Endocrine Therapy For Breast Cancer Research Articles

Impact of cytochrome P450 2D6 polymorphisms on decision-making and clinical outcomes in adjuvant hormonal therapy for breast cancer

BACKGROUNDThere are concerns that tamoxifen is less effective in Asian women because of the high prevalence of impaired function cytochrome P450 2D6 (CYP2D6) polymor-phisms.AIMTo evaluate how knowledge of CYP2D6 genotype impacted the choice of hormonal agent and how CYP2D6 genotype and agent were associated with clinical outcomes.METHODSEighty-two women were recruited. Seventy-eight completed CYP2D6 genotyping and were categorized into poor, intermediate (IM) and extensive or ultra metabolizer phenotypes. Women with poor metabolizer and IM phenotypes were recommended aromatase inhibitors as the preferred agent.RESULTSMore than 70% of the women had an IM phenotype, 32% an extensive or ultra metabolizer phenotype, and 0% had a poor metabolizer phenotype. Regardless of genotype, more women opted for aromatase inhibitors. Overall, 80% of women completed 5 years of hormonal therapy. Five women developed recurrence, 3 contralateral breast cancer, 5 died, and 1 was diagnosed with a second primary cancer. Five-year recurrence-free and overall survival were slightly better in women with the extensive or ultra metabolizer phenotype compared to those with the IM phenotype, though not statistically significant [P = 0.743, hazard ratio (HR): 1.441, 95% confidence interval (CI): 0.191 to 10.17 and P = 0.798, HR: 1.327, 95%CI: 0.172 to 9.915, respectively]. Women receiving aromatase inhibitors also appeared to have a better, but also nonsignificant, 5-year recurrence-free and overall survival (P = 0.253, HR: 0.368, 95%CI: 0.031 to 0.258 and P = 0.292, HR: 0.252, 95%CI: 0.005 to 4.951, respectively).CONCLUSIONThe IM phenotype was highly prevalent but was not associated with clinical outcome.

Psychometric properties of the French Hot Flash Related Daily Interference Scale (HFRDIS)

Objective Hot flashes are one of the major symptoms of climacteric syndrome. Despite the high prevalence of these symptoms, few questionnaires assessing the impact of hot flashes on quality of life have been validated. The aim of this study was to validate a French version of the Hot Flash Related Daily Interference Scale (HFRDIS) in a sample of French women. Methods In this prospective study, data were obtained from two groups of women aged between 40 and 60 years from both women without breast cancer and women under hormone therapy for breast cancer between March 2021 and February 2022. Translation was made by an official English–French translator using the forward–backward method. Results One hundred and sixty-seven women completed the HFRDIS questionnaire. The scree plots confirmed unidimensional structure. Cronbach’s α coefficient was 0.92 [0.90–0.94] similar to the original version. The intra-class correlation coefficients of each item ranged between 0.58 and 0.71 Concordance of the scores of each item with those obtained during the validation of the original version of the HFRDIS was confirmed. Conclusion The validation results show that the French version of the HFRDIS questionnaire is a valid tool to evaluate the impact of hot flashes on the daily life activities of patients.

Combining Immune-Related Genes For Delineating the Extracellular Matrix and Predicting Hormone Therapy and Neoadjuvant Chemotherapy Benefits In Breast Cancer.

Breast cancer (BC) is the most prevalent cancer in women worldwide. A systematic approach to BC treatment, comprising adjuvant and neoadjuvant chemotherapy (NAC), as well as hormone therapy, forms the foundation of the disease’s therapeutic strategy. The extracellular matrix (ECM) is a dynamic network that exerts a robust biological effect on the tumor microenvironment (TME), and it is highly regulated by several immunological components, such as chemokines and cytokines. It has been established that the ECM promotes the development of an immunosuppressive TME. Therefore, while analyzing the ECM of BC, immune-related genes must be considered. In this study, we used bioinformatic approaches to identify the most valuable ECM-related immune genes. We used weighted gene co-expression network analysis to identify the immune-related genes that potentially regulate the ECM and then combined them with the original ECM-related gene set for further analysis. Least absolute shrinkage and selection operator (LASSO) regression and SurvivalRandomForest were used to narrow our ECM-related gene list and establish an ECM index (ECMI) to better delineate the ECM signature. We stratified BC patients into ECMI high and low groups and evaluated their clinical, biological, and genomic characteristics. We found that the ECMI is highly correlated with long-term BC survival. In terms of the biological process, this index is positively associated with the cell cycle, DNA damage repair, and homologous recombination but negatively with processes involved in angiogenesis and epithelial–mesenchymal transition. Furthermore, the tumor mutational burden, copy number variation, and DNA methylation levels were found to be related to the ECMI. In the Metabric cohort, we demonstrated that hormone therapy is more effective in patients with a low ECMI. Additionally, differentially expressed genes from the ECM-related gene list were extracted from patients with a pathologic complete response (pCR) to NAC and with residual disease (RD) to construct a neural network model for predicting the chance of achieving pCR individually. Finally, we performed qRT-PCR to validate our findings and demonstrate the important role of the gene OGN in predicting the pCR rate. In conclusion, delineation of the ECM signature with immune-related genes is anticipated to aid in the prediction of the prognosis of patients with BC and the benefits of hormone therapy and NAC in BC patients.

