Adjuvant CDK4/6 inhibitors in early‐stage breast cancer: Clinical evidence and considerations for risk stratification and treatment selection

Abstract

Hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer is the most common biologic subtype and carries a persistent risk of recurrence, particularly in patients with high‐risk, early‐stage disease. Cyclin‐dependent kinase 4 and 6 inhibitors, initially established as a standard component of first‐line therapy in the metastatic setting based on improvements in progression‐free and overall survival, have since been evaluated in the adjuvant setting. While adjuvant palbociclib did not improve invasive disease‐free survival, the monarchE and NATALEE trials demonstrated that abemaciclib and ribociclib, respectively, reduce recurrence risk in patients with high‐risk, early‐stage disease, with emerging overall survival data further supporting their use. However, the absolute magnitude of benefit varies substantially with baseline risk, and treatment‐related toxicity and adherence challenges must be considered, as approximately 20% to 25% of patients discontinue therapy before completion. The integration of these agents into clinical practice also intersects with ongoing efforts to deescalate axillary surgery, as treatment eligibility has been largely defined by anatomic staging, particularly nodal status. Available data suggest that the incremental impact of axillary surgery on identifying candidates for cyclin‐dependent kinase 4 and 6 inhibition is modest, especially among the favorable‐risk populations now eligible for surgical deescalation. As the field evolves, advances in molecular risk stratification, genomic profiling, and dynamic biomarkers are poised to shift treatment selection from anatomic staging toward biologically driven approaches. Multidisciplinary decision‐making that integrates tumor biology, anticipated absolute benefit, toxicity, patient preferences, and surgical considerations will be essential to ensure individualized care.

Short abstract

Building on established efficacy in metastatic disease, adjuvant CDK4/6 inhibitors reduce recurrence in high‐risk HR+/HER2− early‐stage breast cancer, but eligibility does not uniformly translate into clinical benefit. Individualized, multidisciplinary treatment planning that incorporates tumor biology, absolute benefit, toxicity, and axillary management decisions is critical as the field evolves beyond anatomic staging alone.

INTRODUCTION

Hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer represents the most common biologic subtype of breast cancer and is characterized by a prolonged natural history with a persistent risk of recurrence extending well beyond the initial diagnosis. ¹ , ² High‐risk, early‐stage HR+/HER2− breast cancer is generally defined by features associated with elevated recurrence risk, including node‐positive disease (particularly with four or more positive nodes), large tumor size, high histologic grade, and elevated Ki‐67. Genomic assays such as Oncotype DX and MammaPrint further refine risk classification by quantifying the likelihood of distant recurrence independent of anatomic staging. ³ , ⁴ Standard adjuvant endocrine therapy for HR+/HER2− breast cancer includes tamoxifen, aromatase inhibitors, and ovarian function suppression, used alone or in combination based on menopausal status and recurrence risk. Extended endocrine therapy beyond 5 years is recommended for patients at higher risk of late recurrence. ⁵ , ⁶ Patients with sufficiently high clinicopathologic or genomic risk may also be candidates for adjuvant chemotherapy. ³ , ⁷ Recent data have also expanded the adjuvant endocrine therapy landscape beyond traditional agents with giredestrant, a next‐generation oral selective estrogen receptor degrader (SERD) that showed invasive disease‐free survival (iDFS) improvement when compared with standard endocrine therapy. ⁸ , ⁹

Despite many advances in screening and treatment, patients with high‐risk, early‐stage HR+ disease have experienced high rates of recurrence. Even with optimal local and systemic treatment, the risk of distant recurrence in node‐positive or otherwise high‐risk patients may exceed 20% at 10 years, with a substantial proportion of events occurring after completion of standard adjuvant endocrine therapy. ¹⁰ , ¹¹ , ¹² One explanation for these late recurrences is resistance to endocrine therapy, reflecting both intrinsic tumor biology and acquired mechanisms that emerge under the selective pressure of standard adjuvant therapy. ¹³

The management of early‐stage breast cancer has shifted toward treatment individualization with a concerted, multidisciplinary effort to both escalate and deescalate therapy based on specific clinicopathologic features. Treatment is deescalated in patients with favorable biology to minimize unnecessary morbidity, whereas it is escalated in those at highest risk for recurrence to improve long‐term oncologic outcomes. This has led to substantial changes across treatment modalities, including omission of axillary surgery in selected patients, ¹⁴ refinement of radiation strategies, ¹⁵ , ¹⁶ , ¹⁷ and the use of genomic assays to guide systemic therapy. ³ , ⁷ At the same time, advances in systemic therapy have enabled effective escalation strategies for patients with HR+/HER2− breast cancer, most notably with the introduction of cyclin‐dependent kinase 4 and 6 (CDK4/6) inhibitors in the adjuvant setting, which have resulted in both iDFS and overall survival (OS) benefits for high‐risk patients. ¹⁸ , ¹⁹ , ²⁰ , ²¹

The integration of CDK4/6 inhibitors into early‐stage breast cancer management presents a challenge at the intersection of surgical and systemic therapy decision‐making. Although these agents reduce recurrence in high‐risk patients, their use has largely been guided by anatomic staging, particularly nodal status. As efforts to deescalate axillary surgery continue to expand, this raises a critical question about whether more aggressive surgical approaches should be used to guide systemic therapy decisions.

