Endocrine Therapy For Breast Cancer Research Articles

LncRNA-42060 Regulates Tamoxifen Sensitivity and Tumor Development via Regulating the miR-204-5p/SOX4 Axis in Canine Mammary Gland Tumor Cells.

Tamoxifen is the drug of choice for endocrine therapy of breast cancer. Its clinical use is limited by the development of drug resistance. There is increasing evidence that long non-coding RNAs (lncRNAs) are associated with tumor drug resistance. Therefore, we established two TAM-resistant cell lines, CHMpTAM and CHMmTAM. The different expression levels of lncRNA and miRNA in CHMmTAM and CHMm were screened by RNA sequencing, and the lncRNA-miRNA interactions were analyzed. LncRNA ENSCAFG42060 (lnc-42060) was found to be significantly upregulated in drug-resistant cells and tumor tissues. Further functional validation revealed that the knockdown of lnc-42060 inhibited proliferation, migration, clone formation, restoration of TAM sensitivity, and reduction of stem cell formation in drug-resistant cells, whereas overexpression of lnc-4206 showed opposite results. Bioinformatics and dual-luciferase reporter gene assays confirmed that lnc-42060 could act as a sponge for miR-204-5p, further regulating SOX4 expression activity and thus influencing tumor cell progression. In conclusion, we screened lncRNAs and miRNAs associated with TAM resistance in canine mammary gland tumor cells for the first time. lnc-42060 served as a novel marker that may be used as an important biomarker for future diagnosis and treatment.

Identification of Ten Mitosis Genes Associated with Tamoxifen Resistance in Breast Cancer

BackgroundEndocrine therapy is the backbone therapy in estrogen receptor α (ER)-positive breast cancer, and tamoxifen resistance is a great challenge for endocrine therapy. Tamoxifen-resistant and sensitive samples from the international public repository, the Gene Expression Omnibus (GEO) database, were used to identify therapeutic biomarkers associated with tamoxifen resistance.Materials and MethodsIn this study, integrated analysis was used to identify tamoxifen resistance-associated genes. Differentially expressed genes (DEGs) were identified. Gene ontology and pathway analysis were then analyzed. Weighted correlation network analysis (WGCNA) was performed to find modules correlated with tamoxifen resistance. Protein–protein interaction (PPI) network was used to find hub genes. Genes of prognostic significance were further validated in another GEO dataset and cohort from Shanghai Ruijin Hospital using RT-PCR.ResultsA total of 441 genes were down-regulated and 123 genes were up-regulated in tamoxifen-resistant samples. Those up-regulated genes were mostly enriched in the cell cycle pathway. Then, WGCNA was performed, and the brown module was correlated with tamoxifen resistance. An overlap of 81 genes was identified between differentially expressed genes (DEGs) and genes in the brown module. These genes were also enriched in the cell cycle. Twelve hub genes were identified using PPI network, which were involved in the mitosis phase of the cell cycle. Finally, 10 of these 12 genes were validated to be up-regulated in tamoxifen-resistant patients and were associated with poor prognosis in ER-positive patients.ConclusionOur study suggested mitosis-related genes are mainly involved in tamoxifen resistance, and high expression of these genes could predict poor prognosis of patients receiving tamoxifen. These genes may be potential targets to improve efficacy of endocrine therapy in breast cancer, and inhibitors targeted these genes could be used in endocrine-resistant patients.

Factors associated with weight gain during endocrine therapy for breast cancer.

