Aromatase Inhibitors In Patients Research Articles

Abstract PO1-17-05: Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in metastatic breast cancer patients with cardiovascular diseases

Abstract Background Breast cancer survivors are at risk for mortality from cardiovascular diseases (CVD). CVD and their treatments can impact breast cancer treatment selection and clinical outcomes. A cyclin dependent kinase 4/6 inhibitor (CDK4/6i) combined with endocrine therapy (ET) is more effective than ET alone for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2) metastatic breast cancer (MBC). CDK4/6i plus ET is now the standard of care in the first-line setting for HR+/HER2 MBC. However, data on the effectiveness of CDK4/6i in MBC patients with CVD are limited. We compared overall survival (OS) and real-world progression-free survival (rwPFS) of palbociclib plus AI (PAL+AI) vs AI alone in HR+/HER2 MBC patients with CVD in routine US clinical practices. Methods The Flatiron Health longitudinal database contains electronic health records from >280 cancer clinics, representing >3 million actively treated cancer patients in the US. Using the Flatiron database, we conducted a retrospective analysis of 469 patients with HR+/HER2 MBC and CVD who started PAL+AI or AI as first-line therapy between February 2015 and March 2020. CVD prior to the initiation of PAL+AI or AI were identified based on their definitions within the National Cancer Institute-Comorbidity Index (NCI-CI), including myocardial infarction, congestive heart failure, peripheral vascular diseases, and cerebrovascular diseases. Patients were assessed from start of PAL+AI or AI to September 30, 2020 (data cutoff date), death, or last visit, whichever came first. OS was defined as months from start of PAL+AI or AI to death. rwPFS was defined as months from start of PAL+AI or AI to death or disease progression, evaluated based on clinical assessment or radiographic scan/tissue biopsy. Stabilized inverse probability treatment weighting (sIPTW) as primary analysis was used to balance baseline demographics and clinical characteristics. Cox proportional-hazards models were used to estimate the relative effectiveness of PAL+AI vs AI alone. Results Of the 469 eligible patients, 160 (34.1%) were treated with PAL+AI and 309 (65.9%) were treated with AI alone. Compared with AI-alone patients, those treated with PAL+AI were younger and were more likely to have de novo MBC, ≥2 metastatic sites, and lung/liver involvement. After sIPTW, patient characteristics were generally balanced. After sIPTW, median OS (95% confidence interval [CI]) was 40.7 months (30.956.0) in PAL+AI patients and 26.5 months (23.337.3) in AI patients (hazard ratio [HR]=0.732, 95% CI=0.5370.997, p=0.0476). Median rwPFS (95% CI) was 20.0 months (11.7–27.5) in PAL+AI patients and 12.5 months (9.718.3) in AI patients (HR=0.679, 95% CI=0.5120.900, p=0.0070). Consistent results were observed with multivariate Cox proportional-hazards models as sensitivity analysis. See Table for baseline patient characteristics and outcome results. Conclusions First-line PAL in combination with AI is associated with prolonged OS and rwPFS in patients with HR+/HER2 MBC and CVD in a real-world setting compared with AI alone. Further studies with larger cohorts and comprehensive assessments of comorbidities are needed to provide additional evidence of outcomes and safety of CDK4/6i plus AI for MBC patients with various comorbid conditions in routine clinical practice. Citation Format: Adam Brufsky, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Doris Makari, Rachel Layman, Hope Rugo. Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in metastatic breast cancer patients with cardiovascular diseases [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 PO1-17-05.

Abstract PO5-01-12: Factors Influencing Late Recurrence in Breast Cancer: A Comprehensive Analysis of the Impact of Hormone Therapy Regimens

