Therapy In Postmenopausal Patients Research Articles

Outcome of Primary Endocrine Therapy in Postmenopausal Patients with Endocrine-responsive Breast Cancer

Purpose: The purpose of this study was to investigate the efficacy and toxicity of primary endocrine therapy in postmenopausal elderly patients with endocrine-responsive breast cancer.Patients and Methods: The study included 11 postmenopausal patients with breast cancer aged 70 years and over who started primary endocrine therapy between April 2004 and November 2007. Treatment consisted of 1 mg/day anastrozole or 25 mg/day exemestane and was continued until progressive disease was noted. In patients who had progressive disease, another aromatase inhibitor or tamoxifen was administered.Results: The drugs used as primary therapy were anastrozole and exemestane in 7 and 4 patients, respectively. Seven patients had a performance status of 0 to 1 and 4 had 3 to 4. The best clinical response was a complete remission in 2 patients, in addition to partial remission in 4, stable disease in 4 (including 2 patients with long-term stabilization), and disease progression in 1, with a response rate of 55% and a clinical benefit rate of 73%. The average duration of primary treatment was 15.5 months, and 2 patients died during the study (one from cerebral hemorrhage and the other from breast cancer). With regard to safety, a fracture of the right fourth finger was observed in 1 patient.Conclusion: Primary endocrine therapy with aromatase inhibitors resulted in a high response rate and a long-term clinical benefit, along with a superior tolerability. Therefore, this therapy can be effective in extremely elderly patients with endocrine-responsive breast cancer.

Controversies in adjuvant endocrine therapy for pre- and post-menopausal women with breast cancer

Nearly 80% of breast cancer are hormone receptor positive. The efficacy of hormonal adjuvant therapy of breast cancer was expressed in the most recent EBCTG overview analysis of randomised trials using adjuvant tamoxifen. Five years of adjuvant tamoxifen led to proportional risk reduction, in terms of recurrence and mortality for hormone receptor positive patients, of 47% and 26%, respectively. This benefit was constant, regardless of menopausal status, age or whether or not chemotherapy was administered. More recent trials evaluating the use of aromatase inhibitors have challenged the standard of hormonal therapy in post-menopausal patients. However, many questions have been raised from these trials: (a) the optimal management of patients with hormone receptor positive breast cancer in terms of selection of hormonal agents and its sequence and duration; (b) the role of ovarian suppression in pre-menopausal patients; and (c) the actual role of biomolecular markers in clinical decision.

Target and reality of adjuvant endocrine therapy in postmenopausal patients with invasive breast cancer

Previous research evaluating the use of adjuvant endocrine therapy among postmenopausal breast cancer patients showed with 15–50% wide ranges of non-adherence rates. We evaluated this issue by analysing an unselected study group comprising of 325 postmenopausal women, diagnosed from 1997 to 2003 with hormonal receptor-positive invasive breast cancer. The different clinical situations that led to the discontinuation of adjuvant endocrine therapy were clearly defined and differentiated: non-adherence was not simply the act of stopping medication, but rather the manifestation of an intentional behaviour of the patient. Of the 287 patients who initiated endocrine therapy, 191 (66.6%) fully completed this treatment. Thirty-one patients (10.8%) showed non-adherence to therapy. Patients who had follow-up with a general practitioner, rather than in an oncologic unit, were more likely to be non-adherent (P=0.0088). Of 25 patients who changed medication due to therapy-related adverse effects, 20 (80%) patients fully completed the therapy after drug change. In adjuvant endocrine therapy, a lowering of the non-adherence rate to 10.8%, the lowest reported in the literature, is realistic when patients are cared for by a specialised oncologic unit focusing on the individual needs of the patients.

