Administration Of Aromatase Inhibitor Research Articles

Sleep oscillations related to memory consolidation during aromatases inhibitors for breast cancer

Aromatase inhibitors (AIs) are associated with sleep difficulties in breast cancer (BC) patients. Sleep is known to favor memory consolidation through the occurrence of specific oscillations, i.e., slow waves (SW) and sleep spindles, allowing a dialogue between prefrontal cortex and the hippocampus. Interestingly, neuroimaging studies in BC patients have consistently shown structural and functional modifications in these two brain regions. With the aim to evaluate sleep oscillations related to memory consolidation during AIs, we collected polysomnography data in BC patients treated (AI+, n = 17) or not (AI-, n = 17) with AIs compared to healthy controls (HC, n = 21). None of the patients had received chemotherapy and radiotherapy was finished since at least 6 months, that limit the confounding effects of other treatments than AIs. Fast and slow spindles were detected during sleep stage 2 at centro-parietal and frontal electrodes respectively. SW were detected at frontal electrodes during stage 3. Here, we show lower frontal SW densities in AI + patients compared to HC. These results concord with previous reports about frontal cortical alterations in cancer following AIs administration. Moreover, AI + patients tended to have lower spindle density at C4 electrode. Regression analyses showed that, in both patient groups, spindle density at C4 electrode explained a large variance of memory performances. Slow spindle characteristics did not differ between groups and sleep oscillations characteristics of AI- patients did not differ significantly from those of both AI + patients and HC. Overall, our results add to the compelling evidence of the systemic effects of AIs previously reported in animals, with deleterious effects on cortical activity during sleep and associated memory consolidation in the current study. There is thus a need to further investigate sleep modifications during AIs administration. Longitudinal studies are needed to confirm these findings and investigation in other cancers on this topic should be conducted.

Abstract PO4-19-09: Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20)

Abstract Background The current standard first-line treatment in advanced or metastatic hormone receptor (HR) positive breast cancer is combination of aromatase inhibitor (AI) and cyclin D kinase-4/6 (CDK4/6) inhibitor. Emergence of ESR1 mutation is a key mechanism of resistance during first-line AI + CDK4/6 inhibitor treatment. Selective estrogen receptor downregulator (SERD) such as elacestrant or fulvestrant is suggested as second-line treatment, but the progression-free survival (PFS) outcome of second-line treatment is reported up to 3.78 months in patients who harbour ESR1 mutation. Recently, early switch of AI + CDK4/6 inhibitor to fulvestrant + CDK4/6 inhibitor at the point of rising ESR1 mutation showed prolongation of PFS up to 6 months, suggesting there may be a new strategy to overcome ESR1 mutation by modifying endocrine treatment. SWOG S0226 suggested that upfront fulvestrant + AI is feasible and associated with prolongation of PFS compared to AI alone. After CDK4/6 inhibitor has been introduced to standard treatment, there were no trials evaluating the role of AI + fulvestrant with CDK4/6 inhibitor. In this trial, we investigated triplet combination of AI + fulvestrant + CDK4/6 inhibitor as a treatment to overcome resistant mechanism such as development of ESR1 mutation when compared to current standard treatment of AI + CDK4/6 inhibitor as the first line treatment in HR positive advanced or metastatic breast cancer. Methods This study is a randomized, multicenter, open-label phase II trial comparing AI plus ribociclib versus AI, fulvestrant plus ribociclib in HR-positive advanced or metastatic breast cancer. De novo patients or patients with treatment-free interval (TFI) over 12 months after completion of adjuvant AI can be enrolled. If patients received adjuvant tamoxifen, patients with TFI less than 12 months can be also enrolled for the study. Prior endocrine treatment or cytotoxic chemotherapy at metastatic setting was not allowed. In cases of premenopausal women, gonadotropin releasing hormone agonist (GnRHa) is administered every 4 weeks with treatment. A total of 202 patients will be enrolled for 30 months, and 30 months of follow-up is planned after last-patient enrolment. Patients are randomized to 1:1, stratified based on the presence of visceral metastasis and previous administration of adjuvant AI. Study treatment of the control arm consists of letrozole 2.5mg daily with ribociclib 600mg (Day 1-Day 21 daily by month, 1 week off) until progression. In the experimental arm fulvestrant 500mg intramuscular injection is added (Day 1, Day 15, Day 29 and every 4 weeks thereafter) until progression. For exploratory analysis of ESR1 mutations, circulating tumor DNA (ctDNA) is collected at baseline, and then every 3 months thereafter. Primary endpoint is to evaluate the difference of 24-months PFS rate. Secondary endpoint included PFS, overall survival (OS), emergence and frequency of ESR1 mutation, overall response rate (ORR) and clinical benefit rate (CBR). The analysis is planned after completion of 30 months of follow-up, which provides approximately 90% power to detect superiority 24 months-PFS rate assumed by Kaplan-Meier curve of letrozole + fulvestrant + ribociclib versus letrozole + ribociclib using a log-rank test, assuming a hazard ratio of 0.64 at a two-sided alpha of 0.2. Citation Format: Jieun Lee, Su-Jin Koh, Jung Hye Kwon, Gun Min Kim, Jee Hung Kim, Ho Young Kim, Hee-Jun Kim, Keon-Uk Park, Kyong Hwa Park, Yeon Hee Park, Mi Sun Ahn, Hee Kyung Ahn, Gyeong-Won Lee, Kyoung Eun Lee, Kyung-Hun Lee, Moon Hee Lee, Sung Sook Lee, Jung Lim Lee, Kyung Hae Jung, Joo Young Jung, In Hae Park. Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-09.

