Alternative Endocrine Therapy Research Articles

Advances in Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer.

To provide an overview of the current management of hormone receptor-positive (HR +) advanced breast cancer as well as highlight ongoing clinical investigation and novel therapies in development. CDK4/6 inhibition plus endocrine therapy is standard front-line therapy for HR + advanced breast cancer. Continuation of CDK4/6 inhibitors in combination with alternative endocrine therapy has been evaluated in the second-line setting. Alternatively, endocrine therapy in combination with PI3K/AKT pathway targeting agents has been studied, particularly in patients with PI3K pathway alterations. The oral SERD elacestrant has also been evaluated in patients with ESR1 mutation. Many novel endocrine agents and targeted agents are in development. An improved understanding of combination therapies and sequencing of therapies is needed to optimize the treatment paradigm. Biomarker development is needed to guide treatment decisions. Advances in the treatment of HR + breast cancer have resulted in improved patient outcomes in recent years. Continued development efforts with identification of biomarkers to better understand response and resistance to therapy are needed.

Development of di(2-ethylhexyl) phthalate-containing thioglycolic acid immobilized chitosan mucoadhesive gel as an alternative hormone therapy for menopausal syndrome.

Menopausal syndrome includes the symptoms that most women experience owing to hormone changes after menopause. Although hormone replacement therapy is a common treatment for menopausal syndrome, there are still many side effects and challenges hindering research. In this study, thioglycolic acid (TGA)‐immobilized chitosan mucoadhesive gel was synthesized by a new method of low concentration of 1,4‐butanediol diglycidyl ether (BDDE) would encapsulate di(2‐ethylhexyl) phthalate (DEHP) as an alternative hormone replacement therapy for menopausal syndrome. The efficacies of the DEHP‐containing TGA‐chitosan gel (CT‐D) were confirmed and evaluated by materials characterization and in vitro study. Results showed that CT‐D was not cytotoxic and had better mucoadhesive ability than chitosan. The animal model was constructed 1 month after bilateral ovariectomy in SD rats. CT‐D was administered intravaginally every 3 days. Bodyweight, wet weight of the uterus and vagina, vaginal smears, histology, blood element analysis, and serological analysis was used to assess the ability of the material to relieve menopausal syndrome. The results indicated that the combination of the sustained release of DEHP and mucoadhesive TGA‐immobilized chitosan allows the developed CT‐D to relieve the menopausal syndrome through low concentrations of DEHP, which falls in the safety level of the tolerable daily intake of DEHP.

MURINE AVATARS FOR PRECISION MEDICINE IN ENDOMETRIOSIS

Endometriosis is a chronic, gynecologic disease afflicting 1-in-10 reproductive-aged women. Response to medical therapy is highly variable as endometriotic lesions do not consistently respond to first-line, progestin-based therapy. We have previously demonstrated in a retrospective study that progesterone receptor (PR) status in lesions can predict response to progestins. Low PR status was associated with a <10% chance of response, suggesting that some women may benefit from alternative hormonal therapy as first-line.

Effects of Hibiscus sabdariffa calyces on spatial memory and hippocampal expression of BDNF in ovariectomized rats

ABSTRACT Ovarian hypofunction is characterized by decay in brain-derived neurotrophic factor (BDNF), a neurotrophin associated with cognitive and memory function. Hormone replacement therapy is the most common treatment to counteract the negative effects of ovarian insufficiency; however, this therapy may increase the odds of endometrial cancer, blood clots, stroke, and breast cancer. Therefore, a safer alternative to synthetic estrogens is needed. One possible candidate may be phytoestrogens. Hibiscus sabdariffa L. (Malvaceae) is a source of natural food colorants; the calyces and leaves of the plant are consumed in drinks and culinary preparations and are recognized for several health benefits related to their high content of anthocyanins. In the present study, we used an ovariectomized rat model to assess the phytoestrogenic effect of H. sabdariffa, and evaluated spatial memory and BDNF expression. Ninety-day-old female Wistar rats were randomly separated into six groups. Rats from four groups were ovariectomized and injected with a physiological dose of estradiol, or given, in drinking water, an extract prepared from calyces of H. sabdariffa at doses of 50 or 100 mg/kg body weight. Both Intact and Sham groups were included as controls. At day 42, short- and long-term memories were assessed by the Barnes maze test, and hippocampal BDNF expression was evaluated by RT-qPCR and Western blot. Ovariectomy significantly decreased memory performance and BDNF expression, compared with controls. However, administration of H. sabdariffa extract reversed the negative effect of ovariectomy on short- and long-term memory parameters and BDNF expression. A stronger effect was observed at a lower dose of the extract. In conclusion, the extract from H. sabdariffa acted as a phytoestrogen in ovariectomized rats, improving spatial memory performance and hippocampal BDNF expression. Based on these promising results, further clinical experimentation is recommended to study the benefits of H. sabdariffa as an alternative hormonal therapy in patients with ovarian hypofunction.

