Adjuvant Aromatase Inhibitor Therapy Research Articles

Adjuvant aromatase inhibitor therapy in early breast cancer: what factors lead patients to discontinue treatment?

Aromatase inhibitors (AIs) are standard hormone therapy (HT) for the adjuvant treatment of postmenopausal endocrine-sensitive early breast cancer. Treatment discontinuation due to toxicity is an important issue that may help clinicians identify effective clinical interventions to allow adequate treatment duration. We reviewed the main reasons for interruption of AIs at our institution from 2006 to 2009. 236 patients treated with adjuvant AIs were eligible for analysis. Median age was 64 years (35-89), median follow-up 53 months (6-60). Prior adjuvant chemotherapy was taxane based in 47 patients and anthracycline based in 43 patients. 118 patients had received letrozole, 101 anastrozole, and 17 exemestane. Twenty-four patients (10%) needed discontinuation of the first AI assigned as a result of toxicity. Grade 2/3 arthralgia was the main reason for discontinuation in 13/24 patients. No differences in the incidence of arthralgia were noted in patients who had received taxanes or anthracyclines. Headache, alopecia, itching, diffuse skin reaction, allergic reaction with hypertensive crisis, xerostomia and xerophthalmia, insomnia and somnolence were the other reasons for discontinuation. In multivariate logistic regression analysis, age (65 years) and HT were independent factors associated with the onset of arthralgia (p = 0.006 and p = 0.008, respectively; OR 2.65, 95% CI 1.32-5.31). Alternative HT (AI or tamoxifen) was offered to patients who wanted or needed to permanently interrupt the ongoing drug. In our analysis, 10% of patients discontinued the first AI assigned because of toxicity. Median time course of all adverse events leading to HT discontinuation was 155 days and 135 days for arthralgia. A switch to alternative HT with toxicity monitoring is a recommended option for avoiding premature and permanent interruption of an effective treatment.

Abstract ES5-1: Adherence and persistence with adjuvant aromatase inhibitor therapy

Abstract Aromatase inhibitors (AI) are medications that inhibit the aromatase enzyme, which converts androgens to estrogens, resulting in suppression of estrogen production in postmenopausal women. Treatment of postmenopausal women diagnosed with hormone receptor positive breast cancer with adjuvant AI therapy for 5 years has resulted in significant improvements in disease free and overall survival. Despite their proven benefit, however, adherence to and persistence with AI therapy is poor. A key reason for non-persistence with therapy is the development of bothersome side effects that can have a negative impact on quality of life. Retrospective analyses have identified possible predictors of poor tolerance of therapy. Studies have also suggested that development of toxicity may be associated with better response to therapy. Because of the concern about non-persistence with therapy, especially in the setting of prescription of an oral medication for many years, there has been considerable research into understanding the mechanism underlying development of toxicity as well as treatment of these side effects. Ultimately the goal is to improve breast cancer survival outcomes while minimizing the negative impact of therapy on quality of life. Citation Format: Norah Lynn Henry. Adherence and persistence with adjuvant aromatase inhibitor therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES5-1.

Abstract P5-15-03: Baseline joint pain predicts severity of subsequent joint symptoms in women initiating aromatase inhibitors for early stage breast cancer

