At a recent international academic conference on breast cancer, Professor Claudio Vernieri from the University of Milan and the Fondazione IRCCS Istituto Nazionale dei Tumori shared the latest results of the multicenter, real-world study PALMARES-2. The study focuses on patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). It explores the clinical benefits and patient characteristics associated with continuing the original treatment regimen ("Treatment Beyond Progression," TBP) after experiencing disease progression (PD) on first-line endocrine therapy (ET) combined with a CDK4/6 inhibitor (CDK4/6i), providing an important reference for the TBP strategy in clinical practice.01 Current Clinical Status: Treatment Dilemmas After Progression on First-Line CDK4/6i
Currently, ET combined with CDK4/6i (such as palbociclib, ribociclib, and abemaciclib) has become the first-line standard of care for HR+/HER2- ABC patients. However, the choice of subsequent treatment regimens after disease progression during first-line therapy remains controversial. Although various options exist—including endocrine monotherapy switching, ADC drugs, PI3K/AKT/mTOR pathway inhibitors, or chemotherapy—the balance between efficacy and tolerability is often unsatisfactory. Professor Claudio Vernieri noted that in real-world clinical practice, many physicians adopt a “Treatment Beyond Progression” strategy for specific patients (such as those with oligoprogression or locally manageable lesions), which involves continuing the original first-line ET+CDK4/6i regimen after PD. Although such practices were not permitted in previous pivotal Phase III clinical trials (such as the PALOMA, MONALEESA, and MONARCH series), their application rate and actual value in the real world urgently require validation through large-scale data.
02 PALMARES-2 Study Design: A Multicenter, Large-Sample Real-World Exploration
PALMARES-2 is a multicenter, population-based Italian real-world study combining retrospective and prospective designs. The study included HR+/HER2- ABC patients from 26 Italian institutions (latest data expanded to 37 institutions). In the second data lock conducted in January 2025, the study screened a total of 4,236 patients receiving first-line ET+CDK4/6i treatment. The analysis focused on 2,264 patients who clearly experienced PD during first-line therapy. The study aimed to evaluate the proportion of these patients continuing the first-line regimen after PD, real-world progression-free survival (rwPFS), and overall survival (OS), and to explore the impact of loco-regional therapies on prognosis.
03 Patient Profile: Approximately 20% of Patients Choose Continuous Treatment Beyond Progression
Research data shows that among 2,264 patients with PD, approximately 20% (over 450 cases) chose to continue the original first-line ET+CDK4/6i regimen after progression (the Beyond PD group). Through a comparative analysis of the baseline characteristics of the two groups, the Beyond PD group exhibited superior prognostic features: • Age and Physiological Status: Patients were relatively younger, and the proportion of premenopausal patients was higher. • Tumor Pathology: A higher proportion of patients had “No Special Type” (NST) tumors. • Receptor Expression: Higher expression levels of estrogen receptor (ER) and progesterone receptor (PgR). • Metastatic Sites: A higher proportion of patients had bone metastasis, while the proportion of liver metastasis (an indicator of poorer prognosis) was significantly lower. These characteristics indicate that when choosing a treatment-beyond-progression strategy, clinicians tend to select patients with relatively mild tumor biological behavior and manageable overall tumor burden.
04 Core Efficacy Data: Beyond PD Strategy Significantly Prolongs rwPFS and OS
In the PALMARES-2 study, the benefit data for the Beyond PD group was clinically and statistically significant: • rwPFS Benefit: By continuing the original regimen after PD, patients achieved a median real-world progression-free survival of 10.5 months. This data suggests that treatment beyond progression can provide an additional clinical control period of nearly one year for some patients. • OS Analysis: In both unadjusted analysis and inverse probability of treatment weighting (IPTW) adjusted analysis, the real-world overall survival (rwOS) of the Beyond PD group was superior to that of the non-TBP group. • Subsequent Treatment Continuity: The study also observed the attrition rate in subsequent lines of therapy. Results showed that the dropout rate in the Beyond PD group for later lines was not higher than that of patients who immediately switched regimens after PD. This means the Beyond PD strategy did not affect the implementation of later-line regimens by over-consuming patient physical strength or causing cumulative toxicity.
05 Prognostic Factor Analysis: The Guiding Role of Local Therapy and Biomarkers
The study further identified independent predictors associated with Beyond PD benefit through a multivariate Cox regression model: • Value of Loco-regional Therapy: The vast majority of patients in the Beyond PD group received concomitant local therapy, primarily radiotherapy for progressive lesions. Data showed that the combination of loco-regional therapy was independently associated with improved rwPFS. This supports the therapeutic logic of clearing drug-resistant clones via radiotherapy while maintaining systemic control under an “oligoprogression” model. • Biomarker Characteristics: Better performance status (PS score), higher ER/PgR expression levels, and lower Ki-67 expression (usually with a threshold of 14% or 20%; the study emphasized low proliferation characteristics) are key indicators for predicting benefit from treatment beyond progression.
06 Study Limitations and Clinical Implications
Professor Claudio Vernieri objectively analyzed the limitations of the study in his summary: as a real-world retrospective study, there is an inherent selection bias (the Beyond PD group had better baseline prognosis); furthermore, the study lacked centralized imaging evaluation. However, the results of PALMARES-2 provide strong evidence for the chronic disease management of HR+/HER2- ABC. For patients with local progression, low tumor proliferation index, and high receptor expression during first-line ET+CDK4/6i treatment, continuing the original regimen after necessary local radiotherapy is a feasible strategy that can bring significant survival benefits. This helps delay the application of more toxic regimens (such as chemotherapy).
Conclusion and Outlook
The PALMARES-2 study confirmed through a large-scale real-world cohort that continuing treatment beyond progression after first-line ET+CDK4/6i for HR+/HER2- advanced breast cancer can achieve a 10.5-month median rwPFS improvement and shows a trend toward OS benefit. Future research directions should further integrate circulating tumor DNA (ctDNA) monitoring (such as ESR1 and PIK3CA mutation status) to precisely screen the patient populations most likely to benefit from the Beyond PD strategy, thereby achieving individualized and precise sequential therapy.
Expert Background:
Professor Claudio Vernieri works at the University of Milan and the Fondazione IRCCS Istituto Nazionale dei Tumori. He has long been dedicated to research on metabolic reprogramming and precision targeted therapy for breast cancer. As a core lead investigator of the PALMARES series of studies, he possesses deep academic expertise in real-world study design and CDK4/6 inhibitor resistance mechanisms.
