Breast Cancer Care Timeliness Framework: A Quality Framework for Cancer Control.

PURPOSE: The aim of this study is to determine the pathway that women follow for Breast Cancer Care (BCC) and the time intervals from symptom discovery to treatment initiation and to develop a quality matrix framework. METHODS: A retrospective cohort study was conducted at six tertiary centers in Malaysia. All women with newly diagnosed breast cancer were interviewed, and a medical records review was conducted using a structured questionnaire. The BCC timeliness framework showed that the total time between a woman discovering their first breast changes and the date of initial treatment was divided into three distinct intervals: presentation interval, diagnostic interval, and treatment interval. Four diagnosis subintervals, referral, biopsy, report, and diagnosis resolution intervals, were also looked into. RESULTS: The BCC timeliness framework was used to capture important time points. The median total time, presentation interval, diagnostic interval, and treatment interval were 4.9 months (range, 1 month to 10 years), 2.4 months (range, 7 days to 10 years), 26 days (range, 4 days to 9.3 months), and 21 days (range, 1 day to 7.2 months), respectively. Meanwhile, the median time for the diagnosis subinterval of referral, biopsy, report, and diagnosis resolution was 8 days (range, 0 day to 8 months), 0 day (range, 0 day to 20 days), 7 days (range, 3 days to 3.5 months), and 4 days (range, 1 day to 1.8 months), respectively. CONCLUSION: The BCC timeliness framework is based on the current sequenced trajectory of the BCC journey. Clarity in the measurement of timeliness provides a standardized language for monitoring and outcome research. It can serve as a quality indicator for community and hospital-based breast cancer programs.

Mitochondrial DNA mutations in Malaysian female breast cancer patients.

Cancer development has been ascribed with diverse genetic variations which are identified in both mitochondrial and nuclear genomes. Mitochondrial DNA (mtDNA) alterations have been detected in several tumours which include lung, colorectal, renal, pancreatic and breast cancer. Several studies have explored the breast tumour-specific mtDNA alteration mainly in Western population. This study aims to identify mtDNA alterations of 20 breast cancer patients in Malaysia by next generation sequencing analysis. Twenty matched tumours with corresponding normal breast tissues were obtained from female breast cancer patients who underwent mastectomy. Total DNA was extracted from all samples and the entire mtDNA (16.6kb) was amplified using long range PCR amplification. The amplified PCR products were sequenced using mtDNA next-generation sequencing (NGS) on an Illumina Miseq platform. Sequencing involves the entire mtDNA (16.6kb) from all pairs of samples with high-coverage (~ 9,544 reads per base). MtDNA variants were called and annotated using mtDNA-Server, a web server. A total of 18 of 20 patients had at least one somatic mtDNA mutation in their tumour samples. Overall, 65 somatic mutations were identified, with 30 novel mutations. The majority (59%) of the somatic mutations were in the coding region, whereas only 11% of the mutations occurred in the D-loop. Notably, somatic mutations in protein-coding regions were non-synonymous (49%) in which 15.4% of them are potentially deleterious. A total of 753 germline mutations were identified and four of which were novel mutations. Compared to somatic alterations, less than 1% of germline missense mutations are harmful. The findings of this study may enhance the current knowledge of mtDNA alterations in breast cancer. To date, the catalogue of mutations identified in this study is the first evidence of mtDNA alterations in Malaysian female breast cancer patients.

Complementary and alternative medicine (CAM) use and delays in presentation and diagnosis of breast cancer patients in public hospitals in Malaysia.

