Efficacy Of Endocrine Therapy Research Articles

A GINECO randomized phase II assessing addition of an aromatase inhibitor to oral vinorelbine in pretreated metastatic breast cancer patients.

1043 Background: For ER+/HER2- metastatic breast cancer (mBC), efficacy of endocrine therapy + chemotherapy combination remain an open question. We hypothesized that continuing ER targeted therapy after progression in combination with chemotherapy may improve disease control. The objective of the CHEOPS trial was to assess the benefit of adding aromatase inhibitor (AI) to metronomic chemotherapy,oral vinorelbine, 50mg/3 time a week (OV) for AI pre-treated, ER+/HER2- mBC patients. Methods: Eligible patients had to have progressed on endocrine therapy and one or two lines of chemotherapy. They were randomized between vinorelbine (OV) and vinorelbine + AI (OV+AI). Primary end point was progression-free survival (PFS). To show an increase of median PFS (from 3.5 to 5.5 month, HR 0.636), with alpha = 5% and power = 80%, 130 evaluable patients were needed. Results: 121 patients were Included (OV = 61; OV+AI = 60). Median age was 68 (range: 49-87), Median time from metastatic diagnosis was 3.2 years (range 0 - 16.9). 109 patients (90%) had visceral metastases. They all had previously received an AI and had been treated with one line (N = 66, 54.5%), or 2 lines (N = 55, 45.5%) of chemotherapy. Median PFS was increased from 2.3 months with OV to 3.7 months with OV+AI, but this difference was not significant (HR 0.73 [95 % CI 0.50-1.06], log-rank test: P = 0.09) 81 patients (67%) had at least one adverse event (AE) of grade ≥ 3 (40 (66%) for OV vs 41 (68%) for OV+AI). The most common grade ≥ 3 AE were: GT gammas (23%), neutropenia (18%), arterial hypertension and lymphopenia (17%). The occurrence of 3 toxic deaths (OV = 1; OV+AI = 2) secondary to febrile aplasia motivated the early cessation of this clinical trial. 9 patients (5 OV (10%) and 4 OV+AI (8%) presented an objective complete or partial response. Conclusions: The addition of AI to OV over OV alone in AI resistant mBC was associated with a non-significant improvement of PFS, but both PFS are lower than expected. Metronomic OV schedule, at 50 mg three times a week, requires close biological monitoring. The question of hormonal treatment and chemotherapy combination remains open. Clinical trial information: EudraCT Number: 2015-000401-39.

Everolimus in hormone receptor-positive metastatic breast cancer: PIK3CA mutation H1047R was a potential efficacy biomarker in a retrospective study

BackgroundEverolimus, an inhibitor of mammalian target of rapamycin (mTOR), has been shown to increase the efficacy of endocrine therapies in hormone receptor (HR)-positive metastatic breast cancer. However, because breast cancer is a highly heterogeneous disease, the responses of different patients to everolimus may vary. Therefore, we performed this study to better select patients who will benefit most from or be resistant to everolimus.MethodsPatients with HR-positive breast cancer who were treated with everolimus at the Cancer Hospital, Chinese Academy of Medical Sciences from February 2014 to March 2017 were enrolled in the present study. Mutations in ctDNA were assayed in 1021 tumor-related genes via gene panel target capture-based next-generation sequencing.ResultsIn total, 120 patients with metastatic breast cancer who were treated with everolimus were enrolled in the present study. The median progression-free survival (PFS) of all patients was 5.1 months (95% confidence interval [CI] 3.9–6.3 months). No difference in survival was observed between patients who received endocrine drugs used in previous treatment regimens and patients who did not receive these drugs (median PFS 5.2 and 5.1 months, respectively, p > 0.05). Additionally, we did not find any difference in outcomes between patients who had primary resistance to previously used endocrine drugs and patients who had nonprimary resistance to previous treatments (p > 0.05). Multivariate analysis showed that < 3 metastatic sites, < 2 lines of previous endocrine therapy, < 2 lines of previous chemotherapy, and treatment with everolimus combined with fulvestrant were associated with improved survival (p < 0.05). Sixteen patients underwent ctDNA analysis before everolimus treatment. The frequency of PIK3CA gene mutations was 62.5%, and H1047R was the most frequently detected mutation. Patients with the PIK3CA/H1047R mutation had longer PFS than patients with wild-type or other mutant forms of PIK3CA, and the median PFS in these two groups of patients was 8.8 and 4.1 months, respectively (p < 0.05).ConclusionsOur data suggest that patients who receive more lines of chemotherapy or endocrine therapy are less likely to benefit from everolimus. For everolimus combination therapy, we can even select endocrine drugs that gave rise to primary resistance in previous treatments. Additionally, the PIK3CA/H1047R mutation may be a potential biomarker of sensitivity to everolimus.

