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Purpose: Everolimus in combination with endocrine therapy (ET) was formerly approved as 2nd-line therapy in HR(+)/HER2(-) advanced breast cancer (aBC) patients (pts) progressing during or after a non-steroidal aromatase inhibitor (NSAI). Since this approval, the treatment landscape of aBC has changed dramatically, particularly with the arrival of CDK 4-6 inhibitors. Endocrine monotherapy after progression to CDK4/6 inhibitors has shown a limited progression-free survival (PFS), below 3 months. Evidence of the efficacy of everolimus plus ET after CDK4/6 inhibitors is scarce., Methods: A retrospective observational study of patients with aBC treated with everolimus and ET beyond CDK4/6-i progression compiled from February 2015 to December 2022 in 4 Spanish hospitals was performed. Clinical and demographic data were collected from medical records. The main objective was to estimate the median progression-free survival (mPFS). Everolimus adverse events (AE) were registered. Quantitative variables were summarized with medians; qualitative variables with proportions and the Kaplan-Meier method were used for survival estimates., Results: One hundred sixty-one patients received everolimus plus ET (exemestane: 96, fulvestrant: 54, tamoxifen: 10, unknown: 1) after progressing on a CDK4/6 inhibitor. The median follow-up time was 15 months (interquartile range: 1-56 months). The median age at diagnosis was 49 years (range: 35-90 years). The estimated mPFS was 6.0 months (95%CI 5.3-7.8 months). PFS was longer in patients with previous CDK4/6 inhibitor therapy lasting for > 18 months (8.7 months, 95%CI 6.6-11.3 months), in patients w/o visceral metastases (8.0 months, 95%CI 5.8-10.5 months), and chemotherapy-naïve in the metastatic setting (7.2 months, 95%CI 5.9-8.4 months)., Conclusion: This retrospective analysis cohort of everolimus plus ET in mBC patients previously treated with a CDK4/6 inhibitor suggests a longer estimated mPFS when compared with the mPFS with ET monotherapy obtained from current randomized clinical data. Everolimus plus ET may be considered as a valid control arm in novel clinical trial designs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Although changes in circulating tumour DNA (ctDNA) in breast cancer are well described, the kinetics of their fluctuations has not been described over short timescales. We investigated ctDNA dynamics during alternating cycles of chemotherapy and hormonal treatment in pre-treated patients with oestrogen receptor-positive metastatic breast cancer., Methods: Patients received alternating, 9-week cycles of eribulin and aromatase inhibitors (AIs). The clinical primary endpoint, progression-free survival (PFS), was monitored at 3, 6 and 9 months; secondary endpoints, clinical benefit rate (CBR), safety and tolerability profiles, were also assessed. Importantly, ctDNA fluctuations were monitored using the Oncomine™ Breast cfDNA assay to test whether biomarkers may change rapidly between chemotherapy and aromatase inhibitor (AI) treatment in the setting of advanced breast cancer, potentially reflecting disease dynamics., Results: The median PFS was 202 days (95% CI: 135-undefined) and 235 days (95% CI: 235-undefined) at 6 and 9 months, respectively, with a 50% CBR at both 6 and 9 months. Dynamic changes in ctDNA were observed in short timescales between chemotherapy and AI treatment and support the clinical benefit (CB) seen in individual patients and, critically, appear informative of acquired resistance in real time., Conclusion: Changes in ctDNA can occur rapidly and reflect changes in patients' clinical tumour responses (NCT02681523)., (© 2024. The Author(s).)

Purpose: Aromatase inhibitor (AI) therapy reduces risk of recurrence and death for postmenopausal women with breast cancer (BC); however, AI-induced arthralgia (AIIA) can lead to discontinuation of treatment. Curcumin, a bioactive polyphenolic substance, may help ameliorate inflammation-related conditions including osteoarthritis and pain., Methods: We conducted a multisite randomized placebo-controlled, double-blind pilot trial (Alliance A22_Pilot9) to evaluate the effects of nanoemulsion curcumin (NEC, 200 mg/day) in postmenopausal women experiencing AIIA for ≥ 3 months. The primary objective was to determine the feasibility of using Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) to detect changes from 0 (T0) to 3 months (T3) of NEC treatment in AI-induced symptoms and well-being; secondary objectives included evaluation of changes in Disabilities of the Shoulder, Arm, and Hand (DASH), Brief Pain Inventory-short form (BPI-SF), grip strength, and biomarkers at T0 and T3., Results: Forty-two patients were randomized to NEC or placebo; 34 women completed the 3-month study. Patient-reported outcome measures (PROMs: FACT-ES, DASH, BPI-SF) and biospecimens were collected at T0-T3 in > 80% of participants. Adherence was ≥ 90% for both arms. PROMs and grip strength did not differ significantly by treatment arm. Plasma curcumin was detected only in NEC arm participants. Serum estradiol and estrone levels were below detection or low on study agent. Gastrointestinal adverse effects were commonly reported in both arms., Conclusion: NEC versus placebo in a multisite randomized trial is feasible and well-tolerated. Additional studies with larger sample size are needed to further evaluate the efficacy and safety of NEC in treatment of AIIA., Clinicaltrials: gov Identifier: NCT03865992, first posted March 7, 2019., (© 2024. The Author(s).)

Purpose: We performed a cost-effectiveness analysis of three strategies for the adjuvant treatment of early breast cancer in women age 70 years or older: an aromatase inhibitor (AI-alone) for 5 years, a 5-fraction course of accelerated partial-breast irradiation using intensity-modulated radiation therapy (APBI-alone), or their combination., Methods: We constructed a patient-level Markov microsimulation from the societal perspective. Effectiveness data (local recurrence, distant metastases, survival), and toxicity data were obtained from randomized trials when possible. Costs of side effects were included. Costs were adjusted to 2019 US dollars and extracted from Medicare reimbursement data. Quality-adjusted life-years (QALY) were calculated using utilities extracted from the literature., Results: The strategy of AI-alone ($12,637) was cheaper than both APBI-alone ($13,799) and combination therapy ($18,012) in the base case. All approaches resulted in similar QALY outcomes (AI-alone 7.775; APBI-alone 7.768; combination 7.807). In the base case, AI-alone was the cost-effective strategy and dominated APBI-alone, while combined therapy was not cost-effective when compared to AI-alone ($171,451/QALY) or APBI-alone ($107,932/QALY). In probabilistic sensitivity analyses, AI-alone was cost-effective at $100,000/QALY in 50% of trials, APBI-alone in 28% and the combination in 22%. Scenario analysis demonstrated that APBI-alone was more effective than AI-alone when AI compliance was lower than 26% at 5 years., Conclusions: Based on a Markov microsimulation analysis, both AI-alone and APBI-alone are appropriate options for patients 70 years or older with early breast cancer with small cost differences noted. A prospective trial comparing the approaches is warranted.

