Malaysian Breast Cancer Patients Research Articles

Abstract A210: Single nucleotide polymorphisms of ABCB1, SLCO1B3, and CYP3A5: Potential biomarkers of docetaxel adverse effects in Malaysian breast cancer patients.

Abstract Docetaxel is an antitubulin chemotherapeutic agent approved for the treatment of breast, lung, ovarian and non-hormonal dependent prostate cancers. However, the success of this drug is limited by adverse effects (AEs), the severity of which ranged from tolerable to life threatening. Tapering the dose or diverting to another regimen would limit the use of docetaxel. Single nucleotide polymorphisms (SNPs) of genes encoding for enzymes and proteins involved in the metabolism and transport of docetaxel can cause accumulation of the drug and consequent AEs. Hence, we embarked on a study to investigate the association between SNPs of ABCB1, SLCO1B3 and CYP3A5 genes with docetaxel AEs in Malaysian breast cancer patients. Seventy five breast cancer patients receiving docetaxel as single agent chemotherapy in the adjuvant and metastatic settings were enrolled in this study. They were recruited from University Malaya Medical Centre and Universiti Kebangsaan Malaysia Medical Centre. The doses given were 90-100 mg/m2 in adjuvant setting and 75 mg/m2 in metastatic setting. The SNPs (CYP3A5 6986AG, ABCB1 3435CT and SLCO1B3 334TG) were analyzed using PCR-RFLP technique followed by DNA sequencing of selected samples. AEs were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The SNPs were correlated with AEs using Chi-square and Fisher's exact tests. The patients aged 53.7±9.4 years consisted of three main ethnic groups (Chinese 37 (49%), Malays 32 (43%) and Indians 6 (8%). The most commonly reported AEs were fatigue (55%), nausea (40%), and mucositis (35%). There was a significant association of vomiting with race (p<0.05), where Indians significantly developed vomiting. The presence of ABCB1 3435CT (heterozygous) was significantly associated with rash (p<0.05). Simultaneous presence of SLCO1B3 334GG (mutant) and CYP3A5 6986GG (mutant) was found to have significantly protected the patients from developing mucositis. Although CYP3A5 6986AG polymorphism alone was not significantly associated with mucositis, presence of CYP3A5 6986AA (wild type) and ABCB1 3435TT (mutant) had a significant association with mucositis (p<0.05). On the contrary, patients exhibiting CYP3A5 6986AG (heterozygous) and ABCB1 3435TT (mutant) did not develop mucositis (p<0.05). In conclusion, the SNPs of CYP3A5 6986AG, ABCB1 3435CT and SLCO1B3 334TG had significant influence on the development of docetaxel AEs. Simultaneous interaction between SLCO1B3 334GG (mutant) and CYP3A5 6986GG (mutant); CYP3A5 6986AA (wild type) and ABCB1 3435TT (mutant); CYP3A5 6986AG (heterozygous) and ABCB1 3435TT (mutant) appeared to be significant factors determining whether or not specific AE develops. The SNPs-AEs association provides a great avenue for potential application of biomarkers to personalize treatment to reduce AEs of docetaxel. We would like to thank the Malaysian Ministry of Higher Education (MOHE) and University Malaya for supporting this project through FRGS (04-04-10-848FR) and HIR (UM.C/625/1/HIR) grants, respectively. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A210. Citation Format: Rafid Salim Jabir, Gwo Fuang Ho, Muhammad Azrif bin Ahmad Annuar, Johnson Stanslas. Single nucleotide polymorphisms of ABCB1, SLCO1B3, and CYP3A5: Potential biomarkers of docetaxel adverse effects in Malaysian breast cancer patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A210.

Survival Rate of Breast Cancer Patients In Malaysia: A Population-based Study

Breast cancer is the most common cancer among Malaysian women. Other than hospital-based results, there are no documented population-based survival rates of Malaysian women for breast cancers. This population- based retrospective cohort study was therefore conducted. Data were obtained from Health Informatics Centre, Ministry of Health Malaysia, National Cancer Registry and National Registration Department for the period from 1st Jan 2000 to 31st December 2005. Cases were captured by ICD-10 and linked to death certificates to identify the status. Only complete data were analysed. Survival time was calculated from the estimated date of diagnosis to the date of death or date of loss to follow-up. Observed survival rates were estimated by Kaplan- Meier method using SPSS Statistical Software version 17. A total of 10,230 complete data sets were analysed. The mean age at diagnosis was 50.6 years old. The overall 5-year survival rate was 49% with median survival time of 68.1 months. Indian women had a higher survival rate of 54% compared to Chinese women (49%) and Malays (45%). The overall 5-year survival rate of breast cancer patient among Malaysian women was still low for the cohort of 2000 to 2005 as compared to survival rates in developed nations. Therefore, it is necessary to enhance the strategies for early detection and intervention.

