Adjuvant CDK4/6 inhibitors in hormone receptor-positive early breast cancer: one fits all?

Hormone receptor positive (HR⁺), human epidermal growth factor receptor 2 negative (HER2⁻) breast cancer is the most common subtype of breast cancer encompassing up to 75% of cases (1). Endocrine therapy (ET) is the backbone of treatment for this cancer subtype across all stages. In HR⁺/HER2⁻ early breast cancer (EBC), treatment is administered with curative intent, and the addition of adjuvant ET following local treatment with or without chemotherapy, has significantly improved patient outcomes by reducing the risk of recurrence (2). However, around 30% of patients still experience relapse over time (2). Even among those patients with node-negative disease, 22% will eventually relapse within 20 years of diagnosis. Considering this risk and the significant outcomes improvements observed with the introduction of cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors among patients with HR⁺/HER2⁻ advanced breast cancer, these agents have been investigated in the early setting (3). Abemaciclib was the first CDK4/6 inhibitor approved for use in the adjuvant setting for clinically-pathologically defined high-risk EBC patients, based on the results of the MonarchE trial, which demonstrated a significant benefit in terms of invasive disease-free survival (iDFS) after 2 years of treatment in combination with ET (4).

Slamon et al. reported the positive results of NATALEE trial, an open label randomized phase III study in which patients considered at high-risk of recurrence with stage II and III EBC (including node negative patients) were randomly assigned 1:1 to standard adjuvant ET (non-steroidal aromatase inhibitors, NSAI) for ≥5 years with or without ribociclib for 3 years (5). The NATALEE trial enrolled a total of 5,101 patients from January 2019 to April 2021, with a median age of 52 years (range, 24–90 years). The trial met its primary endpoint of iDFS. The preplanned second interim efficacy analysis after 426 events had occurred, showed a 3-years iDFS favoring the ribociclib arm [hazard ratio (HR), 0.75: 95% confidence interval (CI): 0.62–0.91: P=0.003] with an absolute iDFS improvement of 3.3% (90.4% vs. 87.1%). It should be noted that 33.8% of patients in the ribociclib arm discontinued treatment early, compared to the 24.2% of patients in the ET-only arm. Moreover, at the time of the analysis, only 20% of patients had completed the 3 years of ribociclib plus ET; however, the primary results maintained significance at a recent update including 42.8% patients completing 3 years of experimental treatment (HR, 0.749; 95% CI: 0.628–0.892; P=0.0006) (6). The iDFS benefit was consistent among prespecified subgroups, including stage and nodal status. A potential lower benefit was suggested in the subset of patients who did not receive chemotherapy. The update presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting focused on the efficacy in the node negative (N0) population (n=613). Patients with N0 disease were included in the study if they had T2–4 tumors (i.e., ≥ stage IIA). For those with T2N0 disease (stage IIA), eligibility required an additional high-risk feature: grade 3 tumors or grade 2 with Ki67 ≥20% or classification as high-risk according to a genomic profiling assay. The N0 population was constituted predominantly by stage IIA patients (74%) with high-risk features, especially grade 3 and Ki67 ≥20%. The data showed consistent results in this population, with ribociclib plus ET improving the 3-year iDFS rate of 2.6% vs. NSAI alone (93.2% vs. 90.6% respectively; HR, 0.72; 95% CI: 0.41–1.27) after a median follow-up of 38.7 months (7). Regarding the type of first iDFS event in the whole population, distant recurrences were the most common, with 120 cases (4.7%) vs. 170 cases (6.7%) in the ribociclib and ET-only arms respectively, mostly in bone and liver in both groups. The magnitude of benefit persists across all subgroups also at the latest update of this study presented at the recent 2024 European Society for Medical Oncology (ESMO) Congress after 4 years of follow-up with an overall reduction of invasive disease recurrence by 28.5% compared with ET only (8).

All CDK4/6 inhibitors (palbociclib, abemaciclib, and ribociclib) have been tested in high-risk EBC setting. The PALLAS and the PENELOPE B trials failed to demonstrate the potential value of adding palbociclib to ET (9,10). In the PENELOPE-B trial, 1,250 HR⁺/HER2⁻ EBC patients defined at high risk of relapse because of residual disease after neoadjuvant chemotherapy were randomized to receive palbociclib for 1 year vs. placebo, in addition to ET. Instead, the PALLAS study was more similar to the MonarchE and NATALEE trials, enrolling HR⁺/HER2⁻ EBC patients (n=5,796) based on anatomical stage (II and III) to receive 2 years of palbociclib plus ET vs. ET alone. Potential explanations for the lack of efficacy may include different duration of drug exposure (1 year for the PENELOPE-B trial), known different drug efficacy (11), more important probably the variations in the enrolled populations with different risk definitions, duration of planned treatment, adherence to the drug (cumulative incidence of early palbociclib discontinuations was 44.9% in the PALLAS trial) and side effects (9,10).