Background: Endocrine therapy with aromatase inhibitors (AIs) is the cornerstone of adjuvant systemic treatment for postmenopausal patients with hormone receptor-positive breast cancer. It has become clear that hormone receptor-positive breast cancer carries a consistent risk of relapse up to 15 years after diagnosis. Extended duration of adjuvant AIs therapy after completing initial standard adjuvant AIs-containing therapy may prevent late recurrence and death. We performed a meta-analysis to assess the real impact of the extended adjuvant therapy with AIs., Methods: A literature-based meta-analysis of the randomized controlled trials (RCTs) was undertaken. Relevant publications from PubMed, Embase, Cochrane Library, and abstracts from American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer (SABCS) symposia were searched. The endpoints were disease-free survival (DFS), overall survival (OS), local recurrence, distant recurrence, contralateral breast cancer, non-breast cancer-related death, and toxicity., Results: Eight trials comprising 15,966 patients met the inclusion criteria. The pooled analysis revealed a significant improvement in DFS (RR = 0.79; 95% CI 0.68-0.91), distant recurrence (RR = 0.75; 95% CI 0.58-0.96), and contralateral breast cancer (RR = 0.53; 95% CI 0.40-0.70) in the extended AIs group. While there was not significant improvement in OS (RR = 1.00, 95% CI 0.99-1.01), non-breast cancer-related death (RR = 1.16, 95% CI 0.96-1.41), and local recurrence (RR = 0.82; 95% CI 0.64-1.06), the subgroup analysis showed that the patient with tumor size > 2 cm (HR = 0.74, RD = - 0.31, P = 0.05 vs. HR = 0.85, RD = - 0.16, P = 0.20), node positive status (HR = 0.77, RD = - 0.27, P = < 0.0001 vs. HR = 0.89, RD = -0.12, P = 0.19) and previous chemotherapy use (HR = 0.75, RD = - 0.29, P = 0.003 vs. HR = 0.91, RD = -0.10, P = 0.44) would get a greater DFS benefit with extended AIs. Longer treatment with AIs was associated with an increased risk ratio of bone pain (RR = 1.26, RD = 0.04, P = 0.003), bone fractures (RR = 1.59, RD = 0.02, P = 0.002), osteoporosis (RR = 1.53, RD = 0.07, P = 0.005), myalgia (RR = 1.26, RD = 0.04, P = 0.02), and treatment discontinuation for adverse events (RR = 1.51, RD = 0.06, P = 0.0009)., Conclusion: After initial standard AIs-containing adjuvant therapy, extended AIs therapy could further bring a DFS benefit for postmenopausal patients with early breast cancer, especially in the patients with high-risk characteristics.

Purpose: The most frequent adverse effects of aromatase inhibitors (AI) are arthralgia and bone loss induction. These reduce the quality of life of patients and their adherence to the treatment. This study evaluates the early AI cessation caused by AI intolerance, and the evolution of joint pain and health-related quality of life (HRQoL) during AI treatment until 1-year after AI completion., Methods: Data of 910 women diagnosed with early breast cancer and candidates for AI were recruited in B-ABLE cohort. AI discontinuation was analyzed by survival analysis, including Kaplan-Meier estimation and Cox regression. Patients were distributed in three groups of the study according to previous tamoxifen (TAM) exposure and length of AI treatment: TAM-2yAI, TAM-3yAI, and 5yAI. Evolution of joint pain and HRQoL in osteoporosis was evaluated using Visual Analog Scale (VAS) and ECOS-16 tests, respectively, from baseline to 1-year after AI completion through repeated-measures ANOVA., Results: Risk of AI discontinuation was increased in patients previously exposed to tamoxifen compared to non-exposed (adjusted HR 5.30 [95% CI 2.23 to 12.57]). VAS and ECOS-16 scores of TAM-2yAI and TAM-3yAI groups increased during AI treatment, mainly during the first 3-12 months. After 1-year from AI completion, values tend to decrease to baseline levels. In 5yAI group, VAS and ECOS-16 levels increased at three months, and VAS remained significantly higher at 1-year post-treatment., Conclusions: AI therapy increased joint pain and reduced HRQoL, mainly during the first year of treatment. Patients previously treated with tamoxifen experienced greater pain when they switched to AI therapy and had an excess risk of discontinuation during the first 12 months., Trial Registration: ClinicalTrials.gov: NCT03811509. Registered 28 January 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03811509 .

Purpose: UGT2B17 gene deletion (UGT2B17*2) has been reported to affect bone health as well as the pharmacokinetics of aromatase inhibitor (AI) drugs such as exemestane. The goal of this study was to assess associations between UGT2B17 gene deletion and bone health prior to and after 24 months of AI treatment in postmenopausal women with hormone receptor positive (HR+) breast cancer., Methods: Bone health in women with HR+ breast cancer enrolled on the prospective randomized Exemestane and Letrozole Pharmacogenetics (ELPh) trial was determined by measuring bone turnover markers (BTM) and bone mineral density (BMD) pre-treatment and after 3 BTM and 24 BMD months of treatment with either the steroidal AI exemestane or the nonsteroidal AI letrozole. DNA samples were genotyped for UGT2B17*2., Results: Of the 455 subjects included in the analyses, 244 (53.6%) carried at least one copy of UGT2B17*2. UGT2B17*2 was associated with lower pre-treatment BMD at the hip (P = 0.01) and spine (P = 0.0076). Letrozole treatment was associated with a greater decrease in BMD of the hip (P = 0.03) and spine (P = 0.03) than exemestane. UGT2B17 genotype was not associated with changes in BMD from 24 months of AI treatment, though in UGT2B17*2 homozygous patients, there was a trend toward greater decreases in BMD of the spine from treatment with letrozole compared with exemestane (P = 0.05)., Conclusion: UGT2B17*2 may be associated with lower baseline BMD in women with HR+ breast cancer. Exemestane is less detrimental to bone health than letrozole in postmenopausal women treated with AI, and this effect may be confined to patients carrying UGT2B17*2, though this finding requires independent validation.

Purpose: Venous thromboembolism (VTE) is the second most common cause of death in hospitalized patients with cancer, and cancer treatments may exacerbate VTE risk. Patients with hormone-receptor-positive breast cancer usually receive adjuvant endocrine therapy for 5 years or longer. The aim of this study is to examine VTE risk following long-term use of aromatase inhibitor (AI) compared with tamoxifen use among breast cancer survivors., Methods: A prospective cohort of 12,904 postmenopausal women who were diagnosed with a first primary hormone-receptor-positive breast cancer and free from previous cardiovascular disease or VTE from 1991 to 2010 were followed through December 2011. Data elements were captured from the comprehensive electronic health records of a large California health plan, Kaiser Permanente. Women who developed deep vein thrombosis (DVT) or pulmonary embolism (PE) were identified as having VTE. We calculated person-year rates of VTE by endocrine therapy groups. Multivariable Cox proportional hazards models were applied to assess the association between time-dependent endocrine therapy and VTE risk., Results: We identified 623 VTE events during a median follow-up of 5.4 years. The crude rates were 4.6 and 2.8 per 1000 person-years for DVT and PE, respectively. Compared with tamoxifen use, AI use was associated with at least 41% lower VTE risk (adjusted HR 0.59, 95% CI 0.43, 0.81). Greater risk reductions in AI users were seen in women who also underwent adjuvant chemotherapy., Conclusions: These findings supplement existing evidence to inform treatment decisions that balance cancer control and cardiovascular toxic outcomes.

