Adjuvant Aromatase Inhibitor Use Research Articles

Association of adjuvant aromatase inhibitor with cataract risk in postmenopausal women with breast cancer.

BackgroundAromatase inhibitor (AI) is a cornerstone drug for endocrine therapy of postmenopausal hormone receptor-positive breast cancer. The relationship between AI medication and subsequent cataract risk is yet inconclusive.MethodsA total of 1,697 postmenopausal, early-staged, and hormone receptor-positive breast cancer patients from the prospectively-maintained database of the Breast Surgery Department at Fudan University Shanghai Cancer Center were included, with 542 patients received no endocrine therapy and 1,155 treated with AI only. We explored the influence the use of AI or not and the duration of AI on the subsequent incidence of cataract.ResultsA total of 146 (8.6%) cataracts were observed in the whole study population. The incidence of cataract is highly related to age, with incidence of cataract in patients <50 years old, 50–60 years, ≥60 years was 2.9%, 6.9%, and 13.3%, respectively (P<0.001). There was no significant relationship between adjuvant AI use and cataract (7.4% in no endocrine group vs. 9.2% in the AI group) with an adjusted hazard ratio of 1.20 (95% confidence interval: 0.8–1.7, P=0.30). The incidence of cataract in patients with long-term AI (more than 5 years) could be high up to 14.7%, but without statistical significance compared to those the shorter duration (P=0.52).ConclusionsThere is no significant association between use of AI and cataract in postmenopausal breast cancer patients. Of note, age is an important risk factor for cataract and it is necessary to surveil the eye health in postmenopausal elderly women.

Aromatase inhibitors and cardiac outcomes in women undergoing cardiac angiography after early breast cancer.

558 Background: Data show that in post-menopausal women with early breast cancer, longer use of aromatase inhibitor (AI) is associated with increased odds of ischemic heart disease. Here we explore the association between adjuvant AI use and cardiac disease in women undergoing cardiac angiography after a diagnosis of early breast cancer. Methods: We linked a database of 7,681 women who underwent cardiac angiography at the University Clinical Center of Ljubljana between December 2004 and November 2010 with the Cancer Registry for Slovenia. Women with early breast cancer that subsequently underwent cardiac angiography were identified. Information on cardiovascular risk factors was retrieved from the patients’ charts and from discharge letters after cardiac angiography. The endpoint of interest was a diagnosis of ischemic heart disease or left ventricular dysfunction (IHD-LVD) without evidence of valvular heart disease at the time of angiography. Conditional, logistic regression was used to test for associations between variables. Results: Among 117 eligible women 75% (n=88) were postmenopausal and 62% (n=73) had hormonal receptor positive (HR+) disease. Of these 42% (n=31) were treated with AI. Overall, 48% (n=56) of women were found to have IHD-LVD. In patients with HR+ breast cancer, use of AIs was significantly associated with IHD-LVD as compared to tamoxifen alone (HR 2.50, 95% CI 1.01-6.29, p=0.046). For each year of AI therapy, there was a trend for higher odds of IHD-LVD (OR: 1.25, 95% CI 0.95-1.67, p=0.116). This effect appeared independent of age, body mass index, baseline hypertension, hypercholesterolemia, diabetes and heart disease or prior anthracyclines exposure. Among all patients, use of anthracyclines and left-sided irradiation was associated with non-significant increases in IHD-LVD (HR 2.37, 95% CI 0.89-6.09, p=0.45 and HR 1.28, 95% CI 0.69-2.40, p=0.44 respectively). Conclusions: Compared to tamoxifen, AIs are associated with a time dependent increase in IHD-LVD. This risk appears independent of other risk factors for heart disease. Anthracycline exposure and left breast or chest wall radiation showed non-significant associations with IHD-LVD in this small cohort.