SAT-LB003 Nonsmokers Benefit from Lower Doses of an Estradiol/Progesterone Combination: Results of the REPLENISH Trial

Smoking has previously been reported to result in decreases in estradiol exogenous metabolism1,2,3 and may influence the efficacy of hormone therapy (HT) in postmenopausal women2,3. Importantly, differences in smoking rates among clinical trial populations may also contribute to differences in effects of HT observed across the trials.2 The REPLENISH trial (NCT01942668) was a 12-month, phase 3, randomized, double-blind, placebo-controlled, multicenter trial that evaluated 4 doses of TX-001HR (17β-estradiol and progesterone [E2/P4]; 1/100, 0.5/100, 0.5/50, 0.25/50) combined in a single, oral softgel capsule vs placebo in 1835 menopausal women (40−65 y; intact uterus) for the treatment of menopausal, moderate to severe vasomotor symptoms (VMS). The 1 mg E2/100 mg P4 dose is FDA approved as BIJUVATM (TherapeuticsMD, Boca Raton, FL). In this trial, statistically significant improvements in the frequency and severity of moderate to severe VMS were observed for the two highest doses of TX-001HR (1/100 and 0.5/100) and is reported in detail elsewhere.4 The objective of this analysis was to assess the impact of smoking on estradiol metabolism by analyzing estradiol and estrone concentrations measured throughout the study and to assess the potential impact on efficacy. The overall percentage of current smokers was higher in the Replenish trial (26%) than in many other trials of HT, making analysis of the impact of smoking on estrogen levels and efficacy possible. Estradiol and estrone concentrations at baseline were similar between current smokers and nonsmokers (former/never smokers) for all treatment groups (active and placebo). However, at Weeks 4 and 12, Months 6, 9, and 12, estradiol (25%-32%) and estrone (30%-36%) concentrations were statistically significantly lower in smokers than in nonsmokers for all active estradiol/progesterone treatment groups (1/100, 0.5/100, 0.5/50, 0.25/50). There were no significant differences at any time point in the placebo group. Efficacy in reducing the frequency and severity of VMS was greater in nonsmokers. When evaluating nonsmokers, the 0.25/50 dose also demonstrated statistically significant improvements at Weeks 4 and 12, with a weekly reduction of greater than 14 hot flushes compared to placebo beginning at Week 4 and sustained through week 12. Results from this large Phase 3 clinical trial demonstrated a significant impact of current smoking on estradiol and estrone concentrations and indicate that non-smokers may benefit from lower doses of estradiol and progesterone than smokers. 1. Jensen J, et al. NEJM. 1985;313(16):973-975. 2.Tansavatdi B, et al. Minerva Ginecol. 2004;56:105-114. 3. Ruan X and Mueck AO. Climacteric. 2015;18:38-46. 4. Lobo RA, et al. Obstet Gynecol. 2018;132:161-170. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Short article: Hormone therapy for severe gastrointestinal bleeding due to multiple angiodysplastic lesions.

This study aims to assess the efficacy of hormone therapy in patients with severe gastrointestinal bleeding due to multiple angiodysplastic lesions. Between May 2010 and July 2017, we included 12 consecutive patients with anaemia or recurrent bleeding due to angiodysplasia who had been started on hormone therapy. The therapy given was a combination of levonorgestrel (between 0.10 and 0.25 mg) and ethinylestradiol (between 0.02 and 0.05 mg). We determined the mean number of transfusions required in the 6 months before and after the start of the treatment, as well as the mean haemoglobin levels, number of admissions for anaemia due to gastrointestinal bleeding and length of hospital stay in these periods. The mean age of patients included was 77.83 years old and 75% were male. The follow-up period after treatment initiation was 6 months. Of the 12 patients included, only one stopped the treatment owing to it not being effective. Overall, 83.3% of the patients reported subjective improvement. Furthermore, we found significant differences comparing before and after starting treatment regarding the mean number of transfusions (7±4.8 vs. 3.4±4.6; P=0.005), the mean haemoglobin levels (9.5±1.2 vs. 10.8±2.6; P=0.034) and the mean number of admissions (1.6±1.6 vs. 0.2±0.4; P=0.024). On the contrary, differences between pretreatment and post-treatment length of hospital stay were not significant. Hormone therapy is a potentially useful therapeutic tool in patients with refractory bleeding and anaemia due to angiodysplasia.

Abstract P5-11-11: A preliminary assessment of knowledge, attitudes, and awareness surrounding ESR1 mutations and biomarker testing amongst medical oncologists

Abstract Background: Estrogen receptor gene (ESR1) mutations present in breast cancer patients are associated with resistance to endocrine therapy and worse patient outcomes. Recent findings suggest ESR1 mutations are present in up to 40% of metastatic breast cancer (mBC) patients' tumors. The objective of this study was to evaluate the perceptions of precision medicine and biomarker testing specific to ESR1 mutations among medical oncologists. Methods: Ten 60-minute web-assisted, telephone interviews were conducted with medical oncologists. Each physician was prescreened prior to being interviewed to ensure board certification and practice experience between 2 and 35 years. Each participant spent greater than 30% of their time on direct patient care and managed the treatment of more than 30 different cancer patients per month, with a minimum of 15 breast cancer patients, including at least five who had metastatic breast cancer and at least one patient with an ESR1 mutation. Results: A 10-20% prevalence of ESR1 mutation was estimated by the oncologists. However, the practitioners did accept the possibility of a 40% prevalence. Physician knowledge of ESR1 mutations included the relationship between ESR1 mutations and efficacy of endocrine therapies and its association with poorer outcomes. None of the medical oncologists interviewed were highly satisfied with the existing armamentarium of treatments for patients with an ESR1 mutation. In general, the interview participants were highly comfortable ordering ESR1 companion diagnostics to test for an ESR1 mutation, pending viable treatment options are available. Nonetheless, most physicians will wait until the patient has progression of disease before ordering a biomarker test. Several areas of unmet need in the mBC arena were offered by the survey participants, including more efficacious hormonal options for later-line therapies, better durability of remission, improved drug tolerability profiles, and lower treatment costs. Conclusion: Most oncologists acknowledged that personalized treatment is beneficial because it allows for better efficacy than a “one size fits all” approach. The study results also suggest that there are few barriers and drawbacks to the use of personalized medicine in the mBC arena, as most physicians expect precision medicine to account for the majority of advances in breast cancer treatments in the foreseeable future. Support: Sermonix Pharmaceuticals Citation Format: Goldfarb SB, Goetz MP, Plourde PP, Attias E, Portman DJ. A preliminary assessment of knowledge, attitudes, and awareness surrounding ESR1 mutations and biomarker testing amongst medical oncologists [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 P5-11-11.

