Aromatase Inhibitors Initiation Research Articles

Bone Mineral Density Screening Among Women with a History of Breast Cancer Treated with Aromatase Inhibitors

Understanding adherence to bone mineral density (BMD) screening after breast cancer (BC) treatment with aromatase inhibitors (AI) is an important first step in preventing or treating BC-related osteoporosis. This retrospective cohort study assessed receipt and adherence to BMD screening among 342 women diagnosed with BC who were at high risk for osteoporosis after BC treatment with AI between 2004 and 2007. Nonadherence to baseline and annual BMD screening (recommended by 2003 American Society of Clinical Oncology Guidelines) was assessed using descriptive statistics and Poisson regression models accounting for length of AI use and follow-up. In the year before AI initiation, 16% of women received BMD screening. Fifty-six percent had no BMD screening in the 14 months after a minimum of 9 months of continuous AI use, and 75% and 66% failed to have BMD screens during the second (14.1-26 month) and third (26.1-38 month) annual time periods after continuous AI use for at least 23 and 35 months, respectively. Overall, 24% had no BMD screening after 35 months of continuous AI use. Statistically significant predictors of nonadherence included predominant exemestane use, BMD screening before AI initiation, and diabetes mellitus history. Postcollege education, geographic region of primary care clinic, and never smoking were associated with a reduced risk of nonadherence. A significant proportion of breast cancer patients treated with AI did not receive guideline-recommended BMD screening. Findings should raise awareness of the importance of BMD screening and targeting women at increased risk of screening nonadherence.

Abstract P2-13-03: Prevalence of non-metastatic breast cancer patients treated with aromatase inhibitors in the United States

Abstract Background: Aromatase inhibitors (AIs) are adjuvant therapies (tx) of choice for post-menopausal estrogen-receptor (ER) positive (+ve) breast cancer (BC) because of superior efficacy and favorable side-effects over selective ER modulators such as tamoxifen. However, tamoxifen is thought to have a better bone safety profile as it binds specifically to ER +ve cells, whereas AIs block the conversion of androgens to estrogens. AIs are associated with increased risk of bone loss and osteoporosis compared to tamoxifen. In the US, many women are diagnosed with ER +ve BC and, since 2000, adjuvant AI use increased in tandem with a decrease in tamoxifen. As higher rates of utilization are anticipated, we report estimates of the prevalence (1-year period prevalence) of women with non-metastatic BC treated with AIs. Methods: The Oncology Services Comprehensive Electronic Records (OSCER) database was used to identify women with BC (ICD-9 174), ≥1 clinic visit, and confirmed AI (anastrozole, letrozole, or exemestane) in 2011. Women with metastases (ICD-9 196–198, stage IV, or M1 disease) were excluded. OSCER captures electronic medical record data on >500,000 cancer patients since 2004 from US outpatient community and hospital affiliated oncology practices. OSCER is projected nationally through methods of direct estimations utilizing claims data (Smith et al. submitted). To identify subgroups of women at increased risk of bone loss, estimates were stratified by age and number of AIs received. Bone loss was defined by diagnosis of osteoporosis (ICD-9 733.0), osteopenia (ICD-9 733.90), or receipt of bone tx either before initiation of first AI (proxy for pre-existing bone loss) or any time before or during 2011 (proxy for current bone loss). Results: When projected to the US population, it is estimated that 489,664 (95% CI 467,642—511,686) women with non-metastatic BC were treated with an AI in 2011. Of these, 52% (253,672 [95% CI 239,229—268,115]) were 65 or older. The table summarizes results for the projected cohorts. These data indicate that 19% of women receiving AIs were in the pre-/peri-/early post-menopausal age group (55 or younger), and approximately 66% of women treated with AIs did not have evidence of pre-existing bone loss (i.e., either osteoporosis diagnosis or receipt of bone tx before AI). Conclusions: This is the first study to estimate prevalence of women with non-metastatic BC treated with AIs in the US. As a large proportion of women are diagnosed with ER+ve BC and eligible for AIs (Jemal et al. 2007), a growing number will face increased subsequent risk of fractures. These findings suggest that up to 500,000 women annually are treated with AIs, and over 40% have evidence of bone loss before or during AI. These women will face increased risk of fractures, highlighting the need for prevention of fractures and intervention with targeted bone tx to increase bone mass and prevent or treat osteoporosis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-03.

Abstract P2-12-01: Prospective Evaluation of Joint Symptoms in Postmenopausal Women Initiating Aromatase Inhibitors for Early Stage Breast Cancer