Symposium zeroes in on new discoveries in breast cancer

Symposium zeroes in on new discoveries in breast cancer

Abstract P1-10-03: CARIATIDE: The Impact of Educational Materials and Demographic Characteristics on Compliance with Adjuvant Aromatase Inhibitor Treatment

Abstract Background Long-term use of adjuvant aromatase inhibitors (AI) can be associated with patient non-compliance, but the factors that impact this are currently unclear. A comprehensive understanding of the reasons behind non-compliance is important to inform the design of future interventions intending to improve patient compliance. Educational materials (EM) may improve patients’ treatment compliance, as may demographic characteristics such as country, post-operative chemotherapy, age and BMI. Methods This 2 year, global observational study (NCT00681122) was designed to investigate whether EM could influence patients’ motivation and behavior, and improve treatment compliance with adjuvant AI treatment. Across 18 countries, 2758 patients were randomized 1:1 to Group A: Standard Therapy or Group B: Standard Therapy + EM. EM received by Group B consisted of a range of information on breast cancer related topics. The primary endpoint was compliance rate for the adjuvant AI medication. Secondary endpoints included persistence rate after 1 and 2 years, and reasons for and time to treatment discontinuation of AI. Compliance rate was defined as proportion of subjects being ‘compliant’ with regard to the adjuvant AI medication; switching from AI to tamoxifen would result in a non-compliance score at time of switching. For compliance to initial adjuvant AI medication, switching to another AI or hormone therapy would result in a non-compliance score. A subject was considered a ‘persistent’ user if, during the first year, they did not switch AI medication, AI medication was uninterrupted or there was no discontinuation of the AI medication. Patients’ compliance and behavior were assessed using validated questionnaires (EORTC-INPATSAT-32, GHQ-12, FACT-ES), specifically developed OPTIMA-X, compliance questionnaire and EM feedback in Group B. Results Analysis of 1 year data did not demonstrate statistically significant differences between compliance rates for Groups A and B. Overall compliance was 81% and 82% for Groups A and B, respectively. Compliance with initial AI was reported as 75% for Group A and 77% for Group B, with persistence rates of 84% and 86%, respectively. EM only significantly improved overall compliance in Sweden/Finland (85% and 100%, Groups A and B respectively, p=0.0264, data combined). Demographic sub-group analysis at 1 year gave overall compliance rates of 83% for patients who received post-operative chemotherapy compared with 79% in patients who did not receive post-operative chemotherapy (p=0.0163). Age-group specific compliance for Groups A and B was 70% and 82% at &amp;lt;50y, 83% and 81% at 50-60y, 80% and 82% at 60-70y, and 81% and 82% at &amp;gt;70y, respectively. Compliance reported in Groups A and B for specific BMI groups was 79% and 81% at BMI &amp;lt;25; 82% and 83% at BMI 25-35, and 78% and 77% at BMI &amp;gt;35, respectively. Discussion At 1 year, overall compliance, compliance to initial AI and persistence with therapy was not significantly different between treatment arms. Out of 18 countries, only Sweden/Finland demonstrated a significant improvement in compliance when EM were used. Post-operative chemotherapy was a predictor for patient compliance with AI, but age-group and BMI do not appear to be predictors. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-10-03.

Reversal of skeletal effects of endocrine treatments in the Intergroup Exemestane Study

The adjuvant use of aromatase inhibitors in breast cancer is associated with adverse effects on bone health. We previously reported a decline in bone mineral density (BMD) following the switch from tamoxifen to exemestane in the Intergroup Exemestane Study (IES). Here we report effects of endocrine treatment withdrawal on BMD, bone turnover markers (BTM) and fracture rates. 4,724 patients took part in IES, and 206 patients were included in a bone sub-study. BMD and BTM were assessed pre-randomization, during and after the end of treatment (EOT). To evaluate treatment withdrawal effects, 12- and 24-month post EOT BMD results are available for 122 and 126 patients, respectively. Similar patient numbers had BTM measured post EOT. Following treatment withdrawal, the differences in BMD observed between the two endocrine strategies were partially reversed. At 24 months from EOT, spine BMD increased by 1.53% (95%CI 0.63-2.43; p = 0.001) after stopping exemestane and fell by 1.93% (95%CI -2.91 to 0.95; p = 0.0002) following tamoxifen withdrawal. A similar pattern of changes was observed at the hip. At 2 years post EOT, BMD changes from baseline were similar with both treatment strategies. Corresponding inverse changes in BTM were seen, with an increase following tamoxifen withdrawal and a reduction after exemestane. A higher number of fractures occurred during exemestane treatment, but fracture rates were similar after treatment withdrawal. With the switch strategy used in IES, the on treatment adverse bone effects of exemestane are reversed. Ongoing monitoring of BMD is therefore not routinely required.

