Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy

Are pharmacogenomic biomarkers an effective tool to predict taxane toxicity and outcome in breast cancer patients? Literature review

“…A trial analyzed 257 breast cancer patients, treated in neo-adjuvant setting with doxorubicin/cyclophosphamide (AC) or doxorubicin/pemetrexed (AP), both followed by docetaxel; all these patients were genotyped for CD24 polymorphisms and CD24 Val/Val genotype resulted a significant predictor of pCR (pathological complete response) [94], suggesting a possible role of CD24 SNPs in patient outcome after taxanes chemotherapy. Another more recent trial investigated the association between 38 new genetic polymorphisms in 15 genes involved in paclitaxel and gemcitabine pathways in relation to clinical outcomes in 85 metastatic breast cancer women: SNP in solute carrier family 28 member 3 (SLC28A3) rs7867504, C/T was associated with longer OS, while patients carrying SLC29A1 G/A haplotype had a significantly shorter overall survival; furthermore, SNP of ribonucleotide reductase large subunit M1 (RRM1) gene and haplotypes ATAA and ATGA were significantly associated with chemotherapy-related neurotoxicity [95].…”

PharmGKB summary

“…Associations between rs2072671 with survival outcomes, or response to gemcitabine are similarly inconclusive. Two studies report no association between rs2072671 with patient outcomes [19, 21], and one reports an association between the A allele with improved outcomes in patients with non-small cell lung cancer (NSCLC) [25]. …”

“…An independent study, however, reports no association between rs1048977 and enzymatic activity of CDA when assessed in whole blood from healthy volunteers [28]. Two studies report no association between the C allele and patient outcomes [21, 22]. Another reports an association between the CC genotype with improved response to gemcitabine, including a longer median time to progression, but no association with risk of hematologic toxicity [19].…”

“…The rs60369023 (G >A) variant, which has only been reported in Korean and Japanese patients [8, 21, 33, 35], changes an alanine residue to a threonine (Ala70Thr). One in vitro study reports that the A allele is associated with decreased CDA enzymatic activity, and a second in vitro study reports that the A allele is associated with decreased CDA activity towards AraC, another deoxycytidine analog, but not towards gemcitabine [26, 36].…”

“…In vivo studies show an association between decreased DCK protein levels with shorter progression free survival in patients treated with gemcitabine [14, 41, 42]. Despite some well-established correlations between DCK protein levels with resistance to gemcitabine, no SNPs in DCK have shown a consistent association with patient response, or risk of toxicity in clinical studies [21, 22, 26, 43]. The results of those studies are summarized in Table 6.…”