Endocrine Treatment Research Articles

Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells.

This study advances the understanding of therapy-induced dormancy with potential clinical implications for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine treatment by entering a dormant state characterized by strong heterochromatinization with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation of cancer cells to ETs. See related commentary by Llinas-Bertran et al., p. 704. This article is featured in Selected Articles from This Issue, p. 695.

Abstract 6047: Discovery and characterization of PVTX-321, an estrogen receptor heterobifunctional degrader

Abstract The estrogen receptor α (ERα) is a clinically validated target for the treatment of estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. However, resistance to early line endocrine treatments due to mutations of the ESR1 gene encoding ERα is associated with poor prognosis and remains an area of unmet clinical need. ERα degradation using heterobifunctional degraders has emerged as a promising approach to tackle endocrine resistance through proteasome mediated degradation of the receptor. Here, we present the preclinical results for the development candidate, PVTX-321, an ERα heterobifunctional degrader. PVTX-321 is a rapid and potent ER heterobifunctional degrader as well as a full ERα antagonist. Both properties translate into potent antiproliferative activity across multiple ER+ breast cancer cell lines bearing either wild-type or clinically relevant ERα mutations (E380Q, Y537S and D538G). PVTX-321 demonstrates favorable oral bioavailability across different species and effectively induces dose-dependent degradation of ERα in vivo. Moreover, PVTX-321 achieves tumor regression as an oral agent at 10 mg/kg in MCF-7 mouse xenograft model. Furthermore, PVTX-321 possesses excellent in vitro and in vivo safety profiles and warrants further development for the treatment of ER+/HER2- breast cancer. Citation Format: Courtney G. Havens, Guozhang Xu, Cass Lowenstein, Debangshu Samanta, Brian Vidal, Elham Behshad, Rakesh Nagilla, Mike Russell, Peter Orth, Winston Wu, Larry Jolivette, Scott Priestley, Helai Mohammad, Zhihua Sui. Discovery and characterization of PVTX-321, an estrogen receptor heterobifunctional degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6047.

Abstract 4838: Impact of social determinants of health (SDH) on systemic therapy and survival in young women with breast cancer