This review synthesizes the current evidence supporting adjuvant CDK4/6 inhibitors in HR+/HER2− breast cancer, with attention to trial eligibility, treatment benefit, toxicity, adherence, and the implications of evolving risk stratification for multidisciplinary treatment planning.

BIOLOGICAL RATIONALE FOR CDK4/6 INHIBITION IN EARLY‐STAGE BREAST CANCER

HR+ breast cancer is defined by its dependence on estrogen receptor (ER) signaling, and recently there is increasing recognition of the central role of CDK4/6‐mediated cell‐cycle progression. ²² Activation of the ER promotes cell proliferation through downstream engagement of the cyclin D–CDK4/6 pathway. The interaction between ER signaling and the CDK4/6 pathway is illustrated in Figure 1.

FIGURE 1.

Estrogen receptor signaling, G1/S cell‐cycle checkpoint regulation, and therapeutic targets in HR+/HER2– breast cancer. Left panel (ER signaling): estrogen (E2) binds the estrogen receptor (ER), which translocates to the nucleus and drives transcription of target genes including CCND1, encoding cyclin D1 protein. Therapeutic agents targeting this axis include aromatase inhibitors (AIs), which block estrogen biosynthesis; selective estrogen receptor degraders (SERDs; fulvestrant, giredestrant), which promote ER degradation; and selective estrogen receptor modulators (SERMs; tamoxifen), which competitively antagonize ER‐mediated transcription in breast tissue. Center panel (G1/S Checkpoint): Cyclin D1 partners with CDK4/6 to form the cyclin D–CDK4/6 complex, which phosphorylates the retinoblastoma protein (Rb). Hyperphosphorylated Rb (pRb) releases E2F transcription factors, enabling transcription of S‐phase genes required for DNA synthesis and cell‐cycle progression from G1 to S phase. Endogenous CDK inhibitors negatively regulate this pathway: p16 (INK4a, encoded by CDKN2A) directly binds and inhibits CDK4/6; p21 (CDKN1A), transcriptionally activated by p53, and p27 (CDKN1B) inhibit cyclin‐CDK complexes, with predominant activity against cyclin E–CDK2. CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) pharmacologically block CDK4/6 kinase activity, preventing Rb phosphorylation and maintaining G1 arrest. Right panel: Schematic of the cell cycle phases (G1, S, G2, M) with the G1/S checkpoint indicated. Solid arrows denote activation/promotion; flat‐headed red lines denote inhibition; circled “P” symbols denote phosphate groups; dashed arrow indicates proteasomal degradation.

Although endocrine therapy is quite effective in most patients with HR+ breast cancer, recurrence risk persists, particularly among patients with higher risk disease. ¹ , ² Late recurrences in HR+ breast cancer are attributed to both tumor cell dormancy, in which residual micrometastatic cells persist in a quiescent state before reactivating, and acquired endocrine resistance, driven by mechanisms such as ESR1 mutations, activation of alternative growth factor signaling pathways, and epigenetic reprogramming. ¹⁰ , ²³ , ²⁴ Residual disease may therefore remain biologically active despite initial therapy.

CDK4/6 inhibitors block phosphorylation of retinoblastoma protein (Rb), preventing E2F‐mediated transcription and arresting cells in G1. Their synergy with endocrine therapy reflects convergent suppression of the cyclin D‐CDK4/6‐Rb axis: endocrine therapy reduces upstream cyclin D1 expression, whereas CDK4/6 inhibitors directly block kinase activity, resulting in more complete cell‐cycle arrest than either approach alone. ²⁵ , ²⁶ The rationale for their use in early‐stage disease is that sustained suppression of both estrogen signaling and cell‐cycle activity may reduce the risk of recurrence by limiting the development, survival, and proliferation of endocrine therapy–resistant clones. ²⁷

FROM METASTATIC SUCCESS TO ADJUVANT THERAPY

The clinical development of CDK4/6 inhibitors was initially established in the metastatic setting, where multiple randomized trials demonstrated substantial improvements in progression‐free survival when these agents were combined with endocrine therapy. Currently, there are three CDK4/6 inhibitors approved for the treatment of metastatic breast cancer: palbociclib, ribociclib, and abemaciclib. Multiple studies, including PALOMA‐2, ²⁸ MONALEESA‐2, ²⁹ and MONARCH‐3, ³⁰ consistently showed that the addition of a CDK4/6 inhibitor delayed disease progression. Notably, ribociclib and abemaciclib demonstrated improvements in OS, whereas palbociclib has not shown a statistically significant OS benefit. These results established CDK4/6 inhibition as a standard component of first‐line therapy for HR+/HER2− metastatic breast cancer and provided the foundation for evaluation in early‐stage disease.

