Exploring the treatment gap and outcome risks in patients with node-positive, high-risk, HR-positive, HER2-negative early breast cancer: analyses of real-world data.

Introduction
Most breast cancers are diagnosed early, before metastatic spread to distant sites.1 Hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer comprises ∼70% of all early breast cancers (EBCs).2 Until recently, adjuvant endocrine therapy (ET) has been the standard of care for patients with HR-positive disease. However, subgroups of patients at high risk of recurrence can now be offered cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor treatment in addition to ET to reduce their risk of recurrence.3, 4, 5, 6 The monarchE trial of adjuvant abemaciclib added to ET enrolled two distinct cohorts of patients with node-positive (N+) disease. Cohort 1 comprised patients with four or more positive axillary lymph nodes (ALNs) or those with one to three positive ALNs with additional high-risk clinicopathological features (histological grade 3 or tumor size ≥5 cm), and cohort 2 comprised patients with one to three positive ALNs with Ki-67 ≥20%, histological grade <3, and tumor size <5 cm.7 Adjuvant abemaciclib plus ET is approved by the United States Food and Drug Administration (FDA) for reducing the risk of recurrence in N+, high-risk, HR-positive, HER2-negative EBC (based on the monarchE cohort 1 population which represented 91% of patients in the trial) and is recommended in treatment guidelines.8, 9, 10 In the monarchE trial, patients received adjuvant abemaciclib for 2 years plus the choice of either tamoxifen or an aromatase inhibitor followed by ET alone for 3-8 years versus ET alone for 5-10 years.3 The primary endpoint was invasive disease-free survival (IDFS) and a key secondary endpoint was overall survival (OS), both of which were alpha-controlled, allowing statistical significance to be tested.3,11 Two years of treatment with abemaciclib in combination with ET resulted in sustained efficacy at 5 years (hazard ratio 0.680). Five-year IDFS rates were 83.6% for abemaciclib plus ET versus 76.0% for ET alone, representing a 7.6% absolute benefit at a median follow-up of 54 months.4,11 Notably, the addition of abemaciclib to ET reduced the proportion of patients who developed metastatic disease by ∼50%.4 A recent analysis with median follow-up of 76 months demonstrated a statistically significant and clinically meaningful OS benefit (hazard ratio 0.842) and sustained IDFS and distant relapse-free survival (DRFS) benefits at 7 years.11
Despite the well-known treatment benefit of adjuvant abemaciclib plus ET for patients with N+ disease at high risk of recurrence, single-institution studies report adjuvant abemaciclib utilization rates of <50% in eligible patients since the 2021 United States FDA approval of abemaciclib for EBC.12,13 Rajendran et al.13 reported lower utilization rates among eligible patients, particularly those with one to three positive ALNs, potentially reflecting a misperception that these patients have a low risk of recurrence. Lower prescribing rates were also observed for older patients; however, this is not unexpected and is consistent with previous reports of older patients receiving lower intensities of adjuvant therapy.14
A previous real-world study reported that about one in three patients meeting the inclusion criteria for the monarchE intent-to-treat population experienced disease recurrence within 5 years, mostly as distant metastases, which contrasts with the ∼1 in 10 risk of recurrence at 5 years for patients without these high-risk features.15 However, the risks of recurrence and mortality by nodal status within the FDA-approved population have not been reported. Evaluating these risks in nonclinical trial datasets offers an additional perspective in a broader real-world population when compared with clinical trial observations. Hence, the current study aimed to characterize the utilization patterns of adjuvant abemaciclib within a large, contemporary, multi-institutional, United States-based cohort and to describe real-world risks of recurrence and death by nodal status in patients with N+, high-risk, HR-positive, HER2-negative EBC meeting eligibility for adjuvant abemaciclib but receiving standard ET alone. Results will help to inform optimal care and treatment decisions in this curative setting.

Materials and methods
To address the study objectives, two different datasets were used, along with separate analyses for each. Patient consent was not required as this study used deidentified data and does not constitute human subject research according to the Common Rule; as such, institutional review board approval was not required.

