Use Of Aromatase Inhibitors Research Articles

Endocrine therapy initiation among women diagnosed with ductal carcinoma in situ breast cancer from 2001-2016.

487 Background: Endocrine therapy (ET) initiation in people within 1 year of diagnosis of estrogen-receptor-positive (ER+) ductal carcinoma in situ (DCIS) has ranged from 21-45% in prior studies; however, these studies did not evaluate initiation post-2011 and may not reflect current patterns of use. ET use following ER+ DCIS diagnosis can reduce the relative risks of recurrence and contralateral breast cancer by 30-50%. We evaluated ET initiation over time and by demographic, tumor, and treatment characteristics in the Kaiser Permanente Breast Cancer Survivors Study between 2001-2016. Methods: We included people aged 20+ years diagnosed with unilateral DCIS with at least 1 year of cancer-free follow-up from three U.S. integrated health systems. We excluded people with ER-negative disease, no surgery, and those who received chemotherapy or unknown radiation therapy. ET dispensings (tamoxifen and aromatase inhibitors) were extracted from electronic pharmacy records within 1 year of a person’s initial DCIS breast cancer diagnosis. Using generalized linear models with a log link and Poisson distribution, we estimated relative rates (RRs) of ET use (vs none) over time and by demographic, tumor, and other treatment characteristics. Results: Among 1,782 pre- and postmenopausal people, 577 (32%) initiated ET within 1 year of diagnosis. From 2001-2016, ET use did not change over time (34% vs 36%), tamoxifen use declined slightly (34% vs 29%), and aromatase inhibitor use increased slightly (0% vs 7%). People were less likely to initiate ET if they were ≥65 years, Black, had borderline or unknown ER status, were not tested for ER, had breast conserving surgery (BCS) without radiation, or had a unilateral mastectomy. Conclusions: Only one-third of people with DCIS diagnosed in a community healthcare setting and potentially eligible for ET, initiated treatment within 1 year of their diagnosis. Previous studies have shown long-term benefits of ET use in people with DCIS; however, we saw no increase in use over time. Concerns about side-effects, overdiagnosis and overtreatment of DCIS, and confusion about treatment guidelines may explain relatively low ET initiation.[Table: see text]

B-178 Clinical Routine Ultrasensitive LC-MS/MS Method Development for Analysis of 17β-Estradiol in Human Serum

Abstract Background The increasing clinical demand for the measurement of circulating 17β-Estradiol at very low concentrations consolidates the need of highly sensitive and specific analytical methodologies. These assays are suitable in situations such as antiestrogen therapy monitoring (use of aromatase inhibitor in breast cancer treatment); diagnosis of suspect inherited sex-steroid metabolic disorders; diagnosis of precocious and delayed puberty in female; hormone replacement therapy in postmenopausal women; and estrogen deficiency in men. Time-consuming methods and lack of sensitivity are common in the quantification of 17β-Estradiol in serum by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The strategy of chemical derivatization is common for analysis of estrogens because it enhances specificity and sensitivity, but this approach becomes laborious in the sample preparation process. For the purpose of solving these analytical challenges, the aim of this work was developing a reliable, sensitive and low-cost LC-MS/MS method without derivatization for clinical routine analysis. Methods Isotope-labeled internal standard 17β-Estradiol-D5 were added to calibrators, quality controls (QC) and serum samples before a liquid-liquid extraction with the organic solvent Diethyl Ether. After reconstitution, the extracts were injected into a Biphenyl column 50 × 2.1 mm, 2,6 µm, chromatographic separated by solvent gradient (Ammonium Fluoride in Water – Acetonitrile) and detected in positive electrospray ionization mode. The analytical method was validated using reference material grade standards and spiked QCs in charcoal stripped pool patient serum at 4 levels by the assessment of linearity, limit of quantification (LoQ), precision inter and intra-assay, accuracy, carryover, method comparison, cross-reactivity and stability (freeze-thawing cycles, bench top, postoperative and stock solution). Results The method has been validated with the analytical measurement range of 2–500 pg/mL. It was successfully optimized to achieve low levels of 17β-Estradiol as proposed with limit of quantitation of 2 pg/mL. Within-run and between-run precision (coefficient of variation) study yielded 1.3%–7.2% and accuracy within 95.7%–112.1%. No carryover, matrix effect and significant cross-reactivity was observed. Estradiol was found to be stable in serum samples under 3 freeze/thawing cycles, 4 h at ambient temperature and 72 h after extraction procedure in auto-injector. The stability of stock solutions was tested in −20 °C freezer and remained stable for 1 month. Method comparison between two reference laboratories (LC-MS/MS method) was performed and the results showed acceptable data for regression statistics (slope (a) = 0.9184; intercept (b) = −0.1576), t-test statistics (bias = 8.5%) and difference plot. Conclusion An ultrasensitive and derivatization-free LC-MS/MS method was developed and it may be beneficial for patients with endocrine disorders associated with estradiol levels.

