HR+/HER2+ is a unique subtype of luminal breast cancer characterized by concurrent positivity of estrogen receptor (ER) and/or progesterone receptor (PR) in addition to HER2. This co-expression often leads to drug resistance when targeting a specific receptor type, thus making treatment a clinical challenge. Overexpression of HER2 can lead to intrinsic resistance to hormone-based treatments, while HR signaling can enable tumor survival even when HER2 is blocked [1]. Mechanistic insights from preclinical studies have helped clarify this resistance. Shou et al. demonstrated that HER2 overexpression alone, whether acquired or engineered, was sufficient to drive tamoxifen resistance through activation of growth factor signaling pathways and suppression of classical ER genomic function [10]. Supporting this, evidence shows that ERBB2 gene amplification, which often underlies HER2 overexpression, similarly enhances bidirectional crosstalk between HER2-driven kinase signaling and ER pathways [11]. This interaction promotes ligand-independent ER activation and sustained tumor proliferation, contributing to both intrinsic resistance at treatment initiation and acquired resistance during the course of endocrine therapy [11].

In ER+ breast cancer, HER2 overexpression is associated with resistance to endocrine therapies. This resistance is attributed to increased crosstalk between the ER and HER2 pathways, activating downstream signaling cascades such as MAPK and PI3K/AKT, which support cell survival and growth [1]. For example, HER2 overexpression can cause ER to shift from the nucleus to the cytoplasm, impairing its function and leading to resistance to treatments such as tamoxifen [12]. Conversely, blocking HER2 can trigger an adaptive upregulation of ER signaling as a survival mechanism. Preclinical studies and clinical studies have shown that HER2-targeted therapies, such as lapatinib, resulted in parallel upregulation of ER and Bcl2 expression, indicating an ER-dependent survival pathway that contributes to resistance against HER2 inhibition [13].

In preclinical trials, CDK4/6 inhibitors have demonstrated the ability to prevent resistance to both endocrine and HER2 therapy. Notably, CDK4 and CDK6 are kinases that act downstream of the processes driving HER2 therapy resistance [14]. In models of acquired resistance to HER2 inhibition it was found that cyclin D1 control is deregulated. Moreover, the models, xenografts, and primary human tissue were all sensitive to CDK4/6 inhibition [14]. Finn et al. found that cell lines representing luminal ER+ (including those that were HER2 amplified) were most sensitive to CDK4/6 cell cycle arrest and inhibition of proliferation [15].

This meta-analysis suggests that adding CDK4/6 inhibitors to treatment regimens in metastatic HR+/HER2+ breast cancer provides meaningful clinical benefit. The pooled CBR was 69%, with an ORR of 35%. However, there was notable variability across studies, which was likely due to differences in treatment regimens, patient populations, and study designs. Despite this heterogeneity, the findings indicate that CDK4/6 inhibitors help prolong disease control and enhance response rates, likely by addressing resistance mechanisms related to HER2 and hormone receptor signaling. The high SD rate of 40% suggests that CDK4/6 inhibition contributes to disease stabilization, which could be particularly relevant for patients with visceral or CNS metastases.

Owing to the limited survival data available in the literature, we were unable to perform a comprehensive analysis of PFS and OS. However, recent phase III trials have further validated the efficacy of CDK4/6 inhibition in metastatic HR+/HER2+ disease. The PATINA trial evaluated the combination of palbociclib, anti-HER2 therapy, and endocrine therapy versus anti-HER2 therapy plus endocrine therapy [16]. The addition of palbociclib significantly improved PFS, with a HR of 0.667. The median PFS was 44.3 months in the palbociclib arm compared with 29.1 months in the control arm. Although overall survival data remain immature, the median OS was not reached in the palbociclib arm compared with 77.0 months in the control arm (thus indicating a favorable trend that requires longer follow-up for confirmation [16]). Similarly, the DETECT V trial examined two treatment arms, both incorporating CDK4/6 inhibitors [17]. One arm included trastuzumab and pertuzumab combined with chemotherapy plus a CDK4/6 inhibitor, while the other combined trastuzumab and pertuzumab with endocrine therapy plus a CDK4/6 inhibitor. Both OS and PFS were significantly improved in patients receiving ribociclib in addition to chemotherapy or endocrine therapy-based treatment (OS HR 0.42, median PFS 0.52).

Hematologic toxicity is most prominent with palbociclib, with neutropenia being the dominant adverse event. Across the PALOMA clinical trial program, neutropenia of any grade occurred in approximately 75–83% of patients, with grade 3–4 neutropenia reported in 54–66% while febrile neutropenia remained uncommon at approximately 1–2% [18]. Long-term pooled safety analyses demonstrated that palbociclib-associated neutropenia typically occurs early during treatment, is reversible with dose interruption or reduction, and does not worsen cumulatively over time, consistent with a cytostatic effect on bone marrow precursors rather than irreversible myelotoxicity [19]. Observational cohorts have corroborated these findings, confirming that neutropenia is a frequent reason for dose modification or treatment interruption but is otherwise generally manageable without clear detrimental effects on clinical outcomes [20].