Immunological imbalance, gene polymorphism of biotransformation enzymes, and steroid hormone receptors in tumors in breast cancer patients

It is well known that results of breast cancer (BC) hormonal therapy depend on expression of tumor estradiol and progesterone receptors (ER and PR) in tumor tissue. Mechanisms of ER+/PR+ tumors conversion to ER+/PR- and ER-/PR- tumors remain scarcely studied. The decrease of steroid receptors expression seems to depend on action of genotoxic metabolites of environmental carcinogens (particularly, benzo[a]pyrene, BP) and endogenous steroids (in particular, estradiol, E2). The formation of these metabolites is regulated by the biotransformation enzymes. On the other hand, the formation of DNA-adducts with genotoxic metabolites may induce the synthesis of specific antibodies. Previously, it was shown that increase of the serum IgA-antibodies levels against Bp and E2 over the levels of IgA-antibodies against progesterone (IgA-Bp/IgA-Pg > 1 and IgA-E2/IgA-Pg), could be interpreted as immunological imbalance associated with high BC risk in healthy women. The purpose of this study was to detect the suggested associations between ER+/PR+ tumors conversion to ER+/PR+ and ER-/PR- tumors and immunological imbalance in the BC patients with distinct gene variants of biotransformation enzymes: CYP1A1*2A (rs 4646903), CYP1B1 (rs1056836), CYP19A1 (rs2470152), GSTT1 (del), GSTP1 (rs1695). The IgA-Bp, IgA-E2 and IgA-Pg were studied in 1321 non-smoking BC patients by non-competitive solid phase immunoassay. The conjugates of Bp, E2 and Pg with bovine serum albumin were adsorbed as target antibodies. The goat antibodies against human IgA conjugated with horseradish peroxidase were used for detection of the studied specific antibodies. Gene polymorphisms of biotransformation enzymes were analyzed by the real-time PCR. Tumor ER and PR were detected by the standard immunohistochemical methods.ER+/PR+ tumors in BC patients at the stage I (N = 534) were found in 68.7%, ER+/PR- in 15.6%, ER-/ PR- in 15.7%. In BC patients at the II-IV stage (N = 787), frequency of ER+/PR+ tumors decreased to 60.2%, ER+/PR- was similar (15.8%), and ER-/PR- increased to 24.0% (p < 0.0001). These alterations were revealed in BC patients at the IgA-Bp/IgA-Pg ratios > 1, and IgA-E2/IgA-Pg > 1 only. There were no differences found between BC patients at stage I and II-IV at the ER+/PR+, ER+/PR-, ER-/PR- frequencies when these ratios were low.The frequency of ER+/PR+ tumors in homozygotes TT of CYP19A1 was 77.1% at the I stage and 60.1% at the II-IV stages. Respectively the frequencies of ER-/PR- tumors were 11.8% and 26.1% (p < 0.001). ER+/ PR+ tumors were revealed in GSTT1 “+” BC patients at the I stage in 68.7% and at the II-IV stages in 58.0%. Respectively ER-/PR- tumors were found in 16.6% and 24.5% (p < 0.0004). The frequency of ER+/PR+ tumors was 57.1% in homozygotes GG of GSTP1 at the I stage and 60.7% at the II-IV stages. Respectively the frequencies of ER+/PR- were 14.3% and 22.2% and ER-/PR- were 28.6% and 19.0% (p < 0.001). Proportions of low and high IgA-Bp/IgA-Pg and IgA-E2/IgA-Pg ratios were the same at the any enzyme genotype of studied CYP or GST variants. In conclusion, we have revealed a sufficient contribution of immunological imbalance to the conversion of steroid receptors in breast cancer growth, being independent of several CYP and GST gene polymorphisms.

Accuracy of tumor registry versus pharmacy dispensings for breast cancer adjuvant endocrine therapy.