Building on this success, CDK4/6 inhibitors were evaluated in the adjuvant setting to determine whether similar benefits could be achieved in patients with high‐risk, early‐stage disease. Trials adding palbociclib to adjuvant endocrine therapy, including PALLAS (n = 5796) and PENELOPE‐B (n = 1250), did not demonstrate an improvement in iDFS, highlighting differences between metastatic and early‐stage disease. ³¹ , ³² In contrast, the monarchE trial (n = 5637) demonstrated that the addition of 2 years of abemaciclib to adjuvant endocrine therapy improved iDFS, with an absolute benefit of 7.6% at 5 years in patients with high‐risk, node‐positive HR+/HER2− disease. ¹⁸ , ³³ In addition to this recurrence benefit, the most recent analysis demonstrated a statistically significant improvement in OS at a median follow‐up of 76 months. ¹⁹ The absolute magnitude of survival benefit was modest at 1.8% at 7 years and was dependent on baseline risk factors such as the extent of nodal involvement, tumor size, and tumor grade, reinforcing that the clinical impact of CDK4/6 inhibition is not uniform across all eligible patients. More recently, the NATALEE trial (n = 5101) demonstrated an improvement in iDFS with the addition of 3 years of ribociclib to standard adjuvant endocrine therapy in a broader population of patients with stage II and III disease, including those with lower nodal burden and select node‐negative patients. ²⁰ Follow‐up analyses of NATALEE have demonstrated an increasing absolute benefit over time, with the most recent analysis showing a 4.5% absolute improvement in 5‐year iDFS. ²¹ The lower absolute benefit observed in NATALEE compared with monarchE likely reflects differences in baseline risk, underscoring that the magnitude of benefit from CDK4/6 inhibition is closely tied to patient selection. Additionally, the difference in OS data maturity is a relevant consideration when selecting between agents in clinical practice because a confirmed survival advantage may influence treatment decisions, particularly in patients for whom both agents are options. Key features of these trials are summarized in Table 1.

TABLE 1.

Key design features and outcomes of the monarchE and NATALEE trials in early‐stage HR+/HER2− breast cancer.

	monarchE (abemaciclib)	NATALEE (ribociclib)
Number of patients	5637	5101
Population	Node‐positive, high‐risk (≥4 positive lymph nodes, or 1–3 positive nodes with grade 3 disease, tumor ≥5 cm, or Ki‐67 ≥ 20%)	Stage II–III disease, including select stage IIA patients (node‐positive or node‐negative if grade 2 and Ki‐67 ≥20% or high genomic risk
CDK4/6 inhibitor dose and duration	150 mg twice daily, continuous dosing for 2 years	400 mg daily, 3 weeks on/1 week off, for 3 years
Endocrine therapy backbone	Aromatase inhibitor or tamoxifen	Nonsteroidal aromatase inhibitor (letrozole or anastrozole); goserelin for premenopausal women and men
Primary endpoint met	Yes—iDFS	Yes—iDFS
Absolute 5‐year iDFS benefit	7.6%	4.5%
Overall survival	Statistically significant improvement (HR = 0.842; absolute benefit ∼1.8% at 7 years)	Not yet statistically significant; numerical improvement observed (HR 0.80; not statistically significant)
Longest follow‐up reported	76 months (7‐year data)	55 months (5‐year data)
Key toxicities	Diarrhea, fatigue, VTE	Neutropenia, hepatotoxicity, QT prolongation
Dose reductions/interruptions	41‐57%	27%
Discontinuation due to adverse effects	18.5%	20%
FDA approval (adjuvant)	October 2021 (expanded March 2023)	September 2024

Abbreviations: iDFS, invasive disease‐free survival; FDA, Food and Drug Administration; HR, hazard ratio; VTE, venous thromboembolism.

Subgroup analyses from both trials demonstrated consistent relative risk reductions across prespecified subgroups, including nodal status, tumor grade, Ki‐67, menopausal status, and prior chemotherapy exposure. ³⁴ , ³⁵ In monarchE, benefit was observed regardless of Ki‐67 index, and patients who received neoadjuvant chemotherapy derived similar relative benefit. ³⁶ In NATALEE, iDFS benefit was consistent across stage II and III disease, node‐negative and node‐positive subgroups, and Ki‐67 status. ³⁷ Recent gene expression analyses from NATALEE demonstrated benefit across all PAM50 subtypes, with a trend toward greater benefit in patients with higher genomic risk. ³⁸ However, although relative risk reductions were consistent, the absolute benefit varied substantially with baseline recurrence risk. Patients with four or more positive nodes or residual disease after neoadjuvant chemotherapy derived the largest absolute benefit, whereas patients with lower risk features had smaller absolute gains. This distinction is critical for individualized treatment decisions, as a consistent hazard ratio translates into meaningfully different absolute benefits depending on baseline risk. Accordingly, patients with identical relative benefit may derive substantially different clinical value from treatment depending on their baseline risk of recurrence.