Purpose: Approximately 70-80% of breast cancers are hormone receptor-positive (HR+). OET, including tamoxifen and aromatase inhibitors, is considered standard adjuvant therapy for HR+ breast cancer. Despite demonstrated benefits, nearly half of patients are non-adherent and over two-thirds discontinue therapy before the recommended 5 years. Our objective was to identify and summarize literature-reported barriers associated with non-adherence/non-persistence to OET among breast cancer survivors., Methods: A PUBMED literature search was conducted using the following terms: 'breast cancer,' 'oral endocrine therapy' or 'Tamoxifen' or 'Aromatase Inhibitors,' 'adherence,' or 'barriers.' The search was restricted to past six years. The abstracts of each result were reviewed and categorized as either patient-reported or physician-reported. All patient- and physician-reported factors that affected adherence and persistence were listed and grouped together into the three main categories: Socio-demographic and medical parameters, general psychosocial parameters, and psychosocial parameters related to OET., Results: A total of 320 articles were identified, of which 19 met inclusion criteria. Adverse drug reactions were the most commonly reported barrier but were generally underreported among physicians. Among patient-reported barriers, common social-demographic and medical parameters were age, comorbidity, and financial status. General psychosocial variables were lack of patient-provider communication, depressive symptoms, and lack of perceived self-efficacy. Treatment toxicity was the most commonly reported psychosocial parameter related to OET., Conclusion: The determinants of non-adherence and non-persistence are multi-dimensional and influenced by several factors. The three categories of adherence barriers should be evaluated and considered when designing future interventions to enhance OET adherence for a tailored approach.

Purpose: This study was designed to determine the safety and clinical efficacy of metronomic chemotherapy combined with aromatase inhibitors (AIs) for hormone receptor (HR)-positive advanced breast cancer (ABC) patients who cannot tolerate conventional-dose chemotherapy., Methods: Postmenopausal patients with HR-positive ABC, who exhibited disease progression after first-line AIs treatment and who could not tolerate or rejected conventional chemotherapy, were enrolled in this study. Patients received capecitabine 500 mg PO TID (could be reduced to 500 mg QD in case of adverse effects) and exemestane 25 mg QD (after PD with letrozole) or letrozole 2.5 mg QD (after PD with exemestane). The primary endpoints were safety and tolerance, the secondary endpoints were objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and time to treatment failure (TTF)., Results: In our analysis of 44 patients, the median age was 64 years (range 38-90) and 68.2% patients had at least two recurrences or metastatic lesions. Grade 3 toxicities (hand-foot syndrome) were observed only in 4 of the patients. Most patients exhibited no or mild toxicities. After a median follow-up of 14.8 months, ORR was 70.5%, CBR-77.3%, PFS-16.2 months, and TTF-14.4 months., Conclusions: Metronomic oral capecitabine combined with AIs showed good efficacy, minimal toxicities, and good tolerance in HR-positive patients with ABC. It is a potential treatment option especially for postmenopausal HR-positive ABC patients in poor general condition who cannot tolerate conventional chemotherapy., Trial Registration: Clinicaltrials.gov NCT01924078.

Purpose: Neoadjuvant endocrine therapy (NAET) for estrogen receptor-positive primary breast cancer causes adequate tumor shrinkage, and is expected to be helpful for breast-conserving surgery, but the adaptation criteria, especially in regard to treatment duration, have never been elucidated. Re-visiting past gene expression profiles, we explored the data for specialized pre-therapeutic predictors and validated the results using our in-house clinical cohorts., Methods: We sorted the genes related to a > 30% tumor volume reduction through NAET from a cDNA microarray data-set of GSE20181, then selected the top 40 genes. We validated these gene expression levels using pre-therapeutic biopsy samples obtained from patients treated with long-term NAET (over 4 months; N = 40). A short-term (2-8 weeks; N = 37) NAET cohort was also validated to clarify whether expression of these genes is also related to a rapid response of Ki67 and PEPI score., Results: In the long-term group, higher expression of KRAS, CUL2, FAM13A, ADCK2, and LILRA2 was significantly associated with tumor shrinkage, and KRAS, MMS19, and IVD were related to lower PEPI score (≤ 3). Meanwhile in the short-term group, none of these genes except CUL2 showed a direct correlation with Ki67 reduction or PEPI score. This suggested that tumor shrinkage by NAET might be induced by response to the hypoxic environment (CUL2, FAM13A, KRAS) and activation of tumor immune system (LILRA2), without involving inhibition of proliferation., Conclusion: Expression of specific genes may allow selection of the most responsive patients for maximum tumor shrinkage with NAET.

Purpose: To examine factors associated with non-adherence during 5 years of endocrine treatment, including the possible influence of comorbidity burden and specific medical conditions., Methods: From all women diagnosed with stage I-III, ER-positive breast cancer in Stockholm-Gotland, Uppsala-Örebro and Northern Sweden between 2006 and 2009, we included 4645 women who had at least one dispensation of tamoxifen or aromatase inhibitors (AIs) and 5 years of follow-up without distant recurrence. A medical possession ratio of < 80% was used to define non-adherence. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of non-adherence., Results: During follow-up, 977 (21%) women became non-adherents. Non-adherence was associated with greater comorbidity burden assessed by Charlson comorbidity index (CCI) during follow-up (OR 1.43; 95% CI 1.08-1.88 for ≥ 2 additional scores compared to 0), pre-diagnostic HRT use (OR 1.99; 1.58-2.49), not married (OR 1.42; 1.23-1.64), high educational level (OR 1.25; 1.02-1.53 compared to lowest level), and use of symptom-relieving drugs. HER-2 positivity (OR 0.61; 0.45-0.81) and adjuvant chemotherapy (OR 0.42; 0.35-0.52) were associated with lower odds of non-adherence. Similar patterns were observed for the presence of lymph node metastasis, higher tumour grade, and use of AIs compared to tamoxifen. Myocardial infarction and chronic pulmonary disease was suggested as leading conditions associated with non-adherence in women with increasing CCI., Conclusion: We identified subgroups of women with breast cancer at increased risk of non-adherence. Our findings related to comorbidity suggest the importance of focusing on the presence of specific co-existing conditions when monitoring adherence.

Purpose: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia., Methods: We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms., Results: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline., Conclusions: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

Purpose: Endocrine therapies, including tamoxifen or aromatase inhibitors, are indispensable for the treatment of patients with estrogen receptor (ER)- and/or progesterone-positive breast cancer. Whereas tamoxifen displays partial ER agonistic effects in bone, aromatase inhibitors increase bone resorption and fracture risk. The Wnt inhibitors dickkopf-1 (DKK-1) and sclerostin negatively impact bone formation and are considered targets for the treatment of bone disorders. However, the effect of endocrine therapies on serum DKK-1 and sclerostin levels in patients with primary breast cancer remains elusive., Methods: Serum DKK-1 and sclerostin levels were measured at primary diagnosis as well as 3-5 days and 12 months after surgery in a cohort of 45 pre- and postmenopausal women with primary estrogen receptor-positive breast cancer treated with adjuvant tamoxifen or aromatase inhibitors., Results: Mean baseline levels ±SD for DKK-1 and sclerostin were 29.7 ± 14.6 and 27.1 ± 16.2 pmol/l, respectively. A significant negative correlation of DKK-1 levels and age was observed (r = -0.32; p < 0.05), but not for sclerostin. Of note, DKK-1 levels were significantly lower in peri- and postmenopausal women compared to premenopausal patients (-47%; p < 0.05). In tamoxifen-treated patients, DKK-1 levels were reduced by 35% (p < 0.01) one year after surgery but remained unaltered in patients treated with aromatase inhibitors. No significant changes were observed for sclerostin., Conclusion: DKK-1 serum levels were reduced in breast cancer patients receiving an adjuvant therapy with tamoxifen, possibly contributing to its bone-protective properties.

