Therapy In Premenopausal Patients Research Articles

Long-term survival outcomes for hormonal therapy in premenopausal patients with clinical stage I endometrial cancer.

Long-term survival outcomes for hormonal therapy in premenopausal patients with clinical stage I endometrial cancer.

Adverse effects of tamoxifen treatment on bone mineral density in premenopausal patients with breast cancer: a systematic review and meta-analysis.

It is well known that adjuvant tamoxifen treatment for breast cancer in postmenopausal women decreased bone loss. However, the effects of adjuvant tamoxifen therapy on bone mineral density (BMD) in premenopausal patients with breast cancer remains uncertain. Tamoxifen would have a potential impact of premenopausal BMD on health. The aim of this meta-analysis was to assess this in premenopausal women with primary breast cancer. Through April 2020, studies reporting BMD changes of lumbar spine or hip in premenopausal women with primary breast cancer treated with adjuvant tamoxifen and tamoxifen plus chemotherapy or ovarian function suppression (OFS) were collected from EMBASE and PubMed. The meta-analysis was performed using random effects model of the standardized mean difference (SMD) of BMD in patients. A total of 1432 premenopausal patients were enrolled in eight studies, involving 198 patients treated with tamoxifen alone in three studies. After a 3-year median follow-up, adjuvant tamoxifen decreased the lumbar spinal and hip BMD by as much as an SMD of -1.17 [95% confidence interval (CI); -1.58 to -0.76)] and -0.66 (95% CI, -1.55 to 0.23), respectively. In subgroup analysis in patients treated adjuvant tamoxifen and tamoxifen plus chemotherapy or OFS according to follow-up duration, the bone change of < 3years follow-up group was -0.03 SMD (95% CI, -0.47 to 0.41) and that of ≥ 3years follow-up group was -1.06 SMD (95% CI, -1.48 to -0.64). Compared with patients who received tamoxifen alone, patients who received combination therapy with chemotherapy or OFS showed lesser bone loss at the lumbar spine. Our meta-analysis demonstrated that adjuvant tamoxifen therapy in premenopausal patients caused bone loss after 3years of follow-up, especially at the lumbar spines. For a definite evaluation of the adverse effects of tamoxifen on bone, it is necessary to accumulate more relevant studies.

Systemic Therapy of Premenopausal Patients with Early Stage Hormone Receptor-Positive, HER2-Negative Breast Cancer - Controversies and Standards in Healthcare.

In patients with existing ovarian function, there are some special aspects to adjuvant endocrine therapy in premenopausal patients with hormone receptor-positive, HER2-negative (HR pos./HER2 neg.) breast cancer. Treatment options include tamoxifen with or without a GnRH analog, and aromatase inhibitors with a GnRH analog. Furthermore, ovarian function is affected by previous chemotherapy. Both aromatase inhibitors (+GnRH analogs) and GnRH analogs in combination with tamoxifen are supposed to be indicated for patients at increased risk of recurrence. However, national and international guidelines and therapy recommendations do not provide a clear definition of intermediate or high risk; as a result, therapy decisions are often made for each patient on an individual basis. This is also reflected in the considerable variability at national and international levels, e.g., with regard to the use of aromatase inhibitors + GnRH analogs. This review summarizes the data on completed studies (e.g., SOFT, TEXT, EBCTCG meta-analyses) and the current multigene testing studies (TailorX, RxPonder, ADAPT), discusses the rationale for current studies (e.g., CLEAR-B), and looks ahead to future questions.

Intermediate results of the prospective randomized controlled trial VOG-01: "Evaluation of the efficacy of neoadjuvant combination hormone therapy in premenopausal patients with ER+ HER2- breast cancer"

To date, the standard of care for neoadjuvant treatment of HER2-negative breast cancer remains chemotherapy with the inclusion of anthracyclines and taxanes in both luminal and triple-negative tumor subtypes. The purpose of this article was to scientifically substantiate the use of combined hormone therapy at the preoperative treatment of premenopausal patients with ER+ HER2- breast cancer. After analyzing the scientific data presented in scientific databases (PubMed, MEDLINE, BMS), as well as studying active clinical trials on the ClinicalTrials.gov, we concluded that most of the studies where hormone therapy was used in the preoperative regimen were conducted in the postmenopausal patient. In this regard, a randomized controlled clinical trial was initiated to study the efficacy and safety of a new method of preoperative treatment in premenopausal women with ER+ HER2- breast cancer, the preliminary results of which will be reported in this article. Currently, the study included 28 patients, of which 13 patients were analyzed who received the neoadjuvant and surgical stages of complex treatment. The research is ongoing.

