Third-generation Aromatase Inhibitors Research Articles

Steroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1.

Use of aromatase inhibitors (AIs), exemestane, letrozole and anastrozole, for breast cancer therapy is associated with severe pain symptoms, the underlying mechanism of which is unknown. The electrophilic nature of AIs suggests that they may target the transient receptor potential ankyrin 1 (TRPA1) channel, a major pathway in pain transmission and neurogenic inflammation. AIs evoke TRPA1-mediated calcium response and current in rodent nociceptors and human cells expressing the recombinant channel. In mice, AIs produce acute nociception, which is exaggerated by pre-exposure to proalgesic stimuli, and, by releasing sensory neuropeptides, neurogenic inflammation in peripheral tissues. AIs also evoke mechanical allodynia and decreased grip strength, which do not undergo desensitization on prolonged AI administration. These effects are markedly attenuated by TRPA1 pharmacological blockade or in TRPA1-deficient mice. TRPA1 is a major mediator of the proinflammatory/proalgesic actions of AIs, thus suggesting TRPA1 antagonists for the treatment of pain symptoms associated with AI use.

Potential role of aromatase inhibitors in the treatment of endometriosis.

Endometriosis is an estrogen-dependent chronic inflammatory disease affecting 5%–10% of reproductive-age women, with a prevalence of 5%–50% in infertile women and >33% of women with chronic pelvic pain. Third-generation aromatase inhibitors (AIs) are approved adjuvants for the treatment of estrogen receptor-positive breast cancer. Molecular studies have revealed the presence of aromatase P450, the key enzyme in the biosynthesis of ovarian estradiol, inside the endometriotic tissue, indicating local synthesis of estradiol. Thereby, AIs represent an appealing medical option for the management of different aspects of this enigmatic disease, especially pelvic pain and infertility. Accordingly, this review aims to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms, mainly pain and infertility. Notably, several studies have demonstrated that the combination of AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin-releasing hormone analogs can be used to control endometriosis-associated pain and pain recurrence in premenopausal women, particularly those with pain due to rectovaginal endometriosis refractory to other medical or surgical treatment. Some case reports have shown promising results in the treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. Third-generation AIs, especially letrozole, have challenged clomiphene citrate as an ovulation-induction agent in patients with polycystic ovary syndrome and in cases of unexplained infertility. However, few studies are available regarding the use of AIs to treat endometriosis-associated infertility. Therefore, larger multicenter randomized trials using AIs for the treatment of endometriosis-associated infertility are needed to clarify its effect. The safety of AIs for ovulation induction or superovulation has generated a lively discussion. Data from recent retrospective and prospective studies have supported its safety.

Aromatase inhibitors in the breast cancer clinic: focus on exemestane

Breast cancer is the most prevalent type of cancer in women and responsible for significant female cancer-related mortality worldwide. In the Western world, over 80% of breast cancers are hormone-receptor positive for which endocrine therapy is administered. The main anti-estrogen treatments in use consist of selective estrogen-receptor modulators, such as tamoxifen, and third-generation aromatase inhibitors (AIs), such as exemestane, letrozole, and anastrozole. In this review, the focus will lie on exemestane, its clinical use, and its side-effect profile. Exemestane is the only third-generation steroidal AI. Its efficacy as a first-line treatment in metastatic breast cancer has been demonstrated. Therefore, exemestane could be considered a valid first-line therapeutic option, but it also can be used in second-line or further situations. Exemestane is mostly used as part of sequential adjuvant treatment following tamoxifen, but in this setting it is also active in monotherapy. Furthermore, this AI has been studied in the neoadjuvant setting as presurgical treatment, and even as chemoprevention in high-risk healthy postmenopausal women. It may reverse side effects of tamoxifen, such as endometrial changes and thromboembolic disease but may also cause some inconvenient side effects itself. Additionally, there is a lack of total cross-resistance between exemestane and nonsteroidal AIs as far as their anti-tumoral efficacy is concerned; moreover the two classes of AIs display a nontotal overlapping toxicity profile. Taking together, exemestane can be considered as a useful treatment option at all stages of breast cancer.