Abstract Background: Aromatase inhibitors (AIs) are widely prescribed to postmenopausal women for the adjuvant treatment of hormone-sensitive breast cancer (BC). However, musculoskeletal complaints can lead to nonadherence and early discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia syndrome and determine predictors of worsening symptoms. Methods: Postmenopausal women with stage I-III BC initiating adjuvant AI therapy were enrolled. All patients completed the following questionnaires at baseline and every 3 months for a year: Modified Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the Modified Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH). Higher scores reflect worse symptoms. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES). Hand grip strength was measured at each visit with a Martin dynamometer. Paired t-tests were performed to compare follow-up evaluations to baseline. Linear Regression was performed to evaluate the association between baseline symptoms and change in symptoms. Results: A total of 169 patients have been consented, 3-month data is available on 102; 6-month data on 85. Median age: 63 (42–89); White/Black/Asian/Hispanic: 61.48/30.33/3.28/25.6; median BMI (kg/m2): 28 (12–50). Compared to baseline, there was a statistically significant increase in BPI pain severity and endocrine related symptoms on the FACT-ES at 3 and 6 months. Significant changes in the BPI pain interference, M-SACRAH pain and stiffness, WOMAC function, physical well-being on the FACT-ES, trial outcome index and pinch grip strength were seen at 3 months; however these changes did not remain significant at 6 months. Logistic regression models evaluating predictors of patient reported outcome measures and grip strength were performed. Baseline score was the strongest predictor of worsening symptoms (p < 0.01) after correcting for age, prior chemotherapy and baseline joint conditions. Conclusions: Treatment with adjuvant AI therapy is associated with significant worsening of joint pain and stiffness which is most prominent at the 3 months evaluation. Patients with baseline joint symptoms are at greatest risk for worsening symptoms on AIs. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-01.

Changes in adjuvant endocrine therapy over one year among postmenopausal women with early-stage breast cancer initiating aromatase inhibitors.

11 Background: Aromatase inhibitors (AIs) are standard of care for adjuvant endocrine therapy (AET) to prevent recurrence of early stage breast cancer in postmenopausal women. Previous AET adherence research has focused on the 25-96% adherence observed with, but more information is needed about AI adherence, especially regarding the role of arthralgia (joint pain or stiffness) in AET changes. Our objective was to understand AET changes within a year of AI initiation. Methods: We examined AET switching (either to another AI or to tamoxifen), overall changes in AET (including switching and temporary or permanent discontinuation), and physician- and patient-reported arthralgia, using data abstracted from medical records and self-administered surveys among 93 patients initiating AI. We conducted Chi-square and Wilcoxon univariate analyses. Results: Anastrazole was initially prescribed to 64 patients (69%), letrozole to 28 patients (30%), and exemestane to 1 patient. A year after AI initiation, 64 patients (69%) had no change in AET. Among the 29 patients (31%) who had an AET change, 14 switched to at least one other AI, 11 switched to tamoxifen, 9 temporarily discontinued AET, and 7 entirely discontinued AET (categories not mutually exclusive). Average time to first AET switch was 182.7 days. Average number of AET switches was 1.4. Arthralgia was the most common reason for AET changes, noted in the records of 19 patients (66% of those who changed AET). Patients who changed AET reported more severe arthralgia (median pain from 0-10 among 8 joint groups =1.4, interquartile range [IQR]=0.3-2.6) at week 12 than those who did not (median=0.3, IQR=0-1.1), p=0.03. A higher proportion (46%) of the 28 patients who initiated with letrozole changed AET due to arthralgia, compared with 20% of the 64 patients who initiated with anastrazole (p=0.01). Conclusions: A substantial proportion of women initiating AI change AET over one year. Arthralgia appears to play a key role in AET changes, particularly for letrozole as compared with anastrazole. More longitudinal patient-reported arthralgia data are needed to guide clinical decision making about AI initiation and AET changes.

An Unusual Case of a Hemolytic Crisis associated with the Initiation of an Aromatase Inhibitor in a Patient with Known History of Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare hemolytic disorder characterized by partial or complete absence of the glycosylphosphatidylinositol-anchored proteins (GPI-AP) on the cell membrane of erythrocytes, platelets, and granulocytes rendering them vulnerable to destruction by the complement system. Various medications can provoke hemolytic crises in PNH or healthy subjects. Aromatase inhibitors (AI), which have revolutionized breast cancer management, are not known to trigger hemolytic crises. We report on a case of a 70-year-old female with PNH who was also diagnosed with breast cancer. Following lumpectomy and adjuvant radiation therapy, she was started on an AI to decrease risk of breast cancer recurrence. A few weeks later, she developed malaise, insomnia, and gross hematuria. Diagnostic workup including flow cytometry revealed a hemolytic crisis related to her PNH. An exhaustive investigation to uncover a potential mechanism that may explain the relation between AI initiation and onset of hemolytic crisis was unrevealing.

Changes in bone biomarker concentrations and musculoskeletal symptoms among breast cancer patients initiating aromatase inhibitor therapy and women without a history of cancer