Locally Advanced Breast Cancer Patient’s Recurrence Rates Comparison Received Steroidal and Nonsteroidal Aromatase Inhibitor Based on Luminal

ABSTRACT Introduction: Aromatase inhibitors are hormonal therapies used in menopausal breast cancer with positive progesterone receptors and/or estrogen receptors. A third-generation aromatase inhibitor is divided into two categories: reversible nonsteroids and irreversible steroids. According to the previous studies, there are no consistent research findings on the recurrence after aromatase inhibitor therapy in luminal-type locally advanced breast cancer (LABC). Methods: This study is an analytical observational study with a retrospective cohort design. The data taken are secondary data from medical records on patient visits with luminal-type LABC in the oncology clinic in 2018–2021. The statistical test was the Chi-square test to determine the relationship between age, luminal subtype, radiotherapy, steroid and nonsteroid aromatase inhibitors, and the recurrence rate. Results: It was found that 30% of luminal B patients who received steroidal aromatase inhibitor and 68.43% who received nonsteroidal aromatase inhibitor experienced recurrence, with an odds ratio (OR) of 5.056 (1.560–16.384; P = 0.012). Meanwhile, in luminal A patients, 17.2% of patients who received steroidal aromatase inhibitor and 68.2% who received nonsteroidal aromatase inhibitor experienced recurrence, with an OR of 10.286 (2.757–38.370; P = 0.000). Based on multivariate analysis, the luminal type had no significant impact on the increased risk of recurrence (P = 0.141), but the administration of aromatase inhibitor had a significant impact (P = 0.000). Conclusion: Luminal A LABC patients who received nonsteroidal aromatase inhibitors had a 10.286-fold higher risk of recurrence compared to those who received steroidal aromatase inhibitors.

Compliance and tolerability of breast cancer patients to aromatase inhibitors administration

Compliance and tolerability of breast cancer patients to aromatase inhibitors administration

FRI323 Prolactinoma Recurrence With Testosterone Treatment In Transgender Male

Abstract Disclosure: N. Arnouk: None. P.R. Schroeder: None. Introduction: We present a case of recurrent hyperprolactinemia due to testosterone treatment for gender-affirming hormonal therapy in a transgender male after being controlled on cabergoline for more than a year. Case: A 27-year-old female with history of HTN and polycystic ovary syndrome was diagnosed with pituitary microadenoma after hospital admission for headache and blurry vision. MRI brain showed a mass in the sella and right parasella measuring 36 mm W x 36 mm D x 44 mm H. Hormonal workup showed prolactin (PRL) >999 ng/mL in the diluted assay. The patient was treated medically with cabergoline and discharged home. PRL level improved to 22 ng/mL on treatment. Cabergoline was continued at 0.5 mg twice weekly. The patient was lost to follow-up but returned to clinic after 8 months with PRL level of 58 ng/mL. Cabergoline 0.5 mg twice weekly was continued. PRL level monitoring every ∼6 weeks showed an increase to 184 ng/mL and then 199 ng/mL. Cabergoline was increased to 1 mg twice weekly. PRL level 1 month later was 222 ng/mL. Repeat brain MRI showed markedly decreased microadenoma 4.8 X 2.6 mm. The patient was asymptomatic with no headache, blurry vision, or galactorrhea. On further questioning, the patient reported starting transgender female to male testosterone cypionate 200 mg/mL once weekly for the past 6 months. After discussion with the primary care provider who was managing testosterone treatment, he was started on 60 mg weekly, and the dose was gradually increased to 80 mg weekly to stop the menstrual period. With the 60-mg weekly cypionate dose, the testosterone level was 346 pg/mL, and PRL level was 184 ng/mL. With the cypionate dose of 80 mg weekly, PRL increased to 194 ng/mL and 222 ng/mL. The cypionate dose was decreased to 60 mg weekly, based on literature noting elevated PRL level with testosterone replacement in patients with prolactinoma and hypogonadism. Based on repeat blood work showing elevated testosterone 366 pg/mL with PRL 318 ng/mL, the plan is to start an aromatase inhibitor. Discussion: Testosterone treatment as hormonal affirming therapy in some transgender female to male patients may exacerbate pre-existing hyperprolactinemia or induce PRL secretion, thus close monitoring is required. Testosterone is aromatized to estradiol, which then stimulates the release of PRL from the pituitary gland. The serial measurement of estradiol may serve as an index of aromatization. Hyperprolactinemia in this setting is resistant to dopamine agonist therapy, as noted in multiple case reports. There are no established reference ranges for PRL levels for transgender patients on gender-affirming hormone therapy and no current guidelines regarding routine imaging or biochemical assessment during follow-up. Transgender patients with prolactinoma may require additional treatment with non-aromatizable androgens or the concomitant administration of aromatase inhibitors. Presentation: Friday, June 16, 2023