12076 Background: Weight gain is common after a breast cancer diagnosis. The incidence of and risk factors for weight gain during adjuvant endocrine therapy (ET) are poorly described. Limited data support an association between emergent symptoms and weight gain after a breast cancer diagnosis. Methods: We enrolled women with stage 0-III breast cancer initiating ET in a prospective clinic-based cohort. We assessed symptoms with the FACT-ES and PROMIS pain interference, depression, anxiety, fatigue, sleep disturbance and physical function measures at baseline (BL), 3, 6, 12, 24, 36, 48 and 60 months (mo). We defined emergent symptoms at 3 and/or 6 mo as worsening of 4 points from BL on PROMIS measures and 5 points from BL on the FACT-ES. We abstracted weight and menopausal status from charts. The primary outcome of this secondary analysis was weight gain (dichotomized as ≥5% vs < 5% of body weight compared to BL) through 60 mo. We evaluated the association between weight gain during ET and menopausal status. We also evaluated the associations between clinicodemographic factors and emergent symptoms with weight gain and if these associations differed by menopausal status. We performed logistic regression modeling with GEE to account for the longitudinal design. We identified a multivariable model for the set of factors associated with weight gain among pre-menopausal women taking ET. Results: 309 of 321 participants with BL and ≥1 follow-up (FU) weight were included. 263 (85%) had stage I-II disease, 99 (32%) were pre-menopausal, 259 (84%) were White and 32 (10%) were Black. Prior to ET, 45% had mastectomy, 66% had radiation, and 28% received chemotherapy. 4% of pre- and 82% of post-menopausal participants initiated an aromatase inhibitor (AI); all others initiated tamoxifen (Tam). 17% of pre-menopausal participants received ovarian suppression. At BL, 75% of Black and 59% of White participants were overweight/obese. With a median FU of 56 mo, 51% of pre- and 34% of post-menopausal participants gained ≥5% body weight (OR 1.09, 95% CI 1.07-1.13, p < 0.001). For each PRO measure, > 20% of participants had emergent symptoms. Worsening of physical function and pain interference scores at 3 and/or 6 mo were differentially associated with weight gain according to menopausal status (interaction p-values ≤0.05). On multivariate analysis, factors associated with weight gain among pre-menopausal participants were ET (AI vs Tam) (OR 2.8, 95% CI 0.90- 8.77, p = 0.08), prior mastectomy (OR 2.06, 95% CI 0.89-4.77, p = 0.09), emergent pain interference (OR 2.49, 95% CI 0.99-6.24, p = 0.05) and race (White vs other) (OR 7.13, 95% CI 1.29-39.4], p = 0.02). Conclusions: Weight gain during ET for breast cancer is more frequent among pre-menopausal than post-menopausal women. Worsening pain soon after ET initiation, receipt of AI, prior mastectomy and race may identify pre-menopausal women at risk for weight gain for whom prevention strategies are a priority.

Cost sharing for breast cancer hormone therapy: How do dual eligible patients' copayment impact adherence.

ObjectiveTo examine the different levels of copayment assistance and treatment adherence among Medicare and Medicaid dual eligible beneficiaries with breast cancer in the U.S.Research designPropensity Score methodology was adopted to minimize potential selection bias from the nonrandom allocation of the treatment group (i.e., full Medicaid beneficiaries) and control group (i.e., Medicare Savings Programs [MSPs] beneficiaries). Longitudinal hierarchical model and Cox proportional-hazard model were adopted to examine patients’ adherence over their full five-year course of adjuvant hormone therapy.ResultsOur study cohort consisted of 1,133 dual eligible beneficiaries diagnosed with hormone receptor-positive early stage breast cancer in years 2007 –mid 2009. About 80.5% of them received MSPs benefits, while the rest received full Medicaid benefits. On average for a standardized 30-day hormone therapy medication, full Medicaid beneficiaries spent $0.5-$2.0 and MSP beneficiaries spent $1.4-$4.8 in copayment. After adjusting for other factors, this copayment reduction wasn’t associated with a significantly better adherence. However, when the catastrophic coverage threshold was reached (copayments reduced to zero), significant improvement in adherence was found in both groups.ConclusionsOur study found that small amount of cost-sharing reduction did not affect Medicare and Medicaid dual eligible patients’ medication treatment adherence, however, the elimination of cost-sharing (even a minimal amount) was associated with improved adherence. Future legislative and advocacy efforts should be paid on eliminating cost sharing for dual eligibles, and possibly even a broader group of financially vulnerable patients.

Bacterial extracellular vesicles affect endocrine therapy in MCF7 cells.

Background: The microbiome is important in the development and progression of breast cancer. This study investigated the effects of microbiome derived from Klebsiella on endocrine therapy of breast cancer using MCF7 cells. The bacterial extracellular vesicles (EVs) that affect endocrine therapy were established through experiments focused on tamoxifen efficacy.Methods: The microbiomes of breast cancer patients and healthy controls were analyzed using next-generation sequencing. Among microbiome, Klebsiella was selected as the experimental material for the effect on endocrine therapy in MCF7 cells. MCF7 cells were incubated with tamoxifen in the absence/presence of bacterial EVs derived from Klebsiella pneumoniae and analyzed by quantitative real-time polymerase chain reaction and Western blot.Results: Microbiome derived from Klebsiella is abundant in breast cancer patients especially luminal A subtype compared to healthy controls. The addition of EVs derived from K pneumoniae enhances the anti-hormonal effects of tamoxifen in MCF7 cells. The increased efficacy of tamoxifen is mediated via Cyclin E2 and p-ERK.Conclusion: Based on experiments, the EVs derived from K pneumoniae are important in hormone therapy on MCF7 cells. This result provides new insight into breast cancer mechanisms and hormone therapy using Klebsiella found in the microbiome.

