Endocrine Treatment Research Articles

Endometrioma patients are under-treated with endocrine endometriosis therapy.

Is there a difference in the use of endocrine endometriosis therapy in endometriosis patients with and without endometrioma? Patients with endometriomas received significantly less endocrine endometriosis treatment (present intake in 42.5%) compared to patients with other forms of endometriosis and without endometriomas (present intake in 52.1%). Endocrine endometriosis therapy in patients with endometriomas reduces the risk of recurrence and therefore the risk of further surgery and subsequent irreversible damage to ovaries which results into reduced antral follicle counts (AFC), anti-Mullerian hormone levels (AMH), and early menopause. However, there is evidence of increasing rejection of endocrine endometriosis treatment in this population. A total of 838 premenopausal woman with dysmenorrhea and/or endometriosis (mean age 30.7 ± 6.9 years, range 15-54 years) were included in this observational cross-sectional multicenter study. Data including the extent of dysmenorrhea, prevalence of other comorbidities like migraine with aura and migraine never with aura, diagnosis of endometriosis, history of endometriosis surgery, and hormone therapy, were collected in a retrospective online survey from May to November 2023. Patients visiting two university hospital endometriosis centers between January 2017 and March 2023, and with available email address, were invited for study participation by email in May 2023. Further recruitment of participants was achieved through the website and social medial channels of the German Endometriosis Association. Participation in the online survey was open between May and November 2023. In the subgroup of women (with dysmenorrhea) without surgically confirmed endometriosis (SCE) (n = 277), 95 (34.3%) were currently undergoing endocrine treatment for dysmenorrhea and contraceptional purposes. On the contrary, in the subgroup of patients with SCE (n = 561), 275 (49.0%) were currently undergoing hormonal treatment. Subjects with SCE therefore significantly more commonly took endocrine treatment (F = 16.587, P < 0.001) compared to those without SCE. Endometriomas were present in 254 patients (45.2% of all SCE patients), and these patients were significantly less likely to have used hormonal treatment (i) in the present and (ii) in the past (i. n = 113 42.5%, ii. n = 187, 73.9%) compared to patients with other forms of endometriosis (n = 261) (i. n = 139, 52.1%, ii. n = 220, 84.3%) (i. F = 3.976, P = 0.047, ii. F = 8.297, P = 0.004). Various reasons for rejection of endocrine endometriosis treatment were analyzed, when comparing endometrioma subjects to patients with other types of endometriosis, but no statistical differences were found. This study is limited by its retrospective design and an online questionnaire with patient-reported outcomes. A selection bias due to the voluntary nature of the study and the online recruitment is also possible. The results show that patients often refuse endocrine endometriosis treatments without a rational medical reason. According to the literature, this unnecessarily exposes these patients to a higher risk for endometrioma recurrence and subsequently a higher risk of repeat surgery and permanent damage to ovarian function. This study was funded by the University of Luebeck (budget for university teaching and research). A.C. was supported by DFG (CRC/TR 296 'Local control of TH action', LocoTact, P07) and by funds of University of Luebeck, medical section (LACS01-2024). N.B. was supported by the DFG (BR4328.2-1, GRK1957), the Michael J Fox Foundation, the Collaborative Center for X-linked Dystonia-Parkinsonism and the EU Joint Programme-Neurodegenerative Disease Research (JPND). C.C., H.G., C.G., I.A., A.K., A.R. received no funding for this study. There were no competing interests. N/A.

Abstract PR001: An immunomodulatory crosstalk between cancer cells and the hepatic microenvironment underlies mutant estrogen receptor-driven breast cancer-to-liver metastasis

