Nonsteroidal Aromatase Inhibitor Research Articles

Health-related quality of life outcomes between non-steroid and steroid aromatase inhibitors and switching hormone therapy in postmenopausal women with ER+ breast cancer

Adjuvant hormone therapy can affect the quality of life of postmenopausal breast cancer patients with the estrogen receptor (ER+). This study aimed to measure the outcomes of health-related quality of life (HRQoL) in postmenopausal women with ER+ breast cancer receiving non-steroidal aromatase inhibitors (NSAI), steroidal aromatase inhibitors (SAI), and hormone change therapy (Switch). This cross-sectional study was conducted by interviewing women with postmenopausal ER+ breast cancer. The EQ-5D-5L instrument was used to measure and compare utility scores among patients who received NSAI, SAI, and switch therapy. As a result, the average utility score EQ-5D-5L for NSAI is 0.864 (SD = 0.117), significantly different (p = 0.025) from SAI 0.777 (SD = 0.211) and switch 0.776 (SD = 0.071). The conclusion is that NSAI, SAI, and Switch significantly affected HRQoL in postmenopausal breast cancer patients with ER+. NSAI has a better quality of life compared to SAI and Switch.

Treatment sequences and survival outcomes in advanced HR + HER2- breast cancer patients: a real-world cohort.

Palliative treatment options for HR + HER2- advanced breast cancer (ABC) patients have increased, but data is lacking about the optimal treatment sequence. We used real-world data from a comprehensive cancer center to describe applied treatment sequences and we determined treatment-related and survival outcomes. Patients aged 18 years and older with HR + HER2- ABC treated with systemic treatment were included in this historic cohort study. Sequential treatment schedules, time to treatment discontinuation, time to chemotherapy, and overall survival (OS) were determined, stratified by first-line treatment. 202 patients were included. They received a total of 650 treatment lines (median 3; range: 1-11). 91 (45%), 25 (12%), 24 (12%), 28 (14%), 22 (11%) and 12 (6%) patients started first-line treatment with non-steroidal aromatase inhibitors (NSAI), NSAI + cyclin dependent kinase 4/6-inhibitors (CDK4/6i), fulvestrant + CDK4/6i, tamoxifen, chemotherapy and other treatment, respectively. 10, 13, and 14 different treatment regimens were given in first, second and third-line, respectively. Of the patients who started first-line NSAI monotherapy (n = 91), 3 (3%) died before receiving second-line treatment. In this real-world cohort, we observed a wide variety of different treatment sequences applied in daily clinical practice, some of which were in discordance with the current guidelines. Fear that patients may never get around to treatment with CDK4/6i if a patient did not start with a CDK4/6i was not supported by our study results.

CDK4/6 inhibitor dalpiciclib combined with non-steroidal aromatase inhibitors in estrogen receptor-positive recurrent/metastatic ovarian cancer and uterine neoplasms

CDK4/6 inhibitor dalpiciclib combined with non-steroidal aromatase inhibitors in estrogen receptor-positive recurrent/metastatic ovarian cancer and uterine neoplasms

Abemaciclib plus non-steroidal aromatase inhibitor or fulvestrant in women with HR+/HER2- advanced breast cancer: Final results of the randomized phase III MONARCH plus trial.