Accounting for endocrine therapy use for breast cancer treatment is important for studies of survivorship. We evaluated the accuracy of Surveillance, Epidemiology, and End Results (SEER) breast cancer endocrine therapy data compared with pharmacy dispensings from an integrated health system. We included women with non-metastatic hormone receptor positive primary breast cancer diagnosed between 1995 and 2017 enrolled in Kaiser Permanente Washington, linking their data with SEER. We used pharmacy dispensings for endocrine therapy within one year following diagnosis as our reference standard. We calculated kappa (concordance), positive predictive value (PPV), and negative predictive values (NPV) overall and stratified by woman and tumor characteristics of interest. Of 5,055 women, mean age at diagnosis was 62years (interquartile range = 53-71); 53% had localized stage, 56% received lumpectomy with radiation, and 31% received chemotherapy. SEER data alone identified 67% of women as having received endocrine therapy; this increased to 75% with pharmacy dispensings. SEER's concordance with pharmacy dispensings was 0.68 (PPV = 91%; NPV = 76%). PPV did not vary by tumor or women characteristics; however, NPV declined with younger age at diagnosis (64% in < 45years vs. 86% in 75+ years), increasing tumor stage (49% in regional stage vs. 91% in DCIS), and chemotherapy treatment (41% in those with chemotherapy vs. 83% in those without chemotherapy). Pharmacy dispensings enable more complete endocrine therapy capture, particularly in women with more advanced tumors or who receive chemotherapy. We determined woman, tumor, and treatment characteristics that contribute to underascertainment of endocrine therapy use in tumor registries.

Research progress and prospects of neoadjuvant endocrine therapy for breast cancer

Research progress and prospects of neoadjuvant endocrine therapy for breast cancer

P-476 Why are they not coming back? A single-center follow-up study on oncological women oocyte's storing for fertility preservation

Abstract Study question Which is the return rate and which factors are responsible for the non-return in cancer patients who underwent oocyte cryopreservation for fertility preservation? Summary answer Return rate was 11.7%. Young age at freezing, lack of a partner and type of cancer were the main factors responsible for the non-return. What is known already Improvements in oncological early diagnoses and therapies have significantly increased the survival rates of patients, allowing clinicians to focus on long-term quality-of-life issues, such as access to motherhood. An extensive literature on the importance of fertility preservation (FP) has been produced thanks to the growing number of patients undergoing FP cycles over the years. Nevertheless, the rates of patients returning to use their cryopreserved material have shown to be considerably low, ranging from 5 to 8%. Significant data regarding the reasons that might explain such low return rates are still scarce. Study design, size, duration This is a single-center follow-up retrospective study that includes all women who underwent oocyte cryopreservation cycles for oncological purposes at referral University affiliated center, from January 2001 to December 2017. Participants/materials, setting, methods The database consists of 171 patients, among those 110 (64%) were diagnosed with breast cancer, 45 (26%) hematological cancer, 5 (3%) gynecologic cancer and 11 (7%) other cancers. Data about returned patients were retrieved from internal registries. Non-returned patients were assessed by standardized phone survey on health and marital status, family projects, spontaneous conceptions, and reasons why they had not returned to use their gametes. A univariate analysis between returned and non-returned patients was performed. Main results and the role of chance Among the 171 women who underwent oocyte cryopreservation, 9 (5%) died and 17 (10%) were lost at follow up. In the remaining 145-patient group, the mean age at freezing was 32.2±6.1 and at follow-up 38.2±6.7 years. A total of 20 patients (11.7%) returned to use their frozen material and 125 did not. In the non-returned group, 37 (29.6%) did not have a partner, 10 (8%) had a previous spontaneous conception and 15 (12%) had recurrent malignancy at the time of follow-up. In the univariate analysis, younger age at freezing (31.8±6.2 vs 35.2±4.7; p 0.018), lack of a partner (p 0.002), type of cancer (other than breast cancer; p 0.024) were the significant factors in the non-returned group. As for the personal reason for not coming back, patients mainly answered as follows: lack of a partner (29, 23.2%), desire of spontaneous motherhood (24, 19.2%), previous spontaneous pregnancies after FP procedures (16, 12.8%), and still ongoing hormonal therapy for breast cancer (13, 10.4%). Nonetheless all of them confirmed their will to keep the storage of their oocytes. Limitations, reasons for caution The study population consists of a limited number of patients from a single Italian Fertility Center. Since the Italian law limits ART access to heterosexual couples, this setting may limit any possible adaptation of the study to other countries, with different legislations. Wider implications of the findings The impact of a cancer diagnosis on a woman’s maternal desire, sentimental status and life priorities should be studied more thoroughly. Moreover, it is important to encourage studies investigating so long hormonal therapy suppression in breast cancer patients seeking pregnancy in order to reduce their time to pregnancy. Trial registration number na

