Ribociclib plus Endocrine Therapy in Early Breast Cancer.

BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer.

BACKGROUND: In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known. METHODS: Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings. RESULTS: After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed. CONCLUSIONS: First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.).

Ameliorating effects of adropin on letrozole-induced polycystic ovary syndrome via regulating steroidogenesis and the microbiota inflammatory axis in rats.

Growing evidence supports the role of gut microbiota in chronic inflammation, insulin resistance (IR) and sex hormone production in polycystic ovary syndrome (PCOS). Adropin plays a pivotal role in the regulation of glucose and lipid metabolism and is negatively correlated with IR, which affects intestinal microbiota and sex hormones. However, the effect of adropin administration in PCOS has yet to be investigated. The present study aimed to assess the effects of adropin on letrozole (LTZ)-induced PCOS in rats and the potential underlying mechanisms. The experimental groups were normal, adropin, letrozole and LTZ + adropin. At the end of the experiment, adropin significantly ameliorated PCOS, as evidenced by restoring the normal ovarian structure, decreasing the theca cell thickness in antral follicles, as well as serum testosterone and luteinizing hormone levels and luteinizing hormone/follicle-stimulating hormone ratios, at the same time as increasing granulosa cell thickness in antral follicles, oestradiol and follicle-stimulating hormone levels. The ameliorating effect could be attributed to its effect on sex hormone-binding globulin, key steroidogenic genes STAR and CYP11A1, IR, lipid profile, gut microbiota metabolites-brain-ovary axis components (short chain fatty acids, free fatty acid receptor 3 and peptide YY), intestinal permeability marker (zonulin and tight junction protein claudin-1), lipopolysaccharides/Toll-like receptor 4/nuclear factor kappa B inflammatory pathway and oxidative stress makers (malondialdehyde and total antioxidant capacity). In conclusion, adropin has a promising therapeutic effect on PCOS by regulating steroidogenesis, IR, lipid profile, the gut microbiota inflammatory axis and redox homeostasis. KEY POINTS: Adropin treatment reversed endocrine and ovarian morphology disorders in polycystic ovary syndrome (PCOS). Adropin regulated the ovarian steroidogenesis and sex hormone-binding globulin in PCOS. Adropin improved lipid profile and decreased insulin resistance in PCOS. Adropin modulated the components of the gut-brain-ovary axis (short chain fatty acids, free fatty acid receptor 3 and peptide YY) in PCOS. Adropin improved intestinal barrier integrity, suppressed of lipopolysaccharides/Toll-like receptor 4/nuclear factor kappa B signalling pathway and oxidative stress in PCOS.

Lasofoxifene as a potential treatment for aromatase inhibitor-resistant ER-positive breast cancer.

BACKGROUND: Breast cancers treated with aromatase inhibitors (AIs) can develop AI resistance, which is often driven by estrogen receptor-alpha (ERα/ESR1) activating mutations, as well as by ER-independent signaling pathways. The breast ER antagonist lasofoxifene, alone or combined with palbociclib, elicited antitumor activities in a xenograft model of ER + metastatic breast cancer (mBC) harboring ESR1 mutations. The current study investigated the activity of LAS in a letrozole-resistant breast tumor model that does not have ESR1 mutations. METHODS: Letrozole-resistant, MCF7 LTLT cells tagged with luciferase-GFP were injected into the mammary duct inguinal glands of NSG mice (MIND model; 6 mice/group). Mice were randomized to vehicle, lasofoxifene ± palbociclib, fulvestrant ± palbociclib, or palbociclib alone 2-3 weeks after cell injections. Tumor growth and metastases were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. The experiment was repeated with the same design and 8-9 mice in each treatment group. RESULTS: Western blot analysis showed that the MCF7 LTLT cells had lower ERα and higher HER2 expressions compared with normal MCF7 cells. Lasofoxifene ± palbociclib, but not fulvestrant, significantly reduced primary tumor growth versus vehicle as assessed by in vivo imaging of tumors at study ends. Percent tumor area in excised mammary glands was significantly lower for lasofoxifene plus palbociclib versus vehicle. Ki67 staining showed decreased overall tumor cell proliferation with lasofoxifene ± palbociclib. The lasofoxifene + palbociclib combination was also associated with significantly fewer bone metastases compared with vehicle. Similar results were observed in the repeat experiment. CONCLUSIONS: In a mouse model of letrozole-resistant breast cancer with no ESR1 mutations, reduced levels of ERα, and overexpression of HER2, lasofoxifene alone or combined with palbociclib inhibited primary tumor growth more effectively than fulvestrant. Lasofoxifene plus palbociclib also reduced bone metastases. These results suggest that lasofoxifene alone or combined with a CDK4/6 inhibitor may offer benefits to patients who have ER-low and HER2-positive, AI-resistant breast cancer, independent of ESR1 mutations.

Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3.

BACKGROUND: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3. PATIENTS AND METHODS: MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint. RESULTS: A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed. CONCLUSIONS: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.

Polypharmacy, over-the-counter medications, and aromatase inhibitor adherence in early-stage breast cancer.

PURPOSE: Polypharmacy is associated with negative health outcomes and decreased medication adherence. Polypharmacy is common in cancer populations, but few studies have evaluated the relationship between polypharmacy and aromatase inhibitor (AI) adherence. No studies have evaluated the relationship between over-the-counter (OTC) supplements and AI adherence. Our primary hypothesis was that polypharmacy would be associated with increased risk of premature AI discontinuation. METHODS: This exploratory analysis used data from the Exemestane and Letrozole Pharmacogenetics (ELPh) trial, a prospective, multicenter, randomized controlled trial that enrolled participants from 2005 to 2009. Included patients were female, postmenopausal, with stage 0-III breast cancer, who had completed indicated chemotherapy, surgery, and radiation. Participants were randomized to adjuvant exemestane or letrozole and completed serial clinical examinations and questionnaires for two years. Concomitant medication data were collected prospectively. Cox proportion models were used for statistical analysis of the relationship between polypharmacy, OTCs, medication class, and AI adherence. RESULTS: In the 490 analyzed participants, use of any prescription medications at baseline was associated with decreased risk of premature AI discontinuation (HR 0.56, p = 0.02). Use of selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) at baseline was associated with decreased risk of premature AI discontinuation (HR 0.67, p = 0.04). Use of any OTCs was not associated with AI discontinuation. CONCLUSION: Baseline use of prescription medications but not OTCs was associated with increased AI persistence. Future research is needed to understand how this can be utilized to promote AI adherence.

Superior suppression of serum estrogens during neoadjuvant breast cancer treatment with letrozole compared to exemestane.

PURPOSE: The aromatase inhibitor letrozole and the aromatase inactivator exemestane are two of the most pivotal cancer drugs used for endocrine treatment of ER-positive breast cancer in all phases of the disease. Although both drugs inhibit CYP19 (aromatase) and have been used for decades, a direct head-to-head, intra-patient-cross-over comparison of their ability to decrease estrogen synthesis in vivo is still lacking. METHODS: Postmenopausal breast cancer patients suitable for neoadjuvant endocrine therapy were randomized to receive either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) for an initial treatment period, followed by a second treatment period on the alternative drug (intra-patient cross-over study design). Serum levels of estrone (E1), estradiol (E2), letrozole, exemestane, and 17-hydroxyexemestane were quantified simultaneously using a novel, ultrasensitive LC-MS/MS method established in our laboratory. RESULTS: Complete sets of serum samples (baseline and during treatment with letrozole or exemestane) were available from 79 patients, including 40 patients starting with letrozole (cohort 1) and 39 with exemestane (cohort 2). Mean serum estrone and estradiol levels in cohort 1 were 174 pmol/L and 46.4 pmol/L at baseline, respectively. Treatment with letrozole suppressed serum E1 and E2 to a mean value of 0.2 pmol/L and 0.4 pmol/L (P < 0.001). After the cross-over to exemestane, mean serum levels of E1 and E2 increased to 1.4 pmol/L and 0.7 pmol/L, respectively. In cohort 2, baseline mean serum levels of E1 and E2 were 159 and 32.5 pmol/L, respectively. Treatment with exemestane decreased these values to 1.8 pmol/L for E1 and 0.6 pmol/L for E2 (P < 0.001). Following cross-over to letrozole, mean serum levels of E1 and E2 were significantly further reduced to 0.1 pmol/L and 0.4 pmol/L, respectively. Serum drug levels were monitored in all patients throughout the entire treatment and confirmed adherence to the protocol and drug concentrations within the therapeutic range for all patients. Additionally, Ki-67 values decreased significantly during treatment with both aromatase inhibitors, showing a trend toward a stronger suppression in obese women. CONCLUSION: To the best of our knowledge, we present here for the first time a comprehensive and direct head-to-head, intra-patient-cross-over comparison of the aromatase inhibitor letrozole and the aromatase inactivator exemestane concerning their ability to suppress serum estrogen levels in vivo. All in all, our results clearly demonstrate that letrozole therapy results in a more profound suppression of serum E1 and E2 levels compared to exemestane.