Exemestane as primary systemic treatment for hormone receptor positive post-menopausal breast cancer patients: a phase II trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-17)

A multicenter phase II study was conducted to analyze the clinical activity of the steroidal aromatase inhibitor exemestane in the neoadjuvant treatment of post-menopausal women with strongly ER- and/or PgR- positive operable breast cancer. From September 2000 to December 2003, 80 women were recruited for treatment with exemestane 25 mg once daily for 4 months. The primary end-point was the clinical response rate according the WHO criteria; the secondary end-points included toxicity and the number of patients who qualified for breast conserving surgery at the end of treatment, comparability of evaluation methods for response, potential alterations of hormone receptor and Her2/neu status during treatment. On an intention to evaluate analysis, according to the prespecified criteria the overall clinical objective response rate was 34%, the pCR rate was 3% and the rate of breast conserving surgery was 76%. When sonographic and mammographic longitudinal measurements were included in patients with missing palpation data, response rates were 38% and 41%, respectively. The tumor response was independent of the Her2/neu status which remained unchanged during treatment. In contrast, while the ER expression remained unaltered, downregulation of the PgR was observed. The treatment was well tolerated with no grade 3 and 4 toxicities except gastrointestinal (one grade 3 case) and hot flushes (two grade 3 cases). This study shows that exemestane is effective and safe as a preoperative therapy in post-menopausal patients with strongly hormone receptor-positive breast cancer.

2044 POSTER Phase II trial with letrozole (2.5 mg) to maximal response as neoadjuvant endocrine therapy in postmenopausal patients with ER/PgR[+] operable breast cancer

2044 POSTER Phase II trial with letrozole (2.5 mg) to maximal response as neoadjuvant endocrine therapy in postmenopausal patients with ER/PgR[+] operable breast cancer

New development in intracrinology of breast carcinoma: therapeutic horizons after aromatase inhibitors

Aromatase inhibitors have become the gold standard of endocrine therapy in postmenopausal patients with estrogen receptor-positive or estrogen-dependent breast carcinoma, replacing tamoxifen. However, it is true that there are some potential problems to be overcome or improved on regarding aromatase inhibitor treatment of breast cancer. This especially includes the presence of the estrogen receptor-positive patients who do not necessarily respond to aromatase inhibitors, may require other modes of endocrine therapy and develop resistance to aromatase inhibitor in their clinical course, and who may also need alternative modes of suppressing intratumoral estrogen signals or other intracellular signal pathways related to tumor progression or development. Intratumoral estrogen production from precursors present in circulation in an ‘intracrine’ manner is considered to play very important roles in the development and progression of estrogen receptor-positive breast cancer. The great majority of estrone in circulation is present as a sulfated form or estrone sulfate, and steroid sulfatase hydrolyzes circulating estrone sulfate to estrone in various human tissues in situ, which confers potent estrogenic actions. Estrone is subsequently reduced to 17β-estradiol by 17β-hydroxysteroid dehydrogenase type 1. Therefore, these two enzymes also play very important roles in intracrinology of estrogen in breast cancer in addition to intratumoral aromatase, and the potential inhibition of these two enzymes could lead to the development of a new mode of endocrine therapy based on intracrinology, which may overcome some of the problems above in aromatase inhibitor therapy. In this review, the potential advantages and pitfalls or problems associated with the inhibition of these two intratumoral enzymes in breast cancer patients will be discussed.

P128 Phase II trial with letrozole (2.8 mg) to maximal response as neoadjuvant endocrine therapy in postmenopausal patients with ER/PgR[+] operable breast cancer

P128 Phase II trial with letrozole (2.8 mg) to maximal response as neoadjuvant endocrine therapy in postmenopausal patients with ER/PgR[+] operable breast cancer

Results of letrozole in postmenopausal women after tamoxifen treatment for advanced breast cancer

To analyze overall and progression-free survival after letrozole in postmenopausal women with advanced breast cancer who failed after tamoxifen therapy. This is a retrospective analysis of 95 patients with breast cancer who were postmenopausal and had failed after tamoxifen therapy. Dose of letrozole was 2.5 mg daily until disease progressed. Patients had estrogen receptor- and/or progesterone receptor-positive tumors or both receptors were unknown. One complete course of (6 cycles) chemotherapy for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, time to treatment failure (TTF), overall survival and tolerability. Median TTP was 10 months. ORR was 21% with complete response rate of 9%. Nine patients died of disease during treatment. Median overall survival was 36 months. Median time to response was three months and median duration of response was 13 months. Time to chemotherapy was 13.5 months and TTF was 9.3 months. Treatment failure was seen in 76% of patients. Disease progression was the main cause for treatment failure. Treatment was well-tolerated by all patients. This retrospective analysis shows that letrozole is quite effective as second line therapy in postmenopausal patients with advanced breast cancer who had failed after tamoxifen therapy.