In contrast, abemaciclib is differentiated within the CDK4/6 inhibitor class by a higher incidence of gastrointestinal toxicity, particularly diarrhea. In the phase III MONARCH 2 and MONARCH 3 trials, diarrhea was reported in approximately 80–90% of patients, with grade ≥ 3 events occurring in 7–13%, typically with early onset during the first treatment cycle [21, 22]. The majority of episodes were low grade and transient. Pooled safety analyses demonstrated that diarrhea was generally manageable for most patients with early antidiarrheal therapy, dose interruption, and subsequent dose reduction without the need for permanent treatment discontinuation [23]. Mechanistically, this gastrointestinal toxicity has been attributed to abemaciclib’s broader kinase inhibition profile and continuous dosing schedule, which may affect intestinal epithelial function without causing overt mucosal injury [24].

Despite frequent gastrointestinal adverse events, abemaciclib is associated with lower rates of high-grade neutropenia compared with other CDK4/6 inhibitors. In MONARCH 2 and MONARCH 3, grade 3–4 neutropenia occurred in approximately 21–27% of patients and was typically early in onset, noncumulative, and managed with dose modification rather than treatment cessation [21, 22]. Across phase III trials, overall treatment discontinuation due to adverse events occurred in approximately 15–20% of patients, with gastrointestinal toxicities representing the most common reason for discontinuation rather than neutropenia [23].

Quality of life (QOL) is a critical outcome in advanced and metastatic breast cancer, where treatment is palliative in intent and patients frequently remain on systemic therapy for prolonged periods [25]. Studies consistently show that addressing symptom burden (physical, emotional, and social) rather than tumor response alone has the largest effect on QOL [25]. Observational studies employing validated patient-reported outcome instruments, including the Functional Assessment of Cancer Therapy-Breast (FACT-B) and the Edmonton Symptom Assessment System, have shown that higher cumulative symptom burden is strongly associated with worse QOL across multiple domains, particularly among patients with visceral disease and those exposed to multiple lines of systemic therapy [25].

In the PALOMA-3 trial, palbociclib plus fulvestrant preserved overall QOL compared with placebo, despite a high incidence of hematologic adverse events [26]. Similarly, QOL analyses from the MONARCH 2 and MONARCH 3 trials demonstrated maintenance of global QOL with abemaciclib-based therapy, while diarrhea and fatigue were the most frequently reported symptoms affecting daily functioning, reflecting the gastrointestinal toxicity profile of abemaciclib [26]. Comparable preservation of health-related QOL has been reported in ribociclib trials, including MONALEESA-2, -3, and -7, despite higher rates of laboratory abnormalities such as neutropenia. Importantly, a systematic review and meta-analysis of CDK4/6 inhibitor trials demonstrated that, while global QOL measures are largely preserved, clinically meaningful deterioration is observed in symptom-specific domains, particularly diarrhea and appetite loss, highlighting the disproportionate impact of treatment-related symptoms on patient experience [26].

Real-world and survey-based studies further reinforce the clinical relevance of symptom burden to QOL. A large multicountry survey of patients with advanced breast cancer reported that treatment-related symptoms such as fatigue, insomnia, diarrhea, back pain, and anxiety had a moderate to severe impact on QOL, and that many patients did not discuss these symptoms with clinicians until QOL was already substantially affected [27]. Collectively, data indicate that, in advanced breast cancer, preservation of QOL is closely linked to proactive assessment and management of treatment-related symptoms, supporting the routine integration of patient-reported outcomes alongside traditional efficacy and safety endpoints.

Emerging biomarker analyses may help clarify heterogeneity in treatment response to CDK4/6 inhibition in HR+/HER2+ metastatic breast cancer. Functional retinoblastoma (RB) protein is essential for CDK4/6 inhibitor activity, and RB1 loss or dysfunction has been consistently associated with primary resistance to these agents [28]. Alterations in CCND1, a convergence point for both ER and HER2 signaling, may increase dependence on CDK4/6-mediated cell-cycle control, although excessive CCND1 signaling can promote resistance through CDK2/cyclin E compensation [29]. Similarly, aberrant p16 (CDKN2A) expression disrupts normal RB–cyclin D regulation and may influence CDK4/6 sensitivity, though sustained p16 loss can also facilitate bypass proliferation pathways [30]. Upstream pathway alterations, particularly within the PI3K/AKT axis, including PIK3CA mutations or PTEN loss, can reduce endocrine dependence and activate alternative survival pathways that may attenuate the therapeutic impact of CDK4/6 inhibition when combined with HER2-targeted or endocrine therapy [31]. In addition, cyclin E1 (CCNE1) overexpression and CDK6 amplification have been implicated in acquired resistance by enabling RB-independent G1–S progression, a mechanism observed across multiple CDK4/6-treated cohorts [32]. Although these biomarkers are not currently used in routine clinical decision-making for HER2+ disease, integrating molecular profiling into future trials may help identify patient subgroups most likely to benefit from CDK4/6 inhibition and guide biomarker-driven therapeutic strategies.

Risk of bias was evaluated using the ROBINS-I tool and is summarized in Fig. 3. The randomized phase II monarcHER trial demonstrated an overall moderate risk of bias, primarily related to selective reporting inherent to early-phase studies. In contrast, the remaining phase Ib/II studies were determined to have serious risk of bias due to confounding, reflecting their single-arm design and lack of comparator groups. Across all studies, risk of bias related to intervention classification and outcome measurement was low, supporting the reliability of reported response outcomes despite limitations in study design.