Breast Cancer Endocrine Therapy Exhausts Adipocyte Progenitors Promoting Weight Gain and Glucose Intolerance

Breast cancer survivors treated with anti-estrogen therapies report weight gain and have an elevated risk of type 2 diabetes. Here, we show that current tamoxifen use did not influence body mass index but associated with larger breast adipocyte diameter only in women with obesity, suggesting adipose tissue may be targeted by breast cancer therapies. To understand the mechanisms behind these clinical findings, we investigated the impact of estrogen deprivation and tamoxifen in a relevant pre-clinical murine model of obesity. Specifically, mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in single-cell RNA sequencing of mesenchymal stem cells from mouse adipose tissue, endocrine therapies associated with adipose accumulation and preadipocyte expansion, but resulted in adipocyte progenitor depletion only in the context of HFHS. Consequently, 7-week endocrine therapy supported adipocyte hypertrophy and was associated with hepatic steatosis, hyperinsulinemia, insulin resistance, and glucose intolerance, particularly in HFHS fed females. We administered HFHS fed females either metformin or pioglitazone, glucose lowering drugs used to treat diabetes, or treadmill interval exercise during endocrine therapy with the goal of improving whole body metabolism. All interventions prevented the effects of tamoxifen but not estrogen deprivation on adipocyte size and insulin resistance in HFHS-fed mice. This translational study suggests that endocrine therapies may act via ER-alpha to directly disrupt adipocyte progenitors and support adipocyte hypertrophy, leading to ectopic lipid deposition that may promote hyperinsulinemia, insulin resistance and type 2 diabetes. Interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

Changes in initiation of adjuvant endocrine therapy for breast cancer after state health reform

BackgroundSocioeconomic differences in receipt of adjuvant treatment contribute to persistent disparities in breast cancer (BCA) outcomes, including survival. Adjuvant endocrine therapy (AET) substantially reduces recurrence risk and is recommended by clinical guidelines for nearly all women with hormone receptor-positive non-metastatic BCA. However, AET use among uninsured or underinsured populations has been understudied. The health reform implemented by the US state of Massachusetts in 2006 expanded health insurance coverage and increased the scope of benefits for many with coverage. This study examines changes in the initiation of AET among BCA patients in Massachusetts after the health reform.MethodsWe used Massachusetts Cancer Registry data from 2004 to 2013 for a sample of estrogen receptor (ER)-positive BCA surgical patients aged 20–64 years. We estimated multivariable regression models to assess differential changes in the likelihood initiating AET after Massachusetts health reform by area-level income, comparing women from lower- and higher-income ZIP codes in Massachusetts.ResultsThere was a 5-percentage point (p-value< 0.001) relative increase in the likelihood of initiating AET among BCA patients aged 20–64 years in low-income areas, compared to higher-income areas, after the reform. The increase was more pronounced among younger patients aged 20–49 years (7.1-percentage point increase).ConclusionsThe expansion of health insurance in Massachusetts was associated with a significant relative increase in the likelihood of AET initiation among women in low-income areas compared with those in high-income areas. Our results suggest that expansions of health insurance coverage and improved access to care can increase the number of eligible patients initiating AET and may ameliorate socioeconomic disparities in BCA outcomes.

P041. Systematic review of surgical and patient reported outcomes of neoadjuvant endocrine therapy for breast cancer

P041. Systematic review of surgical and patient reported outcomes of neoadjuvant endocrine therapy for breast cancer

Impact of adjuvant endocrine therapy on prognosis in small hormone receptor-positive, HER2-negative early breast cancer.