Abemaciclib and ribociclib have both shown a benefit in reducing iDFS events in the early setting. Both were large trials, with more than 5,000 patients enrolled. Nonetheless, not all race groups were equally represented, with low enrollment of Black American patients (2% in both trials). This underrepresentation is a clear limitation in terms of translating the results into everyday clinical practice. Different racial groups may experience adverse events (AEs) and benefit from CDK4/6 inhibitors differently, warranting further investigation (12,13). Moreover, a special note regarding the eligibility criteria, both trials focused on enrolling high-risk patients, though there were important differences. The MonarchE trial enrolled patients with a very high anatomical risk (≥4 positive nodes or 1–3 positive nodes if primary tumor ≥5 cm) or high anatomic risk plus biological risk (1–3 positive nodes with tumor grade 3 or Ki67 ≥20%). The NATALEE trial expanded the cohort of high-risk patients including high genomic risk and stage II N0 disease, which may be the reason for a minor differential iDFS benefit. In both trials, most patients enrolled were stage III.

Both MonarchE and NATALEE trials reduced the number of distant events; however, neither required staging imaging as part of the screening and eligibility assessment before trial enrollment.

In the MonarchE trial, patients randomized to the experimental arm received a standard dose of abemaciclib at 150 mg twice a day for two years. In contrast, the NATALEE trial tested a longer exposure of 3 years with a lower dose (400 mg daily) than the standard 600 mg per day used in the metastatic setting. The main reason for this choice was to improve patients’ compliance to the treatment, as it has been demonstrated that the lower dose does not affect the efficacy of the drug in the advanced setting (14).

While the NATALEE trial marks a significant stride forward in the adjuvant treatment of high-risk HR⁺/HER2⁻ breast cancer patients, it is essential to scrutinize the nuances beneath the surface of these promising results. Amidst the excitement surrounding the potential benefits of ribociclib, there are critical limitations and concerns that must be addressed.

The number of patients needed to treat to prevent one distant event in the trial is 51, based on the available data and follow-up. It is common knowledge that only a portion of patients with EBC will experience recurrence; by definition, adjuvant therapy ends up overtreating many patients in the effort to cure a few additional ones.

These challenges, ranging from financial burdens to the broader implications of widespread adjuvant therapy, paint a complex picture that warrants careful consideration. After the NATALEE trial and the potential approval of ribociclib for this indication, the proportion of patients treated with CDK4/6 inhibitors in the adjuvant setting will increase considerably, prompting a reasonable consideration about cost-effectiveness. Three years of ribociclib treatment costs around $500,000 in the United States, with a $27 million expenditure to avoid one distant iDFS event. This is related to the unequivocable financial toxicity expected with the introduction of this drug into the clinical practice, particularly in middle- and low-income countries. The simple cost of the drug needs to be added to the collateral costs of the increased number of medicalized EBC patients. These costs include more frequent hospital visits, increased demands on physicians and healthcare personnel, additional blood work and tests, and management of potential AEs, which we are already experiencing after the introduction of adjuvant abemaciclib for high-risk EBC patients. It is also important to address that real-world unselected patients may present comorbidities and polypharmacotherapy that may increase the complexity, higher risk of AEs and related medical intervention. The rapid increase in patient volume must be addressed by policymakers and may have consequences for the medical community in determining which CDK4/6inhibitor to reimburse, based on factors such as toxicity, treatment duration, and overall cost. Adaptation from a minimal follow-up to a more intense work-up should be evaluated before a broad implementation in real-world care.

Moreover, improving outcomes of our patients means achieving better duration and quality of overall survival (OS). So far, OS data from the NATALEE trial are not mature and is not possible to extrapolate OS impact based on the iDFS benefit observed, as the latter is not a complete surrogate of the former. The MonarchE trial data showed that OS did not reach statistically significant difference among arms after 54 months of follow-up, showing only a small numerical absolute difference (15). Time will show us if ribociclib will achieve better or similar results. In fact, considering the molecular heterogeneity of HR⁺ metastatic breast cancer (MBC), it is conceivable that progression after adjuvant CDK4/6 inhibitor will present particularly challenging, therefore potentially reducing the benefit of current regimens in advanced setting (16). Experience in the metastatic setting has shown that resistance mechanisms acquired by the tumor after treatment with CDK4/6 inhibitors—such as RB1 and PTEN loss, ESR1 and ERBB2 mutations, among others—can lead to very aggressive disease behavior, reducing OS and limiting the availability of subsequent effective treatments (17,18). The lack of OS benefit observed in the MonarchE trial may be related to the selection of patients with more resistant disease at relapse after adjuvant treatment, potentially still harboring minimal residual disease (MRD), thus representing the first example of introducing CDK4/6 in such a cohort of micrometastatic disease.