Austrian Breast and Colorectal Cancer Study Group (ABCSG)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Austrian Breast and Colorectal Cancer Study Group ABCSG. Clinical trials include:Adjuvant therapy with CMF versus goserelin plus tamoxifen in pre-menopausal, hormone-responsive, lymph node-positive or -negative patients. Study 5Adjuvant endocrine therapy in postmenopausal patients with hormone-responsive breast cancer: tamoxifen versus tamoxifen plus aminoglutethimide. Study 6Pre and postoperative chemotherapy versus conventional adjuvant chemotherapy alone in patients presenting with hormone receptor-negative breast cancer. Study 7Adjuvant endocrine therapy in postmenopausal patients with hormone-responsive breast cancer, G1 and G2 (ARNO). Study 8Adjuvant chemotherapy in postmenopausal patients with hormone-responsive breast cancer, G3. Study 9Adjuvant endocrine therapy and bisphosphonate therapy: tamoxifen in comparison to anastrozole, alone or in combination with zoledronate, in premenopausal patients presenting with hormone-responsive, Stage I and II breast cancer. Study 12Effect of 3 versus 6 cycles of epidoxorubicin/docetaxel G-CSF upon the rate of complete pathological remissions in the neoadjuvant treatment of patients with primary breast cancer and no distant metastases. Study 14SALSA (Secondary Adjuvant Long-term Study with Arimidex): a prospective, randomized, open, multicentre Phase III study to assess the efficacy of secondary adjuvant endocrine anastrozole therapy for 2 further years versus 5 further years in patients with hormone receptor-positive breast cancer after a 5-year primary adjuvant endocrine therapy. Study 16Neoadjuvant hormonal therapy with exemestane in postmenopausal patients with primary hormone receptor-positive breast cancer and no distant metastases. Study 17A randomized, double-blind, placebo-controlled, multi-centre phase 3 study to determine the treatment effect of denosumab in subjects with non-metastatic breast cancer receiving aromatase inhibitor therapy. Study 18A randomised Phase II study comparing anastrozole and fulvestrant to anastrozole for adjuvant treatment of postmenopausal patients with early breast cancer and disseminated tumour cells in bone marrow. Study 21A randomized Phase III study comparing epirubicin, docetaxel and capecitabine G-CSF to epirubicin and docetaxel G-CSF as neoadjuvant treatment for early HER-2 negative breast cancer and comparing epirubicin, docetaxel and capecitabine G-CSF trastuzumab to epirubicin and docetaxel G-CSF trastuzumab as neoadjuvant treatment for early HER-2 positive breast cancer. Study 24

NSABP B-42: A Clinical Trial to Determine the Efficacy of Five Years of Letrozole Compared with Placebo in Patients Completing Five Years of Hormonal Therapy Consisting of an Aromatase Inhibitor (AI) or Tamoxifen Followed by an AI in Prolonging Disease-Free Survival in Postmenopausal Women with Hormone Receptor—Positive Breast Cancer