Anti‐cancer Effects of Melatonin, Estrogen, and Progesterone Hormone Therapy in MCF‐7 and MDA‐MB‐231 Breast Cancer Cells

A novel melatonin, estrogen (E2), and progesterone (P4) hormone therapy (MEPT) was developed as a safe bio‐identical alternative hormone therapy for menopausal women based on the Women’s Health Initiative findings that PremPro™ increased breast cancer (BC) risk and mortality of all types of BC in postmenopausal women. MEPT delayed tumor onset and reduced tumor incidence in Neu female mice (Dodda et al., 2019; Front Oncol). For other BCs, its actions are currently unknown. In this study, MEPT’s anti‐cancer actions (cell viability, migration) were tested in MCF‐7 (human ER+/PR+) and MDA‐MB‐231 (human TNBC with constitutively active ras mutation) using equivalent concentrations of melatonin (1nM), E2 (50pM), and P4 (10nM) observed in serum after an oral dose that produced anti‐tumor actions in neu mice (Dodda et al 2019; Front Oncol). Potential mechanisms underlying MEPT’s anti‐cancer actions were assessed by western blot (pERK1/2, pERK5, NF‐kB, RUNX2, β1‐INTEGRIN, RANKL, and ELF‐5) using MEK1/2 (PD98059) and MEK5 (Bix02189) inhibitors and radioligand binding using 2‐[125I]‐iodomelatonin or [3H]estradiol binding for melatonin and estrogen receptor expression, respectively. For MCF‐7 cells, BIX02189 combined with MEPT blocked MEPT‐mediated inhibition of migration and MEPT‐mediated ELF5 induction in MCF‐7 cells (vs. vehicle) and decreased pERK5 (vs. Bix02189) suggesting that MEK5, through pERK1/2 and ELF5, were involved in the anti‐cancer actions of MEPT in MCF‐7 cells. For MDA‐MB‐231 cells, although PD98059 and Bix02189 alone inhibited viability and migration, when added in combination with MEPT, no further blockade or enhancement occurred suggesting that MEK1/2 and MEK5 were not involved in MEPT’s anti‐cancer actions in MDA‐MB‐231 cells. MEPT’s differential actions on MCF‐7 and MDA‐MB‐231 cells were most likely attributed to unique melatonin/melatonin receptor actions within each cell. Both MCF‐7 and MDA‐MB‐231 cells express high‐affinity melatonin receptors (MCF‐7: Kd = 13 pM; Bmax = 20.55 fmol/mg protein vs. MDA‐231: Kd = 1.7 nM; Bmax = 60.09 fmol/mg protein) but only in MCF‐7 cells were [3H]‐estradiol binding sites detected (MCF‐7: Kd = 2.2 nM; Bmax = 8.6 pmol/mg protein) and stimulatory actions of E2 or P4 on MCF‐7 cell proliferation observed. These findings demonstrate novel anti‐cancer actions of MEPT in ER+ BC and TNBC cells through distinct mechanisms. Future studies assessing MEPT’s actions against ER+ BC and TNBC in vivo are warranted.Support or Funding InformationThis study was funded by the Marie‐Clement Rodier, C.S.Sp. Endowed Chair.

Novel Melatonin, Estrogen, and Progesterone Hormone Therapy Demonstrates Anti-Cancer Actions in MCF-7 and MDA-MB-231 Breast Cancer Cells.

A novel melatonin, estrogen, and progesterone hormone therapy was developed as a safe bio-identical alternative hormone therapy for menopausal women based on the Women’s Health Initiative findings that PremPro™ increased breast cancer risk and mortality of all types of breast cancer in postmenopausal women. For HER2 breast cancer, melatonin, estrogen, and progesterone delayed tumor onset and reduced tumor incidence in neu female mice. For other breast cancers, its actions are unknown. In this study, melatonin, estrogen, and progesterone hormone therapy were assessed in human ER+ (MCF-7) and triple negative breast cancer (MDA-MB-231) cells, and found to decrease proliferation and migration of both breast cancer lines. Inhibition of MEK1/2 and 5 using PD98059 and BIX02189, respectively, inhibited proliferation and migration in MDA-MB-231 cells and proliferation in MCF-7 cells; however, when combined with melatonin, estrogen, and progesterone, BIX02189 blocked melatonin, estrogen, and progesterone–mediated inhibition of migration in MCF-7 cells and induced Elf-5. For MDA-MB-231 cells, BIX02189 combined with melatonin, estrogen, and progesterone inhibited proliferation and increased pERK1/2 and β1-INTEGRIN; levels of pERK5 remained low/nearly absent in both breast cancer lines. These findings demonstrate novel anti-cancer actions of melatonin, estrogen, and progesterone in ER+ and triple negative breast cancer cells through intricate MEK1/2- and MEK5-associated signaling cascades that favor anti-proliferation and anti-migration.