Abstract While major advancements have been made in treatment of primary tumors in estrogen receptor-positive (ER+) breast cancer, reducing mortality from metastatic breast cancer (mBC) in treated patients who develop endocrine resistance to first line therapies remains an unmet clinical need. Wild-type ER activity or availability of its cognate ligand 17-beta estradiol (E2) are major factors in primary tumor progression, which are lost/reduced due to endocrine treatments, such as use of selective estrogen degraders (SERDs) and aromatase inhibitors (AIs), respectively. Over time, this leads to selection of rare cancer cells bearing point mutations in ESR1, the gene encoding ER-alpha, which become the dominant population at metastatic sites, and such mutations are now recognized as a frequent driver of endocrine resistance and metastasis, especially in patients with advanced ER+ breast cancer who have been heavily pre-treated with AIs. Analyses of clinical samples have shown a statistically significant association enrichment of ESR1 mutations in liver metastases, compared to the primary tumor. Other distant tissues commonly colonized by breast cancer cells, such as bones, lungs, or brain, although prevalent, do not display this strong association. While this might be due to ease of biopsy sampling in the liver compared to other sites, an alternate and intriguing hypothesis is that the liver offers a fertile soil for metastatic colonization by mutant ER-expressing cells, compared to other distant sites, such as lungs. Using a combination of pre-clinical models, we assessed if mutant ER could drive metastatic colonization at distant sites, such as the liver. We have uncovered a novel link between cancer cell-intrinsic immunomodulatory signaling pathways that are specifically upregulated in mutant ER-expressing breast cancer cells, which represents at least one major molecular mechanism underlying the observed liver tropism of mutant ER-associated, endocrine resistant ER+ breast cancer. We show that disseminated, mutant ER-expressing BC cells engage in crosstalk with the liver stromal and immune populations post-extravasation to further fuel metastatic outgrowth. Citation Format: Sunny Das, Joana Liu Donaher, Lisa Verhoeven, Ranjan Mishra, Ferenc Reinhardt, Sumeet Gupta, Zheqi Li, Kornelia Polyak, Robert A. Weinberg. An immunomodulatory crosstalk between cancer cells and the hepatic microenvironment underlies mutant estrogen receptor-driven breast cancer-to-liver metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR001.

Abstract C042: TMEM doorway score as a predictive biomarker for therapy selection in ER+/HER2- breast cancer

Abstract Background: Endocrine therapy is the standard of care for ER+/HER- breast cancer; but some patients need additional adjuvant chemotherapy to counter the risk of metastasis. While chemotherapy can reduce metastasis, some patients still relapse. Tumor cells metastasize through TMEM (Tumor Microenvironment of Metastasis) Doorways, consisting of a Mena-expressing tumor cell, a macrophage, and a vascular endothelial cell, all in direct contact. High TMEM doorway scores correlate with increased dissemination in mice and metastatic outcomes in ER+/HER2- breast cancer patients. Recent studies show that adjuvant chemotherapy may activate growth in disseminated tumor cells (DTCs). Thus, we hypothesized that patients with high TMEM doorway scores who receive endocrine plus chemotherapy will have worse distant recurrence-free survival (DRFS) than those with lower TMEM Doorway scores, or those who receive endocrine therapy alone. Methods: We conducted a retrospective study on 119 patients with stage I-III, ER+/HER2- unilateral invasive ductal breast carcinoma (age≥18) from 2005- 2018. All underwent surgery and received adjuvant endocrine treatment alone or with chemotherapy. We excluded patients who had metastatic disease at diagnosis, received neoadjuvant chemotherapy, or lacked treatment data. Formalin-fixed paraffin-embedded primary tumor tissues were stained for TMEM doorways. A pathologist categorized the TMEM doorway scores as low, intermediate, or high. Kaplan-Meier curves and Cox-proportional hazard models compared DRFS based on treatment type and TMEM doorway scores. Multivariate logistic regression analyzed the association between macrophage density or TMEM Doorway Score and metastatic outcomes, adjusting for tumor size, grade, and node positivity. Results: Of all patients, 72 received endocrine plus chemotherapy and 47 endocrine therapy alone. In the chemotherapy group, 34 (47.2%) developed metastases, while 38 (52.8%) remained disease-free. In the endocrine alone group, 37 (78.7%) remained disease-free and 9 (19.1%) developed metastases. There was no significant difference in TMEM Doorway Scores between groups (p=0.07). In patients who received endocrine plus chemotherapy, a high TMEM Doorway Score was associated with greater odds of metastasis (OR 6.8; 95% CI 1.35–33.76; p=0.02), controlling for tumor size, grade, and node positivity but not when endocrine therapy was used alone (p=0.817). Patients with high TMEM Doorway Scores had worse DRFS in the endocrine plus chemotherapy group (HR 2.61; 95% CI 1.08–6.27; p=0.03), but not in the endocrine therapy alone group (p=0.77) adjusted similarly. Conclusions: This study highlights potential clinical utility of TMEM Doorway Scores as a predictive biomarker for chemotherapy selection in ER+/HER2- breast cancer patients. Larger trials are needed to confirm these findings and with confirmation, physicians considering giving chemotherapy to ER+/HER2- breast cancer patients might consider pre-treatment stratification using TMEM Doorway Scores to mitigate the risk of chemotherapy-induced metastasis. Citation Format: Priyanka Parmar, Andrew Miller, Burcu Karadal-Ferrena, Suryansh Shukla, Cien Huang, Mindy Ginsberg, Chedva Rosenbaum, Malka Felder, Chenxin Zhang, John S. Condeelis, Xiaonan Xue, Thomas E. Rohan, Joseph A. Sparano, Jesus D. Anampa, David Entenberg, Maja H. Oktay. TMEM doorway score as a predictive biomarker for therapy selection in ER+/HER2- breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C042.