Complementary and alternative medicine (CAM) is widely used among the breast cancer patients in Malaysia. Delays in presentation, diagnosis and treatment have been shown to impact the disease prognosis. There is considerable use of CAM amongst breast cancer patients. CAM use has been cited as a cause of delay in diagnosis and treatments in qualitative studies, however there had not been any confirmatory study that confirms its impact on delays. The purpose of this study was to evaluate whether the use of CAM among newly diagnosed breast cancer patients was associated with delays in presentation, diagnosis or treatment of breast cancer. This multi-centre cross-sectional study evaluating the time points of the individual breast cancer patients' journey from first visit, resolution of diagnosis and treatments was conducted in six public hospitals in Malaysia. All newly diagnosed breast cancer patients from 1st January to 31st December 2012 were recruited. Data were collected through medical records review and patient interview by using a structured questionnaire. Complementary and alternative medicine (CAM) was defined as the use of any methods and products not included in conventional allopathic medicine before commencement of treatments. Presentation delay was defined as time taken from symptom discovery to first presentation of more than 3 months. The time points were categorised to diagnosis delay was defined as time taken from first presentation to diagnosis of more than 1 month and treatment delay was defined as time taken from diagnosis to initial treatment of more than 1 month. Multiple logistic regression was used for analysis. A total number of 340 patients participated in this study. The prevalence of CAM use was 46.5% (n = 158). Malay ethnicity (OR 3.32; 95% CI: 1.85, 5.97) and not interpreting symptom as cancerous (OR 1.79; 95% CI: 1.10, 2.92) were significantly associated with CAM use. The use of CAM was associated with delays in presentation (OR 1.65; 95% CI: 1.05, 2.59), diagnosis (OR 2.42; 95% CI: 1.56, 3.77) and treatment of breast cancer (OR 1.74; 95% CI: 1.11, 2.72) on univariate analyses. However, after adjusting with other covariates, CAM use was associated with delays in presentation (OR 1.71; 95% CI: 1.05, 2.78) and diagnosis (OR 2.58; 95% CI: 1.59, 4.17) but not for treatment of breast cancer (OR 1.58; 95% CI: 0.98, 2.55). The prevalence of CAM use among the breast cancer patients was high. Women of Malay ethnicity and not interpreting symptom as cancerous were significantly associated with CAM use. The use of CAM is significantly associated with delay in presentation and resolution of diagnosis. This study suggests further evaluation of access to breast cancer care is needed as poor access may cause the use of CAM. However, since public hospitals in Malaysia are heavily subsidized and readily available to the population, CAM use may impact delays in presentation and diagnosis.

Low prevalence of CHEK2 gene mutations in multiethnic cohorts of breast cancer patients in Malaysia.

CHEK2 is a protein kinase that is involved in cell-cycle checkpoint control after DNA damage. Germline mutations in CHEK2 gene have been associated with increase in breast cancer risk. The aim of this study is to identify the CHEK2 gene germline mutations among high-risk breast cancer patients and its contribution to the multiethnic population in Malaysia. We screened the entire coding region of CHEK2 gene on 59 high-risk breast cancer patients who tested negative for BRCA1/2 germline mutations from UKM Medical Centre (UKMMC), Hospital Kuala Lumpur (HKL) and Hospital Putrajaya (HPJ). Sequence variants identified were screened further in case-control cohorts consisting of 878 unselected invasive breast cancer patients (180 Malays, 526 Chinese and 172 Indian) and 270 healthy individuals (90 Malays, 90 Chinese and 90 Indian). By screening the entire coding region of the CHEK2 gene, two missense mutations, c.480A>G (p.I160M) and c.538C>T (p.R180C) were identified in two unrelated patients (3.4%). Further screening of these missense mutations on the case-control cohorts unveiled the variant p.I160M in 2/172 (1.1%) Indian cases and 1/90 (1.1%) Indian control, variant p.R180C in 2/526 (0.38%) Chinese cases and 0/90 Chinese control, and in 2/180 (1.1%) of Malay cases and 1/90 (1.1%) of Malay control. The results of this study suggest that CHEK2 mutations are rare among high-risk breast cancer patients and may play a minor contributing role in breast carcinogenesis among Malaysian population.

Exploring breast carcinogenesis through integrative genomics and epigenomics analyses.