Aromatase Inhibitors as Adjuvant Therapy Adjuvant hormonal therapy significantly improves disease-free and overall survival in patients with stage I, II, or III breast cancer and hormone receptor–positive tumors.1,2 For some time, 5 years of adjuvant tamoxifen has been the gold standard. However, recent results from studies evaluating the third generation aromatase inhibitors (AIs) as adjuvant therapy in postmenopausal women have challenged the primacy of tamoxifen for this group of patients.3-14 In patients with advanced-stage breast cancer, the third generation nonsteroidal AIs anastrozole and letrozole as well as the steroidal inactivator exemestane have been found superior to megestrol acetate as second-line therapy15-21 and at least equivalent (and possibly superior) to tamoxifen as first-line therapy.21-25 Based on these results, several clinical trials have evaluated or are currently evaluating AIs as adjuvant therapy in postmenopausal patients with early-stage breast cancer. In the adjuvant setting, AIs have demonstrated activity in 3 distinct clinical scenarios. In the first, an AI was compared with tamoxifen as initial adjuvant hormonal therapy in patients with resected operable breast cancer.3-5 The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial demonstrated that 5 years of anastrozole significantly improved disease-free survival (DFS) when compared with 5 years of tamoxifen.3,4 More recently, the BIG (Breast Intergroup) 1-98 trial also demonstrated similar benefit for 5 years of letrozole compared with 5 years of tamoxifen.5 In the second scenario, an AI was compared with tamoxifen in patients who had already received 2-3 years of adjuvant tamoxifen.6-10 In 3 randomized trials (the IES [Intergroup Exemestane Study] trial,6,7 the ABCSG [Austrian Breast and Colorectal Cancer Study Group]–8/ARNO [ArimidexNSABP B-42: A Clinical Trial to Determine the Efficacy of Five Years of Letrozole Compared with Placebo in Patients Completing Five Years of Hormonal Therapy Consisting of an Aromatase Inhibitor (AI) or Tamoxifen Followed by an AI in Prolonging Disease-Free Survival in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer

International Breast Cancer Study Group (IBCSG)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by International Breast Cancer Study Group (IBCSG). Clinical trials include: CMF with or without prednisone for pre/perimenopausal patients with breast cancer and 1–3 positive nodes. Ludwig/IBCSG Trial ICMF + prednisone combined with or without oophorectomy for pre/perimenopausal patients with breast cancer and 4 or more positive nodes. Ludwig/IBCSG Trial IIAdjuvant therapy for postmenopausal elderly patients (older than 65): observation versus prednisone tamoxifen. Ludwig/IBCSG Trial IIIAdjuvant therapy for postmenopausal, 65 years or younger, node-positive breast cancer patients: observation versus prednisone + tamoxifen versus CMF + prednisone + tamoxifen. Ludwig/IBCSG Trial IVAdjuvant perioperative chemotherapy. Ludwig/IBCSG Trial VAdjuvant therapy in node-positive pre/perimenopausal breast cancer patients: CMF 3 versus 6 with or without reintroduction of chemotherapy. IBCSG Trial VIAdjuvant chemotherapy in node-positive postmenopausal breast cancer patients: endocrine versus chemo-endocrine versus chemo-endocrine with delayed chemotherapy. IBCSG Trial VIIAdjuvant therapy in pre- and perimenopausal patients with node-negative breast cancer. Observation versus LH-RH analogue versus CMF versus CMF + LN-RH analogue. IBCSG Trial VIIIAdjuvant therapy in postmenopausal patients with node-negative breast cancer. Tamoxifen versus CMF followed by tamoxifen. IBCSG Trial IXSurgical therapy with or without axillary node clearance for breast cancer in elderly patients who receive adjuvant therapy with tamoxifen. IBCSG Trial 10–93Adjuvant therapy for premenopausal patients with node-positive breast cancer who are suitable for endocrine therapy alone. IBCSG Trial 11–93Adjuvant therapy for post/perimenopausal patients with node-positive breast cancer who have estrogen-receptor-positive tumors. IBCSG Trial 12–93Adjuvant therapy for premenopausal patients with node-positive breast cancer who are not suitable for endocrine therapy alone. IBCSG Trial 13–93Adjuvant therapy for post perimenopausal patients with node-positive breast cancer who are not suitable for endocrine therapy alone. IBCSG Trial 14–93High dose EC × 3 supported by PBSC versus EC/AC × 4 followed by CMF as adjuvant treatment for high-risk operable Stage II and Stage III breast cancer in premenopausal and young postmenopausal (<65 years) patients. IBCSG Trial 15–95Adjuvant therapy for postmenopausal patients with operable breast cancer who have estrogen-receptor or progesterone-receptor-positive tumors. Tamoxifen versus letrozole versus tamoxifen followed by letrozole versus letrozole followed by tamoxifen. BIG 1–98 / IBCSG Trial 18–98Maintenance chemotherapy in hormone non-responsive breast cancer: low-dose cytotoxics as “anti-angiogenesis treatment” following adjuvant induction chemotherapy for patients with ER-negative and PgR-negative breast cancer. IBCSG Trial 22–00A randomized trial of axillary dissection versus no axillary dissection for patients with clinically node-negative breast cancer and micrometastases in the sentinel node. IBCSG Trial 23–01Suppression of Ovarian Function Trial (SOFT). A Phase III trial evaluating the role of ovarian function suppression (OFS) and the role of exemestane as adjuvant therapies for premenopausal women with endocrine-responsive breast cancer. Tamoxifen versus OFS + tamoxifen versus OFS + exemestane. BIG 2–02/IBCSG Trial 24–02Tamoxifen and Exemestane Trial (TEXT). A Phase III trial evaluating the role of exemestane plus GnRH analogue as adjuvant therapy for premenopausal women with endocrine-responsive breast cancer. Ovarian function suppression + tamoxifen versus ovarian function suppression + exemestane. BIG 3–02/IBCSG Trial 25–02Premenopausal Endocrine Responsive Chemotherapy Trial (PERCHE) A Phase III trial evaluating the role of chemotherapy as adjuvant therapy for premenopausal women with endocrine-responsive breast cancer who receive endocrine therapy.Chemotherapy + OFS + tamoxifen/exemestane versus OFS + tamoxifen/ exemestane. BIG 4–02/IBCSG Trial 26–02Chemotherapy for radically resected loco-regional relapse. BIG 1-02/IBCSG Trial 27–02/NSABP Protocol B-37Chemotherapy adjuvant study for women at advanced Age (CASA) Phase III trial evaluating the role of adjuvant pegylated liposomal doxorubicin (PLD) for women (age 66 years or older) with endocrine non-responsive breast cancer who are not suitable for being offered a “standard chemotherapy regimen”. BIG 1–05/IBCSG Trial 32–05