ROR1 and BMI-1 proteins as potential predictors of the effectiveness of hormone therapy in luminal breast cancer

The purpose of the study was to generalize information regarding the molecular and biological mechanisms involved in the resistance to endocrine therapy with aromatase inhibitors in patients with luminal breast cancer. Material and Methods. The literature search was conducted using Medline, Cochrane Library, Elibrary and PubMed databases. Results. The review highlights the results of international studies on molecular and biological characteristics of breast tumors and their relationship with the effectiveness of hormone therapy. Particular attention was paid to the description of modern studies on ROR1 and BMI-1 proteins and their contribution to the development of tumor resistance to treatment. Conclusion. The analysis of the world literature confrms the relevance of studying the molecular and genetic characteristics of tumor tissue in patients with luminal breast cancer. The data obtained were compared to the clinical course and response to hormone therapy in order to standardize them for implementation in everyday practice as the “gold standard of diagnosis”.

CO70 Change in KI-67 Index in Patients Receiving Preoperative Endocrine Therapy Among Hormone Positive Breast Cancer Patients: A Systematic Review and Meta-Analysis

Effectiveness of pre-operative endocrine therapy (PoET) in hormone-positive early-stage breast cancer (BC) patients for additional benefits (reduced cell proliferation and risk of recurrence) is being debated. Hence, we aimed to conduct this systematic review and meta-analysis to provide overview and comprehensive data on the effectiveness of PoET in reducing cancer cell proliferation among hormone positive breast cancer patients.

Naringenin in Si-Ni-San formula inhibits chronic psychological stress-induced breast cancer growth and metastasis by modulating estrogen metabolism through FXR/EST pathway

IntroductionChronic psychological stress is a well-established risk factor for breast cancer development. Si-Ni-San (SNS) is a classical traditional Chinese medicine formula prescribed to psychological disorder patients. However, its action effects, molecular mechanisms, and bioactive phytochemicals against breast cancer are not yet clear. ObjectivesThis study aimed to explore the modulatory mechanism and bioactive compound of SNS in regulating estrogen metabolism during breast cancer development induced by chronic psychological stress. MethodsMouse breast cancer xenograft was used to determine the effect of SNS on breast cancer growth and metastasis. Metabolomics analysis was conducted to discover the impact of SNS on metabolic profile changes in vivo. Multiple molecular biology experiments and breast cancer xenografts were applied to verify the anti-metastatic potentials of the screened bioactive compound. ResultsSNS remarkably inhibited chronic psychological stress-induced breast cancer growth and metastasis in the mouse breast cancer xenograft. Meanwhile, chronic psychological stress increased the level of cholic acid, accompanied by the elevation of estradiol. Mechanistic investigation demonstrated that cholic acid activated farnesoid X receptor (FXR) expression, which inhibited hepatocyte nuclear factor 4α (HNF4α)-mediated estrogen sulfotransferase (EST) transcription in hepatocytes, and finally resulting in estradiol elevation. Notably, SNS inhibited breast cancer growth by suppressing estradiol level via modulating FXR/EST signaling. Furthermore, luciferase-reporting gene assay screened naringenin as the most bioactive compound in SNS for triggering EST activity in hepatocytes. Interestingly, pharmacokinetic study revealed that naringenin had the highest absorption in the liver tissue. Following in vivo and in vitro studies demonstrated that naringenin inhibited stress-induced breast cancer growth and metastasis by promoting estradiol metabolism via FXR/EST signaling. ConclusionThis study not only highlights FXR/EST signaling as a crucial target in mediating stress-induced breast cancer development, but also provides naringenin as a potential candidate for breast cancer endocrine therapy via promoting estradiol metabolism.