Abstract Introduction: Health disparities are often influenced by SDH. Breast cancer patients (pts) with negative SDH may experience less access to treatment, which can impact outcomes. This study evaluated the association between SDH, utilization of medical therapy, and outcomes in young pts with early breast cancer. Methods: We performed a retrospective review of female pts 18-40 years old in the Young Women’s Breast Cancer Database at a single institution with non-metastatic breast cancer diagnosed from 2011-2020. Predefined SDH were recorded along with clinical characteristics at diagnosis. Descriptive statistics and logistic regression analyses were performed. Survival analyses were conducted using Kaplan-Meier and Cox Proportional Hazard model. Results: 1,061 pts were eligible for analysis; 67% were White, 27% Black, 4% Asian, and 3% Other. Additional demographic and clinical characteristics are shown in Table 1. Pts with Medicaid received chemotherapy (chemo) more often than pts with private insurance (OR 2.04, p=0.003), as did self-pay/uninsured pts (OR 1.74, p=0.003). Divorced/separated/widowed pts were more likely to receive chemo than married pts (OR 1.85, p=0.049). Pts living in 1st quartile of area deprivation index (ADI) received chemo less than those in the 4th ADI quartile (OR 0.45, p=0.003). Divorced/separated/widowed pts with HR+ disease were less likely to receive endocrine treatment than married pts (OR 0.48, p=0.039). Worse overall survival (OS) was seen for Black vs White pts (HR 1.72, p<.001); pts with Medicaid or self-pay/uninsured vs privately insured (HR 1.67, HR 1.92; p=0.025); and unemployed vs employed pts (HR 2.49, p<.001) adjusted for chemo use and clinical stage. Conclusions: Young pts experiencing negative SDH were more likely to receive chemo, less likely to take endocrine therapy if indicated, and suffered from worse OS. These findings may highlight the influence of a pt’s social network on access to care and treatment completion. Table 1. Demographics & clinical characteristics in young women with early-stage breast cancer Demographic Characteristics Overall, N=1061 Race Asian: 40 (3.9 %) Black or African American: 270 (26.6 %) Other: 29 (2.9 %) White or Caucasian: 677 (66.6 %) Ethnicity Hispanic or Latino: 86 (8.4 %) Non-Hispanic or Non-Latino: 939 (91.6%) Insurance Type Private: 824 (77.7 %) Medicare: 16 (1.5 %) Medicaid: 145 (13.7 %) Self-pay/Uninsured: 75 (7.1 %) Area Deprivation Index (ADI) Quartile* Q1= 1-25: 215 (20.3 %) Q2= 26-50: 375 (35.4 %) Q3= 51-75: 315 (29.7 %) Q4= 76-100: 155 (14.6 %) Median Household Income <45000: 44 (4.1 %) 45000-79,999: 600 (56.6 %) 80000-119,999: 304 (28.7 %) ≥120,000: 112 (10.6 %) Employment status Unemployed: 224 (21.1 %) Employed: 657 (61.9 %) Unknown: 180 (17.0 %) Marital Status Married: 631 (59.8 %) Single: 355 (33.6 %) Separated/Divorced/Widowed: 70 (6.6 %) Clinical Characteristics Clinical AJCC Stage Stage 0: 149 (14.3 %) Stage I: 335 (32.1 %) Stage II: 430 (41.2 %) Stage III: 129 (12.4 %) Receptor Status HR+/HER2+: 174 (19.9 %) HR+/HER2-: 519 (59.3 %) HR-/HER2-: 182 (20.8 %) Utilization of Chemotherapy Yes: 702 (67.1 %) No: 344 (32.9 %) Utilization of Endocrine Therapy Yes: 451 (43.3 %) No: 590 (56.7 %) Recurrence Status Yes: 111 (10.5 %) No: 942 (89.5 %) Survival Status Alive: 868 (81.8 %) Dead: 101 (9.5 %) Lost to follow-up: 92 (8.7 %) *Higher score correlates with greater disadvantage Citation Format: Natalie J. Reed, Ferdous Ahmed, Courtney Schepel, Lejla Hadzikadic-Gusic, Julie Fisher, Antoinette R. Tan, Arielle L. Heeke. Impact of social determinants of health (SDH) on systemic therapy and survival in young women with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4838.

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer.

Estrogen receptor positive (ER+) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER+, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER+ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER+ breast cancer.

Relative Energy Deficiency in Sport (REDs): Endocrine Manifestations, Pathophysiology and Treatments.

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on nonpharmacological, behavioral, and lifestyle modifications that target its underlying cause-energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance.

Application of fluorocarbon nanoparticles of 131I-fulvestrant as a targeted radiation drug for endocrine therapy on human breast cancer

BackgroundBreast cancer is the most prevalent malignant tumor among women, with hormone receptor-positive cases constituting 70%. Fulvestrant, an antagonist for these receptors, is utilized for advanced metastatic hormone receptor-positive breast cancer. Yet, its inhibitory effect on tumor cells is not strong, and it lacks direct cytotoxicity. Consequently, there's a significant challenge in preventing recurrence and metastasis once cancer cells develop resistance to fulvestrant.MethodTo address these challenges, we engineered tumor-targeting nanoparticles termed 131I-fulvestrant-ALA-PFP-FA-NPs. This involved labeling fulvestrant with 131I to create 131I-fulvestrant. Subsequently, we incorporated the 131I-fulvestrant and 5-aminolevulinic acid (ALA) into fluorocarbon nanoparticles with folate as the targeting agent. This design facilitates a tri-modal therapeutic approach—endocrine therapy, radiotherapy, and PDT for estrogen receptor-positive breast cancer.ResultsOur in vivo and in vitro tests showed that the drug-laden nanoparticles effectively zeroed in on tumors. This targeting efficiency was corroborated using SPECT-CT imaging, confocal microscopy, and small animal fluorescence imaging. The 131I-fulvestrant-ALA-PFP-FA-NPs maintained stability and showcased potent antitumor capabilities due to the synergism of endocrine therapy, radiotherapy, and CR-PDT. Throughout the treatment duration, we detected no notable irregularities in hematological, biochemical, or histological evaluations.ConclusionWe've pioneered a nanoparticle system loaded with radioactive isotope 131I, endocrine therapeutic agents, and a photosensitizer precursor. This system offers a combined modality of radiotherapy, endocrine treatment, and PDT for breast cancer.Graphical

Intertumoral heterogeneity of bifocal breast cancer: a morphological and molecular study.