Abstract Late recurrence of breast cancer remains a significant challenge in patient management. Despite the established efficacy of hormone therapy, factors influencing late recurrence and the impact of different hormone therapy regimens on this outcome are not yet fully understood. This study aims to investigate the key determinants contributing to late recurrence within the context of different hormone therapy regimens. This study is a retrospective analysis of medical records from two institutions between 1988 and 2018, specifically examining patients who had HR-receptor positive breast cancer who underwent surgery and completed a 5-year course of standard hormone therapy. Primary endpoint is to identify the demographic, clinical and pathologic factors as associated with late recurrence. Out of 1929 eligible patients, 49.6% (956) received Tamoxifen (TMX), 37.6% (726) received Aromatase inhibitors (AI), and 12.8% (247) switched between regimens (TMX to AI or AI to TMX). Median follow-up was 12.1 years (3.75 - 21.41 years). During this period, all-type recurrence (ATR) occurred in 9.3% of all patients, with higher rates in the TMX recipients (12.2%). Locoregional and contralateral recurrence were identified in 10.6% of TMX recipients, 6.5% of patients who switched regimens, and 5% of AI recipients. In all patients, 5.4% were diagnosed with distant metastasis, with slightly higher rates in the TMX recipients (6.4%). Multiple sites in the bone, lung, liver and brain (34.3%) was the most prevalent location of distant metastasis (DM), followed by soft tissue (20%), liver (16.2%), bone (10.5%), lung (8.6%), and other locations. Significant differences in recurrence-free survival (RFS) were observed between hormone therapy groups (p=0.004, log-rank test). Mean overall RFS was 20.4 years (95% C.I. 20.1-20.9 years). TMX recipients had a mean RFS of 19.8 years, AI recipients had a mean RFS of 18.3 years and those who switched regimens had a mean RFS of 21.9 years. Further analysis showed premenopausal patients who switched regimens had higher RFS (p=0.014). No significant difference in RFS was seen between premenopausal patients receiving AI or Tamoxifen, or amongst post-menopausal patients with different hormone therapy regimens. No significant difference in distant metastasis-free survival (DMFS) was observed between hormone therapy groups (p=0.442). Mean overall DMFS was 21.5 years (95% C.I. 21.2 - 21.8 years), with TMX patients 21.1 years, AI patients at 18.6 years, and those who switched regimens at 21.4 years. Sub-analyses of DMFS in pre and postmenopausal patients with different hormone therapy regimens showed no significant differences. Multivariate analysis showed tumor size ≤ 2cm (p= 0.0001) and negative axillary node involvement (p= 0.0001) significantly decreased odds of developing late all-type recurrence (ATR) in TMX recipients. In patients who switched regimens, Her2 positivity (p=0.04) significantly decreased the odds of late ATR. In AI recipients, not undergoing axillary operation (p = 0.008) significantly increased the odds of late ATR. For TMX recipients, negative axillary node involvement (p=0.004), tumor size ≤ 2cm (p=0.03), and undergoing mastectomy (p=0.02) significantly decreased odds of distant metastasis (DM). Among patients who switched regimens, adjuvant anti-Her2 therapy (p=0.02) significantly decreased odds of DM. For AI recipients, high PR score (p=0.02) and undergoing sentinel lymph node biopsy significantly decreased odds of DM, while age < 50 years significantly increased odds of developing DM. These findings emphasize the significance of the relationship between hormone therapy regimens and factors affecting late recurrence, thereby providing valuable insights for clinical decision-making. Risk stratification based on identified factors can help in identifying patients at higher risk of late recurrence allowing for more intensive surveillance and potentially early intervention. Univariate (Chi-square, Logistic Regression) and Multivariate Analysis (Logistic Regression) for Clinicopathologic factors associated with all-type recurrence and distant metastasis after surgery and completion of 5-years endocrine therapy Table. a. LN lymph node b. SLNB, Sentinel lymph node biopsy c. ALND, Axillary lymph node dissection d. Cutoff values of Ki67 14% in KUAH and 10%in SNUH e. ER and PR cutoff value is 10% f. UV, Univariate analysis, MV multivariate analysis, O.R. Odds Ratio, C.I. Confidence Interval Citation Format: Mary Rose Mendoza, Eun-Shin Lee. Factors Influencing Late Recurrence in Breast Cancer: A Comprehensive Analysis of the Impact of Hormone Therapy Regimens [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 PO5-01-12.

Palbociclib Combined with an Aromatase Inhibitor in Patients with Breast Cancer with Lung or Liver Metastases in US Clinical Practice.

A cyclin-dependent kinase 4/6 inhibitor combined with endocrine therapy is the standard of care for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC), but real-world effectiveness data for patients with lung or liver metastases are limited. This retrospective study included data from the US Flatiron Health database of patients with HR+/HER2- mBC and lung or liver metastases treated with first-line palbociclib (PAL) plus an aromatase inhibitor (AI) or an AI alone in routine clinical practice. Overall survival (OS) and real-world progression-free survival (rwPFS) were assessed. A total of 891 patients were included (622 with lung metastasis, 376 with liver metastasis, and 107 with both lung and liver metastasis). After stabilized inverse probability of treatment weighting to balance patient characteristics, PAL + AI versus AI alone was associated with significantly prolonged OS (HR = 0.62; p < 0.001) and rwPFS (HR = 0.55; p < 0.001) in patients with lung metastases and numerically longer OS (HR = 0.73; p = 0.056) and significantly longer rwPFS (HR = 0.57, p < 0.001) for those with liver metastases. Overall, PAL + AI versus AI alone was associated with prolonged OS and rwPFS in routine clinical practice, supporting the use of first-line PAL + AI for patients with HR+/HER2- mBC with lung and/or liver metastases.

P-REALITY-X: Real-world evaluation of overall survival with palbociclib plus aromatase inhibitor in HR+/HER2- metastatic breast cancer

Dr Hope S. Rugo presents a real-world evaluation of overall survival with palbociclib plus aromatase inhibitor in patients with HR+/HER2- MBC.

280P Adjuvant aromatase inhibitors in patients with PIK3CA mutation early breast cancer

280P Adjuvant aromatase inhibitors in patients with PIK3CA mutation early breast cancer

Real-world treatment patterns and effectiveness of palbociclib plus an aromatase inhibitor in patients with metastatic breast cancer aged 75 years or older.

