Inhibition Of Estrogen Synthesis Research Articles

Structural, Thermodynamic, and Kinetic Traits of Antiestrogen-Compounds Selectively Targeting the Y537S Mutant Estrogen Receptor α Transcriptional Activity in Breast Cancer Cell Lines.

The most frequently diagnosed cancers in women are the estrogen receptor (ER)-positive breast cancer subtypes, which are characterized by estrogen dependency for their growth. The mainstay of clinical treatment for this tumor relies on the modulation of ERα action or on the suppression of estrogen biosynthesis via the administration of Selective ERα Modulators/Down-regulators (SERMs/SERDs) or aromatase inhibitors, respectively. Nevertheless, de novo and acquired resistance to these therapies frequently occurs and represents a major clinical concern for patient survival. Recently, somatic mutations affecting the hormone-binding domain of ERα (i.e., Y537S, Y537N, D538G) have been associated with endocrine resistance, disease relapse and increased mortality rates. Hence, devising novel therapies against these ERα isoforms represents a daunting challenge. Here, we identified five molecules active on recurrent Y537S ERα polymorphism by employing in silico virtual screening on commercial databases of molecules, complemented by ER-transactivation and MTT assays in MCF7 and MDA-MB-231 breast cancer cells expressing wild type or mutated ERα. Among them, one molecule selectively targets Y537S ERα without inducing any cytotoxicity in breast cell lines. Multi-microseconds (4.5 μs) of biased and unbiased molecular dynamics provided an atomic-level picture of the structural, thermodynamics (i.e., binding free energies) and the kinetic (i.e., dissociation free energy barriers) of these active ligands as compared to clinically used SERM/SERDs upon binding to wild type and distinct ERα variants (Y537S, Y537N, D538G). This study contributes to a dissection of the key molecular traits needed by drug-candidates to hamper the agonist (active)-like conformation of ERα, normally selected by those polymorphic variants. This information can be useful to discover mutant specific drug-candidates, enabling to move a step forward toward tailored approaches for breast cancer treatment.

Abstract 3830: Novel bromodomains and extra-terminal motif (BET) inhibitors developed against estrogen receptor positive, fulvestrant- and CDK4/6-resistant breast cancer models

Abstract Approximately 70% of breast cancer patients have estrogen receptor positive (ER+) tumors. Fulvestrant (FUL), a selective estrogen receptor degrader (SERD) able to ablate ER, was first introduced to clinical practice in 2002 as the second and third line treatment for ER+ metastatic breast cancer. In August 2017, FUL was added to first-line therapy in postmenopausal women by demonstrating superiority compared to first-line AI therapy, anastrozole, with improved progression-free-survival (PFS) and a 20% reduction in the risk of disease progression or death. However, acquisition of FUL-resistance in both first-line setting or as combination therapy with CDK4/6 inhibitor has been observed clinically, leaving patients and oncologists with chemotherapy as the only backup therapy. Little is known about resistance mechanisms to FUL alone or in combination with CDK4/6 inhibitors. Here, we showed that targeting epigenetic vulnerabilities in breast cancer using novel bromodomain and extra-terminal (BET) inhibitors can effectively inhibit growth of tamoxifen-, FUL- and CDK4/6- resistant breast cancer cells. We designed and developed a novel series of pyridinone-based BET inhibitors, optimized by growth inhibition in tamoxifen- and FUL- resistant breast cancer cell lines (MCF7:CFR) in both 2D and 3D cultures. Optimized compounds showed superior in vitro activity to BET inhibitors in clinical trials. Selected compounds were further evaluated for pharmacokinetics and shown efficacy in endocrine-resistant xenograft models. Citation Format: Rui Xiong, Yangfeng Li, Jiong Zhao, Debra Tonetti, Gregory Thatcher. Novel bromodomains and extra-terminal motif (BET) inhibitors developed against estrogen receptor positive, fulvestrant- and CDK4/6-resistant breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3830.

Kidney protective effect of acalypha indica linn. root extract in high-fructose and high-cholesterol diet-fed rats

