Global Disparities in Breast Cancer Genetics Testing, Counselling and Management.

Hereditary breast cancers, mainly due to BRCA1 and BRCA2 mutations, account for only 5-10% of this disease. The threshold for genetic testing is a 10% likelihood of detecting a mutation, as determined by validated models such as BOADICEA and Manchester Scoring System. A 90-95% reduction in breast cancer risk can be achieved with bilateral risk-reducing mastectomy in unaffected BRCA mutation carriers. In patients with BRCA-associated breast cancer, there is a 40% risk of contralateral breast cancer and hence risk-reducing contralateral mastectomy is recommended, which can be performed simultaneously with surgery for unilateral breast cancer. Other options for risk management include surveillance by mammogram and breast magnetic resonance imaging, and chemoprevention with hormonal agents. With the advent of next-generation sequencing and development of multigene panel testing, the cost and time taken for genetic testing have reduced, making it possible for treatment-focused genetic testing. There are also drugs such as the PARP inhibitors that specifically target the BRCA mutation. Risk management multidisciplinary clinics are designed to quantify risk, and offer advice on preventative strategies. However, such services are only possible in high-income settings. In low-resource settings, the prohibitive cost of testing and the lack of genetic counsellors are major barriers to setting up a breast cancer genetics service. Family history is often not well documented because of the stigma associated with cancer. Breast cancer genetics services remain an unmet need in low- and middle-income countries, where the priority is to optimise access to quality treatment.

Low Lifetime Risk of Contralateral Breast Cancer in a Middle-Income Asian Country: Evidence to Guide Post-treatment Surveillance.

BACKGROUND: The rate of contralateral risk-reducing mastectomy (CRRM) is increasing in the West with controversial evidence of improved survival in early breast cancer patients. Although uptake of CRRM in Asia appears low, the trends may rise, and there is currently an urgent need to provide evidence for informed decision-making in clinical practice. This study aims to determine the risk of contralateral breast cancer (CBC) and its associated factors in an Asian setting. METHOD: A total of 2937 newly diagnosed patients with stage I and stage II breast cancer in University Malaya Medical Centre between Jan 1993 to Dec 2012 were included in the study. Multinomial logistic regression analysis allowing death to compete with CBC as a study outcome was used; patients with unilateral breast cancer who were alive were taken as reference. A stepwise backward regression analysis including age at diagnosis, ethnicity, family history of breast cancer, TNM stage, hormonal receptor status, HER2 status, chemotherapy, radiotherapy, and hormone therapy was conducted. RESULTS: Fifty women developed CBC, over a median follow-up of 6 years. The 5- and 10-year cumulative risk of contralateral breast cancer was 1.0% (95% CI 0.6-1.4%) and 2.8% (95% CI 2.0-3.6%), respectively. Young age at diagnosis of first cancer, positive family history, and stage I disease were independent predictors of CBC. DISCUSSION: The current study suggests that the risk of CBC is very low in a Southeast Asian setting. Any recommendations or practice of CRRM should be reviewed with caution and patients must be counseled appropriately.

Identification of germline alterations in breast cancer predisposition genes among Malaysian breast cancer patients using panel testing.

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.

Improving outcomes in breast cancer for low and middle income countries.

Breast cancer is the most common cancer in women world-wide. Incidence rates in low- and middle-income countries (LMICs) are lower than in high income countries; however, the rates are increasing very rapidly in LMICs due to social changes that increase the risk of breast cancer. Breast cancer mortality rates in LMICs remain high due to late presentation and inadequate access to optimal care. Breast Surgery International brought together a group of breast surgeons from different parts of the world to address strategies for improving outcomes in breast cancer for LMICs at a symposium during International Surgical Week in Helsinki, Finland in August 2013. A key strategy for early detection is public health education and breast awareness. Sociocultural barriers to early detection and treatment need to be addressed. Optimal management of breast cancer requires a multidisciplinary team. Surgical treatment is often the only modality of treatment available in low-resource settings where modified radical mastectomy is the most common operation performed. Chemotherapy and radiotherapy require more resources. Endocrine therapy is available but requires accurate assessment of estrogen receptors status. Targeted therapy with trastuzumab is generally unavailable due to cost. The Breast Health Global Initiative guidelines for the early detection and appropriate treatment of breast cancer in LMICs have been specifically designed to improve breast cancer outcomes in these regions. Closing the cancer divide between rich and poor countries is a moral imperative and there is an urgent need to prevent breast cancer deaths with early detection and optimal access to treatment.

