Abstract
Background
Despite standard-of-care adjuvant endocrine therapy (ET) and chemotherapy, the risk of recurrence remains in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) early breast cancer (EBC). In phase III trials with different eligibility criteria, adjuvant ribociclib (NATALEE) and abemaciclib (monarchE) demonstrated significant invasive disease survival benefit when added to ET. We present a real-world analysis of patients with HR+/HER2− EBC that are potentially eligible for NATALEE and monarchE.
Patients and methods
Data from the ConcertAI Patient360 database (January 2015-January 2023) were analyzed. The key inclusion criteria were patients ≥18 years of age with stage I-III HR+/HER2− EBC at diagnosis who had surgery and initiated adjuvant ET. NATALEE and monarchE eligibility criteria were defined per their respective trial protocols.
Results
Overall, 7060 patients met the inclusion criteria, of whom 30.6% were eligible for NATALEE and 14.5% for monarchE. All patients with N2 or N3 disease were eligible for both trials. Among 1388 (19.7%) patients with N1 disease, 91.8% and 45.9% were eligible for NATALEE and monarchE, respectively. Patients with N0 disease were 74.9% of the population, of whom 9.5% were eligible for NATALEE and none for monarchE. Among the NATALEE-eligible patients with high-risk N0 disease, most were postmenopausal (72.6%) with a grade 3 tumor (61.6%); 48.9% had received prior chemotherapy.
Conclusions
The results from this large real-world database study indicate that 30.6% of patients with HR+/HER2− EBC met the eligibility criteria for NATALEE versus 14.5% for monarchE, presenting the opportunity to improve outcomes in nearly one-third of patients with HR+/HER2– EBC at high risk of recurrence.
Key words: adjuvant, HR+/HER2− early breast cancer, CDK4/6i, NATALEE, monarchE
Highlights
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This is a real-world study of patients with HR+/HER2− EBC who are potentially eligible for the NATALEE and monarchE trials.
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Patient data from the ConcertAI Patient360 database from January 2015 to January 2023 were included in this analysis.
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Overall, 7060 patients met the study inclusion criteria, of whom 30.6% were eligible for NATALEE and 14.5% for monarchE.
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Among the 1388 (19.7%) patients with N1 disease, 91.8% were eligible for NATALEE and 45.9% for monarchE.
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This study shows outcomes can be improved in nearly one-third of patients with HR+/HER2− EBC at high risk of recurrence.
Introduction
Early breast cancer (EBC), which is localized to breast tissue and nearby lymph nodes, accounts for most patients (95%) diagnosed with breast cancer (BC).1 The hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) subtype is the most common in EBC, comprising approximately three-quarters of all patients with BC.2 Despite standard-of-care adjuvant endocrine therapy (ET) of at least 5 years (with or without chemotherapy) for systemic treatment of HR+/HER2− EBC, the risk of recurrence remains a concern, peaking within 5 years and persisting for decades after.3, 4, 5, 6, 7 A large, retrospective real-world study (N = 7564) recently showed considerable risk of recurrence in patients with positive nodal status but also in patients without nodal involvement who had additional high-risk features; 5-year risk of recurrence was 12.6% for node-negative (N0) high-risk, 12.8% for N1 (one to three positive lymph nodes), and 33.8% for N2 and N3 (four or more positive lymph nodes) subgroups.3 In addition, a recent meta-analysis of ET control arms of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) clinical trials showed that the 3-year pooled risk was 10% in patients with N0 disease (n = 711) and 14% in patients with node-positive disease (n = 7542).4 Longer-term recurrence has been demonstrated by studies in the past two decades that showed risk persisting for as long as 10-20 years after initiation of adjuvant ET.5, 6, 7
In the HR+/HER2− EBC adjuvant setting, ribociclib and abemaciclib have been investigated in the phase III NATALEE and monarchE trials, respectively, with positive results, followed by regulatory approval for both drugs in this setting in the United States.8, 9, 10, 11, 12, 13 At the second interim efficacy analysis (median follow-up, 27.7 months), NATALEE demonstrated a statistically significant invasive disease-free survival (iDFS) benefit with adjuvant ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) versus an NSAI alone [hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.62-0.91; two-sided P = 0.003] in a broad population of patients with stage II or III HR+/HER2− EBC at risk of recurrence.11 Notably, the iDFS benefit was sustained with additional follow-up (median follow-up 44.2 months; HR 0.715) at the 4-year landmark analysis.14 The monarchE trial also demonstrated a significant iDFS benefit with adjuvant abemaciclib plus ET versus ET alone (HR 0.75; 95% CI 0.60-0.93; P = 0.01; median follow-up 15.5 months), which was sustained through additional follow-up (5-year efficacy outcome analysis) at 54 months (HR 0.68) in selected patients with node-positive HR+/HER2− EBC.13,15 NATALEE and monarchE data have led to the inclusion of adjuvant ribociclib and abemaciclib in guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network (category 1) for their respective HR+/HER2− EBC trial populations.16,17 Palbociclib plus ET failed to show any iDFS benefit over ET alone in the adjuvant setting (PENELOPE-B and PALLAS trials).18,19