Efficacy of Aromatase Inhibitors for Azoospermia Caused by AZFc Microdeletion: A Cross-Sectional Descriptive Research Study in Chinese Population

Background. Aromatase inhibitors (AIs) can significantly improve semen parameters in infertile men. In this study, we investigated the efficacy of AIs for azoospermia in a Chinese population with AZFc microdeletion. Aims. Patients with AZFc microdeletion who were treated with AIs were analyzed retrospectively by collecting clinical data, including their hormone profile and treatment outcome. Patients were divided into those with sperm in their semen after AI treatment (group A) and those without sperm in their semen after AI treatment (group B). Results. The rate of Y chromosome AZF microdeletions was 9.30% (313/3364) from March 2015 to March 2021, among which patients with complete AZFc microdeletion accounted for 63.2% (198/313), and of the 198 patients with AZFc microdeletion, 69.7% (138/198) showed azoospermia. Forty-six (33.3%) of the azoospermic patients had sperm in their semen after AI administration. Testosterone (T) and testosterone-to-estradiol ratio (T/E2) levels were higher in group A than those in group B after treatment, and the differences were significant (T, P = 0.038 ; T/E2, P = 0.004 ). Paired t -test demonstrated that the change of T levels before and after treatment was statistically significant ( P = 0.003 ). The increased E2 and T/E2 ratio levels before and after treatment were not statistically significant ( P = 0.057 and 0.080), but they were close to the threshold value ( P = 0.05 ). Conclusions. Patients with AZFc microdeletion accounted for the largest proportion of male infertility caused by Y chromosome microdeletions. AIs can promote spermatogenesis in azoospermic patients with AZFc microdeletion, and sperm could be found in the semen of some patients after AI administration. T and T/E2 levels after AI treatment could be used as biomarkers to distinguish azoospermic patients with AZFc microdeletion who responded better to AIs from those who did not respond well.

First Data on Sexual Dimorphic Growth of Cultured Pacific Bluefin Tuna, Thunnus orientalis (Temminck et Schlegel), and Its Sex Manipulation by Treatment with an Aromatase Inhibitor

Tuna (genus Thunnus), particularly Pacific bluefin tuna (T. orientalis; PBT), are commercially important fish in the aquaculture industry worldwide. The objective of this study was to investigate sexual dimorphism in the growth performance of aquaculture-produced PBT and develop techniques for its sex manipulation, for the first time in tuna. A comparison of the body size between sexes revealed that male-cultured PBTs were larger than females at harvest. We also confirmed that cyp19a1a (encoding a gonadal aromatase) expression increased specifically in the genotypic female PBT gonads during sex differentiation. This suggested that aromatase plays an important role in ovarian differentiation and that the suppression of aromatase activity may effectively induce masculinization in genotypic females. Therefore, we administered letrozole—an aromatase inhibitor (AI)—into sexually undifferentiated PBT through the oral route. AI administration resulted in a 100% sex reversal of genotypic females into phenotypic males at the molecular level. Our results provide the basis for future studies on the establishment of mono-sex male production technology in PBT, which would help improve the productivity of closed-cycle PBT aquaculture. Furthermore, this study offers important insights into the understanding of the sex-wise growth of tuna species in aquacultural settings, and developing sex manipulation techniques.

ATAC-seq and RNA-seq analysis unravel the mechanism of sex differentiation and infertility in sex reversal chicken

BackgroundSex determination and differentiation are complex and delicate processes. In female chickens, the process of sex differentiation is sensitive and prone to be affected by the administration of aromatase inhibitors, which result in chicken sex reversal and infertility. However, the molecular mechanisms underlying sex differentiation and infertility in chicken sex reversal remain unclear. Therefore, we established a sex-reversed chicken flock by injecting an aromatase inhibitor, fadrozole, and constructed relatively high-resolution profiles of the gene expression and chromatin accessibility of embryonic gonads.ResultsWe revealed that fadrozole affected the transcriptional activities of several genes, such as DMRT1, SOX9, FOXL2, and CYP19A1, related to sex determination and differentiation, and the expression of a set of gonadal development-related genes, such as FGFR3 and TOX3, by regulating nearby open chromatin regions in sex-reversed chicken embryos. After sexual maturity, the sex-reversed chickens were confirmed to be infertile, and the possible causes of this infertility were further investigated. We found that the structure of the gonads and sperm were greatly deformed, and we identified several promising genes related to spermatogenesis and infertility, such as SPEF2, DNAI1, and TACR3, through RNA-seq.ConclusionsThis study provides clear insights into the exploration of potential molecular basis underlying sex differentiation and infertility in sex-reversed chickens and lays a foundation for further research into the sex development of birds.