A network meta-analysis of efficacy and safety for first-line and second/further-line therapies in postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer.

BACKGROUND: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 -) advanced breast cancer is a prevalent subtype among postmenopausal women. Despite the growing number of randomized clinical trials (RCTs) exploring this topic, the efficacy and safety of first-line and second/further-line treatments remain uncertain. Accordingly, our aim was to conduct a comprehensive evaluation of the efficacy and safety of these therapies through network meta-analysis. METHODS: RCTs were identified by searching Pubmed, Embase, and major cancer conferences. The efficacy of interventions was assessed using the hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS), while safety was indicated by the incidence of any grade adverse events (AEs), grade 3-5 AEs, AEs leading to treatment discontinuation, and AEs leading to death. Both time-variant HRs fractional polynomial models and time-invariant HRs Cox-proportional hazards models were considered for handling time-to-event data. Safety indicators were analyzed using Bayesian network meta-analysis. Additionally, subgroup analyses were conducted based on patient characteristics. RESULTS: A total of 41 RCTs (first-line 17, second/further-lines 27) were included in the analysis. For first-line treatment, the addition of Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy significantly improved therapeutic efficacy in terms of both PFS and OS, demonstrating the best performance across all mechanisms. Specifically, the combination of Abemaciclib and Letrozole demonstrated the most favorable performance in terms of PFS, while Ribociclib plus Fulvestrant yielded the best outcomes in OS. Incorporating the immune checkpoint inhibitor Avelumab into the regimen with CDK4/6 inhibitors and selective estrogen receptor degraders significantly enhanced both PFS and OS in second-line or later treatments. Regarding safety, endocrine monotherapy performed well. Regarding safety, endocrine monotherapy performed well. There is mounting evidence suggesting that most CDK4/6 inhibitors may demonstrate poorer performance with respect to hematologic AEs. However, additional evidence is required to further substantiate these findings. CONCLUSIONS: CDK4/6 inhibitors, combined with endocrine therapy, are pivotal in first-line treatment due to their superior efficacy and manageable AEs. For second/further-line treatment, adding immune checkpoint inhibitors to CDK4/6 inhibitors plus endocrine therapy may produce promising results. However, to reduce the results' uncertainty, further trials comparing these novel treatments are warranted. TRIAL REGISTRATION: Registration number: PROSPERO (CRD42022377431).

Sodium oligomannate's amelioration of reproductive and metabolic phenotypes in a letrozole-induced PCOS-like mouse model depends on the gut microbiome†.

It has been well established that there is a connection between polycystic ovary syndrome pathology and gut microbiome dysbiosis. A marine-derived oligosaccharide, GV-971, has been reported to alter gut microbiota and alleviate Aß amyloidosis. In this study, the effects of GV-971 on polycystic ovary syndrome-like mice were explored. Mice were randomly assigned into four groups: control, letrozole, letrozole + GV-971, and control + GV-971. Glucose metabolism in polycystic ovary syndrome-like mice was ameliorated by GV-971, while the reproductive endocrine disorder of polycystic ovary syndrome-like mice was partially reversed. The messenger ribonucleic acid levels of steroidogenic enzymes in ovaries of polycystic ovary syndrome-like mice were improved. GV-971 restored the fertility of polycystic ovary syndrome-like mice and significantly increase the number of litters. Furthermore, GV-971 treatment effectively mitigated abnormal bile acid metabolism. Notably, after GV-971 intervention, gut microbiota alpha-diversity was considerably raised and the relative abundance of Firmicutes was reduced. In conclusion, the hyperinsulinemia and hyperandrogenemia of polycystic ovary syndrome-like mice were alleviated by GV-971 intervention, which was associated with mitigating bile acid metabolism and modulating gut microbiota.