TRPV4 Activation and its Intracellular Modulation Mediated by Kinin Receptors Contribute to Painful Symptoms Induced by Anastrozole.

Anastrozole, an aromatase inhibitor, induces painful musculoskeletal symptoms, which affect patients' quality of life and lead to therapy discontinuation. Efforts have been made to understand the mechanisms involved in these painful symptoms to manage them better. In this context, we explored the role of the Transient Receptor Potential Vanilloid 4 (TRPV4), a potential transducer of several nociceptive mechanisms, in anastrozole-induced musculoskeletal pain in mice. Besides, we evaluated the possible sensibilization of TRPV4 by signalling pathways downstream, PLC, PKC and PKCε from kinin B2 (B2R) and B1 (B1R) receptors activation in anastrozole-induced pain. Anastrozole caused mechanical allodynia and muscle strength loss in mice. HC067047, TRPV4 antagonist, reduced the anastrozole-induced mechanical allodynia and muscle strength loss. In animals previously treated with anastrozole, the local administration of sub-nociceptive doses of the TRPV4 (4α-PDD or hypotonic solution), B2R (Bradykinin) or B1R (DABk) agonists enhanced the anastrozole-induced pain behaviours. The sensitizing effects induced by local injection of the TRPV4, B2R and B1R agonists in animals previously treated with anastrozole were reduced by pre-treatment with TRPV4 antagonist. Furthermore, inhibition of PLC, PKC or PKCε attenuated the mechanical allodynia and muscle strength loss induced by TRPV4, B2R and B1R agonists. The generation of painful conditions caused by anastrozole depends on direct TRPV4 activation or indirect, e.g., PLC, PKC and PKCε pathways downstream from B2R and B1R activation. Thus, the TRPV4 channels act as sensors of extracellular and intracellular changes, making them potential therapeutic targets for alleviating pain related to aromatase inhibitors use, such as anastrozole.

Factors associated with adherence to medications for lowering breast cancer risk between female Medicare beneficiaries in Alabama and nationwide.

The U.S. Preventive Services Task Force recommends use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) for breast cancer (BC) prevention. We examined factors associated with adherence to SERMs/AI treatments among female Medicare beneficiaries in Alabama and those nationwide. This retrospective new user cohort study analyzed the 2013-2016 Medicare administrative claims data files (100% Alabama and random 5% national samples). Female Medicare beneficiaries without invasive BC and osteoporosis, continuously enrolled in Medicare Parts A, B, and D for at least 18months (with a 6-month washout and a 12-month follow-up period) in 2013-2016. Among beneficiaries who initiated (6-month washout) any of the SERMs/AIs (tamoxifen, raloxifene, anastrozole, and exemestane), we examined their 1-year treatment adherence using proportion of days covered (PDC) and operationalized as both continuous (0-1) and dichotomized (≥ 80% as adherent and < 80% as non-adherent) outcomes. Multivariable logistic models were used to identify factors associated with adherence (PDC ≥ 80%) among Alabama and national samples, respectively. A total of 885 women in Alabama and 1,213 women in national sample initiated these SERMs/AI treatments. Among those with ≥ 2 prescriptions (n = 479 in Alabama and n = 870 in national sample), Mean PDC was 0.74 [standard deviation (SD) = 0.30] among Alabamian women, similar to those in the national sample [0.71 (SD = 0.31), p = 0.09]. Use of mammography prior to treatment initiation was associated with higher likelihood of adherence to treatments in both samples. Our findings highlight the importance of access to preventive services such as mammography to better adherence to BC preventive treatments among female Medicare beneficiaries.