To analyze concordance rates between individual foci of bifocal BC for histological grade, type and intrinsic subtype based on immunohistochemical (IHC) and mRNA-testing using MammaTyper. We evaluated histological grade and type as well as intrinsic subtype based on IHC status for estrogen and progesterone receptors, HER2 and the mitotic activity index in 158 individual foci of 79 bifocal BC. A subgroup of 31 cases additionally underwent mRNA-based subtyping using the MammaTyper (MT) test. We calculated concordance rates between individual foci, as well as Cohen's Kappa (K). For 79 bifocal BC, concordance rates between individual foci for grade, histological type, and IHC-based subtype were 69.6% (K=0.53), 92.4% (K=0.81), and 74.7% (K=0.62), respectively. In the MT subgroup of 31 bifocal BC, concordance rates between individual foci for grade, histological type, IHC-based and mRNA-based intrinsic subtype were 87.1% (K=0.78), 90.3% (K=0.73), 87.1% (K=0.82), and 87.1% (K=0.7), respectively. Overall concordance between IHC- and mRNA-based subtype in the MT subgroup was 79% (K=0.7). In 6/79 cases (7.6%), testing of the smaller focus added clinically relevant information either on IHC- or mRNA-level: four cases showed high hormonal receptor expression while the expression in the larger focus was negative or low, warranting additional endocrine treatment; two cases presented with higher proliferative activity in the smaller focus, warranting additional chemotherapy. In bifocal BC, intertumoral heterogeneity on the morphological, immunohistochemical and molecular level is common, with discordant intrinsic subtype in up to 25% between individual foci, with about 8% clinically relevant discordances.

Effect of Consultation Number on the Assessment and Treatment of Polycystic Ovary Syndrome.

The basic medical education stage is not enough to support physicians to fully diagnose and evaluate polycystic ovary syndrome (PCOS). The study aims to discover the difference in treatment choice between participants with different annual consultation number of PCOS, to promote lifelong learning, and drive balanced development within healthcare. This is a multicenter cross-sectional survey. Participants' basic information, knowledge of PCOS and treatment options were collected online. According to the annual consultation number of patients with PCOS, physicians were divided into three groups: 0-50 people/yr, 50-200 people/yr, and >200 people/yr, and the results were derived from χ2 test, Fisher exact test, and multivariate logistic regression analysis. The study analyzed 1689 questionnaires, and 1206 physicians (71.4%) received less than 50 women per year, 388 physicians (30.0%) with an annual number of 50-200 women, and 95 physicians (5.6%) with patient turnover for more than 200 people. Reproductive endocrinologists generally have higher access to the clinic. As the number of visits increases, more and more physicians would perceive patients as more likely to have abnormal blood glucose and heavy weight. Physicians with large numbers of consultations are more likely to use Asian or Chinese standards to assess obesity. The multivariate analysis involved variables such as age, hospital level, specialty, and patient turnover annually, and more young doctors actively assessed lipid profile (odds ratio (OR) 1.56, 95% confidence interval (CI) (1.16, 2.16)), and primary hospitals (OR 0.65 CI (0.44, 0.89)) chose OGTT for blood glucose assessment less than tertiary hospitals. Physicians in secondary hospitals are more aggressive in evaluating androgens. Our survey found differences in endocrine assessment, metabolic screening, and treatment in PCOS women in terms of the number of obstetrician-gynecologists who received different patient consultation numbers. The importance of continuing education for physicians is emphasized, to promote lifelong learning.

Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence.

Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-α expression and activity in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-α signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance, basal-like differentiation, and invasion. A functional drug screen in co-cultures identified effector pathways involved in the CAF-induced regulation of ER-α signaling. Among these, the Transforming Growth Factor-β and the Janus kinase signaling cascades were validated as actionable targets to counteract the CAF-induced modulation of ER-α activity. Finally, genes that were downregulated in cancer cells by CAFs were predictive of poor response to endocrine treatment. In conclusion, our work reveals that CAFs directly control the luminal breast cancer phenotype by selectively modulating ER-α expression and transcriptional function, and further proposes novel targets to disrupt the crosstalk between CAFs and tumor cells to reinstate treatment response to endocrine therapy in patients.