The efficacy of adjuvant endocrine therapy for hormone receptor-positive breast cancer has been previously established. However, significant adverse events related to endocrine therapy cannot be ignored. T1 breast cancer is expected to have a good prognosis. Therefore, adjuvant endocrine therapy for T1a breast cancer patients is controversial. Thus, in this study, we examined the effect of endocrine therapy on the prognosis of T1N0 hormone receptor-positive, HER2-negative breast cancer patients in each tumor size group, and re-considered the application of endocrine therapy. We retrospectively obtained clinical and pathological data from medical records of 7635 patients who underwent surgery for breast cancer at Aichi Cancer Hospital between January 2000 and December 2017. The primary end point of our analysis was disease-free survival (DFS). The secondary end points were distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS). The log-rank test, cumulative survival generated curves with Kaplan-Meier methods and the hazard ratio (HR) calculated with a Cox regression model were used to assess the effects of endocrine therapy on prognosis. The 5-year DFS was worse in the non-endocrine therapy (non-ET) group (78%) than the endocrine therapy (ET) group (95%) in the T1c population (p < 0.001, HR 0.25). However, there was no statistically significant difference in DFS between the ET and the non-ET groups in T1a (ET 96% vs non-ET 93%, p = 0.9314, HR 0.94) and T1b (ET 96% vs non-ET 93%, p = 0.1481HR 0.53) breast cancer. The OS, DDFS, and BCSS of the patients also showed that endocrine therapy was associated with improvement of the prognosis in the T1c group, but not in the T1a and T1b groups. Adjuvant endocrine therapy may be essential for T1c breast cancer patients. In contrast, this therapy should be discussed for T1a and T1b luminal breast cancer patients under some circumstances, such as suffering from adverse events.

Managing Common Estrogen Deprivation Side Effects in HR+ Breast Cancer: an Evidence-Based Review.

The article reviews the consequences of estrogen deprivation during endocrine therapy for breast cancer and provides an update on alternative therapies for the management of symptoms. Endocrine therapy has progressed substantially in recent years, and its use is recommended for all breast cancer patients expressing hormone receptors. The main adverse events of this treatment can be controlled with medications and nonpharmacological measures. Antidepressants are effective in controlling vasomotor symptoms. Vaginal discomfort can be treated with local lubricants and pelvic floor physiotherapy, which may help in sexual dysfunction. Pathophysiological mechanisms of musculoskeletal symptoms during aromatase inhibitors treatment are not well understood, but some studies evaluating treatment with duloxetine, yoga, and acupuncture have shown some benefits. For prevention of bone loss, patients with risk factors should be offered bisphosphonates or denosumab. Individualization of treatment is crucial. Consideration should be given to therapy effects on quality of life, and strategies for controlling associated symptoms should be offered.

Influence of the competing risk of death on estimates of disease recurrence in trials of adjuvant endocrine therapy for early-stage breast cancer: A secondary analysis of MA.27, MA.17 and MA.17R

BackgroundMany women diagnosed with early-stage hormone-sensitive breast cancer die of causes other than their breast cancer. These competing risks can create challenges in analysing and clearly communicating data on risk of breast cancer recurrence or death. Here, we quantify the impact of competing risks on estimates of disease recurrence and benefit from therapy. Patients and methodsUsing data from the MA.27, MA.17 and MA.17R trials of adjuvant endocrine therapy in early breast cancer, we compared Kaplan-Meier (KM) and competing risk methods for disease-free survival (DFS) and distant recurrence-free survival (DRFS). Each trial was analysed separately. In KM analyses, participants were censored at the time of non-breast cancer death. Competing risk analyses comprised cumulative incidence functions in which non-breast cancer death was a competing risk. ResultsNon-breast cancer deaths were observed more often in older participants, in those with lower risk of breast cancer and after longer follow-up. Compared with conventional analyses, estimates of the proportion of participants with DFS or DRFS events were lower in competing risk analyses, with this difference increasing over the course of follow-up. The absolute treatment benefit was similar or modestly lower in competing risk analyses. ConclusionCompared with KM methods, competing risk analyses result in lower estimates of DFS and DRFS events and similar or modestly lower absolute benefit from experimental endocrine therapy. Over a long time horizon, competing risk methods may be preferable to KM methods when estimating future risk of recurrence in early-stage hormone-sensitive breast cancer. Clinical trials registrationClinicaltrials.gov; NCT00003140, NCT00754845, NCT00066573.

Healthcare Provider Perspectives on Adherence to Adjuvant Endocrine Therapy after Breast Cancer.

Adherence to adjuvant endocrine therapy (AET) for breast cancer is suboptimal. The purpose of this study was to: (1) explore the experiences and perspectives of healthcare providers (HCPs) in providing care to breast cancer survivors prescribed AET, (2) identify how social and structural factors influence the provision of AET-related care, and (3) ascertain HCP recommendations for optimizing AET adherence and related care. Individual, in-depth interviews were conducted with 14 HCPs using an interpretive descriptive approach to inquiry and the theoretical lens of relational autonomy. Data was analyzed using thematic and constant comparative techniques. Healthcare providers focused on four main components of AET-related care: (1) the importance of having careful conversations about AET, (2) difficulties in navigating transitions in care, (3) symptom management as a big part of their role, and (4) dealing with AET discontinuation. Recommendations to improve AET adherence focused on developing sustainable and efficient models of delivering high-quality care to women on AET. Healthcare providers play a pivotal role educating women about AET and supporting their adherence to therapy. Sustainable healthcare system innovations and new models of care that address current system gaps are needed to enhance survivorship care, AET adherence, and ultimately, reduce cancer recurrence and mortality.

