Combination Of Letrozole Research Articles

Особливості контрольованої стимуляції яєчників у поганих відповідачів

The objective: search for an optimal protocol for ovarian stimulation in women with a reduced ovarian response with investigation of its effectiveness by studying the number of oocytes obtained, embryo quality, as well as pregnancy and implantation rate. Materials and methods. The study of the effectiveness of the controlled ovarian stimulation regimen in poor responders women using long acting FSH in the protocol with GnRH antagonists compared with the modified protocol combining the use of aromatase inhibitors (letrozole) and gonadotropins was conducted. Results. The stimulation of the ovaries with Coriophiolotropin alfa and the aromatase inhibitor has been shown to be effective in the treatment of patients with a poor response to stimulation. Patient perceptions of corifolotropin-alpha protocols show better tolerability than traditional protocols due to fewer injections, which reduces the likelihood of early termination of treatment. Modified protocols with the use of aromatase inhibitors should be used in cases of optimization of financial expenses during the CSR protocol with a similar result. Conclusion. The results of the study prove the effectiveness of the stimulation regimens used in controlled ovarian stimulation for poor responders. The use of coriophyllotropin alfa and aromatase inhibitor letrozole in combination with additional FSH doses and gonadotropin-rilising hormone antagonists simplifies the design of the stimulation regimen, minimizes the number of injections with shorter stimulation and optimizes patient financial costs. Key words: controlled ovarian stimulation, poor responders, coriophyllotropin alpha, aromatase inhibitors.

Abstract GS3-02: PALLET: A neoadjuvant study to compare the clinical and antiproliferative effects of letrozole with and without palbociclib

Abstract Background: CDK4/6 inhibitors, such as palbociclib, are used to treat ER+ metastatic breast cancer in combination with endocrine therapy with trials ongoing in patients with primary disease. No biomarkers exist to identify those who do/do not benefit from added CDK4/6 inhibition. PALLET is an investigator-initiated/led phase II randomized trial collaboration between UK and NSABP investigators evaluating the biological and clinical effects of palbociclib with letrozole combination as neoadjuvant therapy. Methods: Postmenopausal women with ER+ primary breast cancer and tumors >2.0cm (ultrasound) were randomized to one of 4 treatment groups (3:2:2:2 ratio): Group A: letrozole (2.5mg/d) for 14 weeks; Group B: letrozole for 2 weeks followed by letrozole + palbociclib to 14 weeks; Group C: palbociclib for 2 weeks followed by letrozole + palbociclib to 14 weeks; Group D: letrozole + palbociclib for 14 weeks. Palbociclib was given 125mg/d PO on a 21 days on, 7 days off schedule. Post-14 week treatment was at the discretion of the treating clinician including letrozole until surgery. Core-cut biopsies were taken at baseline, 2 weeks and 14 weeks. Co-primary endpoints for letrozole alone vs palbociclib groups (Group A vs Groups B+C+D) were: (i) change in Ki67 (IHC) between baseline and 14 weeks (log-fold change, Mann-Whitney test); (ii) clinical response (ultrasound) after 14 weeks (4 group, ordinal, Mann-Whitney test). Complete cell-cycle arrest (CCCA) (Ki67≤2.7%) was analyzed using a logistic regression model adjusting for recruitment region. Pre-specified exploratory biomarkers included c-PARP (apoptosis). Results: 307 patients were recruited between 27 Feb 2015 and 08 Mar 2018; 103 were randomized to letrozole alone and 204 to letrozole + palbociclib. 279 (90.9%) patients were evaluable for 14 week clinical response. Clinical response was not significantly different between letrozole vs letrozole + palbociclib groups [(p=0.20; CR+PR 49.5% (46/93) vs 54.3% (101/186) and PD 5.4% (5/93) vs 3.2% (6/186)] nor was the small proportion of patients with pathological CR (1/87, 1.1% vs 6/180, 3.3%; p=0.43). 190 (61.9%) patients were evaluable for 14 week change in Ki67. The median log-fold change in Ki67 was greater with letrozole + palbociclib vs letrozole alone (-4.1 vs -2.2; p<0.001) corresponding to a geometric mean change of -97.4% vs -88.5%. Similarly, a greater proportion of patients who received letrozole + palbociclib achieved CCCA (90% vs 59%, p<0.001). 146 (47.6%) patients were evaluable for c-PARP and the log-fold change (suppression) was greater with letrozole + palbociclib vs letrozole alone (-0.80 vs -0.42; p=0.003) corresponding to a geometric mean change of -56.8% vs -31.4%. Other biomarkers of response / resistance are being evaluated. A higher proportion of patients had a grade ≥3 toxicity on letrozole + palbociclib than letrozole alone (49.8% vs 17.0%; p<0.001) mainly due to asymptomatic neutropenia. Conclusion: Adding palbociclib to letrozole markedly enhanced the suppression of malignant cell proliferation as assessed by Ki67 but did not substantially increase the clinical response of primary ER+ breast cancer over a 14-week period. Concurrent reductions in cell death may have reduced the speed of tumor shrinkage. Citation Format: Dowsett M, Jacobs S, Johnston S, Bliss J, Wheatley D, Holcombe C, Stein R, McIntosh S, Barry P, Dolling D, Snowdon C, Perry S, Batten L, Dodson A, Martins V, Modi A, Cornman C, Puhalla S, Wolmark N, Julian T, Pogue-Geile K, Robidoux A, Provencher L, Boileau JF, Shalaby I, Thirlwell M, Fisher K, Huang Bartlett C, Koehler M, Osborne K, Rimawi M. PALLET: A neoadjuvant study to compare the clinical and antiproliferative effects of letrozole with and without palbociclib [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-02.