Clinicopathological characteristics and prognostic factors in invasive micropapillary carcinoma of the breast.

Invasive micropapillary carcinoma (IMPC) treatment only relies on the standard treatment of nonspecific invasive breast cancer (NSIBC), and it remains controversial whether the survival of patients improves. Therefore, this study aimed to analyze the clinicopathological features of IMPC and to investigate the factors affecting its prognosis. This retrospective cohort study included 104 IMPC patients who met the study's inclusion criteria out of a total of 4,532 patients with invasive breast cancer between January 2015 and December 2019. A contemporaneous cohort of 230 patients with non-specific invasive breast cancer (NSIBC) who underwent surgery was identified and matched using propensity scores. The survival rate for patients with IMPC ranged from 1.12% to 7.03%. Statistically significant differences were observed in the proportion of endocrine treatment, lymphatic invasion, estrogen receptor (ER)-positive rate, molecular subtypes, molecular typing, and 5-year loco-regional recurrence-free survival (LRRFS) between the two cohorts (p < 0.05). The univariate analysis showed that T stage, N stage, lymphatic invasion, vascular invasion, ER-positive rate, and progesterone receptor (PR)-negative rate were all prognosis risk factors (p < 0.05) for IMPC. Furthermore, the multivariate analysis indicated that lymphatic invasion and N stage were independent prognostic factors (p < 0.05). The incidence of micropapillary IMPC, among other pathological subtypes, is steadily increasing. ER-positive and PR-positive rates, as well as luminal subtypes, are frequent, with a concurrent increase in the 5-year locoregional recurrence rate. It would be interesting to compare the effect following these therapeutic modifications in larger cohorts in future studies.

Abstract A010: AIB1 genotypes impact prognosis in endocrine-treated breast cancer patients – data from a population-based cohort

Abstract Background and purpose: The response to exogenous hormones differs between individuals. Part of the interindividual drug response can be attributed to genetic variation in the host. Previously it has been shown that the estrogen receptor (ER) coactivator amplified in breast cancer-1 (AIB1) genotype plays a role in response to oral contraceptives. Certain AIB1 genotypes have also been associated with breast cancer risk. Since others have shown that tumor AIB1 protein levels may predict response to different types of endocrine treatments, we aimed to investigate the prognostic impact of three functional single nucleotide polymorphisms (SNPs) in the AIB1 gene in patients with ER+ breast cancer. Method and materials: The study comprises 503 patients with a first invasive primary ER-positive breast cancer from the BCBlood cohort. Patients were included October 2002 to October 2008 in Lund, Sweden and followed until June 2019. DNA was extracted from blood. Clinicopathological factors, treatments and breast cancer events were obtained from preoperative questionnaires, patient charts and registry data. The AIB1 SNPs (rs6094752, rs2230782, rs2076546) were analyzed at the Region Skåne Competence Center of Skåne University Hospital in Malmö, Sweden. The software and equipment in the MassARRAY® platform (Sequenom, inc.) with the reagents included in the iPLEX™ genotyping kit were used to perform analyses according to the manufacturer’s instructions. Haplotypes were constructed based on crosstabulation and diplotypes were assembled from haplotypes. Univariable survival analyses were conducted with Kaplan-Meier and Log-rank tests and multivariable Cox regression was used to obtain adjusted hazard ratios (HR) with 95% confidence intervals. Results: In terms of adjuvant endocrine treatment, 127 used no endocrine treatment, 170 received Tamoxifen (TAM), 63 received an aromatase inhibitor (AI), and 143 received sequential treatment with TAM&amp;gt;AI or AI&amp;gt;TAM. During follow-up, 123 patients had breast cancer events. Four haplotypes were found: CGA (77.0%), CCA (12.2%), CGG (7.4%), TGA (3.3%). The common diplotype CGA_CGA (59.9%) was not associated with breast cancer events in TAM-treated patients (Log-rank P=0.54). Conversely, in non TAM-treated patients (± AIs), CGA_CGA was associated with less than half the risk for breast cancer events (HR 0.48 (95% CI 0.26-0.87), adjusted for age, BMI, tumor characteristics and adjuvant treatments. In all patients, there was a significant interaction (Pinteraction=0.023) between TAM and CGA_CGA with a 2-fold risk for breast cancer events in TAM-treated CGA_CGA carriers compared with other patients. Conclusion: The results suggest that AIB1 genotypes have differential prognostic impact depending on type of endocrine treatment in breast cancer patients. The study lends further support that host factors yield important information that can be used to refine selection of adjuvant treatment. If confirmed in a randomized trial of endocrine treatments, AIB1 genotype may be used to better tailor endocrine therapy to each patient. Citation Format: Louise Ebbesen, Alexandra Wiberg, Christopher Godina, Helga Tryggvadottir, Karolin Isaksson, Helena Jernstrom. AIB1 genotypes impact prognosis in endocrine-treated breast cancer patients – data from a population-based cohort [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A010.