The objectives of this study were to examine: (1) changes in bone formation (osteocalcin) and bone resorption (cross-linked N-telopeptides of bone type I collagen [NTXs]) markers, as well as calcium, phosphorus, and intact parathyroid hormone, over the first 6 months of aromatase inhibitor (AI) therapy among a cohort of breast cancer patients compared with a group of unexposed women without a history of cancer; and (2) whether bone marker changes were associated with musculoskeletal pain. Eligible breast cancer patients (n = 49) and postmenopausal women without a history of cancer (n = 117) were recruited and followed for 6 months. At baseline, 3 months, and 6 months, a questionnaire was administered to assess pain and medication use, and a blood sample was drawn. Results showed that, among the breast cancer patients, calcium concentrations decreased significantly (-7.8% change; p = 0.013) and concentrations of NTXs increased significantly from baseline to 6 months (9.6% change; p = 0.012). Changes were not observed for women in the comparison group. Statistically significant differences in percent change between the breast cancer patients and the women in the comparison group were observed for calcium at 6 months (-7.8% versus 0.0%; p = 0.025), phosphorus at 6 months (-5.1% versus 16.7%; p = 0.003), NTXs at 6 months (9.6% versus -0.7%; p = 0.017), and osteocalcin at 6 months (11.5% versus -3.6%; p = 0.016). No statistically significant associations were observed between bone turnover marker changes and musculoskeletal pain among the breast cancer patients, although baseline NTXs were higher among women with onset or increase in pain compared with those reporting no pain (p = 0.08). Findings from this study suggest that AIs cause changes in bone turnover during the first 6 months of treatment; however, these changes are not associated with musculoskeletal pain. Breast cancer patients initiating AI therapy should be assessed and monitored for fracture risk using known clinical risk factors, including bone density, and managed appropriately.

Predictors of Aromatase Inhibitor Discontinuation as a Result of Treatment-Emergent Symptoms in Early-Stage Breast Cancer

Aromatase inhibitors (AIs) are effective for treatment of hormone receptor-positive breast cancer, but adherence and persistence with therapy are poor. Predictors of treatment discontinuation are not clearly defined. It is unknown whether patients with intolerable toxicity from one AI are able to tolerate another. Women with early-stage breast cancer initiating AI therapy were enrolled onto a multicenter, prospective, open-label randomized trial of exemestane versus letrozole. Patients completed symptom questionnaires at baseline and serially during therapy. Patients who developed AI-associated intolerable symptoms and discontinued treatment were given the option to switch to the other study AI after a 2- to 8-week washout period. Of the 503 enrolled women, 32.4% discontinued initial AI therapy within 2 years because of adverse effects; 24.3% discontinued specifically because of musculoskeletal symptoms. Median time to treatment discontinuation as a result of any symptom was 6.1 months (range, 0.1 to 21.2 months) and was significantly shorter in patients randomly assigned to exemestane (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = .02). Younger age and taxane-based chemotherapy were associated with higher likelihood of treatment discontinuation (HR, 1.4; 95% CI, 1.02 to 1.9; P = .04; and HR, 1.9; 95% CI, 1.00 to 3.6; P = .048, respectively). Of the 83 patients who chose to switch to the second AI, 38.6% continued the alternate AI for a median of 13.7 months. Premature discontinuation of initial AI therapy as a result of symptoms is common, although more than one third of patients may be able to tolerate a different AI medication. Additional research is needed to identify predictive tools and interventions for AI-associated treatment-emergent symptoms.

Feasibility study of FDG PET as an indicator of early response to aromatase inhibitors and trastuzumab in a heterogeneous group of breast cancer patients

BackgroundIn breast cancer endocrine therapy, post-therapy Ki-67 assay of biopsy material predicts recurrence-free survival but is invasive and prone to sampling error. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) has shown an early agonist or ‘flare’ response to tamoxifen and estradiol, but has not been tested in response to estrogen-lowering aromatase inhibitors (AIs). We hypothesized that decreased agonistic response to AIs would result in early FDG uptake decline. We also measured early response to trastuzumab (T), another targeted agent for breast cancer with differing mechanisms of action. Our study was designed to test for an early decline in FDG uptake in response to AI or T and to examine association with Ki-67 measures of early response.MethodsPatients with any stage of newly diagnosed or recurrent breast cancer were eligible and enrolled prior to initiation (or resumption) of AI or T therapy. FDG PET and tissue biopsy were planned before and after 2 weeks of AI or T therapy, with pretreatment archival tissue permitted. Cutoffs of ≥20% decline in standardized uptake value (SUV) as FDG PET early response and ≤5% post-treatment expression as Ki-67 early response were defined prior to analysis.ResultsForty-two patients enrolled, and 40 (28 AI, 12 T) completed serial FDG-PET imaging. Twenty-two patients (17 AI, 5 T) had newly diagnosed disease, and 23 (14 AI, 9 T) had metastatic disease (5 newly diagnosed). Post-treatment biopsy was performed in 25 patients (63%) and was either refused or not feasible in 15. Post-treatment biopsy yielded tumor in only 17/25 cases (14 AI, 3 T). Eleven of 14 AI patients with post-therapy tissue showed FDG PET early response, and there was 100% concordance of PET and post-therapy Ki-67 early response. For the T group, 6/12 showed an FDG PET early response, including 2/3 patients with post-therapy biopsy, all with Ki-67 >5%.ConclusionsSubstantial changes in FDG PET SUV occurred over 2 weeks of AI therapy and were associated with low post-therapy proliferation. SUV decline was seen in response to T, but few tissue samples were available to test association with Ki-67. Our results support further investigation of FDG PET as a biomarker for early response to AI therapy.

PD04-01: Predictors of Recovery of Ovarian Function during Aromatase Inhibitor (AI) Therapy.