Managing bone mineral density with oral bisphosphonate therapy in women with breast cancer receiving adjuvant aromatase inhibition

The use of adjuvant aromatase inhibitors is associated with an increased risk of osteoporosis and fractures. The oral bisphosphonate, risedronate - dosed as the US Food and Drug Administration approved for the treatment or prevention of postmenopausal osteoporosis - appears to mitigate bone loss associated with 2 years of adjuvant anastrozole in women with early-stage breast cancer.

Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor–Positive, Aromatase Inhibitor–Resistant Advanced Breast Cancer

Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy. To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer. A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (> or = 24 wk) or relapse (after > or = 2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response. Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily. Primary end point: clinical benefit rate (response plus stable disease at 24 weeks). toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18. The adverse event rate (> or = grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; P = .03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (> or = 12% prospectively defined) was predictive of response (positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation. In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials. clinicaltrials.gov Identifier: NCT00324259.

Predictors and Temporal Trends of Adjuvant Aromatase Inhibitor Use in Breast Cancer

After the first report of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, adjuvant aromatase inhibitor use increased rapidly among National Comprehensive Cancer Network member institutions. Increased aromatase inhibitor use was associated with older age, vascular disease, overexpression of human epidermal growth factor receptor 2 (HER2), or more advanced stage, and substantial variation was seen among institutions. This article examines adjuvant endocrine therapy in postmenopausal women after the first report of the trial, identifies temporal relationships in aromatase inhibitor use, and examines characteristics associated with choice of endocrine therapy among 4044 postmenopausal patients with hormone receptor-positive nonmetastatic breast cancer presenting from July 1997 to December 2004. Multivariable logistic regression analysis examined temporal associations and characteristics associated with aromatase inhibitor use. Time-trend analysis showed increased aromatase inhibitor and decreased tamoxifen use after release of ATAC results (P < .0001). In multivariable regression analysis, institution (P <. 0001), vascular disease (P <. 0001), age (P = .0002), stage (P = .0002), and HER2 status (P = .0009) independently predicted aromatase inhibitor use. Institutional rates of use ranged from 15% to 66%. Adjuvant aromatase inhibitor use increased after the first report of ATAC, with this increase associated with older age, vascular disease, overexpression of HER2, or more advanced stage. Substantial variation was seen among institutions.

Up-Front Use of Aromatase Inhibitors As Adjuvant Therapy for Breast Cancer: The Emperor Has No Clothes

Up-Front Use of Aromatase Inhibitors As Adjuvant Therapy for Breast Cancer: The Emperor Has No Clothes

The impact of aromatase inhibitors on sexual functioning: Current knowledge and future research directions

There is substantial evidence supporting the adjuvant usage of aromatase inhibitors (AIs) in the treatment of postmenopausal women with early breast cancer. However, the exacerbation of postmenopausal gynaecological symptoms such as vaginal dryness and dyspareunia has been reported in several studies investigating the quality of life (QOL) of women taking AIs. If not managed appropriately, these symptoms may result in sexual dysfunction, which can in turn affect a woman's QOL. There is a paucity of comprehensive research into the prevalence, nature and management of sexual dysfunction in women who receive AIs. We have performed a comprehensive literature review of the area and have also offered future research directions, including a description of an intervention study currently underway in Australia, which aims to improve sexual dysfunction and quality of life of women with breast cancer. This review therefore addresses a very topical yet neglected area which takes into consideration the increasing use of adjuvant aromatase inhibitors in women with breast cancer and the importance of recognising and acknowledging the psychosocial impact of this treatment, in this case, sexual functioning, on this population.

