Endocrine Therapy For Breast Cancer Research Articles

Advances in epigenetic mechanism and drug research of reversing resistance to endocrine therapy in breast cancer

Advances in epigenetic mechanism and drug research of reversing resistance to endocrine therapy in breast cancer

ISY3-4 - Issue to be solved in the near future to determine optimal sequential endocrine therapy in metastatic breast cancer

Main objective in palliative therapy for patients with metastatic breast cancer (MBC) is prolonged survival and maintenance of quality of life. In ER-positive/HER2-negative MBC, sequential endocrine therapy is one of the most important treatment strategy for patients who have hormone-responsive and no life-threatening disease. However, the optimal sequential endocrine therapy is not established. Aromatase inhibitor, selective ER modulator, selective ER down-regulator and CDK4/6 inhibitor + aromatase inhibitor are candidates as 1st line endocrine therapy for postmenopausal patients. There is also no clear guidance on subsequent treatment. From the results of several clinical trials, it may be better to sequentially use alternate drugs with different mechanism of action in sequential endocrine monotherapy. However, the advent of CDK4/6 inhibitors have resulted in a paradigm shift in the treatment of ER-positive/HER2-negative metastatic breast cancer. In this presentation, I would like to discuss about 4 issues to be solved in endocrine therapy for postmenopausal ER-positive/HER2-negative metastatic breast cancer. First, should CDK4/6 inhibitor in combination with endocrine agent be used as part of sequential endocrine therapy for all patients? Second, whether CDK4/6 inhibitor are more effective for use in 1st line therapy or subsequent treatment? Third, when using a CDK4/6 inhibitor after 1st line endocrine monotherapy, should it be changed to another endocrine agent or the same endocrine drug? Fourth, what is the optimal treatment in patients who have progressed during or after CDK4/6 inhibitor administration?

Therapeutic predictors of neoadjuvant endocrine therapy response in estrogen receptor-positive breast cancer with reference to optimal gene expression profiling.

Neoadjuvant endocrine therapy (NAET) for estrogen receptor-positive primary breast cancer causes adequate tumor shrinkage, and is expected to be helpful for breast-conserving surgery, but the adaptation criteria, especially in regard to treatment duration, have never been elucidated. Re-visiting past gene expression profiles, we explored the data for specialized pre-therapeutic predictors and validated the results using our in-house clinical cohorts. We sorted the genes related to a > 30% tumor volume reduction through NAET from a cDNA microarray data-set of GSE20181, then selected the top 40 genes. We validated these gene expression levels using pre-therapeutic biopsy samples obtained from patients treated with long-term NAET (over 4months; N = 40). A short-term (2-8weeks; N = 37) NAET cohort was also validated to clarify whether expression of these genes is also related to a rapid response of Ki67 and PEPI score. In the long-term group, higher expression of KRAS, CUL2, FAM13A, ADCK2, and LILRA2 was significantly associated with tumor shrinkage, and KRAS, MMS19, and IVD were related to lower PEPI score (≤ 3). Meanwhile in the short-term group, none of these genes except CUL2 showed a direct correlation with Ki67 reduction or PEPI score. This suggested that tumor shrinkage by NAET might be induced by response to the hypoxic environment (CUL2, FAM13A, KRAS) and activation of tumor immune system (LILRA2), without involving inhibition of proliferation. Expression of specific genes may allow selection of the most responsive patients for maximum tumor shrinkage with NAET.

Inhibitory role of large intergenic noncoding RNA-ROR on tamoxifen resistance in the endocrine therapy of breast cancer by regulating the PI3K/Akt/mTOR signaling pathway.