Value of endometrial thickness in diagnosis of endometrial hyperplasia during selective estrogen receptor modulator therapy in premenopausal breast cancer patients

ObjectiveThe weak estrogenic-like effect of selective estrogen receptor modulator (SERM) may lead to series of endometrial lesions, including proliferation, hyperplasia, polyp formation, and even endometrial cancer. This study aimed to explore the effectiveness of different endometrial thickness in diagnosis of endometrial hyperplasia during SERM therapy in premenopausal patients. MethodsThe clinical data of 115 patients receiving hysteroscopic endometrial biopsy during SERM therapy in Peking Union Medical College Hospital, China from January 2010 to December 2018 were retrospectively analyzed. ResultsAverage age at the beginning of SERM therapy was 43.4 ± 5.7 years old. Mean duration time of SERM therapy was 31.0 ± 22.1 months. The mean endometrial thickness was 14.3 ± 6.1 mm. 4 cases of atypical endometrial hyperplasia (3.5 %), and 4 cases of endometrial hyperplasia without atypia (3.5 %) were detected. Endometrial thickness was higher in endometrial hyperplasia patients than in no endometrial hyperplasia patients (18.8 vs 13.9 mm, p = 0.029). Endometrial thickness in 8 out of 8 endometrial hyperplasia patients and 38 out of 107 no endometrial hyperplasia patients were ≥ 15 mm (p = 0.002). The negative predictive value in the diagnosis of endometrial hyperplasia during SERM therapy in premenopausal patients was 100 % when endometrial thickness < 15 mm chosen as cutoff value. ConclusionEndometrial hyperplasia was less likely to occur in premenopausal patients during SERM therapy when endometrial thickness < 15 mm.

Extended endocrine therapy in premenopausal breast cancer patients: Where are we now?

Approximately 25% of new breast cancers are diagnosed in premenopausal patients, 50%-70% presenting as estrogen receptor-positive (ER+) breast tumors. Five-year adjuvant endocrine therapy (ET) with Tamoxifen is the cornerstone treatment for those patients but the evidence that up to 50% of ER+breast cancer distant recurrences develop after this time has now raised some questions. ATLAS and aTTom trials are the only two studies addressing the extension of Tamoxifen beyond 5years in premenopausal patients. They showed significant DFS and OS benefits at a cost of increased rates of endometrial cancer and pulmonary embolus. Therefore, the selection of the patients at higher recurrence risk and hence deemed to get the most benefit from an extended endocrine therapy has become a major concern. Many clinical and genomic prognostic tools have shown validity in identifying patients at high late recurrence risk, but only the BCI prognostic score was shown to also be predictive of response to extended endocrine therapy. Nevertheless, all the evidence available on extended endocrine therapy in premenopausal patients was derived from trials in which patients were treated with tamoxifen alone and are hardly applicable to the current clinical scenario. In fact, the results of the SOFT and TEXT trials demonstrated the superiority of the addition of ovarian function suppression (OFS) and its association with the aromatase inhibitor (AI) Exemestane to Tamoxifen alone. However, the introduction in the clinical practice of AI+OFS-based endocrine therapy for the premenopausal patients will very soon lead to an impasse since neither data exist on extended therapy after this treatment schedule nor is there an ongoing trial intended to obtain new evidence.

Efficacy and safety of adjuvant endocrine therapy in premenopausal patients with early‐stage hormone receptor‐positive breast cancer: A meta‐analysis of randomized controlled trials

Efficacy and safety of adjuvant endocrine therapy in premenopausal patients with early‐stage hormone receptor‐positive breast cancer: A meta‐analysis of randomized controlled trials

PS6K1 as an efficacy marker of GnRH agonist with premenopausal breast cancer.