A randomized controlled trial of combination letrozole and clomiphene citrate or letrozole alone for ovulation induction in women with polycystic ovary syndrome

To evaluate whether a combination of letrozole and clomiphene citrate (CC) results in higher ovulation rates than letrozole alone in infertile women with polycystic ovary syndrome (PCOS). Open-label randomized controlled trial. Academic medical center using two clinic sites. Women 18-40years of age with a diagnosis of infertility and PCOS as defined by the Rotterdam criteria and no other known cause of infertility. Participants were randomized in a 1:1 ratio, stratified by age and body mass index, to either 2.5mg letrozole alone or the combination of 2.5mg letrozole and 50mg CC daily on cycle days 3-7 for one treatment cycle. Ovulation defined as mid-luteal serum progesterone concentration ≥3ng/mL. Seventy patients were randomized: 35 to letrozole alone and 35 to letrozole and CC. Results were analyzed according to the intention-to-treat principle. Women who received the combination of letrozole and CC had a statistically higher ovulation rate compared with those who received letrozole alone (27 of 35 women [77%] vs. 15 of 35 women [43%]). There were no serious adverse events or multiple-gestation pregnancies in either group. The side-effects profile was similar in the two treatment groups. The combination of letrozole and CC was associated with a higher ovulation rate compared with letrozole alone in women with infertility and PCOS. Further studies are needed to evaluate the effect on live birth rate. NCT02802865.

Efficacy and acceptability of neoadjuvant endocrine therapy in patients with hormone receptor-positive breast cancer: A network meta-analysis.

The optimal sequence of endocrine therapy in a neoadjuvant setting for hormone receptor-positive (HR+) breast cancer is unclear. Our study evaluated the efficacy and acceptability of neoadjuvant endocrine therapy for HR+ breast cancer. We identified studies based on titles and abstracts that were published before 22 June 2018 in the following databases: PubMed, EMBASE, and the Cochrane Library. Eligible studies were randomised controlled trials with at least one arm that evaluated the effectiveness of one or a combination of anastrozole, letrozole, palbociclib, tamoxifen, fulvestrant, abemaciclib, everolimus, gefitinib, ribociclib, taselisib, and exemestane. We pooled effect sizes using the odds ratio (OR) and corresponding 95% credibility interval (95% CrI). The primary outcomes were response rate and treatment completion. Our network meta-analysis included 3,306 participants and 16 eligible studies, which assessed 15 treatments. In terms of response rates, compared with letrozole combined therapy, tamoxifen was associated with a significant reduction in response rate (OR, 0.34; 95% CrI, 0.13-0.85; OR, 0.32; 95% CrI, 0.13-0.80; OR, 0.26; 95% CrI,0.09-0.83; and OR, 0.30; 95% CrI, 0.09-0.96; for letrozole plus everolimus, letrozole plus taselisib, letrozole plus zoledronic acid, and letrozole plus lapatinib, respectively). Based on the surface under the cumulative ranking curves ranking, letrozole plus zoledronic acid was associated with the highest rate of response (87.6%), followed by letrozole plus lapatinib (85.2%), and letrozole plus taselisib (79.3%). Ultimately, our study established that letrozole plus zoledronic acid may be an optimal treatment based on its current rank in a neoadjuvant setting for HR+ breast cancer.