Breast cancer (BC) is the second-leading cause of central nervous system metastases among severe malignancies. This study aimed at investigating the underlying mechanism by which large intergenic noncoding RNA-regulator of reprogramming (lincRNA-ROR) affects the tamoxifen (TAM) resistance of BC cells by regulating the PI3K/Akt/mTOR signaling pathway. Immortalized human mammary epithelial cell line (MCF10A) and BC cell lines (MCF-7, MDA-MB-231, T47D, BCAP-37, and ZK-75-1) were cultured, and BC tissues and adjacent normal breast tissues were collected from 152 BC patients. LincRNA-ROR expression in tissues and cells were detected using reverse transcription quantitative polymerase chain reaction. RNA interference was used to silence lincRNA-ROR in MDA-MB-231 cells, and then the cell proliferation and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and annexin-V and propidium iodide (PI) double staining respectively. The expression of apoptosis-related proteins and PI3K/Akt/mTOR signaling pathway-related proteins was measured by performing western blot assay. The BC tissues and cells presented a higher expression of lincRNA-ROR. MAD-MB-231 cells exhibited the highest lincRNA-ROR expression. After lincRNA-ROR silencing, MAD-MB-231 cells showed decreased proliferation, and increased sensitivity to TAM. Besides, the apoptosis-promoting effect of TAM on MAN-MB-231 cells significantly increased. The expression of PI3K/Akt/mTOR signaling pathway-related proteins and the PI3K/Akt/mTOR signaling pathway were repressed by TAM after silencing lincRNA-ROR. Our study demonstrated that silencing lincRNA-ROR could increase the sensitivity of BC MAD-MB-231 cells to TAM by suppressing the activation of P13K/Akt/mTOR signaling pathway.

Clinical Benefits of Acupuncture for the Reduction of Hormone Therapy–Related Side Effects in Breast Cancer Patients: A Systematic Review

Importance. Acupuncture can help reduce unpleasant side effects associated with endocrine therapy for breast cancer. Nevertheless, comprehensive evaluation of current evidence from randomized controlled trials(RCTs) is lacking. Objective. To estimate the efficacy of acupuncture for the reduction of hormone therapy-related side effects in breast cancer patients. Evidence review. RCTs of acupuncture in breast cancer patients that examined reductions in hormone therapy–related side effects were retrieved from PubMed, EMBASE, Web of Science, Ovid MEDLINE, and Cochrane Library databases through April 2016. The quality of the included studies was evaluated according to the 5.2 Cochrane Handbook standards, and CONSORT and STRICTA (Revised Standards for Reporting Interventions in Clinical Trials of Acupuncture) statements. Intervention. Interventions included conventional acupuncture treatment compared with no treatment, placebo, or conventional pharmaceutical medication. Major outcome measures were the alleviation of frequency and symptoms and the presence of hormone therapy–related side effects. Findings/Results. A total of 17 RCTs, including a total of 810 breast cancer patients were examined. The methodological quality of the trials was relatively rigorous in terms of randomization, blinding, and sources of bias. Compared with control therapies, the pooled results suggested that acupuncture had moderate effects in improving stiffness. No significant differences were observed in hot flashes, fatigue, pain, gastrointestinal symptoms, Kupperman index, general well-being, physical well-being, tumor necrosis factor (TNF), and interleukin (IL). Conclusions. Acupuncture therapy appears to be potentially useful in relieving functional stiffness. However, further large-sample trials with evidence-based design are still needed to confirm these findings.

Patients’ needs and wishes regarding pharmaceutical care provided by the pharmacist for women treated with adjuvant endocrine therapy for breast cancer

The prevalence of complementary and alternative medication (CAM) use in senior adult oncology (SAO) patients is widely variable and little is known about whether polypharmacy (PP) and potentially inappropriate medication (PIM) use influences CAM use given the increased number of comorbidities and polypharmacy. One approach to optimize medication management is through utilization of pharmacists as part of a team-based, healthcare model.Prevalence of CAM and factors influencing CAM use was examined in a secondary analysis of 248 patients who received an initial comprehensive geriatric oncology assessment between January 2011 and June 2013. Data was collected from electronic medical records. CAM was defined as herbal medications, minerals, or other dietary supplements, excluding vitamins. Patient characteristics influencing CAM use (e.g. comorbidities, PP and PIM use) were analyzed.Only 234 patients (evaluated by pharmacists) were included in the final analysis. Mean age was 79.9 years [range 61–98]; 64% women, 74% Caucasian, 87% with a solid tumor, mean comorbidities, 7.69. CAM prevalence was 26.5% (n = 62) and median CAM use was 0 (range 0–10). The proportion of CAM use (1, 2, and 3) was 19.2%, 6.4%, and 0.4%, respectively. Associations with CAM use (versus no-CAM) were polypharmacy (P = 0.045), vision impairment (P = 0.048) and urologic comorbidities (P = 0.021).A pharmacist-led comprehensive medication assessment demonstrated a more precise estimation of CAM prevalence in the ambulatory SAO population. CAM use was associated with polypharmacy, ophthalmic and urologic medical conditions. Integrating pharmacists into team-based (geriatric and oncology) care models is an underutilized yet viable solution to optimize medication use.