Elderly patients are generally underrepresented in oncology clinical trials; therefore, real-world data are needed to inform clinical management of elderly patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). This subanalysis of the P-REALITY X study (NCT05361655) evaluated palbociclib treatment patterns and comparative effectiveness of palbociclib plus an aromatase inhibitor (AI) versus an AI alone among patients with HR+/HER2- mBC aged ≥ 75 years treated in routine clinical practice in the United States. This retrospective observational cohort study used electronic health records from the Flatiron Health Analytic Database. Palbociclib treatment patterns, overall survival (OS), real-world progression-free survival (rwPFS), and time to chemotherapy (TTC) were evaluated. Three methods were used for comparative analyses: (1) an unadjusted analysis, (2) stabilized inverse probability treatment weighting (sIPTW; primary analysis), and (3) propensity score matching (PSM; sensitivity analysis). A total of 961 patients aged ≥ 75 years with HR+/HER2- mBC were identified who started palbociclib plus an AI (n = 313) or an AI alone (n = 648) as first-line (1L) therapy between February 2015 and March 2020 (data cut-off: September 30, 2020). Among patients in the palbociclib plus an AI group with a documented palbociclib starting dose (n = 306), approximately 75% started palbociclib at 125 mg/day, and approximately 40% experienced dose adjustment. After sIPTW, patients treated with palbociclib plus an AI versus an AI alone had significantly improved OS (median of 43.0 vs. 32.4 months; hazard ratio [HR], 0.66 [95% confidence interval (CI), 0.51-0.84]; P = 0.0007), rwPFS (median of 20.0 vs. 15.0 months; HR, 0.72 (0.59-0.89); P = 0.0021), and TTC (median of 40.2 vs. 27.4 months; HR, 0.69 [0.55-0.87]; P = 0.0014). These significant improvements in OS, rwPFS, and TTC remained consistent in the unadjusted analysis and after PSM. This real-world comparative analysis demonstrated that 1L palbociclib plus an AI is associated with improved effectiveness compared with an AI alone among patients with HR+/HER2- mBC aged ≥ 75 years. These findings support palbociclib plus an AI as a standard-of-care 1L treatment for elderly patients with HR+/HER2- mBC.

Real-world outcomes of patients with metastatic endocrine-responsive breast cancer receiving palbociclib-based combinations.

Aim: To describe treatment journey and clinical outcomes after palbociclib initiation in HR+/HER2- breast cancer patients across multiple lines. Materials & methods: Adult patients (n=559) were identified in a population-based study between January 2018 and June 2020. Results: Median follow-up time was 41.2months. The starting dose was 125mg for more than 85% of patients, and a third had dose reduction. Median time on treatment was 30.5months for palbociclib + aromatase inhibitors for patients that receivedfirst-line treatment after metastatic diagnosis, and 12.6months for palbociclib + fulvestrant across multiple lines, andlonger for patients that had adose reduction during treatment. At 48months, 59.3 and 27.3% of patients were still alive, respectively. Subsequent lines resulted in median time on treatment of 4.4-7.7months in both groups. Conclusion: Time on treatment for palbociclib was comparable to data from clinical trials, and follow-up allowed us to examine subsequent treatment after initial treatment failure. Dose reduction was common in the real-world setting and did not adversely affect efficacy.

Initiation of Antiresorptive Drug Treatment during Endocrine Therapy for Breast Cancer—A Retrospective Cohort Study of 161,492 Patients in Germany

The aim of this retrospective cohort study was to measure the proportion of women with an initial prescription of an antiresorptive drug (bisphosphonates or denosumab) during five years of endocrine breast cancer therapy. The study included women with an initial prescription of tamoxifen (TAM) or aromatase inhibitors (AIs) between January 2016 and December 2020. Kaplan-Meier analyses were performed to show the cumulative incidence of antiresorptive drug prescription for TAM and AIs separately for four age groups. A univariable Cox proportional hazards regression model was also used to estimate the relationship between initial endocrine drug (AIs vs. TAM) and antiresorptive drug prescription. Within 5 years, 14.1% of patients on AI and 6.1% on TAM received their first prescription for an antiresorptive drug (p < 0.001). The difference between AI and TAM was greatest in women ≤50 years (12.9% of AI and 2.8% of patients on TAM), and smallest in women >80 years (14.5% of AI and 10.3% of patients on TAM). The proportion of denosumab was 46.2% among AI patients vs. 29.1% among patients on TAM (p < 0.001) as alendronate was prescribed to 36.9% of AI vs. 50.0% of patients on TAM. Across all age groups, the cumulative incidence of antiresorptive drug prescriptions was higher in patients with BC treated with AI than those receiving TAM. Denosumab was most frequently used as an antiresorptive drug in patients treated with AI, while alendronate was administered more often in patients treated with TAM.