Aromatase inhibitor letrozole downregulates steroid receptor coactivator-1 in specific brain regions that primarily related to memory, neuroendocrine and integration

As one of the third generation of aromatase inhibitors, letrozole is a favored drug for the treatment of hormone receptor-positive breast cancer with some adverse effects on the nervous system, but the knowledge is limited and the results are controversial, the mechanism underlying its central action is also unclear. Accumulated evidences have demonstrated that estrogens derived from androgens by aromatase play profound roles in the brain through their receptors, which needs coactivator for the transcription regulation, among which steroid receptor coactivator-1 (SRC-1) has been shown to be multifunctional potentials in the brain, but whether it is regulated by letrozole is currently unknown. In this study, we examined letrozole regulation on SRC-1 expression in adult mice brain using immunohistochemistry. The results showed that letrozole induced dramatic decrease of SRC-1 in the medial septal, hippocampus, medial habenular nucleus, arcuate hypothalamic nucleus and superior colliculus (p<0.01). Significant decrease was detected in the dorsal lateral septal nucleus, bed nucleus of stria terminalis, ventral taenia tecta, dorsomedial and ventromedial hypothalamic nuclei, dorsomedial periaqueductal gray, superior paraolivary nucleus and pontine nucleus (p<0.05). In the hippocampus, levels of estradiol content, androgen receptor, estrogen receptor α and β also decreased significantly after letrozole injection. The above results demonstrated letrozole downregulation of SRC-1 in specific regions that are primarily related to learning and memory, cognition and mood, neuroendocrine as well as information integration, indicating that SRC-1 may be one important downstream central target of letrozole. Furthermore, these potential central adverse effects of letrozole should be taken into serious considerations.

Long-term complete remission of metastatic breast cancer induced by a steroidal aromatase inhibitor after failure of a non-steroidal aromatase inhibitor

Patient: Female, 56Final Diagnosis: Breast cancerSymptoms: Solid mass in the right breastMedication: ExemestaneClinical Procedure: —Specialty: OncologyObjective:Unusual clinical courseBackground:The efficacy of third-generation aromatase inhibitors for hormone receptor-positive postmenopausal metastatic breast cancer is well established. Although several clinical trials have reported incomplete cross-resistance between different aromatase inhibitors, few cases of complete responses of recurrent metastatic breast cancer occurring after substituting a second aromatase inhibitor have been reported. We here present a rare case of non-steroidal aromatase inhibitor-tolerant metastatic breast cancer with long-term complete remission following substitution of a steroidal aromatase inhibitor.Case Report:We present the case of a 56-year-old Japanese woman who underwent right breast-conserving surgery for breast cancer, TNM staging T1, N0, M0, Stage I. She received adjuvant chemotherapy with 6 cycles of FEC100 and radiation therapy, and then began hormonal therapy with anastrozole. Twelve months postoperatively, computed tomography (CT) revealed multiple lung metastases. Exemestane was substituted for anastrozole. After 3 months of exemestane, CT showed that all lung metastases had completely resolved. Her complete response was maintained for 5 years: she died during a tsunami 6 years after the initial surgery.Conclusions:Substitution of a steroidal for a non-steroidal aromatase inhibitor produced a sustained complete remission in a patient with hormonal receptor-positive postmenopausal recurrent breast cancer.Achieving complete response after switching from a non-steroidal to a steroidal aromatase inhibitor in a hormonal receptor-positive postmenopausal recurrent breast cancer contributed to a higher quality of life for the patient. Further investigation is needed to identify the predictors of long-term remission following such a switch.

Validation of QuickDASH Outcome Measure in Breast Cancer Survivors for Upper Extremity Disability

ObjectiveTo validate the QuickDASH as a patient-reported outcome measure for assessing upper extremity disability in breast cancer survivors. DesignLarge cross-sectional survey. SettingAmbulatory care center at a university hospital. ParticipantsPostmenopausal women (N=150) with stage I to III hormone receptor–positive breast cancer currently taking a third-generation aromatase inhibitor. InterventionsNot applicable. Main Outcome MeasureQuickDASH, an 11-item self-administered questionnaire, assesses global arm function over the past 7 days. ResultsOf 150 surveys, 148 (99%) were scorable. The factor analysis demonstrated 1 factor with an eigenvalue of 6.7, which explains 61% of variance. The score was reliable with a Cronbach alpha of .93. The test-retest reliability was .78 over 2 weeks. The mean QuickDASH score ± SD for all patients was 19±19. Those with upper extremity arthralgias reported higher QuickDASH scores than controls without pain (26 vs 12, P=.001). Those with frozen shoulder pain also reported higher QuickDASH scores than controls without pain (37 vs 15, P=.001). ConclusionsThe QuickDASH instrument is a convenient, reliable, and valid patient-reported outcome measure to assess upper extremity disability in patients with breast cancer.