Indicators of reproduction when using complex use of drugs for spontaneous manifestation of heat in cows for mycotoxicosis

Alimentary infertility is becoming increasingly important due to the toxic effects of mycotoxins, especially zearalenone and deoxynivalenol, which leads to a decrease in the efficiency of the cattle breeding industry, so it is necessary to examine this problem. The purpose of the study was to identify the effect of the complex use of sorbents, acidifiers, and aromatase inhibitors on the reproductive capacity of cows in mycotoxicosis. During the study, clinical methods (general examination) and biochemical methods (serum content of calcium, magnesium, urea, total and direct bilirubin, malonic dialaldehyde, aminotransferase activity) were used. Cows were divided into two groups: the first group was a control group, where no treatment was used, and cows of the second group received a comprehensive treatment method. A decrease in the level of calcium to 1.68±0.53 mmol/L, phosphorus – 0.98±0.16, selenium – 0.64±0.1 mmol/L, an increase in the level of magnesium to 1.15±0.17 mmol/L, an increase in aspartate aminotransferase to 121.33±3.91 units, alataminotransferase to 79.31±6.53 units, and total bilirubin to 10.21±0.55 mmol/l, malone aldehyde up to 8.27±0.41 mmol/L, and ceruloplasmin up to mmol/L 2.14±0.39 in chronic mycotoxicosis caused by zearalenone and deoxynivalenol. When using a complex treatment regimen for animals, a substantial change and approximation to the reference levels of selenium, creatinine, AST, ALT, malonic aldehyde, and ceruloplasmin were established. The use of the proposed treatment regimen increases the fertilising capacity of cows after the 1st calving by 18.15%, cows aged 3-4 years – 30.12%, and cows of the older age group – by 40.47%. A complex method of treatment of cows for mycotoxicosis caused by zearalenone is proposed using an acidifier based on organic acids, a sorbent based on celeolite and an aromatase inhibitor, which can be used in livestock farms for the production of milk and meat of various forms of ownership to restore and normalise the reproductive ability of cows

Classifying invasive lobular carcinoma as special type breast cancer may be reducing its treatment success: A comparison of survival among invasive lobular carcinoma, invasive ductal carcinoma, and no-lobular special type breast cancer.

The literature contains different information about the prognosis of invasive lobular carcinoma of breast cancer (BC). We aimed to address the inconsistency by comparatively examining the clinical features and prognosis of invasive lobular carcinoma patients in our university and to report our experience by dividing our patients into various subgroups. Records of patients with BC admitted to Trakya University School of Medicine Department of Oncology between July 1999 and December 2021 were reviewed. The patients were divided into three groups (No-Special Type BC, Invasive Lobular Special Type BC, No-Lobular Special Type BC). Patient characteristics, treatment methods and oncological results are presented. Survival curves were generated using the Kaplan-Meier method. Statistical significance of survival among the selected variables was compared by using the log-rank test. The patients in our study consisted of 2142 female and 15 male BC patients. There were 1814 patients with No-Special Type BC, 193 patients with Invasive Lobular Special Type BC, and 150 patients with No-Lobular Special Type BC. The duration of disease-free survival (DFS) was 226.5 months for the No-Special Type BC group, 216.7 months for the No-Lobular Special Type BC group, and 197.2 months for the Invasive Lobular Special Type BC group, whereas the duration of overall survival (OS) was 233.2 months for the No-Special Type BC group, 227.9 for the No-Lobular Special Type BC group, and 209.8 for the Invasive Lobular Special Type BC group. The duration of both DFS and OS was the lowest in the Invasive Lobular Special Type BC group. Multivariate factors that were significant risk factors for OS were Invasive Lobular Special Type BC histopathology (p = .045), T stage, N stage, stage, skin infiltration, positive surgical margins, high histological grade, and mitotic index. Modified radical mastectomy, chemotherapy, radiotherapy and use of tamoxifen and aromatase inhibitors for more than 5 years were significant protective factors for overall survival. The histopathological subgroup with the worst prognosis in our study was Invasive Lobular Special Type BC. Duration of DFS and OS were significantly shorter in Invasive Lobular Special Type BC than No-Lobular Special Type BC group. The classification of Invasive Lobular BC under the title of Special Type BC should be reconsidered and a more accurate treatment and follow-up process may be required.

Capecitabine Plus Aromatase Inhibitor as First Line Therapy for Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer.