Abstract Background: Aromatase inhibitors (AIs) are the standard adjuvant treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, these therapies are associated with musculoskeletal complaints which may lead to non-adherence and early discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia. Methods: Postmenopausal women with stage I-III BC were prospectively enrolled at the onset of adjuvant AI therapy. Subjects completed the Brief Pain Inventory (BPI) questionnaire at baseline, 3, 6, 9, and 12 months. BPI worst pain scores were categorized as 0-3, 4-6 and 7-8. Multiple logistic regression analysis was used to evaluate the association between baseline factors and having a 2-point worsening in BPI worst pain score. A Cox-proportional hazards model was used to evaluate factors that influenced the time to first 2-point worsening in pain score. Clinically significant change was defined as ≥2-point increase from baseline. Those with a baseline BPI worst pain score of ≥9 were removed from analysis. Results: Among 180 consented subjects, 1 was found to be ineligible due to being perimenopausal, 42 subjects were lost to follow up, 17 subjects came off their AI and 8 subjects dropped out. Mean age was 61; 60% were white, 32% Black, 10%, Asian and 31% were Hispanic; 86% started on anastrazole; 24% had a change in AI. At baseline, 76 women had a BPI worst pain score between 0-3; 28 between 4-6; and 18 had 7+. Seventy subjects (64%) experienced at least a 2-point worsening of BPI from baseline and women who developed a 2-point worsening had a lower mean baseline BPI (2.57 vs. 3.75) compared to those who did not. Those experiencing an initial worsening in the first 6 months of therapy improved over time; while the patients experiencing BPI worsening at 9 months, continued to have progressive increase in BPI. In a multiple logistic regression model adjusting for AI switching, BMI, age, baseline score, prior chemotherapy, osteoarthritis, and prior hormone replacement therapy, those who had a baseline worst pain score between 4-6 (p=0.04) or 7+ (p=0.005) were less likely to develop a 2-point worsening in BPI at 12 months from baseline. Similarly, those with a baseline worst pain categorization of 7+ had a hazard ratio of 0.34 for time to 2-point worsening. Conclusions: Women with low baseline BPI score are more likely to develop worsening BPI score over time. Women who develop symptoms later in the course of their therapy are at greatest risk for persistent symptoms. This has implications for studies evaluating interventions for prevention of AI arthralgias. BPI mean scorePatients with >2 point increase in BPI at any timePatients with >2 point increase in BPI at 3 monthsPatients with >2 point increase in BPI at 6 monthsPatients with >2 point increase in BPI at 9 monthsPatients with >2 point increase in BPI at 12 monthsBaseline score3.752.57*2.592.302.11*1.85*Three month score4.254.526.08*4.684.133.87Six month score4.504.83*5.32*6.37*5.074.22Nine month score4.005.105.115.135.75*5.04Twelve month score4.255.37*5.484.865.666.21**p value <0.05 compared to baseline Citation Format: Lea Baer, Katherine D Crew, Danielle Awad, Kevin Kalinsky, Matt Maurer, Dawn L Hershman. Baseline joint pain predicts severity of subsequent joint symptoms in women initiating aromatase inhibitors for early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-03.

Relations between arthralgia and fear of recurrence: results of a cross-sectional study of breast cancer patients treated with adjuvant aromatase inhibitors therapy.

The aim of this study was to explore associations between arthralgia and fear of recurrence in breast cancer patients treated by aromatase inhibitors (AI). We sent a set of questionnaires to 100 patients examining their pain characteristics, anxiety (STAI), depression (BDI-SF), quality of life (SF-36), fear of recurrence (FCRI), and representations of AI treatment (ad hoc questionnaire). Nonparametric tests were used to investigate between-group comparisons (arthralgia vs. nonarthralgia) in these domains as well as the associations between arthralgia and fear of recurrence. Of the 77 patients who returned the questionnaires (response rate = 77%), 60 (78%) reported arthralgia. The mean score of fear of recurrence exceeded the pathological threshold in the arthralgia group and was significantly higher than that in the nonarthralgia group (14.8 vs. 10.7, p < 0.01). Significant associations were observed between fear of recurrence and pain intensity (r = 0.274, p < 0.05) and pain relief (r = -0.409, p < 0.05). More than 80% of the total sample declared that they were well informed about the aim of AI, their side effects, and the risk of developing arthralgia. Fear of recurrence did not appear to be associated with representations of AI. The study revealed a close relationship between pain intensity and fear of recurrence. In particular, it showed that effective pain management was accompanied by a reduced fear of recurrence. Information, although essential, appeared insufficient to overcome patients' concerns about pain. Therefore, the implement of a systematic screening for arthralgia and the improvement of analgesic treatment are essential issues. New strategies for pharmacological and nonpharmacological treatment must be developed.

Do Adverse Effects Foretell Efficacy of Adjuvant Aromatase Inhibitor Therapy for Breast Cancer

Some reports have suggested that treatment-associated vasomotor symptoms (VMS) or arthralgias predict better response to aromatase inhibitor (AI)

Sexual problems during the first 2 years of adjuvant treatment with aromatase inhibitors.