Although both monarchE and NATALEE demonstrated benefit, the trials differed substantially in how high‐risk disease was defined. In monarchE, eligibility was restricted to patients with node‐positive disease: patients were eligible if they had either four or more positive lymph nodes or one through three positive nodes with additional high‐risk features (tumor size ≥5 cm, histologic grade 3, or elevated Ki‐67). As a result, nodal status functioned as a required determinant of treatment eligibility. In contrast, NATALEE adopted a broader definition of risk, enrolling patients with stage IIB and III disease. Patients with stage IIA disease were also eligible but were required to be node‐positive or, if node‐negative, to have grade 2 tumors with either Ki‐67 ≥20% or high genomic risk. As a result, the final cohort included approximately 12% pathologically node‐negative patients, in contrast to monarchE. These eligibility criteria reflect a shift toward integrating biologic and clinical factors rather than relying on nodal status alone, thereby expanding eligibility for adjuvant CDK4/6 inhibitors to a broader group of patients, although nodal status remains a major factor in patient selection.

CDK4/6 THERAPY AND THE ROLE OF AXILLARY STAGING IN TREATMENT SELECTION

The surgical management of the axilla in early‐stage breast cancer has undergone substantial deescalation over the past several decades. Landmark trials including NSABP B‐32, ³⁹ ACOSOG Z0011, ⁴⁰ and AMAROS ⁴¹ established sentinel lymph node biopsy (SLNB) as an accurate and less morbid alternative to axillary lymph node dissection (ALND) while maintaining equivalent oncologic outcomes. These findings have been reinforced in subsequent studies in patients with higher risk disease by restricting eligibility to those with macrometastases, expanding the proportion of mastectomy patients, and permitting T3 tumors and extranodal extension. ⁴² , ⁴³ More recently, prospective trials such as SOUND, ⁴⁴ INSEMA, ⁴⁵ and BOOG 2013‐08 ⁴⁶ have extended these principles further, demonstrating that omission of SLNB is feasible in selected patients with clinically node‐negative disease and a negative preoperative axillary ultrasound, and is associated with very low rates of axillary recurrence. These studies have informed new recommendations supporting omission of SLNB in postmenopausal patients with clinical T1, grade 1 and 2, HR+/HER2− breast cancer. ¹⁴ Collectively, these data reflect a paradigm shift away from extensive axillary surgery, with an emphasis on minimizing morbidity without compromising cancer control.

The results of these studies underscore a broader principle: durable locoregional control in early‐stage breast cancer is not achieved by surgery alone, but through the combined effects of systemic therapy and radiation. Across trials evaluating omission of ALND, nearly one‐third of patients harbor residual nodal disease after SLNB, yet this does not translate into higher rates of axillary recurrence. ⁴⁰ , ⁴¹ , ⁴² , ⁴³ This highlights the utility of adjuvant therapy in controlling residual disease and the limited therapeutic value of more extensive axillary surgery in well‐selected patients in the modern treatment era.

The introduction of adjuvant CDK4/6 inhibitors raises the question of whether this trajectory toward surgical deescalation should be reconsidered, given the continued importance of nodal status in identifying patients who may be candidates for therapy. Available data suggest that the impact of omitting axillary surgery on CDK4/6 eligibility is modest. Contemporary retrospective analyses of the National Cancer Database and the SENOMAC trial have shown that completion ALND in patients with one to two positive sentinel nodes who do not otherwise meet criteria for adjuvant abemaciclib identifies additional eligible patients in only about 13% of cases. ⁴⁷ , ⁴⁸ When accounting for the absolute iDFS benefit of abemaciclib, completion ALND would need to be performed in 104 patients, resulting in nine cases of severe arm morbidity, to prevent one iDFS event at 5 years. ⁴⁸

Subsequent analyses of institutional datasets and the National Cancer Database have found that omission of SLNB in patients who meet ASCO omission criteria, ¹⁴ a lower risk population than those previously mentioned, would exclude only approximately 8% of patients who would otherwise meet eligibility for CDK4/6 inhibitors based on pathologic nodal stage. ⁴⁹ , ⁵⁰ , ⁵¹ This means at least 13 patients would need to undergo SLNB to identify one patient who meets CDK4/6 inhibitor criteria. Eligibility for CDK4/6 inhibitors does not guarantee clinical benefit, as a substantial proportion of treated patients will not experience recurrence regardless of therapy. At 5 years, the absolute iDFS benefit is approximately 7.6% with abemaciclib and 3% to 5% with ribociclib, reflecting differences in baseline risk across study populations. ²¹ , ³³ As a result, the number of patients in whom omission of axillary staging would translate into a meaningful difference in outcomes is likely smaller than the number identified as eligible for treatment. Contemporary analyses estimate that at least 300 patients would need to undergo SLNB for one patient to derive a 5‐year iDFS benefit attributable to CDK4/6 inhibition. ⁵¹ Data regarding OS are still maturing but will be important to evaluate in the context of surgical morbidity and potential survival benefit as longer term follow‐up becomes available.