Diet high in fructose and cholesterol may lead to the development of diabetic nephropathy (DN). One of the first drugs of choice in DN treatment is captopril. Prolonged use of this drug may lead to some adverse effects and the treatment can be optimized through using other therapy options. Acalypha indica Linn. (AI) may be an alternative herbal therapy for DN. The objective of this research is to investigate the renoprotective effect of AI on DN. For seven weeks, thirty-two Sprague-Dawley rats were divided into groups receiving normal diet and high-fructose and high-cholesterol diet (HFCD). Then, the HFCD-fed rats were divided into four groups receiving different treatment: negative control, AI root extract (250 mg/kgBW), captopril (2.5 mg/kgBW), and combination of captopril and AI. Normal diet group was divided into AI and no treatment. After four weeks of treatment, the rats were terminated and serum urea and creatinine levels were measured. In the normal group, AI therapy decreased serum urea and creatinine levels. In the HFCD groups, AI and captopril monotherapy groups had increased serum urea levels, but lower compared to negative control. Meanwhile, serum creatinine levels decreased in both groups. However, these findings are not statistically significant. We found that combination therapy group had the highest increase in serum urea level, which was significantly different with captopril group (p=0.01). Serum creatinine level was also increased in this group. Our present study showed that AI tend to reduce serum urea and creatinine levels in normal diet group and inhibit the increase of serum urea and creatinine levels in rats fed with HFCD diet. Antagonistic interaction between captopril and AI might be present.

Randomized controlled trial of high-dose versus standard-dose vitamin D3 for prevention of aromatase inhibitor-induced arthralgia

Half of hormone receptor-positive (HR+) breast cancer patients will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA), while taking aromatase inhibitor therapy. Though there is no universally accepted effective treatment for AIA, there has been some evidence to support high-dose vitamin D as a treatment. We randomized post-menopausal women who were beginning adjuvant AI therapy to receive standard-dose vitamin D3 (800IU daily for 52weeks), or high-dose vitamin D3 (50,000IU weekly for 12weeks, followed by 2000IU daily for 40weeks). The primary end point was development of AIA. The trial was designed to enroll 184 patients. This futility analysis was performed after 93 patients were enrolled. The high-dose vitamin D regimen was effective in raising serum vitamin D levels, but there was no significant difference in development of AIA between the two arms. In the high-dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard-dose arm. The planned futility analysis was positive; thus, the study was terminated. Neither baseline vitamin D nor 12-week vitamin D level was predictive of AIA development. Although vitamin D levels were increased in the high-dose arm, there was no significant signal for benefit of high-dose vitamin D supplementation for AIA prevention in this unblinded trial. This study, along with several others, implies that vitamin D likely does not play a significant role in AIA for the majority of patients.

Future directions in endometriosis treatment: discovery and development of novel inhibitors of estrogen biosynthesis

Endometriosis is a chronic benign disease characterized by the presence of endometriotic glands and stroma outside the uterine cavity, which typically affects women during reproductive age. This di...

Extended Adjuvant Therapy With Aromatase Inhibitors for Early Breast Cancer: A Meta-analysis of Randomized Controlled Trials

BackgroundAromatase inhibitors (AIs) are widely used for early breast cancer, whereas the efficacy and safety of extended AI adjuvant therapy compared with shorter AI therapy, observation, or placebo remains controversial. We conducted a quantitative meta-analysis to summarize available randomized controlled trials (RCTs) regarding the efficacy and safety of extended AI therapy for early breast cancer. Materials and MethodsWe systematically searched PubMed, EmBase, and the Cochrane library to select studies published through March 2018. Studies designed as RCTs and that investigated overall survival (OS) or disease-free survival (DFS) for extended AI and shorter AI therapy, observation, or placebo were included. Hazard ratio (HR) and relative risk (RR) with 95% confidence intervals (CIs) were employed to pool analysis according to data type. ResultsWe identified 7 RCTs that involved 16,926 patients with early breast cancer. The summary HRs indicated that extended treatment with AIs was not associated with OS (HR, 0.95; 95% CI, 0.82-1.10; P = .488), whereas it could significantly improve DFS as compared with shorter AI therapy, observation, or placebo (HR, 0.75; 95% CI, 0.66-0.86; P < .001). Treatment with extended AIs significantly reduced contralateral breast cancer recurrence (RR, 0.46; 95% CI, 0.34-0.64; P < .001), whereas it has no significant effect on distant metastatic recurrence (RR, 0.80; 95% CI, 0.64-1.00; P = .055), and locoregional recurrence (RR, 0.76; 95% CI, 0.53-1.08; P = .127). There were no significant differences between treatment with extended AIs and control for grade 3 or more adverse events. ConclusionExtended AI therapy could significantly improve DFS, especially for contralateral breast cancer recurrence. There were no significant differences between treatment with AIs and control for OS, distant metastatic and locoregional recurrence, and serious adverse events.