Breast Cancer Outcomes as Defined by the Estrogen Receptor, Progesterone Receptor, and Human Growth Factor Receptor-2 in a Multi-ethnic Asian Country.

INTRODUCTION: Breast cancer can be divided into four subtypes based on the expressions of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 (HER2). Each subtype has different clinicopathological features and outcomes. OBJECTIVE: To compare the clinicopathological features and survival of ER and/or PR positive HER2 negative (ER+PR+HER2-, ER+PR-HER2- or ER-PR+HER2-), ER and/or PR positive HER2 positive (ER+PR+HER2+, ER+PR-HER2+ or ER-PR+HER2+), ER negative PR negative HER2 positive (ER-PR-HER2+), and ER negative PR negative HER2 negative (ER-PR-HER2-) subtypes. METHODS: 1957 patients with Stage 1-3 breast carcinoma diagnosed between Jan 2005 and Dec 2011 were categorized into the four subtypes. The clinicopathological features between the subtypes were compared using χ (2) test. Kaplan-Meier analysis was performed to estimate 5-year overall survival. Multivariate Cox regression was used to determine the association between subtypes and mortality adjusted for age, ethnicity, stage, pathological features, and treatment. RESULTS: ER-PR-HER2+ and ER-PR-HER2- subtypes were associated with younger age, larger tumors, and higher grade. There was no difference in the 5-year survival of the ER-PR-HER2+ and ER-PR-HER2- subtypes (75.1 and 74.4 %, respectively) and survival was poorer than in the ER and/or PR positive HER2 negative and ER and/or PR positive HER2 positive subtypes (87.1 and 83.1 %, respectively). Only 9.5 % of women with HER2 positive breast cancer had access to trastuzumab. CONCLUSION: In a low resource setting with limited access to trastuzumab, there is no difference in survival between the ER-PR-HER2+ and ER-PR-HER2- subtypes of breast cancer.

Spectrum of very early breast cancer in a setting without organised screening.

BACKGROUND: Within a setting without organised breast cancer screening, the characteristics and survival of very early breast cancer were determined. METHODS: All 4930 women diagnosed with breast cancer in University Malaya Medical Center, Malaysia from 1993 to 2011 were included. Factors associated with very early presentation (stage I) at diagnosis were identified. Tumour characteristics, management patterns, and survival of very early breast cancer were described, and where appropriate, compared with other settings. RESULTS: Proportion of women presenting with stage I breast cancer significantly increased from 15.2% to 25.2% over two decades. Factors associated with very early presentation were Chinese ethnicity, positive family history of breast cancer, and recent period of diagnosis. Within stage I breast cancers, median tumour size at presentation was 1.5 cm. A majority of stage I breast cancer patients received mastectomy, which was associated with older age, Chinese ethnicity, postmenopausal status, and larger tumours. Chemotherapy was administered in 36% of patients. Five-year age-adjusted relative survival for women with stage I breast cancer was 99.1% (95% CI: 97.6-99.6%). CONCLUSIONS: The proportion of women presenting with very early breast cancer in this setting without organised screening is increasing. These women seem to survive just as well as their counterparts from affluent settings.

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

Incidence of chemotherapy-induced ovarian failure in premenopausal women undergoing chemotherapy for breast cancer.

