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  1. Zulkipli AF, Islam T, Mohd Taib NA, Dahlui M, Bhoo-Pathy N, Al-Sadat N, et al.
    Integr Cancer Ther, 2018 06;17(2):312-321.
    PMID: 29218996 DOI: 10.1177/1534735417745248
    BACKGROUND: The use of complementary and alternative medicine (CAM) has increased and little is known on CAM use during the initial period. Therefore, the aim was to determine prevalence of CAM use among newly diagnosed breast cancer patients prior to seeking conventional treatment.

    METHODS: This is a cross-sectional study involved interviewing newly diagnosed breast cancer patients in the University Malaya Medical Centre (UMMC) using a structured questionnaire. Eligible respondents were interviewedduring a routine clinical visit.

    RESULTS: A total of 400 patients were interviewed, of whom 139 (34.8%) were CAM users. Dietary supplementation (n = 107, 77.0%) was the most frequently used type of CAM, followed by spiritual healing (n = 40, 28.8%) and traditional Chinese medicine (n = 32, 23.0%). Malay ethnic group (n = 61, 43.9%) was the largest group of CAM users, followed by Chinese (n = 57, 41.0%) and Indian (n = 20, 14.4%). Majority of these CAM users (n = 87, 73.1%) did not disclose the use of CAM to their doctors. Most of them used remedies based on the recommendation of family and friends. Malay ethnicity and patients with 3 or more comorbidities were more likely to use CAM.

    CONCLUSION: There is substantial use of CAM among breast cancer patients in UMMC prior to seeking hospital treatment, and the most popular CAM modality is dietary supplements. Since, the majority of CAM users do not disclose the use of CAM to their physicians, therefore health care providers should ensure that those patients who are likely to use CAM are appropriately counseled and advised.

  2. Dörk T, Peterlongo P, Mannermaa A, Bolla MK, Wang Q, Dennis J, et al.
    Sci Rep, 2019 08 29;9(1):12524.
    PMID: 31467304 DOI: 10.1038/s41598-019-48804-y
    Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
  3. Sa'at H, Lee YK, Yoon SY, Wong SW, Woo YL, Barlow-Stewart K, et al.
    Fam Cancer, 2022 Jan;21(1):21-33.
    PMID: 33604745 DOI: 10.1007/s10689-021-00232-6
    The decision to have risk-reducing salpingo-oophorectomy (RRSO) by BRCA mutation carriers to reduce the risk of ovarian cancer is difficult. The choice involves trade-offs in terms of its risks and benefits. To date, understanding the decision-making needs of RRSO among Southeast Asian BRCA mutation carriers is limited. This study aimed to explore the decision-making needs of Malaysian BRCA mutation carriers as an exemplar for the Southeast Asian community. In-depth interviews and clinic observations were conducted with 31 BRCA mutation carriers and analysed thematically. The core theme identified was 'Coping with complex information and alleviating uncertainties' with the following subthemes: (1) the need for an adjustment period, (2) information support, (3) social support and, (4) religious support. We found that women required time to accept their BRCA mutation status before they were ready to make a risk-reducing choice; that understanding complex genetic information and multiple risk management options can be an overwhelming experience; and obtaining further information and a second opinion were challenging. Many described the need for experiential information from other peer-carriers who had undergone RRSO. Support from their spouse and family members was thought to be essential for them to feel reassured with their decision. Many relied on religion to positively cope with cancer risk and cancer worry; Muslim BRCA carriers sought religious guidance through prayers and Islamic fatwas to feel more certain about their RRSO decision. These findings underscore the importance of the provision of resources and support that includes input from peers, husband, family members and religion to underpin the decision-making needs of Malaysian BRCA mutation carriers considering RRSO.
  4. Mohd Taib NA, Yip CH, Mohamed I
    Asian Pac J Cancer Prev, 2008 Apr-Jun;9(2):197-202.
    PMID: 18712958
    BACKGROUND: Breast cancer is the commonest cancer amongst Malaysian women but local survival data are scarce. The present study was therefore conducted to assess overall survival and prognostic factors in Malaysian breast cancer patients.