Long-term Follow-up and Safety of Patients after an Upfront Therapy with Letrozole for Early Breast Cancer in Routine Clinical Care - The PreFace Study.

Adjuvant treatment of patients with early-stage breast cancer (BC) should include an aromatase inhibitor (AI). Especially patients with a high recurrence risk might benefit from an upfront therapy with an AI for a minimum of five years. Nevertheless, not much is known about the patient selection for this population in clinical practice. Therefore, this study analyzed the prognosis and patient characteristics of postmenopausal patients selected for a five-year upfront letrozole therapy. From 2009 to 2011, 3529 patients were enrolled into the adjuvant phase IV PreFace clinical trial (NCT01908556). Postmenopausal hormone receptor-positive BC patients, for whom an upfront five-year therapy with letrozole (2.5mg/day) was indicated, were eligible. Disease-free survival (DFS), overall survival (OS) and safety in relation to patient and tumor characteristics were assessed. 3297 patients started letrozole therapy. The majority of patients (n=1639, 57%) completed the five-year treatment. 34.5% of patients continued with endocrine therapy after the mandated five-year endocrine treatment. Five-year DFS rates were 89% (95%CI: 88-90%) and five-year OS rates were 95% (95%CI: 94-96%). In subgroup analyses, DFS rates were 83%, 84% and 78% for patients with node-positive disease, G3 tumor grading, and pT3 tumors respectively. The main adverse events (any grade) were pain and hot flushes (66.8% and 18.3% of patients). The risk profile of postmenopausal BC patients selected for a five-year upfront letrozole therapy showed a moderate recurrence and death risk. However, in subgroups with unfavorable risk factors, prognosis warrants an improvement, which might be achieved with novel targeted therapies.

Neoadjuvant endocrine treatment in hormone receptor-positive breast cancer: Does it result in more breast-conserving surgery?

Patients with locally advanced endocrine positive tumors who will not benefit from chemotherapy can be treated by either primary surgery or neoadjuvant endocrine therapy (NET). How often does NET result in breast-conserving surgery (BCS)? We conducted a literature search in PubMed and Embase, to identify articles on surgical treatment after NET. In 19 studies the pathological complete response (pCR) rate was reported after NET; an overall pCR rate of 1% was found. Compared with neoadjuvant chemotherapy (NCT), the BCS rate was significantly higher after NET (OR 0.60; 95% CI, 0.51-0.69; P < 0.00001). The surgical conversion rate was reported in eight studies [4-75.9%], with a mean of 30.2%. This review found that one out of three patients becomes eligible for BCS after treatment with NET.

Collateral effects of the COVID-19 pandemic on endocrine treatments for breast and prostate cancer in the UK: a cohort study.