A perspective on adverse health outcomes after breast cancer treatment in women with spinal cord injury.

Aging women face increased risks of both breast cancer and spinal cord injury (SCI). Unique treatment challenges for this population warrant consideration. Despite advances in breast cancer treatments, significant adverse health outcomes continue to occur. Cancer treatments can be detrimental to the quality of life of able-bodied women, but more so for women living with pre-existing SCI. The goal of this Perspective Paper is to inform rehabilitation professionals about the needs of women with SCI treated for breast cancer. Specific objectives were: (1) give an overview of breast cancer treatment-related adverse outcomes that need special attention in women with SCI; and (2) inspire researchers to study the consequences of breast cancer-related health conditions in women with SCI. We identified SCI-specific considerations for undergoing breast cancer surgery, chemotherapy, radiation and endocrine therapy. This paper attempts to raise awareness regarding these issues due to the lack of research attention they have received.

Patient Experience of Interpersonal Processes of Care and Subsequent Utilization of Hormone Therapy for Non-Metastatic Breast Cancer

Abstract Purpose: We examined the association between patient experience of care and utilization of hormone therapy (HT) in the treatment of non-metastatic hormone-receptor positive (HR+) breast cancer. Methods: Patients newly diagnosed with non-metastatic breast cancer were recruited from 2006 to 2010 for a longitudinal multisite cohort study in New York, NY, Detroit, MI, and Northern California. Of 1,145 patients surveyed, 797 had HR+ tumors eligible for HT and all necessary data. We assessed patient experience 4 to 8 weeks after recruitment using 6 subscales of the Interpersonal Processes of Care (IPC) survey: compassion, discrimination, and hurriedness in communication, as well as concern elicitation, result explanation, and patient-centered decision-making. Subscales ranged from 1 to 5 where higher values indicated better experiences. HT for 5 years is standard care for HR+ breast cancer so utilization was defined as time from diagnosis to HT initiation and time from HT initiation to early discontinuation before 5 years as calculated from follow-up survey responses. We evaluated the relationship between patient experience and utilization using Cox proportional hazard models, controlling for education, income, insurance, marital status, social support, site of care, age at diagnosis, stage, grade, tumor size, Charlson comorbidity index, and chemotherapy. Results: Median age at diagnosis was 59 years (interquartile range 51–66) with the majority diagnosed at clinical stage 1 (54%) and with low or moderate grade disease (78%). Less hurried communication was associated with increased probability of HT initiation (Hazards Ratio (HR) 1.15; 95% Confidence Interval (CI) 1.03, 1.30; p = 0.018). Conversely, more patient-centered decision-making was associated with increased probability of early discontinuation (HR 1.29; CI, 1.03, 1.63; p = 0.028). All other associations were null. Conclusion: While unhurried communication was associated with initiation of hormone therapy, patient-centered decision-making was associated with early discontinuation. Different aspects of patient experience may have vastly different relationships with patient utilization of health services. Actionable assessments of patient experience may require measurement along multiple dimensions.

Effectiveness of Pilates and circuit-based exercise in reducing arthralgia in women during hormone therapy for breast cancer: a randomized, controlled trial.

To investigate the effect of Pilates compared with circuit-based exercise in reducing arthralgia in women during hormone therapy for breast cancer. Single-blind randomized controlled trial, parallel. University hospital of Brasilia and Brazilian Association for Assistance to People with Cancer. Sixty women with arthralgia were recruited. Eligibility criteria included women complaining of arthralgia during hormone therapy for breast cancer. The exclusion criteria were women with active cancer, lymphedema, limitations to physical exercise, or limitation to answer some questionnaires. Primary: Pain. Secondary: Function, flexibility, and sleep quality. Outcomes were assessed at baseline and the end of the intervention (8 weeks) by the same blinded evaluator. Sixty participants were randomly assigned 20 to each of the three groups: Pilates, circuit-based exercise, and control groups. Exercise was performed twice per week for 75 min, over a period of 8 weeks. Participants in the control group were instructed to continue their usual activities. The Kolmogorov-Smirnov test was used to verify the normality of the outcomes. Intergroup differences were calculated using Kruskal-Wallis test with post hoc Mann Whitney U testing and the parametric data between the three groups with ANOVA of repeated measures with Bonferroni post hoc. The Pilates group demonstrated a significant difference in pain reduction compared to the circuit group (mean difference: -1.95 points, p = 0.020). Pilates was more effective than circuit-based exercise in reducing arthralgia in women during hormone therapy for breast cancer. http://www.ensaiosclinicos.gov.br/rg/RBR-3wsdhs/ Registered on Octob 16th 2017.