    METHODS: The research sample was a prospective cohort of 413 patients diagnosed with breast cancer in the University of Malaya Medical Centre between 1993 to 1997. Survival data were obtained from the National Registry of Birth and Deaths in December 2000. The clinico-pathological variables studied were age, ethnic group, stage, tumour size, lymph node status, oestrogen receptor status and grade. The data were analysed utilizing Splus statistical software. The important prognostic factors were identified by fitting the Cox's proportional hazard model to the data set. Survival probabilities were estimated using the Kaplan-Meier method and differences were compared by the log-rank test.

    RESULTS: The overall 5-year survival was 59.1%. The Cox's proportional hazard model identified stage, lymph node status, size and grade as factors that correlated with prognosis. Age was not a significant prognostic factor. The Cox regression model by stepwise selection showed stage, nodal status and grade of tumour to be independent prognostic factors, whereas ethnicity, age and ER status were not.

    INTERPRETATION: The overall survival in our centre was low. Recognizing factors that affect prognosis of breast cancer patients in Malaysia may improve delivery of health care to at-risk groups by strategizing interventions as survival depends on early detection and effective treatment.
  5. Ho PJ, Khng AJ, Tan BK, Tan EY, Tan SM, Tan VKM, et al.
    Breast Cancer, 2022 Sep;29(5):869-879.
    PMID: 35543923 DOI: 10.1007/s12282-022-01366-w
    BACKGROUND: Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry.

    METHODS: A total of 12,901 breast cancer cases and 12,583 controls from 12 case-control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15-55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined.

    RESULTS: We did not observe associations between any HLA allele and breast cancer risk at P 

  6. Kang PC, Phuah SY, Sivanandan K, Kang IN, Thirthagiri E, Liu JJ, et al.
    Breast Cancer Res Treat, 2014 Apr;144(3):635-42.
    PMID: 24578176 DOI: 10.1007/s10549-014-2894-x
    Although the breast cancer predisposition genes BRCA1 and BRCA2 were discovered more than 20 years ago, there remains a gap in the availability of genetic counselling and genetic testing in Asian countries because of cost, access and inaccurate reporting of family history of cancer. In order to improve access to testing, we developed a rapid test for recurrent mutations in our Asian populations. In this study, we designed a genotyping assay with 55 BRCA1 and 44 BRCA2 mutations previously identified in Asian studies, and validated this assay in 267 individuals who had previously been tested by full sequencing. We tested the prevalence of these mutations in additional breast cancer cases. Using this genotyping approach, we analysed recurrent mutations in 533 Malaysian breast cancer cases with <10 % a priori risk, and found 1 BRCA1 (0.2 %) and 5 BRCA2 (0.9 %) carriers. Testing in a hospital-based unselected cohort of 532 Singaporean breast cancer cases revealed 6 BRCA1 (1.1 %) and 3 BRCA2 (0.6 %) carriers. Overall, 2 recurrent BRCA1 and 1 BRCA2 mutations in Malays, 3 BRCA1 and 2 BRCA2 mutations in Chinese and 1 BRCA1 mutation in Indians account for 60, 24 and 20 % of carrier families, respectively. By contrast, haplotype analyses suggest that a recurrent BRCA2 mutation (c.262_263delCT) found in 5 unrelated Malay families has at least 3 distinct haplotypes. Taken together, our data suggests that panel testing may help to identify carriers, particularly Asian BRCA2 carriers, who do not present with a priori strong family history characteristics.
  7. Padmanabhan H, Hassan NT, Wong SW, Lee YQ, Lim J, Hasan SN, et al.
    PLoS One, 2022;17(2):e0263675.
    PMID: 35167615 DOI: 10.1371/journal.pone.0263675
    There is an increasing number of cancer patients undertaking treatment-focused genetic testing despite not having a strong family history or high a priori risk of being carriers because of the decreasing cost of genetic testing and development of new therapies. There are limited studies on the psychosocial outcome of a positive result among breast cancer patients who are at low a priori risk, particularly in women of Asian descent. Breast cancer patients enrolled under the Malaysian Breast Cancer Genetic Study between October 2002 and February 2018 were tested for BRCA1, BRCA2 and PALB2 genes. All 104 carriers identified were invited by a research genetic counsellor for result disclosure. Of the 104 carriers, 64% (N = 66) had low a priori risk as determined by PENN II scores. Psychosocial, risk perception and health behaviour measures survey were conducted at baseline (pre-result disclosure), and at two to six weeks after result disclosure. At baseline, younger carriers with high a priori risk had higher Cancer Worry Scale scores than those with low a priori risk but all scores were within acceptable range. Around 75% and 55% of high a priori risk carriers as well as 80% and 67% of low a priori risk carriers had problems in the "living with cancer" and "children" psychosocial domains respectively. All carriers regardless of their a priori risk demonstrated an improved risk perception that also positively influenced their intent to undergo risk management procedures. This study has shown that with sufficient counselling and support, low a priori risk carriers are able to cope psychologically, have improved perceived risk and increased intent for positive health behaviour despite having less anticipation from a family history prior to knowing their germline carrier status.
  8. Zainal NZ, Ng CG, Wong A, Andrew B, Mohd Taib NA, Low SY
    J Taibah Univ Med Sci, 2021 Aug;16(4):497-503.
    PMID: 34408606 DOI: 10.1016/j.jtumed.2021.01.013
    Objective: This study aims to determine the prevalence of depression, trait anxiety, and social support among women suspected of breast cancer (BC) and to investigate the association of these factors with the diagnosis of BC.