Abstract GS3-03: Effects of prolonging adjuvant aromatase inhibitor therapy beyond five years on recurrence and cause-specific mortality: An EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 women

Abstract Effects of prolonging adjuvant aromatase inhibitor therapy beyond five years on recurrence and cause-specific mortality: an EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 women Background: Five years of endocrine therapy with tamoxifen and/or an aromatase inhibitor is highly effective in reducing the risk of recurrence but a substantial risk remains after treatment discontinuation. Continuing treatment with an aromatase inhibitor may mitigate this risk. Methods: We sought individual patient data for meta-analysis from 12 randomised trials that compared 3-5 years of aromatase inhibitor versus no further treatment after five or more years of endocrine therapy. Primary outcomes were recurrence, and breast cancer mortality. Predefined subgroup comparisons were or prior endocrine therapy (tamoxifen alone, tamoxifen then AI, AI alone), site of recurrence (distant, local, contralateral), age, nodal status, tumour size, grade, and period of follow-up (yrs 0-1, 2-5, 5-9, 10+). Five trials randomised 2-3 years prior to treatment divergence and the primary analyses included only women who were recurrence and second primary cancer free and still alive at the point of treatment divergence. Results: Data have so far been received on 7,488 women (100% of those randomised) in trials of extended AI following tamoxifen alone, 10,796 women (82% 0f 13,192 randomised) following prior tamoxifen then AI, and 959 (23% of 4,229 randomised) following AI alone. Preliminary analyses including 1,617 breast cancer recurrences and 854 breast cancer deaths confirm a 35% reduction in recurrence with extended AI following tamoxifen alone but suggest a more moderate reduction after prior AI therapy. Data from two trials (NSABP B-42 &amp; N-SAS BC 05) contributing ˜5666 women should be available before SABCS to allow definitive analyses. Conclusion: This meta-analysis will provide the most reliable possible summary of the available evidence to inform clinicians on the efficacy of extending AI therapy compared to stopping AI after about 5 years of endocrine therapy in preventing disease recurrence and death from breast cancer, both overall and in different categories of women. Citation Format: Gray R, Early Breast Cancer Trialists' Collaborative Group. Effects of prolonging adjuvant aromatase inhibitor therapy beyond five years on recurrence and cause-specific mortality: An EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 women [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 GS3-03.

Aromatase Inhibitors and Newly Developed Nonalcoholic Fatty Liver Disease in Postmenopausal Patients with Early Breast Cancer: A Propensity Score-Matched Cohort Study.

Unlike tamoxifen, the relationship between aromatase inhibitor use in postmenopausal patients with breast cancer and nonalcoholic fatty liver disease (NAFLD) has not been delineated. A retrospective analysis of 253 patients with early breast cancer without baseline NAFLD and treated with nonsteroidal aromatase inhibitors was performed. Among them, 220 patients were matched for sex, age, and menstruation status with healthy patients, and the prevalence of NAFLD was compared. NAFLD was determined by hepatic steatosis index in the absence of other known liver diseases. The presence of significant liver fibrosis in patients with NAFLD was determined noninvasively by AST-platelet ratio index, FIB-4 score, and NAFLD fibrosis score (NFS). Postmenopausal patients with breast cancer undergoing treatment with aromatase inhibitors had higher prevalence of NAFLD independent of body mass index (BMI) and underlying diabetes mellitus (DM). Although the aromatase inhibitor group showed higher fibrotic burden by NFS, independent of BMI and DM, the proportion of advanced fibrosis did not show statistically significant differences between AI-treated patients and the healthy patients. Those with abnormal baseline fasting glucose levels are suggested to have increased risk of NAFLD development after aromatase inhibitor treatment. In addition, patients with NAFLD developed after aromatase inhibitor use had significantly lower disease-free survival than those without NAFLD, although there was no significant difference in overall survival. Results of this study suggest that inhibition of estrogen synthesis in postmenopausal women undergoing treatment with aromatase inhibitors could increase the risk of NAFLD, which might have some influence on the prognosis of patients with breast cancer. Unlike tamoxifen, the role of aromatase inhibitor treatment use in postmenopausal patients with breast cancer in development of fatty liver is not well known. In this propensity-matched cohort study, postmenopausal patients with breast cancer treated with aromatase inhibitors had increased risk of nonalcoholic fatty liver disease compared with healthy women after menopause, independent of obesity and diabetes mellitus. The results show possible adverse influence of the newly developed fatty liver on breast cancer disease-free survival and suggest a necessity for further validation. Fatty liver may need to be considered as an adverse event for aromatase inhibitor treatment.