Comparison between the Effectiveness of Combination of Letrozole with Misoprostol and Tamoxifen with Misoprostol in Medical Termination of First Trimester Missed Miscarriage

Comparison between the Effectiveness of Combination of Letrozole with Misoprostol and Tamoxifen with Misoprostol in Medical Termination of First Trimester Missed Miscarriage

Combined Letrozole and Clomiphene versus Letrozole with low dose gonadotropin protocol for ovulation induction in infertile clomiphene-resistant women with polycystic ovary syndrome: Comparative study

Objectives: To compare the effect of combined clomiphene citrate (100mg) and Letrozole (5mg) versus Letrozole (5mg) followed by gonadotropin injection for one cycle in CC resistant PCOs patients.Design: Prospective randomized trial.Setting: Infertility Outpatient Clinic and Cytogenetic and Endoscopy Unit of Obstetrics and Gynecology Department of Zagazig University Hospitals.Study group: About 212 PCOs patients with CC resistance (anovulatory response with CC at a dose of 100-150 mg for 3 cycles) were divided into two groups (106 in each group).Intervention: A studied group was randomly divided into two groups. Group A received combined Letrozole 5mg (2 tablets) in the morning and clomid 100 mg (2 tablets) in the evening from the 3rd day of menses for 5 days, group B received Letrozole 5 mg (2 tablets) from the 3rd day of menses for 5 days followed by human menopausal gonadotropin (hMG) injection every other day from cycle day 7. Moreover, ultrasound folliculometry started on cycle day 10 then the dose was adjusted according to follicular size. Both groups received treatment regimen for only one cycle.Results: There was higher ovulation rate (85.8%) in letrozole plus hmG group than in the other group receiving letrozole and CC (80.2%), but with no statistical significant difference (P -value =0.65). But, there was statistical significant difference between both groups regarding stimulation characters including total number of mature follicles (≥18 mm) 2.1 ± 1.01 in combined letrozole and CC was greater in group A than in group B (1.66 ± 0.98) with (P - value = 0.009). Stimulation days were longer in group B (18.2 ± 2.5) than in group A (16.2 ± 2.1). Mean total E2 on the day of hCG administration was significantly higher among patients in the clomiphene-letrozole group as compared with that in the other group of letrozole with hmG ( 650 ± 190.3 and 540 ± 180.5, respectively). Also, higher day 21 serum progesterone in group A (11 ± 1.1) than (9.5 ± 0.9) in group B. But, there was no statistical significant difference in mean endometrial thickness in both groups (A and B) (9.6 ± 1.7 versus 9.8 ± 1.5mm, respectively) (P-value = 0.41). The pregnancy rate did not show any statistical significant difference in both groups (P-value = 0.45) ; 32 patients out of 106 (30.1%) in group A compared with 27 patients (25.4%) in group B. Four cases were aborted in group A compared with 3 cases in group B. Four cases had twin pregnancy in group A with only 3 cases in group B. Also, there was no significant difference between both groups regarding ovarian hyperstimulation ; as there were 2 cases with combined clomid and letrozole group and one case only in letrozole plus hmG group.Conclusion: This study showed that lerozole is an effective medication when combined with CC or sequentially with hmG injection in improving the ovulation and pregnancy rate in CC-resistant PCOs patients with higher results when combined with hmG injection, but did not reach statistical significance.

A randomized controlled trial of combination of letrozole and clomiphene citrate versus letrozole alone for ovulation induction in women with polycystic ovary syndrome

A randomized controlled trial of combination of letrozole and clomiphene citrate versus letrozole alone for ovulation induction in women with polycystic ovary syndrome

Higher endometrial receptivity caused by Letrozole in antagonist protocol-stimulated mouse uterus

Background: The implantation rate of IVF remains low due to the adverse effect of ovarian stimulation on endometrial receptivity. Integrin β3, E-cadherin and Leukemia Inhibitory Factor (LIF) are the best markers known for endometrial receptivity evaluation. In this study, the effect of adding Letrozole to antagonist protocol based on the expression of integrin β3, E-cadherin and LIF level during implantation window was investigated. Letrozole is an inhibitor of aromatase that can prevent the supraphysiological estrogen level. The goal of the study was to prove that adding Letrozole to IVF antagonist protocol can increase the expression of Integrin β3, E-cadherin, and LIF concentration of mice uterine. Methods: This is an experimental study with a post-test only group design using Balb/c mice mimicked ovarian stimulated IVF. Antagonist protocol was applied to one group as ovarian stimulation, while the other group received the combination of Letrozole and antagonist protocol.  Uterus samples were collected 48 hours after ovarian stimulation. Integrin β3 and E-cadherin expression were detected by immunohistochemistry technique and LIF level assay by ELISA. Normality test was carried out using Shapiro-Wilk, and homogeneity test by Levene’s T. Comparison between integrin β3 and E-cadherin expression were tested by Mann-Whitney and Fisher's exact, while comparison of LIF was tested by Mann- Whitney, with p<0.05 considered as significant. Path analysis was done to measure each variable contribution.Results: The Letrozole + GnRH antagonist treated mice showed significantly higher integrin β3 (2.71 + 0.61 vs 1.04 + 0.08, p<0.05) and E-cadherin (3.73 + 0.28 vs 1.16 + 0.29, p<0.05) expression in endometrium. It also showed significantly higher level of uterine LIF (1.78 + 0.13 vs 1.66 + 0.17 ng/ml, p<0.05) during implantation window than GnRH antagonist treated mice alone. Expression of integrin β3 (c2= 22.91, p<0.05) and E-cadherin (c2=36.00, p<0.05) were significantly higher in Letrozole group compared to control.Conclusion: Letrozole caused higher expression of Integrin β3, e-cadherin, and, LIF concentration in Mice uterine stimulated by antagonist protocol. Letrozole had the highest contribution to the increase of E-cadherin.  Integrin β3 together with E-cadherin and Letrozole had 31.4% contribution to the increase of LIF.Â