Sexual dysfunction has only recently been recognized as a highly prevalent side effect of adjuvant aromatase inhibitor (AI) therapy for breast cancer. A cross-sectional survey using standardized measures of female sexual function was designed to provide a detailed view of sexual problems during the first 2 years of adjuvant AI therapy and secondarily to examine whether sexual dysfunction leads to nonadherence to this therapy. Questionnaires were mailed to all 296 women in a breast oncology registry who had been prescribed a first-time AI for localized breast cancer 18-24 months previously. Items assessed medication adherence, demographic, and medical information. Scales included the Female Sexual Function Index, the Menopausal Sexual Interest Questionnaire, the Female Sexual Distress Scale-Revised, the Breast Cancer Prevention Trial Eight Symptom Scale to assess menopausal symptoms, and the Merck Adherence Estimator(®) . Questionnaires were returned by 129 of 296 eligible women (43.6%). Respondents were 81% non-Hispanic white with a mean age of 63 and 48% had at least a college degree. Only 15.5% were nonadherent. Ninety-three percent of women scored as dysfunctional on the Female Sexual Function Index, and 75% of dysfunctional women were distressed about sexual problems. Although only 52% of women were sexually active when starting their AI, 79% of this group developed a new sexual problem. Fifty-two percent took action to resolve it, including 24% who stopped partner sex, 13% who changed hormone therapies, and 6% who began a vaginal estrogen. Scores on the Adherence Estimator (beliefs about efficacy, value, and cost of medication) were significantly associated with adherence (P = 0.0301) but sexual function was not. The great majority of women taking AIs have sexual dysfunction that is distressing and difficult to resolve. Most continue their AI therapy, but a large minority cease sexual activity.

Bisphosphonates May Protect against Bone Loss in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Aromatase Inhibitor Therapy: Results from a Meta-analysis

The efficacy of bisphosphonates (BPs) in treating bone loss associated with cancer therapies has been demonstrated in completed studies and ongoing clinical trials. The aim of this study was to investigate the evidence for BP use in treatment of bone loss in postmenopausal, early breast cancer (EBC) patients scheduled to receive aromatase inhibitors (AI). A comprehensive search for relative articles published until December 2013 was performed. The outcomes included the percentage and absolute change in lumbar spine (LS) and total hip (TH) bone mineral density (BMD). Before pooled meta-analysis, the studies were evaluated for publication bias and heterogeneity. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated. We also performed subgroup and sensitivity analyses. A total of 11 trials contributed to the analysis. BP was shown to be efficacious in increasing BMD at the LS and TH. WMD in BMD absolute change was 0.21 g/cm(2) (95% CI, 0.13-0.28) at the LS and 0.27 g/cm(2) (95% CI, 0.02-0.12) at the TH. WMD in BMD percentage change was 5.42 (95% CI, 4.37-6.48) at the LS and 3.03 (95% CI, 2.01-4.01) at the TH. Subgroup analysis revealed that age difference, interventional duration, types of interventions and BP types were associated with variable effects on BMD at the LS and TH. BPs may protect against bone loss in postmenopausal women with EBC receiving adjuvant AI treatment.

Patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor therapy.

Aromatase inhibitor (AI) therapy results in substantial survival benefits for patients with hormone receptor-positive breast cancer. The rates of poor adherence and discontinuation of AI therapy are high, primarily because of treatment-related toxicities like musculoskeletal pain. Although pain-related symptoms may worsen during AI therapy, the authors hypothesized that nonpersistence with AI therapy was associated with symptoms that were present before treatment initiation. Postmenopausal women initiating AI therapy who were enrolled in a prospective clinical trial completed questionnaires at baseline to assess sleep, fatigue, mood, and pain. Reasons for treatment discontinuation during the first year of treatment were recorded. Associations between baseline patient-reported symptoms and treatment discontinuation because of toxicity were identified using logistic regression. Four hundred forty-nine patients were evaluable. The odds of treatment discontinuation were higher in patients who reported a greater number of symptoms before AI initiation. Baseline poor sleep quality was associated with early treatment discontinuation, with an odds ratio (OR) of 1.91 (95% confidence interval [CI], 1.26-2.89; P = .002). Baseline presence of tired feeling and forgetfulness had similar ORs for discontinuation (tired feeling: OR, 1.76; 95% CI, 1.15-2.67; P = .009; forgetfulness: OR, 1.66; 95% CI, 1.11-2.48; P = .015). An increasing total number of baseline symptoms was associated with an increased likelihood of treatment discontinuation, with an OR of 1.89 (95% CI, 1.20-2.96; P = .006) for 3 to 5 symptoms versus 0 to 2 symptoms. Symptom clusters in breast cancer survivors that are present before the initiation of adjuvant AI therapy may have a negative impact on a patient's persistence with therapy. Interventions to manage these symptoms may improve breast cancer outcomes and quality of life.