The COVID-19 pandemic affected cancer screening, diagnosis and treatments. Many surgeries were substituted with bridging therapies during the initial lockdown, yet consideration of treatment side effects and their management was not a priority. To examine how the changing social restrictions imposed by the pandemic affected incidence and trends of endocrine treatment prescriptions in newly diagnosed (incident) breast and prostate cancer patients and, secondarily, endocrine treatment-related outcomes (including bisphosphonate prescriptions, osteopenia and osteoporosis), in UK clinical practice from March 2020 to June 2022. Population-based cohort study using UK primary care Clinical Practice Research Datalink GOLD database. There were 13,701 newly diagnosed breast cancer patients and 12,221 prostate cancer patients with ⩾1-year data availability since diagnosis between January 2017 and June 2022. Incidence rates (IR) and incidence rate ratios (IRR) were calculated across multiple time periods before and after lockdown to examine the impact of changing social restrictions on endocrine treatments and treatment-related outcomes, including osteopenia, osteoporosis and bisphosphonate prescriptions. In breast cancer patients, aromatase inhibitor (AI) prescriptions increased during lockdown versus pre-pandemic [IRR: 1.22 (95% confidence interval (CI): 1.11-1.34)], followed by a decrease post-first lockdown [IRR: 0.79 (95% CI: 0.69-0.89)]. In prostate cancer patients, first-generation antiandrogen prescriptions increased versus pre-pandemic [IRR: 1.23 (95% CI: 1.08-1.4)]. For breast cancer patients on AIs, diagnoses of osteopenia, osteoporosis and bisphosphonate prescriptions were reduced across all lockdown periods versus pre-pandemic (IRR range: 0.31-0.62). During the first 2 years of the pandemic, newly diagnosed breast and prostate cancer patients were prescribed more endocrine treatments compared to pre-pandemic due to restrictions on hospital procedures replacing surgeries with bridging therapies. But breast cancer patients had fewer diagnoses of osteopenia and osteoporosis and bisphosphonate prescriptions. These patients should be followed up in the coming years for signs of bone thinning. Evidence of poorer management of treatment-related side effects will help assess resource allocation for patients at high risk for bone-related complications.

Admission blood glucose and 30-day mortality in patients with acute decompensated heart failure: prognostic significance in individuals with and without diabetes.

Diabetes is a significant risk factor for acute heart failure, associated with an increased risk of mortality. This study aims to analyze the prognostic significance of admission blood glucose (ABG) on 30-day mortality in Chinese patients with acute decompensated heart failure (ADHF), with or without diabetes. This retrospective study included 1,462 participants from the JX-ADHF1 cohort established between January 2019 to December 2022. We conducted multivariate cox regression, restricted cubic spline, receiver operating characteristic curve analysis, and mediation analysis to explore the association and potential mechanistic pathways (inflammation, oxidative stress, and nutrition) between ABG and 30-day mortality in ADHF patients, with and without diabetes. During the 30-day follow-up, we recorded 20 (5.36%) deaths in diabetic subjects and 33 (3.03%) in non-diabetics. Multivariate Cox regression revealed that ABG was independently associated with 30-day mortality in ADHF patients, with a stronger association in diabetics than non-diabetics (hazard ratio: Model 1: 1.71 vs 1.16; Model 2: 1.26 vs 1.19; Model 3: 1.65 vs 1.37; Model 4: 1.76 vs 1.33). Further restricted cubic spline analysis indicated a U-shaped relationship between ABG and 30-day mortality in non-diabetic ADHF patients (P for non-linearity < 0.001), with the lowest risk at ABG levels approximately between 5-7 mmol/L. Additionally, receiver operating characteristic analysis demonstrated that ABG had a higher predictive accuracy for 30-day mortality in diabetics (area under curve = 0.8751), with an optimal threshold of 13.95mmol/L. Finally, mediation analysis indicated a significant role of inflammation in ABG-related 30-day mortality in ADHF, accounting for 11.15% and 8.77% of the effect in diabetics and non-diabetics, respectively (P-value of proportion mediate < 0.05). Our study confirms that ABG is a vital indicator for assessing and predicting 30-day mortality risk in ADHF patients with diabetes. For ADHF patients, both with and without diabetes, our evidence suggests that physicians should be alert and closely monitor any changes in patient conditions when ABG exceeds 13.95 mmol/L for those with diabetes and 7.05 mmol/L for those without. Timely adjustments in therapeutic strategies, including endocrine and anti-inflammatory treatments, are advisable.