Palbociclib in the first line combination hormone therapy of HER2- negative metastatic hormone-dependent breast cancer. Clinical follow-up

According with the present-day ideas, sequential lines of hormone therapy including those in patients with visceral metastases and multiple lesions form the basis of the treatment of HER2-negative metastatic hormone-dependent breast cancer. These measures make it possible to exercise the long-term control of the disease and maintain a good quality of life. In recent years, the clinical practice comprises the next-generation drugs that potentiate the effect of hormone therapy. These include cyclindependent kinases 4/6 inhibitors. Palbociclib (Ibransa, Pfizer) is the first representative of this class approved in Russia for the treatment of disseminated hormone-dependent breast cancer. The PALOMA-2 study demonstrated the high efficacy of the palbociclib combined with letrozole as a first-line hormone therapy. In the palbociclib and letrozole combination arm, the median time to progression was 27,6 months compared to 14,5 months in the letrozole monotherapy arm (p <0,001). The presented clinical case demonstrates the possibility of long-term successful control of the disease using palbociclib combined with letrozole hormone therapy.

Effects of Vorinostat, Letrozole and RG7388 Treatments on Cell Cycle Arrest and Survival of Breast and Prostate Cancer Cells

Alterations in gene expressions are often due to epigenetic modifications that can lead to significant influence on cancer development, growth, and progression. In this respect, HDAC inhibitors such as Vorinostat, which can exert epigenetic alterations, are emerging as a new class of drugs with promising impact on the cancer growth and metastatic process. Letrozole is one of the commonly used aromatase inhibitors that can elicit strong anti‐cancer effects on breast cancers through direct as well as indirect mechanisms. On the other hand, RG7388 is a newly developed inhibitor for an oncogene‐derived protein called MDM2, which is in clinical trials for the treatment of various cancers. Our aim for this study was to understand the molecular mechanism whereby Vorinostat can induce cell cycle arrest and trigger necrosis or apoptosis, when used in monotherapy or in combination with Letrozole or RG7388. We performed assays to measure the cell cycle arrest effects of individual drug treatments alongside of combination treatments with Vorinostat + Letrozole, and Vorinostat + RG7388 using MCF‐7 and LNCaP cancer cells. The cytotoxicity, cell cycle arrest and pro‐apoptotic effects of the treatments were assessed by using Trypan Blue dye exclusion method, MTT assay, immunoblotting, RT‐PCR, and qRT‐PCR methods. Our results from MCF‐7 and LNCaP cells confirmed that Vorinostat, Letrozole and RG7388 treatments were able to induce cell death via combination of cell cycle arrest and cytotoxic mechanisms in a dose and time dependent manner. The IC50 value for Vorinostat and RG7388 were determined to be around 7.5 μM and 2 μM respectively. Although, Letrozole showed stronger cytotoxic effects with the IC50 value of 100 nM in MCF‐7 and LNCaP cells, combination of Letrozole with SAHA did not produce synergy or additive effects. On the other hand, when SAHA was used in combination with RG7388, a significant increase in the cytotoxic effect was obtained. Induction of cell cycle arrest in the cancer cells were evidenced by the elevation of p21 protein levels following SAHA and RG7388 treatments. In addition, the SAHA treatment in LNCaP cells showed significant up regulation in the expression of other cell cycle related genes such as, p27, and p53 and down regulation of AURKB, CDC25C, and CDK1. The effects of SAHA monotherapy and combinations were assessed further by using SYTOX and Ac‐DEVD‐amc [Ac (N‐acetyl)‐DEVD‐AMC (7‐amino‐4‐methylcoumarin)] staining method, to determine the extent of necrotic cell death or apoptosis. Our results confirmed that the cell death caused by SAHA treatment was primarily through induction of necrosis. On the other hand, the RG7388 treatment was able to induce apoptosis by elevating Caspase 3 activity. It appears that, during combination treatments with SAHA and RG7388, two parallel pathways are induced simultaneously that could lead to increased cancer cell death. It has been reported in the literature that the elevated levels of acetylated histones (H2 and H3) and consequent activation of intracellular signals are responsible for the cell cycle arrest and necrosis that are typically observed when HDAC inhibitors (HDACi) are used. So far, the results of SAHA and RG7388 combination experiments have confirmed the abilities of these two agents for eliciting additive or synergistic effects in MCF7 and LNCaP experimental models. We are speculating that our findings could lead to the development of newer treatments for breast and prostate cancers using this type of combinations.Support or Funding InformationThis research was supported by the Royal Dames of Cancer Research, Fort Lauderdale, Florida, USAThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The combination of letrozole and metformin has a better therapeutic effect on uterine and ovarian arteries in PCOS patients

