Aromatase Inhibitors In Postmenopausal Women Research Articles

Adjuvante Therapie des Mammakarzinoms - Bericht über die 10. Internationale Expertenkonsensuskonferenz St. Gallen 2007: „Care Despite Controversies“

Treatment recommendations for operable breast cancer as determined in St. Gallen every two years are the only guidelines in the world concluded by an international panel of experts. Even if discrepancies exist due to the different backgrounds of the experts, several cornerstones for treatment decisions have become apparent. The risk classification of breast cancer is still based on the recommendations of the St. Gallen meeting 2005. HER-2 has changed from being a risk marker to a therapeutic target. The use of trastuzumab is now a new standard in adjuvant treatment settings. The evaluation of breast cancers according to their endocrine responsiveness and non-responsiveness is decisive for determining the decision for treatment. Hormonal treatment should be mandatory for all breast cancers which have an endocrine responsiveness or are at least potentially responsive and should include the risk-adapted use of an aromatase inhibitor for postmenopausal women. Tamoxifen is still a standard treatment for pre- and perimenopausal women. The additional use of a GnRH-analogue should be considered, depending on the individual risk assessment. The importance of anthracyclines and taxanes for adjuvant chemotherapy remains unchallenged. The molecular knowledge of prognostic and predictive markers is increasing and appropriate molecular test systems are currently being evaluated in large phase III trials. Thus, in the near future we can expect a more appropriate evaluation of the benefits of adjuvant therapy combined with an individual risk assessment.

Exemestane after non-steroidal aromatase inhibitors for post-menopausal women with advanced breast cancer

A retrospective analysis was performed on 31 consecutive locally advanced or metastatic breast cancer patients who commenced exemestane 25mg/d orally following previous treatment with Tamoxifen and a non-steroidal third-generation aromatase inhibitor (AI). Patients were seen 3 monthly until clinical or radiological disease progression. Median age was 64 years (range 34-90 yrs). The average number of recurrences before starting exemestane was three (range 1-6). There were two complete responses (CR), four partial responses (PR), 12 with stable disease (SD) and 12 with progressive disease (PD). Objective response rate (CR+PR) was 19.4% and overall clinical benefit (CR+PR+SD >or= 24 weeks) was 54.8%. The median durations of objective response and overall clinical benefit were 18 and 14 months, respectively. This data support the anti-tumour activity of exemestane 25mg daily in patients with locally advanced and/or metastatic breast cancer who have been previously exposed to non-steroidal AIs and Tamoxifen.

Aromatase inhibitors' use in breast cancer

Victoria Harmer discusses the use of aromatase inhibitors in post-menopausal women with breast cancer

Cost-utility of adjuvant hormone therapies with aromatase inhibitors in post-menopausal women with breast cancer: Upfront anastrozole, sequential tamoxifen-exemestane and extended tamoxifen-letrozole

This evaluation adapts a previous Canadian analysis of upfront and sequential adjuvant AI strategies in postmenopausal women with breast cancer to a Belgian perspective and includes an extended aromatase inhibitor (AI) strategy. A Markov model calculated monthly costs and outcomes in a hypothetical cohort of postmenopausal women with early-stage breast cancer. Baseline event rates and hazard ratios were derived from the Arimidex, Tamoxifen Alone or in Combination trial, International Exemestane Study and MA.17 trials. The analysis took a Belgian healthcare payer perspective with a 20-year time horizon. Costs and outcomes were discounted by 3%. Costs are in 2005 Euros. The cost-utility of all three strategies was favourable (<30,000 euros per QALY gained). Based on indirect comparisons using tamoxifen (TAM) alone as a common comparator, sequential TAM-AI was less costly and more effective than upfront or extended strategies. All three AI strategies were cost-effective alternatives to TAM alone, but sequential TAM-AI appears to be the economically preferred strategy.