Dietary Changes Among Breast Cancer Patients in Malaysia

Breast cancer patients often show an interest in making dietary changes after diagnosis of breast cancer to improve their health condition and prevent cancer recurrence. The objective of the study was to determine changes in dietary intake 2 years after diagnosis among breast cancer patients. One hundred sixteen subjects were asked to complete a semiquantitative food frequency questionnaire, diet recalls, and dietary changes questionnaire to assess dietary intake before and after diagnosis. The information on sociodemographic background, cancer treatment history, and anthropometric indices was also collected. Seventy-two subjects considered diet as a contributing factor to breast cancer, and 67 subjects changed their dietary habits after breast cancer diagnosis. The reasons for changes in diet were physician and dietitian advice and desire to cure cancer. The sources of information were derived from their physician, mass media, and family members. Total energy, protein, total fat, fatty acids, and vitamin E intake were significantly decreased after diagnosis. Meanwhile, the intake of β-carotene and vitamin C increased significantly after diagnosis. The changes included reduction in red meat, seafood, noodles, and poultry intake. An increased consumption of fruits, vegetables, fish, low-fat milk, and soy products was observed. The subjects tended to lower high-fat foods intake and started to eat more fruits and vegetables. Breast cancer patients had changed to a healthier diet after breast cancer diagnosis, although the changes made were small. This will be helpful to dietitians in providing a better understanding of good eating habits that will maintain patients' health after breast cancer diagnosis.

Reliability and Validity of the Malay Version of the Breast-Impact of Treatment Scale (MVBITS) in Breast Cancer Women undergoing Chemotherapy

Body image dissatisfaction among breast cancer survivors has been associated with psychological stress resultant from breast cancer and resultant surgery. This study aimed to examine the psychometric properties of the Malay Version of the Breast-Impact of Treatment Scale (MVBITS) and to investigate the associations of retained factors with the Hospital Anxiety and Depression Scale (HADS) and the Rosenberg Self-Esteem Scale (RSES). The MVBITS was 'forward-backward' translated from English to Malay and then administered to 70 female breast cancer patients who came to the Oncology Clinic of University Malaya Medical Centre, Kuala Lumpur, Malaysia to undergo chemotherapy. Principal component analysis (PCA) with varimax rotation was performed to explore the factor structure of the MVBITS. Associations of retained factors were estimated with reference to Spearman correlation coefficients. The internal consistency reliability of MVBITS was good (Cronbach's alpha 0.945) and showed temporal stability over a 3-week period. Principal component analysis suggested two factors termed as 'Intrusion' and 'Avoidance' domains. These factors explained 70.3% of the variance. Factor 1 comprised the effects of breast cancer treatment on the emotion and thought, while Factor 2 informed attempts to limit exposure of the body to self or others. The Factor 1 of MVBITS was positively correlated with total, depression and anxiety sub-scores of HADS. Factor 2 was positively correlated with total and anxiety sub-scores of HADS. MVBITS was also positively correlated with the RSES scores. The results showed that the Malay Version of Breast-Impact of Treatment Scale possesses satisfactory psychometric properties suggesting that this instrument is appropriate for assessment of body change stress among female breast cancer patients in Malaysia.

Abstract 2609: Addition of ER and PTEN, but not cytokeratins, aids identification for BRCA1 carriers in Malaysian breast cancer patients

Abstract Background: Given that BRCA1 carriers are more likely to develop triple negative breast cancers (TNBC) and that current risk assessment models underestimate BRCA carriers in Asian populations, we have sought to determine the prevalence of BRCA mutations amongst TNBC patients and whether addition of pathological features improves the sensitivity of the Manchester scoring method of BRCA risk assessment. Methods: A total of 399 patients from the Malaysian Breast Cancer Genetic Study were fully analysed for BRCA1 and BRCA2 mutations, including 101 patients with TNBC. Pathological features, including estrogen receptor (ER) and PTEN status were assessed and included in a modified Manchester scoring method. Results: Our study in an Asian series of triple negative breast cancer patients has demonstrated that 22% [22/101] of patients have germline mutations in BRCA1 [18/101] and BRCA2 [4/101]. We find that amongst patients who were diagnosed with breast cancer aged 36-50 but with no family history of breast or ovarian cancer, the prevalence of BRCA mutations was similar amongst those who developed triple negative breast cancer (7%) and non-TNBC (7%). By contrast, in two other groups of patients (a) those who were diagnosed with breast cancer β35 years old with no family history of these cancers, and (b) those with family history of breast cancer, the prevalence of mutations was higher in those with TNBC compared to those with non-TNBC [29% and 11%; p=0.07; and 40% and 14%; p=0.001 respectively]. Furthermore, we find that incorporation of estrogen-receptor status improves the sensitivity of the Manchester Scoring method [38% to 62%] and in particular, incorporation of the status of PTEN, further improves sensitivity [43% to 100%]. Conclusion: We find that TNBC is an important criteria for highlighting patients who may benefit from genetic testing, but that this may be most useful for individuals with early onset breast cancer (≥35 years old) or with family history of cancers. Furthermore, addition of ER and PTEN status improves the sensitivity of the Manchester scoring method and may be particularly important in the Asian context when family history is often inaccurately reported. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2609. doi:1538-7445.AM2012-2609