Abstract 797: Role of ESR1 mutation in recurrence of tumorigenesis after therapeutic radiation

Abstract Acquired mutations in ESR1 gene that encodes for Estrogen Receptor (ER) are a common mechanism of acquired resistance to endocrine therapies in breast cancer. However, the role of such mutations in modulation of cell’s response to radiation therapy is poorly understood. In this study, we define the role of ESR1 mutations in altering response to radiation therapy in pre-clinical models of ER-positive breast cancer. To investigate whether ESR1 mutations influence cell’s response to radiation therapy, we employed ER-positive MCF7 and T47D cell lines which have been genome edited to knock-in two of the most common ESR1 mutations, such as Y537S and D538G, found in breast cancer patients. Clonogenic survival assays were carried out to characterize differences in radiation sensitivity of these cells. g-H2AX and Comet assays were employed to study the differences in residual unrepaired DNA damage following radiation in these cell lines. MCF7 cell line-derived xenografts harboring the wild type or mutant ESR1 were employed to study differences in radiation resistance of these tumors in vivo. We found that ER-positive cell lines harboring ESR1 mutations exhibited profound resistance to radiation therapy compared to cell lines harboring the wild type ESR1. These radioresistant cell lines also demonstrated significantly less unrepaired DNA damage following radiation therapy. We observed that mice harboring ESR1 mutant xenografts showed remarkable resistance to radiation therapy. We also observed that ESR1 mutations, which confer resistance to endocrine therapies, also confer profound resistance to radiation therapy. Our findings suggest that oligometastatic ER-positive breast cancer patients who are being treated with radiation therapy (such as those enrolled in NRG BR002 trial) may show significant differences in response to radiation therapy based on their ESR1 mutation status. Recent studies are also exploring the use of neo-adjuvant endocrine therapy in non-metastatic ER-positive breast cancer patients. It is conceivable that some of these patients may acquire ESR1 mutations under selective pressure of neoadjuvant endocrine therapy and may respond poorly to subsequent adjuvant radiation therapy. Overall, our findings support potential personalization of radiation treatments in breast cancer patients based on ESR1 mutation status, heralding an era of precision radiation oncology. Citation Format: S. M. Nashir Udden, Prasanna G. Alluri. Role of ESR1 mutation in recurrence of tumorigenesis after therapeutic radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 797.

Extended endocrine therapy in breast cancer: A basket of length-constraint feature selection metaheuristics to balance Type I against Type II errors

Extended endocrine therapy beyond 5 years is of major concern to ER + breast cancer survivors. However, it might be unsuitable to apply routinely used genomic tests designed for early recurrence risks to distant recurrence within 10 years in extended treatment context. These tests initially aim at high sensitivities with Type I errors much higher than Type II. Having lower positive predictive values (PPVs), these tests can bring many false positives who might not need further treatment options to avoid adversely affecting quality of life. Alternatively, we proposed a top-down approach to the raised issues. We built 149 targeted genes from four genomic tests upon 381 ER-positive node-negative patients with either metastasis free beyond 10 years (n = 202) or metastasis within 10 years (n = 179). By a basket of SVM-wrapped length-constraint feature selection (LCFS), we discovered four genomic SVMs that traded off Type I against Type II errors. Two independent cohorts were used to validate disease outcome predictions. A 36-gene SVM balanced sensitivities with PPVs at good levels: 74% vs 76% on 10-fold cross validation (n = 347) and 75% vs 71% on a test set (n = 34). Neither Oncotype DX RS (cutoff = 18, 31, 60.97) nor PAM50 ROR-S (cutoff = 29, 53, 61.18) could. Independent cohorts showed the 36-gene SVM predicted disease free survival (n = 136, HR = 2.59; 95% CI, 1.4–4.8) and disease specific survival (n = 127, HR = 4.06; 95% CI, 1.63–10.11) better than RS (DFS, HR = 2.15; DSS, HR = 3.86) and ROR-S (DFS, HR = 2.29; DSS, HR = 2.76). The case study demonstrated how we identified a genomic test to balance Type I against Type II errors for risk stratification. The top-down approach centered around the LCFS-metaheuristics basket is a generic methodology for clinical decision-making and quality of life using targeted profiling data where the number of dimensions (p) is smaller than the number of samples (n).

Historical early treatment effects of adjuvant endocrine therapy for breast cancer in high-risk subgroups: Reanalysis of BIG 1-98, SOFT and TEXT.