Update on the use of aromatase inhibitors in breast cancer

Estrogens are biosynthesised from androgens by the CYP450 enzyme complex called aromatase. Aromatase is expressed in the ovary, placenta, brain, bone, adipose tissue and breast tissue. In breast cancer, intratumoural aromatase is the source for local estrogen production in the tissue. Inhibition of aromatase is an important approach for reducing growth stimulatory effects of estrogens in estrogen-dependent breast cancer. The potent and selective third-generation aromatase inhibitors anastrozole, letrozole and exemestane were introduced to the market as endocrine therapy in postmenopausal patients failing anti-estrogen therapy alone, or multiple hormonal therapies. Anastrozole and letrozole are both non-steroidal aromatase inhibitors that compete with the substrate for binding to the enzyme active site. Exemestane is a mechanism-based steroidal inhibitor that mimics the substrate, is converted by the enzyme to a reactive intermediate, and results in inactivation of aromatase. These third-generation aromatase inhibitors are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic estrogen-dependent breast cancer. The use of an aromatase inhibitor as initial therapy, or after treatment with tamoxifen, is now recommended as adjuvant hormonal therapy for postmenopausal women with hormone-dependent breast cancer. Several clinical studies of aromatase inhibitors focus on the use of these agents in the adjuvant setting, for the treatment of early breast cancer. Recently published results show improved responses with these agents compared with tamoxifen.