Abstract Background: AIs may cause a paradoxical rise in estrogen levels due to re-activation of ovarian function in women with chemotherapy-induced ovarian failure (CIOF). Therefore, identification of residual ovarian estradiol production is critical if such women are treated with adjuvant AI therapy rather than tamoxifen. We performed a prospective registry trial to identify predictors of recovery of ovarian function during AI therapy. Methods: Women with hormone receptor (HR) positive breast cancer who were pre- or peri-menopausal at diagnosis and who remained amenorrheic for ≥8 weeks after cyclophosphamide-containing adjuvant chemotherapy were enrolled in a multi-institutional, open-label clinical trial of anastrozole (1 mg/day). Following confirmation that serum estradiol (E2) levels were <20 pg/ml using an ultrasensitive E2 assay (Quest Diagnostics), subjects initiated anastrozole. Serum E2 was assessed biweekly for 12 wks, then less frequently, for 72 wks. Multivariable logistic regression was used to evaluate clinical predictors (age at AI initiation OR chemotherapy, menopausal status at chemotherapy, body mass index (BMI), baseline E2) of recovery of ovarian function defined as elevated serum E2 levels or return of menses. Results: Sixty-nine women were enrolled; current status is given in Table 1. Median age at initiation of chemotherapy was 47.2 yrs (range 37–55), median time since chemotherapy was 0.8 yrs (range 0.3–6.4), and median age at enrollment was 49.8 yrs (range 40–58). Thirty-six had received tamoxifen. We observed elevated E2 concentrations or return of menses during AI therapy in 21 subjects after a median 2.0 mo (range 0.6-17); for that cohort, median age at chemotherapy was 43.8 yrs (range 37–51) and median age at AI initiation was 45.8 yrs (range 40–56). In contrast, for the 15 subjects who had postmenopausal E2 levels for at least 48 wks, median age at chemotherapy was 49.2 yrs (range 44–52) and median age at AI initiation was 50.7 yrs (range 44–55). Age at chemotherapy (p=0.0006) and age at AI initiation (p=0.001) were statistically significant different between the 2 cohorts. On multivariable analysis, age at chemotherapy and age at AI initiation remained significant when each was adjusted for menopausal status, BMI, and baseline E2 (odds ratio (OR) 1.64, p=0.0102 and OR 1.47, p=0.015, respectively). Conclusions: A significant proportion of women who develop CIOF recover ovarian function during AI therapy. Although recovery is usually rapid, it can occur at least one year following initiation of AI therapy. Younger age was the strongest predictor of recovery of ovarian function, although 2 of 21 women who developed elevated E2 levels or return of menses were older than 50 yrs at the time of chemotherapy. Tamoxifen remains the standard of care for women with CIOF; if use of an AI is necessary, patients should be monitored frequently with high-quality E2 assays for recurrent ovarian function. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD04-01.

OT2-07-02: SWOG S0927: A Randomized Double Blind Placebo-Controlled Trial of Omega-3-Fatty Acid for the Control of Aromatase Inhibitor (AI)-Induced Musculoskeletal Pain in Women with Early Stage Breast Cancer.

Abstract Background: Despite the well-proven efficacy of aromatase inhibitors(AIs) for the treatment of hormone-sensitive breast cancer, a significant number of women suffer from musculoskeletal side-effects which can result in early discontinuation of this important medication. Given the proposed anti-inflammatory effects of omega-3-fatty acid and the paucity of therapeutic options for AI-induced arthralgia, it is therefore reasonable to test the efficacy of omega-3-fatty acid in women with breast cancer who have developed moderate to severe joint symptoms after initiating AIs. Specific aims: To assess if omega-3-fatty acid as compared to placebo causes a reduction in worst joint pain/stiffness in women with AI-associated arthralgias at 12weeks as measured by the modified Brief Pain Inventory (BPI). Additional measures will include the WOMAC, M-SACRAH, FACT-ES and global rating of change, which will be assessed at baseline, 6, 12 and 24 weeks. We will evaluate fasting lipids, hormone levels, serum inflammatory markers (TNF, IL2, CRP), and markers of joint destruction (CTX-II) at baseline, 12 and 24 weeks. Eligibility criteria:Pts. must have histologically-confirmed stages I-III breast cancer, with no evidence of metastatic disease and undergone definitive breast cancer surgery. Pts must be post-menopausal and currently be taking a third-generation AI —anastrazole(Arimidex®), letrozole (Femara®), or exemestane (Aromasin®) for at least the previous 90 days prior to registration with plans to continue for at least an additional 180 days after registration.The patient must have a worse joint pain/stiffness score of 5 or greater on the 10-point scale of the BPI which started or increased after initiation of AI. Pts must not have taken omega-3-fatty acid supplements within the past 3 months prior to registration.Pts will be randomized to receive 6 capsules daily (at 1,000 mg each; ∼600mg combination of ethyl esters EPA/DHA) of omega-3-fattyacid or matching placebo daily for 24 weeks. Statistical methods:We stipulate an alpha=.05 two-sided test, with an estimated 5% non-adherenceand 20% dropout rate at the primary endpoint evaluation time of 12 weeks after randomization. For a two point difference in worst joint pain/stiffness and a 3.5 point SD at 12 weeks, 222 eligible patients would be required for 90% power under a two-arm normal design. To allow ineligibility rate of 10%, 246 total pts will be enrolled. The study should be activated September 2011. Funding: Supported by National Cancer Institute grant CA037429 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-07-02.

