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Single-nucleotide polymorphisms and mRNA expression of CYP1B1 influence treatment response in triple negative breast cancer patients undergoing chemotherapy

Abdul Aziz AA, Md Salleh MS, Mohamad I, Krishna Bhavaraju VM, Mazuwin Yahya M, Zakaria AD, et al.

J Genet, 2018 Dec;97(5):1185-1194.
PMID: 30555068

Triple negative breast cancer (TNBC) is typically associated with poor and interindividual variability in treatment response. Cytochrome P450 family 1 subfamily B1 (CYP1B1) is a metabolizing enzyme, involved in the biotransformation of xenobiotics and anticancer drugs. We hypothesized that, single-nucleotide polymorphisms (SNPs), CYP1B1 142 C>G, 4326 C>G and 4360 A>G, and CYP1B1 mRNA expression might be potential biomarkers for prediction of treatment response in TNBC patients. CYP1B1 SNPs genotyping (76 TNBC patients) was performed using allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism methods and mRNA expression of CYP1B1 (41 formalin-fixed paraffin embeddedblocks) was quantified using quantitative reverse transcription PCR. Homozygous variant genotype (GG) and variant allele (G) of CYP1B1 4326C>G polymorphism showed significantly higher risk for development of resistance to chemotherapy with adjusted odds ratio (OR): 6.802 and 3.010, respectively. Whereas, CYP1B1 142 CG heterozygous genotype showed significant association with goodtreatment response with adjusted OR: 0.199. CYP1B1 142C-4326G haplotype was associated with higher risk for chemoresistance with OR: 2.579. Expression analysis revealed that the relative expression of CYP1B1 was downregulated (0.592) in cancerous tissue compared with normal adjacent tissues. When analysed for association with chemotherapy response, CYP1B1 expression was found to be significantly upregulated (3.256) in cancerous tissues of patients who did not respond as opposed to those of patients who showed response to chemotherapy. Our findings suggest that SNPs together with mRNA expression of CYP1B1 may be useful biomarkers to predict chemotherapy response in TNBC patients.

Matched MeSH terms: Carcinoma, Ductal, Breast/drug therapy
Fulltext Outcome after neoadjuvant chemotherapy in Asian breast cancer patients

Lim LY, Miao H, Lim JS, Lee SC, Bhoo-Pathy N, Yip CH, et al.

Cancer Med, 2017 Jan;6(1):173-185.
PMID: 28000426 DOI: 10.1002/cam4.985

We aim to identify clinicopathologic predictors for response to neoadjuvant chemotherapy and to evaluate the prognostic value of pathologic complete response (pCR) on survival in Asia. This study included 915 breast cancer patients who underwent neoadjuvant chemotherapy at five public hospitals in Singapore and Malaysia. pCR following neoadjuvant chemotherapy was defined as 1) no residual invasive tumor cells in the breast (ypT0/is) and 2) no residual invasive tumor cells in the breast and axillary lymph nodes (ypT0/is ypN0). Association between pCR and clinicopathologic characteristics and treatment were evaluated using chi-square test and multivariable logistic regression. Kaplan-Meier analysis and log-rank test, stratified by other prognostic factors, were conducted to compare overall survival between patients who achieved pCR and patients who did not. Overall, 4.4% of nonmetastatic patients received neoadjuvant chemotherapy. The median age of preoperatively treated patients was 50 years. pCR rates were 18.1% (pCR ypT0/is) and 14.4% (pCR ypT0/is ypN0), respectively. pCR rate was the highest among women who had higher grade, smaller size, estrogen receptor negative, human epidermal growth factor receptor 2-positive disease or receiving taxane-based neoadjuvant chemotherapy. Patients who achieved pCR had better overall survival than those who did not. In subgroup analysis, the survival advantage was only significant among women with estrogen receptor-negative tumors. Patients with poor prognostic profile are more likely to achieve pCR and particularly when receiving taxane-containing chemotherapy. pCR is a significant prognostic factor for overall survival especially in estrogen receptor-negative breast cancers.

Matched MeSH terms: Carcinoma, Ductal, Breast/drug therapy*
Risk of treatment related death and febrile neutropaenia with first line palliative chemotherapy for de novo metastatic breast cancer in clinical practice in a middle resource country

Phua CE, Tang WH, Yusof MM, Saad M, Alip A, See MH, et al.

Asian Pac J Cancer Prev, 2014;15(23):10263-6.
PMID: 25556458

BACKGROUND: The risk of febrile neutropaenia (FN) and treatment related death (TRD) with first line palliative chemotherapy for de novo metastatic breast cancer (MBC) remains unknown outside of a clinical trial setting despite its widespread usage. This study aimed to determine rates in a large cohort of patients treated in the University of Malaya Medical Centre (UMMC).
MATERIALS AND METHODS: Patients who were treated with first line palliative chemotherapy for de novo MBC from 2002-2011 in UMMC were identified from the UMMC Breast Cancer Registry. Information collected included patient demographics, histopathological features, treatment received, including the different chemotherapy regimens, and presence of FN and TRD. FN was defined as an oral temperature >38.5° or two consecutive readings of >38.0° for 2 hours and an absolute neutrophil count <0.5x109/L, or expected to fall below 0.5x109/L (de Naurois et al, 2010). TRD was defined as death occurring during or within 30 days of the last chemotherapy treatment, as a consequence of the chemotherapy treatment. Statistical analysis was performed using the SPSS version 18.0 software. Survival probabilities were estimated using the Kaplan-Meier method and differences in survival compared using log-rank test.
RESULTS: Between 1st January 2002 and 31st December 2011, 424 patients with MBC were treated in UMMC. A total of 186 out of 221 patients with de novo MBC who received first line palliative chemotherapy were analyzed. The mean age of patients in this study was 49.5 years (range 24 to 74 years). Biologically, ER status was negative in 54.4% of patients and Her-2 status was positive in 31.1%. A 5-flourouracil, epirubicin and cyclophosphamide (FEC) chemotherapy regimen was chosen for 86.6% of the cases. Most patients had multiple metastatic sites (58.6%). The main result of this study showed a FN rate of 5.9% and TRD rate of 3.2%. The median survival (MS) for the entire cohort was 19 months. For those with multiple metastatic sites, liver only, lung only, bone only and brain only metastatic sites, the MS was 18, 24, 19, 24 and 8 months respectively (p-value= 0.319).
CONCLUSIONS: In conclusion, we surmise that FEC is a safe regimen with acceptable FN and TRD rates for de novo MBC.

Matched MeSH terms: Carcinoma, Ductal, Breast/drug therapy*
Incidence of chemotherapy-induced ovarian failure in premenopausal women undergoing chemotherapy for breast cancer

Tiong V, Rozita AM, Taib NA, Yip CH, Ng CH

World J Surg, 2014 Sep;38(9):2288-96.
PMID: 24700093 DOI: 10.1007/s00268-014-2542-y

Breast cancer is increasingly reported in young premenopausal women in Asia. Adjuvant chemotherapy improves survival; however, it has a unique consequence of ovarian failure in premenopausal patients.

Matched MeSH terms: Carcinoma, Ductal, Breast/drug therapy*