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INTRODUCTION: Neoadjuvant endocrine therapy (NET) is recommended for the treatment of invasive breast cancer (BC), particularly luminal subtypes, in locally advanced stages. Previous randomized studies have demonstrated the benefits of aromatase inhibitors in this context. However, NET is typically reserved for elderly or frail patients who may not tolerate neoadjuvant chemotherapy. Identifying non-responsive patients early and extending treatment for responsive ones would be ideal, yet optimal strategies are awaited. AIMS: This non-randomized phase 2 clinical trial aims to assess NET feasibility and efficacy in postmenopausal stage II and III luminal BC patients, identifying predictive therapeutic response biomarkers. Efficacy will be gauged by patients with Ki67 ≤ 10% after 4 weeks and Preoperative Endocrine Prognostic Index (PEPI) scores 0 post-surgery. Study feasibility will be determined by participation acceptance rate (recruitment rate ≥50%) and inclusion rate (>2 patients/month). METHODS: Postmenopausal women with luminal, HER2-tumors in stages II and III undergo neoadjuvant anastrozole treatment, evaluating continuing NET or receiving chemotherapy through early Ki67 analysis after 2 to 4 weeks. The study assesses NET extension for up to 10 months, using serial follow-ups with standardized breast ultrasound and clinical criteria-based NET suspension. Clinical and pathological responses will be measured overall and in the luminal tumor A subgroup. Toxicity, health-related quality of life, and circulating biomarkers predicting early NET response will also be evaluated.

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BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for advanced breast cancer combined with endocrine therapy (ET). The efficacy of CDK4/6 inhibitors plus ET in hormone estrogen-positive, human epidermal growth factor 2-negative (HR+/HER2-) early-stage breast cancer (esBC) is still to be confirmed. METHODS: We performed a systematic review and a meta-analysis to investigate the efficacy of CDK4/6i plus ET in esBC. Main outcomes included invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS). We included only phase III randomized controlled trials. We used RStudio version 4.2.3, and we considered p < 0.05 to be statistically significant. RESULTS: Four studies were selected, including 14,168 patients, of which 7089 were treated with CDK4/6i plus ET and 7079 received ET monotherapy. Regarding patient characteristics, 6828 (48.2%) were premenopausal. Compared with ET alone, iDFS rates (HR 0.81; 95% CI: 0.67, 0.98; p = 0.034) were significantly in favor of CDK4/6 inhibitors plus ET. However, there were no significant differences in DRFS (HR 0.79; 95% CI: 0.58, 1.07; p = 0.132) nor OS (HR 0.96; 95% CI: 0.69, 1.35; p = 0.829). CONCLUSIONS: Our results show that the addition of CDK4/6 inhibitors is associated with a significant benefit for HR+/HER2- esBC patients in iDFS. More studies and longer follow-up are needed to assess overall survival benefits.

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PURPOSE: Breast cancer is the leading cause of cancer death in Brazil and in many countries around the world. In order to minimize the risk of recurrence and death, adjuvant endocrine therapy (AET) is used in women whose tumors express hormone receptors; however, the therapy is associated with low rates of compliance. Therefore, we sought to evaluate the proportion of patients who are adherent/non-adherent to AET at the beginning of the therapy (1st year) and at its end (5th year). METHODS: Cross-sectional study assessing adherence through the Brief Medication Questionnaire. RESULTS: It was identified that eventual failures in maintaining the correct adherence to the treatment have risen from 23% of patients in the 1st year of treatment to 35% of patients in the 5th year (p = 0.005). In both groups, use of aromatase inhibitors, polypharmacy of at least 3 mediations and the previous diagnosis of diabetes mellitus (DM) or systemic arterial hypertension (SAH) have contributed to low adherence among patients. CONCLUSION: The proportion of patients who are not adherent to AET was high in both cohorts, and the rate of non-adherent patients rises over time. It is essential to incorporate screening methods for lack of compliance to AET, as well as measures to try to reduce non-persistence to the treatment, such as educating the patients on the benefits of the treatment, managing comorbidities through lifestyle changes and, therefore, reducing polypharmacy and, above all, detecting and treating very early the adverse effects of AET that might interfere with its correct use.