Although surgical morbidity may outweigh the potential benefit of CDK4/6 inhibition in lower risk patients who meet criteria for SLNB omission, decisions regarding axillary management should be made using a concerted multidisciplinary approach. Notably, patients who meet current criteria for omission of SLNB represent a highly selected, favorable‐risk population, typically with small, low‐grade, clinically node‐negative, HR‐positive, HER2−negative tumors, for whom the absolute benefit of adjuvant CDK4/6 inhibition, if eligible at all, is expected to be small. Nonetheless, axillary staging may influence both systemic therapy and radiation planning, and therefore a tailored, individualized approach is warranted.

Notably, NATALEE enrolled approximately 12% node‐negative patients who qualified based on stage IIA disease with grade 2 tumors and Ki‐67 ≥ 20% or high genomic risk, demonstrating that CDK4/6 inhibitor eligibility can be established without nodal involvement. ²⁰ This supports the broader principle that recurrence risk, and therefore candidacy for treatment escalation, can be defined by tumor biology rather than nodal status alone. Genomic assays such as Oncotype DX and MammaPrint, Ki‐67 proliferation index and tumor grade provide complementary risk information that may identify patients who benefit from adjuvant CDK4/6 inhibition regardless of axillary staging results.

TOXICITY, ADHERENCE, AND SHARED DECISION‐MAKING

The incorporation of CDK4/6 inhibitors into early‐stage breast cancer management introduces additional considerations related to toxicity, treatment duration, and patient adherence. Although generally well tolerated, these agents are associated with clinically relevant adverse effects that differ by agent. Abemaciclib is most commonly associated with gastrointestinal toxicity, particularly diarrhea (82%, grade ≥3 in 8%), as well as fatigue (40%), neutropenia (grade ≥3 in 25%), and less frequent but clinically significant risks such as venous thromboembolism (5%) and pneumonitis (3%). ⁵² In contrast, ribociclib is more commonly associated with neutropenia (grade ≥3 in approximately 44%), fatigue (23%), hepatotoxicity (27%, with grade ≥3 in 9%), and QT interval prolongation (grade ≥3 in ∼1%), necessitating electrocardiographic monitoring in addition to routine laboratory assessment. ³⁷ In the adjuvant setting, where therapy is administered for prolonged durations of 2 to 3 years in patients without evidence of active disease, even low‐grade toxicities may have a meaningful impact on quality of life and treatment persistence.

Adherence to therapy represents an additional challenge in the adjuvant setting. In clinical trials, approximately 20% to 25% of patients discontinue CDK4/6 inhibitors before completion of planned therapy, with rates varying by agent and setting. In monarchE, 16.6% of patients discontinued abemaciclib because of adverse events, with total early discontinuation approaching 25% when including nonrecurrence reasons, and most discontinuations occurring within the first 6 months. ⁵² Notably, treatment modification was common, with more than half of patients requiring dose interruptions and more than 40% requiring dose reductions. In NATALEE, discontinuation rates were similar, with approximately 19% to 20% of patients stopping ribociclib because of adverse events, most commonly related to hepatotoxicity, and a median time to discontinuation of approximately 4 months. ²⁰ , ³⁷ At 4 years, fewer than two‐thirds of patients completed the planned 3‐year course of therapy. Real‐world experience suggests that rates of discontinuation and noninitiation may be even higher, further limiting the effective delivery of therapy. ⁵³ , ⁵⁴

Importantly, exploratory analyses from monarchE demonstrated that efficacy was not compromised by dose reductions; 4‐year iDFS rates were consistent across relative dose intensity subgroups (87.1%, 86.4%, and 83.7% for ≤66%, 66%‐93%, and ≥93% dose intensity, respectively). ⁵⁵ The TRADE trial, a prospective phase II study, evaluated a dose‐escalation strategy in which abemaciclib was initiated at 50 mg twice per day and titrated to 150 mg twice per day over 4 weeks. At 12 weeks, 70.8% of patients reached and maintained the target dose, with only 6.7% discontinuing therapy, compared with historical rates of approximately 40% composite discontinuation or dose inability in monarchE. ⁵⁶ At 24 weeks, 82% of patients remained on therapy with no clinically meaningful decline in quality of life. ⁵⁷ This approach is increasingly adopted in clinical practice as a strategy to mitigate early toxicity and improve treatment persistence.

Although strategies have been developed to improve adherence and toxicity, the observation about treatment initiation and discontinuation reinforces that treatment decisions should not be based solely on eligibility criteria. The anticipated magnitude of benefit must be weighed against the risks of toxicity, treatment burden, and patient priorities, particularly in the adjuvant setting where therapy is administered over prolonged periods to patients without evidence of active disease.