Improved relapse-free survival on aromatase inhibitors in breast cancer is associated with interaction between oestrogen receptor-\u03b1 and progesterone receptor-b

BackgroundRecent pre-clinical studies indicate that activated progesterone receptor (PR) (particularly the PR-B isoform) binds to oestrogen receptor-α (ER) and reprogrammes transcription toward better breast cancer outcomes. We investigated whether ER and PR-B interactions were present in breast tumours and associated with clinical parameters including response to aromatase inhibitors.MethodsWe developed a proximity ligation assay to detect ER and PR-B (ER:PR-B) interactions in formalin-fixed paraffin-embedded tissues. The assay was validated in a cell line and patient-derived breast cancer explants and applied to a cohort of 229 patients with ER-positive and HER2-negative breast cancer with axillary nodal disease.ResultsHigher frequency of ER:PR-B interaction correlated with increasing patient age, lower tumour grade and mitotic index. A low frequency of ER:PR-B interaction was associated with higher risk of relapse. In multivariate analysis, ER:PR-B interaction frequency was an independent predictive factor for relapse, whereas PR expression was not. In subset analysis, low frequency of ER:PR-B interaction was predictive of relapse on adjuvant aromatase inhibitor (HR 4.831, p = 0.001), but not on tamoxifen (HR 1.043, p = 0.939).ConclusionsThis study demonstrates that ER:PR-B interactions have utility in predicting patient response to adjuvant AI therapy.

Problems with the Use of Aromatase Inhibitors in Breast Cancer

The use of Aromatase Inhibitors (AI’s) in the adjuvant therapy of operable breast cancer is ubiquitous. All guidelines in widespread use advocate their use in hormone-receptor-positive breast cancer in post-menopausal women. Premenopausal hormone-receptor-positive women who are considered at high risk of relapse are also treated with drug- or surgically-induced ovarian suppression plus an AI following chemotherapy, producing somewhat better results than those seen with chemo followed by tamoxifen [1]. A major side effect of these drugs is the accelerated loss of bone mineral density (BMD). The use of bone-sparing agents such as bisphosphonates has become widespread but not routine in these patients. Whether or not they receive bone-sparing agents, patients on AI’s should receive periodic assessment of bone density. How do doctors comply with this common-sense approach? The answer: not as often as they should. The best data on this practice was published in the Journal of Oncology Practice in May 2017 from a group of investigators at Yale [2]. Using the SEER Medicare database they identified over 135,000 women diagnosed with breast cancer from 2007 to 2010. Using robust exclusion criteria for such things as metastasis at presentation, too brief exposure to bisphosphonates, in situ only cancer, and prior diagnosis of osteoporosis, they identified 2409 women who met all entry criteria and served as the population studied. Within this group only 51% received a DEXA scan at initiation of AI and only 34% had a second scan within three years of being on therapy. What the authors were not able to ascertain was how many of these patients were placed on a prophylactic bisphosphonate or equivalent at the start of AI therapy. What was clear is that age and race had a lot to do with who received a DEXA scan. 30% of women over 85 vs. 56% ages 67-69 were scanned. 53% of causasian women were scanned vs. 33% non-caucasian. Wonen with higher stage and more comorbidities were also less likely to have been scanned.

Abstract 4950: MPS1 as a novel target in endocrine- and palbociclib-resistant estrogen receptor positive breast cancer

Abstract Background: Despite treatment, many estrogen receptor positive (ER+) breast cancer (BC) patients, relapse with de novo or acquired endocrine resistant disease. Using a kinome siRNA library screen, we identified MPS1, which is required for recruitment of the spindle assembly checkpoint complex, as strongly associated with resistance to both endocrine therapy and CDK4/6 inhibitor palbociclib, a contemporary first-line combination for advanced ER+ BC. Until now, the target population for MPS1 inhibitors has been triple negative BC. Here we show for the first time, potential efficacy of MPS1 inhibitors in endocrine resistant BC models. Methods: A panel of ER+ BC cell lines adapted to estrogen independent growth (LTED) or after additional resistance to palbociclib (palboR), was subjected to a siRNA kinome screen targeting 709 genes. Kinases causative of resistance were identified using Z-scores. Cell viability upon MPS1 inhibition (MPS1i) with BOS172722 was assessed 2D and 3D, and the class effect confirmed with other compounds targeting MPS1. Impact of MPS1i on ER-mediated transcription was assessed using luciferase reporter assays. Effect of MPS1i on chromosomal alignment and time spent in mitosis was established by time lapse and confocal microscopy. Cell cycle and DNA content were analysed by FACS. Apoptosis was assessed using PARP cleavage. Efficacy of BOS172722 in a xenograft model of LTED was evaluated. Results: Kinome knockdown identified MPS1 as the top common hit in LTED and palboR cell lines. Increased MPS1 was evident in MCF7-LTED at the transcript and protein level. Notably, BOS172722 significantly reduced viability of the majority of LTED and palboR cell lines tested (IC50 between 25-100nM), an effect shown to be class specific using a second MPS1i. Upon MPS1i, cells demonstrated shorter time in mitosis, aberration of cell cycle, increased mitotic errors, culminating in apoptosis. Of note, as little as 48hr exposure to BOS172722 reduced colony formation over 3 weeks suggesting early accumulation of errors is sufficient to provide a long term anti-proliferative effect. To evaluate the clinical relevance of MPS1 in ER+ BC treated with endocrine therapy, we interrogated publicly available datasets from patients treated with neoajuvant AI therapy. In the anastrozole cohort, on-treatment MPS1 expression was significantly (p&amp;lt;0.0001) associated with poor response to anastrozole based on a 2-week residual Ki67 score &amp;lt;10%. In the letrozole cohort, increased on-treatment expression of MPS1 (p=0.0118) was associated with poor response based on tumor shrinkage &amp;lt;50%. Finally, in a xenograft model of AI relapse, BOS172722 caused significant tumor shrinkage, compared to vehicle. Conclusion: For the first time, we show that MPS1 inhibitors are capable of inducing mitotic aberrations and apoptosis in ER+ BC resistant to endocrine therapy and palbociclib providing a new therapeutic strategy. Citation Format: Joanna Nikitorowicz-Buniak, Sunil Pancholi, Nikiana Simigdala, Ricardo Ribas, Spiros Linardopoulos, Mitch Dowsett, Stephen Johnston, Lesley-Ann Martin. MPS1 as a novel target in endocrine- and palbociclib-resistant estrogen receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4950.