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BACKGROUND: Breast cancer (BC) remains a significant health care challenge, and treatment approaches continue to evolve. Among these, neoadjuvant endocrine therapy (NET) has gained prominence, particularly for postmenopausal, hormone-receptor positive, HER2-negative (HR+/HER2-) BC patients. Despite this, a significant gap exists in identifying patients who stand to benefit from NET. The objective of this study was to assess whether Magee equations (MEs) could serve as predictors of response to NET. METHODS: This retrospective study included adult patients with invasive BC who underwent NET followed by curative surgery. Assessment of sociodemographic, clinical, and tumor-related variables was conducted. The ME1, ME2, ME3, and ME mean were analyzed to explore their predictive role for NET response. Receiver operating characteristic (ROC) curves were employed, along with the determination of optimal cutoff points. Logistic regression models were utilized to identify the most significant predictors of pathological response. RESULTS: Among the 75 female participants, the mean age was 69.4 years, with the majority being postmenopausal (n = 72, 96%) and having an ECOG-PS of 0/1 (n = 63, 84%). Most patients were classified as luminal A (n = 41, 54.7%). ME3 emerged as a promising predictor, boasting an AUC of 0.734, with sensitivity of 90.62% and specificity of 57.50% when the threshold was ≤ 19.97. In univariate analysis, clinical staging (p = 0.002), molecular subtype (p = 0.001), and ME3 (continuous = 0.001, original 3-tier: p = 0.013, new 2-tier: <0.001) categories exhibited significant associations with pathological response. In the multivariate model, clinical staging and new 2-tier ME3 (<20 vs. ≥20) were included as significant variables. CONCLUSIONS: Patients with ME3 < 20 have a higher likelihood of presenting a pathological response, offering a cost-effective alternative tool to Oncotype DX. Larger future studies with a prospective design are awaited to confirm our findings.

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Advanced breast cancer represents a challenge for patients and for physicians due its dynamic genomic changes yielding to a resistance to treatments. The main goal is to improve quality of live and survival of the patients through the most appropriate subsequent therapies based on the knowledge of the natural history of the disease. In these guidelines, we summarize current evidence and available therapies for the medical management of advanced breast cancer.

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Although endocrine therapies involving pharmaceuticals, such as tamoxifen and aromatase inhibitors, had initially demonstrated good responses in patients with estrogen receptor-positive (ER+) breast cancer, they often led to drug resistance. ER plays a vital role in the progression of metastatic diseases. Fulvestrant, a first generation selective estrogen receptor degrader (SERD), can effectively downregulate the ER protein and inhibit its downstream signaling pathways. However, as the drug needs to be intramuscularly injected, its widespread use is limited owing to poor patient compliance. Herein, we described a novel class of orally bioavailable fluorine-substituted SERDs that exhibit improved pharmacokinetic profiles. We substituted the hydroxyl group of clinical SERD candidate 6 with a fluorine atom to diminish phase II metabolism. The subsequent structure-activity relationship (SAR) investigation identified 22h and 27b, which can effectively degrade ER in a dose-dependent manner and exhibit considerable antiproliferative potency and efficacy in vitro and in vivo. The excellent pharmacokinetic profiles of 27b render it promising candidate of clinically useful oral SERD.

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Breast cancer (BC) leads to the most amounts of deaths among women. Chemo-, endocrine-, and targeted therapies are the mainstay drug treatments for BC in the clinic. However, drug resistance is a major obstacle for BC patients, and it leads to poor prognosis. Accumulating evidences suggested that noncoding RNAs (ncRNAs) are intricately linked to a wide range of pathological processes, including drug resistance. Till date, the correlation between drug resistance and ncRNAs is not completely understood in BC. Herein, we comprehensively summarized a dysregulated ncRNAs landscape that promotes or inhibits drug resistance in chemo-, endocrine-, and targeted BC therapies. Our review will pave way for the effective management of drug resistance by targeting oncogenic ncRNAs, which, in turn will promote drug sensitivity of BC in the future.