INTRODUCTION: 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. OBJECTIVE: This study's aim was to find the incidence of chemotherapy-induced ovarian failure (CIOF) and reversible amenorrhea in premenopausal non-metastatic breast cancer patients. METHOD: This mixed retrospective and prospective study follows premenopausal breast cancer patients receiving chemotherapy between 2008 and 2012. Patients in the prospective arm were followed up with menstrual history and serum ovarian hormones (follicle-stimulating hormone [FSH] and estradiol) until 1 year post-chemotherapy, and patients in the retrospective arm were contacted for their menstrual history. RESULTS: The mean age of the 102 subjects was 43.3 years. Of the patients, 93.1 and 77.9 % were amenorrheic at completion of chemotherapy and at 12 months post-chemotherapy, respectively. Of those who developed amenorrhea, 24.6 % regained menstruation, on average after 7.86 (range 1-15) months post-chemotherapy. Age was the only statistically significant risk factor. CIOF and reversible amenorrhea was 57 and 50 % at <35 years, 95 and 31.6 % at 35-45 years, and 97.9 and 14.9 % at >50 years, respectively. The 33 prospective patients' estradiol and FSH levels seem to correlate well with onset of amenorrhea, with a falling estradiol and rising FSH trend. Tamoxifen use was associated with elevated estradiol levels 1 year post-chemotherapy. CONCLUSION: This study found a high incidence of CIOF, with a relatively low rate of reversible amenorrhea. Premenopausal patients should be counselled prior to treatment and education and support provided.

Prediction of lymph node involvement in patients with breast tumors measuring 3-5 cm in a middle-income setting: the role of CancerMath.

BACKGROUND: In settings with limited resources, sentinel lymph node biopsy (SNB) is only offered to breast cancer patients with small tumors and a low a priori risk of axillary metastases. OBJECTIVE: We investigated whether CancerMath, a free online prediction tool for axillary lymph node involvement, is able to identify women at low risk of axillary lymph node metastases in Malaysian women with 3-5 cm tumors, with the aim to offer SNB in a targeted, cost-effective way. METHODS: Women with non-metastatic breast cancers, measuring 3-5 cm were identified within the University Malaya Medical Centre (UMMC) breast cancer registry. We compared CancerMath-predicted probabilities of lymph node involvement between women with versus without lymph node metastases. The discriminative performance of CancerMath was tested using receiver operating characteristic (ROC) analysis. RESULTS: Out of 1,017 patients, 520 (51 %) had axillary involvement. Tumors of women with axillary involvement were more often estrogen-receptor positive, progesterone-receptor positive, and human epidermal growth factor receptor (HER)-2 positive. The mean CancerMath score was higher in women with axillary involvement than in those without (53.5 vs. 51.3, p = 0.001). In terms of discrimination, CancerMath performed poorly, with an area under the ROC curve of 0.553 (95 % confidence interval CI 0.518-0.588). Attempts to optimize the CancerMath model by adding ethnicity and HER2 to the model did not improve discriminatory performance. CONCLUSION: For Malaysian women with tumors measuring 3-5 cm, CancerMath is unable to accurately predict lymph node involvement and is therefore not helpful in the identification of women at low risk of node-positive disease who could benefit from SNB.

Differentiation between benign and malignant breast lesions using quantitative diffusion-weighted sequence on 3 T MRI.