    Methods: A cross-sectional study was conducted on 745 women who presented with breast symptoms in a university breast clinic in Malaysia. Participants were instructed to respond to self-report questionnaires on depression, trait anxiety, and social support while they were waiting for assessment of their suspected BC. The final diagnoses of these patients were traced one month after examining their medical records. Descriptive statistics were performed to examine the socio-demographic and clinical characteristics of all participants. A multiple regression analysis was carried out to determine the association of the abovementioned factors with the diagnosis of BC.

    Results: The analysis showed that BC was diagnosed in 109 (14.6%), benign breast disease (BBD) in 550 (73.8%), and healthy breast (HB) in 86 (11.5%) women. The prevalence of depression was 53.2% in women with BC, 53.6% in women with BBD, and 60.5% in women with HB prior to diagnosis. The prevalence of trait anxiety was 33%. Mean scores for trait anxiety were 42.2 ± 9.0 and 41.8 ± 9.1 for the BC group and BBD group, respectively. The level of perceived social support was similar in all three groups.

    Conclusion: We found no significant difference in depression, trait anxiety, and social support among women with newly diagnosed BC, BBD, and HB in women with breast symptoms while undergoing diagnostic evaluation. A longitudinal study is essential to establish the association between chronic mental stress and BC.

  9. Syed Alwi SM, Narayanan V, Mohd Taib NA, Che Din N
    Support Care Cancer, 2022 Mar;30(3):2793-2801.
    PMID: 34841453 DOI: 10.1007/s00520-021-06686-9
    PURPOSE: Health-related quality of life (QoL) is an important outcome measure in breast cancer management. Evidence of QoL of breast cancer patients in lower and middle-income countries remains scarce. We examined the level of QoL, cognitive impairment, psychological distresses, and the predictors of QoL among multiethnic Malaysian early-stage breast cancer survivors 1 to 3 years following chemotherapy.

    METHODS: A total of 160 breast cancer survivors from the University of Malaya Medical Centre (UMMC) participated in this cross-sectional study. Their QoL was evaluated with the Malay version of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) version 3.0. Cognitive functioning and psychological distress were evaluated using the Malay version of the Montreal Cognitive Assessment (MoCA-BM) and Hospital Anxiety and Depression Scale (HADS), respectively. Data analysis was performed with Pearson's correlation and multiple regression analyses.

    RESULTS: At 1- to 3-year post-chemotherapy, the mean EORTC QLQ-C30 global health status of the breast cancer survivors was relatively low (60.5 over 100, SD = 10.88). One-third (31.9%) of them demonstrated cognitive impairment, and another 3.2% showed moderate to severe anxiety levels. The significant predictors for global health status and functioning included age, psychological distresses, cognitive performance, fatigue, appetite loss, insomnia, pain, and constipation.

    CONCLUSION: Our breast cancer survivors demonstrated poor global health status. Health care providers and policymakers must strive to provide holistic intervention strategies to improve the multiple dimensions of QoL and the cognitive and psychological functioning of this vulnerable population.