FUTURE DIRECTIONS IN RISK STRATIFICATION AND TREATMENT SELECTION

The role of CDK4/6 inhibitors in early‐stage breast cancer continues to evolve alongside broader advances in systemic therapy and risk stratification. As outlined in Table 2, emerging clinical trials increasingly incorporate molecular selection, dynamic biomarkers, and adaptive treatment strategies. These approaches move beyond traditional clinicopathologic features and instead rely on tumor biology, treatment response, and mechanisms of resistance to guide clinical decision‐making.

TABLE 2.

Selected clinical trials evaluating emerging strategies for CDK4/6 inhibitor use in early‐stage and advanced breast cancer.

Category	Trial (ClinicalTrials.gov ID)	Phase/design	Population	Selection strategy	Intervention/comparator	Primary endpoint/focus	Status	Primary outcome (if reported)	Key concept and implication
Early‐stage adjuvant and neoadjuvant development	EarLEE‐1 (NCT03078751)	Phase II; amended open‐label	HR+/HER2− high‐risk early breast cancer	Clinical/pathologic high‐risk features	Ribociclib + endocrine therapy	Safety and tolerability	Completed	Acceptable safety profile; supported NATALEE design	Early feasibility of adjuvant CDK4/6 inhibition based on clinical risk
	neoMONARCH (NCT02441946)	Phase II, randomized	Postmenopausal HR+/HER2− early breast cancer	Ki‐67 suppression	Abemaciclib ± anastrozole	Biologic response	Completed	Significant Ki‐67 suppression with abemaciclib; CCCA rate 68% with combination	Demonstrates early biologic response as a marker of treatment effect
	CORALLEEN (NCT03248427)	Phase II, randomized	Postmenopausal HR+/HER2− early breast cancer (Luminal B)	PAM50 Luminal B subtype	Ribociclib + letrozole vs chemotherapy	PAM50‐based ROR at surgery	Completed	Low‐ROR at surgery: 46.9% (ribociclib + letrozole) vs 46.1% (chemotherapy); similar molecular downstaging between arms	Molecular downstaging as a surrogate for neoadjuvant CDK4/6 inhibitor efficacy
	NeoPAL (NCT02400567)	Phase II, randomized	HR+/HER2− early breast cancer	Clinical/pathologic high‐risk features	Palbociclib + letrozole vs chemotherapy	Residual cancer burden (RCB)	Completed	RCB 0‐I: 7.7% (letrozole + palbociclib) vs 15.7% (chemotherapy); poor pathologic response but similar clinical response and BCS rates	Comparison of neoadjuvant CDK4/6 inhibition vs chemotherapy in HR + disease
	PELOPS (NCT02764541)	Phase II, randomized	HR+/HER2− early breast cancer	Clinical/pathologic	Palbociclib + letrozole vs letrozole ± tamoxifen	CCCA, pCR	Completed	CCCA 22% with palbociclib + letrozole vs 12% letrozole alone	Neoadjuvant CDK4/6 inhibition with biologic and pathologic endpoints
	Neoadjuvant Palbociclib + ET (NCT05069038)	Phase II, single‐arm	HR+/HER2− stage IIA‐IIIC breast cancer	Response‐based (Ki‐67)	Palbociclib + letrozole ± goserelin	Clinical response, feasibility	Recruiting	‐‐	Supports response‐guided therapy rather than reliance on baseline staging
	ADAPTcycle (NCT04055493)	Phase III, randomized	Intermediate‐risk HR+/HER2− early breast cancer	Dynamic Ki‐67 response	Ribociclib + ET vs chemotherapy followed by ET	iDFS	Active, not recruiting	‐‐	Testing whether CDK4/6 inhibition can replace chemotherapy guided by biomarker response
	RADIANT (NCT06139107)	Phase Ib, single‐arm	HR+/HER2− early‐stage breast cancer	None	Radiation + abemaciclib + letrozole	Safety	Recruiting	‐‐	Integration of systemic and local therapy prior to full pathologic staging
	Trilaciclib Neoadjuvant TNBC (NCT05112536)	Phase II, single‐arm	Early‐stage TNBC	None	Trilaciclib + chemotherapy ± mmunotherapy	Pathologic response	Completed	pCR rate 56.8%; trilaciclib did not impair chemotherapy efficacy and preserved immune cell populations	Explores CDK4/6 modulation of tumor biology beyond HR+ disease
Adjuvant dose optimization	TRADE (NCT06001762)	Phase II, randomized	HR+/HER2− early breast cancer eligible for adjuvant abemaciclib	Clinical/pathologic	Abemaciclib dose escalation (50 to 100 to 150 mg twice daily) vs standard 150 mg twice daily	Discontinuation rate, tolerability	Active, not recruiting	70.8% reached target dose at 12 weeks; 6.7% discontinuation rate	Dose escalation strategy to improve adherence and reduce early discontinuation
Dynamic biomarker‐guided treatment adaptation	SIGNAL‐ER‐101	Phase II, single‐arm treat‐on‐MRD	HR+/HER2− early breast cancer meeting criteria for CDK4/6 inhibition	ctDNA‐guided use of CDK4/6	ctDNA+: ribociclib or abemaciclib + ET; ctDNA‐: ET alone	iDFS	Recruiting	‐‐	ctDNA‐guided de‐escalation of adjuvant CDK4/6 inhibition
Predictive modeling and AI‐guided selection	AIM‐BRIGHT (NCT07227233)	Phase II, randomized	HR+/HER2− advanced breast cancer post‐CDK4/6 inhibitor	AI/ML genomic model	CDK4/6 inhibitor rechallenge vs physician's choice	PFS	Recruiting	‐‐	Data‐driven prediction of treatment benefit
Molecularly selected and targeted combination strategies	INAVO123 (NCT06790693)	Phase III, randomized	PIK3CA‐mutated HR+/HER2− advanced breast cancer	PIK3CA mutation	Inavolisib + CDK4/6 inhibitor + letrozole vs placebo combination	Efficacy and safety	Recruiting	‐‐	Molecular selection using PI3K pathway alterations
Resistance mechanisms and genomically guided therapy selection (metastatic)	GERTRUDE (NCT05933395)	Phase II umbrella	ER+/HER2− advanced breast cancer post‐CDK4/6 inhibitor	Genomic assignment	Targeted combinations (neratinib, alpelisib, everolimus, etc.)	Efficacy by subgroup	Recruiting	‐‐	Precision therapy guided by resistance pathways
Biomarker‐defined strategies challenging CDK4/6‐based standards	EvoPAR‐BR01 (NCT06380751)	Phase III, randomized	BRCA1/2 or PALB2‐mutated HR+/HER2− breast cancer	DNA repair mutations	Saruparib + camizestrant vs CDK4/6‐based therapy	Efficacy	Recruiting	‐‐	Genomically defined alternatives to CDK4/6 inhibition
Next‐generation CDK pathway targeting after resistance (metastatic)	GDC‐0587 Study (NCT07214662)	Phase Ia/Ib	ER+/HER2− advanced breast cancer post‐CDK4/6 inhibitor	Prior CDK4/6 exposure	Selective CDK4 inhibitor ± endocrine therapy	Safety, PK, activity	Recruiting	‐‐	Refinement of CDK pathway targeting after resistance