Patient-reported predictors of early treatment discontinuation: treatment-related symptoms and health-related quality of life among postmenopausal women with primary breast cancer randomized to anastrozole or exemestane on NCIC Clinical Trials Group (CCTG) MA.27 (E1Z03).

Aromatase inhibitors are the most commonly prescribed adjuvant endocrine therapy for hormone-dependent early breast cancer in postmenopausal women. Among Canadian Cancer Trials Group MA.27 participants, anastrozole and exemestane had comparable 5-year event-free survival. This companion study examined differences in patient-reported treatment-related symptoms (TRS) and health-related quality of life (HRQL) among postmenopausal women randomized to anastrozole or exemestane. MA.27 participants (N=686, of 7576) randomized to 5 years of anastrozole (1mg/day, n=371, Arm A) or exemestane (25mg/day, n=315, Arm E) completed the 56-item Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire to assess TRS and HRQL. The FACT-ES was completed at baseline, 3, 6, 12, and 24months. No significant differences in FACT-ES median scores measuring TRS and HRQL were observed between treatment arms at any time point. Change in TRS from baseline was statistically significant at 3, 6, 12, and 24months. HRQL was stable over time in both arms. Greater TRS burden was associated with poorer HRQL (coefficient=0.57, p<0.001). Twenty percent of patients discontinued AI therapy by month 24 and 32% discontinued AIs at 4years. In both arms, patients reporting more side effect bother prior to initiating study treatment had a higher risk of discontinuing treatment before completing protocol therapy (hazard ratio [HR] 1.29, 95% CI 1.08-1.55, p=0.01). TRS and HRQL were comparable between anastrozole and exemestane. TRS negatively affect HRQL. Women who report being bothered by treatment side effects prior to initiating an AI are at increased risk for early treatment discontinuation.

Abstract PD5-05: Genomic instability and poor antiproliferative response to aromatase inhibitor treatment: A POETIC study