In the interim analysis of MONARCH plus, adding abemaciclib to endocrine therapy (ET) improved progression-free survival (PFS) and objective response rate (ORR) in predominantly Chinese postmenopausal women with HR+/HER2- advanced breast cancer (ABC). This study presents the final pre-planned PFS analysis. In the phase III MONARCH plus study, postmenopausal women in China, India, Brazil, and South Africa with HR+/HER2- ABC without prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) were randomized (2:1) to abemaciclib (150mg twice daily [BID]) or placebo plus: anastrozole (1.0mg/day) or letrozole (2.5mg/day) (cohort A) or fulvestrant (500mg) (cohort B). The primary endpoint was PFS of cohort A. Secondary endpoints included cohort B PFS (key secondary endpoint), ORR, overall survival (OS), safety, and health-related quality of life (HRQoL). In cohort A (abemaciclib: n =207; placebo: n =99), abemaciclib plus a non-steroidal aromatase inhibitor improved median PFS vs . placebo (28.27months vs . 14.73months, hazard ratio [HR]: 0.476; 95% confidence interval [95% CI]: 0.348-0.649). In cohort B (abemaciclib: n =104; placebo: n =53), abemaciclib plus fulvestrant improved median PFS vs . placebo (11.41months vs . 5.59months, HR: 0.480; 95% CI: 0.322-0.715). Abemaciclib numerically improved ORR. Although immature, a trend toward OS benefit with abemaciclib was observed (cohort A: HR: 0.893, 95% CI: 0.553-1.443; cohort B: HR: 0.512, 95% CI: 0.281-0.931). The most frequent grade ≥3 adverse events in the abemaciclib arms were neutropenia, leukopenia, anemia (both cohorts), and lymphocytopenia (cohort B). Abemaciclib did not cause clinically meaningful changes in patient-reported global health, functioning, or most symptoms vs . placebo. Abemaciclib plus ET led to improvements in PFS and ORR, a manageable safety profile, and sustained HRQoL, providing clinical benefit without a high toxicity burden or reduced quality of life. ClinicalTrials.gov (NCT02763566).

7975 TLR4 Signaling Modulates Reproductive and Metabolic Outcomes in a Mouse Model of Polycystic Ovary Syndrome

Abstract Disclosure: K.D. Wiggins: None. Z. Del Mundo: None. J.A. Ayala Angulo: None. M. Lopez: None. C. Garcia: None. C. Nguyen: None. J. De La Torre: None. A. Saba: None. D. Trinh: None. D. Nicholas: None. Polycystic Ovarian Syndrome (PCOS), characterized by disruptions in both reproductive and metabolic functions, is associated with abnormal immune system activity and chronic inflammation. Although the precise mechanistic drivers of chronic inflammation in PCOS are not fully elucidated, elevated serum levels of lipopolysaccharide (LPS) have been observed. We propose that Toll-like receptor 4 (TLR4) signaling, influenced by dysregulated LPS levels, is a central driver of chronic inflammation affecting both reproductive and metabolic pathways. To investigate this hypothesis, we subcutaneously implanted a nonsteroidal aromatase inhibitor, Letrozole (LET), in pubertal TLR4 knockout mice (TLR4KO) and C57BL/6J (wild type) mice. Our five-week LET treatment revealed that TLR4KO mice successfully entered all phases of the estrous cycle, with normalized Luteinizing Hormone (LH) and increased Follicle Stimulating Hormone (FSH) levels. These findings highlight TLR4's role in shaping cycling patterns and regulating fundamental hormonal pathways vital for reproductive health. Despite the genetic manipulation of the inflammatory pathway leading to a reduction in overall body weight gain, it had no discernible impact on the overall body composition of fat and lean mass. Additionally, our study found that dysregulation of blood glucose levels over time was independent of reduced body weight. TLR4KO mice demonstrated inefficient glucose clearance compared to wild-type mice, hinting at potential increases in insulin resistance, imbalances in adipose tissue inflammation, or possible alterations in the gut microbiota. Our study underscores the significance of disrupting the pro-inflammatory TLR4 pathway in shaping the reproductive and metabolic phenotypes in Letrozole-induced PCOS. The investigation into TLR4 becomes pivotal for comprehending the role of chronic inflammation in PCOS development or progression, offering valuable insights into potential therapeutic targets. Presentation: 6/2/2024

A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial

NATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus NSAI compared with a nonsteroidal aromatase inhibitor (NSAI) alone in a broad population of patients with HR+/HER2- early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease-free survival (iDFS). Premenopausal/postmenopausal women and men were randomized 1:1 to ribociclib (n=2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n=2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS (DDFS), and overall survival (OS). This final iDFS analysis was planned after ≈500 events. At data cutoff (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI vs NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone (Hazard Ratio 0.749, 95% Confidence Interval [CI] 0.628-0.892; P=0.0012). The 3-year iDFS rates were 90.7% (95% CI 89.3%-91.8%) vs 87.6% (95% CI 86.1%-88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (+/-). DDFS and RFS favored ribociclib plus NSAI. OS data were immature. No new safety signals were observed. With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable.