Note: Trials were identified through a search of ClinicalTrials.gov and review of published literature and conference proceedings. Selection prioritized studies that illustrate key emerging strategies for CDK4/6 inhibitor development, including adjuvant and neoadjuvant applications, biomarker‐driven selection, dynamic treatment adaptation, resistance mechanisms, and novel combination approaches. This table is not intended to be an exhaustive listing of all ongoing CDK4/6 inhibitor trials.

Abbreviations: AI, aromatase inhibitor; BCS, breast‐conserving surgery; CCCA, complete cell‐cycle arrest; CDK4/6, cyclin‐dependent kinase 4 and 6; ctDNA, circulating tumor DNA; ET, endocrine therapy; FGFR, fibroblast growth factor receptor; HR+, hormone receptor‐positive; HER2−, human epidermal growth factor receptor 2‐negative; iDFS, invasive disease‐free survival; MRD, minimal residual disease; OFS, ovarian function suppression; pCR, pathologic complete response; PFS, progression‐free survival; PK, pharmacokinetics; RCB, residual cancer burden; ROR, risk of recurrence; SERD, selective estrogen receptor degrader; TNBC, triple‐negative breast cancer.

A similar shift has already occurred in the use of adjuvant chemotherapy, where genomic assays have largely supplanted anatomic staging as the primary determinant of benefit in many patients with HR+/HER2− disease. RxPONDER demonstrated that biologic risk, rather than nodal status alone, more accurately identifies patients who derive meaningful benefit from systemic therapy. ⁷ A comparable paradigm may emerge for CDK4/6 inhibitors, in which biomarkers, rather than nodal status, play a central role in identifying patients most likely to benefit from treatment escalation.

This trajectory is further illustrated by the OPTIMA trial, which demonstrated that patients with ER+/HER2− early breast cancer and Prosigna ROR scores ≤60, including those with pN2 disease, can safely omit chemotherapy without compromising outcomes. ⁵⁸ These data demonstrate that the incremental value of identifying higher nodal burden for chemotherapy decision‐making has substantially diminished. A similar evolution may occur for CDK4/6 inhibitors, where eligibility criteria remain anchored to nodal status as defined by completed trial designs but may shift toward molecular selection as biomarker‐driven approaches mature.