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Aromatase inhibitors (AIs) cause symptoms of musculoskeletal pain, and some mechanisms have been proposed to explain them. However, signaling pathways downstream from kinin B2 (B2R) and B1 (B1R) receptor activation and their possible sensitizing of the Transient Receptor Potential Ankyrin 1 (TRPA1) remain unknown. The interaction between the kinin receptor and the TRPA1 channel in male C57BL/6 mice treated with anastrozole (an AI) was evaluated. PLC/PKC and PKA inhibitors were used to evaluate the signaling pathways downstream from B2R and B1R activation and their effect on TRPA1 sensitization. Anastrozole caused mechanical allodynia and muscle strength loss in mice. B2R (Bradykinin), B1R (DABk), or TRPA1 (AITC) agonists induced overt nociceptive behavior and enhanced and prolonged the painful parameters in anastrozole-treated mice. All painful symptoms were reduced by B2R (Icatibant), B1R (DALBk), or TRPA1 (A967079) antagonists. We observed the interaction between B2R, B1R, and the TRPA1 channel in anastrozole-induced musculoskeletal pain, which was dependent on the activation of the PLC/PKC and PKA signaling pathways. TRPA1 seems to be sensitized by mechanisms dependent on the activation of PLC/PKC, and PKA due to kinin receptors stimulation in anastrozole-treated animals. Thus, regulating this signaling pathway could contribute to alleviating AIs-related pain symptoms, patients' adherence to therapy, and disease control.

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BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been recently developed and introduced into clinical practice. METHODS: We retrospectively analyzed data from patients with confirmed HR+/HER2 metastatic breast cancer treated with hormonal therapy in combination with ribociclib (R), palbociclib (P), or abemaciclib (A). OUTCOMES: median progression-free survival (mPFS), time to treatment discontinuation (mTTD), and objective response rate (ORR). RESULTS: Between January 2016 - June 2021, 142 patients were treated with an CDK4/6i (79 P, 42 R, 21 A). The median age was 59 years and 67.6% had recurrent disease. Roughly 35.2%, 36.6%, 28.2% of the patients had 1, 2 or 3+ metastatic sites, respectively, and 55.6% of the patients received CDK4/6i as a first-line treatment. The mPFS was 28m(R) vs. 14m(P) vs. 6m(A) (P = 0.002), with a higher proportion of patients receiving R in the first-line setting. However, no difference was seen when the analysis was restricted to the first-line scenario (P = 0.193). Sixty-four patients required one dose reduction, and 19 patients required two. ORR was 76.2% (R) vs 62% (P) vs 42.9% (A). More patients achieved a complete response with R and P, with no difference in the incidence of partial response and stable disease. Adverse events occurred in 94.4% of the population, with the most common grade 3-4 AE being neutropenia (59.1%). CONCLUSIONS: Our results confirm the efficacy and tolerability of CDK4/6i in routine clinical practice. This is the first real-world data describing and comparing the efficacy and toxicity of CDK4/6i in the Brazilian population.