Adipokines level in plasma, hypothalamus, ovaries, and adipose tissue of rat's polycystic ovary syndrome model

Research questionDo the levels of adipokines (adiponectin, apelin, chemerin and vaspin) in plasma, hypothalamus, ovaries, and periovarian adipose tissue differ during polycystic ovarian syndrome (PCOS)? DesignThe PCOS was induced in rats by oral administration of nonsteroidal aromatase inhibitor letrozole. To determine the plasma levels of adiponectin, apelin, chemerin, and vaspin we performed enzyme-linked immunosorbent assays. To assess the expression (gene and protein) and immunolocalization of these adipokines and their receptors, namely Adipor1 and Adipor2 for adiponectin; Aplnr for apelin; Ccrl2, Cmklr1, and Gpr1 for chemerin; and Grp78 for vaspin in the hypothalamus, ovaries, and periovarian adipose tissue we conducted by real-time PCR, Western blot and immunohistochemistry, respectively. ResultsWe noted that PCOS modulates the plasma levels of adipokines (decreased adiponectin, increased apelin, chemerin, and vaspin) and the expression of adipokines and their receptors in the hypothalamus, ovaries, and periovarian adipose tissue compared with healthy rats. ConclusionsThis study confirmed a strong relationship between PCOS and adipokines and suggest that adipokines may be a biomarker of PCOS.

Impact of Letrozole on Prevention of Early Onset Ovarian Hyperstimulation Syndrome in GnRH Antagonist Protocol: A Randomized Controlled Trial

Abstract Background Ovarian hyperstimulation syndrome (OHSS) is a risk associated with assisted reproductive technology. There is a link between higher incidences of OHSS and higher blood estrogen levels. With its strong, targeted, and reversible inhibition of aromatase and E synthetase, the nonsteroidal aromatase inhibitor letrozole can prevent the conversion of androgens into estrogens. Methods Study populations were divided into two equal groups: Group I: Consisted of 85 women who received controlled ovarian stimulation with a conventional antagonist protocol and letrozole. Group II: Consisted of 85 women who received controlled ovarian stimulation with a conventional GnRH antagonist protocol and a placebo. Results There were statistically significant differences among the groups in terms of Estradiol level on Trigger Day (p = 0.037), Number of oocytes retrieved (p = 0.018). The total days of stimulation and cumulative Gonadotropin dose were significantly lower in the Letrozole group (p = 0.045). There were no significant differences between the groups as regard endometrial thickness at trigger day, number of fertilized oocytes, fertilization rate, embryos transferred per cycle, and fresh embryos transferred, mild and critical early onset OHSS, Cycle cancels, Biochemical pregnancy, and Clinical pregnancy between the two groups (P > 0.05). There was a significant difference as regard moderate and severe early onset OHSS between the two groups (P < 0.05). Conclusion We've concluded that for PCOS patients facing a high risk of OHSS, supplementing the GnRH-ant protocol with LE offers a safer, more effective, cost-efficient, and patient-friendly approach compared to the traditional GnRH-ant protocol. The use of LE alongside conventional protocols might alleviate severe forms of OHSS, even among those at extreme risk, without compromising the potential for implantation, pregnancy, and delivery

Nanoemulsion-based transdermal delivery of third-generation steroidal and non-steroidal aromatase inhibitors in preclinical models.