Endocrine therapy for breast cancer in the primary care setting.

■ Hormone-positive bca is the most prevalent form of bca and, compared with the other subtypes, is usually associated with better survival.■ Survivorship has significantly increased for all stages of hormone-positive bca, making the primary care physician a key player in the care of affected patients.■ The two most common classes of anti-hormonal agents used in these patients are selective estrogen receptor modulators and aromatase inhibitors. Each class of medication is associated with signature side effects.■ Within the past decade, multiple novel estrogen receptor blockers (for example, fulvestrant) and agents aimed at circumventing resistance to endocrine therapy [inhibitors of cyclin-dependent kinase 4/6 and of mtor (the mechanistic target of rapamycin)] have gained clinical ground. Understanding their side effects will be increasingly relevant to primary care physicians.■ Multidisciplinary care is always encouraged in the care of cancer patients receiving anti-hormonal therapy.

Endocrine Therapy for Breast Cancer: A Model of Hormonal Manipulation.

Oestrogen receptor (ER) is the driving transcription factor in 70% of breast cancer. Endocrine therapies targeting the ER represent one of the most successful anticancer strategies to date. In the clinic, novel targeted agents are now being exploited in combination with established endocrine therapies to maximise efficacy. However, clinicians must balance this gain against the risk to patients of increased side effects with combination therapies. This article provides a succinct outline of the principles of hormonal manipulation in breast cancer, alongside the key evidence that underpins current clinical practice. As the role of endocrine therapy in breast cancer continues to expand, the challenge is to interpret the data and select the optimal strategy for a given clinical scenario.

Neoadjuvant Endocrine Therapy in Breast Cancer Upregulates the Cytotoxic Drug Pump ABCG2/BCRP, and May Lead to Resistance to Subsequent Chemotherapy

IntroductionNeoadjuvant treatments for primary breast cancer are becoming more common; however, little is known about how these impact on response to subsequent adjuvant therapies. Conveniently, neoadjuvant therapy provides opportunities to consider this question, by studying therapy-induced expression changes using comparisons between pre- and posttreatment samples. These data are relatively lacking in the context of neoadjuvant endocrine therapy, as opposed to the more common neoadjuvant chemotherapy. Here, we investigate the relevance of expression of the xenobiotic transporter ABCG2/BCRP, a gene/protein associated with chemoresistance, in the context of neoadjuvant endocrine therapy and particularly with reference to subsequent chemotherapy treatment. Materials and MethodsABCG2/BCRP expression was assessed by immunohistochemistry or by expression arrays in matched patient samples pre- and post-neoadjuvant endocrine therapy. Cell culture was used to model the impact of endocrine therapy-induced changes in ABCG2/BCRP on subsequent chemotherapy response, using Western blots, quantitative polymerase chain reaction, survival assays, and cell cycle analyses. ResultsABCG2/BCRP was commonly and significantly upregulated in breast cancers after treatment with neoadjuvant endocrine therapy in 3 separate cohorts encompassing a total of 200 patients. Treatment with the endocrine therapeutic tamoxifen similarly induced ABCG2/BCRP upregulation in a relevant model cell line, the estrogen receptor-positive line T47D. Critically, this upregulation was associated with significantly increased chemoresistance to subsequent treatment with epirubicin, an anthracycline commonly used in breast cancer adjuvant chemotherapy. ConclusionOur data suggest that neoadjuvant endocrine therapy may induce poor responses to adjuvant chemotherapy, and therefore, that clinical outcomes following this treatment sequence warrant further study.