(1) Background: recent evidence suggests that long low-dose capecitabine regimens have a synergistic effect with endocrine therapy as aromatase inhibitors (AIs), and might increase overall survival for hormone-receptor-positive, HER2-negative, metastatic breast cancer compared to both treatments. We performed a retrospective study to confirm the efficacy and expand the safety data for capecitabine plus AI (a combination henceforth named XELIA) for this indication. (2) We conducted a single-center retrospective cohort study of 163 hormone receptor-positive metastatic breast cancer patients who received either the XELIA regimen, capecitabine, or an aromatase inhibitor (AI) as single agents in first-line treatment. The primary endpoint was progression-free survival, and the secondary endpoints were overall survival, best objective response, and toxicity incidence. (3) Results: the median progression-free survival for patients receiving XELIA, AI, and capecitabine was 29.37 months (20.91 to 37.84; 95% CI), 20.04 months (7.29 to 32.80; 95% CI) and 10.48 (8.69 to 12.28; 95% CI), respectively. The overall response rate was higher in the XELIA group (29.5%) than in the AI (14.3%) and capecitabine (9.1%) groups. However, the differences in overall survival were not statistically significant. Apart from hand-foot syndrome, there were no statistically significant differences in adverse events between the groups. (4) Conclusions: this retrospective study suggests that progression-free survival and overall response rates improved with the XELIA regimen compared to use of aromatase inhibitors and capecitabine alone. Combined use demonstrated an adequate safety profile and might represent an advantageous treatment in places where CDK 4/6 is not available. Larger studies and randomized clinical trials are required to confirm the effects shown in our study.

Development of cardiometabolic risk factors following endocrine therapy in women with breast cancer.

Studies comparing the effect of aromatase inhibitor (AI) and tamoxifen use on cardiovascular disease (CVD) risk factors in hormone receptor-positive breast cancer (BC) survivors report conflicting results. We examined associations of endocrine therapy use with incident diabetes, dyslipidemia, and hypertension. The Pathways Heart Study examines cancer treatment exposures with CVD-related outcomes in Kaiser Permanente Northern California members with BC. Electronic health records provided sociodemographic and health characteristics, BC treatment, and CVD risk factor data. Hazard ratios (HR) and 95% confidence intervals (CI) of incident diabetes, dyslipidemia, and hypertension in hormone receptor-positive BC survivors using AIs or tamoxifen compared with survivors not using endocrine therapy were estimated using Cox proportional hazards regression models adjusted for known confounders. In 8985 BC survivors, mean baseline age and follow-up time was 63.3 and 7.8years, respectively; 83.6% were postmenopausal. By treatment, 77.0% used AIs, 19.6% used tamoxifen, and 16.0% used neither. Postmenopausal women who used tamoxifen had an increased rate (HR 1.43, 95% CI 1.06-1.92) of developing hypertension relative to those who did not use endocrine therapy. Tamoxifen use was not associated with incident diabetes, dyslipidemia, or hypertension in premenopausal BC survivors. Postmenopausal AI users had higher hazard rates of developing diabetes (HR 1.37, 95% CI 1.05-1.80), dyslipidemia (HR 1.58, 95% CI 1.29-1.92), and hypertension (HR 1.50, 95% CI 1.24-1.82) compared with non-endocrine therapy users. Hormone receptor-positive BC survivors treated with AIs may have higher rates of developing diabetes, dyslipidemia, and hypertension over an average 7.8years post-diagnosis.

Indian oncologists’ perception of the benefit of antiestrogen therapy in premenopausal women with hormone receptor positive non-metastatic breast cancer: An implementation science study.

