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Future Oncology (London, England) May 2024To understand the real-world use of abemaciclib in Japanese patients with early breast cancer (EBC). This retrospective observational study was conducted using a...
To understand the real-world use of abemaciclib in Japanese patients with early breast cancer (EBC). This retrospective observational study was conducted using a Japanese administrative claims database in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative EBC who received abemaciclib adjuvant therapy from December 2021-March 2023. Patient characteristics and treatment patterns were summarized. Among 374 patients, 38.2, 51.6 and 63.4% patients received neoadjuvant chemotherapy, adjuvant chemotherapy and radiotherapy, respectively; 13.1% were chemotherapy naive. Tamoxifen (37.7%), letrozole (35.6%), anastrozole (24.3%) were the commonly prescribed concomitant adjuvant endocrine therapies. Abemaciclib dose reductions were observed in 42.0% patients. Use of abemaciclib for treatment of high-risk EBC was described, which could help inform patient selection and treatment patterns.
PubMed: 38861285
DOI: 10.1080/14796694.2024.2346464 -
International Journal of Environmental... Jun 2024In our study, the protective role of synthetic aromatase inhibitors anastrozole (ANS), letrozole (LTZ) and exemestane (EXM) and natural aromatase inhibitors resveratrol...
In our study, the protective role of synthetic aromatase inhibitors anastrozole (ANS), letrozole (LTZ) and exemestane (EXM) and natural aromatase inhibitors resveratrol (RSV) and apigenin (APG) against testicular failure caused by exposure to Bisphenol A (BPA) was investigated. The epididymal sperm concentration, sperm motility and sperm morphology were determined. Oxidative stress and inflammatory response parameters were examined and histological examinations were performed in testicular tissues. Our results revealed that BPA exposure decreased serum testosterone and estrogen levels, increased FSH and LH levels ( < 0.05). BPA has been found to increase oxidative stress and inflammatory response and disrupt the histological structure. Also, BPA exposure decreased testicular weight, epididymal sperm concentration and motility, and increased abnormal sperm rate ( < 0.05). These results show that ANS, LTZ and RSV treatments reduce the BPA-induced testicular damage.
PubMed: 38825800
DOI: 10.1080/09603123.2024.2362810 -
Journal of Clinical Oncology : Official... Jun 2024ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining....
Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.
PURPOSE
ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes.
METHODS
MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance < .05.
RESULTS
Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS ( < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated ( = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS ( = .001) in models with ER.
CONCLUSION
Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.
PubMed: 38824432
DOI: 10.1200/JCO.24.00835 -
Frontiers in Oncology 2024Breast cancer is the most prevalent malignancy in women, and is characterized by its heterogeneity; exhibiting various subgroups identifiable through molecular... (Review)
Review
Breast cancer is the most prevalent malignancy in women, and is characterized by its heterogeneity; exhibiting various subgroups identifiable through molecular biomarkers that also serve as predictive indicators. More than two thirds of breast tumors are classified as luminal with positive hormone receptors (HR), indicating that cancer cells proliferation is promoted by hormones. Endocrine therapies play a vital role in the effective treatment of breast cancer by manipulating the signaling of estrogen receptors (ER), leading to a reduction in cell proliferation and growth rate. Selective estrogen receptor modulators (SERMs), such as tamoxifen and toremifene, function by blocking estrogen's effects. Aromatase inhibitors (AI), including anastrozole, letrozole and exemestane, suppress estrogen production. On the other hand, selective estrogen receptor degraders (SERDs), like fulvestrant, act by blocking and damaging estrogen receptors. Tamoxifen and AI are widely used both in early- and advanced-stage disease, while fulvestrant is used as a single agent or in combination with other agents like the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, abemaciclib, ribociclib) or alpelisib for advanced-stage disease. Currently, SERDs are recognized as an effective therapeutic approach for the treatment of ER-positive breast cancer, showing proficiency in reducing and blocking ER signaling. This review aims to outline the ongoing development of novel oral SERDs from a practical therapeutic perspective, enhancing our understanding of the mechanisms of action underlying these compounds.