508 Background: Clinical trials testing adjuvant endocrine therapy (ET) have not historically limited enrollment to patients with clinically high-risk breast cancer (BC), nor estimated treatment (trt) effects prior to 5 yrs. In light of recent trial results for adjuvant CDK4/6 inhibitors, we estimated early relative and absolute trt effects of aromatase inhibitor (AI) vs tamoxifen (T), with ovarian suppression (OFS) if premenopausal, in high risk subgroups. Methods: From pts enrolled in adjuvant phase 3 randomized clinical trials BIG 1-98 (postmenopausal, 5yr AI v T), TEXT (5yr AI+OFS v T+OFS) and SOFT (5yr AI+OFS v T+OFS v T), we identified subgroups with HR+/HER2- BC and high risk features (≥4 pLN; or 1-3 pLN with grade 3, pT≥5 cm and/or Ki-67≥20% [retrospectively centrally assessed]). TEXT randomized at start of adjuvant trt; BIG 1-98 and SOFT after chemotherapy. Disease-free survival (DFS) was defined from randomization to invasive recurrence at local, regional, distant or contralateral breast, second non-breast malignancy or death. We estimated trt effects as differences in 2, 3 and 5yr DFS Kaplan-Meier estimates (KM diffs at t yrs) and hazard ratios over time intervals of 0-2, 0-3 and 0-5 yrs (HRs over 0 to t yrs) to approximate the maturity of trial results with increasing follow-up. Results: The high-risk HR+/HER2- subgroups were 695/4922, 707/2660 and 526/3047 pts in BIG 1-98, TEXT and SOFT with 202, 122, 142 DFS events observed by 5 yrs since randomization. 60%, 46% and 44% of pts had ≥4 pLNs; 42%, 90% and 92% had chemotherapy. The table summarizes results. Conclusions: In re-analysis of clinical high risk HR+/HER2- subgroups of 3 trials each ̃700 pts, 5 yrs AI vs T had similar magnitude of early trt effects after 2-3 yrs follow-up of all pts vs trt effects observed after 27 mos median follow-up in monarchE trial (HR=0.70; KM diffs 2.7% at 2 yrs, 5.4% at 3 yrs; n=5637). Relative and absolute trt effects sometimes diminished when estimated over 5 yrs rather than over 2 yrs, but meaningful absolute differences remained at 5 yrs in contrast to Penelope-B trial results. Design and interpretation of high risk HR+/HER2- early BC trials may depend on timing of randomization and selection of backbone adjuvant trts; follow-up &gt;5 yrs must remain standard. [Table: see text]

Optimizing hormone therapy for breast cancer: Translating gains to the early-stage setting

First-line CDK4/6 inhibitor ribociclib plus letrozole improves survival in the metastatic setting, but lack of accrual of African American women is a shortcoming. Predicting benefit in the early-stage setting and diverse enrollment in trials need to be priorities.1

Acupuncture for hot flashes in hormone receptor-positive breast cancer, a pooled analysis of individual patient data from parallel randomized trials.

12124 Background: Hot flashes are a common side effect of endocrine therapy in breast cancer patients (pts). In a coordinated multinational study, we evaluated the impact of acupuncture on hot flashes and related symptoms in hormone receptor-positive breast cancer pts undergoing adjuvant endocrine therapy in the USA, China, and South Korea. Methods: Parallel randomized trials were conducted at three sites: Dana-Farber Cancer Institute, USA; Jiangsu Hospital of Traditional Chinese Medicine, China; and Daegu Catholic University Medical Center, Republic of Korea, using the same inclusion/exclusion criteria, randomization, and measures. Breast cancer pts receiving adjuvant endocrine therapy and having ≥14 hot flashes per week were randomized equally to acupuncture (A) or usual care (UC); randomization was stratified by number of hot flashes per day (2-6 or 7+). Pts in arm A received a standardized acupuncture protocol twice per week for 10 weeks; pts in the UC arm received usual care. Symptoms were assessed at baseline and week 10. The primary endpoint was change in the Endocrine Symptom Subscale (ESS) of the Functional Assessment of Cancer Therapy-Endocrine Systems (FACT-ES). Secondary endpoints included changes in the FACT-Breast (FACT-B) and Daily Hot Flash Score (DHFS), a measure incorporating hot flash frequency and severity. Target enrollment was 160 pts (USA 80, China 40, Korea 40) providing 84% power to detect a clinically meaningful change in the ESS. Analyses were intention-to-treat. A pooled analysis of individual patient data was performed using linear models adjusted for site and baseline number of hot flashes. Results: Between Jan. 2019 and June 2021, 158 female pts with stage 0-III breast cancer were randomized from the USA (n=78), China (n=40), and South Korea (n=40). Median age was 48 years (range: 25 to 73). At baseline, pts reported similar numbers of hot flashes between study arms (6.2± 4.3 vs. 6.5± 3.8 per day). At week 10, pts in arm A reported statistically significant improvements in ESS score, FACT-B total score and DHFS compared with the UC arm (Table). The reduction in the DHFS from baseline in arm A was 53%. There were no serious adverse events. Conclusions: Acupuncture led to statistically and clinically meaningful improvements in hot flashes, endocrine symptoms, and breast cancer-specific quality of life in women undergoing adjuvant hormonal therapy for breast cancer in the USA, China and South Korea. Clinical trial information: NCT00797732, ChiCTR2100045888, KCT0003618. [Table: see text]

Efficacy and safety of initial five years of adjuvant endocrine therapy in postmenopausal hormone receptor-positive breast cancer: A systematic review and network meta-analysis.