Abstract Background: More than 20% of early-stage patients with estrogen positive (ER+) disease relapse. Higher levels of the proliferation marker Ki67, and lack of reduction of Ki67 in response to AI indicate poorer prognosis. Somatic mutations have been the focus of research in treatment resistance. However, recurrent somatic copy number alterations (SCNAs) are more common and affect more genes in primary breast cancer (BC) than somatic mutations. Previous studies have suggested an increased risk of recurrence for patients with high genomic instability and for patients with loss of heterozygosity (LOH) at the TP53 locus, but it is unknown if these SCNA events impact response to AI treatment. In addition, LOH and mutations at the TP53 locus had a higher risk of recurrence than LOH or mutations at TP53 alone. We hypothesised that genomic instability and SCNAs at particular loci would be increased in early BC patients with high baseline Ki67, and particularly in patients with high Ki67 despite pre-operative AI therapy. Methods: In a substudy of POETIC (UK-wide, phase III, randomised trial with 4483 women testing perioperative AI in postmenopausal women with early BC), SNParray technology was used to determine SCNAs in baseline and surgical tumour core-cuts and blood from 76 patients (59 AI-treated, 17 controls). Proliferation rate was estimated as percentage (%) of cancer cells staining for Ki67 by IHC. Poor AI responders (PR, &amp;lt;60% reduction in Ki67 between baseline and surgery, n=31) and good AI responders (GR, &amp;gt; 75% reduction in Ki67, n=28) were selected from POETIC samples. Mutation data from exome sequencing was available for tumours from 75 of the patients. Results: The fraction of the genome with SCNAs correlated with Ki67 expression in both baseline and surgical samples (baseline Spearman rho=0.5, p &amp;lt; 10-5; surgical Spearman rho=0.44, p &amp;lt; 10-3). In paired baseline vs surgical samples, 24% of samples showed discordance in SCNAs that covered &amp;gt; 10% of the genome. The samples showing the highest discordance were from PRs. The fraction of the genome with LOH was greater in PR (median PR 20%, GR 10%, p = .065), and the best SCNA to predict the fraction of the genome altered in a sample were segments with LOH at Chr17p13.3 (adjusted p &amp;lt; .001, logistic regression). There was a higher percentage of patients with LOH at Chr17p13.3 that contains the TP53 gene in the PR compared to GR group (PR 71%, GR 39%, p = .029), and integration of previously generated mutation data with SCNA showed that 9 out of 31 PRs have mutations and LOH at the TP53 locus compared to 3 out of 28 GRs (p = 0.16). Conclusions: There is discordance between the observed SCNAs in paired samples with high genomic instability and multiple biopsies may be needed to confidently assess all SCNAs. However, LOH at Chr17p13.3 is a biomarker for genomic instability and frequency of LOH is significantly greater in patients that show a poor response to AI treatment. Finally, high genomic instability is associated with high proliferation rates at baseline and surgery after 2 weeks of AI treatment suggesting de novo resistance in tumours with high instability that may lead to a higher rate of recurrence seen in these patients. Citation Format: Schuster EF, Gellert P, Segal CV, López-Knowles E, Buus R, Morden J, Robertson J, Bliss J, Smith I, Dowsett M, POETIC Trial Management Group and Trialists P. Genomic instability and poor antiproliferative response to aromatase inhibitor treatment: A POETIC study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-05.

Abstract IA23: Lessons for ER+ breast cancer from neoadjuvant endocrine therapy trials

Abstract For postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) breast cancer, neoadjuvant endocrine therapy (NET) is an underutilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates (1). Several studies from a decade or more ago showed marked improvements in breast conservation after 3 to 4 months of treatment with an aromatase inhibitor with a 50% reduction in the mastectomy rate in patients designated for a mastectomy at presentation. More recently the American College of Surgeons Oncology Group (ACOSOG) Z1031 study confirmed that for patients who are told they need a mastectomy, about half can undergo successful breast-conserving surgery after 16 to 18 weeks of AI treatment (2). Improvements in surgical outcomes are not the only advantage of NET since individual responses to endocrine therapy can be used to tailor patient treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify extreme responders to NET such that subsequent management could be modified to avoid chemotherapy in a population at low risk of relapse post NET (3). Z1031 therefore provided an opportunity to further evaluate the PEPI. This study was run in two phases, Z1031A enrolled postmenopausal women with stage II/III ER+ (Allred 6 to 8) breast cancer (BC) whose treatment was randomized to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For Z1031B the protocol was amended to include a tumor Ki67 determination after 2-4 weeks of AI. If the Ki67 was &amp;gt;10%, patients were switched to neoadjuvant chemotherapy because the chance of a PEPI=0 score (best prognostic group) is very low in this subpopulation. A pCR rate of &amp;gt;20% was the predefined efficacy threshold. Only two of the 35 patients on Z1031B switched to neoadjuvant chemotherapy experienced a pCR (5.7%, 95%CI: 0.7-19.1%). After 5.5 years of median follow-up, 4 of the 109 (3.7%) patients with a PEPI=0 score relapsed versus 49 of 341 (14.4%) PEPI&amp;gt;0 patients, recurrence hazard ratio (PEPI=0/PEPI&amp;gt;0) = 0.27 (p=0.014; 95%CI: 0.092-0.764). Chemotherapy efficacy was therefore lower than expected in ER+ tumors exhibiting AI-resistant proliferation. For patients with PEPI=0 disease the relapse risk over 5 years was only 3.6% without chemotherapy supporting the study of adjuvant endocrine monotherapy in this group (4). These Ki67 and PEPI triage approaches are being definitively studied in new studies. In particular, new approaches are needed for the poor responders given the low efficacy of chemotherapy. Preliminary studies demonstrate that tumors that exhibit AI-resistant proliferation in the neoadjuvant setting often remain sensitive to CDK4/6 inhibition (5). Serial Ki67 monitoring could logically be considered as an approach to tailored use of adjuvant CDK4/6i treatment. Finally, serial sampling of the tumor inherent in the PEPI approach allows us to study of the genomic evolution of the tumor and to identify new therapeutic targets (6) and monitor tumor evolution in response to AI therapy (7).