Adjuvant Therapy With Aromatase Inhibitors for Postmenopausal Women With Early Breast Cancer: Evidence and Ongoing Controversy

Results of five major randomized trials have increased our understanding of the role of aromatase inhibitors in the adjuvant setting. Two of these trials, the Anastrozole or Tamoxifen Alone or in Combination (ATAC) trial and the International Breast Cancer Study Group's BIG 1-98 trial compared an aromatase inhibitor versus tamoxifen as initial hormonal therapy. Three other trial were designed as cross-over studies; the Intergroup Exemestane Study (IES) and the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8/German ARNO 95 trial compared a crossover from tamoxifen to an aromatase inhibitor versus continued tamoxifen in women who had completed 2 to 3 years of tamoxifen. The MA-17 trial compared the use of letrozole with placebo for 5 years, following 5 years of tamoxifen. Based on the results of these studies, the use of an aromatase inhibitor for the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer has largely replaced the previous standard of 5 years of tamoxifen. Still unanswered, however, are questions regarding optimal sequencing, selection of aromatase inhibitor, and duration of treatment. This review will provide an overview of the major studies with an emphasis on these important questions.

The balance between risks and benefits: Long-term use of aromatase inhibitors

The third-generation aromatase inhibitors (AIs) are gradually displacing tamoxifen as the preferred adjuvant endocrine treatment for hormone-receptor-positive early breast cancer in postmenopausal women, having demonstrated superior efficacy in clinical trials. However, for the AIs to gain widespread acceptance in the adjuvant setting, good long-term tolerability must also be demonstrated, particularly as many women with early breast cancer can now expect to live for over a decade after initial diagnosis. Tamoxifen has been widely used in this setting for over 30 years, and the side effects associated with its long-term use are well documented. Many adverse events that occur with tamoxifen are predictable consequences of its antiestrogenic actions, including hot flushes and mood disturbances. However, tamoxifen also has estrogenic properties in some tissues, which are associated with desirable and undesirable effects. Of particular importance, tamoxifen can cause unwanted gynecological events, including an increased risk of developing endometrial cancer, and thromboembolic disease. Conversely, tamoxifen protects against postmenopausal bone loss, modestly lowers cholesterol levels and may protect against cardiac disease. As the number of women treated with AIs increases, long-term safety data relating to these agents will gradually accumulate. Safety data are currently available from early adjuvant trials comparing an AI with tamoxifen during the first 5 years after surgery (sequential and substitution strategies), and from the extended adjuvant setting, comparing letrozole with placebo after completion of 5 years of tamoxifen therapy (the MA.17 trial). In early adjuvant studies, the use of tamoxifen as a comparator can complicate the analysis of safety data, particularly in tissues where tamoxifen has beneficial, estrogenic effects. Studies in the early adjuvant setting have shown that AIs are generally well tolerated and are associated with a lower incidence of vaginal bleeding, thromboembolic disease and endometrial cancer than tamoxifen. Results from these studies have suggested that AIs are associated with musculoskeletal side effects, including bone loss, osteoporosis and fractures, cardiovascular disease and hypercholesterolemia. However, analysis of safety data from MA.17, with a placebo control, showed no evidence of adverse effects of letrozole on the cardiovascular system or lipid profiles. When the data from early and extended adjuvant studies are considered together, it can be concluded that the increased incidences of hypercholesterolemia and cardiovascular disease seen in patients taking an AI probably reflect the lack of the protective effects of tamoxifen in these patients rather than a detrimental effect of the AI. Bone loss is a predictable consequence of the near-complete elimination of circulating estrogen achieved by third-generation AIs in postmenopausal women. In the MA.17 trial, although more women on letrozole reported new, self-diagnosed osteoporosis than those on placebo, the number of clinical fractures did not differ significantly between the two treatment arms, however, further follow-up is needed. Furthermore, ongoing studies are evaluating the role of bisphosphonates and other agents to better characterize and potentially ameliorate AI-associated bone loss in postmenopausal women. The adverse events associated with AI use are predictable and manageable. On the basis of current data, the tolerability of AIs in the adjuvant setting appears as good as that of tamoxifen, and some serious adverse events associated with tamoxifen use are avoided. Further studies and longer follow-up from current trials will help to determine in more detail the long-term effects of this class of drugs.