  10. Soh WH, Rajaram N, Mariapun S, Eriksson M, Fadzli F, Ho WK, et al.
    Cancer Causes Control, 2018 Sep;29(9):883-894.
    PMID: 30062608 DOI: 10.1007/s10552-018-1064-6
    BACKGROUND: Physical activity is a modifiable lifestyle factor associated with reduced breast cancer risk. Mammographic density is a strong, independent risk factor for breast cancer, and some breast cancer risk factors have been shown to modify mammographic density. However, the effect of physical activity on mammographic density, studied predominantly among Caucasians, has yielded conflicting results. In this study, we examined, in an Asian population, the association between physical activity and mammographic density.

    METHODS: We conducted a cross-sectional study of 2,377 Malaysian women aged 40-74 years. Physical activity information was obtained at screening mammogram and mammographic density was measured from mammograms by the area-based STRATUS method (n = 1,522) and the volumetric Volpara™ (n = 1,200) method. Linear regression analyses were performed to evaluate the association between physical activity and mammographic density, adjusting for potential confounders.

    RESULTS: We observed that recent physical activity was associated with area-based mammographic density measures among postmenopausal women, but not premenopausal women. In the fully adjusted model, postmenopausal women with the highest level of recent physical activity had 8.0 cm2 [95% confidence interval: 1.3, 14.3 cm2] lower non-dense area and 3.1% [0.1, 6.3%] higher area-based percent density, compared to women with the lowest level of recent physical activity. Physical activity was not associated to volumetric mammographic density.

    CONCLUSIONS: Our findings suggest that the beneficial effects of physical activity on breast cancer risk may not be measurable through mammographic density. Future research is needed to identify appropriate biomarkers to assess the effect of physical activity on breast cancer risk.

  11. Baskaran P, Subramanian P, Rahman RA, Ping WL, Mohd Taib NA, Rosli R
    Asian Pac J Cancer Prev, 2013;14(12):7693-9.
    PMID: 24460355
    AIMS: A main reason for increasing incidence of cervical cancer worldwide is the lack of regular cervical cancer screening. Coverage and uptake remain major challenges and it is crucial to determine the perceived susceptibility to cervical cancer, as well as the benefits of, and barriers to, cervical cancer screening among women.

    MATERIALS AND METHODS: A cross-sectional survey was conducted among 369 women attending an outpatient centre in Malaysia and data were collected by administering a self-report questionnaire.

    RESULTS: The majority of the participants (265, 71.8%) showed good level of perception of their susceptibility to cervical cancer. Almost all responded positively to four statements about the perceived benefits of cervical cancer screening (agree, 23.1% or strongly agree, 52.5%), whereas negative responses were received from most of the participants (agree, 29.9%or strongly agree, 14.6 %) about the eleven statements on perceived barriers. Significant associations were observed between age and perceived susceptibility(x2=9.030, p=0.029); between employment status (p<0.001) as well as ethnicity and perceived benefits (p<0.05 [P=0.003]); and between education and perceived barriers to cervical cancer screening (p<0.001).

    CONCLUSIONS: Perceived susceptibility, including knowledge levels and personal risk assessment, should be emphasized through education and awareness campaigns to improve uptake of cervical cancer screening in Malaysia.
  12. Rajaram N, Lim ZY, Song CV, Kaur R, Mohd Taib NA, Muhamad M, et al.
    Psychooncology, 2019 01;28(1):147-153.
    PMID: 30346074 DOI: 10.1002/pon.4924
    OBJECTIVES: Patient-reported outcomes (PROs) in high-income countries (HICs) suggest that physical, emotional, and psychological needs are important in cancer care. To date, there have been few inconsistent descriptions of PROs in low-income and middle-income Asian countries. Using a standard questionnaire developed by the International Consortium for Health Outcomes Measurement (ICHOM), we compared the perceived importance of PROs between patients in Malaysia and those in HICs and between clusters of Malaysian women.

    METHODS: Breast cancer patients were recruited from three Malaysian hospitals between June and November 2017. We compared the proportion of patients who rated PROs as very important (scored 7-9 on a 9-point Likert scale) between Malaysian patients and data collected from patients in HICs via the ICHOM questionnaire development process, using logistic regression. A two-step cluster analysis explored differences in PROs among Malaysian patients.