The combination of letrozole and metformin has a better therapeutic effect on uterine and ovarian arteries in PCOS patients

Letrozole pretreatment prior to medical termination of pregnancy: a systematic review

ObjectiveThe purpose of this systematic review was to evaluate the efficacy of pretreatment with letrozole prior to either a first- or second-trimester medical termination of pregnancy. Study designWe searched letrozole, femara, aromatase inhibitors, abortifacient agents, termination of pregnancy and labor induction in MEDLINE, EMBASE, Cochrane Database, Google Scholar and PubMed from inception of each database until September 2015 with no language limitation. A systematic review of all randomized controlled trials (RCTs) was performed where women received either letrozole and misoprostol or placebo and misoprostol for termination of pregnancy. The primary outcome was complete abortion rate, defined as complete evacuation of the products of conception from the uterus. Relative risk with 95% confidence intervals was used to report data. ResultsOur systematic review identified 7 studies; 4 RCTs were included in the review. Two RCTs evaluated terminations of pregnancy up to 9 weeks’ gestation, while 2 evaluated terminations over 9 weeks’ gestation. For each gestational age group, one trial supported an increase in complete abortion rate, while the other showed no difference, with letrozole and misoprostol compared with placebo and misoprostol. Time-to-abortion interval for terminations up to 9 weeks’ gestation was not improved with the addition of letrozole to misoprostol. For terminations over 9 weeks’ gestation, one trial supported and one trial refuted a decrease in time-to-abortion interval with letrozole and misoprostol. Similarly, for each gestational age group, one study supported a decrease and one study showed no difference in rate of dilation and curettage (D&C) with letrozole and misoprosol. Medication side effects were similar between both treatment groups. There was significant heterogeneity between the trials, and therefore, the results were not meta-analyzed. ConclusionsSome studies and trials report better outcomes (i.e., complete abortion rates, time-to-abortion and D&C rates) in women exposed to letrozole and misoprostol compared to placebo and misoprostol, while other trials demonstrate no difference. Further research exploring letrozole pretreatment prior to medical abortion is required. ImplicationsThis systematic review demonstrated that a combination of letrozole and misoprostol increased the rate of complete abortion compared to misoprostol alone in some studies but not in others; additional well-designed RCT's are needed.

Evaluation of effect of letrozole prior to misoprostol in comparison with misoprostol alone in success rate of induced abortion

BackgroundAbortion, spontaneous or induced, is a common complication of pregnancy and exploration of available and safe regimens for medical abortion in developing countries seems crucial. AimsThe present study was aimed to assess the effect of letrozole in combination with misoprostol in women eligible for legal therapeutic abortion with gestational age ≤14weeks. Materials and methodsThis clinical randomized trial was conducted on 78 women who were candidate of medical abortion and eligible for legal abortion with gestational age ≤14 weeks that were randomly divided into two groups of case and controls. Case group received daily oral dose of 10mg letrozole for three days followed by vaginal misoprostol. In control group the patients received only vaginal misoprostol. The rate of complete abortion, induction-of-abortion time, and side-effects were assessed. ResultsComplete abortion was observed in 30 patients (76.9%) in case group and 9 (23.1%) cases were failed. In control group there was 16 (41.03%) complete abortions and 23 (58.97%) cases were failed to abort. Patients with gestational age of between 6 and 10 weeks did not show significant difference in both groups (P=0.134). Regarding pregnancy remnants there were significant differences between two groups (P=0.034). The time form admission to discharge in case groups were significantly shorter than those in control group (P=0.001). The indication for curettage in case group was significantly less than control group (P=0.001). ConclusionA 3-day course of letrozole (10mg/daily) followed by misoprostol was associated with a higher complete abortion and lower curettage rates and reduction in time from admission to discharge in women with gestational age ≤14 weeks compared to misoprostol alone.

Increased sperm cell production in ageing roosters by an oral treatment with an aromatase inhibitor and a natural herbal extract designed for improving fertility.