A Review on The Role of VEGF in Tamoxifen Resistance.

Certain molecular deviations can lead to the development of breast cancer. For instance, estrogen and estrogen receptors play a significant role in inducing tumor proliferation. However, the efficacy of endocrine therapy through the administration of anti-estrogen drugs, such as Tamoxifen, is challenged by acquired resistance. Relevant articles were retrieved from Medline and google scholar. All were screened to select the ones discussing the molecular mechanisms of angiogenesis and Tamoxifen resistance. The molecular interactions contributing in the resistant network were studied from the eligible articles. Tamoxifen resistance occurs as a consequence of over-activated signal transduction pathways such as RTK s dependent cascades. It has been shown that microvessel count was greater in Tamoxifen resistant tissues than in responsive ones. In this review, the interaction between estrogen, Tamoxifen, VEGF, and VEGF receptors (VEGFRs) in Tamoxifen resistant cells has been discussed. VEGF and estrogen-independent growth cascades, especially MAPK have a positive feedback loop in Tamoxifen resistant cells. It has been proposed that over-activated pathways in Tamoxifen resistant cells induce pin1 mediated VEGF over-expression, which in turn result in enhanced activation of MAPK.

Abstract P5-04-25: Characterization of FGFR1/2 genetic alterations reveals novel fusions of FGFR1 in Chinese breast cancer

Abstract Background: Deregulation of fibroblast growth factor receptor 1 (FGFR1) signalling has been extensively studied in various tumor types, and has been implicated in driving endocrine resistance in breast cancer. Genetic alterations of FGFR1, especially FGFR1 amplification, is one of particularly important mechanisms leading to enhanced FGFR signaling in breast cancer. However, the prevalence of FGFR1/2 genetic variations in Chinese breast cancer patients has not been well explored. Methods: To investigate the characteristics of FGFR1 and FGFR2 genetic variations in Chinese breast cancer, we employed customized next-generation sequencing panel to screen the somatic mutation or copy number variations of FGFR1/2 in primary breast cancer tissues by using two ongoing breast cancer Cohorts, in which we have recruited 289 of early breast cancer patients (EBC Cohort) and 74 of advanced breast cancer patients (ABC Cohort). Results: In EBC Cohort, we found FGFR1 amplification in 9.0% (26/289) patients and FGFR2 amplification in 2.1% (6/289) patients, and also found 3 of somatic FGFR1 mutations (FGFR1 p.W4C; p.E334K; p.V396I ) and 2 of FGFR2 mutations (FGFR2 p.S702L; p.Y779*). Unlike the comparable prevalence of FGFR2 genetic variations in 2.8% (8/289) of EBC Cohort and 2.7% (2/74; one amplification event and one FGFR2 p.E499D mutation) of ABC Cohort, there were more FGFR1 genetic alterations in ABC Cohort (27%; 20/74 patients; p&amp;lt;0.001), including 19 events of FGFR1 amplification and 1 of FGFR1 c.2186+20G&amp;gt;A intron mutation. More importantly, we identified 5 novel FGFR1 fusion genes in our cohorts, including TACC1-FGFR1, FGFR1-KCNU1, FGFR1-MIR1268A, FGFR1-LZTS1-AS1 and FGFR1-RNF5P1. Although FGFR1-TACC1 fusion gene has been previously reported in breast cancer and TACC1 is fused to the C-terminal of FGFR1 protein leading to aberrant activation of FGFR1, we found TACC1 was fused to the N-terminal of FGFR1 at exon 6 of FGFR1 in our study. In addition, we identified and verified FGFR1-MIR1268A fusion gene at mRNA level using RNA-seq analysis, and further found this fusion gene might result in the truncation of FGFR1. Conclusions: Collectively, we characterized the prevalence of FGFR1/2 genetic alterations in Chinese breast cancer, and identified 5 of novel FGFR1 fusion genes. The potential roles for novel FGFR1 fusion genes in regulating breast cancer cellular biology and in affecting the efficacy of endocrine therapy have been under the investigation in our laboratory, and the result from which will help us better elucidate the molecular mechanism of FGFR1 in driving the resistance of endocrine therapy. This study was supported by funding from National Natural Science Foundation of China (Grant No. 81602645), Guangdong Provincial Natural Science Foundation (Grant No. 2016A030313768) and Research Funds from Guangzhou Science and Technology Bureau (Grant No. 201707010418 and 201804010430). Citation Format: Wang Y, Guo L, Cao L, Jia M, Wen L, Ren C, Zhang G, Liao N. Characterization of FGFR1/2 genetic alterations reveals novel fusions of FGFR1 in Chinese breast cancer [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 P5-04-25.