    RESULTS: The most important PROs for both cohorts were survival, overall well-being, and physical functioning. Compared with HIC patients (n = 1177), Malaysian patients (n = 969) were less likely to rate emotional (78% vs 90%), cognitive (76% vs 84%), social (72% vs 81%), and sexual (30% vs 56%) functioning as very important outcomes (P 

  13. Breast Cancer Association Consortium, Mavaddat N, Dorling L, Carvalho S, Allen J, González-Neira A, et al.
    JAMA Oncol, 2022 Mar 01;8(3):e216744.
    PMID: 35084436 DOI: 10.1001/jamaoncol.2021.6744
    IMPORTANCE: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction.

    OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies.

    DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021.

    EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.

    MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes.

    RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger.

    CONCLUSIONS AND RELEVANCE: The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

  14. Tan WM, Ng WL, Ganggayah MD, Hoe VCW, Rahmat K, Zaini HS, et al.
    Health Informatics J, 2023;29(3):14604582231203763.
    PMID: 37740904 DOI: 10.1177/14604582231203763
    Radiology reporting is narrative, and its content depends on the clinician's ability to interpret the images accurately. A tertiary hospital, such as anonymous institute, focuses on writing reports narratively as part of training for medical personnel. Nevertheless, free-text reports make it inconvenient to extract information for clinical audits and data mining. Therefore, we aim to convert unstructured breast radiology reports into structured formats using natural language processing (NLP) algorithm. This study used 327 de-identified breast radiology reports from the anonymous institute. The radiologist identified the significant data elements to be extracted. Our NLP algorithm achieved 97% and 94.9% accuracy in training and testing data, respectively. Henceforth, the structured information was used to build the predictive model for predicting the value of the BIRADS category. The model based on random forest generated the highest accuracy of 92%. Our study not only fulfilled the demands of clinicians by enhancing communication between medical personnel, but it also demonstrated the usefulness of mineable structured data in yielding significant insights.
  15. Mohamed E, Abdul-Rahman PS, Doustjalali SR, Chen Y, Lim BK, Omar SZ, et al.
    Electrophoresis, 2008 Jun;29(12):2645-50.
    PMID: 18494030 DOI: 10.1002/elps.200700828
    A 35 kDa glycoprotein whose abundance was previously demonstrated to be enhanced in sera of patients with endometrial adenocarcinoma (n = 12), was isolated from pooled sera of three of the cancer patients using champedak galactose-binding lectin affinity chromatography in the present study. Subjecting it to 2-DE and MS/MS, the glycoprotein was identified as the O-glycosylated fragment of inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4). When compared to control sera (n = 17), expression of the 35 kDa ITIH4 cleavage fragment was demonstrated to be significantly enhanced in sera of patients with breast carcinoma (n = 10), epithelial ovarian carcinoma (n = 10), and germ cell ovarian carcinoma (n = 10) but not in patients with nasopharyngeal carcinoma (n = 13) and osteosarcoma (n = 7). The lectin-based electrophoretic bioanalytical method adopted in the present study may be used to assess the physiological relevance of ITIH4 fragmentation and its correlation with different malignancies, their stages and progression.
  16. Kang P, Mariapun S, Phuah SY, Lim LS, Liu J, Yoon SY, et al.
    Breast Cancer Res Treat, 2010 Nov;124(2):579-84.
    PMID: 20617377 DOI: 10.1007/s10549-010-1018-5
    Early studies of genetic predisposition due to the BRCA1 and BRCA2 genes have focused largely on sequence alterations, but it has now emerged that 4-28% of inherited mutations in the BRCA genes may be due to large genomic rearrangements of these genes. However, to date, there have been relatively few studies of large genomic rearrangements in Asian populations. We have conducted a full sequencing and large genomic rearrangement analysis (using Multiplex Ligation-dependent Probe Amplification, MLPA) of 324 breast cancer patients who were selected from a multi-ethnic hospital-based cohort on the basis of age of onset of breast cancer and/or family history. Three unrelated individuals were found to have large genomic rearrangements: 2 in BRCA1 and 1 in BRCA2, which accounts for 2/24 (8%) of the total mutations detected in BRCA1 and 1/23 (4%) of the mutations in BRCA2 detected in this cohort. Notably, the family history of the individuals with these mutations is largely unremarkable suggesting that family history alone is a poor predictor of mutation status in Asian families. In conclusion, this study in a multi-ethnic (Malay, Chinese, Indian) cohort suggests that large genomic rearrangements are present at a low frequency but should nonetheless be included in the routine testing for BRCA1 and BRCA2.
  17. Lim KK, Yoon SY, Mohd Taib NA, Shabaruddin FH, Dahlui M, Woo YL, et al.
    Appl Health Econ Health Policy, 2018 06;16(3):395-406.
    PMID: 29572724 DOI: 10.1007/s40258-018-0384-8
    OBJECTIVE: Previous studies showed that offering BRCA mutation testing to population subgroups at high risk of harbouring the mutation may be cost effective, yet no evidence is available for low- or middle-income countries (LMIC) and in Asia. We estimated the cost effectiveness of BRCA mutation testing in early-stage breast cancer patients with high pre-test probability of harbouring the mutation in Malaysia, an LMIC in Asia.