Estradiol is a key factor for tumorigenesis and prognosis of hormone receptor-positive breast cancer. Adipocytes are one source of estradiol in patients with breast cancer. Recent studies have shown that phosphorylated ribosomal protein S6 kinase-1 plays a critical role in adipogenesis. Therefore, estrogen depletion therapy might have beneficial effects in phosphorylated ribosomal protein S6 kinase-1-positive breast cancer. This study was conducted to evaluate the value of phosphorylated ribosomal protein S6 kinase-1 as a marker for gonadotropin-releasing hormone agonist treatment, a form of estrogen depletion therapy, for premenopausal patients with HR-positive, human epidermal growth factor receptor 2-negative breast cancer. We reviewed the medical records of 296 premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary invasive breast cancer treated between 2008 and 2015. Phosphorylated ribosomal protein S6 kinase-1 positivity was defined by immunohistochemical staining scores of 1+, 2+ and 3+, whereas a score of 0 was considered negative. Phosphorylated ribosomal protein S6 kinase-1-positive tumors were found in 74.0% of the patients. In the phosphorylated ribosomal protein S6 kinase-1-positive group, disease-free survival of patients treated with a gonadotropin-releasing hormone agonist was significantly longer than that of patients treated without a gonadotropin-releasing hormone agonist (mean 106.7 months vs mean 91.1 months, P = 0.018). Phosphorylated ribosomal protein S6 kinase-1 is a potential biomarker for predicting the efficacy of gonadotropin-releasing hormone agonist therapy in premenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer.

Individual approach to choosing an appropriate regimen of adjuvant hormone therapy in patients with early-stage breast cancer

Adjuvant hormone therapy is considered the gold standard of therapy for hormone receptor-positive operable breast cancer. The approach to adjuvant hormone therapy in premenopausal patients has changed significantly in recent years. This change was caused by clinical trials, which have confirmed the advantage of adding ovarian suppression to tamoxifen or aromatase inhibitors monotherapy. Individual approach to choosing an appropriate regimen of adjuvant hormone therapy in premenopausal patients with breast cancer should be based on the assessment of risks for relapse, expected effectiveness of treatment and evaluation of drug safety.

An Italian Delphi study to evaluate consensus on adjuvant endocrine therapy in premenopausal patients with breast cancer: the ERA project

BackgroundSeveral trials evaluated the role of ovarian function suppression for the adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer. Based on the results of the SOFT and TEXT trials, international guidelines recommend the addition of ovarian function suppression to standard adjuvant endocrine therapy for patients at higher risk of relapse.MethodsThe ERA project (Evaluation of Risk factors in the Adjuvant treatment of breast cancer in premenopausal patients) was devised with the objective of obtaining a consensus on the identification of risk factors and the use of ovarian function suppression in the adjuvant treatment of these women. To this aim, a panel of 31 Italian oncologists with expertise in breast cancer participated in a Delphi consensus study in June 2017.ResultsA total of 29 statements related to prognostic factors, therapeutic strategies and ovarian function suppression were defined and voted to gain final consensus. For each topic we report data supporting the acquired consensus and the relevant issues discussed.ConclusionsThe SOFT and TEXT trials have changed the standard adjuvant treatment of premenopausal patients with hormone receptor-positive early breast cancer, but the available treatment options require a careful risk assessment and toxicities evaluation to ensure the greatest clinical benefit for each patient.

Abstract P1-09-09: Role of endocrine therapy in premenopausal patients with hormone receptor-positive metastatic breast cancer, compared with postmenopausal patients: Diachronic analyses from nationwide cohort in Korea (KCSG BR 14-07)