Abstract P4-14-05: Confirmation of the TAILORx 21-gene expression trial using a real world observational database

Abstract Background: The TAILORx study (NCT00310180)(TRx) has demonstrated the efficacy of endocrine therapy alone in early stage, lymph node negative, hormone receptor positive, her2neu oncogene negative breast cancer harboring an intermediate recurrence score (RS) on a 21-gene profile (OncotypeDx), obviating the need for adjuvant chemotherapy in a large subset of women. The study randomized and followed 6711 patients (pts) and required 9 years to reach its conclusion endpoints. The availability of the electronic health record (EHR) permits automated reviews, facilitating more rapid “real world” hypothesis testing (but not a replacement for randomized clinical trials), especially when there are clear variations in common practice patterns. However physician bias in treatment selection needs to be considered. Methods: A retrospective review of the Cota Observational Cancer database, drawn from EHRs, of female pts with breast cancer who were 18 to 75 years of age; had hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer harboring an OncotypeDx RS 11-25 receiving adjuvant therapy following surgical resection of a 11-50 mm primary tumor (similar to TRx eligibility). Results: 1009 pts from 23 cancer centers (107 oncologists) were identified, 850 (84.2%) received adjuvant endocrine therapy alone (E) and 159 (15.8%) received adjuvant chemoendocrine therapy (CE) as part of standard care (no randomization). 285 pts were age &amp;lt;50 yrs (E:218, CE:67) and 601 pts has RS 16-25 (E:453, CE:148). Treatment selection was imbalanced with oncologists more likely to utilize CE in younger pts (median age E: 59 yrs, CE: 53 yrs; p&amp;lt;0.01), larger tumors (median tumor size E: 16mm, CE: 20mm; p&amp;lt;0.001) and higher RS (median RS E: 16, CE: 21; p&amp;lt;0.001). With a median follow-up for survival since diagnosis of 3.7 years, the Kaplan-Meier estimated 5 yr overall survival rates were 98.9% with E and 97.8% with CE (p=0.23); the corresponding 5-yr OS in TRx were E: 98% and C: 98.1%. With a median 1.7 years follow-up for recurrence, 19 pts have suffered a disease distant or local recurrence (E: 13, CE: 6) yielding a 5-year recurrence-free survival of E: 95.2% and CE: 91% (p=0.05); the corresponding TRx result was E: 96.9% and CE: 97%. The 5-yr invasive disease-free survival (IDFS = death, local/distant, second primary) with 32 events was E: 92.7% and CE: 81.9% (p= 0.05); corresponding TRx E: 92.8 % and CE: 93.1%. Given the imbalance in treatment allocations, a multivariate analysis was performed, with older age (&amp;lt;0.001), CE choice (&amp;lt;0.006) and larger tumor size (p&amp;lt;0.05) remaining significant, but not increased RS (p=0.16) for 5-year IDFS. Among women age &amp;lt;50 with RS 16-25 (E: 118; CE: 60) the 5-yr IDFS was E: 95% and CE: 94%; the corresponding RS 16-20 TRx E: 92% and CE: 94.7% and RS 21-25 E: 86.3% and CE: 92.1%. Conclusions: Using a real world data source, endocrine therapy alone appears to yield excellent 5-yr survival rates among pts with 21-gene RS 11-25 similar to the TAILORx trial. Treatment selection bias (with perceived higher risk pts allocated to CE) and shorter median follow-up limits full confirmation by this dataset. Citation Format: Waintraub SE, Isaacs C, Norden AD, Graham DA, McNamara DM, O'Neill SC, Lakshmanan A, Wu T, Maresca A, Pecora AL, Goy AH, Goldberg SL. Confirmation of the TAILORx 21-gene expression trial using a real world observational database [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 P4-14-05.