Bone health in a prospective cohort of postmenopausal women receiving aromatase inhibitors for early breast cancer

ObjectiveBaseline bone health in postmenopausal women is poorly characterized in prospective series of early breast cancer (EBC) patients candidates to aromatase inhibitor (AI) therapy. Our objective is to comprehensively evaluate bone health in a prospective clinical cohort of patients recruited prior to adjuvant AI therapy, with the aim of establishing potential AI impact on bone loss and fractures. MethodsFrom January 2006 to April 2010, we consecutively included 343 women with EBC who were about to start adjuvant AI therapy. Participants were assessed at baseline (before AI initiation) and at 3 months, with annual assessments thereafter. Bone mineral density (BMD), spine X-ray, bone metabolism (vitamin D [25(OH)D], bone turnover markers [BTM]), arthralgia and quality of life are measured. ResultsMean age was 61.9 years; 197 (57.4%) had been previously treated with tamoxifen; 145 (42.3%) were taking exemestane, 187 (54.5%) letrozole, and 11 (3.2%) anastrozole.Analysis of baseline data shows only 59 women (17.7%) had normal BMD; 200 (60.1%) had osteopenia and 74 (22.2%) had osteoporosis; 39 women (11.4%) had a prevalent fracture, 293 (89.1%) had 25(OH)D insufficiency (<30 ng/ml), and 61 (18.5%) severe deficiency (<10 ng/ml). Low 25(OH)D concentrations were associated with lower BMD and 233 (67.9%) participants had some degree of arthralgia. ConclusionsLow bone mass, prevalent fractures and vitamin D insufficiency were highly prevalent among candidates to adjuvant AI for EBC. Therefore, it is crucial to assess BMD, prevalent fractures and 25(OH)D concentrations before starting AI therapy and during follow-up.

A prospective study of aromatase inhibitor therapy, vitamin D, C-reactive protein and musculoskeletal symptoms

This study compared type, severity and location of musculoskeletal symptoms and associations with 25-hydroxyvitamin D (25(OH)D) and C-reactive protein (CRP) concentrations between women initiating aromatase inhibitor (AI) therapy and an unexposed comparison group. A 6-month prospective cohort study was conducted, enrolling 100 breast cancer patients prior to initiating AI treatment and an unexposed comparison group of 200 postmenopausal women. Multivariate associations were assessed with generalized linear models. At baseline, 55% of breast cancer patients and 63% of the comparison group reported any musculoskeletal symptoms. Among the unexposed group, prevalence and severity of symptoms remained constant with no statistically significant change over 6 months. Among breast cancer patients, but not unexposed women, the pain severity score significantly increased over the 6 month period for joint (P (trend) < 0.001), muscle (P (trend) = 0.004), and bone pain (P (trend) = 0.01). Women treated with AIs were more likely to report pain in wrists/palms (63% at 6 months) compared to unexposed women (31% at 6 months) (P < 0.001). 25(OH)D concentrations increased over the study period among breast cancer patients (P (trend) = 0.004). An increase in pain severity and prevalence was observed among breast cancer patients despite an increase in 25 (OH)D concentration. CRP concentrations were not associated with symptoms. Musculoskeletal symptoms are common among postmenopausal women. Breast cancer patients initiating AI treatment were at increased risk for developing new onset and more severe joint, muscle and bone pain compared to unexposed women, with a distinct distribution. AI-associated symptoms were not associated with 25(OH)D or CRP concentrations.

When to start an aromatase inhibitor: Now or later?

Among women who have undergone surgery for breast cancer, the risk of recurrence, especially distant metastases, peaks 1-2 years postsurgery. Recent clinical trial evidence suggests that initial adjuvant therapy with an aromatase inhibitor (AI) can reduce this early risk of recurrence. According to the recently updated St Gallen consensus statement, initial AI therapy is the preferred strategy for adjuvant endocrine therapy in postmenopausal women with hormone receptor-positive breast cancer.