Mutations Matter: Unravelling the Genetic Blueprint of Invasive Lobular Carcinoma for Progression Insights and Treatment Strategies.

Invasive Lobular Carcinoma (ILC) presents a distinct subtype of breast cancer, representing 10-15% of cases, with unique clinical and molecular features. Characterized by a non-cohesive, single-file invasion pattern, ILC is typically estrogen receptor (ER)- and progesterone receptor (PR)-positive but human epidermal growth factor receptor 2 (HER2)-negative. Despite favorable prognostic features, its highly metastatic nature and predilection for atypical sites contribute to lower long-term survival compared to invasive breast carcinoma of no special type (NST). ILC's genetic landscape includes mutations in various genes (CDH1, BRCA2, ATM, etc.) and signaling pathways that impact treatment responses, especially in endocrine treatment. Furthermore, the diverse ILC subtypes complicate its management. Current challenges in chemotherapy, along with the targeted therapies, are also discussed. The present article aims to comprehensively review the recent literature, focusing on the pathological and molecular aspects of ILC, including associated genetic mutations influencing disease progression and drug resistance.

Advancements and Challenges in Nanoscale Zero-Valent Iron-Activated Persulfate Technology for the Removal of Endocrine-Disrupting Chemicals.

Endocrine-disrupting chemicals are a new class of pollutants that can affect hormonal metabolic processes in animals and humans. They can enter the aquatic environment through various pathways and gradually become enriched, thus posing a serious threat to the endocrine and physiological systems of both animals and humans. Nano zero-valent iron has promising applications in endocrine disruptor removal due to its excellent reducing properties and high specific surface area. However, given the dispersed focus and fragmented results of current studies, a comprehensive review is still lacking. In this paper, it was analyzed that the types of endocrine disruptors and their emission pathways reveal the sources of these compounds. Then, the main technologies currently used for endocrine disruptor treatment are introduced, covering physical, chemical, and biological treatment methods, with a special focus on persulfate oxidation among advanced oxidation technologies. Also, the paper summarizes the various activation methods of persulfate oxidation technology and proposes the nZVI-activated persulfate technology as the most promising means of treatment. In addition, this paper reviews the research progress of different modification methods of nZVI in activating persulfate for the removal of EDCs. Finally, the discussion includes recycling studies of nZVI/PS technology and emphasizes the urgency and importance of endocrine disruptor treatment. The review of this paper provides further scientific basis and technical support for nZVI/PS technology in the field of endocrine disruptor management.

The impact of curative cancer treatment on sexual health – clinical results from the EORTC QLQ-SH22 validation study

BackgroundThe European Organization of Research and Treatment of Cancer (EORTC) has recently developed and validated a patient-reported outcome measure (PROM) for sexual health (SH) in cancer patients. Here, we present results from a secondary analysis of the EORTC QLQ-SH22 validation study. The objective was to investigate the impact of cancer treatment on SH over the disease trajectory into survivorship in patients who underwent curative treatment.MethodsParticipants completed the EORTC QLQ-SH22 and the EORTC QLQ-C30 assessing SH and Quality of Life. We analyzed differences in SH of patients on active cancer treatment compared to patients off-treatment (cross sectional group comparison) as well as changes in SH during the course of treatment (from pre-treatment to follow-up).ResultsOur sample consisted of n = 394 (66.2% females) curatively treated cancer patients with 34% of patients being on-treatment and 66% of patients being in their follow-up after primary treatment (off-treatment group). Compared to patients off- treatment, patients on active cancer treatment experienced less sexual satisfaction (p = .021, Cohen’s d = .36) and libido (p < .001, d = .60) and had higher levels of fatigue (p < .001, d = .50). Importance of sexual activity, masculinity and femininity did not differ between groups. Treatment effects on sexual activity decreased with treatment completion (p < .001, d = .50). Patients undergoing intensified treatment (chemotherapy, radiation, or endocrine treatment) reported more treatment effects (subscale EORTC QLQ-SH22) compared to patients undergoing surgery only.ConclusionOur results highlight the negative impact of oncological treatment on SH and how increasing treatment intensity further impair SH. Sexual satisfaction and libido improve after treatment completion while other aspects (e.g. masculinity/femininity) do not change during survivorship. We suggest monitoring of SH from the start of cancer treatment on and beyond into survivorship using PROMs as part of routine cancer care. Routine monitoring allows systematic identification of patient’s SH problems and may improve awareness as well as target intervention for those in need of care.

Clinicopathological features and prognosis of mucinous breast carcinoma with a micropapillary structure.