Abstract PL2: Neoadjuvant Endocrine Therapy: The Times They are A-Changing

Abstract Neoadjuvant endocrine therapy (NET) in hormone-receptor positive breast cancers (HR+ BC) has been, in general, under-utilized, mostly because the majority of HR+ BC are diagnosed as stage I or II, and undergo surgical management as their first strategic step. However, NET is a suitable therapeutic choice for HR+ BC in cases where downsizing of the tumor is necessary (i.e. achievement of breast conservation). A seminal clinical trial comparing NET with neoadjuvant chemotherapy (NAC) in post-menopausal patients with HR+ BC revealed that the rates of overall response and breast conservation surgery were almost identical. NET also allows clinicians to infer prognosis based on simple pathologic characteristics: several clinical trials, including the phase III POETIC clinical trial (n=4486) showed that low Ki67 (less than 10%) at baseline and after 2 weeks had excellent long term outcome, whereas Ki67 larger than 10% at baseline and after 2 weeks had significantly worse long term outcome. Additionally, the Preoperative Endocrine Prognostic Index (PEPI), which is based on pathologic tumor size, node status, Ki67 level and ER status (Allred score) at the time of surgery, post NET, can accurately predict long term outcome. Interestingly, the early (about 2 weeks) Ki67 levels post NET has consistently predicted results of several phase III adjuvant or metastatic endocrine therapy trials (IMPACT - ATAC; Z1031 - MA-27) even in combination with targeted agents (LORELEI - SANDPIPER; NET + everolimus - BOLERO-2). Results of the ALTERNATE (A011106), a NET comparing AI with fulvestrant in post-menopausal patients with stage II and III HR+ BC is eagerly awaited, as it is bound to mimic the results of phase II and III trials comparing fulvestrant and AI in HR+ MBC (FIRST, FALCON, FACT, SWOG0226). Ultimately, these tools help clinicians decide if the addition of chemotherapy is necessary or not in patients with HR+ BC. Finally, NEC is an excellent tool in providing insights into the biologic basis of endocrine therapy efficacy (biomarkers of response and mechanisms of resistance studied in the post-treatment residual cancer). NET incorporating targeted therapies such as PI3K pathway inhibitors have yielded somewhat disappointing results compared to endocrine therapy alone (LORELEI, Neo-ORB), considering that PIK3CA mutations are the most common genomic alterations seen in HR+ BC. However, several ongoing trials of NET with CDK4/6 inhibitors were recently completed or are ongoing (NeoPalAna, NeoMONARCH, PALLET, PELOPS), and these trials may be instrumental not only in predicting the success of the large phase III adjuvant endocrine therapy with or without CDK4/6 inhibitors clinical trials. Ultimately, relatively small NET clinical trials could help with the design of more intelligent large clinical trials, providing the opportunity of residual tissue availability as a platform of discovery for biomarkers of sensitivity and resistance, an excellent platform for the development of investigational drugs and triaging of novel combinations. Citation Format: Mayer I. Neoadjuvant Endocrine Therapy: The Times They are A-Changing [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 PL2.

Arsenic‑induced BRCA1 CpG promoter methylation is associated with the downregulation of ERα and resistance to tamoxifen in MCF7 breast cancer cells and mouse mammary tumor xenografts.

A significant percentage (~30%) of estrogen receptor-α (ERα)-positive tumors become refractory to endocrine therapies; however, the mechanisms responsible for this resistance remain largely unknown. Chronic exposure to arsenic through foods and contaminated water has been linked to an increased incidence of several tumors and long-term health complications. Preclinical and population studies have indicated that arsenic exposure may interfere with endocrine regulation and increase the risk of breast tumorigenesis. In this study, we examined the effects of sodium arsenite (NaAsIII) exposure in ERα-positive breast cancer cells in vitro and in mammary tumor xenografts. The results revealed that acute (within 4 days) and long-term (10 days to 7 weeks) in vitro exposure to environmentally relevant doses reduced breast cancer 1 (BRCA1) and ERα expression associated with the gain of cyclin D1 (CCND1) and folate receptor 1 (FOLR1), and the loss of methylenetetrahydrofolate reductase (MTHFR) expression. Furthermore, long-term exposure to NaAsIII induced the proliferation and compromised the response of MCF7 cells to tamoxifen (TAM). The in vitro exposure to NaAsIII induced BRCA1 CpG methylation associated with the increased recruitment of DNA methyltransferase 1 (DNMT1) and the loss of RNA polymerase II (PolII) at the BRCA1 gene. Xenografts of NaAsIII-preconditioned MCF7 cells (MCF7NaAsIII) into the mammary fat pads of nude mice produced a larger tumor volume compared to tumors from control MCF7 cells and were more refractory to TAM in association with the reduced expression of BRCA1 and ERα, CpG hypermethylation of estrogen receptor 1 (ESR1) and BRCA1, and the increased expression of FOLR1. These cumulative data support the hypothesis that exposure to AsIII may contribute to reducing the efficacy of endocrine therapy against ERα-positive breast tumors by hampering the expression of ERα and BRCA1 via CpG methylation, respectively of ESR1 and BRCA1.

Kinesin family member-18A (KIF18A) is a predictive biomarker of poor benefit from endocrine therapy in early ER+ breast cancer.

Identification of effective and reliable biomarkers that could be used to predict the efficacy of endocrine therapy is of crucial importance to the management of oestrogen receptor positive (ER+) breast cancer (BC). KIF18A, a key regulator of cell cycle, is overexpressed in many human cancers, including BC. In this study, we investigated the role of KIF18A as a biomarker to predict the benefit from endocrine treatment in early ER + BC patients. KIF18A expression was assessed at the genomic level using the METABRIC dataset to explore its prognostic and predictive value in ER + BC patients (n = 1506). Predictive significance of KIF18A mRNA was validated using KM-Plot datasets (n = 2061). KIF18A protein expression was assessed using immunohistochemistry in a large annotated series of early-stage ER + BC (n = 1592) with long-term follow-up. High mRNA and protein expression of KIF18A were associated with short recurrence-free survival (RFS), distant-metastasis free survival (DMFS) and BC specific survival (all P < 0.05) in ER + BC in patients who received no adjuvant treatment or adjuvant endocrine therapy. In multivariate analysis, high KIF18A expression was an independent prognostic biomarker for poor RFS (P = 0.027) and DMFS (P = 0.028) in patients treated with adjuvant endocrine therapy. KIF18A appears to be a candidate biomarker of a subgroup of ER + BC characterised by poor clinical outcome. High KIF18A expression has prognostic significance to predict poor benefit from endocrine treatment for patients with ER + BC. Therefore, measurement of KIF18A on ER + BC patients prior to treatment could guide clinician decision on benefit from endocrine therapy.