Abstract P2-09-03: Mammographic Density Response to Aromatase Inhibitor Therapy

Abstract Background: Mammographic density, the variation in fat, epithelial and stromal tissues seen on screening mammography, is a strong risk factor for breast cancer and can be modified by hormonal agents. Changes in density from tamoxifen or postmenopausal hormone (PMH) use are associated with risk, suggesting that density may be a surrogate marker of therapeutic efficacy. Aromatase inhibitors (AIs) are given as adjuvant therapy in hormone receptor positive postmenopausal breast cancer and are known to decrease levels of estrone and estradiol in both serum and breast tissue. Our goal here was to examine the influence of AIs on mammographic density in women with early breast cancer. Methods: We conducted a case-control study of postmenopausal breast cancer patients initiating adjuvant AI therapy (anastrozole or exemestane) on protocols NCIC CTG MA27, NCCTG N063I and MC (Mayo Clinic) 0532. Eligibility included; an intact contralateral breast with no prior surgery; a screening mammogram within twelve months before AI initiation and at 9-15 months on therapy; no prior endocrine therapy and informed consent. Controls were sampled from the Mayo Mammography Health Study, a cohort of 19,924 receiving screening mammography at the Mayo Clinic, and matched to cases on age, prior PMH use, baseline body mass index (BMI) and interval between mammograms. Pre-treatment and on-study mammograms for cases (corresponding mammograms for controls) were digitized. Change in percent density was estimated on the craniocaudal view of the non-cancerous breast using two methods: a subjective assessment of change by an expert radiologist (within 5%; 5-10% increase, 10-25% increase, 25%+ increase, 5-10% decrease, 10-25% decrease and 25%+ decrease) and a quantitative assessment of absolute change using a computer-assisted thresholding program (Cumulus). Analyses compared magnitude of change in density by both the subjective and quantitative methods between cases and matched controls. Results: 574 pairs were eligible for analyses (MA27-505 cases; N063I-12 cases; MC0532-57 cases). Characteristics of the two groups are shown in the table below. Using either density estimation method, there was a greater decrease in density among women on AI therapy vs. matched controls. In 33% (95% CI: 29-37%) of pairs, there was at least a one greater category decrease for the case relative to her control by subjective estimation. In 14% (95% CI: 11-18%) of the pairs, there was at least a 5% greater decrease for the case relative to her control by quantitative estimation. Data will be available according to AI class (non-steroidal versus steroidal) in November. Conclusions: In the largest report to date to examine the influence of AI therapy on mammographic density, we provide evidence that AI is associated with decreases in density in a small subgroup of women. We are currently examining factors that influence these AI-associated decreases in density and whether these differences are unique to one class of AI. (Supported in part by NIH grants P50CA116201, U01GM61388, U10CA77202, U10CA25224) Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-03.

A Qualitative Systematic Review of the Evidence Base for Non-cross-resistance between Steroidal and Non-steroidal Aromatase Inhibitors in Metastatic Breast Cancer

Aims The most effective sequence of tamoxifen and both steroidal (SAIs) and non-steroidal aromatase inhibitors (NSAIs) has been extensively studied in the adjuvant setting. However, treatments for women who have failed initial aromatase inhibitor therapy in the metastatic setting have received relatively little attention. A systematic review was undertaken to assess the use of SAIs and NSAIs in metastatic breast cancer. Materials and methods Medline, Embase and the Cochrane library were searched using free text and MeSH terms. Studies assessing the cross-resistance, efficacy and safety of SAIs and NSAIs for postmenopausal women with advanced metastatic breast cancer confirmed by histology/cytology were included. Patients had progressed/relapsed from previous adjuvant, first- or second-line aromatase inhibitor treatment and had undergone treatment with at least two regimens consisting of aminoglutethimide, anastrozole, letrozole and/or exemestane. Results Nine studies reported results for patients treated with an SAI after treatment failure with an NSAI. For SAI after NSAI, clinical benefit was the most frequently reported outcome. The clinical benefit for exemestane (SAI) after any NSAI failure or before treatment ranged from 12% (complete response not recorded, partial response 2%, stable disease 10%) to 55% (complete response 6%, partial response 13%, stable disease 35%) Survival outcomes were infrequently reported; four studies reported disease progression. The time to progression ranged from 3.7 to 5.2 months. Only one study reported a median overall survival with exemestane at 15.2 months. Only one study reported information for an NSAI after SAI and an NSAI followed by another NSAI. Discussion This review suggests that switching from an NSAI to an SAI is a reasonable option. This would be particularly important for patients who would probably respond to further endocrine manoeuvres; strongly oestrogen receptor-positive disease, non-visceral disease, a good prior response or a long duration of response. Further research to optimise the sequence of endocrine therapies in metastatic breast cancer is needed.

High Prevalence of Low Vitamin D and Musculoskeletal Complaints in Women with Breast Cancer

Reduced vitamin D levels may play a significant role in the development of fractures and musculoskeletal pains reported in patients on aromatase inhibitors (AIs) for breast cancer. In this study, we evaluated the vitamin D status in postmenopausal women with non-metastatic breast cancer who were about to start AI therapy. This study was conducted on community dwelling postmenopausal subjects, aged 35-80 years, with early non-metastatic breast cancer (up to stage IIIA), who were about to start therapy using third generation AIs. Symptoms of joint and muscle pains were obtained using a modified Leuven menopausal questionnaire. 25-hydroxyvitamin D [25(OH)D] was evaluated by radioimmunoassay while bone mineral density (BMD) of the lumbar spine and the proximal femur by dual energy x-ray absorptiometry (DXA). Of the 145 participants (mean age = 60.96 ± 0.88 years), 63 of 145 (43.5%) had baseline levels of 25(OH)D of < 20 ng/mL (deficient), 50 of 145 (34.5%) had levels between 20 and 29 ng/mL (insufficient), and only 32 of 145 (22%) had ≥ 30 ng/mL (sufficient); thus, 113 of 145 (78%) had low 25(OH)D levels (i.e., < 30 ng/mL). Arthralgias and myalgias were found in 61.3% and 43% of patients, respectively; and of those, 83.3% and 88.1% had 25(OH)D of < 30 ng/mL, respectively. Prevalence of vitamin D deficiency is high in breast cancer women and this may increase the risk of bone loss and fractures in those who are going to start AIs. Moreover, musculoskeletal pains are common in breast cancer women, even before the initiation of AIs and in association with low vitamin D in the majority. Future studies may be needed to establish the contribution of low vitamin D, if any, on the prevalence of musculoskeletal pains in women on AIs.