Esr1 but Not CYP19A1 Overexpression in Mammary Epithelial Cells during Reproductive Senescence Induces Pregnancy-Like Proliferative Mammary Disease Responsive to Anti-Hormonals.

Molecular-level analyses of breast carcinogenesis benefit from vivo disease models. Estrogen receptor 1 (Esr1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) overexpression targeted to mammary epithelial cells in genetically engineered mouse models induces largely similar rates of proliferative mammary disease in prereproductive senescent mice. Herein, with natural reproductive senescence, Esr1 overexpression compared with CYP19A1 overexpression resulted in significantly higher rates of preneoplasia and cancer. Before reproductive senescence, Esr1, but not CYP19A1, overexpressing mice are tamoxifen resistant. However, during reproductive senescence, Esr1 mice exhibited responsiveness. Both Esr1 and CYP19A1 are responsive to letrozole before and after reproductive senescence. Gene Set Enrichment Analyses of RNA-sequencing data sets showed that higher disease rates in Esr1 mice were accompanied by significantly higher expression of cell proliferation genes, including members of prognostic platforms for women with early-stage hormone receptor-positive disease. Tamoxifen and letrozole exposure induced down-regulation of these genes and resolved differences between the two models. Both Esr1 and CYP19A1 overexpression induced abnormal developmental patterns of pregnancy-like gene expression. This resolved with progression through reproductive senescence in CYP19A1 mice, but was more persistent in Esr1 mice, resolving only with tamoxifen and letrozole exposure. In summary, genetically engineered mouse models of Esr1 and CYP19A1 overexpression revealed a diversion of disease processes resulting from the two distinct molecular pathophysiological mammary gland-targeted intrusions into estrogen signaling during reproductive senescence.

Apelin receptor modulation mitigates letrozole-induced polycystic ovarian pathogenesis in mice.

AIMS: Polycystic ovarian syndrome (PCOS) is one of the most common (about 5-20%) reproductive disorders in women of reproductive age; it is characterized by polycystic ovaries, hyperandrogenism, and oligo/ anovulation. The levels and expression of ovarian adipokines are deregulated in the PCOS. Apelin is an adipokine that acts through its receptor (APJ) and is known to express in the various tissues including the ovary. It has also been suggested that apelin and APJ could be targeted as therapeutic adjuncts for the management of PCOS. However, no study has been conducted on the management of PCOS by targeting the apelin system. Thus, we aimed to evaluate its impact on combating PCOS-associated ovarian pathogenesis. METHODS: The current work employed a letrozole-induced-hyperandrogenism PCOS-like mice model to investigate the effects of apelin13 and APJ, antagonist ML221. The PCOS model was induced by oral administration of letrozole (1 mg/kg) for 21 days. A total of four experimental groups were made, control, PCOS control, PCOS + aplein13, and PCOS + ML221. The treatment of apelin13 and ML221 was given from day 22 for two weeks. KEY FINDINGS: The letrozole-induced PCOS-like features such as hyperandrogenism, cystic follicle, decreased corpus luteum, elevated levels of LH/FSH ratio, and up-regulation of ovarian AR expression were ameliorated by apelin13 and ML221 treatment. However, the PCOS-augmented oxidative stress and apoptosis were suppressed by apelin 13 treatments only. ML221 treatment still showed elevated oxidative stress and stimulated apoptosis as reflected by decreased antioxidant enzymes and increased active caspase3 and Bax expression. The expression of ERs was elevated in all groups except control. Furthermore, the PCOS model showed elevated expression of APJ and apelin13 treatment down-regulated its own receptor. Overall, observing the ovarian histology, corpus luteum formation, and decreased androgen levels by both apelin13 and ML221 showed ameliorative effects on the cystic ovary. SIGNIFICANCE: Despite the similar morphological observation of ovarian histology, apelin13 and ML221 exhibited opposite effects on oxidative stress and apoptosis. Therefore, apelin13 (which down-regulates APJ) and ML221 (an APJ antagonist) may have suppressed APJ signalling, which would account for our findings on the mitigation of polycystic ovarian syndrome. In conclusion, both apelin13 and ML221 mediated mitigation have different mechanisms, which need further investigation.