Purpose: Aromatase inhibitors (AI), which decrease circulating estradiol concentrations in post-menopausal women, are associated with toxicities that limit adherence. Approximately one-third of patients will tolerate a different AI after not tolerating the first. We report the effect of crossover from exemestane to letrozole or vice versa on patient-reported outcomes (PROs) and whether the success of crossover is due to lack of estrogen suppression., Methods: Post-menopausal women enrolled on a prospective trial initiating AI therapy for early-stage breast cancer were randomized to exemestane or letrozole. Those that discontinued for intolerance were offered protocol-directed crossover to the other AI after a washout period. Changes in PROs, including pain [Visual Analog Scale (VAS)] and functional status [Health Assessment Questionnaire (HAQ)], were compared after 3 months on the first versus the second AI. Estradiol and drug concentrations were measured., Results: Eighty-three patients participated in the crossover protocol, of whom 91.3% reported improvement in symptoms prior to starting the second AI. Functional status worsened less after 3 months with the second AI (HAQ mean change AI #1: 0.2 [SD 0.41] vs. AI #2: -0.05 [SD 0.36]; p = 0.001); change in pain scores was similar between the first and second AI (VAS mean change AI #1: 0.8 [SD 2.7] vs. AI #2: -0.2 [SD 2.8]; p = 0.19). No statistical differences in estradiol or drug concentrations were found between those that continued or discontinued AI after crossover., Conclusions: Although all AIs act via the same mechanism, a subset of patients intolerant to one AI report improved PROs with a different one. The mechanism of this tolerance remains unknown, but does not appear to be due to non-adherence to, or insufficient estrogen suppression by, the second AI.

Purpose: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%)., Methods: This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] × 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd × 5 days/week. The primary endpoint was progression-free survival (PFS)., Results: Median PFS was 21.4 weeks for ridaforolimus 30 mg qd × 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy., Conclusions: The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.

Purpose: The benefits of adding ovarian suppression to either tamoxifen or aromatase inhibitors as adjuvant breast cancer therapy in premenopausal women are controversial. Therefore, we performed a systematic literature review and meta-analysis of relevant randomized trials., Methods: We identified and combined four qualifying trials reporting disease-free survival (DFS) and overall survival (OS) using meta-analysis., Results: Combining ABCSG-12, SOFT, and TEXT studies, there were 65 fewer DFS events (HR 0.89, 95% CI 0.57-1.39) but 30 more deaths for ovarian suppression plus aromatase inhibitor compared to ovarian suppression plus tamoxifen (HR 1.31, 95% CI 0.93-1.84, P = 0.12, τ = 0.03, heterogeneity, P = 0.18). DFS and OS were more concordant for combined SOFT and E-3193 findings; for ovarian suppression plus tamoxifen compared to tamoxifen alone, there were 24 fewer DFS events (HR 0.83, 95% CI 0.67-1.07, P = 0.09, τ 2  = 0) and 14 fewer deaths (HR 0.76, 95% CI 0.53-1.07). The SOFT Estrogen Substudy demonstrated inconsistent estrogen suppression with combined ovarian suppression and aromatase inhibitor., Conclusion: Given the discordance between DFS and OS and inconsistent estrogen suppression with ovarian suppression plus aromatase inhibitor, adding aromatase inhibitor to ovarian suppression as adjuvant therapy in premenopausal women is premature.

The purpose of the study was to evaluate the efficacy and safety of vitamin D3 at 4000 IU/day as a treatment option for aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) when compared with the usual care dose of 600 IU D3. We conducted a single site randomized, double-blind, phase 3 clinical trial in women with AIMSS comparing change in symptoms, reproductive hormones and AI pharmacokinetics. Postmenopausal women ≥18 years with stages I-IIIA breast cancer, taking AI and experiencing AIMSS [breast cancer prevention trial symptom scale-musculoskeletal (BCPT-MS) subscale ≥1.5] were admitted. Following randomization, 116 patients had a run-in period of 1 month on 600 IU D3, then began the randomized assignment to either 600 IU D3 (n = 56) or 4000 IU D3 (n = 57) daily for 6 months. The primary endpoint was a change in AIMSS from baseline (after 1 month run-in) on the BCPT-MS (general MS pain, joint pain, muscle stiffness, range for each question: 0 = not at all to 4 = extremely). Groups had no statistically significant differences demographically or clinically. There were no discernable differences between the randomly allocated treatment groups at 6 months in measures of AIMSS, pharmacokinetics of anastrozole and letrozole, serum levels of reproductive hormones, or adverse events. We found no significant changes in AIMSS measures between women who took 4000 IU D3 daily compared with 600 IU D3. The 4000 IU D3 did not adversely affect reproductive hormone levels or the steady state pharmacokinetics of anastrozole or letrozole. In both groups, serum 25(OH)D remained in the recommended range for bone health (≥30 ng/mL) and safety (<50 ng/mL)., Competing Interests: Compliance with Ethical Standards No conflicts of interest reported by any of the authors.

Bone loss is a significant clinical problem for female cancer survivors (FCS) and increases fracture risk. The aim of the Yale Fitness Intervention Trial (Yale FIT) was to determine the effects of a 12-month aerobic-resistance exercise intervention compared to a home-based physical activity group on bone outcomes [bone mineral density (BMD)] and biomarkers bone turnover). Early postmenopausal FCS (N = 154) were randomized to the exercise intervention (3 times/week) or to a home-based physical activity group. Calcium (1200 mg) and Vitamin D (400 IU) supplements were provided to both groups. BMD was measured at baseline and 12 months. No significant difference in BMD was observed for the exercise vs home-based group. However, subjects on Tamoxifen or no endocrine therapy did not significantly lose BMD, with the exception of the femoral neck (FN). In contrast subjects on aromatase inhibitors (AIs) had significant BMD loss at all sites. The majority of subjects had sufficient serum levels of Vitamin D (>20 ng/mL) but there was significantly less bone loss in subjects in the 20-29 ng/mL range at the LS (p = 0.01), hip (p = 0.03), and GT (p = 0.008) compared to lower or higher levels. Exercise stimulates bone remodeling but the intervention was not superior for BMD outcomes at one year. The dose of the osteogenic stimulus in the intervention has been effective in preserving BMD in healthy postmenopausal women but it may be inadequate for survivors with chemotherapy-induced menopause and for those on adjuvant AI therapy.