Regulation of tamoxifen sensitivity by the PLAC8/MAPK pathway axis is antagonized by curcumin-induced protein stability change

Tamoxifen resistance remains the major obstacle to the estrogen receptor positive breast cancer endocrine therapy. Placenta-specific 8 (PLAC8) has been implicated in epithelial-mesenchymal transition and tumorigenesis. However, the molecular mechanisms underlying PLAC8 function in the context of tamoxifen resistance are unclear. Curcumin has attracted considerable attention in the last decades. It is isolated from Curcuma longa and has beneficial effects in cancer therapy. We studied this property by using MCF-7 and tamoxifen-resistant breast cancer cells (MCF-7/TAM) cell lines. PLAC8 can regulate MCF-7/TAM cell drug sensitivity through the MAPK/ERK pathway and shows the potential effects of curcumin or as a possible druggable target against tamoxifen failure.

Proteolytic Targeting Chimeras with Specificity for Plasma Membrane and Intracellular Estrogen Receptors.

Decisions regarding the assignment of hormonal therapy for breast cancer are based solely upon the presence of nuclear estrogen receptors (ERs) in biopsied tumor tissue. This is despite the fact that the G-protein-coupled estrogen receptor (GPER) is linked to advanced breast cancer and is required for breast cancer stem cell survival, an observation that suggests that effective endocrine therapy should also target this receptor. Here, two ER/GPER-targeting proteolytic chimeras (UI-EP001 and UI-EP002) are described that effectively degrade ERα, ERβ, and GPER. These chimeras form high-affinity interactions with GPER and ER with binding dissociation constants of ∼30 nM and 10-20 nM, respectively. Plasma membrane and intracellular GPER and nuclear ER were degraded by UI-EP001 and UI-EP002, but not by a partial proteolytic targeting chimera (PROTAC) lacking its estrogen-targeting domain. Pretreatment of cells with the proteasomal inhibitor, MG132, blocked UI-EP001 and UI-EP002 proteolysis, while the lysosomotrophic inhibitor, chloroquine, had no effect. The off-target activity was not observed against recombinant β1-adrenergic receptor or CXCR4. Target specificity was further demonstrated in human MCF-7 cells where both drugs effectively degraded ERα, ERβ, and GPER, sparing the progesterone receptor (PR). UI-EP001 and UI-EP002 induced cytotoxicity and G2/M cell cycle arrest in MCF-7 breast cancer and human SKBR3 (ERα-ERβ-GPER+) breast cancer cells but not human MDA-MB-231 breast cancer cells that do not express functional GPER/ER. These results suggest that it is possible to develop a receptor-based strategy of antiestrogen treatment for breast cancer that targets both plasma membrane and intracellular estrogen receptors.