Abstract Background Endocrine therapy (E) has a major role in treatment of hormone receptor (HR)-positive metastatic breast cancer (MBC). However, in contrast to western countries, premenopausal patients (PRE) more prevalent (50% of all breast cancer patients) and have less options of E than postmenopausal patients (POST) in Korea where the use of LHRH agonist in combination aromatase inhibitors (AIs) in PRE is restricted. Recently we have been successfully established nationwide cohort for the patients MBC (575 patients from 26 institutes). This study was designed to evaluate the role of E especially in PRE. Methods The patients with MBC were prospectively or retrospectively enrolled between September 2014 and May 2015. Only menopausal status-confirmed patients (296) were analyzed. Postmenopause was defined, based on NCCN guideline. Total duration of treatment was defined as the time from start day of any first treatment to end of any last treatment. Total duration of E was defined as the sum of time duration of each E. Overall survival was calculated from the start day of any treatment for MBC to any causes of death. This work is supported by National Strategic Coordinating Center for Clinical Research (H110C2020). Results A total of 296 patients with HR-positive MBC were analyzed [PRE, 169 (57.1%) and POST, 127 (42.9%)]. Except age (mean 44 and 60 years), baseline characteristics including in pathology, HER2 status, initial pathologic stage, de novo metastasis versus recurrence, surgery and adjuvant treatment (chemotherapy, endocrine therapy and radiotherapy) were well balanced. 92 (54.4%) of PRE and 77 (60.6%) of POST received at least one or more E through all treatment course. 41 (24.2%) of PRE and 44 (34.6%) received E as 1st-line treatment (p=0.034). Among PRE who received 1st-line of E, 30 (71.4%) and 9 (21.4%) of PRE received 2nd- and 3rd-line E. 20 (45.4%) and 10 (22.7%) of POST received 2nd- and 3rd- or more line of E. Most of PRE (54%) received tamoxifen+/-goserelin and 32% of PRE received AIs along with ovarian suppression. 71% of POST received AIs. As initial treatment, E was more frequently used in POST than in PRE (34.6% and 24.3%, p=0.053). Overall survival (OS) of all patients was 18.2 months (95% CI, 14.8-21.5). There was no difference in OS between PRE (17.8 months, 10.9-24.8) and POST (18.5 months, 95% CI, 13.2-23.9) (P=0.337). No difference of OS was observed (E, 18.1 moths, 95% CI, 13.0-23.3; chemotherapy 21.2 moths, 95% CI, 16.8-25.5), regardless of initial treatment. Total duration of treatment of PRE and POST were 15.2 and 13.6 months, respectively with no significant difference (p=0.389). PRE (8.3 moths, 95% CI,5.7-10.8) showed the trend toward longer duration of E in comparison with POST (5.5 moths, 95% CI,4.4-6.7), however the difference did not reach statistical significance (p=0.051). Conclusion E was more commonly used as 1st-line therapy in POST than in PRE. Although PRE had limited options of E, E was used in long duration of treatment especially in PRE. These findings suggested that E had a role in treatment for PRE with HR-positive MBC and could be used in treatment for PRE with good efficacy. Citation Format: Kim T-Y, Ahn J-H, Yoon JH, Sohn JH, Kim GM, Lee KH, Park YH, Koh S-J, Lee SE, Chae Y, Lee KS, Lee KE, Won HS, Kim JH, Jeong J, Park KH, Cho EK, Im Y-H, Im S-A, Jung KH. Role of endocrine therapy in premenopausal patients with hormone receptor-positive metastatic breast cancer, compared with postmenopausal patients: Diachronic analyses from nationwide cohort in Korea (KCSG BR 14-07). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-09-09.

Abstract P5-12-07: Hormone dynamics, pharmacokinetics, safety and efficacy of leuprorelin acetate 6-month depot formulation and tamoxifen adjuvant endocrine therapy combination in premenopausal patients with hormone receptor-positive breast cancer