Although both ribociclib and abemaciclib demonstrated significant iDFS benefit, there were differences in the patient populations eligible for participation in the respective trials.13,20 monarchE excluded patients with N0 disease and included patients with N1 disease with high-risk clinical features (Ki-67 ≥20%, grade 3, and tumor size ≥3 cm) and all patients with N2/N3 disease.8,13 By contrast, NATALEE included patients with N0 disease [if stage IIA and N0 (T2N0), then grade 3, or grade 2 with Ki-67 ≥20% or high genomic risk, was required], all patients with N1 disease [except T0/T1N1 micrometastatic disease (T0/T1N1mi)], and all patients with N2 and N3 disease.11,20
Given the differences in eligibility between the trials, there is a need to understand the epidemiology of patients with HR+/HER2− EBC who are eligible for NATALEE and monarchE, including the clinicopathologic characteristics of patients in each group. Therefore, we undertook a real-world analysis of patients with HR+/HER2− EBC who are potentially eligible for NATALEE and monarchE.
Patients and methods
Overview
This was a retrospective study of patients enrolled in the ConcertAI Patient360 United States electronic health record database from January 2015 to January 2023. This database includes deidentified electronic medical records of patients treated at academic and community clinics in the United States. The study analyzed the distribution and characteristics of a real-world HR+/HER2− EBC patient population eligible for NATALEE and monarchE, including patient demographics, clinical characteristics, treatment history, and treatment patterns. Details of the study designs for NATALEE and monarchE have been published previously.8,11,13,20 Ethical review was not required for this study because the analyzed data were derived from a database, and no individual patients were identifiable.
Study population
Patients in the ConcertAI Patient360 database with a curated diagnosis for BC [any recorded International Classification of Diseases, 10th Revision (ICD-10) code for C50 or ICD-9 code for 174 or 175] were eligible to be included in the analysis. Eligible patients needed to have nonmissing sex information and be aged ≥18 years at the time of initial BC diagnosis. In addition, these patients should have undergone resection surgery, had stage I-III disease [according to the American Joint Committee on Cancer (AJCC) anatomic stage, as identified by TNM (tumour–node–metastasis) mapping closest to the time of initial diagnosis], had HR+ (estrogen receptor and/or progesterone receptor positive) and HER2− disease, and had initiated adjuvant ET. The data were analyzed at the date of first ET initiation postresection surgery (index date).
Eligibility criteria for NATALEE
Patients in the ConcertAI Patient360 database were identified as eligible for NATALEE per the criteria of the anatomic classification in the AJCC Cancer Staging Manual, eight edition. Patients with anatomic stage II or III disease regardless of nodal status were included; patients with stage IIA N0 (T2N0) disease were required to have grade 3 disease, or grade 2 disease with evidence of additional high-risk features [i.e. Ki-67 ≥20% or determination of high risk by genomic assay: Oncotype DX Breast Recurrence Score ≥26 (Exact Sciences, Madison, WI) or high-risk scores by Prosigna/PAM50 (Veracyte, Inc, South San Francisco, CA), MammaPrint (Agendia, Irvine, CA), or EndoPredict EPclin (Eurobio Scientific, Les Ulis, France)].11,20
Eligibility criteria for monarchE
Patients in the ConcertAI Patient360 database were identified as eligible for monarchE if they had four or more positive lymph nodes or if they had one to three positive lymph nodes with at least one of the following features: tumor size ≥5 cm (≥T3 was used to identify patients with tumor size ≥5 cm because details of tumor size were not available) or histological grade 3 disease regardless of Ki-67 status; these patients corresponded to cohort 1 of monarchE. Patients were also eligible if they had one to three positive lymph nodes with Ki-67 ≥20%, tumor grade <3, and tumor size <5 cm; these patients corresponded to cohort 2 of monarchE.8,13
Results
Patient selection
Attrition from patients with EBC identified from the ConcertAI Patient360 database, which comprises patient data from academic and community clinics in the United States, is shown in Figure 1. A total of 22 621 patients were diagnosed with BC, of which 22 436 patients were ≥18 years of age at diagnosis. Of those patients, 18 851 had resection surgery, with 14 639 patients having stage I, II, or III disease at initial diagnosis. Among the patients with stage I-III disease, 11 632 had an estrogen receptor-positive or progesterone receptor-positive tumor; 9967 of these patients were HER2−. Among these patients, 7060 had initiated ET in an adjuvant setting. Thus, a total of 7060 patients met the selection criteria and were included in this analysis.