Detection of ESR1 Mutations in Single Circulating Tumor Cells on Estrogen Deprivation Therapy but Not in Primary Tumors from Metastatic Luminal Breast Cancer Patients

Mutations in the ligand-binding domain (LBD) of the ESR1 gene result in resistance to estrogen deprivation therapy (EDT) in breast cancer. Their detection might enable optimization of therapy strategies. However, the predictive utility of the primary tumor (PT) is limited, and obtaining serial biopsies of metastatic lesions is challenging. To underline their application as a liquid biopsy, single circulating tumor cells (CTCs) were analyzed with a next-generation sequencing approach for the ESR1 coding region. CTCs from 46 metastatic luminal breast cancer patients were enriched using CellSearch system and isolated by micromanipulation. Their genomic DNA was amplified and the ESR1 gene was sequenced. Furthermore, tissue samples from corresponding PTs and/or metastatic lesions were investigated. ESR1 mutations were detected in 12 patients-exclusively in patients treated with EDT (P=0.048). In seven cases mutations were located in the hotspot regions in the LBD. Six novel mutations were identified. ESR1 mutations were absent in PT tissue samples and were detected only in metastases obtained after CTC characterization. Single-cell CTC analysis for ESR1 mutations could be of clinical value to identify patients who progress under EDT and therefore benefit from an early switch to an alternative endocrine therapy or other treatment regimens. Furthermore, our data indicate that mutations outside the LBD's hotspot regions might also contribute to resistance to EDT.

A meta-analysis of clinical benefit rates for fulvestrant 500\xa0mg vs. alternative endocrine therapies for hormone receptor-positive advanced breast cancer

BackgroundFulvestrant, a selective estrogen receptor degrader, is approved for first- and second-line treatment of postmenopausal women with hormone receptor-positive advanced breast cancer (ABC).MethodsMeta-analysis of randomized controlled trials (RCTs) evaluating fulvestrant 500 mg in postmenopausal hormone receptor-positive ABC, to evaluate differences in clinical benefit rate (CBR; proportion of patients experiencing best overall response of complete response, partial response, or stable disease for ≥ 24 weeks) between fulvestrant 500 mg and comparator endocrine therapies. Odds ratios (OR) and 95% confidence intervals (CI) for CBR were calculated; fixed effects (FE) models were constructed (first- and second-line data, alone and combined).ResultsSix RCTs were included. Four studies evaluated fulvestrant 500 mg vs. fulvestrant 250 mg; two evaluated fulvestrant 500 mg vs. anastrozole 1 mg. In total, 1054 and 534 patients were included (first- and second-line treatment, respectively). Analysis of OR and 95% CI of CBR by therapy line favored fulvestrant 500 mg vs. comparator therapy. Assessing all results combined in the FE model indicated significant improvement in CBR with fulvestrant 500 mg vs. comparator treatments (OR 1.33; 95% CI 1.13–1.57; p = 0.001). Restricting the FE model to therapy line demonstrated significant improvement in CBR vs. comparator treatments (OR 1.33; 95% CI 1.02–1.73; p = 0.035) for first-line, and a trend to improvement vs. comparator treatments (OR 1.27; 95% CI 0.90–1.79; p = 0.174) for second-line.ConclusionsIn postmenopausal patients with hormone receptor-positive ABC, fulvestrant 500 mg first-line was associated with significantly greater CBR (more patients benefiting from treatment) vs. comparator endocrine therapy.

Analysis of Adjuvant Endocrine Therapy in Practice From Electronic Health Record Data of Patients With Breast Cancer.

Adjuvant endocrine therapy is a long-term drug therapy prescribed to prevent recurrence of hormone receptor-positive breast cancer. Data on adjuvant endocrine therapy are reported though clinical trials, which may differ from treatment practice and outcomes in the general population of patients with breast cancer. With secondary use of electronic health record (EHR) data, we summarize adjuvant endocrine treatment practice and outcomes in real-world settings. We analyzed treatment data derived from EHR data on 1,587 patients with stage I to III breast cancer at a National Cancer Institute-designated comprehensive cancer center to learn the frequencies of real-world adjuvant endocrine drug switches and discontinuation and to explore the potential cause for drug switches and discontinuation from medical records. We measured rates of drug use, drug switches, early drug discontinuation, adverse events, recurrence, and death. We also measured adverse events and change in menopause status as potential causes for drug switch and discontinuation. Within the study population, approximately 49% of patients were lost to follow-up or did not complete adjuvant treatment through 5 years. Fifty-two percent of patients switched to a different endocrine therapy drug during their treatment. We found that age is correlated with drug switches and that adverse events are correlated with drug switches and discontinuation. We also found that patients who switched to an alternative endocrine therapy during treatment were more likely to complete 5 years of treatment. This study describes long-term adjuvant endocrine treatment in real-world settings and demonstrates the ability to leverage longitudinal EHR data to characterize oral medication treatment patterns in patients with cancer.