Abstract Background: Luteinizing hormone-releasing hormone agonist + tamoxifen is standard postoperative adjuvant endocrine therapy for premenopausal patients with hormone receptor-positive breast cancer. Postoperative adjuvant endocrine therapy is now used for a longer period, and the longer-lasting leuprorelin acetate 6-month depot formulation (TAP-144-SR[6M]) is expected to increase patients' quality of life and decrease medical practitioners' burden. Methods: The hormone dynamics, pharmacokinetics (PK), safety, and efficacy of TAP-144-SR(6M) were compared with those of the 3-month depot formulation (TAP-144-SR[3M]) in a 96-week, phase 3 open-label parallel-group comparison study in premenopausal breast cancer patients after surgery (ClinicalTrial.gov ID: NCT01546649). Inclusion criteria were estrogen receptor (ER) and/or progesterone receptor (PgR) positive; TNM classification of T1-T3, any N, M0; and premenopausal (menstruation confirmed within the previous 12 weeks or both follicle-stimulating hormone [FSH] &amp;lt;40 mIU/mL and estradiol [E2] ≥10 pg/mL at enrollment). Patients were randomized to TAP-144-SR(6M) (6M group [6MG]) or TAP-144-SR(3M) (3M group [3MG]) based on number of axillary lymph node metastases, tumor size, age, ER/PgR status, chemotherapy or not, and study site. The primary endpoint was serum E2 suppression rate based on the menopausal level (≤30 pg/mL) from 4 to 48 weeks after the first administration. Secondary endpoints were serum hormone dynamics, efficacy (disease-free survival [DFS] and distance DFS [DDFS]), PK and safety. The planned number of patients was 164 (82 in each group). Results: A total of 180 patients were enrolled from Apr 2012 to Feb 2013 and 167 patients were randomized. We compared 83 patients in 6MG (age: mean 44.2; SD 4.90) and 84 patients in 3MG (44.0; 5.18). There were no significant differences in background factors between the groups. 6MG showed non-inferior suppression of serum E2 levels to 3MG (See Table). Serum LH and FSH levels were also decreased. DFSs and DDFSs at 96 weeks after randomization were similar in both groups. A double-peak PK profile and sustainable release of the study drug for 24 weeks were found with 6MG. All-grade adverse events (AEs) occurred in 98.8% and 97.6% and grade 3 or higher AEs in 18.1% and 21.4% with 6MG and 3MG, respectively. There were no significant differences in lumbar spine bone mineral density change rates in both groups. Table Serum E2 suppression rate based on the menopausal level (≤30 pg/mL) from 4 to 48 weeks after the first administration 6MG (n = 83)3MG (n = 84)Serum E2 suppression rate (%) (95% CI)97.6 (91.565, 99.707)96.4 (89.916, 99.257)6MG − 3MG (95% CI)1.2 (−5.241, 7.806)Note: Noninferiority margin of 10%. Conclusion: This first clinical study of TAP-144-SR(6M) in premenopausal breast cancer patients showed clinically noninferior serum E2 suppression levels to TAP-144-SR(3M), and no significant safety differences between the groups. TAP-144-SR(6M) was confirmed to have excellent usability in premenopausal breast cancer patients after surgery, and is considered valuable for the appropriate treatment of these patients. Citation Format: Kurebayashi J, Toyama T, Sumino S, Fujimoto T. Hormone dynamics, pharmacokinetics, safety and efficacy of leuprorelin acetate 6-month depot formulation and tamoxifen adjuvant endocrine therapy combination in premenopausal patients with hormone receptor-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-07.

Ovarian function suppression: To what extent is it necessary for premenopausal patients with operable hormone-sensitive breast cancer?

The use of tamoxifen is conventional adjuvant hormone therapy in premenopausal patients with receptor-positive breast cancer. Clinical trials demonstrating the benefits of ovarian function suppression as adjuvant treatment had an ambiguous interpretation. There is no scientific evidence favoring the empiric use of ovarian suppression for these patients. The members of the American Society of Clinical Oncology consider that ovarian ablation or suppression should be used during adjuvant hormone therapy only in certain cases. Irreversible ovarian function ablation may improve time to relapse, by simultaneously deteriorating the quality of life in patients. Irreversible fertility loss in the patients who have experienced breast cancer may become a leading stressful factor for these patients. Many investigators believe that chemotherapy-induced amenorrhea reduces the risk of recurrence. The paper discusses the usage of gonadotropin-releasing hormone agonists in combination with tamoxifen and aromatase inhibitors during adjuvant hormone therapy for early breast cancer. Whether ovarian suppression is needed during hormone therapy is considered, it is the reversible ovarian function suppression that must be standard treatment in premenopausal patients.

Efficacy and Tolerability of Toremifene and Tamoxifen Therapy in Premenopausal Patients with Operable Breast Cancer: A Retrospective Analysis

Given the use of tamoxifen as standard treatment for hormone receptor-positive breast cancer, the use of toremifene as an adjuvant endocrine therapy has not been widely examined. The present retrospective study compared the efficacy and safety of toremifene and tamoxifen in the treatment of operable hormone receptor-positive breast cancer in premenopausal women. Premenopausal patients with hormone receptor- positive operable breast cancer were eligible. Enrolled patients (n = 1847) received either 60 mg toremifene (n = 396) or 20 mg tamoxifen (n = 1451) daily for a minimum of 5 years after surgery. Disease-free survival (dfs) was the primary endpoint. Overall survival (os) and time to distant recurrence were secondary endpoints. Treatment with toremifene and tamoxifen resulted in no between-group differences in dfs (p = 0.659) or os (p = 0.364). Mean dfs was 10.3 years for both groups. Mean os was 11.2 years for the toremifene group and 11.1 years for tamoxifen group. The 5-year dfs rate was 87.0% in the toremifene group and 85.0% in the tamoxifen group. The 5-year survival rate was 94.3% in the toremifene group and 93.5% in the tamoxifen group. Adverse events rates were similar in the two groups, with the exception of irregular menses, which occurred at a higher rate in the tamoxifen group than in the toremifene group (10.0% vs. 6.3%, p = 0.025). In this retrospective study, the efficacy and safety profiles of toremifene and tamoxifen for the treatment of operable hormone receptor-positive breast cancer in premenopausal women were similar.