Adjuvant and extended adjuvant use of aromatase inhibitors: Reducing the risk of recurrence and distant metastasis

In patients with early-stage breast cancer, all recurrences are associated with an increased risk of mortality, especially distant metastases. Adjuvant tamoxifen therapy for 5 years is effective in postmenopausal patients for the prevention of disease recurrence but is associated with increased risk of rare, potentially fatal adverse events such as endometrial cancer, stroke, and pulmonary embolism. Recently, randomized clinical trials have shown aromatase inhibitor therapy to be superior to tamoxifen therapy for the prevention of disease recurrence. Switching to an aromatase inhibitor after 2–3 years of tamoxifen treatment has been shown to provide superior disease-free survival compared with completing 5 years of tamoxifen. Among approved aromatase inhibitors (letrozole, anastrozole, and exemestane), letrozole is the only one approved as extended adjuvant therapy after completing 5 years of tamoxifen. These results suggest that 10 years of adjuvant endocrine therapy is superior to 5 years of tamoxifen alone.

Patterns of care regarding adjuvant hormonal agents and treatment of bone health in postmenopausal women with breast cancer in community and academic centers before and after the availability of ATAC (Adjuvant Tamoxifen, Armidex or Combination) study

6621 Background: Results from the ATAC trial comparing Tamoxifen to the Aromatase inhibitors (AIs) anastrozole in PM women with early stage breast cancer were initially presented in San Antonio, Texas, in December 2001. ASCO issued guidelines for the adjuvant use of AIs in 2002, updated in 2003. We compared patterns of usage of adjuvant hormonal agents and bone health management before and after availability of the ATAC data in community versus academic centers. Methods: We conducted a retrospective analysis of 432 patients between 1999–2005 from group practices affiliated with two large community hospitals and one academic center. Data were collected from tumor registries regarding demographics, first-line hormonal agent choice, and use of bone density studies, vitamin D/calcium supplements and bisphosphonates. Results: Demographics were identical in both groups before and after January 2002. Before 2002, 96% of the patients were prescribed Tamoxifen in both community and academic centers. After the initial presentation of the ATAC data, 55.08% (65/118) of patients from the community centers versus only 17.11% (19/111) from the academic center were prescribed AIs (p=0.0001). Of the 84 patients who received an AI after January 2002, similar proportions of patients had baseline bone density scans (38.5% community vs. 36.8% academic; p=0.89) and follow up annual/biannual scans (33 % vs. 32%; p=0.85). In addition, similar proportions of patients on AIs were prescribed calcium/vitamin D supplements (47.4% vs. 52.6%; p=0.69) and bisphosphonates (36.8% vs. 21.05%; p=0.20) in community and academic centers, respectively. Conclusions: Community oncologists adopted AIs into clinical practice sooner than academic physicians on the basis of unpublished clinical trial results, even before ASCO published guidelines. Although patients on AIs are deemed to be at higher risk for bone fractures, fewer than 40% were evaluated with baseline or surveillance bone density scans in both community and academic practices. Similar proportions of patients received calcium/vitamin D supplements or bisphosphonates among centers. No significant financial relationships to disclose.

Diffusion of aromatase inhibitors for breast cancer therapy between 1996 and 2003 in the Cancer Research Network