Management and monitoring of arthralgias in breast cancer patients treated with aromatase inhibitors in an outpatient oncology clinic.

e11062 Background: Aromatase inhibitors (AIs) are often used as first-line adjuvant treatment of breast cancer in postmenopausal women with hormone receptor positive tumors. Recommended length of AI treatment is five years. Arthralgias are common and are often cited as the primary reason for lack of compliance and discontinuation of therapy. The incidence of AI-induced arthralgias in literature ranges from 25%-40%. The initial purpose of this retrospective study was to describe the incidence and management of AI-induced arthralgias in KCCC patients. Further evaluation led to the development and the implementation of a treatment algorithm and electronic chart documentation. Methods: The institutional review board approved study included women with hormone receptor positive breast cancer who received adjuvant therapy with an AI. Data was collected concerning whether patients had experienced arthralgias, onset of arthralgias in relation to previous chemotherapy, and which arthralgia management strategies had been tried. Confidentiality was maintained according to HIPPA. A multidisciplinary oncology team met to develop a standardized treatment algorithm and electronic chart documentation tools. Results: Incidence of arthralgias at KCCC was 48% and of those, 88% were managed without a change in AI therapy. Patients who reported AI-induced arthralgias were younger than patients who did not report arthralgias (61 vs. 65 yrs, p = 0.002). There was no statistical difference in incidence of arthralgias in patients with a history of chemotherapy versus those who did not receive chemotherapy (p = 0.352). Of patients presenting with AI-induced arthralgias, 41% did not have documented physician-managed treatment. Of KCCC patients, 32% were documented as having arthralgias within the first 6 months of therapy initiation. The modality used to manage arthralgias (OTC, Rx meds, herbals or non-pharm) did not affect whether patients were able to continue on initial AI therapy. Conclusions: A standardized treatment algorithm and electronic chart documentation tools were developed and implemented in order to facilitate the management of AI-induced arthralgia patients by their oncologists. No significant financial relationships to disclose.

Prospective Evaluation of Joint Symptoms in Postmenopausal Women Initiating Aromatase Inhibitors for Early Stage Breast Cancer.

Abstract Background: Aromatase inhibitors (AIs) are widely prescribed to postmenopausal women for the adjuvant treatment of hormone-sensitive breast cancer. However, musculoskeletal complaints, including joint pain and stiffness, are common, and can lead to nonadherence and treatment discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia syndrome.Methods: Postmenopausal women with stage I-III breast cancer initiating adjuvant AI therapy were enrolled. All patients completed the following questionnaires at baseline and every 3 months for a year: Modified Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the Modified Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH). Higher scores reflect worsening joint symptoms. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES), where higher scores signify improved well-being. Hand grip strength was measured at each visit with a Martin dynamometer. Paired t-tests were performed to compare follow-up evaluations to baseline.Results: A total of 34 patients have been enrolled to date. Three-month data is available on 22; six-month data on 12. Median age: 60 (42-81); White/Black/Hispanic/Asian: 13/6/2/1; median BMI (kg/m2): 28 (20-43). Compared to baseline, there was a statistically significant increase in BPI pain severity and pain-related interference at 3 and 6 months. Significant changes in the M-SACRAH were seen as early as 3 months, but no difference in grip strength was detected. Participants reported significantly more endocrine-related symptoms on the FACT-ES at 3 and 6 months after initiating AI therapy.Conclusions: Treatment with adjuvant AI therapy is associated with significant worsening of joint pain and stiffness which was seen as early as 3 months and persisted at the 6 month evaluation. Understanding the natural history of this toxicity and validating appropriate measures to be used in interventions to prevent and treat AI-induced arthralgias are critical. Baseline3 Months6 Months Mean (SD)Mean (SD)P-value*Mean (SD)P-value*BPI-SF Pain Severity (0-10)2.66 (2.52)3.85 (2.48)0.053.96 (2.42)0.02Pain Interference (0-10)1.40 (1.95)3.25 (2.53)0.022.60 (2.51)0.01M-SACRAH Pain (0-200)47 (46)74 (52)0.0373 (65)0.08Stiffness (0-200)51 (45)85 (54)0.0383 (54)0.01Function (0-800)59 (74)129 (143)0.14168 (190)0.05WOMAC Pain (0-500)67 (95)110 (126)0.19113 (135)0.06Stiffness (0-200)29 (40)45 (54)0.4643 (56)0.06Function (0-1700)271 (324)445 (400)0.15468 (373)0.06FACT-ES Functional (0-28)20 (7)20 (6)0.9619 (6)0.15Physical (0-28)22 (5)20 (6)0.4420 (5)0.32Endocrine (0-72)58 (9)52 (14)0.0451 (11)0.01* Based on paired t-test, as compared to baseline. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5044.