Use of Adjuvant Endocrine Therapy in Postmenopausal Hormone Receptor-Positive Breast Cancer at German Breast Cancer Centers and University Hospitals - Results of an Enquiry (Adjuvant Endocrine Therapy Enquiry)

Background: Many studies about the adjuvant endocrine therapy of postmenopausal patients with hormone receptor-positive breast cancer have shown significant superiority of aromatase inhibitors (AIs) compared to tamoxifen only. Within these studies, different AIs (anastrozole, letrozole, exemestane) and treatment strategies (upfront, switch, extended adjuvant) were applied. Material and Methods: The intention of our enquiry was to evaluate the implementation of the results of these studies in German breast cancer centers and university hospitals. Questionnaires were sent to 200 breast cancer centers and university hospitals (returns: 108). Results: Our enquiry showed that most centers preferred anastrozole as upfront therapy in patients with an intermediate or high risk of relapse. Furthermore, during AI therapy, additional bisphosphonate treatment was applied ‘always' in only 9% of cases, and in 78% of cases of proved osteopenia/osteoporosis. Surprisingly, 50% of the participating centers do not exclude AIs in premenopausal women. Conclusion: At the time of our enquiry, anastrozole as upfront therapy was consistent with the recommendations of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) from 2009. Compared to tamoxifen, AIs increase the risk of osteoporosis, which can, however, be prevented and treated with concomitant bisphosphonate therapy. The rare use of bisphosphonates as well as contraindicated AI therapy in premenopausal patients show amongst others the substantial need for more information.

Abstract B108: The novel HDAC inhibitor PCI-24781 synergizes with tamoxifen in ER-positive breast cancer by concertedly downregulating AKT1 expression.

Abstract Breast cancer continues to be the most frequently diagnosed malignancy in women, and is second only to lung cancer as the cause of cancer death. While aromatase inhibitors are more commonly used in postmenopausal women, tamoxifen remains the only approved hormonal therapy for premenopausal patients presenting with estrogen receptor (ER)-positive disease. However, the effectiveness of tamoxifen is limited, as many tumors develop resistance. As such, substantial effort has been made to improve and extend the effectiveness of tamoxifen. To this end, we have demonstrated that histone deacetylase (HDAC) inhibitors potentiate the anti-tumor activity of tamoxifen in preclinical models, and in an early phase trial durable responses were achieved in a heavily pre-treated patient cohort. Mechanistic studies have revealed that HDAC inhibition directs breast cancer cells into mitochondrial-mediated apoptosis in part by altering the balance of apoptotic gatekeepers (e.g. Bax, Bak, and Bcl-2). In the current study, we extend our mechanistic understanding of this combination in ER-positive cells using the novel hydroxamic acid type HDAC inhibitor PCI-24781. Early clinical evaluation suggests that PCI-24781 is a potent HDAC inhibitor and is well tolerated at doses exceeding those needed for preclinical synergy. Here we demonstrate that PCI-24781 and tamoxifen act individually to additively abrogate AKT cell signaling by down regulating AKT1 mRNA and protein expression. Furthermore, PCI-24781 represses ESR1 transcription and thus exerts its effect on AKT1 expression in part through the regulation of ER expression. Attenuated AKT signaling manifests in elevated GSK3α/β phosphorylation, Bim, and p21 and a reduction in cyclin D. Cells exhibit an induction of an array of pro-apoptotic drivers, mitochondrial release of cytochrome C, caspase activation, and cell death. These results suggest that HDACs regulate the response of AKT to tamoxifen and that the cooperative effects of HDAC inhibitors and tamoxifen lead to enhance cell death. Therefore, early introduction of an HDAC inhibitor into hormonal therapy in patients with ER-positive breast cancer may counter the emergence of tamoxifen resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B108.

Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial

Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid. ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 premenopausal women with endocrine-receptor-positive early-stage (stage I-II) breast cancer receiving goserelin (3.6 mg every 28 days), comparing the efficacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defined as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing. At a median follow-up of 62 months (range 0-114.4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0.68, 95% CI 0.51-0.91; p=0.009), although the difference was not significant in the tamoxifen (HR 0.67, 95% CI 0.44-1.03; p=0.067) and anastrozole arms (HR 0.68, 95% CI 0.45-1.02; p=0.061) assessed separately. Zoledronic acid did not significantly affect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0.67, 95% CI 0.41-1.07; p=0.09). There was no difference in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1.08, 95% CI 0.81-1.44; p=0.591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1.75, 95% CI 1.08-2.83; p=0.02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121). Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no difference in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer. AstraZeneca; Novartis.

Effect of change of body mass index (BMI) during therapy on the efficacy of endocrine therapy in premenopausal patients with breast cancer: An analysis of the ABCSG-12 trial.

514 Background: Aromatase inhibitors (AIs) are effective as adjuvant endocrine treatment in breast cancer (BC) patients. Recently, it has been argued that BMI at BC diagnosis impacts on the efficac...

Impact of Body Mass Index on the Efficacy of Endocrine Therapy in Premenopausal Patients With Breast Cancer: An Analysis of the Prospective ABCSG-12 Trial

Aromatase inhibitors are effective as endocrine treatment for patients with hormone receptor-positive breast cancer. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, we investigated the influence of body mass index (BMI) on the efficacy of adjuvant endocrine therapy in premenopausal patients in a retrospective analysis of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial. ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg subcutaneously every 28 days) in combination with anastrozole or tamoxifen with or without zoledronic acid (4 mg intravenously every 6 months) in premenopausal women with endocrine-responsive breast cancer. BMI was calculated using the prospectively collected data on patients' height and weight at study entry. BMI categories have been differentiated according to the WHO definition. Overweight patients treated with anastrozole had a 60% increase in the risk of disease recurrence (hazard ratio [HR], 1.60; 95% CI, 1.06 to 2.41; P = .02) and more than a doubling in the risk of death (HR, 2.14; 95% CI, 1.17 to 3.92; P = .01) compared with normal weight patients treated with anastrozole. In the overweight group, patients treated with anastrozole had a nearly 50% increase in the risk of disease recurrence (HR, 1.49; 95% CI, 0.93 to 2.38; P = .08) and a three-fold increase in the risk of death (HR, 3.03; 95% CI, 1.35 to 6.82; P = .004) compared with patients treated with tamoxifen. BMI significantly impacts on the efficacy of anastrozole plus goserelin in premenopausal patients with breast cancer, probably through influencing aromatase availability and/or ovarian suppression by goserelin.

Tamoxifen-induced hepatic steatosis in premenopausal breast cancer patients

While aromatase inhibitors are replacing tamoxifen in postmenopausal breast cancer patients, tamoxifen continues to be the first-line hormonal therapy in premenopausal patients. Tamoxifen-induced hepatosteatosis may lead to nonalcoholic steatohepatitis (NASH), and NASH may develop into cirrhosis. If the development of hepatosteatosis is predicted, these patients may be treated with fibrates and statins. This study examines the development of hepatosteatosis in our premenopausal breast cancer patients that were taking tamoxifen for adjuvant therapy and were positive for the hormone receptors. Patients histopathologically diagnosed with breast cancer and with immunohistochemically demonstrated estrogen and/or progestron receptor expression were recruited for the study. All patients were assessed with ultrasonography by the same radiologist before tamoxifen therapy, at the sixth month of the follow-up and at the end of the first year. The study results were evaluated in thirty patients. Initial ultrasonography revealed grade 2 hepatosteatosis in four patients (13.3%), no change occurring at the repeat ultrasonography performed at the sixth month of the follow-up. Seven patients (23. 3%) were diagnosed as having grade 1 hepatosteatosis. A total of 12 patients (40%) were found to have hepatosteatosis at the end of the first year. Findings at the outset and those at the end of the first year were significantly different (p=0.021) as determined with the Wilcoxon test and Bonferroni correction performed to ascertain the difference in hepatosteatosis between the outset and the follow-up periods. No difference was obtained between the findings for the sixth month and those obtained at the end of the first year. In conclusion, the rate of hepatosteatosis as assessed with ultrasonography shows an increase with tamoxifen use in premenopausal patients. There was no difference between ultrasonography findings at the end of the first year and those at the sixth month of the follow-up. We think that the sitxh-month ultrasonography bears importance from the viewpoint of hepatosteatosis in these patients.