Abstract P3-01-15: Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in African American (AA) patients with metastatic breast cancer (MBC)

Abstract Background: Randomized clinical trials and a growing body of real-world evidence have demonstrated clinical benefit of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy for HR+/HER2- (MBC). In the National Comprehensive Cancer Network (NCCN) guidelines, CDK4/6i + AI or Fulvestrant is recognized as a preferred regimen for HR+/HER2- MBC. Disparities in survival and clinical outcomes between AA and white breast cancer patients are well documented, but AA patients were not well represented in CDK4/6i randomized clinical trials. We compared real-world progression free survival (rwPFS) and overall survival (OS) of palbociclib plus AI (PB+AI) vs AI alone in AA patients with HR+/HER2- MBC in US clinical practices. Methods: The Flatiron Health longitudinal database contains electronic health records from &amp;gt;280 cancer clinics representing &amp;gt; 2.4 million actively treated cancer patients in the US. We conducted a retrospective analysis of 270 AA patients from the Flatiron database with HR+/HER2- MBC who started PB+AI or AI as first-line therapy between February 2015 and March 2020, Patients were evaluated from start of PB+AI or AI to September 30, 2020 (Data cutoff date), death, or last visit, whichever came first. OS was defined as months from start of PB+AI or AI to death. Patients were censored at the end of the study if they were living. rwPFS was defined as months from start of PB+AI or AI to death or disease progression, evaluated based on clinical assessment or radiographic scan/tissue biopsy. Cox proportional-hazards models were used to estimate the relative effectiveness of PB+AI vs AI without and with adjustment of baseline demographics and clinical characteristics. Results: Of the 270 eligible patients, 127 (47.0%) were treated with PB+AI and 143 (53.0%) were treated with AI. Median age was 64.0 years in PB+AI patients and 68.0 years in AI patients, respectively. Median follow-up was 24.0 months for PB+AI and 18.2 months for AI treated patients. Compared with AI patients, those treated with PB+AI were more likely to have de novo MBC (48.6% vs 30.8%) and to have ≥2 metastatic sites (41.7% vs 29.4%). Of the PB+AI patients, 82.7% started PB at 125mg/day and 30.7% experienced dose adjustment. Median OS was not reached (NR, 95%CI=(38.2-NR)) in PB+AI patients vs 28.2 months (95%CI=19.2-52.8) in AI patients (HR=0.46, 95%CI=0.31-0.68, p =&amp;lt; 0.001; adjusted HR=0.56, 95%CI=0.36-0.89, p=0.013). Median rwPFS was 18.0 months (95%CI = 12.4 – 26.7) in PB+AI patients and 10.5 months (95%CI=7.0-13.4) in AI patients (HR=0.63, 95%CI=0.44-0.88, p &amp;lt; 0.007; Adjusted HR=0.74, 95%CI=0.47-1.17, p =0.199). Conclusions: This comparative analysis of palbociclib plus AI vs AI alone provides evidence that first-line palbociclib in combination with endocrine is associated with improved effectiveness for AA patients with HR+/HER2- MBC in the real-world setting. Additonal studies with larger cohorts are needed to provide additional evidence of outcomes and safety for AA patients in routine clinical practice. Table. Patient characteristics and effectiveness outcomes Citation Format: Hope Rugo, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Rachel M. Layman, Adam M. Brufsky. Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in African American (AA) patients with metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-15.

Abstract P6-05-35: Cost-effectiveness of CDK4/6 inhibitors in the first-line treatment of HR+/HER2- metastatic breast cancer in postmenopausal women in Panama

Abstract Background: 4/6 kinase-dependent cyclin inhibitors have been approved for use in combination with first-line aromatase inhibitors in patients with hormone-sensitive, Her 2neu negative metastatic breast cancer. These agents have significantly improved progression-free survival compared to monotherapy aromatase inhibitors. The purpose of this study was to evaluate the cost-evaluation of each of these new agents (palbociclib, ribociclib, and abemaciclib) in the first line in Panama with the perspective of the National Oncological Institute. Methods: A partition survival analysis was carried out that includes three states (free of progression, progression, and death) with cycles of one month and a time horizon of 7.5 years. The efficacy data were taken from pivotal clinical trials, and the costs were estimated locally. A deterministic and probabilistic sensitivity analysis of the Monte Carlo was performed. Results; According to the base case, the update of each of these strategies involved an increase of USD 355,184 per additional QALY for ribociclib with Letrozole compared to Letrozole; USD 944,148/additional QALY for Palbociclib plus Letrozole; and USD 223,956 for Abemaciclib plus Letrozole, when compared with Letrozole, all above the availability threshold to pay 50,000/QALY. Conclusion: Despite the improvement in progression-free survival, none of the strategies have proved cost-effectiveness in our setting. Price negotiations, cost reduction, and risk-sharing agreements between pharmaceutical companies and payers might improve access to new drugs in countries with limited resources. Citation Format: Omar O. Castillo-Fernandez, Maria Lim, Lilian Montano. Cost-effectiveness of CDK4/6 inhibitors in the first-line treatment of HR+/HER2- metastatic breast cancer in postmenopausal women in Panama. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-35.

