and estrogen-progestin formulations who began use less than 5 years after menopause. Conclusions: There was substantial heterogeneity in breast cancer risk among current users of hormonal therapy. Risks were greater among users of estrogen-progestin than estrogen-only formulations and if hormonal therapy started at around the time of menopause than later

Hormonal Therapy and Chemoprevention.

Hormone replacement therapy (HRT) can increase the quality as well as the length of life, but a prolonged use can also increase the risk of breast cancer. The combination of HRT and a selective estrogen receptor modulator (SERM) such as tamoxifen may retain the benefits while reducing the risks of either agent. A post hoc analysis of the Italian Tamoxifen Prevention Study showed a borderline significant reduction of breast cancer among women who were on HRT continuously and tamoxifen as compared with continuous HRT users who received placebo. Recent studies suggest that the standard dose of tamoxifen may be reduced to one-quarter (i.e., 10 mg every other day) without loss of its beneficial biological effects. Since the endometrial effect of tamoxifen seems to be both dose and time dependent, a dose reduction could substantially reduce the risk of endometrial cancer while retaining its preventive efficacy. On the other hand, the addition of HRT containing progestins could also minimize the risk of endometrial cancer associated with tamoxifen. Moreover, estrogen should reduce the incidence of vasomotor and urogenital symptoms, which are a major reason for tamoxifen withdrawal in prevention studies. Notably, in the National Surgical Adjuvant Breast Project (NSABP) P-1 trial, women ages 50 or younger had no increased incidence of adverse events, including endometrial cancer and venous thromboembolic events. One possible explanation for the lack of toxicity in premenopause is the presence of adequate circulating estrogen levels which prevent tamoxifen to act as an estrogen agonist at these target tissues. Moreover, data from the current Italian tamoxifen prevention trial indicate that the compliance was substantially higher for de novo and current HRT users as compared to women who never received HRT during the study. The combination of HRT and tamoxifen at low doses could thus reduce the risks and side effects while retaining the benefits of either agent

Management of Hormone Receptor-Positive Metastatic Breast Cancer

Hormone-receptor positive HER2-negative breast cancer constitutes about 2/3 of breast cancer. Hormonal therapy such as tamoxifen and aromatase inhibitors has been the main stay of treatment which gives favorable quality of life compared with traditional chemotherapy. However, the efficacy of subsequent hormonal therapy declines rapidly after the patients develops resistance to first line hormonal therapy. In recent years, there have been many breakthrough in the treatment of this cancer. A number of targeted agents including CDK4/6 inhibitor and mTOR inhibitor are now part of standard treatment paradigm to help prolong the use of hormonal therapy. New understanding in potential biomarker of resistance such as ESR1 mutation or PIK3CA mutation has also empowered us to develops personalized approach in treatment. This article will explain the treatment logistic for this cancer, current knowledge in hormonal resistance, findings of key clinical trials that define the current treatment paradigm, efficacy and major side effect precaution of the targeted agents, and the unmet needs

Long-term clinical outcomes of 420 consecutive prostate cancer patients in a single institute.

This study was undertaken to reveal the trends of prostate cancer and the outcome of treatment modalities for each disease stage in patients in a single institute over a 10-year period. From January 1994 through December 2003, 420 consecutive patients with previously untreated and histologically confirmed prostate cancer were analyzed for annual distributions of disease stages and treatment modalities and for long-term clinical progression-free survival, prostate cancer-specific survival, and prostate-specific antigen (PSA) failure-free survival rates for each stage and treatment modality. Annual trends showed that the number of patients, especially those with clinically localized cancer, increased dramatically. The 5-year disease-specific survival rates for patients with clinically localized disease were 100 percent for all treatment modalities, including hormonal therapy alone. Patients with PSA levels less than 10 ng/ml showed an 81 percent 5-year PSA failure-free survival rate with radical prostatectomy. Stage C patients treated by surgery or radiation-based therapy with concomitant hormonal therapy obtained 93 percent and 100 percent cause-specific survival rates, respectively, and those treated by hormonal therapy alone showed a 79 percent rate. The number of patients with localized prostate cancer was increasing in this decade. While long-term hormonal therapy alone was highly efficient in controlling localized prostate cancer, radical therapies in conjunction with neo-adjuvant hormonal therapy produced better survival rates in cases of locally advanced disease.</p

Reconsideration of Hormonal Therapy in the Era of Next‐ Generation Hormonal Therapy

Hormonal therapy is a major and effective tool in the treatment of prostate cancer patients. This is especially true for patients in the advanced stages of disease. Unfortunately, almost all prostate cancer cells will develop into castration‐resistant prostate cancer (CRPC) despite continued therapy and suppression of testosterone levels. Up until 5–6 years ago, there was little effective therapy for the treatment of CRPC patients. However, recently, a variety of methodologies and drugs such as cabazitaxel and sipuleucel‐T have been approved globally for the treatment of CRPC. Two novel drugs, abiraterone acetate and enzartamide, have also become available as potential treatment options. However, the anticancer effects of these two drugs are not always satisfactory in terms of prolonging survival. These drugs are also associated with adverse events and are expensive when compared with the costs of previously used anticancer drugs. In this section, we pay particular attention to hormonal therapies that do not include the use of abiraterone acetate or enzartamide. We believe that a detailed understanding of the range of currently available hormonal therapies, including their associated benefits and limitations, is important for supporting the prolongation of survival in patients with advanced prostate cancer. Therefore, this section offers a valuable discussion on the treatment strategies for prostate cancer including CRPC

Public Health Rep

Midlife care should consider the whole woman, with preventive attention to osteoporosis and cardiovascular disease. A new delivery system, using a skin patch, is available for replacement or additive hormonal therapy. Useful hormonal therapy may include both estrogen and progesterone.3120209PMCnul

Hormonal therapy followed by chemotherapy or the reverse sequence as first-line treatment of hormone-responsive, human epidermal growth factor receptor-2 negative metastatic breast cancer patients: Results of an observational study

Introduction Although hormonal-therapy is the preferred first-line treatment for hormone-responsive, HER2 negative metastatic breast cancer, no data from clinical trials support the choice between hormonal-therapy and chemotherapy. Methods Patients were divided into two groups according to the treatment: chemotherapy or hormonal-therapy. Outcomes in terms of clinical benefit and median overall survival (OS) were retrospectively evaluated in the two groups. To calculate the time spent in chemotherapy with respect to OS in the two groups, the proportion of patients in chemotherapy relative to those present in either group was computed at every day from the start of therapy. Results From 1999 to 2013, 119 patients received first-line hormonal-therapy (HT-first group) and 100 first-line chemotherapy (CT-first group). Patients in the CTfirst group were younger and with poorer prognostic factors as compared to those in HT-first group. Clinical benefit (77 vs 81%) and median OS (50.7 vs 51.1 months) were similar in the two groups. Time spent in chemotherapy was significantly longer during the first 3 years in CT-first group (54-34%) as compared to the HT-first group (11-18%). This difference decreased after the third year and overall was 28% in the CT-first group and 18% in the HT-first group. Conclusions The sequence first-line chemotherapy followed by hormonal-therapy, as compared with the opposite sequence, is associated with a longer time of OS spent in chemotherapy. However, despite the poorer prognostic factors, patients in the CTfirst group had a superimposable OS than those in the HT-first group