Denosumab: A bone antiresorptive drug

Bone remodeling is the continuous process by which old bone is removed by bone-resorbing cells, the osteoclasts and replaced by new bone synthesized by bone forming cells, the osteoblasts. Osteoporosis is characterized by a progressive loss of bone mass and microarchitecture, which leads to increased fracture risk. Denosumab, a human monoclonal antibody resembling natural IgG2 immunoglobulin, has antiresorptive activity and is distinguished from other antiresorptive drugs. It mimics osteoprotegerin (OPG) that binds to RANKL and hence does not allow RANKL to bind with RANK receptor, thereby inhibiting osteoclast differentiation, activation and survival exerting primarily antiresorptive action. Denosumab trials have shown its efficacy in postmenopausal women with osteoporosis, unresectable giant cell tumor of bone and significant effect in non-metastatic prostate cancer and delay in the time-to-first skeletal related events (SRE) and subsequent SRE with denosumab than zoledronic acid in patients. It is available as 60 mg/ml in pre-filled syringes and approved for osteoporosis in postmenopausal women (60 mg s.c. twice yearly), unresectable giant cell tumor of bone in adults and skeletally mature adolescents (120 mh s.c. monthly), prevention of skeletal-related events and to increase bone mass in patients at high risk for fracture including androgen deprivation therapy for non-metastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer. Denosumab offers advantages of twice yearly dosing in osteoporosis and monthly dosing in giant cell tumor of bone with its novel mechanism of action and better tolerability.

Hypovitaminosis D is a Predictor of Aromatase Inhibitor Musculoskeletal Symptoms

The aromatase inhibitor (AI)-associated musculoskeletal (MSK) pain symptoms are often debilitating and limit compliance with this important hormonal breast cancer therapy. The etiology of this syndrome is unknown. Hypovitaminosis D has been suggested as a possible risk factor for the development of MSK symptoms in women starting AIs. The objective of this substudy was to define the prevalence of low 25(OH)D in this population, to assess risk of low levels on developing pain and to define a target therapeutic goal for 25(OH)D in this population. This analysis was part of a 6-month prospective cohort study examining the MSK side effects of adjuvant AI therapy in postmenopausal women. Patients were evaluated by a rheumatologist with a joint examination, had 25(OH)D levels measured and completed quality of life questionnaires at baseline, 3 and 6 months. Symptomatic patients were defined as those that self-reported new or worsening MSK symptoms. Of 52 patients, 28 (54%) were symptomatic, and two (3.8%) stopped AIs due to MSK ailments. Thirteen patients had objective evidence of tendonitis on rheumatologic examination. Thirty-three percent of all subjects had baseline 25(OH)D levels <40 ng/mL, 19.2% had levels <30 ng/mL and 5.8% had levels <20 ng/mL. Symptomatic patients were more likely to have had baseline levels below 40 ng/mL, compared with asymptomatic patients (46.4% versus 16.7%, p = 0.037). In multivariate regression analyses, levels <40 ng/mL were associated with developing objective tenosynovitis (p = 0.033) but not with developing nonspecific myalgias. Our findings suggest hypovitaminosis D may be contributing to the AI-associated MSK pain syndrome and in particular to the development of tendonitis. Repletion to 25(OH)D levels >40 ng/mL is advisable. Further research should be carried out on identifying additional modifiable risk factors for this syndrome.

Abstract S3-02: Associations between baseline patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor (AI) therapy