NCCN Task Force Report: Adjuvant Therapy for Breast Cancer

The National Comprehensive Cancer Network (NCCN) first published the NCCN Breast Cancer Treatment Guidelines in 1996. The Guidelines address the treatment of all stages of breast cancer across the spectrum of patient care and have been updated yearly. Adjuvant therapy for breast cancer has undergone an especially rapid evolution over the past few years. Therefore, the NCCN Breast Cancer Guidelines Panel was supplemented by additional experts to form the Adjuvant Therapy Task Force to provide a forum for an extended discussion and expanded input to the adjuvant therapy recommendations for the Breast Cancer Treatment Guidelines. Issues discussed included methods of risk-stratification for recurrence; how biologic markers such as HER2 status, quantitative estrogen receptor, or genetic markers can be incorporated as prognostic or predictive factors; and how age, menopausal status, and estrogen receptor levels impact benefits from chemotherapy and endocrine therapy. Additionally, the task force discussed the strategies for use of aromatase inhibitors in postmenopausal women and the potential incorporation of trastuzumab into adjuvant therapy of women with HER2/neu positive breast cancer. This supplement summarizes the background data and ensuing discussion from the Adjuvant Task Force meeting.

Exemestane after non-steroidal aromatase inhibitors for post-menopausal women with advanced breast cancer

Exemestane after non-steroidal aromatase inhibitors for post-menopausal women with advanced breast cancer

Is there a role for hormone replacement therapy after breast cancer?

Breast cancer is the most common female malignancy in the UK, with an overall lifetime risk of 1 in 9. Despite the high incidence, breast cancer mortality is decreasing. Approximately 40,000 women were diagnosed with breast cancer in England and Wales in 2000 but the majority will have normal or near-normal life expectancy. One of the main contributory factors to this marked improvement in survival over the last 20 years in women of all ages has been the more widespread use of systemic therapy in early-stage disease. For women with hormone-sensitive cancer, this involves adjuvant endocrine therapy that reduces estrogen synthesis (i.e. ovarian suppression in premenopausal women or aromatase inhibitors in postmenopausal women) or estrogen activity (the anti-estrogen tamoxifen, irrespective of menopausal status). Many women experience health and quality-of-life problems related to estrogen deficiency as a result, the commonest being vasomotor symptoms and vaginal dryness. This article summarizes and interprets key recent papers on the use of hormone replacement therapy (HRT) and selective serotonin reuptake inhibitors in breast cancer survivors. HRT may be safe in women with receptor-negative disease or receptor-positive cancers in the presence of tamoxifen. However, there is a dearth of useful alternatives.

Analogues de la LHRH : leur utilisation dans le traitement du cancer du sein en situation métastatique et adjuvante☆

Breast cancer is often an estrogen-dependent disease. The primary goals of the treatment of breast carcinomas are multiple, depending on the situation in which the patients are treated. In adjuvant setting, the aims are to delete the time of relapse, to increase the overall survival, and to offer to the patients the best quality of life they may expect. Tamoxifen is the standard hormonal agent for premenopausal women with receptor-positive breast cancer. Recent data show an increasing role for aromatase inhibitors in postmenopausal women. In metastatic setting, the primary goals are improved quality of life and prolonged survival; effective therapies with minimal toxicity, such as endocrine therapy, are highly desirable and should be considered a primary option over chemotherapy for selected estrogen-receptor positive patients. Ovarian ablation has been worldwide used. Methods of irreversible ovarian ablation include surgical oophorectomy and ovarian irradiation. Potentially reversible castration can be medically accomplished using luteinizing hormone releasing hormone analogues (LHRH agonists). In the metastatic setting, ovarian ablation (induced by the use of LHRH agonists or by surgical ovarian ablation) and tamoxifen monotherapies produce comparable outcomes, and may be more effective when used together (combined estrogen blockade). In advanced breast cancer, the combination prolongs the progression-free survival and increases response rates and duration of response rate relative to the use of LHRH agonist alone. In the adjuvant setting, data suggest that ovarian ablation followed by tamoxifen produces similar results to those obtained with adjuvant chemotherapy in hormone-receptor positive breast cancer women. The value of combining these modalities remains unclear, but the addition of the LHRH analogue goserelin to standard treatment results in a significant benefit in terms of relapse-free and overall survival, especially for estrogen-receptor positive patients. Finally, considering the efficacy of the new aromatase inhibitors, the interest of combining these drugs with the LHRH analogues has yet to be defined, both for pre- and post-menopausal patients.