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PURPOSE: To evaluate the effects of 24 weeks of Mat Pilates in breast cancer survivors (BCS) undergoing hormone therapy on lower and upper body muscle strength parameters and flexibility. MATERIALS AND METHODS: Forty-three BCS (≥40 years) with confirmed breast cancer stage 0-III undergoing hormone therapy were included. Participants were randomized into Mat Pilates (three times/week, 60 min session) or control group (relaxation activities every two weeks). The difficulty and number of exercise repetitions were increased over the weeks. Assessments were performed at three times points (baseline, 12 weeks, and 24 weeks). The generalized estimating equations (GEE) model was used to compare each outcome measure during the analysis of intention to treat (ITT) and "Per protocol analysis" (PPA). RESULTS: The Pilates group presented significantly increased (p < 0.05) isometric flexor-extensor PT, and concentric and eccentric flexor PT and mechanical work (MW) after the intervention. Most of the upper body strength parameters, time to achieve maximal force (TFmax), maximal force (Fmax), and rapid force index (RFI) and right-left upper and lower body flexibility (p < 0.05) also improved. CONCLUSIONS: From our findings, we conclude that 24 and 12-weeks of Mat Pilates induced strength and flexibility gains for lower and upper body, respectively.Implications for rehabilitationMat Pilates can be adapted to the fitness level of breast cancer survivors, with a great variety of exercises that can be performed using a mat only or a few pieces of equipment.Patients can practice at home to gain different health benefits (i.e., increasing strength, flexibility, and functional capacity level), which could positively impact on quality of life.Mat Pilates performed three times per week with systematized increments in exercise level, load, and volume throughout the intervention was effective to improve hip extensor-flexor muscles peak torque and mechanical work at different muscle contractions, as well as upper and lower body flexibility.Mat Pilates was also able to improve right-left shoulder abductor and trunk extensor muscles strength parameters after 12 weeks of intervention, as well as both surgery and non-surgery sides of the upper body.

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Background: The addition of cyclin-dependent kinases inhibitors (CDKi) to endocrine therapy (ET) as the first- or second line treatment improves progression-free and overall survival (OS) in hormone receptor-positive, HER2 negative (HR+/HER2-) advanced stage breast cancer (ABC). Our study compared survival rates and prognostic factors in Chilean patients that used palbociclib as first or subsequent (≥second) lines of treatment in a real-world setting. Methods: Our retrospective population-cohort study included HR+/HER2- ABC patients. We calculated 5-year OS and performed a multivariate analysis to determine prognostic factors. Results: A total of 106 patients were included. Median age was 49 years (19-86), 28.3% (30) had de novo stage IV disease; 63% received palbociclib with ET as first line, 54% of them with aromatase inhibitor over fulvestrant. Median OS for the entire cohort was 99 months and 5-year OS was 69%. Patients that received first line palbociclib had a 5-year OS of 89% versus 43% for ET monotherapy or ≥second line palbociclib (p = 0.0062). Multivariate analysis showed that the year at diagnosis and CDKi timing (first line versus ≥second line) were significantly associated with OS. Conclusion: Our real-world data show that first-line CDKi + ET provides a statistically significant benefit in OS versus ≥second line in HR+/HER2- ABC patients.

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Abstract Objectives: This study aimed to compare progression-free survival, overall survival, clinical benefits, and adverse effects in postmenopausal women with hormone receptor-positive and HER2-negative breast cancer who received buparlisib plus fulvestrant against those of women who received dalpiciclib plus fulvestrant, considering ribociclib plus letrozole treatment as the reference standard. Methods: Women received buparlisib plus fulvestrant (BF cohort, n = 108), dalpiciclib plus fulvestrant (DF cohort, n = 132), or ribociclib plus letrozole (RL cohort, n = 150) until unacceptable toxicity was observed. Results: A total of 117 (89 %), 80 (74 %), and 84 (56 %) women in the BF, DF, and RL cohorts, respectively, had clinical benefits. After treatment, the clinical benefits for women and after 42 months of follow-up progression-free survival and overall survival were higher in the DF cohort than in the BF and RL cohorts (p < 0.05 for all). Neutropenia, vomiting, constipation, nausea, diarrhea, and anorexia were reported higher in women of the DF and BF cohorts than in women of the RL cohort. Leukopenia and increased levels of alanine aminotransferase and aspartate aminotransferase were reported to be higher in women in the RL cohort than in women in the DF and BF cohorts. Depression, anxiety, and increased levels of alanine aminotransferase and aspartate aminotransferase were reported to be higher in women in the BF cohort than in women in the DF and RL cohorts. Conclusions: Dalpiciclib plus fulvestrant is effective and comparatively safe in postmenopausal women with hormone receptor-positive and HER2-negative breast cancers. Dalpiciclib, buparlisib, fulvestrant, and ribociclib cause neutropenia, severe depression, adverse gastroenterological effects, and adverse hepatological effects, respectively.