Aromatase inhibitors (AIs) are used for treatment of estrogen receptor α (ER)-positive breast cancer; however, resistance is a major obstacle for optimal outcome. This preclinical study aimed at identifying potential new treatment targets in AI-resistant breast cancer cells. Parental MCF-7 breast cancer cells and four newly established cell lines, resistant to the AIs exemestane or letrozole, were used for a functional kinase inhibitor screen. A library comprising 195 different compounds was tested for preferential growth inhibition of AI-resistant cell lines. Selected targets were validated by analysis of cell growth, cell cycle phase distribution, protein expression, and subcellular localization. We identified 24 compounds, including several inhibitors of Aurora kinases e.g., JNJ-7706621 and barasertib. Protein expression of Aurora kinase A and B was found upregulated in AI-resistant cells compared with MCF-7, and knockdown studies showed that Aurora kinase A was essential for AI-resistant cell growth. In AI-resistant cell lines, the clinically relevant Aurora kinase inhibitors alisertib and danusertib blocked cell cycle progression at the G2/M phase, interfered with chromosome alignment and spindle pole formation, and resulted in preferential growth inhibition compared with parental MCF-7 cells. Even further growth inhibition was obtained when combining the Aurora kinase inhibitors with the antiestrogen fulvestrant. Our study is the first to demonstrate that Aurora kinase A and B may be treatment targets in AI-resistant cells, and our data suggest that therapy targeting both ER and Aurora kinases may be a potent treatment strategy for overcoming AI resistance in breast cancer.

Obesity is associated with a worse breast cancer prognosis, particularly in estrogen receptor alpha (ERα) positive, postmenopausal patients. We hypothesized that this is mediated in part by an elevation in breast cancer cell cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production that results in greater local pre-adipocyte aromatase expression. We utilized an in vitro model of the obese patient's tumor microenvironment in which cultured MCF-7 breast cancer cells and pre-adipocytes were exposed to pooled serum from obese (OB; BMI ≥ 30.0 kg/m(2)) or normal weight (N; BMI 18.5-24.9 kg/m(2)) postmenopausal women. Exposure to OB versus N sera significantly increased MCF-7 cell COX-2 expression and PGE2 production. Pre-adipocyte aromatase expression was 89 % greater following culture in conditioned media (CM) from MCF-7 cells exposed to OB versus N sera (OB-CM and N-CM, respectively), a difference nullified by MCF-7 cell treatment with the COX-2 inhibitor celecoxib. Previous analysis of the sera revealed significantly higher interleukin-6 (IL-6) concentrations in the OB versus N samples. Depletion of IL-6 from the sera neutralized the difference in pre-adipocyte aromatase expression stimulated by OB-CM versus N-CM. Finally, CM from pre-adipocyte/MCF-7 cell co-cultures exposed to OB sera stimulated greater MCF-7 and T47D breast cancer cell ERα activity and proliferation in comparison to N sera. This study indicates that obesity-associated systemic IL-6 indirectly enhances pre-adipocyte aromatase expression via increased breast cancer cell PGE2 production. Investigation regarding the efficacy of a COX-2 inhibitor/aromatase inhibitor combination therapy in the obese postmenopausal patient population is warranted.

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE₁₀₀C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

Musculoskeletal adverse events (MSAEs) and vasomotor symptoms (VMSs) are known side-effects of aromatase inhibitors, and may be related to genetic variations of the aromatase gene (CYP19A1). We investigated the relationship between these specific AEs and single nucleotide polymorphisms (SNPs) in the CYP19A1 gene in postmenopausal, hormone receptor-positive early breast cancer (BC) patients treated with adjuvant exemestane for 5 years. Dutch patients who were randomized to receive 5 years of exemestane in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. A tagging-SNP approach was performed, covering 80 % of variations of the CYP19A1 gene with 30 SNPs. Logistic regression analyses were used to assess the risk of reporting VMSs or MSAEs in relation to genotypes within selected SNPs. Of 737 included patients, 281 patients reported at least one MSAE (n = 210) or VMS (n = 163). Homozygous AA genotype of rs934635 was associated with a significantly higher odds of MSAEs (multivariate odds ratio (OR) 4.66, p = 0.008) and VMSs (multivariate OR 2.78, p = 0.044). Regarding both rs1694189 and rs7176005, the homozygous variant genotypes (TT) were associated with a higher odds of VMSs, but not MSAEs (OR 1.758, p = 0.025 and OR 6.361, p = 0.021, respectively). Our exploratory analysis demonstrated that some CYP19A1 gene variations may be associated with MSAEs and/or VMSs. Specifically, patients with the homozygous variant rs934635 genotype reported more MSAEs and VMSs. Although further confirmatory studies are warranted, genomic profiling can help identify patients at an increased risk of reporting these specific AEs, potentiating further personalized BC treatment.

The aim of this multicenter, prospective, longitudinal phase IV study was to establish the optimal duration of neoadjuvant letrozole that would allow breast conservation surgery (BCS) in patients with early breast cancer who were initially unsuitable. Primary, invasive, estrogen-receptor- and/or progesterone-receptor-positive breast cancer patients, with large tumors (≥T2 i.e., >20 mm) not initially suitable for BCS, received 2.5 mg letrozole p.o. daily. Patients continued treatment until they became eligible for BCS, progressed, failed to meet criteria for BCS and withdrew for scheduled mastectomy, withdrew for other reasons, or completed 12 months of letrozole treatment without a BCS decision being made. A total of 146 patients were enrolled; seven patients who did not have a valid postbaseline tumor assessment were excluded from the final efficacy analysis. At study closure, 69 % of patients (96 of 139) were eligible for BCS. The median time to achieve a tumor response sufficient to allow BCS with neoadjuvant letrozole was 7.5 months (95 % CI 6.3-8.5 months). Letrozole was well tolerated, and most adverse events were mild-to-moderate (grade 1-2). The results from this trial suggest that extended letrozole therapy in the neoadjuvant setting (7.5 months), as opposed to conventional treatment of 4 months, is optimal to achieve maximum reduction in tumor volume sufficient for BCS.

Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or first-line) endocrine therapy may be treated multiple times with one of several endocrine or combinatorial targeted treatment options before initiating chemotherapy. In the absence of direct head-to-head comparisons of these treatment options, an indirect comparison can inform treatment choice. This network meta-analysis compared the efficacy of everolimus plus exemestane with that of fulvestrant 250 and 500 mg in the advanced breast cancer setting following adjuvant or first-line endocrine therapy. The reported hazard ratios (HRs) for progression-free survival (PFS) or time to progression from six studies that formed a network to compare everolimus plus exemestane (BOLERO-2 trial) with fulvestrant were analyzed by means of a Bayesian network meta-analysis. In the primary comparison (PFS analysis based on the local review of disease progression from BOLERO-2 with the data from the other studies), everolimus plus exemestane appeared to be more efficacious than both fulvestrant 250 mg (HR = 0.47; 95 % credible interval [CrI] 0.38-0.58) and 500 mg (HR = 0.59; 95 % CrI 0.45-0.77). Similar results were obtained in an alternate comparison based on central review of disease progression from BOLERO-2 with the data from the other studies (HR = 0.40; 95 % CrI 0.31-0.51 and HR = 0.50; 95 % CrI 0.37-0.67, respectively), and in a subgroup analysis of patients who had received prior aromatase inhibitor therapy (HR = 0.47; 95 % CrI 0.38-0.58 and HR = 0.55; 95 % CrI 0.40-0.76, respectively). These results suggest that everolimus plus exemestane may be more efficacious than fulvestrant in patients with advanced breast cancer who progress on or after adjuvant or first-line therapy with a nonsteroidal aromatase inhibitor.