Effect of aromatase inhibitors for preventing ovarian hyperstimulation syndrome in infertile patients undergoing in vitro fertilization: a systematic review and meta-analysis.

PURPOSE: To summarize the findings of relevant randomized controlled trials (RCTs) and conduct a meta-analysis to investigate the potential effect of aromatase inhibitors on preventing moderate to severe ovarian hyperstimulation syndrome (OHSS) in infertile women undergoing in vitro fertilization (IVF). METHODS: We searched for relevant RCTs in electronic databases, including MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov (from inception to August 2023). In addition, we manually searched the related reviews and reference lists of included studies for further relevant studies. We included RCTs where aromatase inhibitors prescribed either during controlled ovarian stimulation (COS) or in early luteal phase. The meta-analysis was performed using RevMan 5.4.1 software. The primary outcome was the incidence of moderate to severe OHSS. A descriptive analysis was conducted in cases where a meta-analysis was not feasible due to heterogeneity or lack of comparable data. RESULTS: 2858 records were retrieved and 12 RCTs were finally included. Letrozole was administered in the treatment group during COS in seven RCTs, whereas in the early luteal phase in five RCTs. Compared with the control group, the risk of moderate to severe OHSS significantly reduced by 55% in the letrozole group (RR 0.45, 95% CI 0.32 to 0.64, I2 = 0%, 5 RCTs, 494 patients). Moreover, serum estradiol (E2) levels on hCG trigger day significantly decreased with the administration of letrozole during COS (MD -847.23, 95% CI -1398.00 to -296.47, I2 = 93%, 5 RCTs, 374 patients). And serum E2 levels on the 4th, 5th and 7th to 10th day after hCG trigger were also significantly lower than those in the control group when letrozole was administered in the early luteal phase. CONCLUSIONS: Patients with high risk of OHSS probably benefit from letrozole, which has been revealed to reduce the incidence of moderate to severe OHSS by this systematic review. However, the very limited number of participants and the quality of the included studies does not allow to recommend letrozole for the prevention of severe OHSS.

Letrozole delays acquisition of water maze task in female BALB/c mice: Possible involvement of anxiety.

Letrozole, an aromatase inhibitor preventing estrogen synthesis from testosterone, is used as an adjuvant therapy in estrogen receptor-positive breast cancer patients. However, like other aromatase inhibitors, it induces many side effects, including impaired cognition. Despite its negative effect in humans, results from animal models are inconsistent and suggest that letrozole can either impair or improve cognition. Here, we studied the effects of chronic letrozole treatment on cognitive behavior of adult female BALB/c mice, a relevant animal model for breast cancer studies, to develop an appropriate animal model aimed at testing therapies to mitigate side effects of letrozole. In Morris water maze, letrozole 0.1 mg/kg impaired reference learning and memory. Interestingly, most of the letrozole 0.1 mg/kg-treated mice were able to learn the new platform position in reversal training and performed similar to control mice in a reversal probe test. Results of the reversal test suggest that letrozole did not completely disrupt spatial navigation, but rather delayed acquisition of spatial information. The delay might be related to increased anxiety as suggested by increased thigmotactic behavior during the reference memory training. The learning impairment was water maze-specific since we did not observe impairment in other spatial tasks such as in Y-maze or object location test. In contrast, the dose of 0.3 mg/kg did not have effect on water maze learning and facilitated locomotor habituation and recognition in novel object recognition test. The current study shows that letrozole dose-dependently modulates behavioral response and that its effects are task-dependent.

Oocyte in-vitro maturation primed with letrozole-HCG versus FSH-HCG in women with oocyte maturation abnormalities: a retrospective study.