    METHODS: We developed a decision analytic model to estimate the lifetime costs and quality-adjusted life-years (QALYs) accrued through BRCA mutation testing or routine clinical surveillance (RCS) for a hypothetical cohort of 1000 early-stage breast cancer patients aged 40 years. In the model, patients would decide whether to accept testing and to undertake risk-reducing mastectomy, oophorectomy, tamoxifen, combinations or neither. We calculated the incremental cost-effectiveness ratio (ICER) from the health system perspective. A series of sensitivity analyses were performed.

    RESULTS: In the base case, testing generated 11.2 QALYs over the lifetime and cost US$4815 per patient whereas RCS generated 11.1 QALYs and cost US$4574 per patient. The ICER of US$2725/QALY was below the cost-effective thresholds. The ICER was sensitive to the discounting of cost, cost of BRCA mutation testing and utility of being risk-free, but the ICERs remained below the thresholds. Probabilistic sensitivity analysis showed that at a threshold of US$9500/QALY, 99.9% of simulations favoured BRCA mutation testing over RCS.

    CONCLUSIONS: Offering BRCA mutation testing to early-stage breast cancer patients identified using a locally-validated risk-assessment tool may be cost effective compared to RCS in Malaysia.

  18. Wen WX, Allen J, Lai KN, Mariapun S, Hasan SN, Ng PS, et al.
    J Med Genet, 2018 02;55(2):97-103.
    PMID: 28993434 DOI: 10.1136/jmedgenet-2017-104947
    BACKGROUND: Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls.

    METHODS: Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing.

    RESULTS: Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing.

    CONCLUSION: Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2. While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia.

  19. Ng PS, Wen WX, Fadlullah MZ, Yoon SY, Lee SY, Thong MK, et al.
    Clin Genet, 2016 10;90(4):315-23.
    PMID: 26757417 DOI: 10.1111/cge.12735
    Although an association between protein-truncating variants and breast cancer risk has been established for 11 genes, only alterations in BRCA1, BRCA2, TP53 and PALB2 have been reported in Asian populations. Given that the age of onset of breast cancer is lower in Asians, it is estimated that inherited predisposition to breast cancer may be more significant. To determine the potential utility of panel testing, we investigated the prevalence of germline alterations in 11 established and 4 likely breast cancer genes in a cross-sectional hospital-based cohort of 108 moderate to high-risk breast cancer patients using targeted next generation sequencing. Twenty patients (19%) were identified to carry deleterious mutations, of whom 13 (12%) were in the BRCA1 or BRCA2, 6 (6%) were in five other known breast cancer predisposition genes and 1 patient had a mutation in both BRCA2 and BARD1. Our study shows that BRCA1 and BRCA2 account for the majority of genetic predisposition to breast cancer in our cohort of Asian women. Although mutations in other known breast cancer genes are found, the functional significance and breast cancer risk have not yet been determined, thus limiting the clinical utility of panel testing in Asian populations.
  20. Hasmad HN, Sivanandan K, Lee V, Yip CH, Mohd Taib NA, Teo SH
    Clin Genet, 2015 Apr;87(4):392-4.
    PMID: 25066186 DOI: 10.1111/cge.12451
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