AIM: To investigate the capability and diagnostic accuracy of diffusion-weighted imaging (DWI) in differentiating benign from malignant breast lesions using 3 T magnetic resonance imaging (MRI). MATERIALS AND METHODS: Women with suspicious or indeterminate breast lesions detected at MRI, mammogram and/or ultrasound were recruited for dynamic contrast-enhanced (DCE)-MRI and DWI prior to their biopsy. Image fusion of DCE-MRI with apparent diffusion coefficient (ADC) map was utilized to select the region of interest (ROI) for ADC calculation in the area that showed the most avid enhancement. DWI was performed using two sets of b-values at 500 and 1000 s/mm(2), respectively. RESULTS: Fifty women were recruited and the final analysis comprised 44 breast lesions, 31 of which were malignant and 13 were benign. Significant results were obtained between ADC values of benign and malignant lesions (p < 0.001). The cut-off ADC values for benign and malignant lesions were 1.21 × 10(-3) mm(2)/s for b = 500 s/mm(2) and 1.22 × 10(-3) mm(2)/s for b = 1000 s/mm(2), respectively. The sensitivity of DCE-MRI alone was 100% with a specificity of 66.7%. When DCE-MRI was combined with b = 1000 s/mm(2), the specificity rose to 100%, while only mildly affecting sensitivity (90.6%). No significant correlation was found between ADC values and prognostic factors, such as lymph node metastasis, tumour size, oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, and tumour grades. CONCLUSION: The present study provides consistent evidence to support DWI as a diagnostic tool for breast lesion characterization. A combination of DCE-MRI with DWI is suggested to improve the sensitivity and specificity of lesion characterization.

Breast health in developing countries.

Breast cancer is one of the leading cancers world-wide. While the incidence in developing countries is lower than in developed countries, the mortality is much higher. Of the estimated 1 600 000 new cases of breast cancer globally in 2012, 794 000 were in the more developed world compared to 883 000 in the less developed world; however, there were 198 000 deaths in the more developed world compared to 324 000 in the less developed world (data from Globocan 2012, IARC). Survival from breast cancer depends on two main factors--early detection and optimal treatment. In developing countries, women present with late stages of disease. The barriers to early detection are physical, such as geographical isolation, financial as well as psychosocial, including lack of education, belief in traditional medicine and lack of autonomous decision-making in the male-dominated societies that prevail in the developing world. There are virtually no population-based breast cancer screening programs in developing countries. However, before any screening program can be implemented, there must be facilities to treat the cancers that are detected. Inadequate access to optimal treatment of breast cancer remains a problem. Lack of specialist manpower, facilities and anticancer drugs contribute to the suboptimal care that a woman with breast cancer in a low-income country receives. International groups such as the Breast Health Global Initiative were set up to develop economically feasible, clinical practice guidelines for breast cancer management to improve breast health outcomes in countries with limited resources.

A review of breast cancer research in malaysia.

Four hundred and nineteen articles related to breast cancer were found in a search through a database dedicated to indexing all original data relevant to medicine published in Malaysia between the years 2000-2013. One hundred and fifty four articles were selected and reviewed on the basis of clinical relevance and future research implications. Overall, Malaysian women have poor survival from breast cancer and it is estimated that half of the deaths due to breast cancer could be prevented. Five-year survival in Malaysia was low and varies among different institutions even within the same disease stage, suggesting an inequity of access to optimal treatment or a lack of compliance to optimal treatment. Malaysian women have poor knowledge of the risk factors, symptoms and methods for early detection of breast cancer, leading to late presentation. Moreover, Malaysian women experience cancer fatalism, belief in alternative medicine, and lack of autonomy in decision making resulting in delays in seeking or avoidance of evidence-based medicine. There are ethnic differences in estrogen receptor status, HER2 overexpression and incidence of triple negative breast cancer which warrant further investigation. Malay women present with larger tumours and at later stages, and even after adjustment for these and other prognostic factors (stage, pathology and treatment), Malay women have a poorer survival. Although the factors responsible for these ethnic differences have not been elucidated, it is thought that pharmacogenomics, lifestyle factors (such as weight-gain, diet and exercise), and psychosocial factors (such as acceptance of 2nd or 3rd line chemotherapy) may be responsible for the difference in survival. Notably, survivorship studies show self-management programmes and exercise improve quality of life, highlighting the need to evaluate the psychosocial impact of breast cancer on Malaysian women, and to design culturally-, religiously- and linguistically-appropriate psycho-education programmes to help women cope with the disease and improve their quality of life. Research done in the Caucasian populations may not necessarily apply to local settings and it is important to embark on local studies particularly prevention, screening, diagnostic, prognostic, therapeutic and psychosocial research.