Aromatase inhibitors are effective in treating hormone receptor-positive breast cancer, particularly in postmenopausal women. However, the challenges of inconsistent dissolution, variable absorption and side effects with oral administration persist. To address these issues, transdermal delivery has emerged as a viable alternative. In our study, we have developed nanoemulsion-based transdermal creams containing third-generation aromatase inhibitors Exemestane (EXE) or Letrozole (LE) and evaluated their toxicity, anti-tumour effects and androgenic potency using preclinical models including Bama minipigs, DMBA-induced breast cancer rats and orchidectomized male rats. The results of our study are significant, suggesting that both creams effectively penetrated the skin, demonstrating an impressive anti-breast cancer effect. Importantly, EXE cream had no organ toxicity at the tested dose, providing a reassuring safety profile for its use. In contrast, LE cream displayed reversible toxicity from drug molecule itself in animals at the given dose, dissipating after 3 weeks of withdrawal and recovery. This study establishes a solid foundation for the safe clinical use of third-generation aromatase inhibitors. It highlights transdermal creams as a promising drug delivery carrier for administering them.

Synthesis, Characterization, and In vitro and In Silico Studies of New Triazole Derivatives as Aromatase Inhibitors

Introduction: Breast cancer is the most common type of cancer among women. Steroidal or non-steroidal aromatase inhibitors (NSAIs) are used clinically, and in most cancer diseases, resistance is the most important problem. Method: The nitrogenous heterocyclic ring is noteworthy in the structure of non-steroidal aromatase inhibitors. This is the pharmacophore structure for aromatase inhibition. Because the enzyme interacts with the Fe2+ cation of the HEM structure in its active site, the most used agents in the clinic, such as anastrozole and letrozole, contain triazoles in their structures. Within the scope of this study, hybrid compounds containing both imidazole and triazole were synthesized. Result: The synthesis was carried out by a 4-step reaction. The anticancer effects of the compounds were evaluated by MTT assay performed on A549 and MCF-7 cancer cells. Compound 4d showed anticancer activity against the MCF-7 cell line with IC50=6.7342 uM value. This compound exhibited anticancer activity against the A549 cell line with an IC50 = 17.1761 μM. In the MTT test performed on a healthy cell line to determine the cytotoxic effects of the compounds, the compound showed activity with a value of 4d IC50=13.2088 uM. This indicates that the compound is not cytotoxic. Additionally, BrdU analysis was performed to evaluate whether the compound inhibits DNA synthesis. These selective effects of the compounds on breast cancer strengthened their aromatase enzyme inhibitor potential. For this reason, experiments conducted with both in vitro and in silico methods revealed a compound with high aromatase inhibitor potential. Conclusion: The interactions observed as a result of molecular docking and dynamics studies are in harmony with activity studies. In particular, interactions with HEM600 demonstrate the activity potential of the compound.

Efficacy and Safety of Abemaciclib in Combination With Endocrine Therapy for HR+/HER2- Advanced or Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

Breast cancer, particularly the hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) subtype, remains a major global health concern. Abemaciclib, a CDK4/6 inhibitor, has shown promising results in treating advanced cases. This study comprehensively assesses the efficacy and safety of abemaciclib in combination with endocrine therapy for HR+/HER2- advanced or metastatic breast cancer. Following PRISMA guidelines, a systematic review and meta-analysis was conducted. A thorough literature search was conducted on PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov til December 2023. Inclusion criteria encompassed randomized controlled trials and retrospective cohort studies reporting on abemaciclib in approved doses, either as monotherapy or in combination. Outcome assessments included progression-free survival (PFS), overall response rate (ORR), side effects/adverse effects (SE/AE), and overall survival (OS). Quality assessment utilized Cochrane's revised risk of bias tool and Newcastle-Ottawa scale. Pooled results of 22 studies involving 14,010 patients revealed that abemaciclib significantly improved PFS (hazard ratio=0.53; 95% CI: 0.48-0.59; P=0.00; I2=0%), ORR (risk ratio=2.31; 95% CI: 1.93-2.75; P=0.00; I2=0%), and OS (risk ratio=0.76 (95% CI: 0.65-0.87; P=0.001; I2=0%). However, abemaciclib increased the risk of adverse events in the fulvestrant and nonsteroidal aromatase inhibitor (NSAI) combinations, respectively. Abemaciclib, particularly in combination with fulvestrant, emerges as an effective therapeutic option for HR+/HER2- advanced or metastatic breast cancer, improving PFS and OS. The higher toxicity profile warrants cautious use, especially in treatment-naive patients.