Effects of ovarian hormones on emotional behaviors in dopamine D3 receptor knockout mice

Ovarian hormones reportedly have beneficial effects on affective behaviors. However, the functions of ovarian hormones in neurotransmitter signaling must be identified to understand their role in anxiety and depression. Several studies have provided evidence of the relationship between ovarian hormones and the dopaminergic system, but the interaction between ovarian hormones and dopamine D3 receptor (DRD3) is poorly understood. The aim of the present study was to examine the role of DRD3 in the anxiety-like and depression-like behavioral changes induced by estrogen and progesterone. We subjected D3 receptor knockout (D3KO) and wild-type (WT) mice to a series of behavioral tests. Mice were ovariectomized 4 weeks before testing, and we randomly administered 17β-estradiol (E2, 0.2 mg/kg), progesterone (P4, 10 mg/kg), E2 (0.2 mg/kg) plus P4 (10 mg/kg) or vehicle (VEH, corn oil, 0.2 ml) subcutaneously daily for 9 consecutive days, starting 4 days before the testing day. On the testing day, the mice were injected 30 min prior to behavioral testing. Compared with WT mice in the same treatment group, D3KO mice displayed hyperactivity in the light-dark box test (LDBT) but lower activity in the open field test (OFT). In addition, D3KO mice but not their WT littermates showed behavioral changes after E2 treatment compared with those after VEH treatment in the LDBT only. In depression tests, D3KO-VEH mice displayed significantly longer immobility times than did WT-VEH mice. In addition, only D3KO mice exhibited an obvious decrease in immobility time after E2 and P4 administration. These results indicate that the anxiolytic and antidepressant effects of ovarian hormones can be influenced by DRD3 expression and that DRD3 knockout may induce varying sensitivities to ovarian hormones that depend on various factors, including test paradigms and experiences in animal models. Our research provides a novel insight, i.e., DRD3 may play a role in the efficacy of hormone therapy.

Everolimus plus endocrine vs endocrine therapy in treatment advanced ER+, HER2− breast cancer patients: A meta-analysis

The purpose of this review was to compare the efficacy and safety of everolimus plus endocrine therapy with endocrine therapy for hormone receptor-positive, human epidermal growth factor 2 negative advanced breast cancer patients. We comprehensively searched the PubMed, the Cochrane Library, EMBASE, Web of Science, Chinese biomedicine literature database, WanFang Data, CNKI, and VIP database for relevant articles. The retrieval time limit is from building the database to July 2018. The computer search was supplemented with a manual search of reference lists for all available review articles. We scanned references of all included studies for additional studies. We included 7 randomized trials involving 1527 patients. Meta-analysis results are as follows: Everolimus plus endocrine therapy group is significantly better than endocrine therapy group in progression-free survival and clinical benefit rate, (hazard ratio [HR] = 0.48, 95% confidence interval [CI 0.42-0.55], P < 0.00001) and (risk ratio = 1.9, 95% CI [1.60-2.26], P < 0.00001). But there was no significant difference between the 2 groups in overall response rate and time to definitive deterioration (risk ratio = 4.37, 95% CI [0.79-24.27], P = 0.21) and (HR = 0.74, 95% CI [0.49-1.11], P = 0.15). In terms of safety, the incidence rate in everolimus plus endocrine therapy was higher than that in endocrine therapy group. Most frequently reported adverse events associated with everolimus treatment were stomatitis, rash, fatigue, diarrhea, decreased appetite, cough, dyspnea, and pneumonitis. The incidences of grade 3-4 adverse events were stomatitis, fatigue, diarrhea, pneumonitis, and hyperglycemia. Everolimus increased the efficacy of endocrine therapy in treatment advanced endocrine receptor-positive, human epidermal growth factor 2 negative breast cancer patients, and the safety profile of the combination is acceptable.

The predictive ability of plasma ESR1 mutations for the efficacy of endocrine therapy in hormone-receptor-positive advanced breast cancer.

PurposeThe predictive ability of plasma ESR1 mutations for outcomes among patients with advanced breast cancer undergoing endocrine therapy (ET) remains disputable. We performed a comprehensive meta-analysis of published studies to clarify the impact of plasma ESR1 mutations on clinical outcomes for patients after subsequent ET.Materials and methodsAn electronic search was performed to identify eligible studies. Studies analyzing progression-free survival (PFS) and/or overall survival (OS) according to plasma ESR1 mutation status after subsequent ET were included. HRs were calculated using a fixed- or random-effects model according to heterogeneity. Pooled HRs and 95% CIs were used to estimate the effects.ResultsSix studies including 705 patients with advanced breast cancer met the inclusion criteria. The impact of plasma ESR1 mutations on PFS and OS after subsequent ET was reported in six studies (seven groups) and two studies, respectively. Meta-analysis results showed that the pooled HR for ESR1 mutations was 1.70 (95% CI, 1.05–2.74; P=0.03) for OS, which was statistically significant for predicting poor survival, and 1.56 (95% CI, 1.13–2.14; P=0.006) for PFS; however, Begg’s and Egger’s test results identified the presence of bias. The trim-and-fill method was used, and after incorporation of the imputed studies, the HR was 1.16 (95% CI, 0.88–1.53, P=0.30) for PFS, which indicates that plasma ESR1 mutation had no effect on PFS after subsequent ET. Subgroup analysis suggested that plasma ESR1 mutations were correlated with shorter PFS (HR, 1.98; 95% CI, 1.12–3.51; P=0.02) in patients subsequently treated with aromatase inhibitors (AIs), whereas no association with PFS was observed for patients subsequently treated with non-AI ET (HR, 1.08; 95% CI, 0.85–1.38; P=0.54) or fulvestrant (HR, 1.03; 95% CI, 0.79–1.34; P=0.83).ConclusionThe current meta-analysis demonstrates that plasma ESR1 mutation status is not a predictor of ET efficacy for all drugs without distinction in patients with hormone-receptor-positive advanced breast cancer. ESR1 mutation predicted a poor response to AIs, whereas it was not predictive of non-AI ET efficacy, especially for fulvestrant.