To conduct a comparative analysis of clinicopathological data between mucinous micropapillary breast carcinoma (MUMPC) and pure mucinous carcinoma (PMC) without a micropapillary structure to elucidate the distinctive clinicopathological characteristics of MUMPC and their impact on prognosis. This retrospective analysis included 325 patients diagnosed with mammary mucinous carcinoma admitted to Tianjin Cancer Hospital between July 2014 and December 2019, including 197 patients with MUMPC and 128 patients with PMC without a micropapillary structure. Clinicopathological features were compared, and factors influencing the prognosis of MUMPC were analyzed. Survival analysis was conducted using the Kaplan-Meier method, and univariate and multivariate prognostic analyses for MUMPC were performed using the Cox proportional hazard regression model. The median follow-up period was 76 months. In the MUMPC and PMC groups, the disease-free survival (DFS) rates at 3, 5, and 7 years were 95.4%, 90.4%, 89.8%, and 100%, 98.4%, and 96.9%, respectively, with a statistically significant difference between the two groups (p = 0.009). Tumor, node, and metastasis (TNM) stage, lymph node metastasis, and endocrine treatment were significant factors influencing the prognosis of the MUMPC group (p < 0.001). Multivariate analysis revealed that lymph node metastasis and endocrine therapy were independent prognostic factors in patients with MUMPC (p < 0.001). Compared with PMC, the MUMPC group exhibited a higher prevalence of HER2 (11.2% vs. 3.1%, p = 0.009) and Ki-67 overexpression (79.7% vs. 60.2%, p < 0.001). The lymph node stage is the most crucial clinicopathological feature of MUMPC. Endocrine treatment strategy is an independent risk factor affecting the prognosis of MUMPC.

Timing of puberty suppression in transgender adolescents and sexual functioning after vaginoplasty.

Sexual function in transgender adolescents after puberty suppression has been a topic of recent clinical and scientific questions. This study aimed to explore the long-term effects of early treatment with puberty suppression on sexual functioning of transfeminine individuals after vaginoplasty. This retrospective cohort study included 37 transfeminine individuals treated with a gonadotropin-releasing hormone agonist (puberty suppression), estrogen, and vaginoplasty (penile inversion technique or intestinal vaginoplasty) at the Center of Expertise on Gender Dysphoria in Amsterdam, the Netherlands, between 2000 and 2016. Experiences regarding sexual functioning and difficulties were assessed with a self-developed questionnaire ~1.5years after genital gender-affirming surgery and compared between early (Tanner stage G2-3) and late (Tanner stage G4-5) treatment with puberty suppression. Following surgery, 91% of transfeminine individuals was able to experience sexual desire, 86% experienced arousal, and 78% could attain an orgasm. Seventy-five percent of transfeminine individuals who had not experienced an orgasm pre-surgery were able to experience one post-surgery. Of all participants, 62% reported having tried penile-vaginal intercourse post-surgery. The majority reported the presence of one or multiple sexual challenges. There were no significant differences in postoperative sexual function or sexual difficulties between groups treated with early versus late puberty suppression. With these findings, more adequate and tailored information on the expected effects of early endocrine gender-affirming treatment (including puberty suppression) can be given by healthcare professionals. This is the first study that has assessed sexual functioning of transgender individuals treated with puberty suppression, and has differentiated between the pubertal stage at treatment initiation. Limitations were the small cohort size and retrospective study design. This study focuses on sexual functioning, however, it is important to realize sexual wellbeing is multifactorial and encompasses more than genital functioning or the ability to have certain sexual experiences. This study found that post-vaginoplasty transfeminine individuals after both early and late suppression of puberty have the ability to experience sexual desire and arousal, and to achieve orgasms. Outcomes are comparable to previous findings in those who started treatment in adulthood.

KIF1A promotes neuroendocrine differentiation in prostate cancer by regulating the OGT-mediated O-GlcNAcylation.

Neuroendocrine prostate cancer (NEPC) arises from prostate adenocarcinoma after endocrine treatment failure and implies lethality and limited therapeutic options. Deciphering the molecular mechanisms underlying transdifferentiation from adenocarcinoma to NEPC may provide valuable therapeutic strategies. We performed a pan-cancer differential mRNA abundance analysis and identified that Kinesin-like protein (KIF1A) was highly expressed in NEPC. KIF1A knockdown impaired neuroendocrine(NE) features, including NE marker gene expression, stemness, and epithelial-mesenchymal transition (EMT), whereas KIF1A overexpression promoted these processes. Targeting KIF1A inhibited the growth of NE differentiated prostate cancer (PCa) cells in vitro and in vivo. Mechanistically, KIF1A bound with O-linked N-acetylglucosamine transferase (OGT) and regulated its protein expression and activity. Nuclear accumulation of OGT induced by KIF1A overexpression promoted intranuclear O-GlcNAcylation of β-catenin and OCT4 in nucleus. More importantly, our data revealed that OGT was critical for KIF1A induced NE differentiation and aggressive tumor growth. An OGT inhibitor, OSMI-1, can significantly inhibited NE differentiated PCa cell proliferation in vitro and tumor growth in vivo. Our findings showed that KIF1A promotes NE differentiation to NEPC by regulating the OGT-mediated O-GlcNAcylation. Targeting O-GlcNAcylation may impede the development of NEPC for a group of PCa patients with elevated KIF1A expression.