Haplotype structures and functional polymorphic variants of the drug target enzyme aromatase (CYP19A1) in South Indian population

CYP19A1 gene product aromatase (CYP19A1) is a 58-kDa protein and belongs to the member of the cytochrome P450 superfamily, which facilitates the bioconversion of estrogens from androgens. Single-nucleotide polymorphisms (SNPs) of CYP19A1 affect the activity of the enzyme and have been implicated in the association of estrogen-dependent disease, prognosis, therapeutic efficacy, and toxicity of third-generation aromatase inhibitors (AIs). Based on ethnicity, the frequency distribution of CYP19A1 alleles will differ, and until now, no data are available for Indians. Using qRT-PCR with TaqMan assays, the frequencies of functionally important polymorphic variants of CYP19A1 gene were determined in 163 healthy subjects of South Indian origin. The observed frequencies of the CYP19A1 minor alleles for the SNPs rs4646 (T), rs10046 (T), rs700519 (T), rs700518 (G), rs727479 (G), rs4775936 (T), rs10459592 (G), rs749292 (A), rs6493497 (T), and rs7176005 (A) are 41.1 (35.8-46.4), 20.0 (15.6-24.3), 33.7 (28.6-38.9), 17.8 (13.6-21.9), 25.8 (21.0-30.5), 19.9 (15.6-24.3), 33.7 (28.6-38.9), 24.9 (20.2-29.5), 35.9 (30.7-41.1), and 35.9 (30.7-41.1), respectively. Strong linkage disequilibrium existed between CYP19A1 SNPs, and sixteen different haplotype structures with a frequency >1% were derived from all the 10 SNPs tested. The most common being the haplotype (H1) GCTATCTGTG with a frequency of about 17.8%. Gender-specific assessment showed significant difference in the allele frequency for rs749292 (p < 0.04), and greater inter-ethnic variation was detected in the distribution of CYP19A1 variants except for rs727479. Our results could provide preliminary insight for further pharmacogenetic investigations of AIs as well as for subsequent molecular epidemiological studies on the contribution of these variants to the occurrence and development of estrogen-dependent disease in South Indians.

Steroidal aromatase inhibitors inhibit growth of hormone-dependent breast cancer cells by inducing cell cycle arrest and apoptosis

Different hormonal therapies are used for estrogen receptor positive (ER(+)) breast cancers, being the third-generation of aromatase inhibitors (AIs), an effective alternative to the classical tamoxifen. AIs inhibit the enzyme aromatase, which is responsible for catalyzing the conversion of androgens to estrogens. In this study, it was evaluated the effects of several steroidal AIs, namely 3β-hydroxyandrost-4-en-17-one (1), androst-4-en-17-one (12), 4α,5α-epoxyandrostan-17-one (13a) and 5α-androst-2-en-17-one (16), on cell proliferation, cell cycle progression and cell death in an ER(+) aromatase-overexpressing human breast cancer cell line (MCF-7aro). All AIs induced a decrease in cell proliferation and these anti-proliferative effects were due to a disruption in cell cycle progression and cell death, by apoptosis. AIs 1 and 16 caused cell cycle arrest in G0/G1, while AIs 12 and 13a induced an arrest in G2/M. Moreover, it was observed that these AIs induced apoptosis by different pathways, since AIs 1, 12 and 13a activated the apoptotic mitochondrial pathway, while AI 16 induced apoptosis through activation of caspase-8. These results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer cells and will also highlight the importance of AIs as inducers of apoptosis in hormone-dependent breast cancers.