Bioinformatics-based interaction analysis of miR-92a-3p and key genes in tamoxifen-resistant breast cancer cells

The abnormal expression of miR-92a-3p was detected in multiple cancers. However, the biological role and underlying mechanism of miR-92a-3p in tamoxifen-resistant cells are still unknown. The main objective of our study was to find potential miR-92a-3p regulating pathways involved in tamoxifen resistance and to construct their regulatory network using bioinformatics. Four gene expression profiles were retrieved from GEO database and the GEO2R tool was used for analysis. GSE41922 and GSE42072 were applied to investigate aberrant miR-92a-3p expression in breast cancer serum and tissue. We found that miR-92a-3p expression was higher in breast cancer serum or tissue than in healthy volunteer serum or adjacent normal tissue, and high expression of miR-92a-3p could predict poor prognosis of breast cancer patients. In our qRT-PCR validation, we found that miR-92a-3p was upregulated in tamoxifen-resistant cells. MiR-92a-3p might play a role in tamoxifen resistance. In order to find the relationship between miR-92a-3p and some key genes and their potential molecular mechanisms in tamoxifen-resistant cells. The microarray data GSE26459 and GSE28267 were analyzed to determine the differentially expressed genes (DEGs) or miRNAs (DEMs). Furthermore, the related long non-coding RNAs (lncRNAs) were screened with starBase v2.0. Finally,microRNA.org,miRDB, targetminer and targetscan were applied to predict the targets of miR-92a-3p. Through analysis, we find that miR-92a-3p may be used as a potential biomarker for early detection of cancer and monitoring the efficacy of endocrine therapy.

Impact of multidisciplinary collaborative pharmaceutical care on knowledge, adherence, and efficacy of hormone therapy in climacteric women.

BackgroundThe objective of this study was to evaluate the impact of pharmaceutical care on the knowledge, adherence, and efficacy of hormone therapy in climacteric women participated in multidisciplinary collaborative clinic, launched by Peking University First Hospital (Beijing, People’s Republic of China) in 2012.MethodsA total of 296 patients were recruited (intervention group n=150, control group n=146). The patients in the intervention group visited the multidisciplinary collaborative clinic for their initial hormone therapy, receiving individualized pharmaceutical care (PC), whereas the control group visited only the general clinic without PC. The pill count method, knowledge assessment questionnaire (Cronbach’s α=0.80), and the modified Kupperman Index were used to assess the knowledge, adherence, and efficacy at months 3, 6, and 12.ResultsThe intervention group, which received PC, showed significantly higher and better knowledge, adherence, and efficacy than the control group, demonstrating the effectiveness of the PC provided. The knowledge scores of the intervention and control groups at months 3, 6, and 12 were (73.12 vs 59.28), (77.63 vs 66.19), and (80.81 vs 66.64); the data for adherence were (90.97% vs 82.17%), (93.21% vs 87.79%), and (95.81% vs 93.38%); and the values of the modified Kupperman Index were (17.15 vs 24.05), (13.22 vs 22.01), and (12.21 vs 23.15), respectively.ConclusionPC improved the knowledge, adherence, and efficacy of hormone therapy in climacteric women. Therefore, the multidisciplinary collaborative model investigated in our study should be advocated in other health care institutions for the benefit of more patients. Further large-sample and long-term studies should be conducted to evaluate the effects of PC on patient clinical outcomes, including its impact on the safety and efficacy of long-term use of hormone therapy, as well as the economic benefits.

Study TTC-352-101: Phase 1 study of TTC-352 in patients with metastatic breast cancer (BC) progressing on endocrine therapy.

TPS1108Background: 75% of all breast cancers (BC) are hormone receptor-positive (HR+). Despite the efficacy of endocrine therapies, HR+ BC develop resistance, and cytotoxic chemotherapy is ultimate...