Study designs and patient populations

Study 1: utilization of adjuvant abemaciclib
The first retrospective study used data from the electronic health record-derived, deidentified United States-based Flatiron Health research database.16 Selection criteria included female or male patients with a breast cancer diagnosis after 1 January 2011 who were ≥18 years of age at the time of abemaciclib EBC approval, had stage IA-IIIC disease at initial diagnosis, and had undergone breast cancer surgery. Patients must have had N+ disease with a high risk of recurrence, defined as N1 or N1 with micrometastases (N1/N1mi) disease with histological grade 3 or tumor size ≥5 cm (defined as T3 or T4, which could have been based on clinical staging if the patient received neoadjuvant chemotherapy), N2 disease, or N3 disease (i.e. patients meeting monarchE cohort 1 criteria) (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2025.106021). Patients were required to have initiated standard adjuvant ET, with their HR-positive, HER2-negative status determined before the start of adjuvant ET, and have ≥3 months of follow-up. Patients were excluded if they received adjuvant fulvestrant, participated in a clinical trial, or received a neoadjuvant or adjuvant CDK4/6 inhibitor before the abemaciclib approval date in the United States for EBC. To reflect the current indication and recent adoption in practice, the cohort was restricted to patients who initiated standard adjuvant ET between 1 January 2023 and 31 March 2024. Utilization of adjuvant abemaciclib was assessed through 30 June 2024, allowing for ≥3 months of follow-up.

Study 2: recurrence and mortality by risk features
In the second retrospective study, data were also obtained from the United States-based Flatiron Health database16 but were limited to a smaller dataset of ∼16 000 patients diagnosed with EBC since January 2011 for whom more abstracted variables were available. Patients were selected if they met monarchE inclusion criteria and had received adjuvant ET only. A second group of patients with early triple-negative breast cancer (eTNBC)—recognized as one of the highest-risk breast cancer subtypes with an urgent need for effective therapeutic intervention17—was included for context. Selection criteria included patients who are female or male, ≥18 years of age at initial diagnosis, with pathological stage IA-IIIC disease or pathological complete response (in which case clinical staging was used), and who had undergone breast cancer surgery. For the HR-positive, HER2-negative cohort, patients must have initiated standard oral adjuvant ET on or before 31 December 2023, with their HR-positive, HER2-negative status determined before the start of adjuvant ET. Patients were excluded if they received any adjuvant targeted agent, fulvestrant, or had inflammatory breast cancer. Patients were grouped on the basis of whether they met inclusion criteria for the monarchE trial [N+ high-risk disease (N+ high-risk group)] or not (non-high-risk group) and whether or not they met the eligibility criteria for monarchE cohort 1 (as described in the study 1 description), with patients further categorized by nodal status. When reporting results for cohort 1, patients with features of monarchE cohort 2 (i.e. N1/N1mi disease with Ki-67 ≥20%, histological grade <3, and tumor size <5 cm) were not included in the non-high-risk group.
For the eTNBC cohort, patients must have initiated adjuvant chemotherapy on or before 31 December 2023, and had their HR-negative, HER2-negative status determined before the start of adjuvant chemotherapy. Details for patient groups are listed in the attrition Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025.106021. The data cut-off date was 30 June 2024.

Statistical analysis

Study 1: utilization of adjuvant abemaciclib
Baseline characteristics were summarized descriptively for patients who did and did not receive abemaciclib. A multivariable logistic regression model was used to evaluate the association between selected covariates and abemaciclib utilization. Odds ratios with 95% confidence intervals were estimated for each covariate. Covariates included age, race/ethnicity, region/practice setting, Eastern Cooperative Oncology Group performance status, medical insurance, socioeconomic status index, Ki-67, BRCA status, group stage, tumor stage, nodal status, histological grade, menopausal status, radiotherapy, adjuvant chemotherapy, neoadjuvant chemotherapy, and time from surgery to adjuvant ET.

Study 2: recurrence and mortality by risk features
Patient and disease characteristics were summarized descriptively for all groups. The Kaplan–Meier method was used to estimate IDFS, DRFS, and OS. For the HR-positive, HER2-negative EBC and eTNBC groups, outcomes were calculated from the initiation of adjuvant ET and adjuvant chemotherapy, respectively. To address the difference in time points from which outcomes were calculated, sensitivity analyses were conducted using initial diagnosis for the N+ high-risk, non-high-risk, and eTNBC groups. IDFS was defined as the earliest event of locoregional recurrence, distant recurrence, or death. DRFS was defined as the earliest event of distant recurrence or death. Patients without events were censored at the last structured electronic health record activity date before the data cut-off date. For the HR-positive, HER2-negative cohort, multivariable Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals for the high-risk versus non-high-risk groups. Adjustment factors were age, race, menopausal status, resection status, histology, progesterone receptor status, BRCA status, Eastern Cooperative Oncology Group performance status, and Oncotype DX Breast Recurrence Score®. For the HR-positive, HER2-negative cohort, outcomes were also assessed for N+ subgroups.
Results for patients with disease features corresponding to the monarchE cohort 1 population and associated nodal groups are presented in the ‘Results’ section. Results for patients with disease features similar to the monarchE intent-to-treat population are presented in the Supplementary Material (Supplementary Table S1, Supplementary Figures S3-S6 available at https://doi.org/10.1016/j.esmoop.2025.106021).