Figure 1.
Flowchart showing patient selection by characteristics starting with the total population of patients with BC in the ConcertAI database (N = 22 621) and culminating with patients eligible for NATALEE (n = 2163, 30.6%) and monarchE (n = 1023, 14.5%). BC, breast cancer; ER, estrogen receptor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.
Patient characteristics in the overall population
In the overall EBC patient population analyzed (N = 7060), the median age was 63 years (range 24-87 years), and the majority of the patients were white [5694 (80.7%)] (Table 1). Among patients with known menopausal status (88.6%; n = 6257), 20.2% were pre- or perimenopausal, and 79.8% were postmenopausal. Adjuvant or neoadjuvant chemotherapy, before initiating adjuvant ET, was received by 24.1% of patients. Among patients with known Eastern Cooperative Oncology Group performance status (ECOG PS), most patients had ECOG PS ≤1 (96.4%). Patients with stage 1 disease (60.4%) represented the largest group, followed by patients with stage 2 (30.8%) and stage 3 (8.9%) disease. Most patients had N0 disease (74.9%), followed by patients with N1 (19.7%) and N2 or N3 (5.5%) disease.
Table 1.
Patient characteristics
| Total population (N = 7060) | NATALEE-eligible patients (n = 2163) | monarchE-eligible patients (n = 1023) | |
|---|---|---|---|
| Age group, n (%) | |||
| 18-49 years | 1070 (15.2) | 496 (22.9) | 250 (24.4) |
| 50-64 years | 2694 (38.2) | 846 (39.1) | 405 (39.6) |
| 65-74 years | 2164 (30.7) | 531 (24.5) | 230 (22.5) |
| >74 years | 1132 (16.0) | 290 (13.4) | 138 (13.5) |
| Median (range) | 63 (24-87) | 60 (24-87) | 59 (25-86) |
| Mean (SD) | 62.42 (11.71) | 59.69 (12.74) | 59.03 (13.06) |
| Race, n (%) | |||
| American Indian or Alaska Native | 57 (0.8) | 22 (1.0) | 13 (1.3) |
| Asian | 198 (2.8) | 68 (3.1) | 33 (3.2) |
| Black or African American | 615 (8.7) | 235 (10.9) | 112 (10.9) |
| Native Hawaiian or other Pacific Islander | 1 (<0.1) | 1 (<0.1) | 1 (0.1) |
| White | 5694 (80.7) | 1659 (76.7) | 769 (75.2) |
| Other or unknown race | 495 (7.0) | 178 (8.2) | 95 (9.3) |
| Menopausal status, n (%)a | |||
| Pre- or perimenopausal | 1265 (20.2) | 528 (28.1) | 266 (30.1) |
| Postmenopausal | 4992 (79.8) | 1351 (71.9) | 617 (69.9) |
| ECOG PS pre-endocrine index, n (%)b | |||
| 0 | 1843 (71.9) | 805 (67.4) | 446 (67.3) |
| 1 | 628 (24.5) | 333 (27.9) | 186 (28.1) |
| 2 | 74 (2.9) | 49 (4.1) | 27 (4.1) |
| ≥2 | 19 (0.7) | 8 (0.7) | 4 (0.6) |
| Tumor grade, n (%) | |||
| Grade 1 | 2203 (31.2) | 314 (14.5) | 84 (8.2) |
| Grade 2 | 3353 (47.5) | 979 (45.3) | 419 (41.0) |
| Grade 3 | 1205 (17.1) | 776 (35.9) | 478 (46.7) |
| Not available | 299 (4.2) | 94 (4.3) | 42 (4.1) |
| Tumor size, n (%) | |||
| T0 | 4 (0.1) | 4 (0.2) | 3 (0.3) |
| T1 | 4802 (68.0) | 541 (25.0) | 235 (23.0) |
| T2 | 1796 (25.4) | 1160 (53.6) | 439 (42.9) |
| T3 | 362 (5.1) | 362 (16.7) | 272 (26.6) |
| T4 | 95 (1.3) | 95 (4.4) | 73 (7.1) |