LBA13 Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (Pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial

LBA13 Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (Pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial

240P Efficacy and safety of ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) in older patients (pts) with HR+/HER2− early breast cancer (EBC) in NATALEE

240P Efficacy and safety of ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) in older patients (pts) with HR+/HER2− early breast cancer (EBC) in NATALEE

235MO Efficacy and safety of ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) in younger patients (pts) with HR+/HER2− early breast cancer (EBC) in NATALEE

235MO Efficacy and safety of ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) in younger patients (pts) with HR+/HER2− early breast cancer (EBC) in NATALEE

Discovery of potential 1,2,4-triazole derivatives as aromatase inhibitors for breast cancer: pharmacophore modelling, virtual screening, docking, ADMET and MD simulation

ABSTRACT Hormone receptor (HR)-positive breast cancer represents tumours that express estrogen and/or progesterone enzymes, which play a crucial role in the growth and proliferation of breast cancer cells. Aromatase inhibitors (AIs) are drugs that inhibit the enzyme aromatase, involved in the biosynthesis of estrogen and are used for the treatment of HR-positive breast cancer. The USFDA-approved nonsteroidal AIs contain 1,2,4-triazole heterocycle. So, in the present study, we screened seventy-eight 1,2,4-triazole analogues from different literature resources and generated a pharmacophore model. After several validation protocols, Hypo1 was selected as the best model and was used as a 3D query for screening 1,2,4-triazole analogues (15,583) obtained from the CHEMBL database. A dataset containing 320 ligands with estimated activity (IC50< 0.1 µM) was subjected to molecular docking against the aromatase enzyme (PDB ID: 3S79). Amongst the 320 ligands, 30 compounds exhibited better binding energy compared to the standard drug letrozole. These 30 hits were further considered for the design of two novel molecules which were initially assessed for their ADMET properties followed by pharmacophore mapping, docking and molecular dynamics simulation. The in silico findings suggest that both the designed molecules can be considered drug-like candidates for the treatment of breast cancer through aromatase inhibition.

Initial ribociclib plus endocrine therapy for HR+/HER2- advanced breast cancer in pre- and postmenopausal Chinese women: Primary results from a phase 2 randomized study.

AbstractBackgroundThe MONALEESA‐7 and ‐2 phase 3 randomized trials demonstrated a statistically significant progression‐free survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre‐ and postmenopausal patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre‐ and postmenopausal patients with HR+/HER2– ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA‐7 and ‐2 studies.MethodsPatients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigator‐assessed PFS.ResultsAs of April 25, 2022, the median follow‐up was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies.ConclusionsThese data demonstrate a favorable benefit–risk profile for ribociclib + ET in Chinese patients.

Baseline (BL) characteristics and efficacy endpoints for patients (pts) with node-negative (N0) HR+/HER2− early breast cancer (EBC): NATALEE trial.