Effects of the Chinese medicine Yi Shen Jian Gu granules on aromatase inhibitor-associated musculoskeletal symptoms: A randomized, controlled clinical trial

Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are prevalent among patients on AI therapy, which leads to a lower quality of life and poor adherence to AI treatment. We evaluated whether Yi Shen Jian Gu granules (YSJG) is effective and safe to relieve AIMSS in patients with breast cancer.Eligible participants were randomly assigned to the YSJG group or the placebo group. Both groups had a 12-week treatment period and a 12-week follow-up period. Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index, and the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) were obtained at baseline and at 4, 8, 12 and 24 weeks.Of 146 participants enrolled, 84 were randomly assigned, and 77 were evaluable at 12 weeks. Baseline characteristics were comparable between two groups. The primary outcome was the differences in mean BPI-SF scores at 12 weeks. The worst pain scores decreased by 3.10 points (50.2%; 95% CI, 2.50 to 3.65) for YSJG group compared with a 1.63-point decrease (26.9%; 95% CI, 3.86 to 4.97) for the placebo group (P = 0.001). Significantly improvements were also observed for the WOMAC and M-SACRAH. Possibly YSJG-related side effects were grade 1 nausea (10%) and grade 2 diarrhea (2%). Serum follicle-stimulating hormone and serum estradiol were kept in the postmenopausal range before and after YSJG treatment.Patients with AIMSS treated with YSJG granules had significant improvements in musculoskeletal symptoms. YSJG is effective, safe and well-tolerated in managing AIMSS. Trial registrationISCTN: ISRCTN06129599 (assigned 14 August 2013).

Treatments for Breast Cancer That Affect Cognitive Function in Postmenopausal Women

About one of every eight women will develop breast cancer during her lifetime. Approximately a quarter of a million new cancer cases are expected in 2017. Of those breast cancers, 60% to 75% will have characteristics suggesting that estrogens are likely to promote growth of those tumors. Consequently, inhibiting estrogen synthesis is one of the main treatments of choice. Therefore, women must understand the potential adverse effects of those treatments on quality of life. This review discusses (a) the role of estrogens locally synthesized in the brain in laboratory animals and women, (b) the effects of estrogens and blockers of estrogen synthesis on cognitive function, and (c) the limitations in experiments on women taking inhibitors. This article aims to provide women and oncologists with information that will encourage them to consider side effects of aromatase inhibitors (AIs) treatment on the brain.

Evaluating the Role of Extended Aromatase Inhibitor Therapy in Early Hormone-Positive Breast Cancer

Purpose of Review As adjuvant therapy for early-stage, hormone receptor-positive breast cancer has improved, late recurrences have become a significant issue. Endocrine therapies such as tamoxifen and aromatase inhibitors play a central role in reducing the risk of recurrence of hormone-positive breast cancers. However, the continued risk of breast cancer recurrence even with 5 years of adjuvant AI therapy has led to interest in extended therapy. This review intends to discuss and analyze recent trials that have reported results with extending AI therapy beyond 5 years of treatment.

Lessons in precision oncology from neoadjuvant endocrine therapy trials in ER+ breast cancer

For post-menopausal women with clinical stage II/III estrogen receptor positive (ER+) breast cancer neoadjuvant endocrine therapy (NET) is an under-utilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates. Individual responses to endocrine therapy can also be used to tailor systemic treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify patients at low risk of relapse after NET so that adjuvant chemotherapy can safely be avoided. In a recent validation study, patients with pathological stage 1 or 2A breast cancers with a Ki67 value of 2.7% or less in the surgical specimen (PEPI = 0) after 16–18 weeks of aromatase inhibitor therapy had a 97% disease free survival after 5.5 years of median follow up. Two approaches are currently underway to extend the PEPI model. The first is to determine whether fulvestrant increases the PEPI-0 rate versus anastrozole, as this would increase the number of patients who could be safely managed without adjuvant chemotherapy. The second is to develop new approaches for tumors that exhibit endocrine therapy resistance identified during NET. Preliminary studies demonstrate that tumors that exhibit AI resistant proliferation in the neoadjuvant setting is often sensitive to palbociclib, a CDK4/6 inhibitor. Serial Ki67 monitoring before surgery is therefore logical approach to tailored use of adjuvant CDK4/6i adjuvant treatment. Finally serial sampling of the tumor inherent in the PEPI approach facilitates the identification of new therapeutic targets, mechanisms of resistance and monitoring of tumor evolution in response to AI therapy.