Abstract GS1-01: Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer

Abstract Background monarchE is a phase 3, open-label study evaluating abemaciclib combined with endocrine therapy (ET) compared to ET alone in patients with node positive, HR+, HER2-, high risk early breast cancer (EBC) that resulted in a statistically significant improvement in invasive disease-free survival (IDFS) at a pre-planned interim analysis. Following the positive interim analysis, patients continued to be followed for IDFS, distant recurrence, and overall survival. Methods After surgery and, as indicated, radiotherapy and/or chemotherapy, 5,637 patients with HR+, HER2-, high risk EBC were randomized (1:1) to standard of care adjuvant ET with or without abemaciclib (150 mg BD for 2 years). Patients with ≥4 positive nodes, or 1-3 nodes and either grade 3 disease, tumor size ≥5 cm, or central Ki-67 ≥20% were eligible. Here we present results of the primary outcome IDFS analysis which was planned after approximately 390 IDFS events. Results At the primary outcome analysis, median follow-up was approximately 19 months in both arms (an increase of 3.5 months from the interim analysis). A total of 1437 (25.5%) patients had completed the 2-year treatment period; 3281 (58.2%) were still in the 2-year treatment period. With 395 IDFS events observed in the intent-to-treat population, abemaciclib plus ET continued to demonstrate superior IDFS versus ET alone, with a 28.7% reduction in the risk of developing invasive disease (p=.0009; HR = 0.713; 95% CI = 0.583, 0.871). Two-year IDFS rates were 92.3% in the abemaciclib plus ET arm and 89.3% in the ET alone arm. There was a consistent benefit of abemaciclib in all prespecified subgroups. The addition of abemaciclib to ET also resulted in an improvement in distant relapse-free survival (DRFS). Overall survival was immature at the time of analysis. A key secondary endpoint was efficacy in patients with centrally assessed high Ki-67 (≥20%) (Ki-67H) (n=2498). Disease characteristics were well balanced between the arms of this population. Abemaciclib plus ET demonstrated superior IDFS vs ET alone, with a 30.9% reduction in risk of developing invasive disease (p=.0111; HR = 0.691; 95% CI = 0.519, 0.920) and 2-year IDFS rates of 91.6% and 87.1%, respectively. An improvement in DRFS treatment effect was also observed in the Ki-67H population. At the time of data cutoff, the median treatment duration of abemaciclib was 17.3 months and the median duration of ET was balanced between the arms (18.3 months in the abemaciclib arm and 18.7 months in the ET alone arm). Safety was consistent with the results at the interim IDFS analysis and with the known safety profile of abemaciclib. Conclusions At the primary outcome analysis, with a median follow-up of approximately 19 months, abemaciclib combined with ET continued to demonstrate a clinically meaningful improvement in IDFS in patients with HR+, HER2-, node-positive, high risk, EBC with a statistically significant improvement in IDFS in patients with central Ki-67 ≥20%. ClinicalTrials.gov: NCT03155997 Table 1: PrimaryOutcome EfficacyIntent-to-Treat PopulationIntent-to-Treat PopulationKi-67 ≥20% (Ki-67H) PopulationKi-67 ≥20% (Ki-67H) PopulationEndpointAbemaciclib + ET N=2808ET alone N=2829Abemaciclib + ET N=1262ET alone N=1236IDFS# events, n (%)163 (5.8)232 (8.2)82 (6.5)115 (9.3)log rank P value, HR (95% CI)p=.0009 0.713 (0.583, 0.871)p=.0111 0.691 (0.519, 0.920)Rate (%) at 2 years (95% CI)92.3 (90.9, 93.5)89.3 (87.7, 90.7)91.6 (89.4, 93.4)87.1 (84.3, 89.5)Difference (%) in 2-year rates (95% CI)3 (1.1, 5.0)4.5 (1.2, 7.7)DRFS# events, n (%)131 (4.7)193 (6.8)65 (5.2)102 (8.3)log rank P value, HR (95% CI)p=.0009 0.687 (0.551, 0.858)0.609 (0.445, 0.833)Rate (%) at 2 years (95% CI)93.8 (92.6, 94.9)90.8 (89.3, 92.1)93.6 (91.6, 95.1)88.5 (85.7, 90.7)Difference (%) in 2-year rates (95%CI)3 (1.2, 4.8)5.1 (2.1, 8.1) Citation Format: Joyce A. O'Shaughnessy, Stephen Johnston, Nadia Harbeck, Masakazu Toi, Young-Hyuck Im, Mattea Reinisch, Zhimin Shao, Pirkko Liisa Kellokumpu Lehtinen, Chiun-Sheng Huang, Alexey Tryakin, Matthew Goetz, Hope S Rugo, Elzbieta Senkus, Laura Testa, Michael Andersson, Kenji Tamura, Guenther G. Steger, Lucia Del Mastro, Joanne Cox, Tammy Forrester, Sarah Sherwood, Xuelin Li, Ran Wei, Miguel Martin, Priya Rastogi. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-01.