Abstract Background: Non-adherence and non-persistence with AI therapy are common and have been associated with increased mortality. A major reason for premature discontinuation of therapy is toxicity of AI therapy. We performed an exploratory analysis to investigate associations between patient-reported symptoms at the time of AI initiation and discontinuation of AI therapy due to toxicity. Methods: 503 postmenopausal women with early stage ER positive breast cancer were enrolled into a randomized open label clinical trial of exemestane versus letrozole for 2 years. Questionnaires about sleep quality (PSQI), mood disorders (CESD), and general symptoms (NSABP symptom questionnaire) were completed prior to AI initiation. For each item on the symptom questionnaire, responses were dichotomized as not at all vs any. To analyze total number of symptoms the following 4 symptoms were included: PSQI&amp;gt;5, CESD≥16, any degree of joint pain, and any degree of difficulty concentrating. Subjects were evaluated 1, 3, 6, 12, and 24 months after AI initiation. Reasons for treatment discontinuation were prospectively recorded. The primary endpoint of this exploratory analysis was treatment discontinuation due to toxicity ≤12 months following AI initiation. Linear and logistic regression analyses were performed to analyze associations between clinical factors and baseline symptoms and treatment discontinuation by 12 months. Results: One hundred forty-two subjects (28.8%) discontinued therapy because of toxicity by or at 12 months. On univariate analysis, poor sleep quality (PSQI&amp;gt;5), depression (CESD≥16), forgetfulness, and total number of symptoms were statistically significantly associated with treatment discontinuation. On multivariable logistic regression, treatment discontinuation due to toxicity was statistically significantly associated with AI medication, and there was a trend towards an association with both younger age and increasing total number of symptoms present at baseline. Univariate and multivariate analysis of baseline predictors of AI treatment discontinuation Univariate analysisMultivariate analysisSymptom/characteristic% subjectsOR (95% CI)P valueOR (95% CI)P valueAge (yrs) mean 58.0 (9.0)0.98 (0.96-1.00)0.060.98 (0.95-1.00)0.076Drug (vs letrozole) 49.5%1.47 (0.99-2.18)0.0541.57 (1.04-2.38)0.033Estradiol (BL, pg/ml) mean 10.6 (37.2)1.01 (0.997-1.02)0.151.01 (1.00-1.02)0.091Prior taxane (vs no) 32.7%1.23 (0.82-1.85)0.331.14 (0.73-1.78)0.57Total # symptoms1 vs 028.2%1.56 (0.89-2.73)0.0241.27 (0.70-2.31)0.092 2 vs 021.5%1.52 (0.84-2.77) 1.54 (0.83-2.88) ≥3 vs 023.7%2.41 (1.37-4.23) 2.10 (1.15-3.84) Depression 15.2%1.03 (1.01-1.06)0.012 Forgetfulness (vs none) 45.5%1.64 (1.11-2.43)0.014 Difficulty concentrating (vs none) 23.7%1.35 (0.86-2.11)0.19 Joint pain (vs none) 57.6%1.42 (0.95-2.12)0.09 Poor sleep quality (vs good) 47.4%1.84 (1.23-2.75)0.003 Vaginal dryness (vs none) 31.5%1.37 (0.91-2.08)0.14 CI: confidence interval; OR: odds ratio Conclusions: Patient-reported symptoms present prior to initiation of AI therapy may predispose patients to early discontinuation of treatment. Pre-emptive management of these symptoms, rather than treatment of AI toxicity after its development, may improve adherence to and persistence with therapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-02.

Abstract P1-08-11: Association of variants in candidate genes on lipid profiles in women with early breast cancer on adjuvant aromatase inhibitor therapy

Abstract Background Aromatase inhibitors (AI) can exert unfavorable effects on lipid profiles, but previous studies have reported inconsistent results. Given the intricate biological relationship between estrogen and lipid profiles, these mixed results may be explained in part by variation in genes encoding proteins involved in the drug's target and in estrogen metabolism and signaling. The purpose of this study was to investigate associations of single-nucleotide polymorphisms (SNP) in candidate genes with AI-mediated changes in lipid profiles. Methods We completed a prospective multicenter randomized observational open-label study to test the association of SNPs in candidate genes on biomarkers of estrogenic and anti-estrogenic activity in post-menopausal women with early breast cancer who were recommended adjuvant AI therapy. Eligible women were randomly assigned to exemestane or letrozole, and were followed for 2 years. We genotyped 137 SNPs from germ line DNA in the following candidate genes: ARVCF, COMT, CYP19A1, ESR1, ESR2, PGR, EP300, EZH2, NCOA1-3, NCOR1-2, NRIP, and PELP1. Lipid profiles including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) were measured at baseline and 3 months after initiating AI. We conducted genetic association data analysis and multivariate linear regressions to analyze the genetic effects using dominant, recessive, and additive models. Multivariate analysis included age, body mass index, prior hormone replacement therapy, and prior tamoxifen. To adjust for multiple comparisons, only SNPs with a p&amp;lt;0.0003 were considered significant. Results We enrolled 502 women in to the study, but for this analysis we excluded women who did not have genetic data (n = 33), had incomplete data (n = 23), discontinued or crossed over AI therapy (n = 48), women not fasting at both time points (n = 89), or those on lipid-lowering medications (n = 162). A total of 200 women were evaluable (letrozole 107, exemestane 93). Lipid profiles in all patients (n = 200) at baseline and 3 months after initiating AI, respectively, were as follows: TC 204.9 and 203.3 (unchanged, p = 0.43); HDL 61.3 and 56.8 (decreased, p = 6.3E-10); LDL 122.2 and 124.6 (unchanged, p = 0.22); and TG 107.1 and 103.6 (unchanged, p = 0.26). Genetic association and multivariate analysis revealed that SNPs in ESR1 and NCOR1 are significantly associated with additional changes in lipid parameters as summarized in Table 1. Table 1.Significant findings of multivariate linear regressions analyzing genetic associations between candidate gene SNPs and lipid profiles of AI-treated women.CohortNumberSNP (gene)Minor Allele FrequencyLipid ParameterModel UsedMean Absolute Change (mg/dL)P-valueAll patients184rs9340958 (ESR1)0.07TCRecessive-2.250.0003Letrozole96rs9340958 (ESR1)0.07TCRecessive5.280.00009 101rs3020368 (ESR1)0.09TCRecessive6.350.00007Exemestane93rs3798758 (ESR1)0.03HDLDominant, additive-7.970.00001 88rs926848 (ESR1)0.03HDLDominant, additive-7.970.00002 93rs61753150 (NCOR1)0.01TGDominant, additive-11.630.00003 Conclusions Variants in genes involved in estrogen metabolism and signaling are associated with changes in lipid profiles in AI-treated women and should be validated in other studies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-11.