Role of ribociclib in treatment of luminal Her-2-negative mBC with CNS metastases

For patients with the metastatic subtype of luminal HER-2-negative (HR+/HER2-) breast cancer (mBC) in the absence of visceral crisis, the gold standard of treatment is a combination of CDK4/6 inhibitors and aromatase inhibitors, regardless of their menopausal status and the sites of metastasis. The effectiveness of this approach was confirmed in the MONARCH, PALOMA, MONALEESA study cycles for the drugs abemaciclib, palbociclib and ribociclib, respectively. Metastasis in the central nervous system (CNS) in breast cancer complicates the treatment of patients and leads to the search for new approaches to the choice of therapy. To date, neurosurgical and radiosurgical techniques are actively used, however, drug therapy still stands for the leading positions. Data on the use of CDK4/6 inhibitors or aromatase inhibitors in patients with CNS metastases are limited. Most studies did not include patients with CNS metastases, only PALOMA-2,3 and MONALEESA-3 studies allowed the inclusion of patients with either “inactive” CNS metastases or after exposure to local treatment methods (for example, radiosurgery, radiotherapy, or surgery). In the study of real clinical practice of combined endocrine therapy with ribociclib (CompLEEment-1) allowed the inclusion of patients with active brain metastases (n = 51), while the subgroup analysis demonstrated the benefits of using a combination of ribociclib and aromatase inhibitors in patients in this difficult clinical situation. In the article, the authors review the available data from randomized clinical trials and real clinical practice, and also illustrate with their own observation.

Hormone Receptor Expression in Primary and Recurrent High-Grade Serous Ovarian Cancer and Its Implications in Early Maintenance Treatment.

Endocrine therapy is an effective treatment for low-grade serous ovarian cancer. However, the role of estrogen and progesterone receptors as biomarkers for high-grade serous ovarian cancer (HGSOC) is yet to be elucidated because not all estrogen and progesterone receptor-positive tumors benefit from anti-estrogen therapy. The degree of expression is presumed to play a vital role; however, that role is not well-defined in ovarian cancer. We aimed to determine the role of estrogen and progesterone receptor expression in primary and paired relapsed HGSOC. In this study, primary and matched relapsed tumor samples were collected from 80 patients with International Federation of Gynecology and Obstetrics Stage II-IV HGSOC. Tissue microarray was conducted and immunohistochemistry for estrogen and progesterone receptor expression was performed. Two independent pathologists performed the tissue microarray analysis with the Immunoreactive Score and Allred Total score. In the paired analysis, no significant difference in estrogen receptor expression was observed. However, progesterone receptor expression was significantly lower in patients with recurrent platinum-sensitive HGSOC. We conclude that anti-estrogen therapy targeting estrogen receptor positive HGSOC could be administered in primary and relapsed settings. The use of endocrine maintenance with an aromatase inhibitor in patients with estrogen receptor positive HGSOC needs to be further evaluated and validated in a randomized controlled trial.

Phase II Study Combining Pembrolizumab with Aromatase Inhibitor in Patients with Metastatic Hormone Receptor Positive Breast Cancer.

Simple SummaryAromatase inhibitors (AIs) remain key elements of endocrine therapy for patients with hormone receptor positive HER2 negative metastatic breast cancer (HR+ HER2− MBC). Recent advances include the use of CDK 4/6 inhibitors or PIK3CA inhibitor in the clinic; however, few immunotherapy trials have been conducted in HR+ HER2− metastatic disease. The current phase II trial was designed to test the safety and efficacy of AIs in combination with immune checkpoint inhibitor pembrolizumab in patients with HR+ HER2− MBC (NCT 02648477). This combination was well tolerated, but minimal clinical activity was observed likely due to lack of PD-L1 pre-selection and heavily pretreated patient population.This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT 02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR+ HER2− MBC; RECIST v1.1 measurable disease; adequate organ function; and ECOG 0-1. Primary endpoints were safety and overall response rate. A 3-at-risk design was used for the safety lead-in with a targeted accrual of 20 patients. Grade 2 adverse events (AEs) included 35% fatigue, 20% rash, and 10% hot flashes. Grade 3 immune-related AEs (irAEs) related to pembrolizumab included 5% elevated AST/ALT, 5% rash, and 5% lymphopenia. Two (10%) patients had partial responses, three (15%) had stable disease, and 15 (75%) had progression of disease. Median progression-free survival was 1.8 months (95% CI 1.6, 2.6), median overall survival was 17.2 months (95% CI 9.4, NA), and median follow-up time was 40.1 months (range 31.3–46.8 months). The combination was well tolerated, but clinical activity was comparable to AI alone.

A multicentre study with real-world data of the use of palbociclib in the treatment of breast cancer: Treatment duration correlates with dose reductions.

Palbociclib, a highly selective reversible CDK4-6 kinase inhibitor, is indicated in combination with an aromatase inhibitor or in combination with fulvestrant in women who had received prior endocrine treatment. Studies have demonstrated the efficacy of palbociclib in combination with fulvestrant in increasing progression-free survival in patients who relapsed or progressed on previous endocrine therapy, or in combination with aromatase inhibitor in patients who had not received previous treatments. We analysed the prescribing patterns of palbociclib in real practice correlating it with the evidence of treatment-related toxicity management and to time-to-treatment discontinuation and treatment adherence. For the observational, retrospective study, data were collected from five Italian hospital centres that prescribed palbociclib between April 2017 and April 2020. Each centre provided data derived from an administrative database of adult patients treated with palbociclib for the two therapeutic indications.Treatment adherence was calculated using the proportion of days covered method while time-to-treatment discontinuation was defined as the difference between the first and last date treatment was administered plus the days ideally covered by the last date treatment was given. There were 375 patients enrolled during the study period, of whom 159 were treated with palbociclib and aromatase inhibitor and 216 were treated with palbociclib and fulvestrant. The time-to-treatment discontinuation was 8.9 months in the case of P + f (95% CI: 7.1-12.7) and 13.7 months in the case of P + ia (95% CI: 8.9-17.5). In both cohorts, treatments that received at least one dose reduction had a statistically higher time-to-treatment discontinuation than those without dose reduction (17.7 months vs. 9.2 and 16.6 vs. 7.4).The mean adherence in our study was 0.9 and remained high in treatments with one dose reduction (0.83) and this with two dose reductions (0.87). Based on these findings, it appears that the management of toxicities through reducing doses, as required by the Summary of Product Characteristics, results in a better outcome in terms of therapy duration, and therefore time to failure due to progression or toxicity.