PubMed: 38800404
DOI: 10.3389/fonc.2024.1385577 -
Pharmaceutics May 2024In the dynamic field of radiopharmaceuticals, innovating targeted agents for cancer diagnosis and therapy is crucial. Our study enriches this evolving landscape by...
Radiological and Molecular Analysis of Radioiodinated Anastrozole and Epirubicin as Innovative Radiopharmaceuticals Targeting Methylenetetrahydrofolate Dehydrogenase 2 in Solid Tumors.
In the dynamic field of radiopharmaceuticals, innovating targeted agents for cancer diagnosis and therapy is crucial. Our study enriches this evolving landscape by evaluating the potential of radioiodinated anastrozole ([I]anastrozole) and radioiodinated epirubicin ([I]epirubicin) as targeting agents against MTHFD2-driven tumors. MTHFD2, which is pivotal in one-carbon metabolism, is notably upregulated in various cancers, presenting a novel target for radiopharmaceutical application. Through molecular docking and 200 ns molecular dynamics (MD) simulations, we assess the binding efficiency and stability of [I]anastrozole and [I]epirubicin with MTHFD2. Molecular docking illustrates that [I]epirubicin has a superior binding free energy (∆) of -41.25 kJ/mol compared to -39.07 kJ/mol for [I]anastrozole and -38.53 kJ/mol for the control ligand, suggesting that it has a higher affinity for MTHFD2. MD simulations reinforce this, showing stable binding, as evidenced by root mean square deviation (RMSD) values within a narrow range, underscoring the structural integrity of the enzyme-ligand complexes. The root mean square fluctuation (RMSF) analysis indicates consistent dynamic behavior of the MTHFD2 complex upon binding with [I]anastrozole and [I]epirubicin akin to the control. The radius of gyration (RG) measurements of 16.90 Å for MTHFD2-[I]anastrozole and 16.84 Å for MTHFD2-[I]epirubicin confirm minimal structural disruption upon binding. The hydrogen bond analysis reveals averages of two and three stable hydrogen bonds for [I]anastrozole and [I]epirubicin complexes, respectively, highlighting crucial stabilizing interactions. The MM-PBSA calculations further endorse the thermodynamic favorability of these interactions, with binding free energies of -48.49 ± 0.11 kJ/mol for [I]anastrozole and -43.8 kJ/mol for MTHFD2-. The significant contribution of Van der Waals and electrostatic interactions to the binding affinities of [I]anastrozole and [I]epirubicin, respectively, underscores their potential efficacy for targeted tumor imaging and therapy. These computational findings lay the groundwork for the future experimental validation of [I]anastrozole and [I]epirubicin as MTHFD2 inhibitors, heralding a notable advancement in precision oncology tools. The data necessitate subsequent in vitro and in vivo assays to corroborate these results.
PubMed: 38794278
DOI: 10.3390/pharmaceutics16050616 -
Journal of Clinical Oncology : Official... May 2024A head-to-head comparison of efficacy between a cyclin-dependent kinase 4/6 inhibitor plus endocrine therapy (ET) versus combination chemotherapy (CT) has never been...
Final results of RIGHT Choice: Ribociclib plus endocrine therapy vs combination chemotherapy in premenopausal women with clinically aggressive HR+/HER2- advanced breast cancer.
PURPOSE
A head-to-head comparison of efficacy between a cyclin-dependent kinase 4/6 inhibitor plus endocrine therapy (ET) versus combination chemotherapy (CT) has never been reported in patients with clinically aggressive hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC).
PATIENTS AND METHODS
In this open-label, multi-center, randomized phase 2 trial, pre/perimenopausal women with clinically aggressive HR+/HER2- ABC were randomized 1:1 to first-line ribociclib (600 mg daily; 3-weeks-on, 1-week-off) plus letrozole/anastrozole and goserelin or investigator's choice of combination CT (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine). The primary endpoint was progression-free survival (PFS).