P–616 Novel approaches for preventing ovarian hyperstimulation syndrome in breast cancer patients

Abstract Study question In this study we tried to assess the effectiveness of the use of aromatase inhibitors (AI) for the rapid relief of symptoms of hyperstimulation in patients with breast cancer. Summary answer AI showed great efficiency for OHSS prevention and are particulary useful in fertility preservation, when supraphysiologic estradiol levels cause a negative impact and delay treatment. What is known already To date the only unequivocally accepted method for fertility preservation is cryopreservation of embryos and unfertilized oocytes. However, controlled ovarian stimulation is associated with supraphysiological serum estradiol level. The majority of guidelines recommend to use aromatase inhibitors during ovarian stimulation (OS) in breast cancer patients with high estrogen receptor expression to protect them from the potential deleterious effects of elevated estrogen. Following oocyte retrieval the patients will be receiving chemotherapy, which is not desirable for hyperstimulated ovaries. The prolonged use of AI seems to be an interesting approach in such cases. Study design, size, duration This research was conducted at the V.I. Kulakov NMRC for OG&P to demonstrate management tactics for OHSS prevention after OS in patients with breast cancer. It included 21 patients seeking cryopreservation of oocytes and embryos. The main outcomes included the results of dynamic steroidogeneses assessment, the size of the ovaries, main features of oogenesis and the onset of the menstrual blleding. All patients signed an informed consent form approved by Ethics Committee. Participants/materials, setting, methods The mean age of the participants was 26.7. The patients presented prior to gonadotoxic treatment for luminal A or B breast cancer, were randomly divided into two groups of 11 and 10 people and underwent conventional OS with letrozol (2.5 mg/day). Starting from the day of oocyte retrieval the AI dosage iIn the 1st group was increased to 0.75 mg/day; the 2nd group received GnRH antagonist (0.5 mg/day) instead of AI for 5 consecutive days. Main results and the role of chance The mean age, BMI and AMH were not different among groups. There was no statistically significant difference in the duration of stimulation and starting and total doses of gonadotropins. The mean number of retrieved oocytes was 15.3 for the 1st group and 16.1 for the 2nd group (p = 0.834). There was no significant difference in a number of mature oocytes between the groups (66.1% vs. 72.4% in the 2nd group, p = 0.059) or in how many of them formed into 2pn embryos after fertilization (80% vs. 73.9% in the 2nd group, p = 0.616). Steroid hormone levels were analyzed during OS and on days 2 and 5 after oocyte retrieval. The rapid decline in serum estradiol and progesterone levels manifested with ovary size reduction and the onset of menstrual bleeding, which were achieved on 3rd to 5th day of AI administration in the 1st group and on 5th to 7th day of GnRH antagonist administration in the 2nd group. Limitations, reasons for caution Further research is required to compare the mechanisms of luteolysis induced by aromatase inhibitors and GnRH antagonists to natural luteal regression. Wider implications of the findings: Our data has demonstrated a greater efficiency of AI compared to GnRH antagonists in reducing the risk of OHSS. These findings could be useful for future research and clinical use in patients without cancer but with a high risk of developing OHSS combined with segmentation of IVF treatment. Trial registration number none

Does the Time of Day at Which Endocrine Therapy Is Taken Affect Breast Cancer Patient Outcomes?

Background: Non-compliance and non-persistence with endocrine therapy for breast cancer is common and usually related to treatment-induced side effects. There are anecdotal reports that simply changing the time of day when taking endocrine therapy (i.e., changing morning dosing to evening dosing or vice versa) can reduce side effects. Literature review: We conducted a literature review to evaluate whether changing the timing of tamoxifen and/or aromatase inhibitor administration impacted patient outcomes. No randomized control trials or prospective cohort studies that looked at time of day of endocrine therapy were identified through our review of literature from 1947 until August 2020. Conclusions: Given the rates of endocrine therapy non-compliance and non-persistence reported in the literature, ranging from 41–72% and 31–73%, respectively, simply changing the time of day when medications are taken could be an important strategy. We could identify no trials evaluating the effect of changes in timing of administration of endocrine therapy on breast cancer patient outcomes. Randomized control trials are clearly indicated for this simple and cost-effective intervention.