A network meta-analysis of fulvestrant vs alternative first-line endocrine therapies for endocrine therapy-naive postmenopausal hormone receptor-positive advanced or metastatic breast cancer.

e12545 Background: Fulvestrant (F) is a selective estrogen degrader for hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (LA/MBC). This network meta-analysis examined the efficacy of F (500 mg) vs alternative endocrine therapies (ETs) for first-line treatment of ET-naïve HR+ LA/MBC. Methods: Randomized controlled trials of first-line F, tamoxifen (Tam), anastrozole (A), exemestane (E), letrozole (L), and toremifene (T) for women (≥18 years) with HR+ LA/MBC and no prior ET were identified in a systematic review of MEDLINE, EMBASE, and Cochrane databases from inception to October 2016. Conference proceedings of the American Society of Clinical Oncology, European Society of Medical Oncology, and San Antonio Breast Cancer Symposium from 2013-2016 were hand searched. Trials of targeted combination therapies were excluded. Studies were checked for heterogeneity. A standard fixed-effect Bayesian network meta-analysis was conducted based on hazard ratios (HRs) and assuming proportional hazards for progression-free and overall survival (PFS/OS). Results: Seven eligible studies (1 Phase [Ph] 2, 5 Ph 3, 1 Ph 2/3) were identified. All had PFS data; five had OS data. Two trials compared F vs A; PFS data were available for both trials; sufficiently mature OS data for F were available from Ph 2 only. The proportional hazards assumption was met for PFS only.F had significantly improved PFS vs Tam (HR 0.57, 95% credibility interval [Crl] 0.44-0.73), A (HR 0.75, 95% Crl 0.62-0.91), E (HR 0.65, 95% Crl 0.47-0.91), and T (HR 0.53, 95% Crl 0.37-0.78). Numerically improved PFS was observed for F vs L (HR 0.81, 95% Crl 0.59-1.11). F had significantly improved OS vs Tam (HR 0.63, 95% Crl 0.40-0.98), A (HR 0.63, 95% Crl 0.42-0.94), and E (HR 0.56, 95% Crl 0.33-0.95). OS was numerically improved with F vs L (HR 0.66, 95% Crl 0.41-1.04). Conclusions: This analysis suggests improved PFS and OS for fulvestrant vs tamoxifen, anastrozole, exemestane, and letrozole, and PFS for fulvestrant vs toremifene. Further analysis should be conducted, using non-proportional hazard methods and more mature OS data, to confirm the OS results.

Use of anastrozole in the chemoprevention and treatment of breast cancer: A literature review.

Aromatase inhibitors have emerged as an alternative endocrine therapy for the treatment of hormone sensitive breast cancer in postmenopausal women. The use of third-generation inhibitors represented by exemestane, letrozol and anastrozole is currently indicated. Anastrozole is a nonsteroidal compound and a potent selective inhibitor of the aromatase enzyme. Although a few studies have shown that its pharmacodynamic and pharmacokinetic properties may be affected by interindividual variability, this drug has been recently used in all configurations of breast cancer treatment. In metastatic disease, it is currently considered the first-line treatment for postmenopausal women with estrogen receptor-positive breast tumors. Anastrozole has shown promising results in the adjuvant treatment of early-stage breast cancer in postmenopausal women. It has also achieved interesting results in the chemoprevention of the disease. Therefore, due to the importance of anastrozole both for endocrine treatment and chemoprevention of hormone-sensitive breast cancer in postmenopausal women, we proposed the current literature review in the SciELO and PubMed database of articles published in the last 10 years.