Efficacy versus toxicity of docetaxel in Asian and Caucasian cancer patients from the pharmacogenomics perspectives: a review of the literature

Docetaxel is a common anticancer agent in the treatment of breast and lung cancers. Metabolism of docetaxel occurs through cytochrome P450 (CYP) and the function of the enzyme can be altered by genetic, environmental and physiological factors. Interindividual differences in pharmacokinetic profiles of anticancer agents due to changes in CYP function lead to variations in drug efficacy and/or toxicity. Unpredictable toxicities of taxanes have been reported, related to interindividual variability of pharmacokinetics of the drugs. It is evident from multiple studies that adverse events, which are mainly haematological amongst Asian patients receiving docetaxel are higher than as reported in the Caucasian population. Most clinicians who treat Asian patients thus prophylactically support patients with growth factors or reduce the dose of docetaxel. Polymorphisms in genes encoding transporters involved in the uptake of docetaxel will lead to accumulation of the drug in the circulation e.g. ABCB1. Polymorphisms in β‐tubulin (target of docetaxel) affect the taxane chemotherapy results. Presently we have embarked on a project to study the pharmacogenomics of docetaxel in Malaysian breast cancer patients for the very first time to address the above issues. This project is funded by UPM and Al‐Malak Universality, Iraq.

Proteomics of Grade 3 infiltrating ductal carcinoma in Malaysian Chinese breast cancer patients

Proteomics of Grade 3 infiltrating ductal carcinoma in Malaysian Chinese breast cancer patients

Proteomics of Grade 3 infiltrating ductal carcinoma in Malaysian Chinese breast cancer patients

Breast cancer is the leading cause of cancer-related mortality and morbidity among women worldwide and IDC (infiltrating ductal carcinoma) is the most common type of invasive breast cancer. The changes in the biological behaviour of cancer tissue can be predicted by measuring the differential protein expression of normal and cancerous tissues. Using a combination of SDS/PAGE and LC (liquid chromatography)-MS/MS (tandem MS), we identified 82 common and differentially expressed proteins from normal and cancerous breast tissues in 20 Malaysian Chinese patients with IDC. These proteins are extracted from the normal and cancerous tissue of patients and therefore represent the actual proteins involved in cancer development. Proteins identified possibly have significant roles in the development of breast cancer in Malaysian Chinese patients in view of their consistent expression in most of the patients, although some of the proteins had not been detected in earlier studies that were mostly carried out in Western countries. This observation suggests that molecular mechanisms leading to breast cancer development in this region may not be identical with those leading to IDC in Western regions.

Single nucleotide polymorphisms (SNPs) of exons 3, 4, 5 and 9 of the matrix metalloproteinase 2 (MMP-2) gene in breast carcinoma of Malaysian women using high resolution melting analysis

Background Breast cancer metastasis is a factor contributing to high disease mortality. Single nucleotide polymorphism (SNP) of the matrix metalloproteinase 2 (MMP-2) gene, which controls the enzyme for degradation of macromolecules of the connective tissues and extracellular matrix, has been associated with cancer invasion and metastasis. Aim The aim was to detect SNPs of exons 3, 4, 5 and 9 of the MMP-2 gene in breast carcinoma of Malaysian women using high resolution melting analysis (HRM). Methods Genomic DNA was obtained of both tumour mass and normal adjacent tissue from 60 Malaysian breast cancer patients. SNP scanning involving all four exons of MMP-2 coding regions was performed by HRM analysis on Rotor-Gene 6000 real-time PCR. The PCR products presented with aberrant melting curve pattern were purified and sequenced. Sequence trace data obtained were analysed with Staden Package for mutation detection. Results The scanning of the MMP-2 exons detected 4 known SNPs in exon 5 (678G>C, 750C>T), intron 5 (832+12C>T) and exon 9 (1380G>A). No SNP was detected on exon 3 and 4. Five patients carried both copies of variant A SNP 1380G>A while only one patient carried homozygous variant T SNP 832+12C>T. Only one patient with homozygous variant T allele SNP 1380G>A and SNP 678G>C had poor outcome with extensive metastasis and failed chemotherapy. Conclusion A relationship between SNP of MMP-2 with disease progression and poor therapeutic response is a strong possibility. The utilisation of HRM, a sensitive and cost effective method for scanning the MMP-2 gene, is suggested on all exons to elucidate the involvement of SNPs in cancer progression.