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Breast cancer is a heterogeneous disease, and the estrogen receptor (ER) remains the most important biomarker in breast oncology. Most guidelines set a positive expression threshold of 1% staining in immunohistochemistry (IHC) to define ER positivity. However, different expression levels may be associated with diverse degrees of sensitivity to endocrine therapy as ER expression may impact breast cancer molecular biology as a continuous variable. ER-lo tumors, defined as those with 1-10% ER expression, represent a relatively small subgroup of breast cancer patients, with an estimated prevalence of 2-7%. These tumors are similar to ERneg disease in their molecular landscape, clinicopathological characteristics, prognosis, and response to therapy. Nevertheless, a proportion may retain some degree of ER signaling dependency, and the possibility of responding to some degree to endocrine therapy cannot be completely ruled out. This review article discusses the most important considerations regarding the definition of ER positivity, pathology assessment, prognosis, and therapeutic implication of ERlo breast cancer from the medical oncology perspective.

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Luminal breast cancer (BrCa) has a favorable prognosis compared with other tumor subtypes. However, with time, tumors may evolve and lead to disease progression; thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review, we focus on one of the many pathways that have been involved in tumor progression, the fibroblast growth factor/fibroblast growth factor receptor (FGFR) axis. We emphasize in data obtained from in vivo experimental models that we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlight the most frequent alterations found in BrCa cell lines and provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. Analysis of these data suggests there are many players involved in this pathway that might be also targeted to decrease FGF signaling, in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.

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Hormonal factors may participate in the development and progression of glioblastoma, the most aggressive primary tumor of the central nervous system. Many studies have been conducted on the possible involvement of estrogen receptors (ERs) in gliomas. Since there is a tendency for a reduced expression of ERs as the degree of malignancy of such tumors increases, it is important to understand the role of these receptors in the progression and treatment of this disease. ERs belong to the family of nuclear receptors, although they can also be in the plasmatic membrane, cytoplasm and mitochondria. They are classified as estrogen receptors alpha and beta (ER⍺ and ERß), each with different isoforms that have a distinct function in the organism. ERs regulate multiple physiological and pathological processes through the activation of genomic and nongenomic pathways in the cell. Nevertheless, the role of each isoform in the development and progression of glioblastoma is not completely clear. Diverse in vitro and in vivo studies have shown encouraging results for endocrine therapy as a treatment for gliomas. At the same time, many questions have arisen concerning the nature of ERs as well as the mechanism of action of the proposed drugs. Hence, the aim of the current review is to describe the drugs that could possibly be utilized in endocrine therapy for the treatment of high-grade gliomas, analyze their interaction with ERs, and explore the involvement of these drugs and receptors in resistance to standard chemotherapy.

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Female adnexal tumor of probable Wolffian origin (FATWO) are a rare type of cancer that originates from Wolffian duct remnants. Due to its rarity, no standard systemic treatment is established for cases of recurrent or metastatic disease. Previous literature reported the use of platinum-based chemotherapy and c-Kit tyrosine kinase inhibitors for FATWO cases with c-Kit positive expression. Currently, however, the broader availability of next-generation sequencing (NGS) tests allows a better molecular characterization of rare cancer such as FATWO and a possibility for the use of personalized, targeted therapy. Previous case series that performed NGS for FATWO patients described the presence of STK11 mutations in a considerable number of cases, representing a potential target in this population. To our knowledge, we describe here the first case report of a patient with FATWO and STK11 mutation exhibiting a considerable and durable response after treatment with an mTOR inhibitor plus endocrine therapy.

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Progesterone receptors (PR) play a pivotal role in many female reproductive tissues such as the uterus, the ovary, and the mammary gland (MG). Moreover, PR play a key role in breast cancer growth and progression. This has led to the development and study of different progestins and antiprogestins, many of which are currently being tested in clinical trials for cancer treatment. Recent reviews have addressed the role of PR in MG development, carcinogenesis, and breast cancer growth. Thus, in this review, in addition to making an overview on PR action in normal and tumor breast, the focus has been put on highlighting the still unresolved topics on hormone treatment involving PR isoforms and breast cancer prognosis.

