Editor’s Note: CDK4/6 inhibitors combined with endocrine therapy have become the standard first-line treatment for HR-positive/HER2-negative advanced breast cancer and have significantly improved patient outcomes. However, in real-world clinical practice, a subset of patients still experiences rapid disease progression early during treatment, suggesting the presence of more aggressive tumor biology and potential intrinsic endocrine resistance mechanisms.How to identify these high-risk patients at an early stage and further optimize precision treatment strategies remains an important clinical challenge.
Recently, at the 2026 ESMO Breast Cancer Congress (ESMO BC), the team led by Professor Zhuangqing Yang from Yunnan Cancer Hospital (The Third Affiliated Hospital of Kunming Medical University) presented a single-center real-world study (Poster No. 478P). The study systematically analyzed the characteristics of early rapid progression in patients with HR+/HER2− advanced breast cancer receiving first-line CDK4/6 inhibitor-based therapy and explored associated clinicopathological factors, providing new real-world evidence for risk stratification and treatment optimization in the CDK4/6 era.
Study Title
Early Rapid Progression After First-Line CDK4/6 Inhibitor-Based Therapy in HR-Positive/HER2-Negative Advanced Breast Cancer: A Single-Center Real-World Study From Yunnan Cancer Hospital
Study Background
CDK4/6 inhibitors combined with endocrine therapy have profoundly changed the treatment landscape for HR+/HER2− advanced breast cancer and are now recommended as standard first-line therapy in international guidelines.
Although most patients derive durable benefit from these regimens, a subset of patients still develops rapid disease progression early during treatment, suggesting the presence of intrinsic endocrine resistance or more aggressive tumor biology.
At the same time, HR+/HER2− advanced breast cancer remains biologically heterogeneous. Identifying patients with particularly poor prognosis and optimizing individualized treatment strategies have therefore become critical clinical priorities in the CDK4/6 era.
Currently, however, there remains a lack of systematic real-world research examining the characteristics and potential risk factors associated with early rapid progression following CDK4/6 inhibitor therapy.
Study Methods
This retrospective study included 341 patients with HR+/HER2− advanced breast cancer who received first-line CDK4/6 inhibitor combined with endocrine therapy at Yunnan Cancer Hospital between January 2020 and December 2024.
Clinical and pathological characteristics, treatment regimens, and survival outcomes were collected and analyzed according to whether patients experienced early rapid progression after treatment initiation.
The investigators further compared clinicopathological features across different patient subgroups, including:
- Luminal subtype classification
- Estrogen receptor (ER) and progesterone receptor (PR) expression status
- Metastatic patterns
- Prior treatment history
Differences in progression-free survival (PFS) among various CDK4/6 inhibitors were also evaluated.
Survival analyses were performed using the Kaplan–Meier method, while univariate and multivariate analyses were conducted to identify potential risk factors associated with early rapid progression.
Study Results
1. Nearly One-Quarter of Patients Experienced Rapid Disease Progression Within Six Months of First-Line CDK4/6 Inhibitor Therapy
A total of 341 patients with HR+/HER2− advanced breast cancer were included in the study, with a median age of 53 years.
Early rapid progression was defined as disease progression occurring within six months after initiation of first-line CDK4/6 inhibitor plus endocrine therapy.
The results showed that 81 patients (23.8%) experienced early rapid progression, indicating that even in the CDK4/6 era, a substantial proportion of patients fail to achieve durable treatment benefit.
2. Luminal B Subtype and Low PR Expression Were Significantly Enriched in the Rapid Progression Population
Further analyses demonstrated that the proportion of Luminal B tumors was significantly higher among patients with early rapid progression compared with those without rapid progression (83.9% vs. 67.4%, P=0.01).
In addition, when stratified using a PR expression cutoff of 20%, patients with low PR expression were significantly more common in the rapid progression group (60.1% vs. 41.9%, P=0.01).
These findings suggest that such patients may possess stronger endocrine resistance tendencies and more aggressive tumor biological behavior.
3. No Significant Efficacy Differences Were Observed Among Different CDK4/6 Inhibitors After Baseline Adjustment
The study also compared treatment outcomes among different CDK4/6 inhibitors.
After adjustment for baseline characteristics, no statistically significant differences in progression-free survival were observed between the different agents.
These findings suggest that intrinsic tumor biology may play a more important role in determining the risk of early rapid progression than the specific CDK4/6 inhibitor selected.
Study Conclusions
This real-world study demonstrated that nearly one-quarter of patients with HR+/HER2− advanced breast cancer experienced disease progression within six months after initiation of first-line CDK4/6 inhibitor plus endocrine therapy.
Further analyses showed that Luminal B subtype and low PR expression (<20%) were significantly enriched among patients with rapid progression, whereas no significant survival differences were observed among different CDK4/6 inhibitors.
Investigator’s Perspective
Early Rapid Progression Remains a Clinical Challenge in the CDK4/6 Era
Although CDK4/6 inhibitors combined with endocrine therapy have significantly improved survival outcomes for patients with HR+/HER2− advanced breast cancer, real-world clinical practice still reveals a subgroup of patients who experience rapid disease progression shortly after treatment initiation.
Our study found that nearly one-quarter of patients developed disease progression within six months after starting first-line CDK4/6 inhibitor therapy, highlighting the substantial biological heterogeneity that still exists within HR+/HER2− advanced breast cancer.
Luminal B Subtype and Low PR Expression May Be Associated With Early Endocrine Resistance
Further analyses demonstrated significant enrichment of Luminal B subtype and low PR expression (<20%) among patients with rapid progression, suggesting that these patients may be more prone to early endocrine resistance.
Previous studies have suggested that reduced PR expression may be associated with increased tumor proliferative activity and decreased endocrine dependence. Similarly, Luminal B tumors are generally characterized by higher proliferative capacity and relatively poorer prognosis.
Precision Identification of High-Risk Patients May Become a Key Clinical Priority in the CDK4/6 Era
Importantly, this study did not observe significant survival differences among different CDK4/6 inhibitors, further suggesting that intrinsic tumor biology may play a more important role in early disease progression than the choice of specific CDK4/6 inhibitor.
Distinct high-risk subgroups with varying treatment sensitivity clearly remain within the HR+/HER2− advanced breast cancer population.
In the future, earlier identification of patients who are less likely to benefit from CDK4/6 inhibitor therapy, together with optimization of individualized treatment strategies, may become an increasingly important direction in precision treatment for HR+/HER2− advanced breast cancer.
In our subsequent studies, we also plan to further investigate the molecular biological differences and resistance-related mechanisms underlying distinct treatment-response populations, with the goal of providing additional evidence to support future precision treatment strategies.”
