Endocrine Therapy For Breast Cancer Research Articles

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.

Atypical vessels in hysteroscopy: Usefulness in prediction of malignant diseases in patients treated with tamoxifen.

Tamoxifen (TAM) is widely used in adjuvant endocrine therapy for invasive breast cancer as a selective estrogen modulator, but this treatment has a risk of developing endometrial malignancy. However, hysteroscopic findings during or after TAM treatment are unclear. The aim of this study is to examine the association between hysteroscopic patterns and malignant histological findings during or after treatment with TAM. The subjects were patients who received TAM after surgery for breast cancer and underwent hysteroscopy at our institution from January 2016 to December 2019. Clinicopathological factors and hysteroscopic findings were collected from medical records and investigated retrospectively. Histologically, atypical endometrial hyperplasia, endometrial cancer, and carcinosarcoma were classified as malignant diseases. A total of 26 patients were eligible for the study. Hysteroscopic findings included an irregular surface of the endometrium (n = 3, 11.5%), atypical vessels (n = 10, 38.5%), papillary structure (n = 3, 11.5%), and polypoid structure (n = 18, 69.2%). Histological examination revealed malignancy in six patients (23.0%). The percentage of atypical vessels in patients with malignancies was significantly higher than that in patients with a normal endometrium or benign lesion (100% vs. 20%, p = 0.0009). The sensitivity and specificity of atypical vessels in hysteroscopy for diagnosis of malignant diseases were 100% and 80%, respectively. Hysteroscopic findings of atypical vessels may be useful for prediction of malignant diseases in patients treated with TAM.

Adherence to Newly Implemented Tamoxifen Therapy for Breast Cancer Patients in Rural Western Ethiopia

Introduction: Endocrine therapy for breast cancer (BC) patients is highly underutilized in rural Ethiopia and other African countries. Objective: This study aims to assess the feasibility of and adherence to tamoxifen therapy in rural Ethiopia. Methods: We ascertained the hormone receptor (HR) status in 101 women diagnosed with BC from January 2010 to December 2015 and who had surgery in Aira Hospital, in rural Ethiopia. From 2013, tamoxifen was offered to patients with HR-positive (HR+) tumors. Prescription refill records and a structured questionnaire were used to assess receipt of and adherence to tamoxifen. Results: Of the 101 BC patients tested for HR status during the study period, 66 (65%) patients were HR+ and were eligible for tamoxifen treatment. However, 15 of the HR+ patients died before tamoxifen became available in 2013. Of the remaining 51 HR+ patients, 26 (51%) initiated tamoxifen but only 9 of them (35%) adhered to therapy (medication possession rate ≥80%, median observation 16.2 months). After 1 year, 52% of the patients were still adherent, and 9 patients had discontinued therapy. The reasons for non-initiation of tamoxifen included patient factors (n = 5), including financial hardship or lack of transportation, and health care provider factors (n = 12). Conclusions: Endocrine therapy for BC patients seems feasible in rural Western Ethiopia, although non-adherence due to financial hardship and a less developed health care infrastructure remains a major challenge. We postulate that the implementation of breast nurses could reduce patient and health system barriers and improve initiation of and adherence to endocrine treatment.

ASO Author Reflections: Tailoring Axillary Surgery After Neoadjuvant Endocrine Therapy for Breast Cancer.

ASO Author Reflections: Tailoring Axillary Surgery After Neoadjuvant Endocrine Therapy for Breast Cancer.

Adherence to lifestyle recommendations of the World Cancer Research Fund/american Institute for Cancer Research of breast cancer survivors on adjuvant hormone therapy and associated factors

About 30% to 40% of cancers can be prevented through healthy diet, adequate body weight and regular physical activity. The adherence to lifestyle recommendations of the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) has been associated with lower risk of death in cancer survivors. The objective of this study was to evaluate adherence to the new recommendations of the WCRF/AICR by Brazilian women in adjuvant hormone therapy for breast cancer and its associated factors. This cross-sectional study was carried out from January to August 2017, in Santa Maria, RS. Regarding the recommendations of the WCRF/AICR the average adherence score was 4.4 points out of a total of 8 points. Higher adherence is associated with higher schooling. In individual recommendations, physical activity showed the lowest adherence whereas alcohol consumption showed the highest adherence. The data suggest that Brazilian breast cancer survivors, especially those with lower levels of education, could benefit from dietary counseling and physical activity.