Abstract S3-07: Letrozole plus dasatinib improves progression-free survival (PFS) in hormone receptor-positive, HER2-negative postmenopausal metastatic breast cancer (MBC) patients receiving first-line aromatase inhibitor (AI) therapy

Abstract Introduction Dasatinib inhibits the protein tyrosine kinase, Src, which can support the development of bone metastases in patients with ER+ breast cancer. The primary objective of this study is to determine if letrozole plus dasatinib increases the clinical benefit rate (CBR) (CR+PR+SD ≥6mo) in first-line MBC patients compared with letrozole alone. Secondary objectives include overall response; progression-free survival; time to treatment failure (TTF); and toxicity. Methods This is a Phase II randomized, noncomparative study of postmenopausal women with locally recurrent or metastatic, measurable or nonmeasurable BC, ER+, HER2-. Patients are allowed to have had prior non-AI endocrine therapy for MBC; prior adjuvant AI therapy if completed at least 1 year prior to study entry; and up to 1 prior chemotherapy regimen for MBC. Patients are stratified by ≤2 yrs vs &amp;gt;2 years disease-free interval (DFI) from initial breast cancer diagnosis (date of definitive surgery) to first locally recurrent or MBC and by prior tamoxifen for MBC. Patients were randomly assigned to Arm 1 (letrozole 2.5mg PO QD + dasatinib 100mg PO QD) or Arm 2 (single-agent letrozole 2.5mg PO QD) on 28-day cycles. Arm 1 patients who experienced intolerable toxicity related to dasatinib discontinued dasatinib and continued single-agent letrozole. Arm 2 patients who developed progressive disease (PD) on letrozole had the option to receive dasatinib plus letrozole. The primary endpoint of CBR was assessed when patients developed progressive disease on their randomly assigned therapies before any crossover therapy. Results Patients with prior adjuvant AI/tamoxifen were 39%/32% Arm 1 and 44%/37% Arm 2; prior metastatic endocrine therapy Arm 1/Arm 2 was 9%/5%; and prior metastatic chemotherapy Arm 1/Arm 2 was 11%/6%. Median DFI Arm 1/Arm 2 was 27.5/21.2 months; patients presenting with de novo MBC Arm 1/Arm 2 was 42%/32%, respectively; measureable disease by RECIST Arm 1/Arm 2 was 58%/75%. The ITT population comprised 120 patients; 57 in Arm 1 and 63 in Arm 2. Clinical benefit rate (CBR) in 116 evaluable patients in Arm 1(55)/Arm 2(61), respectively, was 64% (95% CI, 50-76) and 61% (95% CI, 47-73). Median PFS time was 22 months with letrozole/dasatinib and 11 months with letrozole alone, p = .05. PFS at 6 and 12 months for Arms 1 and 2, respectively, was 78%/66% and 66%/43%. The most common toxicities observed with dasatinib on Arm 1 were fatigue (38%), nausea (38%), anemia (25%), rash (23%), pleural effusion (16%), and edema (13%). 27% of patients required dasatinib dose reduction. Conclusion The addition of dasatinib to letrozole in MBC patients receiving their first AI therapy for metastatic disease did not improve CBR compared with letrozole alone. Median PFS improved from 11 to 22 months (p = .05) with the addition of dasatinib, suggesting dasatinib improved duration of disease control combined with letrozole. Most patients tolerated full dose dasatinib until PD. 25% of patients remain on study therapy; final results will be available at SABCS 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-07.

Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects

Background:Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy.Methods:Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment.Results:Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ⩾20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed.Conclusion:Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.