RESEARCH QUESTION: Are there differences between in-vitro maturation (IVM) primed with letrozole-human chorionic gonadotrophin (HCG) and IVM primed with FSH-HCG in women with oocyte maturation abnormalities (OMAs), defined as at least two failed IVF cycles where immature oocytes were retrieved? DESIGN: This retrospective study was conducted at a private fertility clinic from January 2009 to April 2023. The final analysis included 75 women in Group 1 (IVM primed with FSH-HCG) and 52 women in Group 2 (IVM primed with letrozole-HCG). RESULTS: A significantly higher median number of oocytes was obtained in Group 1 compared with Group 2 {9 [interquartile range (IQR) 1-5] versus 5 (IQR 1-18); P < 0.001}. However, no differences in oocyte maturation stage at collection were found between the groups (P > 0.05). At the end of IVM, Group 1 had 73/666 mature oocytes and Group 2 had 106/322 mature oocytes, and the median metaphase II oocyte rate per patient was higher in Group 2 [33.3% (IQR 66.7-100.0%) versus 0.0% (IQR 0.0-22.2%); P < 0.001]. Moreover, Group 2 demonstrated a higher median fertilization rate [66.7% (IQR 50.0-100.0%) versus 50.0% (IQR 0.0-66.7%); P = 0.027]. Group 2 had a higher proportion of Grade 2 embryos (58.5% versus 6.3%), and Group 1 had a higher proportion of Grade 3 embryos (93.8% vs 24.4%; P < 0.001). Notably, all pregnancies obtained in the study were in Group 2 (5 versus 0; P = 0.042). CONCLUSIONS: IVM primed with letrozole-HCG in women with prior failed IVF cycles due to OMAs may result in mature oocytes, clinical pregnancies and live births. The effectiveness of letrozole priming for the subtypes of OMAs needs further investigation, with studies including greater numbers of cases.

Assessing ovarian stimulation with letrozole and levonorgestrel intrauterine system after combined fertility-sparing approach for atypical endometrial lesions: a retrospective case-control study.

RESEARCH QUESTION: Is ovarian stimulation with levonorgestrel intrauterine system (LNG-IUS) in situ and co-treatment with letrozole safe and effective in patients undergoing fertility-sparing combined treatment for atypical endometrial hyperplasia (AEH) or early endometrial cancer limited to the endometrium? DESIGN: Retrospective case-control study recruiting women who had undergone fertility-sparing 'combined' treatment and ovarian stimulation with letrozole and LNG-IUS in situ. The 'three steps' hysteroscopic technique was used. Once complete response was achieved, the ovaries were stimulated, and mature oocytes cryopreserved. The LNG-IUS was removed, and embryos transferred. A comparative analysis was conducted between the two control groups of the initial outcomes of ART (number of oocytes and MII oocytes retrieved): healthy infertile women undergoing ovarian stimulation for IVF/ICSI (control group A); and patients diagnosed with breast cancer who underwent ovarian stimulation with letrozole (control group B). RESULTS: Of the 75 patients analysed, 15 underwent oocyte cryopreservation after achieving a complete response to fertility-sparing treatment (study group); 30 patients in control group A and B, respectively. No statistically significant differences were observed in retrieved oocytes and mature oocytes between the study and control groups. In the nine patients who underwent embryo transfer, clinical pregnancy (55.6%), cumulative live birth (44.4%) and miscarriage (20%) rates were reported. In three patients with AEH, recurrence occurred (12%) at 3, 6 and 16 months after removing the LNG-IUS to attempt embryo transfer, respectively. CONCLUSION: Fertility-sparing hysteroscopic combined treatment and subsequent ovarian stimulation with letrozole and LNG-IUS in situ could be suggested to women with AEH or early endometrial cancer who ask for future fertility preservation.

Therapeutic Monitoring of Palbociclib, Ribociclib, Abemaciclib, M2, M20, and Letrozole in Human Plasma: A Novel LC-MS/MS Method.