The pharmacokinetics of letrozole in brain and brain tumor in rats with orthotopically implanted C6 glioma, assessed using intracerebral microdialysis

Emerging evidence suggests that primary and metastatic brain tumors may be sensitive to hormonal manipulations. However, the pharmacokinetics of compounds against such targets in the brain and, more importantly, in the brain tumor are not well characterized. Here, we investigated the pharmacokinetics of letrozole, a third-generation aromatase inhibitor, in the normal brain and in orthotopically implanted C6 glioma in Sprague-Dawley rats. Intracerebral microdialysis was employed to determine the concentrations of unbound letrozole in the brain extracellular fluid (ECF) while simultaneously collecting blood samples (via jugular vein) to assess plasma levels of letrozole. Letrozole was administered intravenously at doses of 4, 6, 8 and 12mg/kg, and ECF and blood samples were collected over 8h. For assessing normal versus tumoral brain pharmacokinetics, letrozole (4 or 8mg/Kg; i.v.) was administered 10days after implantation of C6 glioma in the brain. Dual-probe intracerebral microdialysis was employed for assessing ECF samples from tumor-free and tumor-bearing regions of the brain. Normal brain ECF and plasma C max and AUC0-8h increased linearly with letrozole doses up to 8mg/kg dose, but at 12mg/kg, the pharmacokinetics were nonlinear. The relative brain distribution coefficients, AUCECF/AUCplasma (ub), were 0.3-0.98. The tumoral uptake of letrozole was 1.5- to 2-fold higher relative to tumor-free region. Thus, letrozole permeability across the blood brain barrier is high, and the exposure to the brain is dose dependent. Furthermore, the brain tumoral letrozole levels are markedly higher than those in the tumor-free regions, which underscore potential selectivity of its activity against tumor cells.

Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER (+) breast cancer

PurposePolymorphisms in the CYP19A1 (aromatase) gene have been reported to influence disease-free survival and the incidence of musculoskeletal complaints in patients taking aromatase inhibitors (AIs) for estrogen receptor positive (ER+) breast cancer. Bone loss and fractures are well-recognized complications from AI therapy. The objective of this study is to determine the influence of polymorphisms in the CYP19A1 gene on bone loss among patients taking aromatase inhibitors for ER+ breast cancer. Patients and methodsThe subjects consisted of 97 postmenopausal women with ER+ breast cancer who were initiated on third-generation AIs. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at baseline and at 6 and 12months. Twenty-four hour urine N-telopeptide (NTX) was measured by Elisa and serum estradiol was measured by ultrasensitive radioimmunoassay at baseline, and at 6months. Genotyping was done by Taqman SNP allelic discrimination assay. ResultsWomen with the AA genotype for the rs700518 (G/A at Val80) developed significant bone loss at the lumbar spine and the total hip at 12months relative to patients carrying the G allele (GA/GG); both p=0.03. There was a borderline greater increase in urinary NTX in those with the AA genotype compared to patients with the G allele, p=0.05; but no significant difference in changes in estradiol levels among the genotypes. ConclusionPatients with the AA genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for AI-associated bone loss and deserve close follow-up during long-term AI therapy.

Treatment Algorithms for Hormone Receptor-Positive Advanced Breast Cancer: Applying the Results from Recent Clinical Trials into Daily Practice—Insights, Limitations, and Moving Forward

Hormone receptor-positive (HR+) breast cancer is the most prevalent subtype of breast cancer in both early- and advanced-stage disease. Thus, the treatment of HR+ breast cancer has had the greatest global influence in improving clinical outcomes overall. Although the first-line metastatic breast cancer (MBC) trials comparing a third-generation aromatase inhibitor (AI) to tamoxifen have favored the AI, one of the challenges in translating these findings into clinical practice stems from the influence of prior adjuvant endocrine therapy, particularly the increasing use of adjuvant AIs today, on the choice of endocrine agent in the advanced setting because of the development of acquired resistance. Because the majority of patients enrolled into these studies were either endocrine-treatment naïve or exposed to tamoxifen only, the "real-life" applicability of the evidence is unclear. Because a superior dose of the selective estrogen receptor (ER) downregulator fulvestrant has now been established, its role as first-line therapy is being re-established. We are now starting to see the promise realized with blocking cross-talking growth factor pathways in addition to the ER pathway. The greatest efficacy is seen with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with exemestane and, perhaps to a lesser extent, anti-HER2-directed therapy in combination with an AI. Future gains will likely involve a greater understanding of the redundancy and compensation induced by blocking these pathways, trials involving blocking multiple pathways in addition to hormonal agents, and the molecular interrogation of the individual's tumor in search of predictive biomarkers and "actionable" genomic aberrations.

