Genetic 3′UTR variations and clinical factors significantly contribute to survival prediction and clinical response in breast cancer patients

Abstract

The study describes a relationship between the 3′UTR variants, clinicopathological parameters and response to chemotherapy. We analyzed 33 germline polymorphisms in 3′UTRs of ADME genes in 305 breast cancer women treated with FAC regime. Clinical endpoints of this study were: overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS) and overall response defined as treatment failure-free survival (TFFS). The shortened OS was connected with the presence of NR1/2 rs3732359 AA, SLC22A16 rs7756222 CC, as well as SLC22A16 rs9487402 allele G and clinical factors belonging to TNM classification: tumor size >1 cm, nodal involvement and presence of metastases. PFS was related to two polymorphisms PGR rs1824125 GG, PGR rs12224560 CC and SLC22A16 rs7756222 CC as well as preexisting metastases. The RFS was shortened due to the DPYD rs291593 CC, AKR1C3 rs3209896 AG and negative expression of PGR. The presence of ALDH5A1 rs1054899 allele A, lack of pre-chemotherapy surgery and negative status of PGR correlated with worse treatment response. The germline variants commonly present in the population are important factors determining the response to treatment. We observed the effect of the accumulation of genetic and clinical factors on poor survival prognosis and overall treatment response. Breast cancer usually affects women in postmenopausal period, although it is diagnosed increasingly in younger patients often in advanced clinical stages 1. The 5-year survival is around 80% in developed countries 2. Therapeutic strategies for breast cancer include targeted therapy, hormone therapy, radiotherapy, surgery and chemotherapy 1,3. Toxicity and resistance to chemotherapeutic drugs are common problems observed in patients during and after treatment. Lack of sensitivity to chemotherapy is most often associated with dysfunction of protein transporters that remove chemotherapeutic agents from the cells or DNA repair processes 4. The response to systemic treatment is different in patients with the same type of cancer, similar stage of disease and treated with the same medications. Lack of chemotherapy response is observed as cancer-related mortality, disease progression or recurrence 5,6. Metabolism, absorption, distribution and excretion (ADME processes) of drugs are regulated by genes and proteins responsible for biotransformation and metabolic elimination of drugs (enzymes cytochrome P450). Also, proteins belonging to ATP binding cassette (ABC) and solute carrier (SLC) control influx or efflux of toxin and medicines and their cellular distribution 7,8. The expression of ADME genes is regulated at the transcriptional and translational levels. In addition, they undergo posttranslational modifications. ADME dysfunction may lead to reduced drug efficacy or to an adverse drug reaction in pharmacotherapy 9,10. Genetic and epigenetic transformations of ADME genes can modulate the activity and therapeutic effects of chemotherapy and underline interpatient differences in response to therapy 5,11-13 .

Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine

“…Moreover, the progesterone receptor-associated rs1824125-GG was found to be associated with shortening of progression-free survival, while the ALDH5A1-associated rs1054899-AG/AA correlated with reduced chemotherapeutic response to 5-fluorouracil, doxorubicin and cyclophosphamide [316,320,321]. Survival analysis indicated shortening of survival time in patients carrying the rs7756222-CC and rs9487402-TG/GG variations in SLC22A16 gene [316,322]. These data demonstrate the potent existence of clinically associated variations in progesterone signaling pathways.…”

“…The investigated variants included the DPYD-associated rs291593-CC, which is correlated with increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy and the AKR1C3-associated rs3209896-AG, which is linked to elevated risk for breast cancer recurrence. Moreover, the progesterone receptor-associated rs1824125-GG was found to be associated with shortening of progression-free survival, while the ALDH5A1-associated rs1054899-AG/AA correlated with reduced chemotherapeutic response to 5-fluorouracil, doxorubicin and cyclophosphamide [316,320,321]. Survival analysis indicated shortening of survival time in patients carrying the rs7756222-CC and rs9487402-TG/GG variations in SLC22A16 gene [316,322].…”

DPYD Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach

“…No 3′UTR DPYD variants have been associated with toxicity to fluoropyrimidines to date. Nevertheless, a study analyzing 33 germline polymorphisms in the 3′UTR of genes involved in drug absorption, distribution, metabolism and elimination (ADME) showed that DPYD rs291593 was associated with recurrence-free survival in breast cancer patients [ 33 ]. No data on the effect of this SNP on DPYD expression have been reported, but the variant position suggests a putative posttranscriptional regulation, a role that would explain its relationship with treatment response.…”

Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment

“…Drug resistance to chemotherapeutic agents and toxicity are often noticed in breast cancer patients during treatment and worsen the chemotherapy outcome [16,63]. In Caucasian women with breast cancer treated with FAC (doxorubicin, 5 -fluorouracil and cyclophosphamide) the presence of NR1L2 rs3732359 (G > A) was an independent predictor of OS as patients carrying the AA genotype were described to have a 2 times higher risk of death compared to homozygous for the wild type allele (GG) and heterozygous (AG) [63].…”

“…Drug resistance to chemotherapeutic agents and toxicity are often noticed in breast cancer patients during treatment and worsen the chemotherapy outcome [16,63]. In Caucasian women with breast cancer treated with FAC (doxorubicin, 5 -fluorouracil and cyclophosphamide) the presence of NR1L2 rs3732359 (G > A) was an independent predictor of OS as patients carrying the AA genotype were described to have a 2 times higher risk of death compared to homozygous for the wild type allele (GG) and heterozygous (AG) [63]. Regarding the clearance of doxorubicin in Asian women with invasive breast cancer treated with adjuvant chemotherapy with doxorubicin/cyclophosphamide, patients carrying the haplotype cluster tagged by IVS6-17C > T (NR1I2 rs2276707) and 2654T > C (NR1I2 rs3814058) were characterized by reduced doxorubicin clearance [7].…”