ROR1 and BMI-1 proteins as potential predictors of the effectiveness of hormone therapy in luminal breast cancer

The purpose of the study was to generalize information regarding the molecular and biological mechanisms involved in the resistance to endocrine therapy with aromatase inhibitors in patients with luminal breast cancer. Material and Methods. The literature search was conducted using Medline, Cochrane Library, Elibrary and PubMed databases. Results. The review highlights the results of international studies on molecular and biological characteristics of breast tumors and their relationship with the effectiveness of hormone therapy. Particular attention was paid to the description of modern studies on ROR1 and BMI-1 proteins and their contribution to the development of tumor resistance to treatment. Conclusion. The analysis of the world literature confrms the relevance of studying the molecular and genetic characteristics of tumor tissue in patients with luminal breast cancer. The data obtained were compared to the clinical course and response to hormone therapy in order to standardize them for implementation in everyday practice as the “gold standard of diagnosis”.

Phase I study combining pembrolizumab and aromatase inhibitor in patients with metastatic hormone receptor–positive breast cancer.

1053 Background: Aromatase inhibitor (AI) is standard of care for patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). The current phase I trial was designed to test the safety and efficacy of AI and the immune checkpoint inhibitor pembrolizumab (NCT 02648477). Methods: Key eligibility criteria were HR+ HER2- MBC per ASCO/CAP; RECIST 1.1 measurable disease; adequate organ function; and ECOG 0-1. Eligible patients received 200 mg pembrolizumab IV every 3 weeks plus AI until progression or unacceptable toxicity. Primary objectives were to evaluate the safety and efficacy of this combination. This study employed a 3-at-risk design with a lead-in at the standard dosing of both AI and pembrolizumab with a targeted accrual of 20 patients. Results: A total of 20 patients were accrued between March 2016 and April 2017. Median age was 62 (range 34-79), with 75% white, 15% Asian and 10% unknown. Median lines of therapy were 3 (0, 9). All but one patient received aromatase inhibitor and/or fulvestrant prior to enrollment. The combination was well tolerated, and the most common adverse events were grade 2 fatigue (35%), rash (15%), and hot flashes (10%). Grade 3 adverse events were elevated AST/ALT (5%), rash (5%), and lymphopenia (5%). Responses were 10% partial response and 15% stable disease, resulting in a clinical benefit rate (CBR) of 20% at 6 months. Median follow-up time was 40.1 months (range 31.3 – 46.8 months). Median progression free survival was 1.8 months (95% CI 1.6, 2.6) and median overall survival was 17.2 months (95% CI 9.4, NA). 14 tumor specimens had programmed death ligand 1–positive (PD-L1) by 22C3 testing, including 3 PD-L1-positive and 11 PD-L1 negative. No association between PD-L1 and response was found. Conclusions: The combination of pembrolizumab and AI is well tolerated in patients with HR+ HER2- MBC who were not pre-selected for PD-L1. There was minimal overall clinical activity observed beyond what was to be expected with AI alone in this group of patients. Clinical trial information: NCT 02648477.

Socioeconomic disparities in supportive therapy use and tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer.

523 Background: Socioeconomic disparities impact breast cancer survival with significantly higher mortality among women of lower socioeconomic status. Little is known about how disparities affect patients with early-stage hormone receptor positive (HR+) breast cancer (BC) and patients’ tolerance and adherence to standard of care adjuvant aromatase inhibitor (AI) therapy. AI-related adverse effects are common and can cause therapy intolerance and early discontinuation. Supportive therapies have been shown to improve symptom tolerability when utilized by patients. This study assessed socioeconomic disparities in utilization of supportive therapies and adherence to initial AI therapy. Methods: We performed a retrospective chart review of all female patients at our academic institution with early-stage, HR+, BC who were initiated on adjuvant AI between 2011-2020. We collected information on side effects, duration of first AI and use of supportive therapies. We linked median family income with zip codes based on national census data and sorted them based on the Pew Research Center categorization. Primary endpoints were the rate of discontinuation of AI at 1-year and utilization of supportive therapies in relation to income, insurance coverage and primary language. The Fisher's exact test, Pearson's Chi-squared test, and Wald test methods were used to compare rates of discontinuation of front-line AI therapy and use of supportive therapies for each group. Results: We identified 1006 patients of whom 95% (n = 954) had AI related side effects yet only 31% (n = 311) received supportive therapies in the first year of AI treatment. The majority (59%) of patients were in the middle-income range ($52,200-$156,000), followed by upper (24%) and lower (17%) income. Upper-income was associated with higher use of supportive therapies (OR 1.46, p = 0.031) but was not associated with lower 1-year discontinuation rate. Medicare was the most common insurance coverage (45%), followed by Commercial (32%) and Medicaid (23%). English was the primary language for 86% of patients. Neither insurance coverage nor primary language was associated with either endpoint. In evaluating race, Black patients had the least use of supportive therapies (p &lt; 0.001), yet this group had the lowest 1-year discontinuation rate (p = 0.005). Conclusions: Our results demonstrate that income and race were associated with use of crucial supportive therapies that are proven to help patients mitigate AI toxicities. The etiology of these disparities is likely multifactorial and requires further study to ensure equitable care and access for all patients.