| TX | 1 (<0.1) | 1 (<0.1) | 1 (0.1) |
| Nodal status, n (%) | |||
| N0 | 5286 (74.9) | 503 (23.3) | 0 (0) |
| N1mi | 114 (1.6) | 0 (0) | 22 (2.2) |
| N1 | 1274 (18.0) | 1274 (58.9) | 615 (60.1) |
| N2 | 254 (3.6) | 254 (11.7) | 254 (24.8) |
| N3 | 132 (1.9) | 132 (6.1) | 132 (12.9) |
| Attrition stage distribution, n (%) | |||
| I | 4261 (60.4) | 0 (0) | 22 (2.2) |
| IIA | 1510 (21.4) | 874 (40.4) | 154 (15.1) |
| IIB | 662 (9.4) | 662 (30.6) | 242 (23.7) |
| IIIA | 413 (5.9) | 413 (19.1) | 413 (40.4) |
| IIIB | 82 (1.2) | 82 (3.8) | 60 (5.9) |
| IIIC | 132 (1.9) | 132 (6.1) | 132 (12.9) |
| Chemotherapy, n (%)c | |||
| Yes | 1704 (24.1) | 1202 (55.6) | 691 (67.5) |
| No | 5356 (75.9) | 961 (44.4) | 332 (32.5) |
| Neoadjuvant therapy, n (%) | |||
| Yes | 559 (7.9) | 474 (21.9) | 297 (29.0) |
| No | 6501 (92.1) | 1689 (78.1) | 726 (71.0) |
ECOG, Eastern Cooperative Oncology Group; PS, performance status; SD, standard deviation; TX, the size of the tumor cannot be assessed.
Percentage among patients with nonmissing data; 803 patients (11.4%) among the total population, 284 patients (13.1%) in the NATALEE-eligible population, and 140 patients (13.7%) in the monarchE-eligible population had missing menopausal status data.
Percentage in each ECOG performance status category was calculated from the total patients for whom ECOG data were available.
Before initiating endocrine therapy.
Patients eligible for NATALEE and monarchE
Of the 7060 patients, 2163 (30.6%) were eligible for NATALEE and 1023 (14.5%) for monarchE (Table 2). Overall, NATALEE included all patients eligible for monarchE except 22 patients with T1N1mi stage I disease; thus, 14.2% (1001/7060) of patients met the eligibility criteria for both trials. The relatively low availability of Ki-67 test results (35.5% and 33.8%) and gene expression profiling assay (5.3% and 5.7%), respectively, in the overall population and in patients with N0 disease in the database may have led to an underestimation of patient eligibility for both NATALEE and monarchE (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105304). In the case of NATALEE, there were 490 patients with stage IIA, N0 (T2N0) grade 2 disease who required Ki-67 or a gene expression profiling assay to meet inclusion criteria. However, only 248 (50.6%) of these patients had a reported result, among whom 112 (45.1%) met the inclusion criteria; as a result, 136 (54.8%) patients with T2N0 grade 2 disease were excluded from the NATALEE-eligible cohort. In a scenario analysis, to extrapolate the number included if all patients underwent testing, the same percentage of patients (45.1%) was applied to the total number of patients with T2N0 and grade 2 disease. This extrapolation showed that an estimated 109 additional patients would have been included, totaling an estimated 2272 patients eligible for NATALEE, which is 32.2% of the HR+/HER2− EBC patient population.
Table 2.