The Use of Aromatase Inhibitors in Postmenopausal Women With Hormone Receptor Positive Breast Cancer

The Use of Aromatase Inhibitors in Postmenopausal Women With Hormone Receptor Positive Breast Cancer

Adjuvant use of aromatase inhibitors in postmenopausal women with breast cancer

Emerging data from clinical trials on the use of aromatase inhibitors in the management of early-stage, hormone-dependent breast cancer in postmenopausal women are reviewed. Aromatase is the enzyme responsible for the conversion of androgens to estrogens and the only source of estrogens in postmenopausal women. Clinical trials using aromatase inhibitors in the adjuvant treatment of postmenopausal women with breast cancer are few but significant because of their comparative design with tamoxifen given for five years, long regarded as the gold standard for breast cancer treatment. Data from the Anastrozole, Tamoxifen and Combination trial, the MA-17 trial (letrozole compared with placebo), the Italian Tamoxifen Arimidex trial (anastrozole following tamoxifen), and the Intergroup Exemestane Study have shown promising efficacy and safety in the use of these agents. While the optimal aromatase inhibitor for use in the adjuvant setting has not been elucidated, current evidence-based recommendations include using (1) anastrozole as the first adjuvant therapy for five years, (2) tamoxifen for two to three years, then exemestane or anastrozole for the remainder of the five years, and (3) tamoxifen for five years, then letrozole for another five years. While their impact on survival has not been determined, aromatase inhibitors are slowly changing the management of early-stage, hormone-dependent breast cancer in postmenopausal women because of improved disease-free survival rates. Their ultimate role in therapy is unknown, but educating patients about the potential risks and benefits will allow them to make informed decisions regarding these data and their breast cancer care.

Aromatase inhibitors in the management of early breast cancer: Optimizing the clinical benefit

Several adjuvant trials evaluating aromatase inhibitors in postmenopausal women with early breast cancer have shown significant improvement upon, or extension of the efficacy benefits of, standard therapy with tamoxifen, and treatments were generally well tolerated. Disease-free survival was significantly improved by: anastrozole versus tamoxifen for 5 years of adjuvant therapy, in the Arimidex, Tamoxifen Alone or in Combination trial; switching to exemestane after 2 to 3 years of tamoxifen, compared with remaining on tamoxifen for 5 years, in the Intergroup Exemestane Study; and switching to letrozole (v placebo) for 5 years after 5 years of tamoxifen, in the extended adjuvant trial, MA.17. Further analyses of these trials, and data from ongoing trials, will address how to optimally use aromatase inhibitors in the adjuvant breast cancer setting: whether these agents should be used in place of, or sequenced with, tamoxifen; what is the best order of sequencing, before or after tamoxifen, and when is the best time to switch; what the long-term safety issues are associated with aromatase inhibitor treatment; and how toxicities can be effectively managed.

Adjuvant Aromatase Inhibitors Following Tamoxifen for Early-Stage Breast Cancer in Postmenopausal Women: What Do We Really Know?

Adjuvant hormonal therapy in the treatment of women with early-stage, hormone receptor (HR)—positive breast cancer is now considered the standard of care. Adjuvant tamoxifen decreases the risk of breast cancer recurrence and death in women with early-stage breast cancer when taken for 5 years. The benefits of tamoxifen are counterbalanced by toxicities including an increased risk of endometrial cancer and thromboembolic events. The selective aromatase inhibitors (AIs)—including anastrozole, letrozole, and exemestane—are challenging the role of tamoxifen as the adjuvant hormonal therapy of choice in postmenopausal women. Results of the Arimidex and Tamoxifen Alone or in Combination trial favor the use of anastrozole over tamoxifen as initial adjuvant hormonal therapy, with improvement in disease-free survival (DFS) and a favorable toxicity profile. The results of 2 large adjuvant trials using AIs sequentially with tamoxifen in postmenopausal women with early-stage, HR-positive breast cancer have been reported. The MA-17 study randomized women to placebo or letrozole for 5 years after completion of 4.5–6 years of initial tamoxifen. The Intergroup Exemestane Study (IES) randomized women following 2–3 years of adjuvant tamoxifen to continue to receive tamoxifen or switch to exemestane for a total of 5 years of adjuvant hormonal therapy. The MA-17 and IES trials demonstrated superior DFS with the AI and corroborated the smaller GROCTA-4B and Italian Tamoxifen Arimidex trials, which studied sequential therapy with aminoglutethamide or anastrozole. There is now substantial medical evidence supporting the use of AIs in postmenopausal women with early-stage, HR-positive breast cancer.