The role of aromatase inhibitors combined with gonadotropin-releasing hormone analog in metastatic male breast cancer patients remains unknown. In this retrospective study we evaluated the activity of letrozole combined with a gonadotropin-releasing hormone analog as a first- or second-line therapy for metastatic male breast cancer patients. 19 men entered the study. We did not observe any grade 3 or 4 adverse events. 2 patients (10.5 %) had complete response, 7 patients (36.8 %) experienced a partial response, 7 patients (36.8 %) had stable disease lasting ≥ 6 months, and 3 patients (15.8 %) had progressive disease. Overall, the disease control rate was 84.2 %. Median progression-free survival was 12.5 months (95 % CI 8.2-16.9), median overall survival was 35.8 months (95 % CI 24.4-49.2), 1- and 2-year survival rates were 89.5 and 67 %, respectively. Interestingly, 3 out of 4 patients treated with the combination following disease progression while on aromatase inhibitor monotherapy confirmed or improved the best overall response observed in the first-line setting. The combination of letrozole and gonadotropin-releasing hormone analog is effective and safe in hormone-receptor positive, metastatic male breast cancer patients.

The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in a large randomized controlled trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to disease-free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. In addition, exploratory analyses on 24 genetic variants of other metabolic enzymes and the estrogen receptor were performed. For the CYP2D6 analysis, only 2.3 % of the samples were excluded, because influence of LOH could not be ruled out. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t (poor vs. extensive metabolizers: unadjusted hazard ratio 1.33, 95 % CI 0.52-3.43; P = 0.55). DFS-t was associated with UGT2B15*2 (Vt/Vt + Wt/Vt vs. Wt/Wt: adjusted hazard ratio 0.47, 95 % CI 0.25-0.89; P = 0.019) and the estrogen receptor-1 polymorphism ESR1 PvuII (gene-dose effect: adjusted hazard ratio 1.63, 95 % CI 1.04-2.54; P = 0.033). In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype did affect DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin-embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded. Polymorphisms in the estrogen receptor-1 and UGT2B15 may be associated with tamoxifen efficacy, but these findings need replication.

A major side effect of aromatase inhibitor (AI) therapy is AI-related arthralgia (AIA), which often leads to therapy discontinuation. We aimed to identify genetic variants associated with AIA and therapy discontinuation in the first year of AI treatment. Our prospective cohort study included 343 postmenopausal women with early breast cancer starting AI therapy. Single nucleotide polymorphisms (SNPs) in candidate genes involved in estrogen and vitamin D signaling were selected. Univariate and multivariate linear/logistic regressions were fitted in order to asses the association between studied SNPs and AIA intensity (visual analogic scale score) at 3 and 12 months of follow-up, worsening pain, and therapy discontinuation. We also tested for a priori-defined interactions by introducing multiplicative terms in the regression equations. SNPs in CYP17A1 and VDR genes appeared significantly associated with AIA (P = 0.003, P = 0.012, respectively). One SNP in CYP27B1 gene was related to therapy discontinuation [P = 0.02; OR 0.29 (0.09-0.99)]. We revealed interactions between CYP27B1 and both CYP17A1 (P = 0.01) and VDR SNPs (P = 0.06). Furthermore, an additive effect on pain intensity was shown for unfavorable alleles, with two points higher mean absolute pain increase and up to 5.3-fold higher risk of worsening pain compared to favorable genotypes. SNPs in CYP17A1, VDR, and CYP27B1 genes predict the risk of AIA. Their determination would be useful to trigger the monitoring strategies in women at risk of therapy discontinuation.

Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual subclinical ovarian estrogen production), and those with chemotherapy-induced menopause who may experience return of ovarian function. In these situations tamoxifen may be preferable to an aromatase inhibitor. Among 4,922 patients allocated to the monotherapy arms (5 years of letrozole or tamoxifen) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤ 55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither of the subpopulations examined showed treatment effects differing from the trial population as a whole (interaction P values are 0.23 and 0.62, respectively). Indeed, both among the 641 patients aged ≤ 55 years with natural menopause and no chemotherapy (HR 0.77 [0.51, 1.16]) and among the 105 patients with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients.

Aromatase inhibitors (AIs) have become the standard adjuvant therapy of postmenopausal breast cancer survivors. AIs induce a reduction of bioavailable estrogens by inhibiting aromatase, which would be expected to induce alterations in body composition, more extensive than induced by menopause. The objectives are to examine the impact of AIs on (1) DXA-scan derived body composition and (2) gonadal hormone levels. This is a sub-analysis of a 2-year double-blind, placebo-controlled, randomized trial of 82 women with nonmetastatic breast cancer, newly menopausal following chemotherapy, who were randomized to risedronate (35 mg once weekly) versus placebo, and stratified for their usage of AI versus no AI. Outcomes included DXA-scan derived body composition and gonadal hormone levels. As a group, total body mass increased in women over 24 months. Women on AIs gained a significant amount of lean body mass compared to baseline as well as to no-AI users (P < 0.05). Women not on an AI gained total body fat compared to baseline and AI users (P < 0.05). Free testosterone significantly increased and sex hormone binding globulin (SHBG) significantly decreased in women on AIs compared to no AIs at 24 months (P < 0.01) while total estradiol and testosterone levels remained stable. Independent of AI usage, chemotherapy-induced postmenopausal breast cancer patients demonstrated an increase of total body mass. AI users demonstrated maintenance of total body fat, an increase in lean body mass and free testosterone levels, and a decrease in SHBG levels compared to no-AI users. The mechanisms and implications of these changes need to be studied further.

We evaluated the use of sorafenib to overcome resistance to aromatase inhibitors (AIs) in patients with metastatic breast cancer who had disease recurrence or progression while on AIs. We performed a multi-institution phase I/II study of sorafenib and anastrozole 1 mg daily in 35 postmenopausal females with hormone receptor positive metastatic breast cancer resistant to AIs. Primary objectives were to determine the dose of sorafenib in conjunction with anastrozole and the clinical benefit rate (CBR) (complete response [CR], partial response [PR], or stable disease [SD] ≥ 24 weeks). Secondary objectives were to determine toxicity and to evaluate if response was associated with change in number of circulating endothelial cells or circulating endothelial progenitor cells. Based on the phase I portion, sorafenib 400 mg twice daily was selected as the phase II dose. Among 35 patients, 7 had SD ≥ 24 weeks, 1 had PR ≥ 24 weeks, and 14 had progressive disease (PD) ≤ 24 weeks, corresponding to a CBR of 23%. The most common adverse events (all; Grade 3/4) were fatigue (66%; 17%), diarrhea (63%; 6%), nausea (60%; 9%), and hand-foot syndrome (57%; 34%). Dose reduction occurred in 77% of the patients and 31% came off study due to toxicity. The combination of sorafenib and anastrozole demonstrated a 23% CBR in patients with hormone receptor positive, AI-resistant metastatic breast cancer, which may be attributable to the restoration of sensitivity to AIs. Toxicities occurred frequently resulting in a high rate of discontinuation.

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.