There have been many DNA methylation studies on breast cancer which showed various methylation patterns involving tumour suppressor genes and oncogenes but only a few of those studies link the methylation data with gene expression. More data are required especially from the Asian region and to analyse how the epigenome data correlate with the transcriptome. DNA methylation profiling was carried out on 76 fresh frozen primary breast tumour tissues and 25 adjacent non-cancerous breast tissues using the Illumina Infinium(®) HumanMethylation27 BeadChip. Validation of methylation results was performed on 7 genes using either MS-MLPA or MS-qPCR. Gene expression profiling was done on 15 breast tumours and 5 adjacent non-cancerous breast tissues using the Affymetrix GeneChip(®) Human Gene 1.0 ST array. The overlapping genes between DNA methylation and gene expression datasets were further mapped to the KEGG database to identify the molecular pathways that linked these genes together. Supervised hierarchical cluster analysis revealed 1,389 hypermethylated CpG sites and 22 hypomethylated CpG sites in cancer compared to the normal samples. Gene expression microarray analysis using a fold-change of at least 1.5 and a false discovery rate (FDR) at p>0.05 identified 404 upregulated and 463 downregulated genes in cancer samples. Integration of both datasets identified 51 genes with hypermethylation with low expression (negative association) and 13 genes with hypermethylation with high expression (positive association). Most of the overlapping genes belong to the focal adhesion and extracellular matrix-receptor interaction that play important roles in breast carcinogenesis. The present study displayed the value of using multiple datasets in the same set of tissues and how the integrative analysis can create a list of well-focused genes as well as to show the correlation between epigenetic changes and gene expression. These gene signatures can help us understand the epigenetic regulation of gene expression and could be potential targets for therapeutic intervention in the future.

Dietary changes among breast cancer patients in Malaysia.

BACKGROUND: 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. OBJECTIVE: The objective of the study was to determine changes in dietary intake 2 years after diagnosis among breast cancer patients. METHODS: 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. RESULTS: 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 ß-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. CONCLUSION: Breast cancer patients had changed to a healthier diet after breast cancer diagnosis, although the changes made were small. IMPLICATIONS FOR PRACTICE: This will be helpful to dietitians in providing a better understanding of good eating habits that will maintain patients' health after breast cancer diagnosis.

The use of complementary and alternative medicine among Malay breast cancer survivors.

BACKGROUND: A cross-sectional studywas carried out to determine the prevalence of complementary and alternative medicine (CAM) use by breast cancer survivors. METHODS: A descriptivesurveydesignwasdeveloped. Information on sociodemographic characteristics, cancer clinical treatment history, and use of CAM were obtained through a modified self-administered questionnaire from 116 Malay breast cancer survivors aged 21 to 67 years who were 2 years postdiagnosis and currently undergoing follow-up treatment at breast cancer clinics at Hospital Kuala Lumpur and Universiti Kebangsaan Malaysia Medical Centre. RESULTS: Data suggest that 64% of the participants were identified as CAM users; dietary supplements were the most common form used, followed by prayer and Malay traditional medicine. Within the wide range of dietary supplements, multivitamins were most often taken followed by spirulina, vitamin C, evening primrose oil, and herbal products. Contrary to other findings, the CAM users were found to be older, had secondary education levels, and were from middle-income households. However, there was no significant difference between CAM users and nonusers in this study. Family members played an important role as the main source of information along with doctors/health care providers, friends, and printed materials/mass media. The reasons participants gave for using CAM were mainly to assist in healing the body's inner strength, to cure cancer, and to reduce stress. Only half of the participants consulted with their physicians regarding the safety of CAM use. The participants began to use CAM while undergoing clinical treatments. Most of the participants used CAM for more than a year. About RM100 to RM149 (31.88 USD to 47.50 USD at press time) were spent monthly on CAM by 32% of the participants. The CAM use was found to be effective and beneficial for patients' disease states, and they were contented with the usage of the CAM therapies. Multivariate analysis revealed that thedecision to use or not to use CAM was not dependent on sociodemographic background or cancer clinical treatment history. CONCLUSIONS: CAM was commonly used by breast cancer survivors as a coping mechanism to battle the disease.

Fat intake and its relationship with pre- and post-menopausal breast cancer risk: a case-control study in Malaysia.