Rooster fertility peaks between 30 and 40weeks of age and declines rapidly from 50weeks of age. This is linked to a reduction in the number of spermatozoa in the ejaculate due to high density of spermatids in the seminiferous tubules of low-fertility roosters. In this study, we assessed the effects over spermatogenesis of both letrozole, an aromatase inhibitor, and a commercial herbal extract designed for improving fertility composed by Tribulus, Cinnamomum, Zingiber and Sativus. Forty-two-week-old Ross 308 roosters (n=24) were distributed into four groups: control, letrozole (0.03mg/kg), herbal extract (0.04ml/kg) and letrozole+herbal extract. After 14weeks of daily oral supplementation, their testes and epididymides were weighed, fixed and sectioned for assessment of spermatogenesis and quantification of sperm cells inside the lumen. Differences in seminiferous tubules measurements and density of sperm cells were tested using R software (version 3.0.1). Although body weight was not affected by the treatment, testes from animals treated with the combination of letrozole and herbal extracts were heavier than those from control animals. Animals treated with either letrozole or herbal extract, or their combination, showed a significant higher number of sperm cells inside the seminiferous tubules and epididymis than control animals (p<.05). These data suggest that the use of letrozole and the herbal extract could improve sperm cell production in ageing roosters. Future studies are needed to disclose the causal mechanisms involved and its effect on fertility and ejaculate features.

Ovulation induction and controlled ovarian stimulation using letrozole gonadotropin combination: A single center retrospective cohort study

ObjectiveTo assess the effect of letrozole in combination with low dose gonadotropins for ovulation induction in anovulatory infertility from polycystic ovary syndrome (PCOS) and controlled ovarian stimulation for endometriosis, and unexplained infertility patients. Study designRetrospective cohort study in a setting of private Reproductive Endocrinology and Infertility Clinic affiliated with the University. Three hundred couples (650 cycles) requiring OI/COS for PCOS (92 patients, 195 cycles), endometriosis (89 patients, 217 cycles), and unexplained infertility (119 patients, 238 cycles). Patients received 2.5mg or 5mg letrozole for 5days (D3–D7) and recombinant follicle-stimulating hormone on alternating D3-D7 and human menopausal gonadotropin-highly purified alternating D5-D10 until growth of ideally 2 mature follicles. Ovulation was triggered with 10,000 IU of HCG. Maximum number of cycles per patient was four. ResultsMain outcome measures were clinical pregnancy rates, multiple order pregnancy rates, miscarriage rates, number of follicles and endometrial thickness on the day of HCG administration. The cumulative incidence of pregnancy was estimated as 35% (95%CI: 29%–41%) overall and was highest in patients with PCOS (36.6%), followed by unexplained infertility (34.6%) and endometriosis (32.5%). The pregnancy rates per cycle in PCOS, endometriosis and unexplained infertility patients were 17%, 13.2% and 17.2% respectively, no statistically significant difference between the groups. There were three twin pregnancies in PCOS, and one in unexplained infertility group. Monofolliculogenesis was noted in 48% of patients. Conclusion(s)Letrozole-low dose gonadotropins combination appears to be effective across different causes of infertility for superovulation. The letrozole-low dose gonadotropin combination resulted in high rate of monofolliculogenesis, low occurrence of multiple gestations and no case of OHSS or cycle cancellation.

Combined Raloxifene and Letrozole for Breast Cancer Patients

Raloxifene, an anti-osteoporotic drug, is recently approved for prevention of breast cancer in postmenopausal women and thus the drug may be employed to combat the bony adverse effects of letrozole, another anticancer drug. However, the cytotoxic effect of their combination on human breast cancer (MCF-7) and human embryonic kidney (HEK) cell lines is not known. MCF-7 and HEK cell lines were treated with different graded doses of letrozole, raloxifene and their combination, then incubated for 24-48h. MTT assay was performed to check the cytotoxicity of the drugs. The study indicates that the combination of letrozole and raloxifene possess additive effect in terms of cytotoxicity of cancer cell lines (MCF-7) and negligible effects in normal cell lines (HEK). Our study indicates that the addition of raloxifene doesn't interfere with anticancer efficacy of letrozole rather the combination acted additively for the treatment of breast cancer.