Drug Screening of Potential Multiple Target Inhibitors for Estrogen Receptor-α-positive Breast Cancer.

Estrogen receptor α (ERα) antagonist is the most common treatment for ERα-positive breast cancer. However, compensatory signaling contributes to resistance to ERα antagonists. Thus, to explore the potential agents for targeting compensatory signaling, we screened multiple target inhibitors for breast cancer treatment. We attempted to build a structure-based virtual screening model that can find potential compounds and assay the anticancer ability of these drugs by overall cell survival assay. The downstream compensatory phosphorylated signaling was measured by immunoblotting. Hamamelitannin and glucocheirolin were hits for ERα, phosphoinositide 3-kinase (PI3K), and KRAS proto-oncogene, GTPase (KRAS), which were active against estrogen and epidermal growth factor-triggered proliferation. Additionally, we select aminopterin as a hit for ERα, PI3K, KRAS, and SRC proto-oncogene, non-receptor tyrosine kinase (SRC) with inhibitory activities toward AKT serine/threonine kinase 1 (AKT) and mitogen-activated protein kinase kinase (MEK) signaling. Our structure-based virtual screening model selected hamamelitannin, glucocheirolin, aminopterin, and pemetrexed as compounds that may act as potential inhibitors for improving endocrine therapies for breast cancer.

Clinical aspect, pathogenesis and therapy options of alopecia induced by hormonal therapy for breast cancer.

Adjuvant hormonal therapy is one of the most important treatments of hormone-receptor-positive breast cancer and includes selective estrogen receptor modulators, aromatase inhibitors, and luteinizing hormone-releasing hormone analogs. In patients receiving these drugs, a progressive recession of frontal-temporal hairlines is often observed, such as a certain grade of hair miniaturization in the same areas and the central scalp area, producing a pseudo-female androgenic alopecia, which has to be considered oncotherapy-induced alopecia. The aim of this work, is to describe the clinical aspects and pathogenesis of this type of alopecia and to analyze the different drugs which have been proposed until now. The authors concude that topical hormones should not be considered as a therapeutic approach because of their direct or indirect oncogenic potential. A therapeutic approach that could be both safe and effective is proposed.

Resuming Sensitivity of Tamoxifen-Resistant Breast Cancer Cells to Tamoxifen by Tetrandrine.

Background:Tamoxifen is one of the medicines for adjuvant endocrine therapy of hormone-dependent breast cancer. However, development of resistance to tamoxifen occurs inevitably during treatment. This study aimed to determine whether sensitivity of tamoxifen-resistant breast cancer cells (TAM-R) could be reinstated by tetrandrine (Tet).Methods:All experiments were conducted in TAM-R cells derived from the MCF-7 breast cancer cell line by long-term tamoxifen exposure. Cell growth, apoptosis, and autophagy were end-points that evaluated the effect of Tet (0.9 μg/ml, 1.8 μg/ml, and 3.75 μg/ml) alone or in combination with TAM (1 μM). Cell apoptosis was determined by an ELISA assay and autophagy was determined by fluorescent staining using the Enzo autophagy detection kit. Immunoblotting was used to evaluate markers for apoptosis, autophagy, and related signal pathway molecules.Results:Growth of TAM-R cells was significantly inhibited by Tet. Combination of Tet with tamoxifen induced a greater inhibition on cell growth than tamoxifen alone, which was predominantly due to enhancement of pro-apoptotic effect of TAM by Tet. Autophagy was significantly inhibited in TAM-R cells treated with Tet plus TAM as shown by increased autophagosomes and the levels of LC3-II and p62. At 0.9 μg/ml, Tet increased the levels of both apoptosis and autophagy markers. Among them increase in p53 levels was more dramatic.Conclusions:Tet as a monotherapy inhibits TAM-R cells. Tet potentiates the pro-apoptotic effect of TAM via inhibition of autophagy.