Rheumatologic Evaluation of Adjuvant Letrozole in Post-Menopausal Breast Cancer Patients Discontinuing Anastrozole Due to Grade 2-3 Arthralgia – Myalgia.

Abstract Background:Non-steroidal aromatase inhibitors (AIs) are standard of care in the adjuvant treatment of postmenopausal women with hormone receptor positive (HR+) early stage breast cancer. Side effects such as arthralgia and/or myalgia (A/M) occur in 20 -35% of women on AI therapy with onset as early as 1-2 months from AI initiation. As many as 20% of patients may discontinue therapy due to A/M. Switching to another AI could improve the A/M and allow patients to remain on AI therapy. This study evaluated if patients (pts) who discontinued anastrozole (Ana) due to grade 2-3 A/M would be able to continue AI therapy if switched to Let. We measured whether switching to Let resulted in a lower proportion of grade &amp;gt;2 A/M symptoms and less discontinuation among women who previously discontinued Ana therapy due to A/M.Methods: Pts were eligible for treatment with Let (2.5mg/day for 6 months) if they were postmenopausal, HR+, had early stage breast cancer including LCIS and DCIS, and experienced grade 2-3 A/M on Ana resulting in discontinuation. Pts taking analgesics for any reason were excluded. A/M symptoms and self reported quality of life (QoL) outcomes were assessed by Basic Pain Inventory (BPI), Visual Analog Scale (VAS) and Health Assessment Questionnaires (HAQ) at baseline, during Let therapy and upon study completion. Pts tolerating Let therapy at 6 months had the option of continuing Let for their prescribed course of 5 years.Results: The study enrolled 261 pts of which 2 pts were ineligible. The median age of pts was 61, and 235 (90%) were Caucasian, 14 (5.4%) were Black, 3 (1.2 %) were Asian and 9 (3.4%) were other. At baseline, 107 (41.0%) and 70 (26.8%) had grade 2 or higher A/M respectively. At study completion, fewer patients suffered from grade ≥ 2 A/M, 61 (23.6%) and 46 (17.8%) respectively. Changes in QOL assessments showed a statistically significant improvement (p &amp;lt;0.05) according to the BPI composite score, VAS scale and disability index of the HAQ at -0.5, -6.4 and -0.1 respectively. 228 (87.4 %) pts remained on Let therapy until study completion (6 months). Only 25 (9.6%) of the 261 pts enrolled discontinued due to A/M and another 8 (3.1%) discontinued for other reasons. The mean time to AI discontinuation due to A/M was 157 days and the median duration of study drug was 169 days. Baseline A/M grade, age, BMI, prior use of pain medications or baseline vitamin D results were not significantly associated with Let discontinuation.Conclusion:These results suggest that pts who are intolerant of and have discontinued Ana due to A/M may better tolerate AI therapy and avoid discontinuation when switched to Let. Less A/M and QoL function were maintained upon switching to Let with, 228 (87.4 %) of women in this study remaining on therapy with Let despite previous discontinuation of Ana due to A/M. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 805.

Five Years of Exemestane as Initial Therapy Compared to 5 Years of Tamoxifen Followed by Exemestane: The TEAM Trial, a Prospective, Randomized, Phase III Trial in Postmenopausal Women with Hormone-Sensitive Early Breast Cancer.

Abstract Background: Exemestane (E) is a steroidal aromatase inhibitor (AI) with an established role in early breast cancer after 2–3 years of tamoxifen (T). Additionally, AIs have shown superiority to T as initial adjuvant therapy. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) study has been prospectively designed to compare the role of E as initial adjuvant therapy with a sequential approach of T followed by E (T→E).Methods: Postmenopausal patients with hormone receptor–positive early breast cancer were randomized to open-label E 25 mg/d or T 20 mg/d. All patients completed surgery and chemotherapy, if indicated. Data were collected and analyzed by the Central Data Center in Leiden, The Netherlands. The trial was initiated in 2001 with the primary objective being a comparison of disease-free survival (DFS) with T vs E. In 2004, TEAM was modified in response to new data; all those initially receiving T were switched to E after 2.5–3 years. An additional 2500 patients were recruited and randomized at diagnosis to E or T→E for 5 years. The modified study design includes 2 coprimary endpoints: (1) DFS of T vs E that was previously reported at 2.75 years median follow-up (Jones S et al, abstract #15 presented at SABCS 2008); and (2) DFS at 5 years of E vs T→E that will be the focus of results presented here.Results: Between 2001 and January 2006, 9775 women were randomized to TEAM. In total, 99% of patients were ER+ and/or PgR+, 50% were node-negative, 44% underwent mastectomy, 68% received radiotherapy, and 36% received chemotherapy. In September 2009, median follow-up will be 5.5 years and the protocol-specified 1285 overall DFS events (locoregional or distant recurrence, second breast cancers, or death without recurrence) will have occurred, allowing for analysis of the second coprimary endpoint. We will present a detailed analysis of the 5-year results from theTEAM trial, the only prospectively powered randomized trial to compare 5 years of an initial AI vs T→AI, 2 commonly received adjuvant therapies for women with hormone receptor–positive early breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 11.