The role of adjuvant endocrine treatment in ER+, PR−, HER2− early breast cancer: a retrospective study of real-world data

Purpose: Estrogen receptor-positive (ER+), progesterone receptor-negative (PR-) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC) often developed resistance to endocrine treatment (ET). We aimed to explore (1) the different clinicopathological features between ER+/PR+/HER2- and ER+/PR-/HER2- BC, and (2) whether ER+/PR-/HER2- early BC patients could benefit from adjuvant ET. Methods: All patients treated for ER+/HER2- early BC who underwent surgery between 2010 and 2021 from a BC database in China were retrospectively examined. The cases followed up for less than six months were excluded. Results: The records of ER+/PR+/HER2- (n = 10843) and ER+/PR-/HER2- BC (n = 1193) cases were reviewed, with median follow-up times of 35.8 and 47.0 months, respectively. Compared with ER+/PR+/HER2- cases, ER+/PR-/HER2- BC occurred more in postmenopausal women (73.1% vs. 52.9%, p = 0.000) and were more likely to be T > 2 cm (40.6% vs. 37.6%, p = 0.048) and Ki67 > 20%+ (48.1% vs. 36.9%, p = 0.000). However, ER+/PR-/HER2- cases had fewer nodal involvement (32.9% vs. 36.9%, p = 0.000). Approximately 82.2% (981/1193) of ER+/PR-/HER2- patients received ET, while approximately 17.8% (212/1193) did not. Compared to patients did not receive adjuvant ET, the ET group had similar disease-free survival (DFS) (HR = 1.33, 95% confidence interval (CI): 0.68–2.59, p = 0.444) and overall survival (OS) (HR = 1.17, 95%CI: 0.37–3.68, p = 0.799). 65.7% of recurrent ER+/PR-/HER2- patients experienced distant relapse (65.7% vs. 48.2% (for ER+/PR + cases), p = 0.011). By comparison, recurrent ER+/PR+/HER2- patients were more likely to experience only local relapse (31.6% vs. 14.9% (for ER+/PR- cases), p = 0.007). Conclusions: ER+/PR-/HER2- BC was a special subtype with aggressive clinicopathological features and more tend to have distant metastasis rather than nodal involvement or local relapse. ER+/PR-/HER2- early BC did not seem to benefit from adjuvant ET.

Benefit of systemic therapy in MINDACT patients with small, ER-positive, HER2-negative breast cancers

Small, hormone receptor-positive (HR+), HER2-negative (HER2-), lymph node-negative breast cancers are associated with relatively low rates of disease recurrence and have therefore been underrepresented in clinical trials assessing the effects of systemic therapy. Consequently, it remains uncertain if this patient population derives benefit from these treatments. For this exploratory analysis, we selected MINDACT (NCT00433589) patients with a HR+, HER2-, T1ab (≤1 cm) tumor and negative lymph nodes. Patients with discordant clinical risk and MammaPrint genomic risk classification were randmomized to receive chemotherapy based on either the clinical or the genomic risk assessment. Endocrine therapy treatment was based on local guidelines. 715/6693 (10.7%) MINDACT patients had HR+, HER2-, T1abN0 breast cancer and were included in this analysis. All were clinically low-risk, 124/715 (17.3%) were genomic high-risk. For genomic high-risk tumors, 8-year distant metastasis-free survival (DMFS) was 92.9% (95% CI 86.2–96.4%) compared to 95.0% (95% CI 92.8–96.6%) for genomic low-risk tumors. For genomic high-risk tumors treated with or without chemotherapy, 8-year DMFS was 89.2% (95% CI 73.6–95.8%) and 94.1% (95% CI 82.9–98.1%), respectively. For genomic low-risk tumors, the 8-year DMFS and disease-free survival (DFS) were 96.1% (95% CI 93.4–97.6%) and 89.3% (95% CI 85.5–92.2%) when treated with endocrine therapy and 92.9% (95% CI 87.9–95.9%) and 79.4% (95% CI 72.5–84.8%) without. In conclusion, although the number of randomized patients is small, patients with small, genomic high-risk breast cancer did not seem to derive benefit from chemotherapy. Endocrine therapy was associated with improved outcomes even in genomic low-risk breast cancers.