BACKGROUND: Therapeutic drug monitoring (TDM) using cyclin-dependent kinase inhibitors (CDK4/6is) is a novel approach for optimizing treatment outcomes. Currently, palbociclib, ribociclib, and abemaciclib are the available CDK4/6is and are primarily coadministered with letrozole. This study aimed to develop and validate an LC-MS/MS method for the simultaneous analysis of CDK4/6is, 2 active metabolites of abemaciclib (M2 and M20), and letrozole in human plasma for use in TDM studies. METHODS: Sample pretreatment comprised protein precipitation with methanol and dilution of the supernatant with an aqueous mobile phase. Chromatographic separation was achieved using a reversed-phase XBridge BEH C18 column (2.5 µm, 3.0 × 75 mm XP), with methanol serving as the organic mobile phase and pyrrolidine-pyrrolidinium formate (0.005:0.005 mol/L) buffer (pH 11.3) as the aqueous mobile phase. A triple quadrupole mass spectrometer was used for the detection, with the ESI source switched from negative to positive ionization mode and the acquisition performed in multiple reaction monitoring mode. RESULTS: The complete validation procedure was successfully performed in accordance with the latest regulatory guidelines. The following analytical ranges (ng/mL) were established for the tested compounds: 6-300, palbociclib and letrozole; 120-6000, ribociclib; 40-800, abemaciclib; and 20-400, M2 and M20. All results met the acceptance criteria for linearity, accuracy, precision, selectivity, sensitivity, matrix effects, and carryover. A total of 85 patient samples were analyzed, and all measured concentrations were within the validated ranges. The percent difference for the reanalyzed samples ranged from -11.2% to 7.0%. CONCLUSIONS: A simple and robust LC-MS/MS method was successfully validated for the simultaneous quantification of CDK4/6is, M2, M20, and letrozole in human plasma. The assay was found to be suitable for measuring steady-state trough concentrations of the analytes in patient samples.

Comparing letrozole and mifepristone pre-treatment in medical management of first trimester missed miscarriage: a prospective open-label non-inferiority randomised controlled trial.

OBJECTIVE: To investigate whether letrozole pre-treatment is non-inferior to mifepristone pre-treatment, followed by misoprostol, for complete evacuation in the medical treatment of first-trimester missed miscarriage. DESIGN: Prospective open-label non-inferiority randomised controlled trial. SETTING: A university-affiliated hospital. POPULATION: We recruited 294 women diagnosed with first-trimester missed miscarriage who opted for medical treatment. METHODS: Participants were randomly assigned to: (i) the mifepristone group, who received 200 mg mifepristone orally followed 24-48 h later by 800 µg misoprostol vaginally; or (ii) the letrozole group, who received 10 mg letrozole orally once-a-day for 3 days, followed by 800 µg misoprostol vaginally on the third (i.e. last) day of letrozole administration. MAIN OUTCOME MEASURES: The primary outcome was the rate of complete evacuation without surgical intervention at 42 days post-treatment. Secondary outcomes included induction-to-expulsion interval, adverse effects, women's satisfaction, number of doses of misoprostol required, duration of vaginal bleeding, pain score on the day of misoprostol administration and other adverse events. RESULTS: The complete evacuation rates were 97.8% (95% CI 95.1%-100%) and 97.2% (95% CI 94.4%-99.9%) in the letrozole and mifepristone groups, respectively (p ≤ 0.001 for non-inferiority). The mean induction-to-tissue expulsion interval in the letrozole group was longer compared with the mifepristone group (15.4 vs 9.0 h) (p = 0.03). The letrozole group had less heavy post-treatment bleeding and an earlier return of menses. There were no statistically significant differences in the number of doses of misoprostol required, the duration of vaginal bleeding, the pain score on the day of misoprostol administration and the rate of other adverse events between the two groups. The majority of the women (91.2% and 93.9% in the letrozole and mifepristone groups, respectively) were satisfied with their treatment option. CONCLUSIONS: Letrozole is non-inferior to mifepristone as a pre-treatment, followed by misoprostol, for the medical treatment of first-trimester missed miscarriage.

Towards clinical adherence monitoring of oral endocrine breast cancer therapies by LC-HRMS-method development, validation, comparison of four sample matrices, and proof of concept.

Oral endocrine therapies (OET) for breast cancer treatment need to be taken over a long period of time and are associated with considerable side effects. Therefore, adherence to OET is an important issue and of high clinical significance for breast cancer patients' caregivers. We hypothesized that a new bioanalytical strategy based on liquid chromatography and high-resolution mass spectrometry might be suitable for unbiased adherence monitoring (AM) of OET. Four different biomatrices (plasma, urine, finger prick blood by volumetric absorptive microsampling (VAMS), oral fluid (OF)) were evaluated regarding their suitability for AM of the OET abemaciclib, anastrozole, exemestane, letrozole, palbociclib, ribociclib, tamoxifen, and endoxifen. An analytical method was developed and validated according to international recommendations. The analytical procedures were successfully validated in all sample matrices for most analytes, even meeting requirements for therapeutic drug monitoring. Chromatographic separation of analytes was achieved in less than 10 min and limits of quantification ranged from 1 to 1000 ng/mL. The analysis of 25 matching patient samples showed that AM of OET is possible using all four matrices with the exception of, e.g., letrozole and exemestane in OF. We were able to show that unbiased bioanalytical AM of OET was possible using different biomatrices with distinct restrictions. Sample collection of VAMS was difficult in most cases due to circulatory restraints and peripheral neuropathy in fingers and OF sampling was hampered by dry mouth syndrome in some cases. Although parent compounds could be detected in most of the urine samples, metabolites should be included when analyzing urine or OF. Plasma is currently the most suitable matrix due to available reference concentrations.