New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons.

An effective endocrine therapy for breast cancer is to selectively and effectively degrade the estrogen receptor (ER). Up until now, there have been largely only two molecular scaffolds capable of doing this. In this study, we have developed new classes of scaffolds that possess selective estrogen receptor degrader (SERD) and ER antagonistic properties. These novel SERDs potently inhibit MCF-7 breast cancer cell proliferation and the expression of ER target genes, and their efficacy is comparable to Fulvestrant. Unlike Fulvestrant, the modular protein-targeted chimera (PROTAC)-type design of these novel SERDs should allow easy diversification into a library of analogs to further fine-tune their pharmacokinetic properties including oral availability. This work also expands the pool of currently available PROTAC-type scaffolds that could be beneficial for targeted degradation of various other therapeutically important proteins.

Abstract PL01-01: Liquid biopsy: Novel technologies and clinical applications

Abstract PL01-01: Liquid biopsy: Novel technologies and clinical applications

Weight Evolution During Endocrine Therapy for Breast Cancer in Postmenopausal Patients: Effect of Initial Fat Mass Percentage and Previous Adjuvant Treatments

BackgroundWeight changes during adjuvant treatment for early-stage breast cancer has been associated with a poor prognosis. The long-term evolution of body composition during adjuvant treatment for breast cancer, in particular, endocrine therapy, is not well known, and new data on this topic are required. The present study assessed the evolution of weight and body composition among 33 postmenopausal breast cancer patients receiving endocrine therapy after standard adjuvant chemotherapy that included taxanes. Patients and MethodsDual-energy x-ray absorptiometry was used to measure the fat and lean body mass. Body water was assessed using multifrequency bioelectrical impedance analysis. The Hospital Anxiety and Depression questionnaire and the short version of the International Physical Activity Questionnaire were also administered. ResultsDuring endocrine therapy, 5 of the 33 patients (15.2%) lost weight and 12 (36.4%) gained weight. The overall average gain was 2.0 ± 5.5 kg (P = .04). During this period, the fat mass, lean body mass, and body water increased. The factors linked to fat mass gain included an excess fat mass (≥ 36%) before treatment and weight loss during chemotherapy. In the overall period of adjuvant cancer treatment, 30% of the population gained > 5% of their initial weight. The average gain was the same as that during the endocrine therapy period (2.0 ± 5.4 kg; P = .031) and was characterized by an increase in total lean body mass, mainly localized in the trunk region. ConclusionEndocrine therapy appears as a pivotal period in weight and body composition management. Overfat and obese patients and those who lose weight during chemotherapy were more subject to weight and fat mass gain during endocrine therapy.

Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity

Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.

Women's Beliefs on Early Adherence to Adjuvant Endocrine Therapy for Breast Cancer: A Theory-Based Qualitative Study to Guide the Development of Community Pharmacist Interventions.

Adjuvant endocrine therapy (AET) taken for a minimum of five years reduces the recurrence and mortality risks among women with hormone-sensitive breast cancer. However, adherence to AET is suboptimal. To guide the development of theory-based interventions to enhance AET adherence, we conducted a study to explore beliefs regarding early adherence to AET. This qualitative study was guided by the Theory of Planned Behavior (TPB). We conducted focus groups and individual interviews among women prescribed AET in the last two years (n = 43). The topic guide explored attitudinal (perceived advantages and disadvantages), normative (perception of approval or disapproval), and control beliefs (barriers and facilitating factors) towards adhering to AET. Thematic analysis was conducted. Most women had a positive attitude towards AET regardless of their medication-taking behavior. The principal perceived advantage was protection against a recurrence while the principal inconvenience was side effects. Almost everyone approved of the woman taking her medication. The women mentioned facilitating factors to encourage medication-taking behaviors and cope with side effects. For adherent women, having trouble establishing a routine was their main barrier to taking medication. For non-adherent women, it was side effects affecting their quality of life. These findings could inform the development of community pharmacy-based adherence interventions.