Potential Role ofUGT1A4Promoter SNPs in Anastrozole Pharmacogenomics

Anastrozole belongs to the nonsteroidal triazole-derivative group of aromatase inhibitors. Recently, clinical trials demonstrated improved antitumoral efficacy and a favorable toxicity with third-generation aromatase inhibitors, compared with tamoxifen. Anastrozole is predominantly metabolized by phase I oxidation with the potential for further phase II glucuronidation. It also, however, is subject to direct N-glucuronidation by UDP-glucuronosyltransferase 1A4 (UGT1A4). Anastrozole pharmacokinetics vary widely among patients, but pharmacogenomic studies of patients treated with anastrozole are sparse. In this study, we examined individual variability in the glucuronidation of anastrozole and its association with UGT1A4 promoter and coding region polymorphisms. In vitro assays using liver microsomal preparations from individual subjects (n = 96) demonstrated 235-fold variability in anastrozole glucuronidation. Anastrozole glucuronidation was correlated (r = 0.99; P < 0.0001) with lamotrigine glucuronidation (a diagnostic substrate for UGT1A4) and with UGT1A4 mRNA expression levels in human liver microsomes (r = 0.99; P < 0.0001). Recombinant UGT1A4 catalyzed anastrozole glucuronidation, which was inhibited by hecogenin (IC50 = 15 µM), a UGT1A4 specific inhibitor. The promoter region of UGT1A4 is polymorphic, and compared with those homozygous for the common allele, lower enzymatic activity was observed in microsomes from individuals heterozygous for -163G<A, -219T<G, and -217C<T (P = 0.009, P = 0.014, and P = 0.009, respectively). These results indicate that variability in glucuronidation could contribute to response to anastrozole in the treatment of breast cancer.

Treatment of Estrogen Receptor-Positive Breast Cancer

Estrogen receptor (ER) expression is the main indicator of potential responses to endocrine therapy (ET), and approximately 70% of human breast cancers (BCs) are hormone-dependent and ER-positive. The introduction of adjuvant systemic therapy led to a significant improvement in post-surgical survival and a reduction in disease relapse, especially in women with early BC and those with ER+ tumors, who may receive ET alone or in combination with cytotoxic therapy. Adjuvant ET currently consists of (i) ovarian suppression, (ii) selective estrogen receptor modulators (SERMs) and down-regulators, and (iii) aromatase inhibitors (AIs). In patients with ER+ tumors pharmacologic ovary suppression with gonadotropin-releasing hormone agonists in combination with standard adjuvant therapy is generally more effective than adjuvant chemotherapy alone. Tamoxifen is the best established SERM, has favorable effects on BC control and bone metabolism, but also has adverse effects due to its estrogenic activity in other tissues. For these reasons, other SERMs have been developed. Fulvestrant is an ER down-regulator with several potential advantages over SERMs, including a 100-fold increase in its affinity for ER compared with tamoxifen and no estrogen-like activity in the uterus. The inhibition of the aromatase system with third-generation AIs is associated with improved survival in patients with advanced BC compared with SERMs. In postmenopausal patients with ER+ BC adjuvant treatment with AIs should be performed, either as sequential treatment after tamoxifen or as upfront therapy. Studies evaluating the role of AIs as first-line therapy are ongoing and the results are encouraging.