RESULTS
Among 222 patients randomized to ribociclib plus ET (n=112) or combination CT (n=110), 150 (67.6%) had symptomatic visceral metastases, 41 (18.5%) had rapid disease progression per investigator's judgment, and 31 (14.0%) had symptomatic non-visceral disease. Overall, 106 (47.7%) patients had investigator-assessed visceral crisis. Median follow-up time was 37.0 months. At data cutoff, 31.3% (ribociclib arm) and 15.5% (CT arm) of patients had completed study treatment and transitioned to post-trial access. The median PFS was 21.8 months (ribociclib plus ET; 95% CI, 17.4-26.7 months) and 12.8 months (combination CT; 95% CI, 10.1-18.4 months); hazard ratio [HR], 0.61; 95% CI, 0.43-0.87; =.003. The overall response rates and the median time to response in the ribociclib versus CT arms, respectively, were 66.1% and 61.8% and 4.9 months and 3.2 months (HR, 0.76; 95% CI, 0.55-1.06). Lower rates of symptomatic adverse events were observed in the ribociclib versus CT arm.
CONCLUSIONS
First-line ribociclib plus ET showed a significant PFS benefit, similar response rates, and better tolerability over combination CT in patients with clinically aggressive HR+/HER2- ABC.
PubMed: 38771995
DOI: 10.1200/JCO.24.00144 -
Oncology Letters Jul 2024Invasive papillary carcinoma (IPC) of the breast is a rare form of cancer. The current report documents a case of IPC characterized by a large tumor size and skin...
Invasive papillary carcinoma (IPC) of the breast is a rare form of cancer. The current report documents a case of IPC characterized by a large tumor size and skin involvement. Surgical exploration revealed no evidence of axillary lymph node metastasis in breast cancer. Due to financial constraints, the patient opted solely for anastrozole endocrine therapy at a dosage of 1 mg/day for a period of 5 years post-surgery, foregoing other treatments such as radiotherapy and chemotherapy. Since discharge, 2.5 years have passed, during which the patient has been followed up via phone every 3 months, showing a good prognosis. A literature review indicated that IPC is prevalent amongst the elderly population and can be misdiagnosed due to its morphological, cytomorphological and immunophenotypic overlap with other types of papillary neoplasms. This tumor exhibits a more favorable prognosis compared with IDC, primarily attributed to its advantageous gene and molecular expression patterns, coupled with its decreased invasiveness. Despite limited evidence-based research on the treatment of IPC, the present case report, albeit with limitations, underscores the importance of avoiding over-treatment and suggests the feasibility of combining surgery with endocrine therapy for IPC.
PubMed: 38765791
DOI: 10.3892/ol.2024.14433 -
Clinical Cancer Research : An Official... May 2024We previously reported that postmenopausal women with ER+ breast cancer (BC) receiving adjuvant anastrozole 1 mg/day (ANA1) with estrone (E1) ≥1.3 pg/mL and estradiol...
BACKGROUND
We previously reported that postmenopausal women with ER+ breast cancer (BC) receiving adjuvant anastrozole 1 mg/day (ANA1) with estrone (E1) ≥1.3 pg/mL and estradiol (E2) ≥0.5 (inadequate estrogen suppression [IES]) had a 3.0-fold increased risk of a BC event. The objective of this study was to determine if increasing anastrozole to 10 mg/day (ANA10) could result in adequate estrogen suppression (AES: E1 <1.3 pg/mL and/or E2 <0.5) among those with IES on ANA1.