CDK4/6 inhibitor efficacy is restricted to Rb‐proficient tumors, with RB1 loss associated with both de novo and acquired resistance. ⁵⁹ , ⁶⁰ Additional resistance mechanisms include CCNE1 overexpression, CDK6 amplification, activation of the PI3K/AKT/mTOR and FGFR pathways, and ESR1 mutations. ²² , ⁶¹ , ⁶² Interferon pathway activation has also been implicated in both intrinsic and acquired resistance. ⁶³ Dynamic biomarkers such as circulating tumor DNA show promise for early detection of resistance, with rising mutation levels detectable months before radiographic progression. ⁶⁴ However, most biomarker data derive from the metastatic setting, and no validated predictive biomarker currently exists to guide CDK4/6 inhibitor selection in early‐stage disease. Prospective adjuvant studies evaluating these markers are needed, as the biology of micrometastatic disease may differ from established metastatic disease.

In the adjuvant setting, biomarker‐driven approaches to CDK4/6 inhibitor selection remain early in development. Circulating tumor DNA (ctDNA) detection after definitive treatment has emerged as a strong prognostic marker of recurrence risk and is being evaluated as a tool to guide treatment escalation. ⁶⁵ Ki‐67 dynamics and genomic risk scores are also under investigation as predictors of CDK4/6 inhibitor benefit in the adjuvant context. More work is being done to understand other biomarkers in the metastatic setting. The SERENA‐6 trial, which adapts therapy based on emergent ESR1 mutations (frequently acquired under selective pressure from aromatase inhibitor therapy) detected on ctDNA, reflects this metastatic paradigm. ⁶⁶ A comprehensive review of biomarker‐driven strategies in metastatic HR+/HER2− breast cancer is beyond the scope of this article and has been reviewed elsewhere. ⁶⁷ , ⁶⁸

The potential role of CDK4/6 inhibitors is also being explored beyond the traditional adjuvant setting. Based on preliminary data of molecular downstaging from the NeoPAL ⁶⁹ and CORALLEEN ⁷⁰ trials, neoadjuvant studies are evaluating whether earlier integration of CDK4/6 inhibition can enhance tumor response and inform treatment planning before surgery. The PELOPS trial evaluated neoadjuvant palbociclib combined with endocrine therapy in patients with ER+/HER2− early breast cancer and demonstrated improvements in preoperative endocrine prognostic index scores and Ki‐67 suppression, supporting the feasibility of CDK4/6 inhibitor‐based neoadjuvant strategies. ⁷¹ , ⁷² Given the relatively low response rates of HR+/HER2− breast cancers to current neoadjuvant regimens, these approaches may broaden the role of preoperative systemic therapy, Whether combination approaches with novel SERDs further improve outcomes remains unknown. Importantly, no patients in the lidERA trial received a concurrent CDK4/6 inhibitor despite many meeting contemporary eligibility criteria, limiting direct comparison with current standards of care. In addition, emerging data suggest a potential role for CDK4/6 inhibitors in breast cancer subtypes beyond HR+ disease, including combination strategies in triple‐negative breast cancer, highlighting the broader relevance of cell cycle targeting.

Collectively, these developments reflect a shift toward precision oncology, in which treatment decisions are increasingly driven by tumor biology and treatment response rather than anatomic factors alone. In this context, the relevance of axillary staging as a determinant of systemic therapy selection is likely to continue to diminish. Future approaches to early‐stage breast cancer will rely on integrated clinical, pathologic, and molecular risk assessment, with less emphasis on surgical staging as a primary driver of treatment decisions.

CONCLUSION

Adjuvant CDK4/6 inhibitors represent an important advancement in the management of high‐risk HR+/HER2− breast cancer, with demonstrated improvements in iDFS and emerging OS benefit in selected populations. At the same time, evolving eligibility criteria have highlighted both the continued relevance and the limitations of anatomic staging, particularly nodal status, in guiding treatment decisions.

Available data suggest that the incremental impact of axillary surgery in patients eligible for omission on identifying candidates for CDK4/6 inhibition is modest, and that eligibility does not uniformly translate into clinical benefit. Importantly, patients who meet criteria for omission of axillary staging already represent a low‐risk population in whom the expected absolute benefit of CDK4/6 inhibition is small, further narrowing the clinical impact of any missed staging information. In this context, decisions regarding systemic therapy should be made in a multidisciplinary fashion incorporating not only anatomic features, but also tumor biology, anticipated absolute benefit, toxicity, treatment duration, and patient preferences.

Ongoing studies are evaluating CDK4/6 inhibitors in the neoadjuvant setting, where early biologic response may help refine treatment planning. At the same time, integration of genomic assays and dynamic biomarkers, including circulating tumor DNA, is likely to improve patient selection over time. Together, these advances support a shift toward biologically driven, individualized care with less reliance on anatomic staging alone.

AUTHOR CONTRIBUTIONS

Austin D. Williams: Conceptualization; Writing ‐ original draft; and Writing ‐ review & editing. Anna Weiss: Conceptualization and Writing ‐ review & editing.

CONFLICT OF INTEREST STATEMENT

Dr. Williams: Consultant – Elucent Medical (Eden Prairie, MN)