Diacerein mitigates endocrine and cardio-metabolic disruptions in experimental PCOS mice model by modulating AdipoR1/ PON 1.

BACKGROUND: This study aimed to explore the impact of Diacerein (DIC) on endocrine and cardio-metabolic changes in polycystic ovarian syndrome (PCOS) mouse model. METHODS: A total of 18 adult female mice (Parkes strain), aged 4-5 weeks, were randomly assigned to three groups, each comprising 6 animals, as follows: Group I (control), received normal diet and normal saline as vehicle for 51 days; Group II received Letrozole (LET; 6 mg/kg bw) for 21 days to induce PCOS; Group III received LET, followed by daily oral gavage administration of DIC (35 mg/kg bw) for 30 days. RESULTS: This study indicates that treatment with LET resulted in PCOS with characteristics such as polycystic ovaries, elevated testosterone, weight gain, visceral adiposity, high levels of insulin as well as fasting blood glucose in addition to insulin resistance, improper handling of ovarian lipids, atherogenic dyslipidemia, impaired Na + /K + -ATPase activity and serum, cardiac, and ovarian oxidative stress. Serum/ovarian adiponectin levels were lowered in LET-treated mice. In mice treated with LET, we also discovered a reduction in cardiac and serum paraoxonase 1 (PON1). Interestingly, DIC restored ovarian andcardio-metabolic abnormalities in LET-induced PCOS mice. DIC prevented the endocrine and cardio-metabolic changes brought on by letrozole-induced PCOS in mice. CONCLUSION: The ameliorative effects of DIC on letrozole-induced PCOS with concurrent oxidative stress, abdominal fat deposition, cardiac and ovarian substrate mishandling, glucometabolic dysfunction, and adiponectin/PON1 activation support the idea that DIC perhaps, restore compromised endocrine and cardio-metabolic regulators in PCOS.

A phase II, multicenter, open-label study of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancer: ALEPRO trial.

BACKGROUND: Low-grade serous and endometrioid ovarian cancers and adult-type granulosa cell tumors are rare ovarian malignancies that show high estrogen receptor positivity. Recurrences of these subtypes of ovarian cancer are often treated with conventional chemotherapy, although response rates are disappointing. PRIMARY OBJECTIVE: To determine the overall response rate of the combination therapy of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancers. STUDY HYPOTHESIS: The combination therapy of abemaciclib and letrozole will provide a clinically meaningful therapeutic benefit, with an overall response rate of >25%. TRIAL DESIGN: This is a phase II, international, multicenter, open-label, single-arm study to evaluate the efficacy and safety of abemaciclib and letrozole in patients with advanced, recurrent, and/or metastatic estrogen receptor-positive, rare ovarian cancer. The study will follow a tandem two-stage design. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients must have histologically confirmed low-grade serous/endometrioid ovarian cancer or adult-type granulosa cell tumor with estrogen receptor positivity on immunohistochemistry. Patients need to have recurrent and measurable disease according to Radiologic Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A maximum of two prior lines of endocrine therapy are allowed, and patients cannot have previously received a cyclin-dependent kinase inhibitor. Patients with platinum-refractory disease are not allowed in any stage of the study. PRIMARY ENDPOINT: Investigator-assessed confirmed overall response rate, defined as the proportion of patients with a complete or partial response according to RECIST v1.1. SAMPLE SIZE: 40 to 100 patients will be included, depending on the results of the interim analysis. Patients will be included in Belgium, France and the Netherlands. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Patient recruitment will be completed by the end of 2025 and reporting of the final study results will be done by the end of 2027. TRIAL REGISTRATION NUMBER: NCT05872204.