Abstract P1-17-06: Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer

Abstract Background: Aromatase inhibitors (AIs) are part of standard endocrine therapy for hormone receptor (HR)-positive breast cancer (BC) and are used in both adjuvant and metastatic settings. Since AIs work by inhibiting the conversion of androgens to estrogen in peripheral adipose tissue, the higher levels of estrogen in obese patients may lead to incomplete inhibition by AIs and influence their efficacy. A retrospective analysis of the ABCSG-12 trial found that overweight premenopausal patients with early-stage BC treated with anastrozole had a 60% increased risk of disease recurrence and more than doubling in risk of death compared with normal weight patients on anastrozole. Similarly, an exploratory analysis from the ATAC trial found that in post-menopausal women with early-stage BC, overall recurrence rates were lower in patients randomized to anastrozole versus tamoxifen but in women with body mass index (BMI) &amp;gt; 30, there was no significant difference in disease recurrence between anastrozole and tamoxifen. While these findings raise concern for the efficacy of adjuvant AI therapy in obese patients with early-stage BC, this has not yet been demonstrated in the metastatic setting. The aim of this study was to determine the impact of BMI on efficacy of AIs in patients with metastatic HR-positive BC. Methods: We performed a retrospective chart review of all female patients with metastatic HR-positive BC on an AI in first- or second-line settings and seen at our academic institution between 2001-2020. The primary endpoint was progression-free survival (PFS), defined as the time from start of AI to disease progression or death from any cause. PFS was compared across BMI groups using Kaplan-Meier curves and log-rank tests. Cox proportional hazards regression model was used for univariate and multivariate analyses. Results: We identified 219 patients who had received an AI in the first- or second-line settings for metastatic HR-positive BC and with documented information on BMI. The median age was 59 with 45% of patients White, 29% African American, 16% Hispanic/Latino, 5.5% Asian and remainder other/unknown. 32% (71) had HER-2 positive disease. 82% (179) were on an AI in the first-line setting. Overall, 53% were on letrozole, 42% on anastrozole and 5.5% on exemestane. Of the 219 patients, 56% (123) had a low BMI (defined as &amp;lt; 27 kg/m2) and 44% (96) had a high BMI (≥ 27 kg/m2; based on the Breast Cancer Weight Loss [BWEL] trial). The median PFS was 21.9 months (95% CI, 14.5 to 28.4) in the low BMI group versus 20.2 months (95% CI, 14.3 to 27.5) in the high BMI group with no statistically significant difference (p =0.73). There were 8 (6.5%) deaths in the low BMI group and 7 (7.3%) deaths in the high BMI group. Multivariate cox regression model did not demonstrate any significant impact of BMI on PFS when adjusting for age, race/ethnicity, HER2 status, type of AI, line of therapy, drug partner and type of metastatic disease (HR =0.91, 95% CI =0.64 to 1.30, p =0.6 for high BMI group). Subgroup analysis of patients on an AI in the first line setting also did not show a significant difference in PFS with median PFS 19.3 and 18 months in the low and high BMI groups, respectively. Conclusions: In patients on an AI for metastatic HR-positive breast cancer, there was no statistically significant difference in PFS in patients with low versus high BMI. While BMI influences efficacy of AIs in the adjuvant setting, our results demonstrate that in the metastatic setting, BMI does not significantly impact the efficacy of AIs among our patient population. This discrepancy could be due to other differences in disease characteristics that make complete aromatase inhibition more important in the adjuvant setting when disease burden is the lowest. Additional larger studies are needed to confirm this finding. Citation Format: Rima Patel, Zhiqiang Li, Brittney S. Zimmerman, Marc Y. Fink, Jason D. Wells, Xiang Zhou, Kristin L. Ayers, Arielle Redfern, Scott Newman, Rong Chen, William K. Oh, Amy Tiersten. Impact of body mass index on the efficacy of aromatase inhibitors in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-06.