Comparison of Recurrence Rates in Patients with Locally Advanced Breast Cancer after Mastectomy and Received Aromatase Inhibitor Therapy with Steroids and Nonsteroids

Introduction. Breast cancer is a problem that is still faced throughout the world. The incidence of cancer in Indonesia is at number 8 in Southeast Asia. The incidence of breast cancer in women is 42.1 per 100,000 population. Aromatase inhibitors are hormonal therapy used in postmenopausal breast cancer with positive ER and/or positive PR. The third generation aromatase inhibitors are divided into 2 categories, namely non-steroidal agents that are reversible and steroid agents that are irreversible. Based on existing studies, there are no consistent research results regarding the incidence of recurrence after aromatase inhibitor therapy, both steroids and non-steroidal.
 Methods. This study is an analytical observational study with a retrospective cross-sectional design using secondary data from medical records. The research was carried out at the Surgical Clinic of RSUD dr. Soetomo Surabaya on October 1, 2020 until the end with the subject of LABC patients at POSA Surgery RSUD Dr. Soetomo who has undergone mastectomy and radiotherapy and has received adjuvant hormonal aromatase inhibitor therapy for 2 years from January 2018 to January 2020.
 Results. In the nonsteroidal aromatase inhibitor group, 18 subjects (60%) experienced recurrence and 16 subjects in the steroid aromatase inhibitor group (32%) with an OR of 0.314 (0.12-0.81; p=0.014. Based on the results of multivariate analysis, it was found that the increased risk of recurrence was significantly affected only by the administration of aromatase inhibitor p= 0.052
 Conclusion. Women with locally advanced breast cancer after mastectomy who received aromatase inhibitor steroid therapy had a 0.314 times lower risk of recurrence than those who received non-steroidal aromatase inhibitor therapy.

Comparison of Recurrence Rates in Patients with Locally Advanced Breast Cancer after Mastectomy and Received Aromatase Inhibitor Therapy with Steroids and Nonsteroids

Introduction. Breast cancer is a problem that is still faced throughout the world. The incidence of cancer in Indonesia is at number 8 in Southeast Asia. The incidence of breast cancer in women is 42.1 per 100,000 population. Aromatase inhibitors are hormonal therapy used in postmenopausal breast cancer with positive ER and/or positive PR. The third generation aromatase inhibitors are divided into 2 categories, namely non-steroidal agents that are reversible and steroid agents that are irreversible. Based on existing studies, there are no consistent research results regarding the incidence of recurrence after aromatase inhibitor therapy, both steroids and non-steroidal.
 Methods. This study is an analytical observational study with a retrospective cross-sectional design using secondary data from medical records. The research was carried out at the Surgical Clinic of RSUD dr. Soetomo Surabaya on October 1, 2020 until the end with the subject of LABC patients at POSA Surgery RSUD Dr. Soetomo who has undergone mastectomy and radiotherapy and has received adjuvant hormonal aromatase inhibitor therapy for 2 years from January 2018 to January 2020.
 Results. In the nonsteroidal aromatase inhibitor group, 18 subjects (60%) experienced recurrence and 16 subjects in the steroid aromatase inhibitor group (32%) with an OR of 0.314 (0.12-0.81; p=0.014. Based on the results of multivariate analysis, it was found that the increased risk of recurrence was significantly affected only by the administration of aromatase inhibitor p= 0.052
 Conclusion. Women with locally advanced breast cancer after mastectomy who received aromatase inhibitor steroid therapy had a 0.314 times lower risk of recurrence than those who received non-steroidal aromatase inhibitor therapy.

Aromatase and CDK4/6 Inhibitor-Induced Musculoskeletal Symptoms: A Systematic Review.