Efficacy of combined metformin- letrozole in comparison with metformin-laparoscopic ovarian diathermy in ovulation induction and reproductive outcome for women with clomiphene citrate resistant polycystic ovary syndrome

Background and objective: polycystic ovary syndrome(PCOS) is a common cause of infertility and is associated with chronic anovulation and hyperandrogenism.The aim of current study is to compare the effect of combined letrozole metformine to that of metformin-laparoscopic ovarian drilling (LOD) for ovulation induction in patients with PCOS.Materials and Methods: on the whole 138 ovarian cycles were studied in 60 patients with clomiphene citrate resistant PCOS in AL-Diwaniyah Maternity and Pediatrics Teaching Hospital during the period of June 2112-June 2114. All patients (n=60) received metformin 500mg /3times per day ,group A(n=30)received letrozole 5mg daily for 5 days repeated for 6 cycles, group B(n=30) underwent LOD and followed for six cycles. Outcome measures were ovulation rates, endometrialthickness, pregnancyrates, live birth rates and miscarriage rate.Results: ovulation rate was higher in group A than group B(63.33% versus 30.0%),a significant increase in endometrial thickness in group A than group B(9.9mm versus 9.03 mm).Live birth rate was higher in group A 83.33% compared to 33.33% in group B. There were no significant differences regarding miscarriage rates between both groups. No multiple pregnancy or ovarian hyper stimulation syndrome or congenital abnormality among live births were reported.Conclusions: Combinedletrozolemetformin seems to be a suitable second line ovulation inducing alternative to LOD in women with PCOS who do not respondwith clomiphene citrate.

Abstract 4160: Impact of oral selective estrogen receptor degrader RAD1901 in preclinical models of endocrine sensitive/resistant breast cancer

Abstract Aromatase inhibitors (AI) are the mainstay for treatment of postmenopausal estrogen receptor positive (ER+) primary breast cancer (BC). However, many patients relapse whilst retaining a functional ER. The selective ER degrader (SERD) fulvestrant has been evaluated as a potential 2nd or 3rd line therapy for patients who relapse on AI treatment. Although exhibiting promising potential, its low bioavailability has limited its use to combination therapy in metastatic patients. Here, we assessed the efficacy of the orally available SERD, RAD1901, in a panel of BC cells with varying genetic backgrounds modelling patients both sensitive and resistant to AI therapy (LTED). Fulvestrant was used in parallel to allow relative responses to be compared. Cell proliferation assays in 2D and spheroids the presence of 0.01nM 17β-estradiol showed a concentration-dependent decrease in proliferation in response to RAD1901 and fulvestrant. GI50 values for RAD1901 in general were 10-fold higher than fulvestrant but equated to doses that are clinically achievable for RAD1901. Most importantly, RAD1901 effectively suppressed proliferation of two LTED models harbouring naturally occurring ESR1 mutations, MCF7 LTEDY537C (GI50 5nM) and SUM44-LTEDY537S (GI50 100nM). GI50 values of RAD1901 and fulvestrant showed similar reduction of ER, progesterone receptor (PGR) and cyclin D1 together with decreased phosphorylation of retinoblastoma (RB), concordant with cell cycle arrest. Furthermore, chromatin immunoprecipitation (ChIP) for ER in response to RAD1901 or fulvestrant showed a 70% reduction in recruitment of ER to TFF1, GREB1 and PGR promoters and concomitant reduction in mRNA expression of these genes. In MCF7-Arom cells, combination of letrozole with RAD1901 or fulvestrant showed enhanced antiproliferative effect compared to letrozole alone. The addition of RAD1901 to CDK4/6 inhibitor palbociclib or abemaciclib demonstrated additivity compared with monotherapy. In addition, RAD1901 effectively inhibited growth of palbociclib-resistant MCF7 LTED cells.These preclinical findings highlight the potential utility of RAD1901 as a potent drug in the treatment of ER+ BC. Combined with its bioavailability profile, RAD1901 warrants clinical testing versus fulvestrant after relapse on an AI, either alone or in combination with a CDK4/6 inhibitor. Citation Format: Sunil Pancholi, Joanna Nikitorowicz-Buniak, Ricardo Ribas, Nikiana Simigdala, Fiona Garner, Teeru Bihani, Stephen R. Johnston, Mitch Dowsett, Lesley-Ann Martin. Impact of oral selective estrogen receptor degrader RAD1901 in preclinical models of endocrine sensitive/resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4160. doi:10.1158/1538-7445.AM2017-4160

Proof-of concept phase I study of everolimus, letrozole and trastuzumab in hormone receptor-positive, HER2-positive/amplified or mutant metastatic breast cancer or other solid tumors: Evaluating synergy and overcoming resistance.