Number of patients meeting the inclusion criteria for NATALEE and monarchE
| Category | Patients, n | Total patients eligible, n (%) |
|---|---|---|
| NATALEE | ||
| Anatomic stage III | 627 | 2163 (30.6) |
| Anatomic stage IIB | 662 | |
| Anatomic stage IIA | 1510 | |
| N1 | 483 | |
| N0 | 1027 | |
| Grade 3 | 279 | |
| Grade 2 | 490 | |
| Grade 2 with genomic testing used in NATALEE | 248 | |
| Grade 2 meeting NATALEE high-risk testing criteria | 112 | |
| MonarchE | ||
| Cohort 1 (≥4 + LNs or 1-3 + LNs and tumor size ≥5 cm/histological grade 3) | 885 | 1023 (14.5) |
| Cohort 2 (1-3 + LNs and centrally tested Ki-67 ≥20%; tumor size <5 cm, histological grade <3) | 138 | |
LN, lymph node; N, node.
Patient characteristics in the NATALEE- and monarchE-eligible cohorts
The median age was 60 years (range 24-87 years) versus 59 years (range 25-86 years) in the NATALEE-eligible and monarchE-eligible cohorts, respectively; 28.1% versus 30.1% were pre- or perimenopausal, and 71.9% versus 69.9% were postmenopausal in those with known menopausal status (Table 1). Most patients had ECOG PS ≤1 (95.2% versus 95.3%). The proportion of patients with higher-grade disease (grade 3; 35.9% versus 46.7%), larger tumor size (T3; 16.7% versus 26.6%), and Ki-67 ≥20% (27.6% versus 38%) was lower in the NATALEE- versus monarchE-eligible populations (Table 1 and Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105304). Prior chemotherapy was received by 55.6% of patients in the NATALEE-eligible cohort versus 67.5% in the monarchE-eligible cohort.
Eligibility by nodal involvement
Patients with N2 or N3 disease comprised 5.5% (386/7060) of the total population; all were eligible for both NATALEE and monarchE (Figure 2 and Table 3). Patients with N1 disease comprised 19.7% (1388/7060) of the total population, of whom 91.8% [1274/1388; excluding patients with T1N1mi stage I disease, who accounted for the remaining 8.2% (114/1388)] were eligible for NATALEE and 45.9% (637/1388) for monarchE (22 patients with T1N1mi disease were included in the monarchE-eligible N1 patient population, i.e., 22/637, 3.5%). Patients with N0 disease made up 74.9% (5286/7060) of the overall population, of whom 9.5% (503/5286) were eligible for NATALEE and none for monarchE.
Figure 2.
Horizontal bar graph detailing patient numbers and percentages of patients with N0, N1, N2, and N3 disease out of the total EBC population, corresponding to four bar graphs detailing numbers and percentages of patients within each nodal status group who were eligible for NATALEE and monarchE; all patients with N2 and N3 were eligible for both trials. EBC, early breast cancer; LN, lymph node; N1mi, micrometastatic disease. aPatients with N1mi disease (114/1388, 8.3%) were not included in NATALEE. bIncludes 22 patients with N1mi disease.
Table 3.
Distribution of NATALEE- and monarchE-eligible populations by T and N staging
| Anatomical stage | T and N stage | Total population (N = 7060), n (%) | NATALEE eligible (n = 2163), n (%)a | monarchE eligible (n = 1023), n (%)a |
|---|---|---|---|---|
| Stage 1 | 4261 (60.4) | 0 (0) | 22 (19.3) | |
| Stage 1A | T1N0 | 0 (0) | 0 (0) | 0 (0) |
| Stage 1B | T1N1mi | 0 (0) | 0 (0) | 22 (19.3) |
| Stage 2A | 1510 (21.4) | 874 (57.9) | 154 (10.2) | |
| T0N1 | 2 (0.03) | 2 (100) | 1 (50.0) | |
| T1N1 | 481 (6.8) | 481 (100) | 153 (31.8) | |
| T2N0 | 1027 (14.6) | 391 (38.1) | 0 (0) | |
| Stage 2B | 662 (9.4) | 662 (100) | 242 (36.6) | |
| T2N1 | 572 (8.1) | 572 (100) | 242 (42.3) | |
| T3N0 | 90 (1.3) | 90 (100) | 0 (0) | |
| Stage 3A | 413 (5.8) | 413 (100) | 413 (100) | |
| T0N2 | 1 (0.01) | 1 (100) | 1 (100) | |
| T1N2 | 41 (0.6) | 41 (100) | 41 (100) | |
| T2N2 | 143 (2.0) | 143 (100) | 143 (100) | |
| T3N1 | 179 (2.5) | 179 (100) | 179 (100) | |
| T3N2 | 49 (0.7) | 49 (100) | 49 (100) | |
| Stage 3B | 82 (1.2) | 82 (100) | 60 (73.2) | |
| T4N0 | 22 (0.3) | 22 (100) | 0 (0) | |
| T4N1 | 40 (0.6) | 40 (100) | 40 (100) | |
| T4N2 | 20 (0.3) | 20 (100) | 20 (100) | |
| Stage 3C | 132 (1.9) | 132 (100) | 132 (100) | |
| T0N3 | 1 (0.01) | 1 (100) | 1 (100) | |
| T1N3 | 19 (0.3) | 19 (100) | 19 (100) | |
| T2N3 | 54 (0.8) | 54 (100) | 54 (100) | |
| T3N3 | 44 (0.6) | 44 (100) | 44 (100) | |
| T4N3 | 13 (0.2) | 13 (100) | 13 (100) | |
| TXN3 | 1 (0.01) | 1 (100) | 1 (100) | |
N, node; T, tumor.