Abstract P5-18-11: Impact of supportive therapies on tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer

Abstract Background: Aromatase inhibitors (AI) are standard of care in the treatment of early-stage hormone positive (HR+) breast cancer (BC). Commonly, these medications cause significant side effects which limit tolerability and often require a change in therapy. Supportive therapies are an essential part of treatment plans to improve adherence and quality of life. Studies in the last decade have demonstrated the critical role of supportive management in mitigating side effects from AI, such as the reduction in AI related joint pain with acupuncture or use of low dose oxybutynin for hot flashes. The aim of this study was to evaluate the real world use of supportive therapies for AI toxicities over the last decade and to determine if they were associated with patient adherence to initial AI treatment. Methods: We performed a retrospective chart review of all female patients at our academic institution with early-stage, HR+ BC who were initiated on adjuvant AI therapy between 2011-2020. From the electronic medical record, we collected information on patient demographics, AI side effects (hot flashes, vaginal dryness, joint pains, osteopenia/osteoporosis), use of supportive therapies, and duration of first AI therapy. Primary endpoint was the rate of discontinuation of AI at 1 year among those who used supportive therapies compared with those who did not. The Wilcoxon rank sum test, Fisher's exact test, Kruskal-Wallis rank sum test, and Pearson's Chi-squared test methods were used to compare rates of discontinuation of front-line AI therapy for each group. Results: We identified 990 patients (pts) with early-stage, HR+ BC who were started on adjuvant AI between 2011-2020. Of these patients, 97% (n= 963) had AI related side effects yet only 51% (n=504) received supportive therapies. The overall discontinuation rate within 1 year was 14.8% (147 of 990 pts). Patients who received at least 1 supportive therapy were more likely to remain on AI and had a lower 1 year discontinuation rate of 10% (51 of 504 pts) compared to 20% (96 of 486 pts) for those who did not receive any supportive therapy (p&amp;lt;0.001). The most commonly used supportive therapies were bone strengthening agents, with 35.6% (n=352) of patients receiving either denosumab or zoledronic acid, followed by acupuncture used in 11.2% (n=111) of patients. The use of acupuncture increased in 2018, compared to years prior (35 pts from 2011-2017, and 76 pts from 2018-2020). Similarly, oxybutynin use increased in 2019, compared to years prior (9 pts from 2011-2018, and 28 pts from 2019-2020). Upon further analysis, younger age was significantly associated with a higher 1 year discontinuation rate (median age 62 years in &amp;lt;1 year AI treatment group, and 64 years in &amp;gt;1 year AI treatment group, p=0.003). Race also appeared to have an impact on AI tolerance. Although only 31% (39 of 126 pts; p &amp;lt; 0.001) of Black patients received supportive therapy, this group had the lowest 1 year discontinuation rate at 8.7% (11 of 126 pts). Conversely, 56% (277 of 491 pts) of White patients received at least one supportive therapy, yet had the highest 1 year discontinuation rate at 17% (83 of 491 pts). Conclusions: Supportive therapies are essential to help patients mitigate side effects of AI. Patients who received at least one supportive therapy had increased rates of AI adherence beyond 1 year compared to those who did not receive any supportive treatment. The most commonly used therapies were bone strengthening agents and acupuncture. Use of acupuncture and low dose oxybutynin have increased in the past 3 years and 2 years, respectively, following publication of their efficacy. It is critical to further evaluate the impact that race and age have in relation to duration of treatment and use of supportive management. Further studies on how to improve patient tolerability and adherence to AI therapy are needed. Citation Format: Melanie W Kier, Zhiqiang Li, Brittney S Zimmerman, Rima Patel, Yunchen Yang, Mark Y Fink, Jason D Wells, Xiang Zhou, Scott Newman, Rong Chen, Eric Schadt, William Oh, Amy Tiersten. Impact of supportive therapies on tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-11.

Sulindac Improves Stiffness and Quality of Life in Women Taking Aromatase Inhibitors for Breast Cancer.

To examine benefit of sulindac for relief of musculoskeletal symptoms (MSS) in patients stable on aromatase inhibitors (AIs). Sulindac was evaluated at 150mg twice daily for effects on MSS at 3, 6, 9, and 12months in 50 postmenopausal women stable on AI therapy for a median of 12.5months for hormone receptor-positive breast cancer. A separate, non-randomized group of 50 similar patients was observed for change in MSS over 12months. MSS severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Brief Pain Inventory Short Form (BPI-SF). The Functional Assessment of Cancer Therapy-General form (FACT-G) measured quality of life (QOL). Change in MSS and QOL across time was assessed in each group using linear mixed effects models. Stiffness, not pain, was the main complaint at baseline. At 12months, sulindac patients reported decreases (improvements) in mean (95% CI) Total WOMAC score [- 5.85 (- 9.73, - 1.96)] and WOMAC pain [- 5.40 (- 10.64, - 0 .18)], Stiffness [- 9.53 (- 14.98, - 4.08)] and Physical Function [- 5.61 (- 9.62, - 1.60)] subscales, but not BPI-SF worst pain. Among sulindac patients with higher baseline MSS severity, 35% experienced ≥ 50% improvement in Total WOMAC and Total FACT-G scores [6.18 (2.08, 10.27); P = 0.003]. For the observation group, MSS and QOL did not improve over 12months, even among those with higher baseline MSS severity. Sulindac may relieve MSS in AI patients, especially physical function and stiffness. Randomized controlled trials should further evaluate NSAIDs on AI-MSS and AI adherence. NCT01761877, December, 2012.