2583 Background: Preclinical models suggested synergistic antineoplastic activity of anti-estrogen therapy with HER2 and mTOR inhibitors. Methods: We designed a 3+3 dose escalation phase I study of the aromatase inhibitor letrozole 2.5mg PO daily, mTOR inhibitor everolimus 2.5-10mg PO daily and HER2 antibody trastuzumab 4-8mg loading dose followed by 2-4mg maintenance dose IV on day 1 of 21-day cycle in patients with hormone-receptor positive, HER2-positive/amplified or mutant advanced cancers (confirmed by immunohistochemistry and/or FISH and/or next-generation sequencing). The primary objectives were to determine maximum tolerated dose (MTD), dose limiting toxicities (DLT), overall safety and response. Results: A total of 18 patients (men, 1; women, 17; HER2 amplification, 14; HER2 mutation, 4; breast cancer, 15; ovarian cancer, 1; cervical cancer, 1; gastroesophageal junction cancer, 1), median age 56 years, median of 6 prior therapies (including letrozole [9] or other aromatase inhibitor [8]; everolimus [3]; trastuzumab [14] or other HER2 targeted therapy [1]) were enrolled in the planned 6 dose levels. The MTD has not been reached and grade 3 (G3) mucositis at the dose level 4 was the only DLT. Other G3 or G4 drug-related toxicities included G4 hyperglycemia in 1 patient, G3 hyperglycemia in 3 patients, G3 thrombocytopenia in 1 patient, G3 anemia in 1 patient and G3 headache in 1 patient. Of 18 patients, 3 (17%) had a partial response (all with heavily-pretreated breast cancer with HER2 amplification [2] or HER2A775_G776insYVMA mutation [1]), 11 (61%) stable disease (SD) including 7 (39%) patients with SD &gt; 6 months (all with heavily-pretreated breast cancer), 3 (17%) progressed and 1 had pending evaluation. The median change in size of target lesions per RECIST 1.1. was -11% (-68% to +47%). Median progression-free survival was 9 months (95% CI 5.8-12.2). Conclusions: The combination of letrozole, everolimus and trastuzumab is well tolerated with encouraging activity in heavily-pretreated patients with HER2-amplified or mutant advanced breast cancer. Clinical trial information: NCT02152943.

Treatment Effects of Vorinostat and Letrozole Combination on Breast Cancer Cell Survival and Peripheral Blood Mononuclear Cell Differentiation

HDAC inhibitors are new class of drugs that show promising impact on the cancer growth and metastatic process. Letrozole is one of the aromatase inhibitors that could also elicit strong anticancer effects on breast cancers through direct as well as indirect mechanisms. Our aim was to understand the intracellular mechanism whereby Vorinostat, in monotherapy and in combination with Letrozole, can induce cell cycle arrest and apoptosis in breast cancer cells. In addition, we also attempted to determine how Vorinostat and Letrazole can inhibit Peripheral Blood Mononuclear Cell (PBMC) differentiation into osteoclasts and cause programmed cell death. We performed assays to measure the anti‐proliferative, pro‐apoptotic effects of monotherapy (Vorinostat) and combination (Vorinostat + Letrozole) treatments in cancer cells (MCF‐7) as well as in PBMC, that was isolated from healthy individuals and undergoing osteoclast differentiation in a specialized medium that contained RANKL and M‐CSF (Macrophage – colony stimulating factor). Immediately after treatments, determination of cytotoxicity on MCF‐7 was performed using MTT assay and the pro‐apoptotic effects were assessed by immunoblotting and RT‐PCR analyses. Our results confirmed that both Vorinostat and Letrozole were able to induce cell death in MCF‐7 cells in a dose and time dependent manner. The IC50 value for Vorinostat were around 1.5 μM, and 1.2 mM respectively for MCF‐7 and PBMC. In our experiments, Letrozole showed much stronger effects and the IC50 values were 4 nM and 2.5 nM respectively for the above listed cells. Induction of apoptosis in these cells were evidenced by the elevation of p21, Bax, Caspase 3 and down regulation of Bcl2. The induction of apoptosis was further confirmed by DNA fragmentation in our in vitro experimental systems. Furthermore, our experiments with PBMC using both mono therapies and the combination treatments revealed that, they were able to block the osteoclast differentiation at reduced doses when combined together for treatments. It has been reported that the elevated levels of acetylated histones H3 and H4 and consequent intracellular signals are responsible for the cell cycle arrest and pro‐apoptotic events that are seen when HDAC inhibitors are used. Similar mechanisms may be responsible for the intracellular effects observed in our experimental systems. Thus, the results obtained from our in vitro experiments suggest that combination of Vorinostat and Letrozole is very dynamic and effective, not only in blocking the proliferation of MCF‐7 cells but also in inhibiting the differentiation of PBMC into osteoclasts and reducing their survival capacity. This suggests that, during clinical use, the above indicated combination might provide dual benefits, by blocking cancer cell proliferation as well as reduction of breast cancer associated osteoporosis caused by osteoclasts. In essence, the above discussed treatment outcomes may be achieved by minimizing the differentiation and formation of osteoclasts from PBMC in cancer patients, that appears to be further supported by the induction of programmed cell death.