New development in intracrinology of breast carcinoma

Intratumoral metabolism and synthesis of estrogens as a result of the interactions of various enzymes are considered to play very important roles in the pathogenesis and development of hormone dependent breast carcinoma. Among these enzymes, intratumoral aromatase plays as important role converting serum androgens to estrogens in situ, and serves as a source of estrogen, especially in postmenopausal patients with breast carcinoma. However, other enzymes such as the 17beta-hydroxysteroid dehydrogenase (17beta-HSD) isozymes, estrogen sulfatase (STS) and estrogen sulfotransferase, also play pivotal roles in intratumoral estrogen production. The 17beta-hydroxysteroid dehydrogenase (17beta-HSD) isozymes catalyze the interconversion of estradiol (E2) and estrone (E1), and thereby serve to modulate the tissue levels of bioactive E2 in human breast carcinoma. 17Beta-HSD type 1 catalyzes primarily the reduction of estrone (E1) to estradiol (E2), whereas 17beta-HSD type 2 catalyzes primarily the oxidation of E2 to E1. In human breast disease, 17beta-HSD type 1 is expressed in proliferative disease without atypia, atypical ductal hyperplasia, ductal carcinoma in situ and invasive ductal carcinoma. 17Beta-HSD type 2 has not been detected in any of these breast lesions. In addition, 17beta-HSD type 1 coexpression is significantly correlated with estrogen receptor status in invasive ductal carcinoma cases. These results indicate that breast carcinoma can effectively convert E1, produced as a result of in situ aromatization, to E2, a biologically potent estrogen, which exerts estrogenic actions on tumor cells through estrogen receptor, especially the alpha subtype in carcinoma cells. Therefore, inhibiting intratumoral 17beta-HSD type 1 is also considered to contribute to inhibition of cell proliferation by decreasing intratumoral estradiol. Estrogen sulfotransferase (EST; SULT 1E1 or STE gene) sulfonates estrogens to inactive estrogen sulfates, while steroid sulfatase (STS) hydrolyzes estrone sulfate (E1-S) to estrone. EST immunoreactivity was recently demonstrated to be significantly associated with a decreased risk of recurrence or improved prognosis by both uni- and multivariate analyses. STS immunoreactivity was significantly associated with an increased risk of recurrence by univariate analysis. These findings also suggest that EST and STS plays important roles in regulation of in situ estrogen production, and EST especially is a potent prognostic factor in human breast carcinoma. Therefore, the inhibition of intratumoral STS might also serve as an endocrine therapy in postmenopausal patients. It is also important to note that the status of intratumoral aromatase, 17beta-HSD type 1, EST and STS in human breast cancer tissues is variable and not necessarily correlated with each other, which suggests different potential sources of intratumoral estrogens among individual patients with breast cancer. These findings indicate that there are patients who could benefit more from inhibition of these intratumoral enzymes rather than aromatase inhibition as an endocrine therapy. Therefore, it will become very important to examine the intratumoral levels of 17beta-HSD type 1 and STS in the resected specimens of human breast carcinoma as potential targets of novel endocrine therapy in the near future.

Mammakarzinom – therapeutische Fortschritte

The treatment of breast cancer has made significant improvements during the past ten years. For early breast cancer with a clinically negative axilla sentinel node biopsy has become the preferred approach. For endocrine therapy of postmenopausal patients the selective aromatase inhibitors have become standard in metastatic as well as in early breast cancer. Trastuzumab (Herceptin) plays an important role in the treatment of HER2-positive breast cancer in the metastatic and since 2005 also in the adjuvant setting. When chemotherapy is used to treat metastatic breast cancer drug combinations are superior to monotherapy only in terms of response rates. By contrast, in the adjuvant setting combination drug therapy is the standard. New methods of tissue analysis including expression patterns of mRNA and proteins are promising research strategies to further advance the field.

Phase II trial with letrozole (2.5 mg) to maximal response as neoadjuvant endocrine therapy in postmenopausal patients with ER/PgR[+] operable breast cancer

Phase II trial with letrozole (2.5 mg) to maximal response as neoadjuvant endocrine therapy in postmenopausal patients with ER/PgR[+] operable breast cancer

New aromatase inhibitors as second‐line endocrine therapy in postmenopausal patients with metastatic breast carcinoma