Effect of letrozole on endometrosis and apoptosis of ectopic endometrial cells in rats

To investigate the therapeutic mechanism of letrozole, the third-generation aromatase inhibitor, on endometriotic lesions in a rat model and its effect on the apoptosis of ectopic endometrial cells. Endometriosis was induced by autotransplanting pieces of uterus onto the peritoneum in rats. The rats with successful ectopic implants were divided into 2 groups: A letrozole group (n=15) and a control group (n=15). The volume, appearance, and histopathology of ectopic implant were determined before and after the treatment. Expression of P450arom, COX-2, bcl-2, and bax in the ectopic implant was detected by immunohistochemistry and RT-PCR in the 2 groups. The volume of ectopic implant in the letrozole group was significantly reduced compared with the control group (P<0.05). The protein and mRNA levels of P450arom and COX-2 in the ectopic implant were significantly decreased in the letrozole group compared with the control group (P<0.05). There was a positive correlation between the expression of P450arom and the expression of COX-2 (r=0.943, P<0.001; r=0.913, P<0.001). The protein and mRNA expression of bcl-2 was significantly decreased (P<0.05), and the bax protein and mRNA expression was significantly increased (P<0.05) in the ectopic implant with an increased bax/bcl-2 ratio in the letrozole group compared with the control group (P<0.05). Letrozole can obviously reduce the size of ectopic implant through decreasing P450arom and COX-2 expression, suppressing the secretion of estrogen, inhibiting the proliferation, and inducing the apoptosis of ectopic implants.

Treatment Algorithms for Hormone Receptor-Positive Advanced Breast Cancer: Applying the Results from Recent Clinical Trials into Daily Practice—Insights, Limitations, and Moving Forward

Hormone receptor-positive (HR+) breast cancer is the most prevalent subtype of breast cancer in both early- and advanced-stage disease. Thus, the treatment of HR+ breast cancer has had the greatest global influence in improving clinical outcomes overall. Although the first-line metastatic breast cancer (MBC) trials comparing a third-generation aromatase inhibitor (AI) to tamoxifen have favored the AI, one of the challenges in translating these findings into clinical practice stems from the influence of prior adjuvant endocrine therapy, particularly the increasing use of adjuvant AIs today, on the choice of endocrine agent in the advanced setting because of the development of acquired resistance. Because the majority of patients enrolled into these studies were either endocrine-treatment naïve or exposed to tamoxifen only, the "real-life" applicability of the evidence is unclear. Because a superior dose of the selective estrogen receptor (ER) downregulator fulvestrant has now been established, its role as first-line therapy is being re-established. We are now starting to see the promise realized with blocking cross-talking growth factor pathways in addition to the ER pathway. The greatest efficacy is seen with the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with exemestane and, perhaps to a lesser extent, anti-HER2-directed therapy in combination with an AI. Future gains will likely involve a greater understanding of the redundancy and compensation induced by blocking these pathways, trials involving blocking multiple pathways in addition to hormonal agents, and the molecular interrogation of the individual's tumor in search of predictive biomarkers and "actionable" genomic aberrations.

Aromatase Inhibition in Obese Women: How Much Is Enough?

Aromatase Inhibition in Obese Women: How Much Is Enough?

Systematic review of lapatinib in combination with letrozole compared with other first-line treatments for hormone receptor positive(HR+) and HER2+ advanced or metastatic breast cancer(MBC)

Background:Third-generation aromatase inhibitors (letrozole, anastrozole) have shown superior efficacy in early and advanced breast cancer compared with tamoxifen. For HR+, HER2+ MBC, combination of an AI with an anti-HER2 agent (lapatinib or trastuzumab) has shown clinical benefit.Methods:Six databases were searched until January 2009 for randomized controlled clinical trials, assessing the safety and efficacy of first-line treatments for postmenopausal women with HR+ and HER2 (ErbB2) positive MBC, who have not received prior therapy for advanced or metastatic disease. Relevant interventions were lapatinib, aromatase inhibitors, tamoxifen, and trastuzumab. Outcomes included overall survival (OS), progression-free-survival (PFS), time-to-progression (TTP), and objective response rate (ORR).Results:Eighteen studies (62 papers) were included. Lapatinib + letrozole was significantly superior to letrozole alone based on a direct head-to-head study in terms of PFS/TTP and ORR. Using a network meta-analysis, compared with lapatinib + letrozole, tamoxifen (HR = 0.45 (95% CI: 0.32, 0.65) and anastrozole (HR = 0.53 (0.36, 0.80)) scored significantly worse in terms of PFS/TTP and ORR (tamoxifen: OR = 0.25 (0.12, 0.53), anastrozole: OR = 0.27 (0.12, 0.58). The combination also seemed significantly superior to exemestane in terms of PFS/TTP (HR = 0.52 (0.34, 0.79)). Lapatinib + letrozole also seemed better, although not significantly, in terms of OS versus tamoxifen: HR = 0.74 (0.49, 1.12), anastrozole: HR = 0.71 (0.45, 1.14) and exemestane: HR = 0.65 (0.39, 1.11). When compared with trastuzumab + anastrozole, lapatinib + letrozole seemed to be better in terms of OS (HR = 0.85 (0.47, 1.54)), PFS/TTP (HR = 0.89 (0.54, 1.47)) and ORR (OR = 0.92 (0.24, 3.48)), although, none of these results were significant.Discussion:Lapatinib + letrozole was significantly superior to letrozole in terms of PFS/TTP and ORR based on a direct head-to-head study. Indirect comparisons appeared to favor lapatinib + letrozole versus other first-line treatments used in this patient population in terms of three main outcomes: OS, PFS/TTP and ORR. Indirect comparison results are based on a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with caution.