Improved diagnostic accuracy in differentiating malignant and benign lesions using single-voxel proton MRS of the breast at 3 T MRI.

AIM: To investigate the diagnostic accuracy of single-voxel proton magnetic resonance spectroscopy (SV (1)H MRS) by quantifying total choline-containing compounds (tCho) in differentiating malignant from benign lesions, and subsequently, to analyse the relationship of tCho levels in malignant breast lesions with their histopathological subtypes. MATERIALS AND METHODS: A prospective study of SV 1H MRS was performed following dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in 61 women using a 3 T MR system. All lesions (n = 57) were analysed for characteristics of morphology, contrast-enhancement kinetics, and tCho peak heights at SV (1)H MRS that were two-times above baseline. Subsequently, the tCho in selected lesions (n = 32) was quantified by calculating the area under the curve, and a tCho concentration equal to or greater than the cut-off value was considered to represent malignancy. The relationship between tCho in invasive ductal carcinomas (IDCs) and their Bloom & Richardson grading of malignancy was assessed. RESULTS: Fifty-two patients (57 lesions; 42 malignant and 15 benign) were analysed. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), of predicting malignancy were 100, 73.3, 91.3, and 100%, respectively, using DCE-MRI and 95.2, 93.3, 97.6, and 87.5%, respectively, using SV (1)H MRS. The tCho cut-off for receiver operating characteristic (ROC) curve was 0.33 mmol/l. The relationship between tCho levels in malignant breast lesions with their histopathological subtypes was not statistically significant (p = 0.3). CONCLUSION: Good correlation between tCho peaks and malignancy, enables SV (1)H MRS to be used as a clinically applicable, simple, yet non-invasive tool for improved specificity and diagnostic accuracy in detecting breast cancer.

Impact of breast surgery on survival in women presenting with metastatic breast cancer.

BACKGROUND: Advanced breast cancer is common in less affluent parts of Asia. The impact of breast surgery on survival of women presenting with metastatic breast cancer in this setting was investigated. METHODS: Women presenting with metastatic breast cancer at the initial diagnosis at the University Malaya Medical Centre (Malaysia) between 1993 and 2008 were included in the study. Mortality of patients who had primary breast surgery was compared with that of those without surgery, and adjusted for possible confounders by means of a propensity score. RESULTS: Of 3689 patients, 375 (10·2 per cent) presented with metastatic disease. One hundred and thirty-nine patients (37·1 per cent) underwent surgery. A total of 330 deaths occurred during 6814 person-months of follow-up. The 2-year survival rate was 21·2 (95 per cent confidence interval (c.i.) 15·9 to 26·5) per cent in women who did not have surgery and 46·3 (37·7 to 54·9) per cent in those who had breast surgery. Breast surgery was associated with a 28 per cent lower risk of death (hazard ratio 0·72, 95 per cent c.i. 0·56 to 0·94), after adjustment for patient and tumour characteristics, metastatic profile and treatment. CONCLUSION: Surgical resection of the primary breast tumour was independently associated with a survival advantage in patients presenting with metastatic breast cancer.

Reliability and validity of the Brief COPE Scale (English version) among women with breast cancer undergoing treatment of adjuvant chemotherapy: a Malaysian study.

This paper validates the Brief COPE Scale in Malaysian women with breast cancer. Test-retest evaluation was undertaken at two/three weeks and ten weeks following surgery. Internal consistencies ranged from 0.25 to 1.00. Meanwhile, the Intraclass Correlation Coefficient (ICC) ranged from 0.05 to 1.00. Sensitivity of the scale was indicated by the mean differences as observed in most of the domains with Effect Size Index (ESI) ranged from 0 to 0.53. Significant differences between mastectomy and lumpectomy were observed for Active coping, Planning and Acceptance. Brief COPE Scale showed fairly good reliability and validity.

Breast-conserving surgery versus mastectomy in young women with breast cancer in Asian settings.