e18726 Background: The findings of SOFT and the TEXT trials confirm the significant benefit of deeper estrogen deprivation via ovarian function suppression (OFS) with tamoxifen (T) or aromatase inhibitors (AI) in reducing risk of recurrence in premenopausal women with hormone receptor (HR) positive breast cancer when compared with the use of tamoxifen alone. However, the decision to treat with a less or more intensive regimen is subjective to the oncologists' perception of benefit or risk. We aimed to investigate Indian oncologists' perception of benefit of various anti-estrogen therapy options in premenopausal women with high risk of recurrence. Methods: We surveyed practicing oncologists in India who treat breast cancer using a cross-sectional survey study design. We asked participants to review a clinical vignette of a young lady who was expected to have a high risk for breast cancer recurrence. We used breast cancer free interval (BCFI) as the outcome in order to compare the results of our study with the clinical trial data from SOFT and TEXT. BCFI was defined as the first occurrence of invasive loco-regional, distant or contralateral breast cancer. Oncologists were asked to designate a number between 0-100 to represent their estimation of 5-year BCFI for women with similar characteristics if they were to receive adjuvant tamoxifen with or without OFS or aromatase inhibitor with OFS. Results: 74 oncologists completed the survey. Indian oncologists estimated the 5-year BCFI for the patient in the vignette at 75.7% with the combined use of aromatase inhibitors and OFS against 64.6% with tamoxifen alone regimen. The 5 years BCFI with the combined use of tamoxifen and OFS was estimated at 71.6% (Table 1). Conclusions: The estimated absolute benefit was much lower than what was found from the two adjuvant OFS trials. An analysis of these trials have shown that patients with high recurrence risk may have an absolute benefit of 10-15% on 5-year BCFI with the use of aromatase inhibitor and OFS compared with tamoxifen alone. The oncologists in our study underestimated the benefit of such an approach. Oncologists' underestimation of the benefit of antiestrogen therapy can have significant detrimental outcomes in the management of young women diagnosed with breast cancer. We believe that such implementation science studies will help close the gap between 'what we know' and 'what we do' as physicians. [Table: see text]

Factors associated with weight gain after breast cancer: Results from a community-based survey of Australian women.

Weight gain after breast cancer is common. The aim of this study was to determine factors associated with weight gain after breast cancer in Australian women. A cross-sectional online survey was conducted between November 2017 and January 2018. Women living in Australia who self-identified as having breast cancer or ductal carcinoma in-situ were eligible. We created stepwise linear and logistic regression models to evaluate predictors for absolute and clinically significant (≥5%) weight gain respectively. Data from 276 women were analysed. Most were Caucasian and 92% had been diagnosed with Stage 0-III breast cancer. Absolute weight gain was associated with hot flushes, being in the menopausal transition at diagnosis, being less physically active than at diagnosis, lower eating self-efficacy when watching television or using a computer, and higher self-efficacy when anxious or nervous (F-ratio=3.26, R2-adjusted=0.16, p<.001). Clinically significant weight gain was associated with tamoxifen use (OR 2.7), being less physically active than at diagnosis (OR 3.1), and lower eating self-efficacy when watching television or using a computer (OR 0.82) (Chi-square 64.94, df=16, p<.001). Weight gain was not associated with chemotherapy, radiotherapy, aromatase inhibitor use, number of lymph nodes removed, or body mass index at diagnosis. Interventions to prevent weight gain after breast cancer, particularly aiming to maintain physical activity, should be targeted at women receiving tamoxifen. The role of eating self-efficacy, especially attentive eating, in managing weight after breast cancer should be explored.

Systemic Therapy of Premenopausal Patients with Early Stage Hormone Receptor-Positive, HER2-Negative Breast Cancer - Controversies and Standards in Healthcare.

In patients with existing ovarian function, there are some special aspects to adjuvant endocrine therapy in premenopausal patients with hormone receptor-positive, HER2-negative (HR pos./HER2 neg.) breast cancer. Treatment options include tamoxifen with or without a GnRH analog, and aromatase inhibitors with a GnRH analog. Furthermore, ovarian function is affected by previous chemotherapy. Both aromatase inhibitors (+GnRH analogs) and GnRH analogs in combination with tamoxifen are supposed to be indicated for patients at increased risk of recurrence. However, national and international guidelines and therapy recommendations do not provide a clear definition of intermediate or high risk; as a result, therapy decisions are often made for each patient on an individual basis. This is also reflected in the considerable variability at national and international levels, e.g., with regard to the use of aromatase inhibitors + GnRH analogs. This review summarizes the data on completed studies (e.g., SOFT, TEXT, EBCTCG meta-analyses) and the current multigene testing studies (TailorX, RxPonder, ADAPT), discusses the rationale for current studies (e.g., CLEAR-B), and looks ahead to future questions.

A Systematic Review of Systematic Reviews on the Use of Aromatase Inhibitors for the Treatment of Endometriosis: The Evidence to Date.