Adjuvant Aromatase Inhibitor Therapy in Patients with Stage I Breast Cancer at a Regional Oncology Center in Israel: Implementation of a ‘Switching' Policy in Postmenopausal Patients after Initial Tamoxifen

Objective: To analyze the implementation of a switching policy of adjuvant aromatase inhibitor (AI) therapy sequentially after tamoxifen in consecutively treated stage I (T1N0M0) hormone receptor (HR)-positive breast cancer (BC) patients. Methods: The records of 279 consecutive HR-positive BC patients diagnosed between 2002 and 2006 and followed at the Soroka Medical Center were reviewed. Results: Two-hundred-seventeen patients who initially received tamoxifen were suitable for switching and 28 received an AI as initial adjuvant treatment. The switch was accomplished in 82.5% of the 217 patients. Those who switched to an AI had a higher proportion of T1c stage than patients eligible who were not switched, but did not differ in age, histologic grade, or having received chemotherapy. Of the 179 patients who switched, 155 (86.6%) completed at least 4.5-5 years of adjuvant tamoxifen/AI therapy. Eighteen patients discontinued AI therapy prematurely because of toxicity. Conclusions: In this stage I BC population, despite the toxicities of AI therapy, >84% of eligible patients received an AI as adjuvant therapy. Measures to improve the management of AI toxicity, such as changing to a different AI, may reduce early stopping.

Indications of Clinical and Genetic Predictors for Aromatase Inhibitors Related Musculoskeletal Adverse Events in Chinese Han Women with Breast Cancer

BackgroundWomen with breast cancer treated with aromatase inhibitors (AIs) may experience musculoskeletal symptoms that lead to discontinuation of effective therapy. The purpose of the current study is to evaluate the clinical and genetic predictors for AIs-related musculoskeletal adverse events(MS-AEs).Methodology and Principal FindingsWe recruited 436 postmenopausal Chinese Han women receiving adjuvant AIs therapy for early-stage hormone-sensitive breast cancer. Patients completed a self-administered questionnaire assessing the presence of musculoskeletal symptoms that started or worsened after initiating AIs. 27 single nucleotide polymorphisms (SNP) of ESR1, ESR2 and PGR were analyzed by Sequenom MassARRAY assays and /or PCR-based TaqMan assays.Of the 436 enrolled women, 206 cases experienced musculoskeletal symptoms.Patients who received taxane chemotherapy were more than two times more likely than other patients to have AIs-related MS-AEs. Genetic assay had showed that only two ESR1 SNPs, rs2234693 and rs9340799 were associated with AIs-related MS-AEs.TT genotype and the T allele in rs2234693 was statistically significantly lower in AIs-Related MS-AEs group than controls (P = 0.001; P = 9.49E-7). The frequency of AA genotype and the A allele in rs9340799 was higher (P = 2.20E-5; P = 3.09E-4).Conclusions and SignificanceOur results suggested that prior taxane-based chemotherapy was the clinical predictor, while rs2234693 and rs9340799 were the genetic predictors for AIs-related MS-AEs.

Periodontal health in early-stage postmenopausal breast cancer survivors on aromatase inhibitors.

568 Background: Aromatase inhibitors (AIs) are associated with profound estrogen deprivation resulting in reduced bone mineral density (BMD). Periodontal diseases and tooth loss are associated with estrogen withdrawal and decreased systemic BMD. Little is known as to the impact of AIs on oral health. To investigate oral health as a breast cancer (BCA) survivorship concern, a prospective study was initiated to determine the prevalence of periodontal diseases in postmenopausal early stage (I-IIIA) BCA survivors on adjuvant AI therapy. Baseline assessments are presented here. Methods: Women within 6 months of initiating adjuvant AI for hormone receptor positive BCA were eligible to participate in this study of serial assessments of oral health. A control group of women without BCA and not on AI underwent parallel assessments. Periodontal status was evaluated by the following established dental techniques; (1) periodontal pocket depth (PD), (2) number of teeth with bleeding on probing (BOP), (3) the number of teeth with clinical attachment loss (CAL). Questionnaires regarding socio-demographic and dental utilization were administered to all participants. Linear regression modeling was used to analyze the outcomes. Results: The study met its target accrual of 58 postmenopausal women; 29 with BCA on AI and 29 controls. Demographics were similar regarding age, education, income level, frequency of dental visits, and dental insurance status across both groups. Baseline assessments demonstrated no differences in PD (2.0 mm vs. 2.0 mm; p &lt; 0.95) or the number of teeth (26.6 vs 26.1; p&lt; 0.39). Interestingly, the AI group had significantly more sites of BOP (27.9 vs 16.7; p &lt; 0.02), and higher CAL (5.2 mm vs 4.0 mm; p &lt; 0.01) than did controls. In linear regression analysis adjusted for income, AI use increased CAL by 1 mm (95% CI: 0.15 -1.88). There was also a trend for decreased CAL in subjects with incomes over $75,000 per year (p&lt; 0.06). Conclusions: This first investigation of the periodontal status of women initiating adjuvant AI therpay identifies this population to have signs of increased risk for periodontal disease. Serial oral health assessments are being conducted to assess AI therapy and periodontal changes over time. Clinical trial information: NCT01693731.