Background: Mastectomy rates among women with early breast cancer in Asia have traditionally been high. This study assessed trends in the surgical management of young women with early-stage breast cancer in Asian settings. Survival in women treated with breast-conserving surgery (BCS; lumpectomy with adjuvant radiotherapy) and those undergoing mastectomy was compared. Methods: Young women (aged less than 50 years) newly diagnosed with stage I or II (T1-2 N0-1 M0) breast cancer in four hospitals in Malaysia, Singapore and Hong Kong in 1990-2012 were included. Overall survival (OS) was compared for patients treated by BCS and those who had a mastectomy. Propensity score analysis was used to account for differences in demographic, tumour and treatment characteristics between the groups. Results: Some 63·5 per cent of 3536 women underwent mastectomy. Over a 15-year period, only a modest increase in rates of BCS was observed. Although BCS was significantly associated with favourable prognostic features, OS was not significantly different for BCS and mastectomy; the 5-year OS rate was 94·9 (95 per cent c.i. 93·5 to 96·3) and 92·9 (91·7 to 94·1) per cent respectively. Inferences remained unchanged following propensity score analysis (hazard ratio for BCS versus mastectomy: 0·81, 95 per cent c.i. 0·64 to 1·03). Conclusion: The prevalence of young women with breast cancer treated by mastectomy remains high in Asian countries. Patients treated with BCS appear to survive as well as those undergoing mastectomy.

Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer.

INTRODUCTION: The cost of genetic testing and the limited knowledge about the BRCA1 and BRCA2 genes in different ethnic groups has limited its availability in medium- and low-resource countries, including Malaysia. In addition, the applicability of many risk-assessment tools, such as the Manchester Scoring System and BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) which were developed based on mutation rates observed primarily in Caucasian populations using data from multiplex families, and in populations where the rate of breast cancer is higher, has not been widely tested in Asia or in Asians living elsewhere. Here, we report the results of genetic testing for mutations in the BRCA1 or BRCA2 genes in a series of families with breast cancer in the multi-ethnic population (Malay, Chinese and Indian) of Malaysia. METHOD: A total of 187 breast cancer patients with either early-onset breast cancer (at age

Polymorphisms of HER2 Ile655Val and cyclin D1 (CCND1) G870A are not associated with breast cancer risk but polymorphic allele of HER2 is associated with nodal metastases.

The HER2 codon Ile655Val and Cyclin D1 (CCND1) G870A polymorphisms were analyzed in a hospital-based Malaysian population using PCR-RFLP method. Peripheral blood samples were collected from 230 breast cancer patients, and 200 normal and healthy women who had no history of breast disease or breast cancer. We evaluated the association between HER2 or CCND1 polymorphisms and breast cancer risk, and clinico-pathological parameters in the population. The genotype and allele frequencies of HER2 (P=0.163 vs P=0.0622) and CCND1 (P=0.377 vs P=0.284) polymorphisms were not significantly different between the breast cancer cases and normal subjects, respectively. Women who were Ile/Val heterozygotes (OR=1.48; 95% CI, 0.91-2.43), Val/Val homozygotes (OR=1.93; 95% CI, 0.51-7.77) and carriers of Val allele genotype (OR=1.53; 95% CI, 0.95-2.45) were not significantly associated with increased breast cancer risk. Similarly, women who were homozygous (OR=1.34; 95% CI, 0.77-2.34) or heterozygous (OR=0.98; 95% CI, 0.60-1.60) for A allele, or carriers of A allele genotype (OR=1.10; 95% CI, 0.70-1.73) were not associated with breast cancer risk. Analysis on clinico-pathological parameters showed that Val allele genotype was significantly correlated with nodal metastases but A allele genotype was not associated with any of the variables. Our findings suggest that the polymorphic alleles of HER2 and CCND1 may not play an important role as genetic markers for breast cancer risk, but presence of Val allele may be useful for tumor prognosis.