512 Background: NATALEE assessed ribociclib (RIB) + non-steroidal aromatase inhibitor (NSAI) vs NSAI alone in pts with HR+/HER2− EBC at increased risk of recurrence, including pts with N0 disease, and showed a statistically significant invasive disease-free survival (iDFS) benefit. We report BL characteristics, efficacy, and safety for the N0 subgroup. Methods: Pts with stage II/III HR+/HER2− EBC were randomized (R) 1:1 to RIB 400 mg/d (3 wk on/1 wk off for 36 mo) + NSAI (letrozole or anastrozole for ≥60 mo) or NSAI alone. Men and premenopausal women received goserelin. Pts could receive any standard (neo)adjuvant endocrine therapy (ET) ≤12 mo before randomization. In the intent-to-treat (ITT) population, 78% of pts completed 3y of RIB treatment (tx) or discontinued early with 21% still on tx at the time of this analysis (data cutoff: July 21, 2023; median follow up, 33 mo). The N0 subgroup included pts with T2N0 (stage IIA; with grade [G]3, or G2 disease and Ki-67 ≥20% or high genomic risk [HGR]), T3N0 (stage IIB), and T4N0 (stage IIIB); T1N0 was excluded. Results: Of 2549 pts R to RIB + NSAI and 2552 to NSAI alone, 285 (11%) and 328 (13%) had N0 disease, respectively. BL characteristics for the N0 subgroup were balanced across arms. Most pts were premenopausal (RIB + NSAI: 67% vs NSAI alone: 63%). Pts with N0 disease had anatomic stage IIA (RIB + NSAI: 74% vs NSAI alone: 73%), stage IIB (17% vs 13%), or stage IIIB (9% vs 12%) disease (Table). Most pts received prior chemotherapy (RIB + NSAI: 72% vs NSAI alone: 71%); prior ET was received by 59% vs 62% of pts with RIB + NSAI vs NSAI alone. For pts with T2N0 disease treated with RIB + NSAI vs NSAI alone, 49% vs 45% had G3 disease and 49% vs 53% had G2 disease (54% vs 56% with T2N0, G2 &amp; Ki-67 &gt; 20%; 13% vs 23% with T2N0, G2, Ki-67 ≤20%/missing &amp; HGR). Consistent with the ITT population, RIB + NSAI improved iDFS (HR, 0.72; 95% CI, 0.41-1.27; 3y rate with RIB + NSAI vs NSAI alone, 93.2% vs 90.6%), distant disease–free survival (DDFS; HR, 0.70; 95% CI, 0.38-1.29; 3y rate, 94.3% vs 91.5%), and distant recurrence–free survival (DRFS; HR, 0.58; 95% CI, 0.29-1.17; 3y rate, 96.3% vs 92.5%) in pts with high-risk N0 disease. The safety profile of RIB in the N0 subgroup was consistent with the ITT population. The rate of discontinuation due to all grade adverse events was 24% vs 8% with RIB + NSAI vs NSAI alone. Conclusions: This analysis showed a consistent efficacy benefit and manageable safety profile of RIB + NSAI vs NSAI alone in pts with N0 disease in NATALEE. The 3y iDFS, DDFS, and DRFS rates in the control arm at this early follow-up underscore the risk of recurrence for the N0 subgroup. These findings support the use of RIB in pts with HR+/HER2− EBC at increased risk of recurrence, including pts with N0 disease. Clinical trial information: NCT03701334 . [Table: see text]

Switching from nonsteroidal aromatase inhibitors to exemestane and its impact on menopausal symptoms.