Baseline bone mineral density testing among breast cancer patients prescribed aromatase inhibitors (AIs).

6642 Background: Because of the adverse effects of AI’s on bone mineral density (BMD) and fracture risk, current guidelines recommend baseline BMD testing when initiating adjuvant AI’s. Methods: We used a validated breast cancer algorithm of Medicare claims to identify older US female breast cancer patients starting adjuvant AI therapy and to examine baseline BMD testing rates. The cohort included all US non-HMO Medicare D-enrolled women age ≥67 years who initiated AI therapy within one year after a 2006-2007 initial breast cancer surgery. Women receiving IV bisphosphonates consistent with metastatic breast cancer treatment (interval &lt;90 days)were excluded. We examined BMD testing between 24 months prior and 6 months after AI initiation, adjusting for demographic and fracture risk factors, and comparing to a duration-adjusted testing rate for a 5% random sample of all cancer-free women enrolled in Medicare in 2008. Results: A majority of the cancer cohort (67.7%) had baseline BMD testing. This was substantially higher than the 2008 BMD testing rate for the non-cancer sample (15.4%, which translates into a 38.5% 30-month rate). Women of higher age and co-morbidity, as well as women of black race or lower income were less likely to be tested (see Table). Empiric use of oral bisphosphonates increased slightly with age, but this did not fully account for the testing differences by age. Conclusions: Although baseline BMD testing is high among women initiating AIs, approximately one-third do not receive guideline-recommended testing. Furthermore, those with greater risk fracture risk based on age and higher co-morbidity are less likely to have appropriate bone care. [Table: see text]

Mammographic Breast Density Response to Aromatase Inhibition

Mammographic breast density (MBD) is decreased by tamoxifen, but the effect of aromatase inhibitors is less clear. We enrolled early-stage postmenopausal patients with breast cancer initiating adjuvant aromatase inhibitor therapy and ascertained mammograms before and at an average 10 months of aromatase inhibitor therapy. We matched cases to healthy postmenopausal women (controls) from a large mammography screening cohort on age, baseline body mass index, baseline MBD, and interval between mammograms. We estimated change in MBD using a computer-assisted thresholding program (Cumulus) and compared differences between cases and matched controls. In predominantly White women (96%), we found 14% of the 387 eligible cases had a MBD reduction of at least 5% after an average of 10 months of aromatase inhibitor therapy. MBD reductions were associated with higher baseline MBD, aromatase inhibitor use for more than 12 months, and prior postmenopausal hormone use. Comparing each case with her matched control, there was no evidence of an association of change in MBD with aromatase inhibitor therapy [median case-control difference among 369 pairs was -0.1% (10th and 90th percentile: -5.9%, 5.2%) P = 0.51]. Case-control differences were similar by type of aromatase inhibitor (P's 0.41 and 0.56); prior use of postmenopausal hormones (P = 0.85); baseline MBD (P = 0.55); and length of aromatase inhibitor therapy (P = 0.08). In postmenopausal women treated with aromatase inhibitors, 14% of cases had a MBD reduction of more than 5%, but these decreases did not differ from matched controls. These data suggest that MBD is not a clinically useful biomarker for predicting the value of aromatase inhibitor therapy in White postmenopausal women.

Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer

Up to 25 % of patients discontinue adjuvant aromatase inhibitor (AI) therapy due to intolerable symptoms. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity. We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor-positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane versus letrozole. Using multiple genetic models, we evaluated potential associations between discontinuation of AI therapy because of toxicity and 138 variants in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling. To account for multiple comparisons, statistical significance was defined as p < 0.00036. Of the 467 enrolled patients with available germline DNA, 152 (33 %) discontinued AI therapy because of toxicity. Using a recessive statistical model, an intronic variant in ESR1 (rs9322336) was associated with increased risk of musculoskeletal toxicity-related exemestane discontinuation [HR 5.0 (95 % CI 2.1-11.8), p < 0.0002]. An inherited variant potentially affecting estrogen signaling may be associated with exemestane-associated toxicity, which could partially account for intra-patient differences in AI tolerability. Validation of this finding is required.