Estrogen deficiency symptom management in breast cancer survivors in the changing context of menopausal hormone therapy

Vasomotor symptoms associated with menopause or cancer therapies represent an increasingly common problem for breast cancer survivors given the increasing use of ovarian suppression in premenopausal women and aromatase inhibitors in postmenopausal women. Although estrogen and/or progestin effectively reduce vasomotor symptoms, a recent Women’s Health Initiative (WHI) randomized trial identified an unfavorable risk/benefit balance on life-threatening diseases, including increased breast cancer, for combined estrogen plus progestin use in otherwise healthy postmenopausal women. As a result, use of menopausal hormone therapy (MHT) for chronic disease risk reduction in any population cannot be supported. In addition, the safety of estrogen and/or progestin regarding risk of recurrence or new cancer development in breast cancer survivors has not been demonstrated. For vasomotor symptoms in this population, neuroendocrine agents, including selective seratonin reuptake inhibitors (SSRIs) or gabapentin, are reasonable choices with substantial impact on hot flashes and moderate toxicity profiles. When rigorously evaluated, most other nonhormonal pharmacologic and herbal interventions have been found to have either modest or no efficacy and/or limiting toxicity. In breast cancer survivors even local vulvar/vaginal symptoms are best treated by nonhormone products since drug absorption with systemic estrogen-like effects has been reported. Estrogen/progestin use in breast cancer survivors should be considered only for women with severe vasomotor symptoms refractory to other approaches after extensive informed decision-making including review of current Food and Drug Administration labeling concerns with use limited to the lowest dose and shortest duration possible.

NSABP Breast Cancer Clinical Trials: Recent Results and Future Directions

Over the past 40 years, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has conducted several large, randomized clinical trials evaluating various aspects of surgical and adjuvant therapy in patients with operable breast cancer. Results from these trials have contributed significantly in reducing the extent of surgical procedures and in improving the outcome of patients with early-stage breast cancer. Furthermore, they have helped to establish standards of care for the surgical management of invasive and non-invasive disease and for the use of adjuvant hormonal therapy and adjuvant chemotherapy for patients with negative as well as for those with positive axillary nodes. More recent trials are evaluating several new classes of promising drugs such as the aromatase inhibitors in postmenopausal women with invasive or intraductal breast cancer, the taxanes for patients with positive nodes and in the neoadjuvant setting and other targeted molecular therapies such as trastuzumab and bisphosphonates. Results from these ongoing and recently completed trials could improve outcomes and quality of life for patients with early-stage breast cancer.

Towards optimal management of ductal carcinoma in situ of the breast

Ductal carcinoma in situ (DCIS) represents a spectrum of heterogenous disease that accounts for approximately one fifth of all screen-detected breast cancers and is considered as a precursor of invasive breast cancer if left untreated (35–50% risk).DCIS can be treated by total mastectomy with or without immediate breast reconstruction, local excision (LE) plus adjuvant radiotherapy (RT) or LE alone.Total mastectomy is associated with low rates of local recurrence (1.4%) and breast cancer-specific mortality (0.59%). Three recent randomized controlled trials (RCTs) have demonstrated that adjuvant RT after LE of localized DCIS significantly reduces the incidence of local recurrence. However these trials did not identify any subgroups of patients where RT could be safely omitted.Retrospective studies suggest that RT can be safely omitted after adequate LE (margin width ≥1cm) of small (<15mm), non-high grade DCIS not associated with necrosis. Further RCTs are required to validate these retrospective findings, with an emphasis on standradized and meticulous tissue processing and pathological evaluation.The role of adjuvant tamoxifen in the management of DCIS continues to evolve. Formal axillary dissection is not appropriate for DCIS, however, the potential role of the sentinel node biopsy (SNB) in selected high risk cases requires further evaluation. The International Breast Cancer Intervention Study (IBIS-II) trial aims to evaluate the potential role of third generation aromatase inhibitors in postmenopausal women with hormone-sensitive DCIS.Future research will focus on the relevence of gene expression profiling, proteomics, Laser therapy and mammary ductoscopy to the management of DCIS.