Endothelin-1 (ET-1) and endothelin A receptor (ETAR) contribute to the development and progression of breast carcinomas by modulating cell proliferation, angiogenesis, and anti-apoptosis. We investigated antitumoral effects of the specific ETAR antagonist ZD4054 in breast cancer cells and xenografts, and assessed antitumoral efficacy of the combinations of ZD4054 with aromatase inhibitors and fulvestrant. Gene expression changes were assessed by quantitative real-time PCR. Cell proliferation was measured using alamarBlue; migration and invasion assays were performed using modified Boyden chambers. Evaluating the antitumoral efficacy of ZD4054 in vivo, different breast cancer models were employed using nude mice xenografts. ZD4054 reduced ET-1 and ETAR expression in MCF-7, MDA-MB-231, and MDA-MB-468 breast cancer cells in a concentration-dependent manner. ZD4054 inhibited invasion by up to 37.1% (P = 0.022). Combinations of ZD4054 with either anastrozole or letrozole produced significant reductions in migration of aromatase-overexpressing MCF-7aro cells (P < 0.05). Combination of ZD4054 with fulvestrant reduced MCF-7 cell migration and invasion by 36.0% (P = 0.027) and 56.7% (P < 0.001), respectively, with effects significantly exceeding those seen with either compound alone. Regarding tumor volume reduction in vivo, ZD4054 (10 mg/kg) was equipotent to fulvestrant (200 mg/kg) and exhibited additive effects with anastrozole (0.5 mg/kg). These data are the first indicating that selective ETAR antagonism by ZD4054 displays antitumoral activity on breast cancer cells in vitro and in vivo. Our data strongly support a rationale for the clinical use of ZD4054 in combination with endocrine therapies.

Background: Decrement of endometrial thickness was recorded following short-term aromatase inhibitor treatment in breast cancer patients previously treated with tamoxifen. It is necessary to verify if long-term aromatase inhibitor treatment can maintain this phenomenon., Methods: Prospective long-term comparison of the last ultrasonographic endometrial thickness measurement taken before discontinuation of long-term tamoxifen treatment in 64 postmenopausal breast cancer patients, with further repeated measurements, performed following administration of aromatase inhibitors., Results: There was a significant decrement of endometrial thickness, following 36.5 +/- 15.7 months of tamoxifen treatment, from a mean value of 8.7 +/- 5.2 mm, measured at the last ultrasonographic measurement performed before discontinuation of tamoxifen treatment, down to a mean value of 6.2 +/- 4.6 mm, measured following 5.3 +/- 4.8 months of aromatase inhibitor therapy (P < 0.001). Further ultrasonographic studies revealed the same significant trend. In the first ultrasonographic study performed during aromatase inhibitor treatment, five (7.8%) patients demonstrated a significant increase of endometrial thickness. Hysteroscopy revealed a benign endometrial polyp in three patients and atrophic endometrium in the other 2. In 35 patients (54.7%), endometrial thickness was reduced following the administration of aromatase inhibitors and in 24 patients (37.5%) there was no change in endometrial thickness. With longer duration of aromatase inhibitor therapy, more patients showed decrement of endometrial thickness., Conclusions: Reversal of endometrial thickening induced by long-term tamoxifen treatment in postmenopausal breast cancer patients is maintained throughout long-term aromatase inhibitor treatment.

Oestrogens play important roles in the natural history of breast cancer. Consequently, therapies have been developed to reduce oestrogen levels or to block signalling through oestrogen receptors (ER). These therapies include tamoxifen, selective oestrogen receptor modulators (SERMs), aromatase inhibitors (AIs) and selective oestrogen receptor downregulators (SERDs). All have proven clinical efficacy in postmenopausal women with ER-positive breast cancer and can be effective in the neoadjuvant and adjuvant settings, and in the management of advanced disease. This range of endocrine therapies offers the opportunity for prolonging benefit from treatment and delaying tumour recurrence/progression by combining the different classes of drugs or by using them sequentially. Evaluation of the potential clinical benefits of concomitant or sequential endocrine therapies should be based on considerations of efficacy and safety profiles, mechanisms of action/resistance and effects on tumour biology. Evidence from preclinical models and from randomized clinical trials in patients with postmenopausal breast cancer suggests that concomitant endocrine therapies are no more effective than AIs alone. However, using AIs either as initial therapy or sequentially after tamoxifen appears to produce more benefits beyond the use of tamoxifen alone.Currently, there are no proven algorithms for the planned, sequential use of the full range of endocrine therapies, particularly for the majority of patients who present with early breast cancer. Prospective, randomized clinical trials are needed to determine the best use of therapies in particular settings, taking into account the spectrum of molecular phenotypes in different tumours.

Background: Adjuvant Anastrozole (ANA) for 5 years and Tamoxifen followed by Exemestane (TAM-EXE) for 2.5 years each have become acceptable alternatives to 5 years of Tamoxifen (TAM) for post-menopausal women with breast cancer. As these newer options are associated with higher drug costs as well as improved outcomes, an economic evaluation was undertaken to compare the cost-utility of ANA and TAM-EXE relative to TAM alone and to each other in terms of cost per quality-adjusted life year (QALY) gained., Methods: A Markov model was developed to calculate monthly costs and outcomes in a hypothetical cohort of post-menopausal women with early-stage breast cancer. Baseline rates of cancer recurrence and adverse effects with TAM, and hazard ratios associated with ANA and EXE, were derived from the ATAC and IES trials. Patients received hormonal therapy for 5 years and benefit was modeled to persist 5 years beyond treatment. The analysis took a direct payer perspective with a 20-year time horizon. Costs and outcomes were discounted by 3%. Costs are in 2005 Canadian dollars., Results: ANA and TAM-EXE were associated with increased costs and QALYs, though the cost-utility of both relative to TAM alone was strongly favourable (<$50,000/QALY). Based on an indirect comparison of ANA and TAM-EXE, using TAM alone as a common comparator, the cost-utility of ANA relative to TAM-EXE appears unfavourable., Conclusions: Both upfront and sequential AI options were cost-effective alternatives to TAM alone, but TAM-EXE appears to be the economically preferred AI option based on its more favourable cost-utility versus ANA.

Because estrogen contributes to the promotion and progression of breast cancer, a greater understanding of the role of estrogen in breast cancer has led to therapeutic strategies targeting estrogen synthesis, the estrogen receptor, and intracellular signaling pathways. The enzyme aromatase catalyses the final step in estrogen biosynthesis and was identified as an attractive target for selective inhibition. Modern third-generation aromatase inhibitors (AIs) effectively block the production of estrogen without exerting effects on other steroidogenic pathways. The discovery of letrozole (Femara) achieved the goal of discovering a highly potent and totally selective AI. Letrozole has greater potency than other AIs, including anastrozole, exemestane, formestane, and aminoglutethimide. Moreover, letrozole produces near complete inhibition of aromatase in peripheral tissues and is associated with greater suppression of estrogen than is achieved with other AIs. The potent anti-tumor effects of letrozole were demonstrated in several animal models. Studies with MCF-7Ca xenografts successfully predicted that letrozole would be clinically superior to the previous gold standard tamoxifen and also indicated that it may be more effective than other AIs. An extensive program of randomized clinical trials has demonstrated the clinical benefits of letrozole across the spectrum of hormone-responsive breast cancer in postmenopausal women.

