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Pharmaceutics Apr 2023Aromatase inhibitors (AIs) cause symptoms of musculoskeletal pain, and some mechanisms have been proposed to explain them. However, signaling pathways downstream from...
Aromatase inhibitors (AIs) cause symptoms of musculoskeletal pain, and some mechanisms have been proposed to explain them. However, signaling pathways downstream from kinin B (BR) and B (BR) 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 BR and BR activation and their effect on TRPA1 sensitization. Anastrozole caused mechanical allodynia and muscle strength loss in mice. BR (Bradykinin), BR (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 BR (Icatibant), BR (DALBk), or TRPA1 (A967079) antagonists. We observed the interaction between BR, BR, 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.
PubMed: 37111622
DOI: 10.3390/pharmaceutics15041136 -
Breast Cancer Research : BCR Apr 2023Ki67 assessed at diagnosis (Ki67) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after... (Randomized Controlled Trial)
Randomized Controlled Trial
Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015).
PURPOSE
Ki67 assessed at diagnosis (Ki67) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki67) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki67) with recurrence-free survival. The aim was to define the association between Ki67 and after aromatase inhibitor (AI) exposure ∆Ki67 and Ki67 with key prognostic and biologic factors utilising data from the POETIC study.
PATIENTS AND METHODS
In POETIC 4480 postmenopausal patients with primary ER and/or PgR + breast cancer were randomised 2:1 to 2 weeks' presurgical AI (anastrozole or letrozole) or no presurgical treatment (control). Ki67 was measured centrally in core-cut biopsies taken prior to AI and in core-cuts or the excision biopsy at surgery. Relationships between the Ki67 and biologic factors were explored using linear regression.
RESULTS
Established associations of Ki67 with biologic factors including PgR status, tumour grade, tumour size, histological subtype, nodal status, and vascular invasion were confirmed in the HER2- subpopulation. In the HER2 + subpopulation only grade and tumour size were significantly associated with Ki67. In control group Ki67 was 18% lower than Ki67 (p < 0.001) when Ki67 was measured in excision biopsies but not when measured in core-cuts. Median suppression by AIs (∆Ki67) was 79.3% (IQR: -89.9 to -54.6) and 53.7% (IQR: -78.9 to -21.1) for HER2-negative and HER2-positive cases, respectively. Significantly less suppression occurred in PgR- vs PgR + and HER2 + vs HER2- tumours which remained apparent after adjustment for 2-week sample type.
CONCLUSIONS
The magnitude of this study allowed characterisation of relationships between Ki67, ∆Ki67 and Ki67 with high degrees of confidence providing a reference source for other studies. Lower values of Ki67 occur when measured on excision biopsies and could lead to apparent but artefactual decreases in Ki67: this should be considered when either ∆Ki67 or Ki67 is used in routine clinical practice to aid treatment decisions or in clinical trials assessing new drug therapies.
Topics: Female; Humans; Aromatase Inhibitors; Breast Neoplasms; Ki-67 Antigen; Letrozole; Receptor, ErbB-2; Receptors, Progesterone
PubMed: 37046348
DOI: 10.1186/s13058-023-01626-3 -
EClinicalMedicine Apr 2023The DATA study evaluated the use of two different durations of anastrozole in patients with hormone receptor-positive breast cancer who were disease-free after 2-3 years...
Extended adjuvant aromatase inhibition after sequential endocrine therapy in postmenopausal women with breast cancer: follow-up analysis of the randomised phase 3 DATA trial.
BACKGROUND
The DATA study evaluated the use of two different durations of anastrozole in patients with hormone receptor-positive breast cancer who were disease-free after 2-3 years of tamoxifen. We hereby present the follow-up analysis, which was performed after all patients reached a minimum follow-up of 10 years beyond treatment divergence.
METHODS
The open-label, randomised, phase 3 DATA study was performed in 79 hospitals in the Netherlands (ClinicalTrials.gov, number NCT00301457). Postmenopausal women with hormone receptor-positive breast cancer who were disease-free after 2-3 years of adjuvant tamoxifen treatment were assigned to either 3 or 6 years of anastrozole (1 mg orally once a day). Randomisation (1:1) was stratified by hormone receptor status, nodal status, HER2 status, and prior tamoxifen duration. The primary outcome was adapted disease-free survival, defined as disease-free survival from 3 years after randomisation onwards. Adapted overall survival was assessed as a secondary outcome. Analyses were performed according to the intention-to-treat design.
