Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients

Tsuji, Daiki; Ikeda, Mineo; Yamamoto, Keisuke; Nakamori, Harumi; Kim, Yong‐Il; Kawasaki, Yohei; Otake, Aki; Yokoi, Mari; Inoue, Ken‐ichiro; Hirai, Keita; Nakamichi, Hidenori; Tokou, Umi; Shiokawa, Mitsuru; Itoh, Ken

doi:10.1097/md.0000000000005151

Cited by 23 publications

(21 citation statements)

References 32 publications

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“…We found that, patients with CYP2J2 ∗ 7 allele, baseline grade 1 leukocytopenia, and grade 1 or 2 neutropenia, were significantly associated with increased risk of grade 3 or 4 hematologic toxicity. Low baseline WBC count as an important predictor for chemotherapy induced hematologic toxicity was consistent with previous reports (Lyman et al, 2003; Jenkins et al, 2012; Tsuji et al, 2016). However, CYP2J2 ∗ 7 was identified as new pharmacogenetic risk factors of chemotherapy induced hematologic toxicity in Ethiopian breast cancer patients.…”

Section: Discussionsupporting

confidence: 92%

CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients

et al. 2019

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Chemotherapy-induced hematologic toxicity is the primary reasons of dose reductions and/or delays, low relative dose intensity (RDI), and predicts anticancer response. We investigated the incidence and predictors of chemotherapy-induced hematologic toxicities and reduced RDI in Ethiopian breast cancer patients, and implication of pharmacogenetics variations. Breast cancer patients ( n = 249) were enrolled prospectively to receive cyclophosphamide based chemotherapy. Hematological toxicity (neutropenia, anemia, and thrombocytopenia) were monitored throughout chemotherapy cycle. The primary and secondary outcomes were incidence of grade 3 or 4 toxicity and reduced RDI, respectively. CYP2B6 ∗ 6, CYP3A5 ∗ 3, CYP2C9 ( ∗ 2, ∗ 3 ), CYP2C19 ( ∗ 2, ∗ 3), CYP2J2 ∗ 7, POR ∗ 28 , and ABCB1 (rs3842) genotyping were done. Cox proportional hazard and logistic regression were used to estimate risk predictors of toxicity and reduced RDI, respectively. Majority (73.5%) of the patients were < 45 years of age. The incidence of grade 3 or 4 hematological toxicity was 51.0% (95% CI = 44.54–57.46%). Multivariate Cox proportional hazard regression indicated CYP2J2 ∗ 7 genotype [Hazard ratio (HR) = 1.82; 95% CI = 1.14–2.90], pretreatment grade 1 leukopenia (HR = 2.75; 95% CI = 1.47–5.15) or grade 1 or 2 neutropenia (HR = 2.75; 95% CI = 1.73–4.35) as significant predictors of hematologic toxicities. The odds of having hematologic toxicities was lower in CYP2C9 ∗ 2 or ∗ 3 carriers ( p = 0.024). The prevalence of reduced RDI was 56.6% (95% CI = 50.3–62.9%). Higher risk of reduced RDI was associated with CYP2J2 ∗ 7 allele [Adjusted odds ratio (AOR) = 2.79; 95% CI = 1.21–6.46], BMI ≤ 18.4 kg/m 2 (AOR = 5.98; 95% CI = 1.36–26.23), baseline grade 1 leukopenia (AOR = 6.09; 95% CI = 1.24–29.98), and baseline neutropenia (AOR = 3.37; 95% CI = 1.41–8.05). The odds of receiving reduced RDI was lower in patients with CYP2B6 ∗ 6/ ∗ 6 genotype (AOR = 0.19; 95% CI = 0.06–0.77). We report high incidence of chemotherapy-induced hematological toxicities causing larger proportion of patients to receive reduced RDI in Ethiopian breast cancer patients. Patients carrying CYP2J2 ∗ 7 allele and low baseline blood counts are at a higher risk for chemotherapy-induced hematologic toxicities and receiving reduced RDI, and may require prior support and close follow up during chemotherapy.

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Section: Discussionsupporting

confidence: 92%

CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients

et al. 2019

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“…It is therefore intensively analyzed, both its expression and common variants, as the potential marker of cancer risk, chemotherapy responsiveness and side effects [ 28 , 29 ]. ERCC1 is also 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 ]. Two ERCC1 polymorphisms selected for this study, p.Asn118= (rs11615) in exon 4 and c.1510C>A (rs3212986) in 3’UTR are extensively studied in many cancers and chemotherapeutic regimes because of their negative influence on the stability and level of ERCC1 mRNA and on the protein expression [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…Whilst not the focus of this review, it is important to note that the role of pharmacogenetics in the risk of excessive toxicity (due to high levels of bioactivation of this cytotoxic drug) have also been assessed. Associations between CYP2C19 and/or CYP2B6 , as well as other pharmacogenes such as ALDH , GSTP1 and CYP3A4 , and the severity of neutropenia or premature ovarian failure have been reported …”

Section: Therapeutic Outcomesmentioning

confidence: 99%

“…Associations between CYP2C19 and/or CYP2B6, as well as other pharmacogenes such as ALDH, GSTP1 and CYP3A4, and the severity of neutropenia or premature ovarian failure have been reported. 40,65,67,[70][71][72][73][74][75]…”

Section: Therapeutic Outcomesmentioning

confidence: 99%

The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes

Helsby

Yong

Kan

et al. 2019

Brit J Clinical Pharma

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Cyclophosphamide is an alkylating agent used in the treatment of solid and haematological malignancies and as an immunosuppressive agent. As a prodrug, it is dependent on bioactivation to the active phosphoramide mustard metabolite to elicit its therapeutic effect. This focused review will highlight the evidence for the role of germline pharmacogenetic variation in both plasma pharmacokinetics and clinical outcomes. There is a substantial indication from 13 pharmacokinetic and 17 therapeutic outcome studies, in contexts as diverse as haematological malignancy, breast cancer, systemic lupus erythematosus and myeloablation, that pharmacogenetic variation in both CYP2C19 and CYP2B6 influence the bioactivation of cyclophosphamide. An additional role for pharmacogenetic variation in ALDH1A1 has also been reported. Future studies should comprehensively assess these 3 pharmacogenes and undertake appropriate statistical analysis of gene–gene interactions to confirm these findings and may allow personalised treatment regimens.

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Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients

Abstract: Supplemental Digital Content is available in the text

Cited by 23 publications

References 32 publications

CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients

CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients

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

The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes

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