Hormone Receptor Expression on Endocrine Therapy in Patients with Breast Cancer: A Meta-Analysis

To evaluate the role of hormone receptor expression on endocrine therapy in patients with breast cancer. The databases were used to collect the effect of high expression and low expression of hormone receptors on the efficacy of endocrine therapy in breast cancer. Two evaluators independently screened the literature based on preset inclusion and exclusion criteria. The quality of the article was evaluated using a modified Newcastle-Ottawa Scale (NOS) system. The survival data included in the literature were extracted and the ln(hazard ratio (HR)) and se[ln(HR)] of the overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) rates were calculated according to different level of hormone receptors. The RevMan 5.3 software was used to evaluate the meta-analysis. A total of 13 relevant literature were included in the study. There were 8318 estrogen receptor (ER)-positive and 7926 progesterone receptor (PR)-positive patients. Overall survival, DFS, and RFS rates in high expression of ER(+) patients were significantly higher in low expression of ER(+) patients (OS HR = .59, 95% confidence interval (CI): .46-.76, P < .0001; DFS HR = .62, 95%CI: .50-.76, P < .00001; RFS HR = .44, 95% CI: .33-.58, P < .00001). In patients with high expression of PR(+), OS, DFS, and RFS rates were significantly higher than those with low expression of PR(+) (OS HR = .66, 95% CI: .57-.78, P < .00001; DFS HR = .52, 95% CI: .42-.65, P < .00001; RFS HR = .24, 95% CI: .11-.53, P = .0004). The expression of ER and PR are powerful predictors of adjuvant endocrine therapy response. Breast cancer patients with high expression of hormone receptors benefit more from endocrine therapy and have better prognosis.

Effect of Capivasertib in Patients With an AKT1 E17K-Mutated Tumor

In the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, agents targeting genetic tumor abnormalities are administered to patients. In the NCI-MATCH subprotocol EAY131-Y trial, patients with an AKT1 E17K-mutated metastatic tumor received the pan-AKT inhibitor capivasertib. To assess the objective response rate (ORR) of capivasertib in patients with an AKT1 E17K-mutated tumor. Between July 13, 2016, and August 10, 2017, patients in the NCI-MATCH trial were enrolled and assigned to the subprotocol EAY131-Y nonrandomized trial. Patients included adults with an AKT1 E17K-mutated metastatic tumor that had progressed with standard treatment, and these patients were assigned to receive capivasertib. Tumor assessments were repeated every 2 cycles. Data analysis of this evaluable population was performed from November 8, 2019, to March 12, 2020. The study treatment was capivasertib, 480 mg, orally twice daily for 4 days on and 3 days off weekly in 28-day cycles until disease progression or unacceptable toxic effect. If patients continued hormone therapy for metastatic breast cancer, the capivasertib dose was 400 mg. The primary end point was the ORR (ie, complete response [CR] and partial response) according to the Response Evaluation Criteria in Solid Tumors criteria, version 1.1. Secondary end points included progression-free survival (PFS), 6-month PFS, overall survival, and safety. In total, 35 evaluable and analyzable patients were included, of whom 30 were women (86%), and the median (range) age was 61 (32-73) years. The most prevalent cancers were breast (18 [51%]), including 15 patients with hormone receptor (HR)-positive/ERBB2-negative and 3 with triple-negative disease, and gynecologic (11 [31%]) cancers. The ORR rate was 28.6% (95% CI, 15%-46%). One patient with endometrioid endometrial adenocarcinoma achieved a CR and remained on therapy at 35.6 months. Patients with confirmed partial response had the following tumor types: 7 had HR-positive/ERBB2-negative breast cancer, 1 had uterine leiomyosarcoma, and 1 had oncocytic parotid gland carcinoma and continued receiving treatment at 28.8 months. Sixteen patients (46%) had stable disease as the best response, 2 (6%) had progressive disease, and 7 (20%) were not evaluable. With a median follow-up of 28.4 months, the overall 6-month PFS rate was 50% (95% CI, 35%-71%). Capivasertib was discontinued because of adverse events in 11 of 35 patients (31%). Grade 3 treatment-related adverse events included hyperglycemia (8 [23%]) and rash (4 [11%]). One grade 4 hyperglycemic adverse event was reported. This nonrandomized trial found that, in patients with an AKT1 E17K-mutated tumor treated with capivasertib, a clinically significant ORR was achieved, including 1 CR. Clinically meaningful activity with single-agent capivasertib was demonstrated in refractory malignant neoplasms, including rare cancers. ClinicalTrials.gov Identifier: NCT00700882.