Correlation analysis between endocrine therapy adherence and illness perception in breast cancer patients

Objective To explore the correlation between endocrine therapy adherence and illness perception (IP) in breast cancer patients. Methods From January to June 2017, a total of 100 breast cancer patients treated in Oncology Department at a Class Ⅲ Grade A hospital in Daqing City of Heilongjiang Province were selected as subjects by convenience sampling. The endocrine therapy adherence and IP of patients were investigated with the breast cancer endocrine therapy adherence questionnaire and Brief Illness Perception Questionnaire (BIPQ) . Pearson correlation and multiple linear regression were used to analyze the correlation between them. Results A total of 98 valid questionnaires were collected totally. Except for entry 3, 6 and 7, the scores on entries and total score of IP of patients were positively correlated with the endocrine therapy adherence (P<0.05) . Except for entry 7, score of each entry and total score all entered the regression equation of adherence. Conclusions The IP of breast cancer patients has a correlation with the endocrine therapy adherence. We should raise the level of positive IP of patients by positive direction and intervention so as to improve endocrine therapy adherence of patients. Key words: Breast neoplasms; Medication adherence; Illness perception

Bayesian synthesis using prior information on fracture risk from randomized trials to analyze post-market data

ObjectiveTo conduct a Bayesian evidence synthesis using commonly available statistical procedures to estimate fracture risk for postmenopausal women undergoing hormonal therapy for breast cancer. Study Design and SettingUsing linked administrative data, we conducted a retrospective cohort study of women aged 66 years or older diagnosed with stage I to III breast cancer in Ontario, Canada, between April 1, 2003, and February 28, 2010. We used data augmentation to perform Bayesian Cox regression of the hazard of a hip, spine, or wrist/forearm fracture, adjusting for age, history of fragility fracture, corticosteroid use, osteoporosis, rheumatoid arthritis, dementia, or diabetes diagnoses. ResultsOf 10,259 included in the sample, 3,733 initiated on tamoxifen and 6,526 on an aromatase inhibitor. Posterior probabilities that the hazard ratio (HR) exceeded 1 for aromatase inhibitor compared with tamoxifen were 46% (HR = 0.99, 95% credible interval [CrI] 0.71, 1.25), 35% (HR = 0.94, 95% CrI 0.78, 1.26), and 76% (HR = 1.08, 95% CrI 0.88, 1.32) with an uninformative prior, and 63% (HR = 1.04, 95% CrI 0.83, 1.3), 84% (HR = 1.12, 95% CrI 0.89, 1.4), and 89% (HR = 1.13, 95% CrI 0.93, 1.36) with an informative prior, for hip, spine, and wrist/forearm fractures, respectively. ConclusionsPrior information resulted in higher posterior probabilities. The strength of evidence for increased risk varied by fracture site.

The Impact of Perioperative Hormonal Therapy for Breast Cancer on Transverse Rectus Abdominis Myocutaneous Flap Abdominal Complications.

The pedicled transverse rectus abdominis myocutaneous (TRAM) flap is a reliable reconstructive option in breast cancer patients; however, it carries known risk of donor site hernia formation. Some hormonal therapy drugs have been associated with hernia formation in animal models. Minimal data exist concerning impact of hormonal therapy for breast cancer on abdominal donor site complications after breast reconstruction. Patients who underwent TRAM flap for breast cancer or high-risk status at a single institution by the senior author from 2003 to 2015 were identified. Charts were reviewed. Patient demographics, comorbidities, treatments, and abdominal complications were recorded. Patients were divided into groups based on use of hormonal therapy as well as exposure to specific drugs. Statistical analyses were performed. A total of 358 patients were included. Overall hernia rate was 5.9%. About 231 (64.5%) patients had hormonal therapy, whereas 127 (35.5%) did not. Difference in hernia formation was not statistically significant between the hormonal therapy group (6.9%) and the no hormonal therapy group (3.9%; P = 0.359). Patients exposed to tamoxifen and those exposed to anastrozole had no significant difference in complication rates compared with the no hormonal therapy group, whereas patients exposed to letrozole had increased rate of hernia (13.5%; P = 0.037) and infection (21.6%; P = 0.013) compared with the no hormonal therapy group (3.9% and 7.1%, respectively). Hormonal therapy is a useful adjunct for chemoprevention in breast cancer; however, use of letrozole in patients undergoing reconstruction with pedicled TRAM can lead to increase in certain complication rates.