Percentage using the total population in each TN category as the denominator.
Among the N1 subgroup, NATALEE-eligible patients had comparable age versus monarchE-eligible patients [median age 59 years (range 25-87 years) versus 57 years (25-86 years), respectively]. The proportion of pre- or perimenopausal patients was also similar (26.6% versus 30.7%). The subgroup of NATALEE-eligible patients with N1 disease included fewer patients with high-grade disease (grade 3; 26.6% versus 55.1%), prior chemotherapy (55.7% versus 70.7%), and Ki-67 ≥20% (22.0% versus 45.5%) compared with monarchE-eligible patients (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.105304).
Among patients with N0 disease who were eligible for NATALEE, the median age was 60 years (range 24-86 years); among those with known menopausal status, 27.4% were pre- or perimenopausal and 72.6% were postmenopausal (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.105304). Prior chemotherapy was received by 48.9% of the patients. Most tumors were grade 3 (61.6%), followed by grade 2 (33.6%) and grade 1 (4.0%).
Discussion
The results from this large, real-world database study indicated that 30.6% of patients with HR+/HER2− EBC met the entry criteria for NATALEE versus 14.5% for monarchE. With the approval of both adjuvant ribociclib and abemaciclib in the United States, the broader eligibility criteria for NATALEE (compared with monarchE) present the opportunity of adding a CDK4/6i to standard-of-care ET in a substantially larger proportion of patients with HR+/HER2− EBC who have a high risk of recurrence, including those with high-risk N0 disease.10,12 Analysis of eligibility by nodal status demonstrated that all patients with N2 or N3 disease were eligible for NATALEE (and for monarchE), as well as 91.8% of patients with N1 disease (versus 45.9% with monarchE), and 9.5% of patients with N0 disease (versus 0% with monarchE). This finding is particularly relevant in the context of the proportions of these subgroups of patients among the overall HR+/HER2− EBC real-world population; patients with N3 or N2, N1, and N0 disease constitute ∼5%, 20%, and 75% of the HR+/HER2− EBC population, respectively. Among patients with N0 disease eligible for NATALEE (503 patients; 9.5% of N0 population), 48.9% received prior chemotherapy, reflecting the likelihood that these patients were considered to have a substantial risk of recurrence. Exploratory subgroup analysis from NATALEE has shown that the addition of ribociclib to NSAI can reduce the absolute risk of recurrence in patients with high-risk N0 and N1-3 disease in a clinically meaningful way (5.1% and 5.0% at a median follow-up of 49.1 and 44.2 months, respectively).14 Importantly, there is a great unmet need among patients with N1 and N0 disease, where short- (<5 years) and long-term (>5 years) recurrences remain a concern.3, 4, 5, 6, 7 A large, retrospective, real-world study has recently shown that the 5-year risk of recurrence was 12.6% in those with high-risk N0 and 12.8% in those with N1 disease.3 Long-term risk is also a substantial concern: a meta-analysis demonstrated that the 20-year risk of recurrence was 22% in patients with N0 disease and 31% in those with N1 disease.5
The proportion of NATALEE-eligible and monarchE-eligible patients who did not receive prior chemotherapy in this real-world database was 44.4% and 32.5%, respectively, which was higher than the patients with no prior chemotherapy in NATALEE (11.9%) and monarchE (5.0%).11,13 Furthermore, the proportion of NATALEE-eligible patients with N0 disease who did not receive prior chemotherapy was higher (51.1%) than in the NATALEE trial (22.3%).21 In this analysis, all patients in the NATALEE-eligible cohort (median age 60 versus 52 years) and those NATALEE eligible with N0 disease (median age, 60 versus 55 years) were older than the respective patient groups in NATALEE and may have chosen to forgo chemotherapy to avoid the toxic adverse events associated with the treatment.11,22 Importantly, patients with no prior chemotherapy showed an iDFS benefit with ribociclib plus ET over ET alone (HR 0.82; 95% CI 0.47-1.44) in the NATALEE trial (with the caveat that it was a small subset).21