FINDINGS
Between June 28, 2006, and August 10, 2009, 1912 patients were randomly assigned to 3 years (n = 955) or 6 years (n = 957) of anastrozole. Of these, 1660 patients were eligible and disease-free at 3 years after randomisation. The 10-year adapted disease-free survival was 69.2% (95% CI 55.8-72.3) in the 6-year group (n = 827) and 66.0% (95% CI 62.5-69.2) in the 3-year group (n = 833) (hazard ratio (HR) 0.86; 95% CI 0.72-1.01; p = 0.073). The 10-year adapted overall survival was 80.9% (95% CI 77.9-83.5) in the 6-year group and 79.2% (95% CI 76.2-81.9) in the 3-year group (HR 0.93; 95% CI 0.75-1.16; p = 0.53).
INTERPRETATION
Extended aromatase inhibition beyond 5 years of sequential endocrine therapy did not improve the adapted disease-free survival and adapted overall survival of postmenopausal women with hormone receptor-positive breast cancer.
FUNDING
AstraZeneca.
PubMed: 36992863
DOI: 10.1016/j.eclinm.2023.101901 -
Molecules (Basel, Switzerland) Mar 2023CDK4/6 and aromatase are prominent targets for breast cancer drug discovery and are involved in abnormal cell proliferation and growth. Although aromatase inhibitors...
CDK4/6 and aromatase are prominent targets for breast cancer drug discovery and are involved in abnormal cell proliferation and growth. Although aromatase inhibitors have proven to be effective (for example exemestane, anastrozole, letrozole), resistance to treatment eventually occurs through the activation of alternative signaling pathways, thus evading the antiproliferative effects of aromatase inhibitors. One of the evasion pathways is Cylin D-CDK4/6-Rb signaling that promotes tumor proliferation and resistance to aromatase inhibitors. There is significant evidence that the sequential inhibition of both proteins provides therapeutic benefits over the inhibition of one target. The basis of this study objective is the identification of molecules that are likely to inhibit both CDK4/6 and aromatase by computational chemistry techniques, which need further biochemical studies to confirm. Initially, a structure-based pharmacophore model was constructed for each target to screen the sc-PDB database. Consequently, pharmacophore screening and molecular docking were performed to evaluate the potential lead candidates that effectively mapped both of the target pharmacophore models. Considering abemaciclib (CDK4/6 inhibitor) and exemestane (aromatase inhibitor) as reference drugs, four potential virtual hit candidates (1, 2, 3, and 4) were selected based on their fit values and binding interaction after screening a sc-PDB database. Further, molecular dynamics simulation studies solidify the stability of the lead candidate complexes. In addition, ADMET and DFT calculations bolster the lead candidates. Hence, these combined computational approaches will provide a better therapeutic potential for developing CDK4/6-aromatase dual inhibitors for HR+ breast cancer therapy.
Topics: Humans; Female; Aromatase Inhibitors; Aromatase; Molecular Docking Simulation; Anastrozole; Breast Neoplasms; Molecular Dynamics Simulation; Enzyme Inhibitors; Cyclin-Dependent Kinase 4
PubMed: 36985460
DOI: 10.3390/molecules28062490 -
Metabolites Mar 2023Aromatase inhibitor-induced arthralgia (AIA) presents a major problem for patients with breast cancer but is poorly understood. This prospective study explored the...
Aromatase inhibitor-induced arthralgia (AIA) presents a major problem for patients with breast cancer but is poorly understood. This prospective study explored the inflammatory metabolomic changes in the development of AIA. This single-arm, prospective clinical trial enrolled 28 postmenopausal women with early-stage (0-3) ER+ breast cancer starting adjuvant anastrozole. Patients completed the Breast Cancer Prevention Trial (BCPT) Symptom Checklist and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) at 0, 3, and 6 months. The plasma levels of four polyunsaturated fatty acids (PUFAs) and 48 oxylipins were quantified at each timepoint. The subscores for WOMAC-pain and stiffness as well as BCPT-total, hot flash, and musculoskeletal pain significantly increased from baseline to 6 months (all < 0.05). PUFA and oxylipin levels were stable over time. The baseline levels of 8-HETE were positively associated with worsening BCPT-total, BCPT-hot flash, BCPT-musculoskeletal pain, WOMAC-pain, and WOMAC- stiffness at 6 months (all < 0.05). Both 9-HOTrE and 13(S)-HOTrE were related to worsening hot flash, and 5-HETE was related to worsening stiffness (all < 0.05). This is the first study to prospectively characterize oxylipin and PUFA levels in patients with breast cancer starting adjuvant anastrozole. The oxylipin 8-HETE should be investigated further as a potential biomarker for AIA.