Influence of melatonin on the development of obesity

In recent years, increasing attention of researchers has been paid to the role of melatonin in the regulation of body weight. When analyzing literature data, the problem of the mechanism of action of melatonin on the body and its use in the correction of metabolic disorders is considered. Disruption of circadian rhythms caused by the use of artificial light at night leads to decreased melatonin secretion. This helps increase appetite and reduce energy costs. In addition, melatonin plays a major role in modulating the secretion of adipokines by influencing lipid metabolism. Decreased melatonin production causes insulin resistance and metabolic circadian disorganization, leading to obesity. Assessing the role of melatonin in the development of obesity and its accompanying pathologies is a promising area of scientific research in the field of diagnosis, prevention and treatment of endocrine and cardiovascular pathologies.

Overall survival after CDK4/6 inhibitor dose reduction in women with metastatic breast cancer

BackgroundBreast cancer is the most common cancer in women, and the first-line treatment for patients with hormone-receptor positive/HER2-negative metastatic breast cancer is CDK4/6 inhibitor plus endocrine therapy. Understanding the impact of CDK4/6 inhibitor dose reduction, which occurs in about half of the patients, is important.MethodsThis real-world cohort study is based on electronic health records from Capital Region of Denmark. All women with metastatic breast cancer initiating first-line treatment with CDK4/6 inhibitor between May 2017 and October 2022 were included.ResultsA total of 546 patients were eligible for inclusion in the 12-week landmark analysis and 192 (35%) experienced dose reduction. These patients were older, had worse ECOG PS, more received prior adjuvant endocrine treatment, and more received fulvestrant as the endocrine backbone. Dose reduction was associated with reduced overall survival (39.9 vs. 54.3 months) and shorter treatment duration (18.0 vs. 26.9 months). Adjusted hazard ratio for death was 1.38 (95% CI: 1.01–1.89).ConclusionsDose reduction of CDK4/6 inhibitors within the first 12 weeks of treatment was associated with significantly higher mortality and shorter treatment duration. These findings contrast with previous analyses showing no effect of dose reduction, likely due to considering immortal time bias in this study.

Monocyte subsets in breast cancer patients under treatment with aromatase inhibitor and mucin-1 cancer vaccine

BackgroundMonocytes comprise subsets of classical, intermediate and non-classical monocytes with distinct anti- or pro-tumor effects in breast cancer (BC). They are modulated by estrogen, and can contribute to BC control by endocrine therapy in preclinical models.MethodsTo elucidate whether changes in monocyte subsets are associated with treatment and response, we investigated peripheral blood samples of 73 postmenopausal women with estrogen receptor (ER) positive BC, who received aromatase inhibitor therapy with or without the mucin-1 vaccine tecemotide in the ABCSG34 trial. Blood was retrieved at baseline, midterm and end of therapy, and was analyzed for the distribution and ER expression of monocyte subsets by flow cytometry.ResultsWhen 40 healthy, age-matched women were compared with BC patients before treatment start, ER levels of monocytes did not differ, yet patients presented with a higher frequency of classical and fewer non-classical monocytes. Endocrine therapy triggered a significant increase in ER levels in all monocyte subsets, without affecting subset distribution. Vaccination had no overall impact on subset frequency and ER expression. Yet, a shift from intermediate to classical monocytes during therapy correlated with changes in plasma cytokines and chemokines and was significantly associated with low residual cancer burden in vaccinated patients. Without tecemotide, baseline ER levels in classical monocytes were significantly higher in women with good response to endocrine therapy.ConclusionsThis study identified classical monocytes to be associated with ER positive BC and with patient response to neoadjuvant endocrine treatment and cancer vaccination.

Functional activation of the AKT-mTOR signalling axis in a real-world metastatic breast cancer cohort.

Mutations of the PIK3CA/AKT/mTOR axis are common events in metastatic breast cancers (MBCs). This study was designed to evaluate the extent to which genetic alterations of the PIK3CA/AKT/mTOR can predict protein activation of this signalling axis in MBCs. Molecular profiles were generated by CLIA-certified laboratories from a real-world evidence cohort of 171 MBC patients. Genetic alterations of the PIK3CA pathway were measured using next-generation sequencing. Activation levels of AKT and downstream signalling molecules were quantified using two orthogonal proteomic methods. Protein activity was correlated with underlying genomic profiles and response to CDK4/6 inhibition in combination with endocrine treatment (ET). Oncogenic alterations of the PIK3CA/AKT/PTEN pathway were identified in 49.7% of cases. Genomic profiles emerged as poor predictors of protein activity (AUC:0.69), and AKT phosphorylation levels mimicked those of mutant lesions in 76.9% of wild-type tumours. High phosphorylation levels of the PI3K/AKT/mTOR downstream target p70S6 Kinase (T389) were associated with shorter PFS in patients treated with CDK4/6 inhibitors in combination with ET (HR:4.18 95%CI:1.19-14.63); this association was not seen when patients were classified by mutational status. Phosphoprotein-based measurements of drug targets and downstream substrates should be captured along with genomic information to identify MBCs driven by the PI3K/AKT/mTOR signalling.