535 Background: Endocrine therapy has greatly improved the clinical outcomes of hormone receptor-positive breast cancer patients. However, there was an unmet need to identify the potentially best regimen of initial adjuvant endocrine therapy. Therefore, in this network meta-analysis, we synthesized the latest evidence to indirectly compare the efficacy and safety among different 5 years of regimens of initial adjuvant endocrine therapy. Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE in January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival (DFS) and overall survival (OS) and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the SUCRA values were used to obtain rankings. Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) (hazard ratio [HR] 0.91, 95% confidence interval [95%CI] 0.87-0.96), anastrozole (ANA) (0.94, 0.90-0.97), letrozole (LET) (0.93, 0.89-0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87-0.96), and TAM followed by ANA (0.92, 0.87-0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86-0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04-2.98), ANA (1.58, 1.03-2.43), and LET (1.63, 1.02-2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons. Conclusions: The sequential use of aromatase inhibitors may be the optimal treatment mode for hormone receptor-positive postmenopausal early breast cancer patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs.

Phase 3 ENABLAR-2 study to evaluate enobosarm and abemaciclib combination compared to estrogen-blocking agent for the second-line treatment of AR+, ER+, HER2- metastatic breast cancer in patients who previously received palbociclib and estrogen-blocking agent combination therapy.

TPS1121 Background: Targeting the androgen receptor (AR) may be the next important endocrine therapy for advanced breast cancer. The AR has been demonstrated to be a tumor suppressor when activated. Enobosarm is an oral selective AR targeting agonist that activates the AR in breast cancer. Preclinical studies in CDK4/6 inhibitor resistant PDX models demonstrated combinatorial synergistic activity of enobosarm plus CDK 4/6 inhibitors. An open-label, Phase 2 study, was conducted in 136 women with heavily pretreated ER+ HER2- metastatic breast cancer that were randomized to oral daily enobosarm at a dose of 9 or 18 mg. The efficacy evaluable (EE) group were patients that were AR positive (&gt; 10% AR nuclear staining). In the EE population with measurable disease at baseline, 10 patients had received prior endocrine therapy + a CDK 4/6 inhibitor. Subsequent treatment with enobosarm resulted in a clinical benefit rate of 50% and the best overall response rate (ORR) was 30% (2CRs and 1 PR). Of the 10 patients, 7 had AR nuclear staining ≥40%. None of the patients with AR nuclear staining &lt; 40% responded to enobosarm. Although a small subset of the study, it appears that enobosarm has activity in patients who had ≥40% AR staining and who had progressed on standard endocrine therapy with a CDK 4/6 inhibitor. Overall, treatment with enobosarm was well tolerated with significant positive effects on quality-of-life measurements. Methods: The ENABLAR-2 trial is an ongoing Phase 3, randomized, open-label, efficacy and safety study in patients with AR+ ER+ HER2- MBC with AR nuclear staining of ≥40%, who have progressed after one line of systemic therapy comprising estrogen blocking agent and palbociclib. The planned sample size is 186 patients randomized 1:1 to enobosarm + abemaciclib OR fulvestrant if the first line of therapy for MBC was a non-steroidal AI plus palbociclib, until disease progression, toxicity, or loss of clinical benefit. If first line therapy for metastatic breast cancer was fulvestrant plus palbociclib, then the patient will be randomized 1:1 to either enobosarm + abemaciclib OR an AI. Randomization will be stratified by AR% nuclear staining, ≥60% versus &lt; 60%, as well as by estrogen blocking agent such that each cohort will have the same number of subjects previously receiving fulvestrant + palbociclib in first line therapy. The key objectives are to determine the safety and efficacy of enobosarm and abemaciclib combination versus an alternative estrogen blocking agent with the primary endpoint of PFS. Secondary endpoints include ORR, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB), change in EORTC Quality of Life Questionnaire (EORTC-QLQ) and change in body composition as measured by DEXA. Clinical trial information: NCT05065411.

Symptom Profiles and Related Factors Among Breast Cancer Patients Undergoing Endocrine Therapy: A Latent Profile Analysis.