Impact of body mass index on the efficacy of endocrine therapy in patients with metastatic breast cancer - A retrospective two-center cohort study

BakgroundThe aim of this study was to investigate the impact of body mass index (BMI) on the efficacy of endocrine therapy in postmenopausal women with metastatic hormone receptor breast cancer (HR+BC) as well as to identify if the potential difference in efficacy was associated with Fulvestrant only or both aromatase inhibitors (AIs) and Fulvestrant. MethodsA consecutive cohort of postmenopausal women with HR+metastatic breast cancer that have received endocrine therapy including Fulvestrant as a metastatic treatment strategy at the Departments of Oncology in Eskilstuna and Uppsala, Sweden, between 2008 and 2016 were identified. The primary outcome of the study was time to disease progression (TTP) during the treatment with Fulvestrant in overweight and obese women compared to patient with normal BMI. ResultsIn total, 173 patients were enrolled in the study cohort, amongst these, 141 patients received both Fulvestrant and AIs and 32 received only Fulvestrant. No statistical significant association was observed between the three BMI categories and TTP, during Fulvestrant treatment (p = 0.136). The rates of objective response and clinical benefit due to Fulvestrant were similar among patients with normal weight, overweight and obesity, respectively. ConclusionsNo difference in treatment efficacy was seen between normal, overweight and obese women with metastatic HR+BC, when treated with Fulvestrant. Until further research with prospective studies is available, there is no evidence to support any modification in how Fulvestrant treatment is used in patients with metastatic breast cancer in regard to BMI.

SUBSTITUTION ANDROGEN THERAPY AFTER RADICAL TREATMENT OF PROSTATE CANCER

Introduction. The question of safety and efficacy of hormonal therapy with androgen deficiency after successful treatment of the prostate cancer (PC) remains debatable, despite the availability of data of the lack of correlation between the level of endogenous testosterone and the risk of developing PC or even reducing the risk of testosterone replacement therapy (TRT). Objective: a preliminary assessment of the possibility of using the TRT in men with androgen deficiency syndrome after radical treatment of PC – brachytherapy and radical prostatectomy (RP). Materials and methods. At the bases of North-Western State Medical University n. a. I.I. Mechnikov examined 12 men aged 50 to 65 years with history localized PC (T1-2N0M0) and symptoms of androgenic deficiency: 5 patients after brachytherapy (all with Т 1с N0M0G ) and 7 after RP (1 with Т 2aN0M0G , 6 with Т 1с N0M0G ). All patients were prescribed TRT in transdermal form (1 % gel) for 15 months. Before and after TRT determined the total level testosterone in blood, prostate-specific antigen; was performed the evaluation of erectile dysfunction according to the IIEF (International Index о f Erectile Function) and of androgen deficiency according to the AMS (Aging Males’ Symptoms Scale), transrectal ultrasound, multislice computed tomography or magnetic resonance imaging and osteoscintigraphy. Clinical data were not processed by statistical methods due to insufficient number of observations. The actual average value of indicators is given. Further accumulation of sufficient number of cases for the statistical analysis and check of efficiency and safety of the investigated therapy is planned. Results. After TRT the average level of total testosterone increased compared to baseline in patients undergoing brachytherapy, from 3.4 to 18.4 nmol/l, in patients undergoing RP, from 2.7 to 15.3 nmol/l; the level of the prostate-specific antigen decreases from 2.1 to 1.7 ng/ml and from 1.9 to 1.3 ng/ml. Evaluation according to the AMS after TRT decreased in comparison with the initial in patients who underwent brachytherapy from 43 to 20 points, in patients who underwent RP – from 47 to 23 points, which indicated a change in the degree of androgen deficiency from severe to mild; evaluation of IIEF increased from 10 to 19 points, accordingly, and from 8 to 17 points, which reflected a change in the degree of erectile dysfunction from severe to mild. According to control transrectal ultrasound, multislice computed tomography, magnetic resonance imaging, and osteoscintigraphy, there has been detected no progress and recurrence of the tumor process. Conclusion. In patients with androgen deficiency syndrome after radical PC treatment, TRT is possible, since it is associated with improvement of erectile function and reduction of androgen deficiency and does not lead to relapse of the tumor.

Clinical Significance of the Neutrophil-to-Lymphocyte Ratio in Endocrine Therapy for Stage IV Breast Cancer.

Studies have found that patients with cancer exhibit abnormal leukocyte fractions, such as elevated neutrophil count and diminished lymphocyte count, and that the neutrophil-to-lymphocyte ratio (NLR) provides a surrogate marker for prognosis and response to treatment of patients after radical surgery for several different types of cancer. However, few reports have addressed the association between the NLR and response to endocrine therapy. In this study, we carried out a clinical investigation to confirm whether or not the NLR predicted the response to endocrine therapy of stage IV breast cancer. The study subjects were 34 patients who underwent endocrine therapy as initial drug therapy for stage IV breast cancer. The correlation between NLR and prognosis, including the efficacy of endocrine therapy, was evaluated retrospectively. Among the 34 patients, the NLR was high in 10 (29.4%) and low in 24 (70.6%). In analysis of outcomes, the group with low NLR had a significant prolongation of progression-free survival (p=0.003), time to treatment failure (p=0.031), and overall survival (p=0.013) compared to the group with high NLR. Univariate analysis of progression-free survival found that responding to treatment [hazard ratio (HR)=4.310, p=0.004] and low NLR (HR=3.940, p=0.016) were factors associated with a favorable prognosis. Multivariate analysis also showed that responding to treatment (HR=4.329, p=0.006) and low NLR (HR=3.930, p=0.008) were independent factors associated with a favorable prognosis. Our results suggested that the NLR may represent a predictive marker for response to endocrine therapy in stage IV breast cancer.