Results

Study 1: utilization of adjuvant abemaciclib
Among the 3170 patients who met the eligibility criteria to receive adjuvant abemaciclib plus ET, 1902 (60.0%) did not receive this treatment (Figure 1). The median age of eligible patients was 62.0 years, and most were White, non-Hispanic, and treated at community practice sites. Nearly 50% of patients had stage II disease. Among the patients with pathological staging of 1-3 positive ALNs (n = 1738), 81.8% had N1 and 18.2% had N1mi disease. Notably, 69.1% of patients with N1/N1mi disease did not receive abemaciclib (66.9% with N1 high-risk and 78.5% with N1mi high-risk disease; Figure 2A), despite 73.5% of patients with N1/N1mi high-risk disease having grade 3 tumors. Nonutilization was also notable in N2 and N3 groups (49.8% and 44.9%, respectively). Among patients ≥65 years of age, 70.1% did not receive abemaciclib, with nonutilization increasing with older age (Figures 1 and 2B). Despite eligibility, lower utilization of abemaciclib was also observed for Hispanic/Latino patients and patients with stage I disease. Logistic regression models demonstrated consistent results for utilization of abemaciclib (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.106021). Of note, factors that did not impact abemaciclib use included insurance type, socioeconomic status index, and practice setting (academic versus community).

Study 2: recurrence and mortality by risk features

Baseline characteristics
Among the 6350 patients with HR-positive, HER2-negative EBC who met eligibility for study inclusion, 696 were in the N+ high-risk group based on selection criteria for cohort 1 in monarchE,7 5654 were in the non-high-risk group, and 515 met eligibility for the eTNBC group (Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2025.106021). Within the N+ high-risk group, 52.0% had N1/N1mi, 31.0% had N2 (four to nine positive ALNs), and 17.0% had N3 (≥10 positive ALNs) disease. Within the non-high-risk group, 731 patients (12.9%) had N1/N1mi disease with no additional high-risk feature (i.e. grade <3, tumor size <5 cm, or Ki-67 <20%).
Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.106021, describes baseline patient and disease characteristics. Approximately two-thirds (62.7%) of patients in the N1/N1mi high-risk group had stage II disease, and a majority (80.9%) had histological grade 3 tumors. Notably, grade 3 tumors were also common in the eTNBC group (83.5%) (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.106021).

Outcomes in the N+ high-risk, eTNBC, and non-high-risk groups
Overall, 5-year IDFS rates were similar for patients in the N+ high-risk (70.9%) and eTNBC groups (74.3%) and were higher in the non-high-risk group (91.2%). The absolute difference in the 5-year risk of recurrence was 20.3% between the N+ high-risk and non-high-risk groups (Figure 3A). Similar patterns were seen for DRFS and OS but with smaller absolute differences observed between the N+ high-risk and non-high-risk groups (Figure 3B and C). Adjusted hazard ratios for N+ high-risk versus non-high-risk groups were ≥2.3 for all outcomes. Results from the sensitivity analyses using initial diagnosis demonstrated consistent results for all outcomes, with similar 5-year rates for N+ high-risk and eTNBC groups and higher rates for the non-high-risk group (Supplementary Figure S6, available at https://doi.org/10.1016/j.esmoop.2025.106021).

Outcomes in the N+ high-risk group by nodal status versus non-high-risk group
All patients in the N+ high-risk nodal subgroups (i.e. N1/N1mi high-risk, N2, and N3) had a higher probability of developing invasive disease, distant disease, or death at 5 years compared with patients in the non-high-risk group (Figure 4A-C). Adjusted hazard ratios for the N+ high-risk nodal subgroups versus non-high-risk group were ≥2.2 for IDFS and DRFS and ≥1.9 for OS.

Outcomes in the N1/N1mi high-risk group versus non-high-risk group
To better understand risk within the N1/N1mi population, comparisons of IDFS, DRFS, and OS were assessed in the N1/N1mi high-risk versus N1/N1mi non-high-risk groups (Figure 5A-C). The absolute difference in 5-year IDFS and DRFS rates was 14.3% and 12.7%, respectively. Adjusted hazard ratios for the N1/N1mi high-risk versus N1/N1mi non-high-risk groups were ≥1.6 for all outcomes.
Outcome results for patients reflecting monarchE intent-to-treat inclusion criteria were similar to those presented previously for patients with features of the monarchE cohort 1, including sensitivity analyses (Supplementary Table S1, and Figures S3-S5 and S7, available at https://doi.org/10.1016/j.esmoop.2025.106021).