To provide person-centered symptom management, the interindividual variability in breast cancer patients merits further exploration. However, how sociodemographic and clinical characteristics influence symptom profile membership in endocrine therapy for breast cancer is still unknown. This study aimed to explore symptom profiles of breast cancer patients undergoing endocrine therapy and to identify sociodemographic and clinical characteristics among symptom subgroup members. A cross-sectional study was conducted, and participants were invited to complete a general information questionnaire and Functional Assessment of Cancer Therapy-Endocrine Subscale. Latent profile analysis, univariate analysis, and multinomial logistic regression were performed to explore symptom profiles and identify interindividual variability. Three distinct subgroups were identified: "all high" (9.8%), "all moderate but high sexual symptoms" (25.4%), and "all low" (64.8%). Age, body mass index, main payment source for medical expenses, type of endocrine therapy, and history of breast cancer treatment were factors that determined membership in these 3 symptom subgroups. Patients' demographic and clinical characteristics were associated with their endocrine therapy-related symptom profiles. In general, those younger in age who pay out of pocket for medical expenses, use aromatase inhibitors, present a history of chemotherapy, and have a higher body mass index have a greater risk of symptom burden. The findings of this study will contribute to implementing individual cancer care based on the characteristics and needs of patient subgroups, which may improve the allocation of medical resources and provide interventions tailored to patients' unique needs.

Association of Obesity and Luminal Subtypes in Prognosis and Adjuvant Endocrine Treatment Effectiveness Prediction in Chinese Breast Cancer Patients.

PurposeTo evaluate the influence of obesity on clinicopathological characteristics of breast cancer; to explore the effect of obesity on the prognosis and performance of endocrine therapy in breast cancer patients.MethodsPatients with luminal/HER2-negative early breast cancer were included and categorized into the non-obese (BMI<28kg/m2) and obese (BMI≥28kg/m2) groups according to body mass index (BMI). Clinicopathological characteristics and treatment modalities were compared between groups. Interaction of adjuvant endocrine therapy with obesity was analyzed.ResultsA total of 2,875 patients were included: 2,598 non-obese and 277 obese. A higher rate of patients with comorbidities (OR: 2.83, 95%CI 2.13-3.74, P<0.001) or PR-positive tumor (OR: 1.63, 95%CI 1.03-2.58, P=0.037) were identified in the obese group. Obesity was not associated with disease recurrence (P=0.839) or overall survival (P=0.140) in the whole population. Subgroup analysis did show an association with worse relapse-free survival (RFS, HR 3.48, 95%CI 1.31-9.22, P=0.012) and overall survival (OS, HR 4.67, 95%CI 1.28-16.95, P=0.019) in luminal A breast cancer. These results could not be reproduced in the luminal B subtype with a RFS (HR 0.78, 95%CI 0.41-1.49, P=0.454) or OS (HR 1.17, 95%CI 0.50-2.74, P=0.727). Furthermore, obesity did not impact endocrine therapy effectiveness in Tamoxifen or the aromatase inhibitor group (RFS: interact P=0.381; OS: interact P=0.888).ConclusionsThe impact of obesity on prognosis interacted with luminal subtype status in Chinese breast cancer patients which was not related with endocrine treatment modality.

The link between aberrant splicing and B cell infiltration in breast cancer hormone therapy

Increasing evidence has suggested alternative splicing (AS) is an essential mechanism for tumor initiation and progression. However, the functions of aberrant splicing have not been well understood in hormone therapy-treated breast cancer (HTBC) patients yet. By mining the SpliceSeq data of TCGA, we characterized 1388 survival-associated AS events (SASEs) that are markedly related to the overall survival (OS) of HTBC patients. Subsequently, a SASE prognostic signature was deduced via the least absolute shrinkage and selection operator (LASSO) and multivariate Cox analysis, and the HTBC patients were stratified into high- and low-risk groups based on the signature. The differentially expressed genes between the high- and low-risk patients were enriched with immune response genes. Furthermore, we revealed that B cell infiltration was significantly low in the high-risk patients with single-sample gene set enrichment analysis (ssGSEA), suggesting a link between AS abnormality and B cell infiltration in tumor immune microenvironment (TIME). Next, a similar prognostic signature based on splicing factor expression was deduced using Molecular Taxonomy of Breast Cancer (METABRIC) HTBC patients. When this prognostic signature was applied to stratify HTBC patients in the METABRIC and TCGA cohorts, the high-risk subgroups both had significantly low B cell infiltration in TIME. CIBERSORT analysis further demonstrated plasma cells infiltrated less in TIME. Also, both the AS (P < 0.0001) and SF (P = 0.009) prognostic signatures performed well in predicting OS of HTBC patients. In summary, our study has demonstrated that AS abnormality is a potential cause of B cell infiltration alteration, which is a critical factor for cancer death risks in HTBC patients and might be exploited therapeutically in the future.