METHODS
Postmenopausal women with ER+ BC planning to receive adjuvant ANA1 were eligible. E1 and E2 were assessed pre- and post-8-10 weeks of ANA1. Those with IES were switched to 8-10 week cycles of ANA10 followed by letrozole 2.5 mg/day. E1 and E2 were assessed after each cycle. Anastrozole concentrations were measured post-ANA1 and post-ANA10. Primary analyses included patients who documented taking at least 80% of planned treatment (adherent cohort).
RESULTS
132 (84.6%) of 156 eligible patients were ANA1-adherent. IES occurred in 40 (30.3%) adherent patients. 25 (78.1%) of 32 patients who began ANA10 were adherent, and AES was achieved in 19 (76.0%; 90%CI: 58.1-89.0%) patients. Anastrozole concentrations post-ANA1 and post-ANA10 did not differ by estrogen suppression status among adherent patients. AES was maintained/attained in 21 (91.3%) of 23 letrozole-adherent patients.
CONCLUSIONS
Approximately 30% of ANA1-adherent patients had IES. Among those who switched to ANA10 and were adherent, 76% had AES. Further studies are required to validate emerging data that ANA1 results in IES for some patients and to determine the clinical benefit of switching to ANA10 or an alternative AI.
PubMed: 38752717
DOI: 10.1158/1078-0432.CCR-24-0341 -
Translational Breast Cancer Research :... 2023We report a case of hormone receptor (HR) positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer with multiple liver metastases who achieved...
BACKGROUND
We report a case of hormone receptor (HR) positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer with multiple liver metastases who achieved good clinical benefit across cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with endocrine therapy. Prior to this, the patient underwent neoadjuvant therapy and surgery as well as adjuvant endocrine therapy. We present and discuss three important treatment decision nodes associated with it.
CASE DESCRIPTION
A 60-year-old woman was diagnosed with invasive ductal carcinoma of the left breast (cT4bN2M0, stage IIIB, Luminal B HER2-negative type) at the West China Hospital of Sichuan University in 2020, and received neoadjuvant chemotherapy and modified radical mastectomy of the left breast from 2020 to 2021. Postoperative radiotherapy was performed in the left chest wall and left upper and lower clavicular region. Adjuvant therapy is anastrozole endocrine therapy. Multiple liver metastases developed in 2022. The pathological molecular typing of liver metastases was confirmed to be consistent with the primary lesion. In the context of primary endocrine resistance, the first-line treatment of choice was fulvestrant in combination with a targeted CDK4/6 inhibitor (abemaciclib). This combination regimen made the liver metastases visibly shrunk, leading to partial response (PR) and has achieved a progression-free survival of 12 months. And there were no serious drug-related adverse events during first-line treatment.
CONCLUSIONS
CDK4/6 inhibitor is a promising antineoplastic agent for HR positive, HER2 negative breast cancer patients. With the development of research, the application scope of CDK4/6 inhibitors is gradually expanding, and the precision treatment of breast cancer requires more rational drug selection and combination.
PubMed: 38751470
DOI: 10.21037/tbcr-23-27 -
American Journal of Respiratory and... May 2024Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models.
RATIONALE
Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models.
OBJECTIVES
We aimed to determine whether anastrozole improved six-minute walk distance (6MWD) at six months in pulmonary arterial hypertension (PAH).
METHODS
We performed a randomized, double-blind, placebo-controlled Phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four post-menopausal women and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at six months. Using intent-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters.
MEASUREMENTS AND MAIN RESULTS
Forty-one subjects were randomized to placebo and 43 to anastrozole and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued study drug. There was no significant difference in the change in 6MWD at six months (placebo-corrected treatment effect -7.9 m, 95%CI -32.7 - 16.9, p = 0.53). There was no difference in adverse events between the groups.
CONCLUSIONS
Anastrozole did not show a significant effect on 6MWD compared to placebo in post-menopausal women and men with PAH. Anastrozole was safe and did not show adverse effects. Clinical trial registration available at www.
CLINICALTRIALS
gov, ID: NCT03229499.
PubMed: 38747680
DOI: 10.1164/rccm.202402-0371OC