e13098 Background: Aromatase inhibitors (AIs) are the most used adjuvant treatment in post-menopausal women with favorable oncotype, hormone receptor-positive (HR+) early breast cancer. Nonsteroidal AIs, such as anastrozole and letrozole, are associated with menopausal side effects including arthralgias, vaginal dryness, and hot flashes. Steroidal AIs, such as exemestane, however, have mild androgenic activity, thus minimizing the risk for these side effects. While studies show exemestane exhibits less bone toxicity compared to anastrozole, there has not yet been a proven significant difference in all menopausal symptoms. Nevertheless, switching from nonsteroidal to steroidal AI is still commonly seen in clinical practice. In this study, we aimed to examine the impact of switching from nonsteroidal to steroidal AI on menopausal side effects. Methods: We performed a retrospective review of patients diagnosed with HR+ breast cancer managed at an urban academic center from 2010-2023. Patients initially treated with anastrozole or letrozole and switched to exemestane were identified. Pathology records, treatment plans, and documented side effects were abstracted from medical records, as were baseline demographics. Symptoms were graded based on severity before and after each hormone therapy: mild grade described intermittent symptoms that did not require intervention; moderate grade described persistent daily symptoms or those that improved with additional intervention; severe grade described persistent disabling symptoms that required change in hormone therapy. Wilcoxon signed-rank tests were used to compare severity of menopausal symptoms before and after switching to exemestane. Results: There were 128 patients included in the study. Median age at diagnosis was 62.5 years; 13% pre-menopausal, 80% post-menopausal, 4% perimenopausal, and 3% unknown. Most patients were diagnosed with invasive ductal carcinoma (80%) and 45% were found to have stage IA breast cancer. The median amount of time on first and second lines of endocrine therapy were 11 and 25 months, respectively. Ninety-six patients (75%) reported menopausal symptoms on nonsteroidal AI, and 66% subsequently switched to exemestane due to severity of these symptoms. The most reported symptoms were arthralgias (79%), hot flashes (27%), body aches (25%), fatigue (10%), and vaginal dryness (9%). Of those with menopausal symptoms, 51% noted a decrease in symptom severity after switching to exemestane: 4 improved from moderate to mild, 21 from severe to moderate, and 24 from severe to mild. This decrease in severity was statistically significant across all menopausal symptoms (p&lt;0.001). Conclusions: HR+ breast cancer patients exhibited a significant decrease in all menopausal symptoms when switching from nonsteroidal to steroidal AI. Further research is needed to examine the impact of this switch on a wider range of symptoms.

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

In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with HR+, HER2- advanced breast cancer (ABC) with disease progression on prior endocrine therapy (ET). 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. MONARCH 3 is a randomized, double-blind, phase 3 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 (CFS) was an exploratory endpoint. 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 [CI], 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 (sVD), there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% CI, 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 CFS numerically improved with the addition of abemaciclib. No new safety signals were observed. Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (ITT: 13.1 months; sVD: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.

Everolimus plus endocrine therapy beyond CDK4/6 inhibitors progression for HR+ /HER2- advanced breast cancer: a real-world evidence cohort.

Everolimus in combination with endocrine therapy (ET) was formerly approved as 2nd-line therapy in HR(+)/HER2(-) advanced breast cancer (aBC) patients (pts) progressing during or after a non-steroidal aromatase inhibitor (NSAI). Since this approval, the treatment landscape of aBC has changed dramatically, particularly with the arrival of CDK 4-6 inhibitors. Endocrine monotherapy after progression to CDK4/6 inhibitors has shown a limited progression-free survival (PFS), below 3months. Evidence of the efficacy of everolimus plus ET after CDK4/6 inhibitors is scarce. A retrospective observational study of patients with aBC treated with everolimus and ET beyond CDK4/6-i progression compiled from February 2015 to December 2022 in 4 Spanish hospitals was performed. Clinical and demographic data were collected from medical records. The main objective was to estimate the median progression-free survival (mPFS). Everolimus adverse events (AE) were registered. Quantitative variables were summarized with medians; qualitative variables with proportions and the Kaplan-Meier method were used for survival estimates. One hundred sixty-one patients received everolimus plus ET (exemestane: 96, fulvestrant: 54, tamoxifen: 10, unknown: 1) after progressing on a CDK4/6 inhibitor. The median follow-up time was 15months (interquartile range: 1-56months). The median age at diagnosis was 49years (range: 35-90years). The estimated mPFS was 6.0months (95%CI 5.3-7.8months). PFS was longer in patients with previous CDK4/6 inhibitor therapy lasting for > 18months (8.7months, 95%CI 6.6-11.3months), in patients w/o visceral metastases (8.0months, 95%CI 5.8-10.5months), and chemotherapy-naïve in the metastatic setting (7.2months, 95%CI 5.9-8.4months). This retrospective analysis cohort of everolimus plus ET in mBC patients previously treated with a CDK4/6 inhibitor suggests a longer estimated mPFS when compared with the mPFS with ET monotherapy obtained from current randomized clinical data. Everolimus plus ET may be considered as a valid control arm in novel clinical trial designs.