Discussion
Abemaciclib is the first CDK4/6 inhibitor to demonstrate a clinically meaningful reduction in the risk of recurrence in N+ high-risk disease with a 2-year treatment period when combined with physician’s choice of ET. Recent results with a 76-month median follow-up showed that this IDFS/DRFS benefit is sustained for 7 years and that there is a statistically significant OS benefit.11 In the NATALEE trial, 3 years of ribociclib plus a nonsteroidal aromatase inhibitor reduced risk of recurrence in a broader HR-positive, HER2-negative EBC patient population (i.e. patients with N0 disease plus additional risk factors and patients with stage II or III N+ disease), with most recent results at 55 months of median follow-up showing IDFS benefit (hazard ratio 0.716).18 Ribociclib was approved by the FDA for this EBC population in September 2024.19
The present utilization study was assessed through June 2024, when only abemaciclib had regulatory approval in the adjuvant setting.
Despite the substantial reduction in metastatic recurrence with abemaciclib treatment in combination with ET relative to ET alone in patients with N+ high-risk disease, this United States real-world multi-institutional study found that 60.0% of abemaciclib-eligible patients did not receive this treatment in the curative setting despite their high risk of developing incurable metastatic disease. The two main factors associated with adjuvant abemaciclib underutilization were age and nodal status.
The use of adjuvant abemaciclib decreased with increasing age, and 70.1% of eligible patients over 65 years of age did not receive abemaciclib. A possible explanation for this might be that a higher incidence of preexisting comorbidities is known to increase with age and there may be concern that treatment intensification could aggravate these conditions. None the less, data from the monarchE trial demonstrated a consistent treatment benefit across younger and older age subgroups.4,14,20 Similarly, tolerability concerns among older patients may contribute to underutilization. Although most patients experience diarrhea with abemaciclib, it has a predictable onset, is mainly low-grade, and can be effectively managed with dose reductions without impacting efficacy.21 Of note, adverse event rates in monarchE were similar between age subgroups in patients treated with abemaciclib, whether defined as ≤40 years versus >40 years or <65 years versus ≥65 years, although dose reductions and treatment discontinuations were more common in the older age groups.14,20,21 Moreover, in monarchE and in United States clinical practice, the vast majority of patients remained on treatment, and the proportion staying on treatment was higher if they had a dose reduction.21,22 These studies suggest that abemaciclib is tolerated by most patients and a majority of patients in this high-risk population stay on treatment to benefit from the reduction in risk of recurrence.
A second major factor associated with utilization of adjuvant abemaciclib was nodal status. More patients with one to three positive ALNs (which included patients with micrometastases) and an additional high-risk factor of grade 3 or tumor size ≥5 cm did not receive abemaciclib compared with those with N2 or N3 disease. Among eligible patients with one to three positive ALNs who were not treated with abemaciclib, most had grade 3 tumors, suggesting that more attention may be needed for this critical risk factor. Furthermore, there may be a perception that the risk of recurrence is considerably lower in patients with N1/N1mi disease than in patients with four or more positive ALNs and that standard-of-care adjuvant ET may be sufficient to reduce recurrence. Understanding outcomes in the eligible population (N+ high-risk disease) may help guide patient selection and treatment planning; therefore, a second study was conducted to describe the risks of recurrence and mortality in this population.
The 5-year risk of recurrence was 29.1% in the N+ high-risk group compared with 8.8% in the non-high-risk group. A similar trend was observed for mortality, with a 5-year risk of mortality of 18.4% in the N+ high-risk group versus 6.1% in the non-high-risk group. A striking finding was that the risks of recurrence and mortality among patients eligible for adjuvant abemaciclib, when treated with ET alone, were similar to those of patients with eTNBC, underscoring the high unmet need in patients with N+ high-risk features. In eTNBC, the 5-year risk was similar to the N+ high-risk group with 5-year risks for recurrence and mortality of 25.7% and 20.7%, respectively. Together with the consistent results across IDFS and DRFS endpoints, these data collectively highlight the considerable risk of developing metastatic disease with standard ET alone in the N+ high-risk group and the need for additional treatment intensification to prevent recurrence. The 5-year rates of IDFS and DRFS for the N+ high-risk group in this study are all lower than those observed for the ET-alone arm of cohort 1 in the monarchE trial (70.9% versus 75.3% and 72.5% versus 78.5%, respectively).4 These differences further underscore the unmet need in this high-risk population and may be explained by poorer prognostic characteristics in the real-world cohort, including older age, worse performance status, and lower rates of neoadjuvant and adjuvant chemotherapy.4,23
