Effect of dihydropyrimidine dehydrogenase single nucleotide polymorphisms on prognosis of breast cancer patients with chemotherapy

Abstract

Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate to guide patient selection for personalized cancer treatments. DPD (dihydropyrimidine dehydrogenase, encoded by DPYD gene) is the initial and rate-limiting enzyme of metabolic pathway of fluoropyrimidines, and fluoropyrimidines are common used drug therapies for breast cancer. Previous studies on DPYD polymorphism were mainly focused on its association with fluoropyrimidines toxicity. In our present study, 5 DPYD single nucleotide polymorphisms status was detected from tumor tissues of 331 invasive breast cancer patients using standard techniques. We for the first time investigated the prognostic significance of DPYD polymorphisms in breast cancer. We demonstrated non-luminal breast cancer patients carrying DPYD c.1627A>G AG/GG treated with fluoropyrimidine-based regimen presented a shorter overall survival and progression-free survival than carriers treated with non-fluoropyrimidine regimen. However, non-luminal DPYD c.1627A>G AG/GG carriers treated with TE (taxane and anthracycline)-based regimen showed a better prognosis compared with carriers treated with non-TE regimen. Our results suggested TE-based chemotherapy was a suitable regimen for non-luminal patients with DPYD c.1627A>G AG/GG genotype and fluoropyrimidine-based regimen should not be recommended for those patients. Our findings provided a novel strategy, which will guide clinicians to choose more precise chemotherapy treatment for breast cancer patients.

Clinical Importance of Definition of Single Nucleotic Polymorphisms in Patients With Breast Cancer (Literature Review)

“…However, the prognostic value of DPYD polymorphisms in breast cancer has been little studied. Fengxia Qin et al in their work concidered the assosiation between SNPD DPYD and the effect of therapy based on regimens containing taxanes and anthracyclines (TA) [32]. The authors found that patients with non-wild type DPYD carriers treated with the TA regimen had a longer overall survival compared with "wild type" carriers who did not receive this treatment regimen.…”

In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase

“…Of the three metabolic enzymes, DPYD is the most studied gene. More than 500 DPYD polymorphisms to date have been identified and have been linked to FP-related toxicity in cancer patients [22,[37][38][39][40][41][42][43][44][45]. Several of these variants are known to alter amino acid sequence or mRNA splicing, resulting in decreased enzymatic activity.…”

Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase

“…While some studies assessed a role of low DPD expression as a predictive factor for chemosensitivity [94] and for DFS in adjuvant setting [95] , other ones did not found a significant difference between high and low DPD groups in terms of DFS in adjuvantly treated patients [96,97] and OS in metastatic ones [98] . A recent study conducted by Qin et al [99] was the first aimed to investigate the prognostic role of DPYD polymorphisms in breast cancer. They demonstrated that DPYD c.1627A>G AG/GG polymorphism, detected from tumor tissue, was associated with poor OS and PFS in non-luminal patients treated with fluoropyrimidine-based chemotherapy [99] .…”

“…A recent study conducted by Qin et al . [ 99 ] was the first aimed to investigate the prognostic role of DPYD polymorphisms in breast cancer. They demonstrated that DPYD c.1627A>G AG/GG polymorphism, detected from tumor tissue, was associated with poor OS and PFS in non-luminal patients treated with fluoropyrimidine-based chemotherapy [ 99 ] .…”