Endometriosis is a chronic gynecologic condition that affects around 6-10% of reproductive age women. This clinical entity is characterized with pelvic pain, dysmenorrhea, dyspareunia, and infertility which are the most often presenting symptoms. Aromatase P450 is the key enzyme for ovarian estrogen biosynthesis and there is evidence that endometriotic lesions express aromatase and are able to synthesize their own estrogens. Aromatase inhibitors (AIs) are potent drugs that suppress the estrogen synthesis via suppression of aromatase. We performed a systematic review of systematic reviews and narrative reviews on the use of aromatase inhibitors in the medical management of endometriosis. We searched: PubMed (1950-2022), Google Scholar (2004-2022), Cochrane Library (2010-2022) and Researchgate (2010-2022). The search included the following medical subject headings (MeSH) or keywords: "Aromatase Inhibitors" AND "Endometriosis" AND "Systematic reviews" OR "Systematic review" AND "Reviews" OR "Reviews" AND "Endometriosis". The electronic database search yielded initially 12,106 studies from the different databases. Further assessment of the studies resulted in exclusion of (n = 12,015) studies due to duplicates and irrelevance; Finally, 24 studies were selected for inclusion, 5 were Systematic reviews and 19 were Narrative reviews. The 5 systematic reviews were assessed by AMSTAR-2 criteria and were found to have low quality. Narrative reviews were assessed with SANRA criteria and were found to have high-quality aromatase inhibitors are potent drugs that can manage the endometriosis-related symptoms in cases where initial medical management has failed to show positive results. However, their use is limited by the adverse effects that are linked with menopausal symptoms. aromatase inhibitors can be administered as an alternative treatment in patients. Future studies with randomized design are required to reach safer conclusions and further investigation. These studies should define the therapeutic dose, new add-back therapy modalities. Future directions should examine the most-appropriate way of administration and the duration of therapy.

Design of Novel Letrozole Analogues Targeting Aromatase for Breast Cancer: Molecular Docking, Molecular Dynamics, and Theoretical Studies on Gold Nanoparticles

The use of aromatase inhibitors is an established therapy for estrogen-dependent breast cancer in postmenopausal women. However, the only commercially available aromatase inhibitor, letrozole, is not highly selective; in addition to aromatase, it has an affinity for binding to desmolase, an enzyme involved in steroidogenesis, which explains the main side effects. Therefore, we designed new compounds based on the structure of letrozole. More than five thousand compounds were constructed based on the letrozole structure. Then, these compounds were screened for their binding ability toward the target protein, aromatase. Quantum docking, Glide docking, and ADME studies showed 14 new molecules with docking scores of ≤−7 kcal/mol, compared to the docking score of −4.109 kcal/mol of the reference, letrozole. Moreover, molecular dynamics (MD) and post-MD MM-GBSA calculations were calculated for the top three compounds, and the results supported in their interaction’s stability. Finally, the density-functional theory (DFT) study applied to the top compound to study the interaction with gold nanoparticles revealed the most stable position for the interaction with the gold nanoparticles. The results of this study confirmed that these newly designed compounds could be useful starting points for lead optimization. Further in vitro and in vivo studies are recommended for these compounds to verify these promising results experimentally.

GRACE-trial: a randomised active-controlled trial for vulvovaginal atrophy in patients with breast cancer on endocrine therapy – study protocol

IntroductionBreast cancer is the most common cancer type in women worldwide. Due to hormone receptor positivity in the majority of the breast cancer tumours is endocrine therapy a crucial part...

Contemporaneous symptom networks and correlates during endocrine therapy among breast cancer patients: A network analysis.