Fractional microablative CO2 laser in breast cancer survivors affected by iatrogenic vulvovaginal atrophy after failure of nonestrogenic local treatments: a retrospective study.

Vulvovaginal atrophy (VVA) is a condition frequently observed in menopause. Its symptoms can significantly affect the quality of life of patients. Since VVA is related to estrogen deficiency, chemotherapy and hormone therapy for breast cancer (BC) might cause VVA by inducing menopause. Given the lack of effective treatment for VVA in BC survivors, we retrospectively evaluated the efficacy and tolerability of fractional microablative CO2 laser therapy in these patients. We treated 82 BC survivors with three cycles of CO2 laser after failure of topical nonestrogenic therapy. The severity of symptoms was assessed with a visual analog scale (VAS) at baseline and after completion of laser therapy. Differences in mean VAS scores of each symptom before and after treatment were assessed with multiple t tests for pairwise comparisons. Multivariate analyses were used to adjust the final mean scores for the main confounding factors. Pre versus post-treatment differences in mean VAS scores were significant for sensitivity during sexual intercourse, vaginal dryness, itching/stinging, dyspareunia and dysuria (P < 0.001 for all), bleeding (P = 0.001), probe insertion (P = 0.001), and movement-related pain (P = 0.011). Multivariate analyses confirmed that results were significant, irrespective of patients' age and type of adjuvant therapy. This study shows that CO2 laser treatment is effective and safe in BC patients with iatrogenic menopause. However, the optimal number of cycles to administer and the need for retreatment remain to be defined. Prospective trials are needed to compare CO2 laser therapy with therapeutic alternatives.

Overcoming endocrine resistance in hormone receptor-positive breast cancer.

Endocrine therapy, a major modality in the treatment of hormone receptor (hr)-positive breast cancer (bca), has improved outcomes in metastatic and nonmetastatic disease. However, a limiting factor to the use of endocrine therapy in bca is resistance resulting from the development of escape pathways that promote the survival of cancer cells despite estrogen receptor (er)-targeted therapy. The resistance pathways involve extensive cross-talk between er and receptor tyrosine kinase growth factors [epidermal growth factor receptor, human epidermal growth factor receptor 2 (her2), and insulin-like growth factor 1 receptor] and their downstream signalling pathways-most notably pi3k/akt/mtor and mapk. In some cases, resistance develops as a result of genetic or epigenetic alterations in various components of the signalling pathways, such as overexpression of her2 and erα co-activators, aberrant expression of cell-cycle regulators, and PIK3CA mutations. By combining endocrine therapy with various molecularly targeted agents and signal transduction inhibitors, some success has been achieved in overcoming and modulating endocrine resistance in hr-positive bca. Established strategies include selective er downregulators, anti-her2 agents, mtor (mechanistic target of rapamycin) inhibitors, and inhibitors of cyclin-dependent kinases 4 and 6. Inhibitors of pi3ka are not currently a treatment option for women with hr-positive bca outside the context of clinical trial. Ongoing clinical trials are exploring more agents that could be combined with endocrine therapy, and biomarkers that would help to guide decision-making and maximize clinical efficacy. In this review article, we address current treatment strategies for endocrine resistance, and we highlight future therapeutic targets in the endocrine pathway of bca.

Clinical outcomes with first-line chemotherapy versus endocrine therapy for adjuvant endocrine therapy-resistant metastatic breast cancer

Clinical outcomes with first-line chemotherapy versus endocrine therapy for adjuvant endocrine therapy-resistant metastatic breast cancer