Results of this study add to and support the results of a similar real-world analysis conducted in patients with HR+/HER2− EBC eligible for monarchE from a single center in the United States.23 The study found that 11.1% of patients (499/4496) were eligible for treatment with adjuvant abemaciclib, relatively consistent with the 14.5% found in the current study. In addition, the patients eligible for adjuvant abemaciclib in the single-center study were more likely to have high-risk clinicopathologic factors—a finding that is consistent with both the current study and how the monarchE patient population was defined.8,13 However, although both studies are similar in that they are real-world studies that included a relatively large number of patients (4496 and 7060, respectively), it should be noted that key differences are likely between the two study populations. One study was based on experience at a single center (Dana-Farber Brigham Cancer Center), while the current analysis uses the ConcertAI Patient360 database, with data drawn from multiple academic and community clinics in the United States.23
Finally, the results of this study should be interpreted in the context of the unmet need and recurrence risk among patients with HR+/HER2− EBC eligible for adjuvant CDK4/6is receiving standard-of-care ET in the real world. An analysis of a real-world USA electronic health record-derived database (Flatiron Health database) of patients with HR+/HER2− EBC spanning from 2011 to 2024 has shown that despite receiving the current standard-of-care ET, both the NATALEE-eligible and monarchE-eligible patient populations had relatively high incidences of distant recurrence within 5 years (distant recurrence-free survival: 83.1% and 74.6%, respectively), highlighting the unmet need for treatment strategies that can address this risk of recurrence.24
There are some limitations to our study. Only patients who started ET were included, likely excluding those who were eligible for ET but did not initiate it. The proportion of such patients may have differed across N0-3 disease. It should also be noted that only half of the NATALEE-eligible patients with T2N0 grade 2 disease, who required Ki-67 or genomic tests to meet NATALEE criteria, had a reported result, with 45.1% of these patients meeting the NATALEE high-risk criteria. This suggests that this analysis may have underestimated the actual number of patients in the real world who met eligibility criteria for NATALEE. The ConcertAI database has a very low capture rate of genomic risk tests compared with data for patients with Ki-67 tests; real-world data, which better capture genomic testing in addition to Ki-67 tests, may have given a more accurate estimate of NATALEE eligibility. In addition, as the quantitative measurement of tumor size was not available for these data, the tumor T stage ≥T3 was used to identify tumor size ≥5 cm, which may have led to the slight overestimation of the monarchE-eligible population in this study. Finally, the ConcertAI Patient360 database only includes United States-based academic and community clinics and may not reflect patient populations in other regions of the world due to differences in disease diagnosis and management. Additional analyses of different real-world populations in other geographies may be needed to compare and contrast with these results.
In conclusion, the results of this real-world analysis demonstrated that substantially more patients with HR+/HER2− EBC were eligible for NATALEE than for monarchE. The NATALEE criteria encompassed a broader range of patients, including select patients with high-risk N0 disease and all patients with N1 disease, providing the opportunity to address the treatment needs of a larger HR+/HER2− EBC patient population beyond that of monarchE.
Acknowledgements
We acknowledge the patients and their caregivers represented by this real-world dataset, as well as the clinic staff who provided their care. Ribociclib was discovered by Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals. Medical writing assistance was provided by Shashank Tandon, PhD, Safiyya Mohamed Ali, MSc, and William Ho, PhD, of Nucleus Global, and was funded by Novartis Pharmaceuticals.
Funding
This work was supported by Novartis Pharmaceuticals Corporation (no grant number).