PubMed: 36984892
DOI: 10.3390/metabo13030452 -
Brain Sciences Mar 2023Glioblastoma Multiforme (GBM) is a tumor that infiltrates several brain structures. GBM is associated with abnormal motor activities resulting in impaired mobility,...
Glioblastoma Multiforme (GBM) is a tumor that infiltrates several brain structures. GBM is associated with abnormal motor activities resulting in impaired mobility, producing a loss of functional motor independence. We used a GBM xenograft implanted in the striatum to analyze the changes in Y (vertical) and X (horizontal) axis displacement of the metatarsus, ankle, and knee. We analyzed the steps dissimilarity factor between control and GBM mice with and without anastrozole. The body weight of the untreated animals decreased compared to treated mice. Anastrozole reduced the malignant cells and decreased GPR30 and ERα receptor expression. In addition, we observed a partial recovery in metatarsus and knee joint displacement (dissimilarity factor). The vertical axis displacement of the GBM+anastrozole group showed a difference in the right metatarsus, right knee, and left ankle compared to the GBM group. In the horizontal axis displacement of the right metatarsus, ankle, and knee, the GBM+anastrozole group exhibited a difference at the last third of the step cycle compared to the GBM group. Thus, anastrozole partially modified joint displacement. The dissimilarity factor and the vertical and horizontal displacements study will be of interest in GBM patients with locomotion alterations. Hindlimb displacement and gait locomotion analysis could be a valuable methodological tool in experimental and clinical studies to help diagnose locomotive deficits related to GBM.
PubMed: 36979306
DOI: 10.3390/brainsci13030496 -
BMC Women's Health Mar 2023Hormone-positive breast cancer is the most common type and represents a burden in all countries. Treatment satisfaction might be a predictor for adherence, as higher...
BACKGROUND
Hormone-positive breast cancer is the most common type and represents a burden in all countries. Treatment satisfaction might be a predictor for adherence, as higher satisfaction with medication encourages patients to adhere appropriately to the medication and, consequently, successfully achieve the treatment goals. The present study evaluated the adherence of women with hormone-positive breast cancer to oral hormonal drugs and correlated it with treatment satisfaction and other sociodemographic and clinical factors.
METHODS
A cross-sectional design was applied. This study included two cancer centers. Data were collected from patients through face-to-face interviews and medical record reviews. The Medication Adherence Scale was adapted to assess medication adherence, and the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4 was adopted to measure treatment satisfaction.
RESULTS
The final analysis included 106 patients, with a mean age ± SD of 51.9 ± 1.2. Approximately 35% were hospitalized in the past year. Current hormonal therapy among cancer patients included letrozole (38.7%), tamoxifen (31.1%), exemestane (17%), and anastrozole (13.2%). The median adherence score was 5.0 [4.8-6.0], and 62.3% adhered fully to their oral hormonal drugs in the past week. The median scores of effectiveness, side effects, convenience, and global satisfaction were 66.67 [61.11.0-72.22], 75.00 [48.44-100.00], 66.67 [66.67-72.22], and 71.43 [57.14-78.57], respectively. A significantly lower adherence score was identified in patients living in camps (p = 0.020). Patients with comorbidities and those who continued on the same hormonal therapy had higher adherence scores, although they were not statistically significant. Multiple linear regression analysis showed that two domains of treatment satisfaction, side effects (p = 0.013) and global satisfaction (p = 0.018), were predictors of adherence to oral hormonal drugs.
CONCLUSIONS
The current study revealed a significant association between treatment satisfaction and adherence to oral hormonal therapy. We recommend creating a specialized scale to measure adherence, considering the psychosocial factors that affect hormonal anticancer medication adherence.
Topics: Breast Neoplasms; Medication Adherence; Treatment Outcome; Patient Satisfaction; Cross-Sectional Studies; Antineoplastic Agents, Hormonal
PubMed: 36941628
DOI: 10.1186/s12905-023-02276-5 -
Frontiers in Endocrinology 2023Most children with non-classic congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxylase deficiency are asymptomatic and do not require cortisol replacement therapy...
