Which Clinicopathologic Parameters Suggest Primary Resistance to Palbociclib in Combination With Letrozole as the First-Line Treatment for Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer?

In this study, we evaluated clinical parameters to predict the primary resistance of palbociclib in combination with endocrine therapy as the first-line treatment in patients with hormone receptor (HR)+, human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer (MBC). We performed a data analysis of patients diagnosed with HR+, HER2-MBC who received palbociclib plus letrozole as the first-line treatment in the metastatic setting from the clinical data warehouse in Samsung Medical Center. In this study, 305 patients were included in the final data analysis. The median follow-up duration was 31 months, and we observed 123 cases of disease progression. The median progression-free survival (PFS) was 28.7 months, and 38 patients (12.5%) had less than a 6-month PFS. The multivariate analysis suggested that primary resistance to adjuvant endocrine therapy (ET) (hazard ratio: 1.91), presence of liver metastasis (hazard ratio: 2.17), initial elevation of serum CA-15-3 (hazard ratio: 1.99), weak positivity of estrogen receptor (ER) (hazard ratio: 2.28), Ki-67 3+ or 4+ (hazard ratios: 2.58 and 10.28), and presence of mutation (hazard ratio: 9.59) were associated with a short PFS duration. A further prediction model was developed with data from 256 patients and 33 cases of disease progression in 6 months. This model included five factors-primary resistance to adjuvant ET (odds ratio, OR: 1.14), liver metastasis (OR: 1.56), initial CA-15-3 elevation (OR: 1.51), weak ER expression (OR: 2.22), and BRCA2 mutation (OR: 2.85)-and the area under the receiver operating characteristic curve was 0.842 (95% CI: 0.775, 0.909; p < 0.001). Finally, we divided them into four risk groups according to the prediction model with the five risk factors. These four groups had different PFS (p < 0.001) and primary resistance of palbociclib with letrozole [OR of group 2 vs. group 1 (ref): 2.18 (p = 0.002), OR of group 3: 3.91 (p < 0.001), and OR of group 4: 4.25 (p < 0.001)]. We developed a prediction model of primary resistance to palbociclib with letrozole as the first-line treatment for HR+, HER2-MBC. Our prediction model might be helpful for considering the first-line treatment strategies. Further well-designed clinical trials would be warranted to validate our prediction model.