Associations between PIK3CA Mutations and Disease Free Survival in Patients with HR+, HER2− Tumors Treated with Adjuvant Hormonal Therapy: A Real‐World Study in Croatia

Introduction. Disease recurrence in patients with the early hormone receptor‐positive (HR+), human epidermal growth factor receptor 2‐negative (HER2−) breast tumor subtype is particularly challenging to manage due to its complex and very heterogeneous biological nature. Namely, due to primary and secondary resistance, one‐quarter of patients with early‐stage disease will experience disease recurrence. This variability in the timing of recurrence highlights the need to better identify key biomarkers that could predict therapeutic outcomes and guide personalized treatment strategies for these patients. Mutations in the phosphatidylinositol 4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) gene are highly prevalent (30–40%) in HR+/HER2− advanced breast cancer. They lead to activation of the PI3K/AKT/mTOR pathway, promoting cell growth, and proliferation, and are associated with poor prognosis in advanced breast cancer. Our aim was to examine the association between and impact of PIK3CA mutation status on disease‐free survival (DFS) in HR+/HER2− early breast cancer patients. Methods. This cohort study was multicentric and retrospective in nature and was conducted at five Croatian institutions from July 2020 to December 2021. The study included initially early and locally advanced operable HR+/HER2− breast cancer patients who were diagnosed with disease recurrence during adjuvant hormonal treatment or within the first six years of follow‐up. Results. A total of 186 patients were included, 40.9% of whom tested positive for the PIK3CA mutation. Primary and adjuvant treatment, particularly adjuvant endocrine treatment, were similar between the two groups. After adjustment for 14 relevant covariates, we found that patients with a positive PIK3CA status and the H1047 PIK3CA mutation had a significantly lower hazard of disease recurrence than patients with no PIK3CA mutation (HR 0.65; 95% CI 0.45; 0.95; p = 0.024; false discovery rate, FDR &lt;10%). Conclusions. This study highlights the potential impact of PIK3CA mutations on disease recurrence during or following adjuvant endocrine therapy and potentially opens the door for further investigation of possibly more personalized treatment strategies.

Modulatory Effects of Ginsenoside Saponins in Panax notoginseng on Steroid Hormones

Natural compounds with structural similarities to endogenous hormones, such as alkaloids, coumestans, flavonoids, lignans, saponins, and stilbenes, have been recognized increasingly for their potential in preventing and treating endocrine disorders related to steroid hormones. Panax notoginseng (Burk.) F. H. Chen, a member of the Araliaceae family and commonly known as Sanqi or Tianqi, is a valuable herbal medicine used to treat various diseases. The majority of saponins (ginsenosides) found in Panax notoginseng belongs to the dammarane triterpenoid group, exhibiting beneficial biological effects, including the treatment of cardiovascular diseases, pain, inflammation, and injuries, as well as internal and external bleeding caused by injury. The aglycone portion of ginsenosides possesses a steroid-like hydrophobic four-ring structure, similar to steroid hormones. Recent studies have indicated that the Panax notoginseng ginsenoside saponins (PNS) have steroid hormone-like activities, bringing the potential for endocrine disorders treatment. Thus, this review aims to provide the chemical structure and steroid hormone-regulating effects of ginsenoside saponins in Panax notoginseng.&#x0D; Keywords: Panax notoginseng, saponin, steroid hormone, ginsenoside, hormone-like effect.

Adjuvant treatment in hormone receptor-positive early breast cancer: New approaches of endocrine therapy.

Breast cancer is the most common cancer in women, and luminal breast cancer is the predominant subtype, characterized by the presence of estrogen receptors and/or progesterone receptors in tumor cells. Adjuvant endocrine therapy is the pivotal approach in the management of luminal early breast cancer. Hence, new therapeutic approaches have been studied during the last few years, especially in patients with high risk of recurrence.Here we provide a summary of the most recent clinical trials evaluating adjuvant treatment in hormone-receptors-positive early breast cancer. First, the main cornerstone is related to the role of extended endocrine treatment, which has been widely investigated to access a benefit in disease-free survival and overall survival (only the GIM4 trial has positive feedback about survival) and to tailor the treatment according to patient compliance. The results highlighted an advantage in extending the use of endocrine treatment for at least seven full years, considering aromatase inhibitors as principal drugs. Second, the shift of CDK4/6 inhibitors (CDK4/6i) from advanced to early setting reported positive outcomes, with favorable results from MonarchE and NATALEE trials, using Abemaciclib and Ribociclib respectively, even if non-negligible toxicities have been reported. Last, the use of PARP inhibitors for BRCA1/2 mutated patients has been evaluated in the OlympiA trial (Olaparib), observing a comparable benefit between hormone-receptors-positive and triple-negative early breast cancer.However, more data are still required to better select patients that could benefit more from CDK4/6i considering side effects too, and sequential treatments are still not codified.