Simple SummaryAromatase inhibitor-induced musculoskeletal symptoms (AIMSS) occurs in up 50% of postmenopausal patients and is the reason for treatment discontinuation in 25% of patients with breast cancer. CDK4/6 inhibitors have been established in the treatment of hormone receptor-positive (HR) breast cancer. We aimed to assess the effect of treatment with CDK4/6 inhibitors on AIMSS. Arthralgia rate was lower in patients receiving aromatase inhibitors (AIs) in combination with CDK4/6 inhibitors (5.8–33.3%) compared with monotherapy with AIs (1–47%). Myalgias, back pain and bone pain also tended to be reduced in patients treated with CDK4/6 inhibitors. CDK4/6 inhibitors may alleviate musculoskeletal pain caused by AIs, although further studies are warranted.Background: Treatment with aromatase inhibitors (AIs) is fundamental in women with hormone receptor-positive breast cancer in the adjuvant as well as the metastatic setting. Even though it is considered to be a well-tolerated therapy, aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) is the most common adverse event encountered by breast cancer patients. CDK4/6 inhibitors have emerged as a new treatment strategy in metastatic hormone receptor-positive breast cancer. However, the impact of CDK4/6 inhibitors on musculoskeletal symptoms caused by AIs is not well-defined. Objectives: This systematic review aims to identify the frequency of joint symptoms induced by treatment with AIs and CDK4/6 inhibitors in the metastatic setting. Search strategy: Eligible articles were identified by a search of existing literature for the period 2005/01/01–2021/01/01; The algorithm consisted of a predefined combination of the following keywords “breast”, “cancer”, “aromatase inhibitors”, “CDK4/6”, “phase III”. Selection criteria: This study was performed in accordance with PRISMA guidelines. All randomized controlled Phase III trials (RCTs) evaluating the administration of third-generation aromatase inhibitors (AIs) and CDK4/6 inhibitors in postmenopausal women in the metastatic setting were considered eligible for this review. Data collection: Overall, 16 randomized control trials (RCTs) were retrieved, of which nine studies explored the administration of AIs in the metastatic setting and seven studies investigated the combination of CDK4/6 inhibitors and AIs. Arthralgia was reported in 1–47% of patients treated with AIs and 5.8–33.3% of patients treated with CDK4/6 inhibitors. Myalgias occurred in 2–23.7% of patients receiving AIs compared with 4.8–11.9% of patients treated with CDK4/6 inhibitors. The incidence of back pain was 7–32.9% vs. 2.9–8.5% in postmenopausal women with metastatic disease treated with AIs and CDK4/6 inhibitors, respectively. Bone pain was reported in 7–32.9% of postmenopausal women treated with AIs and 2.9–8.5% of women treated with CDK4/6 inhibitors. Conclusions: AI treatment-induced musculoskeletal syndrome is an adverse event affecting over one-third (20–47%) of postmenopausal patients treated with AIs that often leads to treatment discontinuation. Data from RCTs provide evidence that the incidence of musculoskeletal symptoms is relatively decreased upon CDK4/6 inhibitor administration. CDK4/6 inhibitors may provide a protective role against AIMSS development.

Lack of interaction between prenatal stress and prenatal letrozole to induce same-sex preference in male rats

Same-sex partner preference between males has been observed in all species in which this behavior has been studied. Disruption of brain estradiol synthesis during development has been proposed as one of the biological causes underlying this behavior in some mammals. In support of this possibility, perinatal administration of aromatase inhibitors (such as letrozole) to male rat pups, induces around half of them to have same-sex preference and female sexual behavior in adulthood. Another putative factor that modifies sex preference is prenatal stress. Several stress protocols, applied to the pregnant dam, cause some of the adult male progeny to have an increased male preference, a decreased preference for the female, and lordosis behavior. Interestingly, these effects of stress might be mediated by its inhibitory action on brain aromatase. The aim of the present study was to analyze a possible interaction between these two factors in male rats. Pregnant dams were exposed to one of the four treatments across gestation days 10–22 (G10–G22): 1) vehicle-treated non-stressed controls; 2) letrozole (0.56 µg/kg); 3) 30 min immobilization stress); 4) both letrozole and stress combined. The male offspring were tested in adulthood for partner preference in a three-chambered arena, where we also recorded the masculine and feminine sexual behaviors. One week later males were tested for masculine and feminine sexual behavior in cylindrical arenas where they interacted for 30 min with a receptive female and thereafter with a sexually active male for another 30 min. Letrozole, stress and their combination resulted in same-sex preference in 40, 31 and 50% of males, respectively, compared to 5% in the control group. In the sexual behavior tests, prenatal stress reduced the percentage of males displaying intromissions and ejaculation (impaired masculinization), while letrozole mainly increased lordosis (impaired defeminization). The males prenatally submitted to stress and treated with letrozole presented these behavioral features but did not differ from both treatments given independently. The results indicate that the changes induced by stress or the aromatase inhibition produced by letrozole only accounts for a shift in partner preference in around half of the males and that there was no interaction between these two factors.

Quality of life and psychological functioning in postmenopausal women undergoing aromatase inhibitor treatmentfor early breast cancer.