Abstract 1812: Targeting nuclear transport pathways to overcome endocrine resistance and recurrence

Abstract Currently, around 75% of patients with breast tumors test positive for estrogen receptor alpha (ERa) and are treated with endocrine therapies, such as tamoxifen. One-third of the breast tumors eventually become refractory, reducing the survival rate for affected patients. A combination of alternative endocrine therapies and kinase inhibitors is currently used in such patients. However, after an initial period of therapy response, these tumors relapse in a more aggressive form. Further, the alternative therapies are not optimal in terms of pharmacological properties, are poorly tolerated, and have side-effects that severely decrease quality of life of the patient. Thus, there is a critical need for novel, targetable, mechanism-based therapeutic strategies that 1) re-sensitize ERa (+) tumors to endocrine therapies, and 2) include diagnostic methods to select patients likely to benefit from this approach. Our objective in this study is to validate a group of nuclear transport genes as biomarkers for endocrine resistance, and to evaluate their inhibition as a novel means to enhance the effectiveness of endocrine therapies. Our central hypothesis is that high expression of these genes in ERa (+) tumors serve as a viable biomarker for risk of endocrine therapy failure. We focused on XPO1, the main nuclear export protein, which exports ERK5 from the nucleus to the cytoplasm and we used selinexor (KPT-330), the inhibitor of XPO1, which is already used in clinical trials for solid and hematological cancers (clinicalTrials.gov). Our experiments show that estradiol induces nuclear localization of ERK5, which otherwise would contribute to increased invasiveness and metastatic potential in the cytoplasm. Selinexor increases ERK5 nuclear localization in tamoxifen resistant breast cancer cell lines. Our hypothesis is that sequestering ERK5 in the cell nucleus and blocking its recycle into the nucleus by selinexor is directly associated with the improved transcriptional response to endocrine therapies. The nuclear export pathways have not previously been implicated in the development of endocrine resistance, and given the need for better strategies for selecting patients to receive endocrine reagents and improving therapy response of relapsed ERa(+) tumors, our findings show high and significant promise for uncovering the role of these pathways and demonstrating their use in reducing cancer recurrences. Citation Format: Eylem Kulkoyluoglu, Kinga Wrobel, Yiru Chen Zhao, Karen L. Chen, Kadriye Hieronymi, Jamie Holloway, Yosef Landesman, Tania Ray, Partha S. Ray, Alexander E. Lipka, Rebecca L. Smith, Zeynep Madak Erdogan. Targeting nuclear transport pathways to overcome endocrine resistance and recurrence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1812.

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

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

Abstract S6-04: Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: Overall survival from the Phase II ‘FIRST’ study

Abstract Background: A clinically significant improvement in median overall survival (OS) has been reported for fulvestrant 500 mg vs fulvestrant 250 mg (26.4 months vs 22.3 months, respectively; hazard ratio [HR] 0.81; 95% confidence interval (CI) 0.69, 0.96; nominal p=0.02) in the Phase III COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) study, following failure on prior endocrine therapy. Therefore, further evidence for OS effects of fulvestrant 500 mg was sought. The Fulvestrant fIRst-line Study comparing endocrine Treatments (FIRST) compares fulvestrant 500 mg with anastrozole in the earlier first-line treatment setting for postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer. In the primary analysis (6 months after last patient was randomized) fulvestrant 500 mg was at least as effective as anastrozole for clinical benefit rate (primary endpoint) and showed a significantly longer time to progression (TTP; median TTP not reached for fulvestrant 500 mg vs 12.5 months for anastrozole; HR 0.63; 95% CI 0.39, 1.00; p=0.05). In a follow-up analysis when 79.5% of patients (pts) had discontinued study treatment, median TTP was 23.4 months for fulvestrant 500 mg vs 13.1 months for anastrozole (HR 0.66; 95% CI 0.47, 0.92; p=0.01). Here we report OS from FIRST. Methods: FIRST is a Phase II, randomized, open-label, multicenter study (NCT00274469) comparing fulvestrant 500 mg (500 mg im on Days 0, 14 and 28, and every 28 days thereafter) with anastrozole (1 mg/day po). Pts were postmenopausal women with locally advanced or metastatic HR+ breast cancer who had not received prior endocrine therapy for locally advanced or metastatic disease. Kaplan-Meier curves of OS (time from randomization to death from any cause) will be compared by unadjusted log-rank test. Pts not known to have died including those lost to follow-up or with no survival information will be right-censored at last known date alive. Serious adverse events will also be reported. Results: In total, 205 pts (median age 67.0 years) were randomized from 62 centers in 9 countries (fulvestrant 500 mg: n=102; anastrozole: n=103). The first pt enrolled on Feb 6, 2006. As of May 14, 2014, 40/205 pts (19.5%) were alive across both treatment groups. 4 pts (2.0%) were lost to follow-up, 130 pts (63.4%) had died, and 31 pts [15.1%] did not participate in the OS follow-up (20 pts due to non-participation of center in the OS follow-up; other reasons included withdrawal of consent). A total of 130 events had occurred; preliminary data indicate a median OS of 50 months in the total study population. Data cut-off is planned for when approximately 65% pts have died, expected in Aug 2014. Comparative data between fulvestrant 500 mg and anastrozole for OS will be presented. Conclusions: We understand FIRST to be the only study that has demonstrated improved efficacy (ie TTP) for an alternative hormone therapy over a third-generation aromatase inhibitor for treatment of HR+ advanced breast cancer. Improved OS results would provide additional support for superior efficacy of fulvestrant 500 mg over anastrozole as first-line endocrine therapy for postmenopausal women with HR+ locally advanced or metastatic breast cancer. Citation Format: John FR Robertson, Antonio Llombart-Cussac, David Feltl, John Dewar, Marek Jasiówka, Nicola Hewson, Yuri Rukazenkov, Matthew J Ellis. Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: Overall survival from the Phase II ‘FIRST’ study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-04.