Endocrine therapy-related symptoms are associated with early discontinuation and quality of life among breast cancer survivors. Although previous studies have examined these symptoms and clinical covariates, little is known about the interactions among different symptoms and correlates. This study aimed to explore the complex relationship of endocrine therapy-related symptoms and to identify the core symptoms among breast cancer patients. This is a secondary data analysis conducted based on a multicenter cross-sectional study of 613 breast cancer patients in China. All participants completed the 19-item Chinese version of the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES). Multivariate linear regression analysis was performed to identify significant factors. A contemporaneous network with 15 frequently occurring symptoms was constructed after controlling for age, payment, use of aromatase inhibitors, and history of surgery. Network comparison tests were used to assess differences in network structure across demographic and treatment characteristics. All 613 participants were female, with an average age of 49 years (SD = 9.4). The average duration of endocrine therapy was 3.6 years (SD = 2.3) and the average symptom score was 18.99 (SD = 11.43). Irritability (n = 512, 83.52%) and mood swings (n = 498, 81.24%) were the most prevalent symptoms. Lost interest in sex (mean = 1.95, SD = 1.39) and joint pain (mean = 1.57, SD = 1.18) were the most severe symptoms. The edges in the clusters of emotional symptoms ("irritability-mood swings"), vasomotor symptoms ("hot flashes-cold sweats-night sweats"), vaginal symptoms ("vaginal discharge-vaginal itching"), sexual symptoms ("pain or discomfort with intercourse-lost interest in sex-vaginal dryness"), and neurological symptoms ("headaches-dizziness") were the thickest in the network. There were no significant differences in network structure (P = 0.088), and global strength (P = 0.330) across treatment types (selective estrogen receptor modulators vs. aromatase inhibitors). Based on an evaluation of the centrality indices, irritability and mood swings appeared to be structurally important nodes after adjusting for the clinical covariates and after performing subgroup comparisons. Endocrine therapy-related symptoms are frequently reported issues among breast cancer patients. Our findings demonstrated that developing targeted interventions focused on emotional symptoms may relieve the overall symptom burden for breast cancer patients during endocrine therapy.

Estrogen therapy after breast cancer diagnosis and breast cancer mortality risk

PurposeThe safety of local estrogen therapy in patients on adjuvant endocrine treatment is questioned, but evidence on the issue is scarce. This nested case–control registry-based study aimed to investigate whether estrogen therapy affects breast cancer mortality risk in women on adjuvant endocrine treatment.MethodsIn a cohort of 15,198 women diagnosed with early hormone receptor (HR)-positive breast cancer and adjuvant endocrine treatment, 1262 women died due to breast cancer and were identified as cases. Each case was matched with 10 controls. Exposure to estrogen therapy with concurrent use of aromatase inhibitors (AIs), tamoxifen, or both sequentially, was compared between cases and controls.ResultsNo statistically significant difference in breast cancer mortality risk was seen in patients with exposure to estrogen therapy concurrent to endocrine treatment, neither in short-term or in long-term estrogen therapy use.ConclusionsThe study strengthens current evidence on local estrogen therapy use in breast cancer survivors, showing no increased risk for breast cancer mortality in patients on adjuvant AIs or tamoxifen.

The Role of Aromatase Inhibitors in Male Prolactinoma

dopamine agonists are the recommended treatment for male prolactinomas, but some patients may develop dopamine-agonist-resistant hyperprolactinemia, leading to persistent hypogonadism that requires treatment with testosterone. However, testosterone replacement therapy may be associated with a decrease in the efficacy of dopamine agonists due to the aromatization of testosterone to estradiol, which can stimulate the proliferation and hyperplasia of lactotroph cells in the pituitary, inducing resistance to dopamine agonists. this paper systematically reviewed the role of aromatase inhibitors for men with prolactinoma and dopamine-agonist-resistant or persistent hypogonadism following treatment. we performed a systematic review of all studies (according to PRISMA guidelines), assessing the role of aromatase inhibitors, including anastrozole and letrozole, for male prolactinoma. An English-language search for relevant studies was conducted on PubMed from its inception to 1 December 2022. The reference lists of the relevant studies were also reviewed. our systematic review identified six articles (nine patients), including five case reports and a single case series, on the use of aromatase inhibitors for male prolactinomas. Reducing estrogen levels with an aromatase inhibitor improved sensitivity to dopamine agonists, as the addition of anastrozole or letrozole improves the control of prolactin levels and may lead to the shrinkage of tumors. aromatase inhibitors are of potential value to patients with dopamine-agonist-resistant prolactinoma, or when hypogonadism persists while using high-dose dopamine agonists.