Abstract SS2-05: Emerging from COVID-19 pandemic: Provider perspective on use of neoadjuvant endocrine therapy (NET) in early stage hormone receptor positive breast cancer

Introduction During the coronavirus 2019 (COVID-19) pandemic in USA, NET use has been recommended to allowsafe deferral of surgical treatment in early stage, estrogen receptor positive breast cancer (ER+BC) In suchcircumstances, after NET use there is limited guidance on locoregional treatment, especially with management of the axilla We aimed to evaluate patterns of care in early stage ER+BC during the first several months of theCOVID-19 pandemic Method A cross-sectional, 30-item survey was developed using a standardized surveydevelopment framework The survey was administered May 8 - June 12, 2020 to a convenience sample of medicaloncologists (MO), radiation oncologists (RO), and surgeons (SO) - breast committee members of two nationalcooperative groups (Alliance and SWOG) with additional participation through chain referrals Providers were presented with general questions on NET use before and during the pandemic They were asked their propensity foromitting axillary lymph node dissection (ALND) after NET if 1 micrometastatic node is found on sentinel lymph nodebiopsy, based on duration of NET Results 114 providers from 29 US states completed the survey - 42 (37%) MO, 14(12%) RO, and 58 (51%) SO, the majority (N=73/96, 76%) with practices dedicated ≥ 75% to BC, at NCI designatedcomprehensive cancer centers 52% (N=48/94) and in large cities (N=49/94, 52%) Prior to COVID-19, most rarely(N=49/107, 46%) or sometimes (N=36, 33%) used NET for early stage ER+BC Nearly half were willing to delay surgery up to 2 months (46%) and 3 months (21%) without use of NET (Table 1, p<0 05) Most providers wouldperform a genomic assay on the biopsy specimen on all or select patients prior to NET initiation, more frequently byMO compared to RO and SO (90% vs 75% and 60%, p<0 05) The most preferred regimen was tamoxifen (withoutovarian suppression) for premenopausal patients and aromatase inhibitor for postmenopausal patients Mostplanned to use NET for as little time as possible until surgery could proceed When stratified by specialty, more MOstated they would vary the duration of therapy based on patient's risk of cancer progression Most providersrecommended omitting ALND after 1, 2, or 3 months of NET (1 month N=56/93, 60%;2 months N=54/92, 59%;3months N=48/90, 53%) With longer duration of therapy, the propensity for omitting ALND decreased (definitely omitafter 6 months N=25/91, 27%;probably omit after 6 months N=38/91, 42%;definitely omit after 1 year N=26/92,28%;probably omit after 1 year N=29/92, 32%) Omitting ALND was not associated with provider's years in practice,percent of practice dedicated to BC, practice type or setting, participation in multidisciplinary tumor board, or numberof COVID-19 cases in the provider's practicing state ConclusionMost providers changed their management of early stage ER+BC during the COVID-19 pandemic by utilizing NET until surgery could proceed As the duration of NET extended, more providers favored ALND in low volume axillary metastatic disease in early stage ER+BC Additional data to inform the care on post-NET locoregional management is needed

Regulatory Interplay between miR-181a-5p and Estrogen Receptor Signaling Cascade in Breast Cancer.

Simple SummaryDespite huge efforts in breast cancer care programs, patient’s survival rates greatly vary. Differences in response to therapy still represent the major challenge for clinicians and biologists. Define new anticancer mechanisms and innovative predictors for resistance could be a valid strategy to permanently defeat breast cancer. Here we propose the epigenetic based reprogramming of breast cancer, which leverages on the crosstalk between miR-181a-5p and Estrogen Receptor α. This simultaneously approach allows to induce miR-181a-5p and reduce the receptor expression, blocking the estrogen-dependent proliferative pathway underlying breast cancer progression. Since the epigenetic approach insists on transcriptional regulation, it is mostly independent of the acquired resistance mechanisms typically induced by prolonged endocrine therapy and therefore can be used as a sensitizer, neoadjuvant, or in combination with the standard in care treatments against breast cancer.The efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, later- or advanced-stage tumors acquire resistance to treatments. The mechanisms underlying tumor resistance to therapy are still not well understood, posing a major challenge for BC patient care. Epigenetic regulation and miRNA expression may be involved in the switch from a treatment-sensitive to a treatment-resistant state and could provide a valid therapeutic strategy for ERα negative BC. Here, a hybrid lysine-specific histone demethylase inhibitor, MC3324, displaying selective estrogen receptor down-regulator-like activities in BC, was used to highlight the interplay between epigenetic and ERα signaling. MC3324 anticancer action is mediated by microRNA (miRNA) expression regulation, indicating an innovative function for this molecule. Integrated analysis suggests a crosstalk between estrogen signaling, ERα interactors, miRNAs, and their putative targets. Specifically, miR-181a-5p expression is regulated by MC3324 and has an impact on cellular levels of ERα. A comparison of breast tumor versus healthy mammary tissues confirmed the important role of miR-181a-5p in ERα regulation and points to its putative predictive function in BC therapy.