IntroductionAromatase inhibitors (AIs) dramatically increased breast cancer (BC) survival, leading to enhanced attention to their long-term consequences on psychological functioning. Conflicting data has been examined regarding the association between AIs administration and the clinical psychological features in BC survivors (BCSs).PurposeAs psychological symptoms often occur in such chronic diseases, our study aimed at exploring anxious and depressive symptoms and the perceived quality of life (QoL) in BCSs assessed for osteoporosis.MethodsThe total sample consisted of a clinical sample of 51 outpatient postmenopausal women, diagnosed with BC, and a control group composed of 51 healthy postmenopausal women. All recruited participants were evaluated through the clinical gold standard interview and completed the following self-rating scales: the Hamilton Anxiety Rating Scale, Beck Depression Inventory II edition, and 36-Item Short Form Health Survey, which were administered at baseline and after 6 months in BCSs in AIs treatment, compared with controls. Moreover, all participants were assessed for vitamin D status, bone mineral density (BMD) and subclinical vertebral fractures. Data regarding age, age at menopause, body mass index (BMI), smoking habits and alcohol consumption was collected.ResultsBCSs (n = 51) showed higher anxious and depressive symptoms, and lower perceived QoL vs. controls (n = 51) (p<0.05 for all). After 6 months of treatment with AIs, BCSs showed significant reduction of anxious and depressive symptoms and a significantly higher perceived QoL for both physical and mental components, vs. controls.ConclusionsThe improvement of clinical psychological features and perceived QoL was associated with AIs treatment in women being treated with, for early breast cancer. Further studies are needed to obtain a deeper comprehension of the correlation between clinical psychological and physical features in BCSs.

Abstract ES8-1: Adjuvant endocrine therapy in 2020: It's complicated

Abstract Adjuvant endocrine therapy in 2020: It’s complicated Data regarding the use of adjuvant endocrine therapy in patients with hormone receptor-positive early breast cancer has grown over the past decades, and yet still uncertainty remains in management recommendations. In pre-menopausal women, treatment decisions are often driven by estimation of risk of recurrence, measured in terms of clinical and pathological parameters, algorithm-based prognostic modelling derived from breast cancer registries, molecular profiling and gene signature assays. Despite these significant advances, risk of distant disease recurrence is still over-estimated in a significant proportion of women. The addition of ovarian suppression to tamoxifen in pre-menopausal women has been shown to increase rates of both disease-free survival and overall survival than tamoxifen alone, with the use of the steroidal aromatase inhibitor exemestane producing further higher rates of freedom from recurrence. However, the addition of ovarian suppression in this generally low-risk population comes at the cost of increased adverse events and potential to interpose child-bearing years. Further to this, the SOFT/TEXT studies mandated five years of active treatment; little is known as to whether extended treatment beyond those five years would be comparatively equal, better or worse in terms of outcome endpoints. In the post-menopausal population, the updated ASCO Clinical Practice Guideline suggests that all women with node-positive disease should be offered extended therapy including an aromatase inhibitor for a total of ten years, as well as women with node-negative disease possessing high-risk prognostic factors. The question of how best to identify those women who may fare equally well with de-escalated, shorter therapy remains open. The issue of adverse events and drug-related side effects, particularly in the setting of extended therapy, is relevant and may impact negatively on overall treatment compliance and quality of life. As such, the choice of endocrine therapy remains an important consideration, as is evidence that intermittent administration of aromatase inhibitors may be feasible in selected patients. CDK4/6 inhibitors, administered in tandem with endocrine therapy, have radically changed the approach to managing metastatic endocrine receptor-positive disease. There is now much interest in moving these agents forward into the neoadjuvant and adjuvant setting, with a number of phase II and III trials ongoing. If positive data is consistently reported in adjuvant studies, this will undoubtedly create another layer of complexity to the clinical management of endocrine-sensitive disease. Citation Format: A McCartney, A Di Leo. Adjuvant endocrine therapy in 2020: It's complicated [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES8-1.

A higher incidence of smooth endoplasmic reticulum clusters with aromatase inhibitors.

PurposeThis study aimed to analyze whether a regimen of aromatase inhibitor (AI) could reduce the occurrence of smooth endoplasmic reticulum clusters (sERCs) in oocytes.Method(s)The AI and the clomiphene citrate (CC) regimens were compared, regarding the sERC (+) rates and the serum estradiol and progesterone levels on the date of hCG administration, and the duration of AI, CC, and hMG administration.Result(s)The occurrence of sERCs in oocytes from patients treated with AI was significantly higher than that in oocytes from those treated with CC. Both the serum estradiol and progesterone levels were found to be significantly higher in sERC (+) than in sERC (‐) cycles. With regard to the CC cycles, no significant differences were detected. The duration of AI and hMG administration was longer for sERC (+) than for sERC (‐) cycles.ConclusionAs AI did not reduce the occurrence of sERCs, the elevation of estradiol may not be the cause of sERC occurrence but a consequence. Considering the higher levels of progesterone and longer duration of hMG in sERC (+) cycles, the negative effects of premature luteinization, which frequently occur with the AI protocol, should be investigated further.

Adverse Effects of Aromatase Inhibition on the Brain and Behavior in a Nonhuman Primate.