New aromatase inhibitors (AI) (second-generation: formestane and fadrozole; third-generation: letrozole, anastrozole, vorozole, and exemestane) have been tested in several controlled clinical trials after tamoxifen failure in metastatic breast carcinoma (MBC). They have resulted in better survival compared with megestrol acetate (MEG) in a number of studies. The authors performed a pooled analysis including all the Phase III trials published between 1996 and 2004 evaluating the AIs approved or not by the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medical Products (EMEA) as second-line endocrine therapy (ET) for patients with MBC. The overall response rate (ORR) and time to disease progression (TTP) were considered the primary end points, whereas toxicity was regarded as a secondary objective. Relative risk, 95% confidence interval, and heterogeneity were derived using 2 methods. No significant differences in ORR and TTP were noted in the entire group of 9 trials comparing AI with MEG (3908 patients) and in the 6 trials comparing nonsteroidal AI and MEG (2415 patients). AI yielded significantly more hot flashes than MEG (P = 0.004) but caused significantly less toxicity than MEG in weight gain (P = 0.001), dyspnea (P = 0.008), and peripheral edema (P = 0.03). Significant heterogeneity for nausea, weight gain, dyspnea, and peripheral edema was registered. When steroidal AIs were excluded from the toxicity analysis, nausea maintained its strongly significant heterogeneity (P = 0.0002), whereas weight gain, dyspnea, and peripheral edema lost their significance. This pooled analysis suggested that AIs in second-line ET for patients with MBC do not seem to add any significant benefit to MEG in terms of ORR and TTP. With regard to toxicity, the findings in the current study showed that weight gain, dyspnea, and peripheral edema are more frequent with the use of MEG, whereas hot flashes were more represented using AI.

Aromatase Inhibitors as Adjuvant Therapy for Postmenopausal Patients With Early Stage Breast Cancer

Endocrine therapy of hormone receptor-positive breast tumors is widely used as palliative therapy for metastatic breast cancer and as adjuvant therapy for early stage breast cancer. Tamoxifen has been the definitive standard of hormonal therapies for the last 30 years because of its documented efficacy and reasonable safety profile. Based on encouraging results from trials utilizing the selective, third generation aromatase inhibitors (AIs) in metastatic breast cancer, a number of trials were designed to examine these agents as adjuvant therapies. Trials directly comparing AIs with tamoxifen have, to date, demonstrated superior disease-free-survival with AIs. Likewise, trials examining the use of AIs after tamoxifen have demonstrated better outcomes compared with tamoxifen alone. Additionally, letrozole has been demonstrated to result in superior disease-free-survival after 5 years of adjuvant tamoxifen, compared with no further therapy. In general, the AIs are tolerated at least as well as tamoxifen but decrease bone mineral density and increase osteoporosis due to their lack of estrogenic effects on bone. Based on the fact that AIs appear more effective at preventing contralateral breast cancers than tamoxifen, they are being examined as breast cancer preventives. Despite available data using the AIs as adjuvant therapies, many questions remain unanswered, and further trials will be needed to address these important issues.

Aromatase Inhibitors in the Treatment of Breast Cancer

Estradiol, the most potent endogenous estrogen, is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is present in breast tissue, and intratumoral aromatase is the source of local estrogen production in breast cancer tissues. Inhibition of aromatase is an important approach for reducing growth-stimulatory effects of estrogens in estrogen-dependent breast cancer. Steroidal inhibitors that have been developed to date build upon the basic androstenedione nucleus and incorporate chemical substituents at varying positions on the steroid. Nonsteroidal aromatase inhibitors can be divided into three classes: aminoglutethimide-like molecules, imidazole/triazole derivatives, and flavonoid analogs. Mechanism-based aromatase inhibitors are steroidal inhibitors that mimic the substrate, are converted by the enzyme to a reactive intermediate, and result in the inactivation of aromatase. Both steroidal and nonsteroidal aromatase inhibitors have shown clinical efficacy in the treatment of breast cancer. The potent and selective third-generation aromatase inhibitors, anastrozole, letrozole, and exemestane, were introduced into the market as endocrine therapy in postmenopausal patients failing antiestrogen therapy alone or multiple hormonal therapies. These agents are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic estrogen-dependent breast cancer. Several clinical studies of aromatase inhibitors are currently focusing on the use of these agents in the adjuvant setting for the treatment of early breast cancer. Use of an aromatase inhibitor as initial therapy or after treatment with tamoxifen is now recommended as adjuvant hormonal therapy for a postmenopausal woman with hormone-dependent breast cancer.