Abstract P6-10-03: Comparative efficacy of everolimus in combination with exemestane and chemotherapy for advanced breast cancer in terms of progression-free survival

Abstract Background: For hormone receptor-positive (HR+) advanced breast cancer (ABC), guidelines recommend endocrine therapy as the preferred option even in the presence of visceral disease. If there is evidence of endocrine resistance or rapidly progressive disease requiring a fast response then chemotherapy is recommended. The randomized controlled trial (RCT) BOLERO-2 demonstrated that everolimus plus exemestane (EVE+EXE) more than doubled median progression-free survival (PFS) compared with placebo+EXE while still maintaining quality of life in HR+/HER2- ABC patients who recurred or progressed during or after non-steroidal aromatase inhibitors (NSAIs). EVE+EXE offers a viable new line of therapy which can delay treatment with chemotherapy. Therefore, comparative evidence of EVE+EXE versus chemotherapies is relevant. In addition, such data will provide useful information for health technology assessment. Objective: 1) Assess the feasibility of network-meta-analysis (NMA) to compare the efficacy of EVE+EXE with chemotherapies in ABC in terms of PFS. 2) If feasible, to conduct the NMA. Methods: A systematic review of EMBASE, Medline, and Cochrane was performed to identify RCTs concerning the efficacy of everolimus, alternative hormonal therapies, and alternative chemotherapies for ABC in terms of PFS in order to facilitate an indirect comparison of everolimus versus chemotherapy. PFS data from published Kaplan-Meier curves for each treatment and RCT were synthesized and indirectly compared with random effects Bayesian Weibull network-meta-analysis (NMA) models. Analyses were performed assuming treatment effects as expressed with hazard ratios vary over time. Results: Based on a search of 6271 citations 24 RCTs were included. Differences across RCTs were identified in terms of age, post-menopausal status, receptor status, prior exposure to hormonal and chemotherapy, and types of hormonal therapies, visceral metastases, and performance status. Despite the limitations due to these differences, a NMA was performed to provide a broad estimate regarding comparative PFS for everolimus versus chemotherapy to inform current practice. Results of NMA in terms of mean PFS (i.e. area under the curve) up to 20 months are presented in Table 1. Sensitivity analyses will be performed to explore the impact of these differences on the robustness of the results. Table 1. Mean PFS until 20 months as obtained with NMATreatmentMean PFS time up to 20 months95% Credible Interval95% Credible IntervalEpirubicin6.162.5312.17Liposomal doxorubicin6.663.1212.00Paclitaxel7.103.7811.90Pegylated liposomal doxorubicin7.143.0913.56Doxorubicin7.353.9612.09Vinorelbine7.552.9914.28Docetaxel7.924.3712.45Capecitabine9.905.0316.67Nab paclitaxel10.105.4215.75Exemestane+ Everolimus12.216.2116.98 Conclusions: It is feasible to conduct NMA, however, differences in patient characteristics identified among studies are likely to have resulted in over or underestimation of the relative treatment effects. Based on the NMA, EVE+EXE is expected to be at least as efficacious as selected chemotherapies regarding PFS. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-10-03.

Adherence in tamoxifen therapy after conversion to a rebate pharmaceutical in breast cancer patients in Germany

The aim of this study was to investigate the risk of therapy discontinuation in breast cancer patients treated with tamoxifen with and without conversion to a rebate pharmaceutical (tamoxifen) and to analyze the negative consequences of rebate contracts on the compliance of breast cancer patients among gynecologist and general practitioner practices in Germany. This retrospective analysis was performed using the IMS Disease Analyzer® database. Women with a diagnosis of breast cancer and first time prescription of tamoxifen in the time from January 2008 until December 2011 were selected. Main outcome measure was the incident the hormone treatment discontinuation rates within 3 years after index date. Treatment discontinuation of tamoxifen was defined as 90 days without this or alternative hormonal therapy (aromatase inhibitors) during that time. In total, 3,620 patients were included in the persistence analysis. 1,712 (47.3%) patients were converted to a rebate product. Within 3 years of follow-up, the discontinuation rates increased to 51.5% for switched patients and 46.3% for patients without switch (p < 0.01). Hazard ratios for 3-year risk of tamoxifen therapy discontinuation were adjusted for age, sex, gynecologist care, patient and physician's residency, baseline co-morbidities (osteoporosis, diabetes, depression and thrombosis, side effects). These analyses comprised a significantly increased risk for treatment discontinuation for patients who were switched to a rebate pharmaceutical compared to patients without conversion to a rebate pharmaceutical (HR: 1.27, CI: 1.05 - 1.53, p = 0.014). This analysis underlines an association between the initiation of rebate contracts and a negative impact on the compliance of breast cancer patients on an adjuvant hormonal treatment The impact of rebate contracts on the health of patients and the health care costs should be evaluated in further therapeutic fields through additional research projects. *both authors contributed equally to the manuscript.

