Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients.

Karolina Tecza,Dorota Butkiewicz,Joanna Lanuszewska,Jolanta Pamula-Pilat,Ewa Grzybowska

doi:10.18632/oncotarget.24148

Abstract

The differences in patients’ response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy.In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Selected genes and their polymorphisms were involved in FAC drugs transport (ABCB1, ABCC2, ABCG2,SLC22A16), metabolism (ALDH3A1, CBR1, CYP1B1, CYP2C19, DPYD, GSTM1, GSTP1, GSTT1, MTHFR,TYMS), DNA damage recognition, repair and cell cycle control (ATM, ERCC1, ERCC2, TP53, XRCC1).The multifactorial risk models that combine genetic risk modifiers and clinical characteristics were constructed for 12 toxic symptoms. The majority of toxicities was dependent on the modifications in components of more than one pathway of FAC drugs, while the impact level of clinical factors was comparable to the genetic ones. For the carriers of multiple high risk factors the chance of developing given symptom was significantly elevated which proved the factor-dosage effect. We found the strongest associations between concurrent presence of clinical factors - overall and recurrent anemia, nephrotoxicity and early nausea and genetic polymorphisms in genes responsible for DNA repair, drugs metabolism and transport pathways. These results indicate the possibility of selection of the patients with expected high tolerance to FAC treatment and consequently with high chance of chemotherapy completion without the dose reduction, treatment delays and decline in the quality of life.

Highlights

Breast cancer is heterogeneous disease with distinct molecular subtypes that require many therapeutic approaches
ERCC1 is crucial for the repair of cyclophosphamide-induced DNA damage and cells, both normal and cancerous, and low-activity mutants may be hypersensitive to DNA crosslinking agents [30]
Concordant results come from the study by Khrunin [34], where heterozygotes were at increased risk of nephrotoxicity in ovarian cancer patients receiving cisplatin/gemcitabine chemotherapy

Summary

Introduction

Breast cancer is heterogeneous disease with distinct molecular subtypes that require many therapeutic approaches. The combination of fluorouracil, doxorubicin and cyclophosphamide, the FAC protocol, is a chemotherapy regimen commonly administered to breast cancer patients in Poland. It is postulated that the variation, including single nucleotide polymorphisms (SNPs) in the phase I activations, phase II detoxification enzymes, and ABC membrane transporters, plays an important role in the efficacy and toxicities of chemotherapy [5]. The components of metabolic phase I are responsible for both activation and inactivation of FAC drugs. Alongside the genes and enzymes of metabolic pathways, the components of DNA repair systems, as well as the main drug targets and their modifiers, like 5-FU’s thymidylate synthase gene (TYMS) and MTHF, may influence adverse treatment reactions [7, 10,11,12]

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