Polymorphisms of CYP19A1 and response to aromatase inhibitors in metastatic breast cancer patients

Single nucleotide polymorphisms (SNPs) in the gene encoding aromatase (CYP19A1) have been associated with differential benefit from letrozole treatment in metastatic breast cancer (mBC) patients, but validation is lacking. The aim was to investigate whether polymorphic variation of CYP19A1 and enzymes involved in estrogen and aromatase inhibitors (AIs) metabolism are associated with efficacy of AIs. 308 Women with estrogen-receptor-positive metastatic mBC treated with a third-generation AI were identified retrospectively. DNA was extracted from archival formalin-fixed paraffin embedded tumors and genotyped for 71 variants in 16 candidate genes, including CYP19A1. Time to treatment failure (TTF) was significantly improved in patients carrying the minor (T) allele of rs4775936 when compared to patients with the reference allele [HR = 0.79 per T allele (0.66-0.95); P = 0.012]. Patients with >7 TTTA repeats on either allele of CYP19A1 intron 4 had a lower risk of failure than those with a smaller repeat size [HR = 0.84 per >7 TTTA repeats (0.7-0.99); P = 0.04]. However, importantly in multivariate analysis, adjusting for the number of disease sites; disease-free interval from diagnosis to first recurrence, grade at diagnosis and first recurrence type neither variant maintained independent predictive significance. None of the 56 SNPs analyzed as an exploratory set showed significant association with TTF. Variants in CYP19A1 or other selected genes associated with AI metabolism were not independently associated with improved AI efficacy and emphasize the importance in pharmacogenetic studies of considering genetic biomarkers in the context of relevant prognostic factors.

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

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

Putting the Cardiovascular Safety of Aromatase Inhibitors in Patients with Early Breast Cancer into Perspective

In the adjuvant setting, the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane are recommended at some point during treatment, either in the upfront, switch after tamoxifen or extended treatment setting after tamoxifen in postmenopausal patients with hormone receptor-positive early breast cancer. AIs have demonstrated superior disease-free survival and overall benefit-to-risk profiles compared with tamoxifen. Potential adverse events, including cardiovascular (CV) side effects, should be considered in the long-term management of patients undergoing treatment with AIs. AIs reduce estrogen levels by inhibiting the aromatase enzyme, thus reducing the levels of circulating estrogen. This further reduction in estrogen levels may potentially increase the risk of developing CV disease. This systematic review evaluated published clinical data for changes in plasma lipoproteins and ischaemic CV events during adjuvant therapy with AIs in patients with hormone receptor-positive early breast cancer. The electronic databases MEDLINE, EMBASE, Derwent Drug File and BIOSIS were searched to identify English-language articles published from January 1998 to 15 April 2011 that reported data on AIs and plasma lipoproteins and/or ischaemic CV events. Overall, available data did not show any definitive patterns or suggest an unfavourable effect of AIs on plasma lipoproteins from baseline to follow-up assessment in patients with hormone receptor-positive early breast cancer. Changes that occurred in plasma lipoproteins were observed soon after initiation of AI therapy and generally remained stable throughout the studies. Available data do not support a substantial risk of ischaemic CV events associated with adjuvant AI therapy; however, studies with longer follow-up are required to better characterize the CV profile of AIs.