Personalized medicine in breast cancer: tamoxifen, endoxifen, and CYP2D6 in clinical practice

Tamoxifen is metabolized into endoxifen, a potent antagonist of the estrogen receptor, in part through cytochrome p450 (CYP) 2D6. Genotypic variation in CYP2D6 affects endoxifen levels, and some have argued that patients who do not efficiently metabolize tamoxifen might wish to consider alternative hormonal treatments. This study evaluated an algorithm in which endoxifen levels and CYP2D6 genotypes were used to make hormonal therapy recommendations for patients on adjuvant tamoxifen for breast cancer. Patients with stage I-III breast cancer who had been taking adjuvant tamoxifen for 8-56weeks were eligible. At enrollment, baseline whole blood and serum were sent for genotyping by Amplichip and endoxifen measurement, respectively, and endoxifen levels were also measured 3weeks later. Results were returned to oncologists along with an algorithm-generated treatment recommendation. The algorithm recommended that participants with poor metabolizer genotype and/or baseline endoxifen level <6ng/mL consider alternative endocrine therapy. A medical record review evaluated actual treatment decisions. Of 99 patients on study, 18 (18%) had findings that triggered algorithm-based recommendations to consider a change in endocrine therapy due to endoxifen <6ng/mL (all 18 patients) and/or poor metabolizer CYP2D6 genotype (2 of the 18). Endoxifen levels were ≥6ng/mL in four of them 3weeks later. Seven (39% of 18) switched to a different treatment (one based on toxicity, not the algorithm). Hot flash burden was not found to be significantly associated with endoxifen <6ng/mL or genotype. Prospective testing of tamoxifen metabolism as gauged by CYP2D6 genotype and serum endoxifen levels is feasible. Future studies of tamoxifen metabolism and efficacy should consider including measurement of serial endoxifen levels. Although clinical evidence at present is insufficient to warrant routine CYP2D6 or endoxifen testing, some clinicians and patients did utilize this predefined algorithm to inform clinical decisions regarding optimal adjuvant endocrine therapy.

Progression-Free Survival with Fulvestrant 500 mg and Alternative Endocrine Therapies as Second-Line Treatment for Advanced Breast Cancer: A Network Meta-Analysis with Parametric Survival Models

BackgroundOuwens et al. and Jansen have presented methods for (network) meta-analysis of survival data by using a multidimensional treatment effect as an alternative to the synthesis of constant hazards ratios, which allow for a better fit to the data and the expected survival of competing interventions for cost-effectiveness analysis. However, results may be sensitive to the assumed underlying survival function. ObjectiveTo estimate the expected progression-free survival (PFS) for fulvestrant 500 mg versus alternative hormonal therapies for postmenopausal women with advanced breast cancer who relapsed previously by means of a network meta-analysis of currently available randomized controlled trials using alternative underlying survival functions. MethodsEleven randomized controlled trials were included that evaluated fulvestrant 500 mg (n = 3), fulvestrant 250 mg (n = 5), fulvestrant 250 mg loading dose (n = 3), anastrozole 1 mg (n = 3), megestrol acetate (n = 4), letrozole 2.5 mg (n = 3), letrozole 0.5 mg (n = 3), and exemestane (n = 2). PFS percentages and numbers at risk were derived from Kaplan-Meier curves and combined by means of Bayesian network meta-analysis on the basis of the difference in the shape and scale parameters of the Weibull, log-normal, and log-logistic parametric survival functions. ResultsThe log-normal distribution provided the best fit, suggesting that the proportional hazard assumption was not valid. Based on the difference in expected PFS, it was found that fulvestrant 500 mg is more efficacious than fulvestrant 250 mg, megestrol acetate, and anastrozole (−5.73 months; 95% credible interval [CrI]−10.67,−1.67). Expected PFS for fulvestrant 500 mg ranged from 10.87 (95% CrI 9.21, 13.07) to 17.02 (95% CrI 13.33, 22.02) months for the Weibull versus log-logistic distribution. ConclusionsFulvestrant 500 mg is expected to be more efficacious than fulvestrant 250 mg, megestrol acetate, and anastrozole 1 mg and at least as efficacious as exemestane and letrozole 2.5 mg in terms of PFS among postmenopausal women with advanced breast cancer after failure on endocrine therapy. The findings were not sensitive to the distribution, although the expected PFS varied substantially, emphasizing the importance of performing sensitivity analyses.