Abstract P3-04-22: RAD1901 demonstrates anti-tumor activity in multiple models of ER-positive breast cancer treatment resistance

Abstract Estrogen receptor positive (ER+) breast cancer makes up approximately 70% of all newly diagnosed breast cancers and ER remains the single most useful predictive and prognostic marker for these patients. In fact, dependence on ER signaling is retained in recurrent disease and even in disease treated with multiple lines of anti-endocrine agents. Indeed, inhibiting estrogen synthesis (e.g. with aromatase inhibitors) and modulating ER pathway activity (e.g. with tamoxifen) continue to be mainstays in the standard of care for ER+ breast cancer patients both in adjuvant and metastatic setting. While patients initially respond well to these agents, a majority of patients with metastatic disease will relapse. Therefore, it is critical to improve our understanding and model the specific mechanisms that can lead to treatment resistance. Mutations in the ligand binding domain of ESR1 have been described as a mechanism that contributes to clinical resistance to aromatase inhibitors. In addition, some ESR1 mutations can lead to a conformational change of the receptor, leading to decreased binding of tamoxifen, thereby reducing its activity. Recently, selective estrogen receptor degraders, or SERDs, have gained widespread attention as a novel treatment strategy for ER+ disease. Indeed, fulvestrant has been shown to degrade ER and cause tumor growth inhibition in many ER+ breast cancer models. However, in the clinic, fulvestrant appears to be limited by PK exposure properties and this, combined with its intramuscular route of administration underscore the need for an oral SERD with improved PK properties. Recently, we have described RAD1901, a novel, orally available, non-steroidal small molecule SERD that is able to degrade ER and effectively cause tumor growth inhibition in multiple patient-derived xenograft models (PDX) models, including two that harbor a Y537S mutation in ESR1. To further validate that RAD1901 has the potential to be used in the advanced disease setting, we tested its anti-tumor activity in preclinical models representing the most common ESR1 mutations (D538G, E380Q, S463P, Y537N/C). In addition, we have tested RAD1901 in multiple cell line models of anti-endocrine resistance. These include long-term estrogen deprived cells that model progression of disease on aromatase inhibitors, as well as tamoxifen-resistant models. Here, we present anti-tumor activity of RAD1901 both as a single agent and as part of rational clinical combinations (eg. CDK4/6, PI3K/Akt/mTOR inhibitors) in multiple models of anti-endocrine resistance. These results combined with previous studies demonstrating RAD1901 efficacy in treatment naïve models provide strong preclinical evidence for clinical testing of RAD1901 in both adjuvant and metastatic setting. RAD1901 is currently under clinical investigation for the treatment of ER+ breast cancers in post-menopausal women (NCT02650817, NCT02338349). Citation Format: Bihani T, Arlt H, Brechbuhl H, Patel H, Tao N, Purandare DM, Hattersley G, Kabos P, Garner F. RAD1901 demonstrates anti-tumor activity in multiple models of ER-positive breast cancer treatment resistance [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-22.

The nutritional herb Epimedium grandiflorum inhibits the growth in a model for the Luminal A molecular subtype of breast cancer.

The Luminal A subtype of breast cancer expresses the estrogen receptor (ER)-α and progesterone receptor (PR), but not the human epidermal growth factor receptor (HER)-2 oncogene. This subtype of breast cancer responds to endocrine therapy involving the use of selective estrogen receptor modulators and/or inhibitors of estrogen biosynthesis. However, these therapeutic agents are frequently associated with long-term systemic toxicity and acquired tumor resistance, emphasizing the need to identify non-toxic alternative treatments for chemo-endocrine therapy responsive breast cancer. The present study utilized the human mammary carcinoma-derived, ER+/PR+/HER-2- MCF-7 cell line as a model of the Luminal A subtype of breast cancer to examine the growth inhibitory effect of the Chinese nutritional herb Epimedium grandiflorum (EG) and determine the mechanisms underlying this effect. MCF-7 cells maintained in a serum-depleted culture medium retained their ability to grow in response to 17β-estradiol (E2). Treatment of the MCF-7 cells with EG resulted in dose-dependent inhibition of E2-promoted growth. Mechanistically, EG inhibited E2-promoted cell cycle progression through G1 stage arrest and modulated the cellular metabolism of E2, increasing the formation of the anti-proliferative metabolites 2-hydroxyestrone and estriol. Long-term treatment of MCF-7 cells with EG inhibited E2-promoted anchorage independent growth, a surrogate in vitro biomarker of tumorigenesis. In conclusion, the results of the present study demonstrate the growth inhibitory effects of EG on MCF-7 cells and identified clinically relevant mechanistic leads for its anti-tumorigenic efficacy.