BACKGROUND: Fat intake has been shown to play a role in the etiology of breast cancer, but the findings have been inconsistent. OBJECTIVE: To assess the association of premenopausal and postmenopausal breast cancer risk with fat and fat subtypes intake. METHODOLOGY: This is a population based case-control study conducted in Kuala Lumpur, Malaysia from January 2006 to December 2007. Food intake pattern was collected from 382 breast cancer patients and 382 control group via an interviewer-administered food frequency questionnaire. Logistic regression was used to compute odds ratios (OR) with 95% confidence intervals (CI) and a broad range of potential confounders was included in analysis. RESULTS: This study showed that both premenopausal and postmenopausal breast cancer risk did not increase significantly with greater intake of total fat [quartile (Q) 4 versus Q1 OR=0.76, 95% CI, 0.23-2.45 and OR=1.36, 95% CI, 0.30-3.12], saturated fat (ORQ4 to Q1=1.43, 95% CI, 0.51-3.98 and ORQ4 to Q1=1.75, 95% CI, 0.62-3.40), monounsaturated fat (ORQ4 to Q1=0.96, 95% CI, 0.34-1.72 and ORQ4 to Q1=1.74, 95% CI, 0.22-2.79), polyunsaturated fat (ORQ4 to Q1=0.64, 95% CI, 0.23-1.73 and ORQ4 to Q1=0.74, 95% CI, 0.39-1.81), n-3 polyunsaturated fat (ORQ4 to Q1=1.10, 95% CI, 0.49-2.48 and ORQ4 to Q1=0.78, 95% CI, 0.28-2.18), n-6 polyunsaturated fat (ORQ4 to Q1=0.67, 95% CI, 0.24-1.84 and ORQ4 to Q1=0.71, 95% CI, 0.29-1.04) or energy intake (ORQ4 to Q1=1.52, 95% CI, 0.68-3.38 and ORQ4 to Q1=2.21, 95% CI, 0.93-3.36). CONCLUSION: Total fat and fat subtypes were not associated with pre- and postmenopausal breast cancer risk after controlling for age, other breast cancer risk factors and energy intake. Despite the lack of association, the effects of total fat and fat subtypes intake during premenopausal years towards postmenopausal breast cancer risk still warrant investigation.

Expression and mutational analysis of GATA3 in Malaysian breast carcinomas.

The GATA3 gene is a potential tumour marker and putative tumour suppressor gene in breast cancer. Its expression is associated with better prognosis and disease free survival in breast cancer patients. We aimed to evaluate GATA3 transcriptome expression and mutation in breast carcinomas and correlate its expression with oestrogen receptor (ER), progesterone receptor (PR), lymph node (LN) status, tumour grade and c-erbB-2 expression. Twenty-two breast infiltrating ductal carcinomas and paired normal tissues were used in Branch DNA assay to detect GATA3 mRNA expression. Normalized data for GATA3 mRNA expression were grouped according to the ER, PR and LN status, tumour grade and c-erbB-2 expression of the tumours. Statistical significance was tested using t-test and ANOVA at 95% confidence interval level. Mutational analysis of GATA3 was performed by direct sequencing of the coding regions of GATA3 mRNA. Our findings showed that GATA3 gene were over-expressed and under-expressed by > 2 fold change in 12 and 4 tested samples, respectively. Eighty per cent of ER positive breast carcinomas were GATA3 positive. There was a statistically significant correlation between GATA3 expression and ER at 95% confidence interval level between the study groups. On the contrary, GATA3 expression was not statistically significant with PR, LN, tumour grade and c-erbB-2 expression in our study. In addition, we observed that there was no mutation in mRNA coding region in 16 breast carcinomas that showed GATA3 differential gene expression. Our preliminary results suggested that GATA3 is linked to the ER. This scenario suggests that GATA3 may play a crucial role in oestrogen receptor positive breast cancer patients. Whether GATA3 expression is involved in regulating tumour cell growth in oestrogen responsive breast cancer is a key question that remains to be answered.