Factors Associated with Cardiorespiratory Fitness in Breast Cancer Survivors from the State of Santa Catarina, Brazil: Cross-Sectional Study

Introduction: Oxygen consumption (VO2) is indicative of cardiorespiratory fitness (CRF) and lower levels are related to a higher risk of total mortality among individuals with cancer whose therapy can have adverse consequences on the cardiovascular system. Objective: To examine the associations of patient-reported sociodemographic, clinical, anthropometric outcomes and functional variables with CRF in 69 women (55±10 years) and to identify whether walking is a predictor of peak VO2 variation in this population with breast cancer (BC). Method: Female BC survivors receiving hormone therapy after two types of surgery (breast-conserving and mastectomy) underwent a CRF test on a cycle ergometer to measure peak VO2. A questionnaire containing sociodemographic, clinical data, patient reported outcomes (PROs) (depressive symptoms, sleep quality, fatigue, body image) and self-reported walking and tests to measure body fat percentage, waist circumference, flexibility and shoulder range of motion (RoM) were performed. Results: Unemployment and retirement were associated with low CRF, as was the use of aromatase inhibitors instead of tamoxifen. Depressive symptoms, worse body image, greater waist circumference, less flexibility and shoulder RoM were also associated with low CRF. Walking duration, controlled for age and body mass index (BMI), is a 13% predictor of peak VO2 variance in this sample. Conclusion: These factors must be considered in understanding the CRF profile of BC survivors. As walking was a predictor of peak VO2 variance, it should be recommended as a type of physical activity for patients with BC using hormone therapy.

Psychological measures of stress and biomarkers of inflammation, aging, and endothelial dysfunction in breast cancer survivors on aromatase inhibitors

The use of aromatase inhibitors (AIs) is associated with higher rates of cardiovascular events and lower endothelial function in breast cancer survivors. Psychosocial stress is associated with higher levels of inflammatory and aging markers, and lower endothelial function in otherwise healthy subjects. These associations among breast cancer survivors on AIs are not well defined. A cross-sectional study of 30 breast cancer survivors on AIs was performed to assess the associations between self-reported scores of psychosocial measures of depression, anxiety, and stress assessed by validated questionnaires with markers of inflammation (CRP; IL-6; IL-18), aging (p16INK4a), and endothelial function (ICAM-1, EndoPAT ratio). Significant positive correlations were observed between psychosocial measures and inflammatory markers including CRP, IL-6, and ICAM-1. However, no psychosocial scores were related to endothelial function or gene expression of the aging biomarker p16INK4a. Overall, survivors had endothelial dysfunction with reduced EndoPAT ratios. Psychosocial stress is associated with greater inflammation in breast cancer survivors on AIs, corroborating previous studies in cancer-free populations. The lack of association between psychosocial stress and either endothelial function or aging biomarkers could be due to the already low endothelial function and accelerated aging in our cohort of breast cancer survivors on AIs, though our small sample size limits conclusions. Further work in a larger and more diverse cohort of patients is needed to further understand the relationships among inflammation, aging and endothelial function in breast cancer survivors.

Synthesis, antiproliferative evaluation and in silico studies of a novel steroidal spiro morpholinone

Estrogens play a pivotal role in the development of estrogen-dependent breast cancer and other hormone-dependent disorders. A common strategy to overcome the pathological effects of estrogens is the use of aromatase inhibitors (AIs), which bind to the enzyme and prevent the union with the natural substrate, decreasing the amount of estrogens produced. Several AIs have been developed, including inhibitors with a steroidal backbone and a nitrogen heterocycle in their structure. Encouraged by the notable results presented by current and clinical steroidal drugs, herein we present the synthesis of a steroidal spiro morpholinone derivative as a plausible aromatase inhibitor.The morpholinone derivative was synthesized over a six-step methodology starting from estrone. The title compound and its hydroxychloroacetamide derivative precursor were evaluated for their antiproliferative profile against estrogen-dependent and independent solid tumor cell lines: A549, HBL-100, HeLa, SW1573, T-47D and WiDr. Both compounds exhibited a potent antiproliferative activity in the micromolar range against the six cancer cell lines, with the hydroxychloroacetamide derivative precursor being a more potent inhibitor (GI50 = 0.25–2.4 µM) than the morpholinone derivative (GI50 = 2.0–11 µM). Furthermore, both compounds showed, in almost all cases, better GI50 values than the steroidal anticancer drugs abiraterone and galeterone.Docking simulations of the derivatives were performed in order to explain the experimental biological activity. The results showed interactions with the iron heme (derivative 3) and important residues of the steroidal binding-site (Met374) for the inhibition of human aromatase. A correlation was found between in vitro assays and the score obtained from the molecular docking study.