How reliable are “reputable sources” for medical information on the Internet? The case of hormonal therapy to treat prostate cancer

ObjectivesProstate cancer patients, as well as their caregivers and healthcare providers, often search the Internet for information about treatment options. We aimed to assess how accurate and up-to-date information about prostate cancer treatments is on websites owned and managed by health-related organizations that most patients and health care providers would consider to be the most trustworthy, based on the reputations of the site providers. Materials and methodsWe reviewed 43 noncommercial and easily found websites that offered extensive information on treatment options for prostate cancer patients. To assess how comprehensive the sites were, we focused on the information they provided on alternative hormonal therapies to commonly prescribed luteinizing hormone-releasing hormone (LHRH) agonists, namely GnRH antagonists and parenteral estradiol. ResultsOnly 14 of 43 websites presented GnRH antagonists as a therapy option for prostate cancer. Sixteen of these 43 websites presented estrogen as a possible treatment option, but only 1 of the 43 websites contained current information on parenteral estrogen treatments. Less than half of the sites provided time stamps indicating when they were last updated. Furthermore, most sites with time stamps were not in fact up-to-date based on the information posted on the site. ConclusionsFew seemingly reputable Internet sources for medical information provide viewers with the detailed and up-to-date information that they may expect from such sites when searching for alternatives to standard treatment for androgen suppression. Strategies for keeping such websites up-to-date and reliable are discussed. Sites may improve their credibility and usefulness if they (1) present all evidence-based treatment options, (2) regularly update and time stamp their information, (3) acknowledge that their recommendations on treatments may become out-of-date quickly, (4) and direct viewers to information on relevant, active clinical trials. Maintaining high quality sites may ultimately depend on users taking the initiative to inform website owners when their sites are out-of-date.

280P - Adjuvant Aromathase Inhibitors (AIS) Hormone Therapy (HT): Which Reasons Lead Patients (PTS) to Discontinue Treatment? A Mono Institutional Analysis

ABSTRACT Background AIs represents the standard HT for the adjuvant treatment of post menopausal endocrine sensitive early breast cancer. A percentage of pts interrupt treatment because of toxicity. In this setting the switch to other AIs or tamoxifen (TAM) may represent an option to allow the prosecution of HT. We reviewed the main reasons for interruption of the AIs in our institution from 2006 to the present. Methods 236 pts with a minimum treatment time up of 6 months were considered eligible for analysis. Pts characteristics: median age 64 yrs (35-89), median follow up 24 months (6-28). Prior adjuvant CT: taxanes based: 47 pts, anthracyclines based: 43 pts. 118 pts (49%) had received letrozole (L), 101 (43%) anastrozole (A), 18 (8%) exemestane (E). An alternative HT (AIs or tamoxifen [T]) was offered to pts who wanted or needed to interrupt permanently the ongoing drug. Results According to the CTC NCI, arthralgia was the main toxicity observed (G1 19.4%, G2/3 5.5%/1.7%. Overall 24 out of 236 pts (10%) needed discontinuation of AIs as a result of toxicity. Grade 2 and 3 arthralgia was the main reason for discontinuation in 13/24 pts (54%). No differences in the incidence of arthralgia were noted in pts who had received taxanes or anthracyclines. Headache (n = 2), alopecia (n = 2), G3 itching (n = 2), diffuse skin reaction (n = 1) allergic reaction with hypertensive crisis (n = 1), xerostomia and xerophthalmia (n = 1), insomnia (n = 1) and somnolence (n = 1) were the other reasons for discontinuance. In the multivariate logistic regression analysis, age (65 yrs) and HT represent independent factors associated with the onset of arthralgia (respectively p = 0.006 and 0.008, OR 2.65, CI95: 1.32-5.31). 17/24 pts were switched to E, 5 to T and 1 each to L and A. In pts who switched to another AI we observed a reduction in the severity of the arthralgia but not its complete resolution. A complete resolution of symptoms was observed for the other toxicities except for allergic reactions that recurred after switching from L to A. Moreover, the patient with the diffuse skin reaction, chose discontinuation of HT. Conclusions In our analysis, 10% of pts discontinued AIs due to toxicity. Switching to alternative HT, and monitoring the toxicity, represent an option to offer to pts in order to avoid a premature and permanent interruption of an effective treatment. Disclosure All authors have declared no conflicts of interest.