Long-term estrogen deprivation treatment for breast cancer can, in some patients, lead to the activation of alternate cellular pathways, resulting in the re-emergence of the disease. This is a distressing scenario for oncologists and patients, but recent intensive molecular and biochemical studies are beginning to unravel these pathways, revealing opportunities for new targeted treatments. Far from making present therapies redundant, these new discoveries open the door to novel combination therapies that promise to provide enhanced efficacy or overcome treatment resistance. Letrozole, one of the most potent aromatase inhibitors, is the ideal candidate for combination therapy; indeed, it is one of the most intensively studied aromatase inhibitors in the evolving combinatorial setting. Complementary to the use of combination therapy is the development of molecular tools to identify patients who will benefit the most from these new treatments. Microarray gene profiling studies, designed to detect letrozole-responsive targets, are currently under way to understand how the use of the drug can be tailored more efficiently to specific patient needs.

Relapse after completing adjuvant tamoxifen therapy is a persistent threat for women with hormone-responsive breast cancer. Third-generation aromatase inhibitors, such as letrozole, provide a new option for extended adjuvant hormonal therapy after 5 years of tamoxifen. MA.17 was conducted to determine whether letrozole improves outcome after discontinuation of tamoxifen. Postmenopausal women with hormone receptor-positive breast cancer (N=5,187) were randomized to letrozole 2.5 mg or placebo once daily for 5 years. At a median follow-up of 30 months, letrozole significantly improved disease-free survival (DFS; P<0.001), the primary end point, compared with placebo (hazard ratio [HR] for recurrence or contralateral breast cancer 0.58; 95% confidence interval [CI] 0.45, 0.76] P<0.001). Furthermore, letrozole significantly improved distant DFS (HR=0.60; 95% CI 0.43, 0.84; P=0.002) and, in women with node-positive tumors, overall survival (HR=0.61; 95% CI 0.38, 0.98; P=0.04). Clinical benefits, including an overall survival advantage, were also seen in women who crossed over from placebo to letrozole after unblinding, indicating that tumors remain sensitive to hormone therapy despite a prolonged period since discontinuation of tamoxifen. The efficacy and safety of letrozole therapy beyond 5 years is being assessed in a re-randomization study, following the emergence of new data suggesting that clinical benefit correlates with the duration of letrozole. MA.17 showed that letrozole is extremely well-tolerated relative to placebo. Letrozole should be considered for all women completing tamoxifen; new results from the post-unblinding analysis suggest that letrozole treatment should also be considered for all disease-free women for periods up to 5 years following completion of adjuvant tamoxifen.

Neoadjuvant chemotherapy trials have consistently reported lower response rates in hormone receptor-positive (HR+) breast cancer when compared with HR- cases. Preoperative endocrine therapy has therefore become a logical alternative and has gained considerable momentum from the finding that aromatase inhibitors (AIs) are more effective than tamoxifen for HR+ breast cancer in both the neoadjuvant and adjuvant settings. The most convincing neoadjuvant trial to demonstrate the superiority of an AI versus tamoxifen was the P024 study, a large multinational double-blind trial in postmenopausal women with HR+ breast cancer ineligible for breast-conserving surgery. The overall response rate (ORR) was 55% for letrozole and 36% for tamoxifen (P<0.001). Significantly more letrozole-treated patients underwent breast-conserving surgery (45 vs. 35%, respectively; P=0.022). In addition, ORR was significantly higher with letrozole than tamoxifen in the human epidermal growth factor receptor HER1/HER2+ subgroup (P=0.0004). The clinical efficacy of letrozole in HER2+ breast cancer was confirmed by fluorescent in situ hybridization analysis and was found to be comparable to that of HER2- cases (ORR 71% in both subsets). Biomarker studies confirmed the superiority of letrozole in centrally assessed estrogen receptor-positive (ER+) tumors and found a strong relationship with the degree of ER positivity for both agents. Interestingly, letrozole was effective even in marginally ER+ tumors and, unlike tamoxifen, consistently reduced the expression from estrogen-regulated genes (progesterone receptor and trefoil factor 1). Furthermore, when analyzed by Ki67 immunohistochemistry, letrozole was significantly more effective than tamoxifen in reducing tumor proliferation (P=0.0009). Thus, neoadjuvant letrozole is safe and superior to tamoxifen in the treatment of postmenopausal women with HR+ locally advanced breast cancer.

Purpose: MA.17 was a double-blind placebo-controlled trial involving 5187 postmenopausal women that established letrozole to be of value in reducing recurrence of breast cancer when given in the extended adjuvant therapy setting after about 5 years of tamoxifen. Analyses were conducted to examine the relationships between duration of treatment on MA.17 and outcomes., Methods: The final MA.17 database that included all events up to the date of unblinding of the study was interrogated. A non-parametric kernel smoothing method was used to estimate the hazard rates for disease-free survival (DFS), distant DFS (DDFS) and overall survival (OS) at 6, 12, 24, 36 and 48 months of follow-up and the hazard ratios (HRs) of letrozole to placebo were determined. The trend in HRs over time was tested based on a Cox model with a time-dependent covariate., Results: Considering all patients, HRs for events in DFS and DDFS progressively decreased over time, favoring letrozole, with the trend being significant (p < 0.0001 and p = 0.0013, respectively) whereas the trend for OS was not significant. Considering the 2360 patients with node-positive status, the HRs for DFS, DDFS and OS all decreased over time with tests for trend all showing significance (p = 0.0004, 0.0005 and 0.038, respectively). Considering the 2568 patients with node-negative status, the HRs for DFS decreased over time with the test for trend being significant (p = 0.027) whereas the HRs for DDFS and OS showed no significant change over time., Conclusion: These analyses suggest that, at least out to about 48 months, longer duration of letrozole treatment is associated with greater benefit in the extended adjuvant therapy setting.

Introduction: Long-term endocrine therapy for breast cancer may have clinical implications as drugs that potentially alter the lipid profile may increase the risk of developing cardiovascular disease. In this study, a companion sub-protocol to the TEAM (Tamoxifen and Exemestane Adjuvant Multicenter) International trial, we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of postmenopausal women with early breast cancer in the adjuvant setting to that of tamoxifen., Patients and Methods: In this open-label, randomized, parallel group study, 176 postmenopausal patients with estrogen and/or progesterone receptor positive early breast cancer were randomized to either adjuvant exemestane (25 mg/day; n = 90) or tamoxifen (20 mg/day; n = 86). Assessments of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and serum triglycerides (TRG) were performed at baseline and every 3 months for the first 12 months., Results: Serum triglyceride levels were consistently increased above baseline throughout the study in the tamoxifen arm, while there was a trend towards reduction in the exemestane arm. There was also an overall trend for tamoxifen to decrease the levels of LDL throughout the study period. Exemestane did not demonstrate any other significant change in HDL levels; however, there was a consistent trend for a reduction in total cholesterol in both treatment arms. The atherogenic risk determined by the TC:HDL ratio remained stable in both arms throughout the treatment period., Conclusions: Exemestane appears to have a neutral effect on total cholesterol and HDL levels. Unlike tamoxifen's positive effect on LDL levels, exemestane does not significantly alter LDL levels. Tamoxifen on the other hand increases triglyceride levels, while exemestane results in a beneficial reduction in TRG levels. These data offer additional information with regard to the safety and tolerability of exemestane in postmenopausal breast cancer patients and support further investigation of its potential usefulness in the adjuvant setting.