Breast cancer patients using aromatase inhibitors (AIs) as an adjuvant therapy often report side effects, including hot flashes, mood changes, and cognitive impairment. Despite long-term use in humans, little is known about the effects of continuous AI administration on the brain and cognition. We used a primate model of human cognitive aging, the common marmoset, to examine the effects of a 4-week daily administration of the AI letrozole (20 μg, p.o.) on cognition, anxiety, thermoregulation, brain estrogen content, and hippocampal pyramidal cell physiology. Letrozole treatment was administered to both male and female marmosets and reduced peripheral levels of estradiol (E2), but unexpectedly increased E2 levels in the hippocampus. Spatial working memory and intrinsic excitability of hippocampal neurons were negatively affected by the treatment possibly due to increased hippocampal E2. While no changes in hypothalamic E2 were observed, thermoregulation was disrupted by letrozole in females only, indicating some impact on hypothalamic activity. These findings suggest adverse effects of AIs on the primate brain and call for new therapies that effectively prevent breast cancer recurrence while minimizing side effects that further compromise quality of life.SIGNIFICANCE STATEMENT Aromatase inhibitors (AIs) are used as an adjuvant therapy for estrogen-receptor-positive breast cancer and are associated with side effects, including hot flashes, depression/anxiety, and memory deficits severe enough for many women to discontinue this life-saving treatment. AIs are also used by men, yet sex differences in the reported side effects have not been systematically studied. We show that AI-treated male and female marmosets exhibit behavioral changes consistent with these CNS symptoms, as well as elevated hippocampal estradiol and compromised hippocampal physiology. These findings illustrate the need for (1) a greater understanding of the precise mechanisms by which AIs impact brain function and (2) the development of new treatment approaches for breast cancer patients that minimize adverse effects on the brain.

Cognitive Effects of Aromatase and Possible Role in Memory Disorders.

Diverse cognitive functions in many vertebrate species are influenced by local conversion of androgens to 17β-estradiol (E2) by aromatase. This enzyme is highly expressed in various brain regions across species, with some inter-species variation in terms of regional brain expression. Since women with breast cancer and men and women with other disorders are often treated with aromatase inhibitors (AI), these populations might be especially vulnerable to cognitive deficits due to low neuroE2 synthesis, i.e., synthesis of E2 directly within the brain. Animal models have been useful in deciphering aromatase effects on cognitive functions. Consequences of AI administration at various life cycle stages have been assessed on auditory, song processing, and spatial memory in birds and various aspects of cognition in rodent models. Additionally, cognitive deficits have been described in aromatase knockout (ArKO) mice that systemically lack this gene throughout their lifespan. This review will consider evidence to date that AI treatment in male and female rodent models, birds, and humans results in cognitive impairments. How brain aromatase regulates cognitive function throughout the lifespan, and gaps in current knowledge will be considered, along with future directions to better define how aromatase might guide learning and memory from early development through the geriatric period. Better understanding the importance of E2 synthesis on neurobehavioral responses at various ages will likely aid in the discovery of therapeutic strategies to prevent potential cognitive deficits, including Alzheimer's Disease, in individuals treated with AI or those possessing CYP19 gene polymorphisms, as well as cognitive effects of normal aging that may be related to changes in brain aromatase activity.

Aromatase inhibitor use during ovarian stimulation suppresses growth of uterine endometrial cancer in xenograft mouse model.

Could aromatase inhibitors (AI) be used to reduce risks of uterine endometrial cancer growth or recurrence during ovarian stimulation? In a xenograft mouse model of endometrial cancer, concomitant AI administration suppressed the growth of endometrial cancer during ovarian stimulation. Recurrence and mortality rates of estrogen receptor-positive early breast cancer are reduced by long-term AI administration. Concomitant AI use for ovarian stimulation in patients with breast cancer is recommended for reducing estrogen-related potential risks. However, the efficacy of concomitant AI use for estrogen receptor-positive endometrial cancer have not been demonstrated conclusively by clinical or experimental animal studies. Forty nude mice xenografted with uterine endometrial cancer cells were allocated to four groups. Group 1: no ovarian stimulation (control). Group 2: ovarian stimulation. Group 3: AI administration + ovarian stimulation. Group 4: ovariectomy and ovarian stimulation. Tumor growth was evaluated during the 6-week treatment period. Ishikawa 3-H-12 uterine endometrial cancer cells (estrogen and progesterone receptors-positive) were transplanted into 6-week-old BALB/cSlc-nu/nu nude mice, followed by interventions 2 weeks later. Compared to ovarian stimulation alone (Group 2), significant suppressions of tumor growth were observed in other three groups (Groups 1, 3 and 4, all at P < 0.05) and correlated with estrogen levels. AI administration had no apparent impact on embryo development. In this study, we examined the growth of endometrial cancer tumors using one endometrial cancer cell line. Clinical endometrial cancer or hyperplasia cells can have diverse origins and AI may not be effective against other cancer cell types. Concomitant AI use may provide a chance for safer childbirth by for patients with endometrial cancer or hyperplasia. This study was supported by the Graduate Student Aid from the St. Marianna University School of Medicine. The authors declare no competing interests.