Clinical trials demonstrated adjuvant aromatase inhibitor treatment is superior for decreasing breast cancer recurrence risk over adjuvant tamoxifen treatment as early as 2001. Yet clinical use for adjuvant treatment was not recommended by the American Society of Clinical Oncology until 2004. Aromatase inhibitor uptake after the first public presentation of randomized trial results but before the release of national guidelines is unclear. We evaluated diffusion of aromatase inhibitor dispensings for breast cancer treatment in integrated healthcare delivery systems across the United States. We collected automated data for 13,245 women enrolled at seven integrated healthcare delivery systems in the Cancer Research Network. All women were aged >55 and diagnosed with estrogen receptor positive, invasive breast cancer between 1996 and 2003. We used electronic pharmacy data to identify aromatase inhibitor and tamoxifen dispensings through 2004. We evaluated the proportions of women who received hormone dispensings in two ways: (1) at any point after diagnosis to capture all use, and (2) in the two-year period following diagnosis to approximate adjuvant use. Over time, adjuvant aromatase inhibitor use increased whereas tamoxifen use decreased. Aromatase inhibitor dispensings within 2 years of diagnosis increased from 4.1% among women diagnosed in 2000 to 13% in 2001, 24% in 2002, and 40% in 2003. Tamoxifen use declined starting in 2001 at every system. Aromatase inhibitor use rose dramatically after 2001 while tamoxifen use decreased. It appears results from early clinical trials changed practice in these integrated healthcare systems before formal changes in national guidelines.

Towards optimal endocrine therapy for hormone-sensitive breast cancer: Initial versus sequential adjuvant aromatase inhibition

Patients with hormone-receptor-positive early breast cancer have a significant risk of recurrence despite the use of adjuvant tamoxifen. The third-generation aromatase inhibitors letrozole, anastrozole, and exemestane offer promise as alternative or additional therapy to tamoxifen. As extended adjuvant therapy following completion of 5 years of tamoxifen, letrozole further decreased the risk of recurrence compared with placebo. Compared with tamoxifen, both letrozole and anastrozole significantly reduced the risk of recurrence when used as initial adjuvant therapy, and in the short term both were better tolerated than tamoxifen. Anastrozole and exemestane both reduced the risk of relapse when started after 2–3 years of tamoxifen compared with continued tamoxifen treatment; the results of letrozole in this setting are expected in 2008. These data establish adjuvant aromatase inhibitors as effective alternatives to tamoxifen. Only limited data are currently available to inform the choice between an aromatase inhibitor as either initial adjuvant therapy or sequentially after tamoxifen. Future results from the Breast International Group (BIG) 1–98 trial will further clarify strategies for the adjuvant use of aromatase inhibitors. Here, we critically review the evidence for adjuvant use of aromatase inhibitors. Comparison is made between initial aromatase inhibition, switching, and extended adjuvant strategies. Practical recommendations are given for the endocrine treatment of post-menopausal 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.

American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors As Adjuvant Therapy for Postmenopausal Women With Hormone Receptor–Positive Breast Cancer: Status Report 2004

To update the 2003 American Society of Clinical Oncology technology assessment on adjuvant use of aromatase inhibitors. Based on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence. Neither the optimal timing nor duration of aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, or 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen. There are no data on the use of tamoxifen after an aromatase inhibitor in the adjuvant setting. Women with hormone receptor-negative tumors should not receive adjuvant endocrine therapy. The role of other biomarkers such as progesterone receptor and HER2 status in selecting optimal endocrine therapy remains controversial. Aromatase inhibitors are contraindicated in premenopausal women; there are limited data concerning their role in women with treatment-related amenorrhea. The side effect profiles of tamoxifen and aromatase inhibitors differ. The late consequences of aromatase inhibitor therapy, including osteoporosis, are not well characterized. The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.

Advances in Breast Oncology: The 2002 ASCO Meeting

SummaryAt this year's American Society of Clinical Oncology (ASCO) meeting, a number of important advances in breast cancer diagnosis, treatment and prevention were reported. In this article, we review these current developments, focusing particularly on the ASCO technology assessment report - which discussed the adjuvant use of aromatase inhibitors in breast cancer - and other significant studies which were presented or updated: the role of taxanes in neoadjuvant and adjuvant therapy; currentconcepts regarding the timing of hormonal therapy during adjuvant chemotherapy; and cyclooxygenase-2 (COX-2) as a target for disruption in breast cancer treatment and prevention. With regards to advances in surgery, we review studies which were presented concerning the evolving role of sentinel lymph node biopsy in the management of the axilla in breast cancer, and review the latest meta-analysis on this subject presented at the meeting.