Prosigna Assay for Treatment Decisions in Early Breast Cancer: A Decision Impact Study.

Introduction: Therapeutic decisions in early breast cancer are based on clinico-pathological features which are subject to intra- and inter-observer variability. This single-center decision impact study aimed to evaluate the effects of the Prosigna assay on physicians' adjuvant treatment choices. Methods: Between 09/2017 and 02/2018, formalin-fixed tumor samples from 52 newly diagnosed, postmenopausal, hormone receptor-positive, HER2-negative breast cancer (T1-T2; pN0-N1a) patients were analyzed. Pre-test clinical judgements and Prosigna test results were compared. Results: The mean age was 59 (42-77). Invasive ductal carcinoma (79.2%), grade 2 (52.8%) and T1c-N0 tumors (43.4%) were represented. There was 40.4% discordance between the pre- and post-test risk of recurrences. No significant change was observed in the clinical intermediate risk category, while there was a net reclassification of low-risk patients into a high Prosigna recurrence risk group. In addition, clinically determined intrinsic subtypes were 34.6% discordant with the Prosigna results, which is largely driven by the reclassification of the luminal A tumors into the Prosigna-assessed luminal B group. Before the Prosigna test, endocrine treatment was the primary choice in 20 patients (39.2%), and chemotherapy was recommended to 31 patients (60.8%). Overall, the Prosigna assay led to a change in treatment choice for one patient. Conclusions: Although conventional risk assessment methods are relatively inexpensive with shorter turnaround times, their accuracy and value for risk reduction are suboptimal. According to our results, the Prosigna assay was found to be a relevant tool for the clinical decision making process. Long-term follow-up of these patients will elucidate the potential benefits of using multigene molecular tests as biomarkers for treatment.

Surgical outcomes of neoadjuvant endocrine treatment in early breast cancer: meta-analysis.

Neoadjuvant endocrine therapy presents an important downstaging option with lower toxicity than neoadjuvant chemotherapy in oestrogen receptor (ER)-positive early breast cancer. Meta-analysis of the effects of neoadjuvant endocrine therapy on surgical outcomes across randomized clinical trials (RCTs) and cohort studies has not previously been performed. A systematic review and meta-analysis was performed to evaluate the effect of neoadjuvant endocrine therapy on surgical outcomes (PROSPERO (international prospective register of systematic reviews, 2020)) compared with surgery followed by adjuvant endocrine therapy. PubMed and EMBASE were searched to identify RCT and cohort studies between 1946 and 27 March 2024. Two independent reviewers manually screened the identified records and extracted the data. Risk of bias was assessed using the Cochrane Collaboration tools and random-effects meta-analysis was done with ReviewManager. The search identified 2390 articles eligible for screening. The review included 20 studies (12 cohort and 8 RCTs); 19 were included in the meta-analysis with a total of 6382 patients. Overall, neoadjuvant endocrine therapy was associated with a lower mastectomy rate compared with surgery first (risk ratio (RR) 0.53, 95% c.i. 0.44 to 0.64). Subgroup analysis showed similar improvement in the mastectomy rate in the neoadjuvant endocrine therapy group versus control group irrespective of study type (RCT: RR 0.58, 95% c.i. 0.50 to 0.66; cohorts: RR 0.48, 95% c.i. 0.33 to 0.70). There was no difference in the mastectomy rate by duration of neoadjuvant endocrine therapy (more than 4 months: RR 0.57, 95% c.i. 0.42 to 0.78; 4 months or less than 4 months: RR 0.52, 95% c.i. 0.43 to 0.64). Most of the studies were characterized by moderate-quality evidence with significant heterogeneity. Neoadjuvant endocrine therapy is associated with a reduction in mastectomy rate. Given the moderate methodological quality of previous studies, further RCTs are required. CRD42020209257.

The Application of Nanotechnology for the Diagnosis and Treatment of Endocrine Disorders: A Review of Current Trends, Toxicology and Future Perspective.