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BACKGROUND: In resource-constrained settings, data regarding breast cancer patients' adherence to endocrine therapy (ET) and physicians' prescribing practices is limited. This study aims to decrease this knowledge gap in a real-world clinical practice. METHODS: Premenopausal women with stage 0-III hormone-sensitive breast cancer and receiving adjuvant ET during the past 1-5 years were identified in three Mexican referral centers. Participants' self-reported ET compliance, clinicopathologic characteristics, ET-related knowledge and beliefs, experienced adverse effects, social support, and patient-physician relationships were evaluated. Physician ET prescribing practices were compared with the gold standard according to international and national guidelines to assess clinicians' adherence to standard-of-care prescription. RESULTS: In total, 95/132 (72%) and 35/132 (27%) participants reported complete and acceptable adherence, respectively. Incomplete adherence was mainly attributed to forgetfulness, adverse effects, and unwillingness to take ET. Being employed/studying (p = 0.042), worrying about long-term ET use (p = 0.031), and experiencing >7 ET-related symptoms (p = 0.018) were associated with incomplete adherence. Guideline-endorsed regimens were prescribed in 84/132 (64%) patients, while the rest should have undergone ovarian function suppression (OFS) but instead received tamoxifen monotherapy. CONCLUSIONS: Premenopausal Mexican women self-report remarkably high rates of adequate ET adherence. However, a considerable proportion misses ≥1 doses/month, usually because of forgetfulness. Notably, only 64% receive standard-of-care ET due to suboptimal prescription of OFS. Interventions that remind patients to take their ET, refine physicians' knowledge on the importance of OFS in high-risk patients, and increase access to OFS could prove pivotal to enhance optimal ET implementation and adherence, which could translate into improved patient outcomes.

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PURPOSE OF REVIEW: The article reviews the consequences of estrogen deprivation during endocrine therapy for breast cancer and provides an update on alternative therapies for the management of symptoms. RECENT FINDINGS: Endocrine therapy has progressed substantially in recent years, and its use is recommended for all breast cancer patients expressing hormone receptors. The main adverse events of this treatment can be controlled with medications and nonpharmacological measures. Antidepressants are effective in controlling vasomotor symptoms. Vaginal discomfort can be treated with local lubricants and pelvic floor physiotherapy, which may help in sexual dysfunction. Pathophysiological mechanisms of musculoskeletal symptoms during aromatase inhibitors treatment are not well understood, but some studies evaluating treatment with duloxetine, yoga, and acupuncture have shown some benefits. For prevention of bone loss, patients with risk factors should be offered bisphosphonates or denosumab. Individualization of treatment is crucial. Consideration should be given to therapy effects on quality of life, and strategies for controlling associated symptoms should be offered.

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The increased risk for cardiovascular diseases (CVDs) in breast cancer survivors has been widely discussed in the literature and occurs due to the cardiotoxicity of antineoplastic treatments, and also to the common risk factors between these diseases. Thus, the objective of our study was to evaluate, prospectively, the number of risk factors (NRF) for CVDs in women during endocrine therapy, and to associate the NRF with C reactive protein (CRP) and phase angle (PhA). The following risk factors for CVD were evaluated at three times: anthracycline chemotherapy, radiotherapy, comorbidities, inadequate diet, overweight, abdominal adiposity, alcoholism, smoking, physical inactivity and altered lipid profile. There was inadequacy in the most components of the Brazilian Healthy Eating Index-Revised and inadequate consumption of various types of fats and fibers. Most women in this study presented excessive abdominal fat and overweight, but these parameters have not changed over time (p < 0.005). Moreover, a high frequency of systemic arterial hypertension and physical inactivity was observed. The average NRF for CVDs was above ten, at the three evaluation times. Women with higher NRF had higher levels of CRP (p = 0.003), a predictor of cardiovascular risk, however, there was no significance with PhA (p = 0.256). Thus, intervention is needed to improve lifestyle.

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