<i>DPYD</i>-Guided Dosing of Metronomic Capecitabine Plus Vinorelbine in Metastatic Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: A Real-World Retrospective Study.

Abstract

Metronomic chemotherapy with oral capecitabine + vinorelbine (Cape + VNL) provides synergistic cytostatic activity and antiangiogenic and immunomodulatory effects, potentially offering prolonged disease control with limited toxicity in HER2-negative metastatic breast cancer (MBC). However, efficacy in the real-world (RW) setting, especially in late lines, and the impact of dihydropyrimidine dehydrogenase (<i>DPYD</i>) polymorphisms on dose reduction and safety remain limited. In this retrospective study, 200 patients with human epidermal growth factor receptor 2 (HER2)-negative MBC were treated at the ASST Cremona Hospital (2015-2023) with metronomic Cape (1000 mg twice daily, in normal metabolizers; 500 mg twice daily, in <i>DPYD</i> variant carriers) + VNL (20 mg/day, once daily, 5-days-on/2-days-off). All patients underwent pretreatment <i>DPYD</i> genotyping and dose adjustment. Treatment was administered in the second-to-fourth setting. The primary end point was time-to-next treatment or death (TNTD); secondary end points included overall survival (OS), disease control rate (DCR) ≥24 weeks, overall response rate (ORR), safety, and genotype-toxicity correlations. The median age was 61 years, and <i>DPYD</i> variants were present in 14.5% of patients; 34%, 41%, and 25% received therapy as second-, third-, and fourth-line treatment. The median TNTD was 22.0 weeks, and the OS was 64.0 weeks. The DCR was 38.5%, and the ORR was 22.0%. Efficacy was comparable between <i>DPYD</i> variant carriers and normal metabolizers (all <i>P</i> values > .05). In later lines, Eastern Cooperative Oncology Group performance status 2 and >2 metastatic sites were independent negative prognostic factors (all values <i>P</i> < .05). Overall, 7.5% grade 3 toxicities occurred, especially in variant carriers without dose reduction and grade 4-5 events. These RW data suggest that metronomic Cape + VNL may represent a clinically active and manageable option in heavily pretreated HER2-negative MBC. Our findings support prospective evaluation of <i>DPYD</i>-guided dose individualization as a strategy to optimize the benefit-risk balance of fluoropyrimidine-based metronomic regimens.