Considering that in the adjuvant setting we are treating the risk, broadening the pool of patients eligible for adjuvant treatment escalation does not equate identifying those at higher risk of relapse. Therefore, the next step in the era of precision medicine is to identify which high-risk HR⁺/HER2⁻ EBC patients will benefit the most from the escalating adjuvant therapy besides traditional recognized risk factors (19), thereby avoiding unnecessary toxicities and costs. The introduction of MRD monitoring through circulating tumor DNA (ctDNA) detection could help tailor treatment by moving beyond classical risk factors (e.g., stage, grade, and genomic risk profile) and focusing on the actual presence of residual disease. Several studies have reported an increased risk of relapse in patients who are ctDNA-positive after surgery (20), and this should be the primary target for treatment escalation strategies. In the CDK4/6 inhibitor adjuvant studies, blood samples were collected longitudinally for ctDNA analysis. The ctDNA study conducted on a cohort of patients (n=910) of the MonarchE trial, showed the prognostic role of ctDNA dynamics through longitudinal blood collection (pretreatment, 3, 6, 9, and 24 months) using the personalized tumor-informed ctDNA assay Signatera^TM (21). ctDNA detection was highly prognostic for recurrence with a relatively short lead time. Patients who were persistently negative or becoming ctDNA-negative during the treatment with abemaciclib exhibited a more favorable outcome. In the PENELOPE-B trial, a similar longitudinal collection was performed on 78 patients (pre-treatment, at cycle 7, and at the end of treatment), showing consistent high-risk for iDFS events in patients persistently or becoming ctDNA-positive (HR, 6.47, 95% CI: 2.19–19.12, P=0.0007) using a personalized tumor-informed ctDNA assay (RaDaR^TM) (22). Current data on ctDNA utility are still constrained by the use of tumor-informed assays, which may fail to detect relapses that occur under treatment-induced selective pressure, where the disease may exhibit resistance mutations. In the MonarchE trial, approximately 14% of patients with persistently negative ctDNA still experienced a relapse; future studies using tumor-agnostic tests may reveal more insights. The exploratory analysis on the impact of ribociclib benefit based on ctDNA status is awaited. Other ongoing studies like the DARE trial (NCT04567420), which explore ctDNA-guided second-line adjuvant therapy (23), will demonstrate the clinical utility of treatment escalation with CDK4/6 inhibitors through ctDNA monitoring in the early setting. This trial will assess whether treatment with palbociclib and fulvestrant improves relapse-free survival compared to continued standard adjuvant ET in ctDNA-positive patients without evidence of metastatic disease on standard imaging.

The NATALEE trial represents a significant advancement in the adjuvant treatment of high-risk early-stage HR⁺/HER2⁻ breast cancer patients. While the trial demonstrates a clear benefit in iDFS, several challenges remain, including potential financial toxicity, adequate racial representation, and long-term OS outcomes. The expanded eligibility criteria of the NATALEE trial, compared to previous studies, may lead to risky and costly broader applicability in the management of these patients and the real-world benefit would have to be demonstrated. Future research should focus on optimizing patient selection to maximize benefits and minimize unnecessary exposure to treatments and associated AEs. The incorporation of precision medicine approaches, such as MRD monitoring through ctDNA detection, could further refine treatment strategies. Longer follow-up periods are essential for randomized clinical trials in the adjuvant setting, particularly for HR⁺/HER2⁻ patients, to fully understand the impact on OS and ensure that intermediate clinical endpoints strongly correlate with long-term outcomes. Ultimately, while the introduction of ribociclib in the adjuvant setting is promising, it is crucial to balance efficacy with cost-effectiveness and to consider the individual patient’s perspective. Reducing the risk of metastatic relapse remains a critical goal, and individualized, patients-centered approach will be the most effective path forward.

Acknowledgments

Funding: This work was supported by an American-Italian Cancer Foundation Post-Doctoral Research Fellowship (to E.N.).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Breast Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-24-41/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-24-41/coif). M.C. serves as an unpaid editorial board member of Translational Breast Cancer Research from April 2023 to March 2025. M.C. reports personal fees from Lilly, Sermonix, Data Genomics, Foundation Medicine, Guardant Health, Celcuity, Iylon, and Ellipses and grants and personal fees from Pfizer, AZ and Menarini, all outside the submitted work. E.N. is supported by an American-Italian Cancer Foundation Post-Doctoral Research Fellowship. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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