Most children with non-classic congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxylase deficiency are asymptomatic and do not require cortisol replacement therapy unless they develop symptoms of hyperandrogenemia. The current practice is to treat symptomatic children with hydrocortisone aimed at suppressing excess adrenal androgen production irrespective of the child's level of endogenous cortisol production. Once on hydrocortisone therapy, even children with normal cortisol production require stress dosing. Some children with NC-CAH may present with premature adrenarche, growth acceleration, and advanced bone age, but with no signs of genital virilization and normal endogenous cortisol production. In these cases, an alternative therapy to hydrocortisone treatment that does not impact the hypothalamic-pituitary-adrenal axis, but targets increased estrogen production and its effects on bone maturation, could be considered. Aromatase inhibitors (AIs), which block the aromatization of androgen to estrogen, have been used off-label in men with short stature to delay bone maturation and as an adjunct therapy in children with classic CAH. The use of AI as a monotherapy for children with NC-CAH has never been reported. We present three pre-pubertal female children with a diagnosis of NC-CAH treated with anastrozole monotherapy after presenting with advanced bone age, early adrenarche, no signs of genital virilization, and normal peak cortisol in response to ACTH stimulation testing. Bone age z-scores normalized, and all three reached or exceeded their target heights. Monotherapy with anastrozole can be an effective alternative in slowing down bone maturation and improving height outcomes in children with NC-CAH and normal adrenal cortisol production.
Topics: Child; Female; Humans; Adrenal Hyperplasia, Congenital; Anastrozole; Androgens; Estrogens; Hydrocortisone; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Virilism
PubMed: 36936152
DOI: 10.3389/fendo.2023.1101843 -
Scientific Reports Mar 2023Pain caused by the tumor or aromatase inhibitors (AIs) is a disabling symptom in breast cancer survivors. Their mechanisms are unclear, but pro-algesic and inflammatory...
Pain caused by the tumor or aromatase inhibitors (AIs) is a disabling symptom in breast cancer survivors. Their mechanisms are unclear, but pro-algesic and inflammatory mediators seem to be involved. Kinins are endogenous algogenic mediators associated with various painful conditions via B and B receptor activation, including chemotherapy-induced pain and breast cancer proliferation. We investigate the involvement of the kinin B and B receptors in metastatic breast tumor (4T1 breast cancer cells)-caused pain and in aromatase inhibitors (anastrozole or letrozole) therapy-associated pain. A protocol associating the tumor and antineoplastic therapy was also performed. Kinin receptors' role was investigated via pharmacological antagonism, receptors protein expression, and kinin levels. Mechanical and cold allodynia and muscle strength were evaluated. AIs and breast tumor increased kinin receptors expression, and tumor also increased kinin levels. AIs caused mechanical allodynia and reduced the muscle strength of mice. Kinin B (DALBk) and B (Icatibant) receptor antagonists attenuated these effects and reduced breast tumor-induced mechanical and cold allodynia. AIs or paclitaxel enhanced breast tumor-induced mechanical hypersensitivity, while DALBk and Icatibant prevented this increase. Antagonists did not interfere with paclitaxel's cytotoxic action in vitro. Thus, kinin B or B receptors can be a potential target for treating the pain caused by metastatic breast tumor and their antineoplastic therapy.
Topics: Mice; Animals; Aromatase Inhibitors; Hyperalgesia; Cancer Pain; Receptor, Bradykinin B2; Receptor, Bradykinin B1; Bradykinin; Pain; Antineoplastic Agents; Paclitaxel; Neoplasms
PubMed: 36932156
DOI: 10.1038/s41598-023-31535-6 -
Cureus Feb 2023A small but important subset of patients with metastatic breast cancer has an oligometastatic disease. Some of these patients are highly responsive to systemic therapy...
A small but important subset of patients with metastatic breast cancer has an oligometastatic disease. Some of these patients are highly responsive to systemic therapy and have the potential to achieve complete remission with treatment. However, it remains to be clarified the best locoregional and systemic treatment strategy for such patients and what features can determine whose patients are the best candidates. We also don't know what will be the role of cyclin-dependent kinase 4/6 inhibitors in those cases. We report the case of a 41-year-old woman with HR-positive/HER2-negative oligometastatic breast cancer who, after an excellent response to systemic treatment with palbociclib, anastrozole, and goserelin, underwent breast surgery and liver metastasectomy. After completing three years of systemic treatment, the CDK inhibitor was discontinued, maintaining the hormone therapy. The patient remained under regular follow-up with no evidence of disease after eight months.
PubMed: 36925985
DOI: 10.7759/cureus.34893