DOI: 10.1200/po-26-00273 ISSN: 2473-4284

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

Francesco Schettini, Alexandro Membrino, Giuseppe Di Grazia, Aldo Caltavituro, Carla Strina, Manuela Milani, Antonina Impeduglia, Leda Paganini, Anna Bosi, Sara Tedoldi, Marta Gatti, Valeria Cervoni, Marzia Alberio, Mario Giuliano, Sergio Venturini, Daniele Generali
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PURPOSE

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 ( DPYD ) polymorphisms on dose reduction and safety remain limited.

METHODS

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 DPYD variant carriers) + VNL (20 mg/day, once daily, 5-days-on/2-days-off). All patients underwent pretreatment DPYD 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.

RESULTS

The median age was 61 years, and DPYD 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 DPYD variant carriers and normal metabolizers (all P values > .05). In later lines, Eastern Cooperative Oncology Group performance status 2 and >2 metastatic sites were independent negative prognostic factors (all values P < .05). Overall, 7.5% grade 3 toxicities occurred, especially in variant carriers without dose reduction and grade 4-5 events.

CONCLUSION

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 DPYD -guided dose individualization as a strategy to optimize the benefit-risk balance of fluoropyrimidine-based metronomic regimens.

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