The endocrine system regulates many biological systems, and disruptions may result in disorders, such as diabetes, thyroid dysfunction, Cushing's syndrome, and obesity. The total incidence of endocrine illnesses was found to be 47.4%, excluding type 2 diabetes mellitus, with a significant frequency of newly diagnosed endocrine disorders. Nanotechnology manipulates particles at the atomic and molecular levels, opening up new paths for studying disease etiology and therapeutic alternatives. The goal of using nanomaterials in the treatment of endocrine illnesses is to create endogenous nano-biosensors that can detect even modest changes in hormone levels and react spontaneously to restore normal function. The size and surface characteristics of nanoparticles enhances the sensitivity in nano-sensors and are functionalized for targeted drug delivery. Nano-sized carriers composed of lipids, polymers, carbon, or metals have been shown to work much better than standard drug delivery methods. Nanoparticles (NPs) offer various advantages over current methods for diagnosing and treating endocrine disorders, acting as hydrogels for insulin delivery and wound healing. Incorporating selenium NPs into inorganic nanoparticles enhances their bioactivity and targeted delivery. Gold NPs show a promising precise insulin delivery. Mesoporous silica NPs maintain glycemic level effectively and lipid and polymeric NPs protect drugs from degradation in the gastrointestinal tract. Carbon nanotubes (CNTs) have become popular in thyroid surgeries. These characteristics make nanoparticles valuable for developing effective diagnostic and therapeutic systems. NP-based medicines have been thoroughly researched in order to identify the beginning point for the creation of theranostics, which may function in two ways: as imaging agents or therapeutics. The study posits that nanotechnology bridges diagnostics and therapies, potentially revolutionizing endocrine disorder treatments. This review delves into nanotechnology techniques, emphasizing their applications in diagnosing and treating diabetes mellitus.

Cost-effectiveness of adjuvant endocrine treatment with tamoxifen for male breast cancer.

Tamoxifen (TAM) is recommended as the first-line strategy for men with estrogen receptor (ER)-positive early breast cancer who are candidates for adjuvant endocrine therapy in ASCO guideline. Our study aims to analyze the cost-effectiveness of receiving adjuvant endocrine therapy with TAM compared to no TAM, and to assess the cost-effectiveness of using TAM with high adherence over low adherence for ER-positive early male breast cancer in the USA. Two Markov models comprising three mutually exclusive health states were constructed: (1) the first Markov model compared the cost-effectiveness of adding TAM with not using TAM (TAM versus Not-TAM); (2) the second model compared the cost-effectiveness of receiving TAM with high adherence and low adherence (High-adherence-TAM versus Low-adherence-TAM). The simulation time horizon for both models was the lifetime of patients. The efficacy and safety data of two models were elicited from the real-world studies. Model inputs were derived from the US website and published literature. The main outcomes of two models both included the total cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). In the first model, TAM yielded an ICER of $5707.29 per QALY compared to Not-TAM, which was substantially below the WTP threshold of $50,000.00 per QALY in the USA. Probabilistic sensitivity analysis results demonstrated a 100.00% probability of cost-effectiveness for this strategy. In the second model, High-adherence-TAM was dominated absolutely compared to Low-adherence-TAM. The High-adherence-TAM was cost-effective with a 99.70% probability over Low-adherence-TAM when WTP was set as $50,000.00/QALY. All of these parameters within their plausible ranges did not reversely change the results of our models. Our study will offer valuable guidance for physicians or patients when making treatment decisions and provide an effective reference for decision-making to consider the appropriate allocation of funds to this special group.

Male breast cancer and sexual aspects research and analysis (MASARA study): preliminary results

PurposeTo evaluate the impact of male breast cancer and its treatment on patient’s sexual function, including changes in sexual desire, performance, and satisfaction. To investigate changes in the body image experienced by male breast cancer patients and their perception in accessing healthcare in hospital facilities.MethodsWe administered three online questionnaires using Google Forms (Google LLC) to male breast cancer patients treated at our Institution from 2015 to 2023. The surveys were provided in Italian and distributed from March 1st to April 1st, 2024. A panel of one breast radiologist, one oncologist and one clinical psychologist designed a 22-item tailored survey to investigate imaging follow-up routine, sexual habits before and after treatment and perceived male breast cancer stigma. The International Index of Erectile Function and Italian version of the Body Image Scale were also administered. Replies to the three questionnaires were analyzed using descriptive statistical analysis.ResultsAlmost half of the patients completed the three questionnaires (33/70, 47%). The median age was 62 (IR 56–72). Only 27.8% were aware of male breast cancer prior to diagnosis. 86.1% (31/36) underwent regular breast imaging follow-up, with sexual activity declining during treatment. Endocrine treatment was reported by 63.9%. Discomfort was experienced, notably during interactions and communication about their condition. Erectile dysfunction was prevalent, with 18.2% reporting severe dysfunction. The average body image score was 9.1.ConclusionsOur findings emphasize the importance of comprehensive care that attends to the full spectrum of emotional and social well-being beyond medical requirements in male breast cancer patients.