Disclosure
PT reports personal fees from AstraZeneca, Daiichi Sankyo, Novartis, Gilead, Eli Lilly, Roche/Genentech, and Menarini/Stemline. HSR reports grants to the institution from OBI Pharma, AstraZeneca, Pfizer, Novartis, Eli Lilly, F. Hoffmann-La Roche AG/Genentech, Merck, Daiichi Sankyo, Gilead Sciences, Stemline Therapeutics, and Ambrx; personal fees from Daiichi Sankyo, Mylan/Viatris, NAPO, and Eisai. GC reports personal fees from Roche, Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Ellipsis, Veracyte, Exact Science, Celcuity, Merck, Bristol Myers Squibb, Gilead, Sanofi, and Menarini. JAOS reports personal fees from AbbVie, Agendia, Amgen, Aptitude, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunome, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Puma, Prime, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre, Samsung, and Sanofi. WJ reports personal fees from Amgen, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, and Gilead; employment from Universitätsklinikum Ulm; speaker fees to the institution from Novartis, GSK, Sanofi, Amgen, Roche, and Lilly; and chairship of AGO Breast Council. KJ reports research grants and personal fees from Novartis, AstraZeneca, Pfizer, Genentech/Roche, Lilly Pharmaceuticals/Loxo Oncology, Scorpion Therapeutics, Eisai, and Gilead; personal fees from Bristol Myers Squibb, Jounce Therapeutics, Taiho Oncology, AbbVie, Eisai, Blueprint Medicines, Seattle Genetics, Daiichi Sankyo, Olema Pharmaceuticals, Sun Pharma Advanced Research Company, and Menarini/Stemline; research grants from Debio Pharmaceuticals, Zymeworks, Puma Biotechnology, Merck, and Context Therapeutics. JM reports research grants from Bristol Myers Squibb; personal fees from BostonGene, AstraZeneca, Gilead, and Novartis. AB reports personal fees from AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, Seagen, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma, Myriad, and Gilead; and research grants from Agendia and AstraZeneca. EH reports grants to the institution from Novartis, Pfizer, Genentech/Roche, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana, Boehringer Ingelheim, Cascadian Therapeutics, AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stemcentrx, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Millennium, TapImmune, Tesaro, Eisai, H3 Biomedicine, Radius Health, Acerta Pharma, MacroGenics, AbbVie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, NuCana, PharmaMar, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Syros, Clovis, CytomX, InventisBio, Oncothyreon, Amgen, Bristol Myers Squibb, Novartis, Accutar Biotechnology, ADC Therapeutics, Akeso Bio Australia, Aravive, ArQule, Artios, Arvinas, AtlasMedx, BeiGene, Black Diamond, Bliss BioPharmaceutical, Compugen, Context Therapeutics, Cullinan, Dana-Farber Cancer Institute, Dantari, Deciphera, Duality Biologics, Ellipses Pharma, Elucida Oncology, Fochon Pharmaceuticals, G1 Therapeutics, Gilead Sciences, Harpoon, Immunogen, Incyte, Infinity Pharmaceuticals, Inspirna, Jacobio, Karyopharm, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, MabSpace Biosciences, Molecular Templates, Myriad Genetic Laboratories, Olema, ORIC Pharmaceuticals, Orinove, Orum Therapeutics, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Repertoire Immune Medicine, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, Stemline Therapeutics, Sutro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, and Zenith Epigenetics; consulting fees paid to the institution from Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Accutar Biotechnology, Ellipses Pharma, Gilead Sciences, Olema, Stemline Therapeutics, Entos, Fosun Pharma, Jazz Pharmaceuticals, Jefferies, Medical Pharma Services, Olema Pharmaceuticals, Tempus Labs, Theratechnologies, Tubulis, Verascity Science, and Zentalis Pharmaceuticals. ROR reports personal fees from Puma and Pfizer; and research grants from Puma. LS, MA, FY, and AS report employment and stock ownership from Novartis. SLG reports personal fees from Novartis, Pfizer, AstraZeneca, Genentech, Lilly, Daiichi Sankyo, AstraZeneca, Gilead Sciences, Seagen, the Academy for Healthcare Learning, DAVA Oncology, MJH Life Sciences, WebMD/Medscape, IntegrityCE, MedPage Today, MedIQ, Medical Educator Consortium, and Research to Practice; stock ownership from HCA Healthcare; and research grants to institutions from Daiichi Sankyo, Novartis, and AstraZeneca.
Data sharing
The data in this study are from ConcertAI and were used under license.
Supplementary data
References
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