First-line CDK4/6 inhibitor-based combinations for HR+/HER2- advanced breast cancer: A Bayesian network meta-analysis.

International guidelines recommend cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)-based first-line therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, direct drug comparisons are lacking. We aimed to identify the most effective and safe therapy through network meta-analysis (NMA). We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and OpenGrey up to September 30, 2023. Eligible studies included randomized controlled trials (RCTs) assessing endocrine therapy alone or in combination with CDK4/6i as first-line endocrine treatment for HR+/HER2- ABC patients. The hazard ratios for progression-free survival (PFS) and overall survival (OS) and relative risks for objective response rate and adverse events (AEs) were available in selected trials. We performed a Bayesian NMA following PRISMA guidelines. Thirteen RCTs, involving 10 treatments, were included. Most studies were at low risk of bias. Regarding PFS, ribociclib+fulvestrant ranked first with a surface under the cumulative ranking curve (SUCRA) of 85.0%, followed by dalpiciclib+nonsteroidal aromatase inhibitor (NSAI) (SUCRA=78.9%). Considering OS, the top three ranked treatments were ribociclib+fulvestrant (SUCRA=94.1%), abemaciclib+NSAI (SUCRA=69.9%), and ribociclib+NSAI (SUCRA=68.5%). Out of four CDK4/6is, ribociclib minimized the grade 3/4 AEs, while dalpiciclib demonstrated the worst safety. Publication bias could not be ignored in our analyses, and the certainty of evidence was downgraded primarily due to imprecision. Ribociclib+fulvestrant probably represents the best option in a first-line setting. When combined with NSAI, dalpiciclib likely showed the best efficacy but the worst safety. Abemaciclib+NSAI and ribociclib+NSAI could also be promising treatments, while palbociclib presented inferiority. (PROSPERO Registration No. CRD42022370271).

Effect of histological breast cancer subtypes invasive lobular versus non-special type on survival in early intermediate-to-high-risk breast carcinoma: results from the SUCCESS trials

BackgroundInvasive lobular breast carcinomas (ILC) have different histological features compared to non-special type carcinomas (NST), but the effect of histological subtypes on survival is controversial. In this study, we compared clinicopathological characteristics and outcomes between ILC and NST based on a large pooled data set from three adjuvant breast cancer trials (SUCCESS A, B, and C) and investigated a potential differential effect of recurrence risk related to nodal stage on survival.MethodsFrom 2005 to 2017, the large randomized controlled SUCCESS A, B, and C trials enrolled 8190 patients with primary, intermediate-to-high-risk breast carcinoma. All patients received adjuvant chemotherapy, and endocrine and/or HER2-targeted treatment was given where appropriate. Survival outcomes in terms of disease-free survival (DFS), overall survival (OS), breast cancer-specific survival (BCSS), and distant disease-free survival (DDFS) were estimated using the Kaplan–Meier method and analyzed using log-rank tests as well as univariable and adjusted multivariable Cox regression models.ResultsIn the SUCCESS trials, 6284 patients had NST and 952 had ILC. The median follow-up time was 64 months. ILC patients were older, more likely to receive mastectomy, and more likely to have larger tumor sizes, lymph node infiltration, hormone receptor-positive, HER2neu-negative, and luminal A-like tumors than NST patients. In the overall cohort, no significant differences between ILC and NST were detectable regarding the four survival endpoints, with hazard ratios obtained in adjusted multivariable cox regressions of 0.96 (95% CI 0.77–1.21, p = 0.743) for DFS, 1.13 (95% CI 0.85–1.50, p = 0.414) for OS, 1.21 (95% CI 0.89–1.66, p = 0.229) for BCSS, and 0.95 (95% CI 0.73–1.24, p = 0.689) for DDFS. However, a differential effect of nodal stage on survival was observed, with better survival for ILC patients with pN0/pN1 tumors and worse survival for ILC patients with pN2/pN3 tumors compared to NST patients.ConclusionsOur results revealed that ILC was associated with worse survival compared to NST for patients at high risk of recurrence due to advanced lymph node infiltration. These findings should be taken into account for treatment decisions and monitoring.