N1 disease has been previously recognized as lower risk than N2 and N3 disease,24 but special consideration needs to be made when N1 disease is paired with the other high-risk features selected in monarchE. The current analyses demonstrated that patients in all nodal subgroups in the N+ high-risk group were at higher risk than patients in the non-high-risk group, including those in the N1/N1mi group. Furthermore, the 5-year risks of recurrence and mortality for the N1/N1mi high-risk group were almost double that of the N1/N1mi non-high-risk group, with a 14.3% difference in recurrence risk and 6.3% difference in mortality risk. These data demonstrate the distinct elevated risks in the N1/N1mi high-risk group. The increased recurrence risks across nodal groups presented here, together with the consistent treatment benefit across all N+ subgroups in monarchE,4 suggest that all eligible patients should be evaluated for adjuvant abemaciclib. In clinical practice, other strategies are used to differentiate risk in patients with N1/N1mi disease, such as the Oncotype DX Breast Recurrence Score, to predict those who may benefit from chemotherapy.25 In the monarchE trial, where patients were included based on select high-risk clinicopathological risk features, benefit from adjuvant abemaciclib was observed regardless of the derived 21-gene recurrence score or Ki-67 levels.4,26,27
Limitations should be considered for these real-world studies. For the utilization study, it should be noted that patient comorbidities, financial barriers, and discussions between patients, caregivers, and treating physicians were not captured in the database and could have influenced the decision for treatment with abemaciclib. It is also unknown which disease characteristics were accessible or considered when making treatment decisions. Although lower utilization of abemaciclib was also observed among Hispanic/Latino patients, the relatively small size of this population limited further analyses. However, our results align with other studies that have showed lower rates of adjuvant chemotherapy and longer time to treatment among Hispanic patients with breast cancer.28, 29, 30 For the outcomes by risk features, >50% of patients did not have Ki-67 results, and these patients may have been incorrectly classified as non-high-risk, yielding an overestimation of risk for the non-high-risk group and underestimation of relative risk for the N+ high-risk group. This potential misclassification is limited to patients with N1/N1mi disease, but would impact all presented comparisons. Based on differences in real-world IDFS and DRFS between patients who met monarchE cohort 1 and intent-to-treat eligibility, where Ki-67 is included as a high-risk feature, increases of ∼2% in absolute differences in 5-year rates between high-risk and non-high-risk groups and small increases in HRs might be expected. Finally, caution should be considered when comparing outcomes for the HR-positive, HER2-negative EBC and eTNBC groups as the analyses for eTNBC began from the start of adjuvant chemotherapy, although sensitivity analyses using initial diagnosis for all groups provided consistent results.
There are several strengths in these real-world studies. The utilization study was based on a large sample size and multiple institutions of different types. For outcomes by risk features, the 56-month median follow-up time supported reliable 5-year outcome estimates. Furthermore, the outcome assessments from the start of ET facilitate a consistent understanding of potential effects of CDK4/6 inhibitor usage, given the variability in time since the initial diagnosis. In addition, the relatively recent study period captures current treatment options for metastatic disease when evaluating survival outcomes.

Conclusions
Despite FDA approval of adjuvant abemaciclib in the N+, high-risk, HR-positive, HER2-negative EBC population based on the monarchE trial, guidelines recommending its use,9,10 and mature clinical trial data demonstrating a carryover effect in mitigating distant recurrence, 60.0% of eligible patients in United States clinical practice did not receive abemaciclib. Since the increased risks of recurrence and mortality in patients with N+, high-risk, HR-positive, HER2-negative EBC are similar to patients with eTNBC, increased attention is needed to ensure all eligible patients, and especially those with one to three positive ALN (N1/N1mi high-risk), are evaluated for additional high-risk features and considered for treatment with approved CDK4/6 inhibitors, given poorer outcomes when treated with ET alone. Based on the treatment gap identified in this study, timely and effective communication with patients may be needed regarding the elevated risk of recurrence, the benefit of treatment intensification for both reducing recurrence risk and mortality with adjuvant abemaciclib, and the ability to effectively manage side-effects with dose reductions without compromising efficacy.