Observational study of compliance and continuance rates of raloxifene in the prevention and treatment of osteoporosis

Abstract. Medical practitioners face the challenge of noncompliance with prescriptions, particularly in chronic, asymptomatic, diseases such as osteoporosis. The aim of this study was to assess the raloxifene compliance and continuance rates and adverse effects over 24 months in clinical practice. Using a retrospective study of clinical histories obtained from a database at the Metabolic Research Institute, University of El Salvador School of Medicine, Buenos Aires, Argentina, as well as telephone interviews, we assessed compliance and continuance with raloxifene therapy in post-menopausal patients who had received prescriptions for raloxifene to prevent or treat osteoporosis. Patients were contacted by telephone 24 months after they had received a prescription for raloxifene. Compliance and continuance rates were calculated based on the data provided by the patients. Data from 419 patients (mean [SD] age, 61.4 [7.4] years [range, 42-90 years]) were included in the study. At the time of the telephone interview, 225 (53.7%) were still receiving raloxifene, 105 (25.1%) had stopped treatment at their own discretion, 59 (14.1%) had not started treatment, and 30 (7.2%) had discontinued treatment as a result of advice from a physician. The reasons for not starting treatment were fear of thrombolytic events (21 patients [35.6%]); lack of interest in starting treatment (12 [20.3%]); other physician's advice (11 [18.6%]); family problems (3 [5.1%]); dissatisfaction with the prescribing physician, treatment cost, health problems unrelated to osteoporosis, and mistrust in the prescription (each, 2 [3.4%]); and advice from family/friends, fear of breast cancer, belief that raloxifene is hormonal, and that the patient was already polymedicated (each, 1 [1.7%]). Eleven of the 59 patients (18.6%) who had not started therapy were advised by a physician other than the prescribing physician not to start treatment and were excluded from the compliance analysis. Thus, the compliance analysis included 408 patients. The 2 most common reasons for discontinuing treatment at the patient's own discretion were health problems unrelated to osteoporosis (25 [23.8%]) and digestive problems not considered treatment related (16 [15.2%]). The compliance rates were 75.0%, 71.1%, 65.0%, 57.1%, and 52.0% at 3, 6, 12, 18, and 24 months, respectively. In patients who started raloxifene treatment, the continuance rates were 85.0%, 80.6%, 73.6%, 64.7%, and 58.9% at 3, 6, 12, 18, and 24 months, respectively. Sixty-two of the 135 patients who discontinued treatment did so within 3 months of receiving the prescription, accounting for 45.9% of all discontinuations. In the present study of raloxifene compliance and continuance in clinical practice, the compliance rate appeared to be relatively high compared with those of hormone-replacement therapy (HRT) and other non-HRT treatments. Almost half of patients who discontinued treatment did so in the first 3 months.

Safety and efficacy of estrogen therapy in preventing bone loss in primary biliary cirrhosis

Objectives Estrogen therapy has been found to be useful in the treatment of postmenopausal osteoporosis. However, concern about its potential for worsening cholestasis has limited its use in postmenopausal women with primary biliary cirrhosis. The aim of the present study was to determine the safety as well as the efficacy of estrogen replacement therapy with respect to bone mass in postmenopausal women with primary biliary cirrhosis. Methods Bone mineral density of the lumbar spine (measured using dual energy x-ray absorptiometry) of 46 unselected postmenopausal women with primary biliary cirrhosis receiving estrogen replacement therapy was compared with 46 age-matched women with primary biliary cirrhosis not receiving estrogen replacement therapy, and with the expected normal bone mineral density adjusted for age and ethnic group. Results The mean duration of follow-up was 4.8 ± 0.4 yr. Treatment with estrogens resulted in a significantly lower rate of bone loss (0.002 g/cm 2/yr ± 0.028 vs 0.009 g/cm 2/yr ± 0.020, p = 0.05). Worsening cholestasis attributable to estrogen replacement therapy did not occur in any patient. One patient (2%) discontinued therapy because of side effects. Conclusions Estrogen replacement therapy in postmenopausal patients with primary biliary cirrhosis is safe and may be effective in decreasing the rate of bone loss.