Current management of ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) accounts for approximately 20% of all screen-detected breast cancers. Total mastectomy can achieve a 98% cure rate in patients with DCIS, but its impact on quality of life should be weighed against the risk of local recurrence. Skin-sparing mastectomy with immediate reconstruction using autologous tissue can achieve excellent cosmesis and therefore should be considered when mastectomy is indicated. Nevertheless, mastectomy is considered an over-treatment for localized DCIS, and breast conservation is the goal of modern treatment. Three recent randomized controlled trials have demonstrated that adjuvant radiotherapy (RT) after adequate local excision of localized DCIS significantly reduces the incidence of local recurrence. Non-randomized studies suggest that patients with adequately excised small (<15 mm), non-high-grade DCIS not associated with necrosis can be safely spared adjuvant RT. However, this issue requires further evaluation in randomized controlled trials. The role of adjuvant tamoxifen is not well established, especially in relation to the hormone receptor status. Formal axillary dissection is not appropriate for DCIS; however, the potential role of the sentinel node biopsy (SNB) in selected high-risk cases requires further evaluation. The potential role of new selective estrogen receptor (ER) modulators and third-generation aromatase inhibitors in postmenopausal women with ER-positive DCIS, gene and protein expression profiling, and mammary ductoscopy will be the focus of future research.

A novel HPLC-RIA method for the simultaneous detection of estrone, estradiol and estrone sulphate levels in breast cancer tissue

Estrogen deprivation is an effective approach for treatment of hormone sensitive breast cancer. While much is known about plasma estrogen levels with respect to castration in premenopausal women and use of aromatase inhibitors in postmenopausal women, currently there is increasing interest in intra-tumour estrogen production. However, knowledge about alterations in intra-tumour estrogen levels is limited, mainly due to methodological problems with measurements of estrogen fractions in tissue samples. Here we describe a new method for simultaneous measurement of the three main estrogen fractions, estrone (E 1), estradiol (E 2) and estrone sulphate (E 1S) in breast tumour tissue. Following incubation with 3 H -labelled estrogen standards, crude fractions were separated by ether extraction. The E 1S fraction was hydrolysed with sulphatase followed by eluation on a Sephadex column. High pressure liquid chromatography (HPLC) was used to purify the individual estrogen fractions prior to RIA analysis. Estrone and E 1S were converted into E 2, and all three estrogen fractions were finally measured by the same highly sensitive and specific radioimmunoassay using estradiol-6-( O-carboxymethyl)-oximino-2-(2- 125 I -iodo-histamine) as a ligand. Although several purification steps were used, the internal recovery values for tritiated estrogens were found to be 25–50% for E 1 and E 2 and 15–30% for E 1S. The detection limit of this method was 4.3 fmol/g tissue for E 2, 19.8 fmol/g tissue for E 1 and 11.9 fmol/g E 1S, respectively. Using tissue from locally advanced breast cancers ( n = 14), we found median levels of E 1, E 2 and E 1S to be 283.8 fmol/g tissue (range 19.8–547.5), 554.1 fmol/g (9.5–3024.2) and 209.4 fmol/g (11.9–753.4), respectively. The method described here is a promising tool to study intra-tumour estrogen fractions in breast tissue biopsies.

Use of aromatase inhibitors in postmenopausal women with advanced breast cancer

Surgeons have been involved in the management of metastatic breast cancer since the technique of ovarian ablation was introduced in 1896. However, as newer hormonal and chemotherapeutic regimens were developed, drug therapy gradually replaced surgery as the preferred treatment for metastatic breast cancer. Thus, management of metastatic breast cancer has largely shifted from surgeons to medical oncologists. Advances in hormonal pharmacology have placed hormonal therapy alongside surgery and radiation therapy as a standard treatment option for women with advanced breast cancer. The purpose of this article is to update surgeons on the current use of hormonal agents for treatment of advanced breast cancer in postmenopausal women, and to review the aromatase inhibitors, a new line of hormonal agents for the treatment of advanced breast cancer. J. Surg. Oncol. 1997;66:215–220. © 1997 Wiley-Liss, Inc.