ESR1 PvuII polymorphism: from risk factor to prognostic and predictive factor of the success of primary systemic therapy in advanced breast cancer.

BACKGROUND: The ESR1 gene encodes Estrogen Receptor alpha (ERα), which plays a role in the tumourigenesis of breast cancer. A single nucleotide polymorphism (SNP) in intron 1 of this gene called ESR1 PvuII (rs2234693) has been reported to increase the risk of breast cancer. This study aimed to investigate the ESR1 PvuII polymorphism as a prognostic and predictive factor guiding the choice of therapy for advanced breast cancer. METHODS: This retrospective study was conducted in 104 advanced breast cancer patients at Dharmais Cancer Hospital from 2011 to 2018. The ESR1 PvuII polymorphism was analysed by Sanger sequencing of DNA from primary breast tumour samples. RESULTS: The percentages of patients with ESR1 PvuII genotypes TT, TC, and CC were 42.3, 39.4, and 18.3%, respectively. Looking at prognosis, patients with ESR1 PvuII TC + CC had shorter overall survival than those with the TT genotype [HR = 1.79; 95% CI 1.05-3.04; p = 0.032]. As a predictive marker, TC + CC was associated with shorter survival (p = 0.041), but TC + CC patients on primary hormonal therapy had a median overall survival longer than TC + CC patients on primary chemotherapy (1072 vs 599 days). CONCLUSION: The ESR1 PvuII TC + CC genotypes confer poor prognosis in advanced breast cancer, but these genotypes could be regarded as a good predictor of the therapeutic effect of hormonal treatment.

The predictive value of methylene blue dye as a single technique in breast cancer sentinel node biopsy: a study from Dharmais Cancer Hospital.

BACKGROUND: Axillary lymph node dissection (ALND) has been the standard treatment of breast cancer axillary staging in Indonesia. The limited facilities of radioisotope tracer and isosulfan or patent blue dye (PBD) have been the major obstacles to perform sentinel node biopsy (SNB) in our country. We studied the application of 1% methylene blue dye (MBD) alone for SNB to overcome the problem. METHODS: This prospective study enrolled 108 patients with suspicious malignant lesions or breast cancer stages I-III. SNB was performed using 2-5 cc of 1% MBD and proceeded with ALND. The histopathology results of sentinel nodes (SNs) were compared with axillary lymph nodes (ALNs) for diagnostic value assessments. RESULTS: There were 96 patients with invasive carcinoma from July 2012 to September 2014 who were included in the final analysis. The median age was 50 (25-69) years, and the median pathological tumor size was 3 cm (1-10). Identification rate of SNs was 91.7%, and the median number of the identified SNs was 2 (1-8). Sentinel node metastasis was found in 53.4% cases and 89.4% of them were macrometastases. The negative predictive value (NPV) of SNs to predict axillary metastasis was 90% (95% CI, 81-99%). There were no anaphylactic reactions, but we found 2 cases with skin necrosis. CONCLUSIONS: The application of 1% MBD as a single technique in breast cancer SNB has favorable identification rates and predictive values. It can be used for axillary staging, but nevertheless the technique should be applied with attention to the tumor size and grade to avoid false negative results.

Prognostic Values of CD8+, PARP, and EGFR on Overall Survival in Patients with Triple-Negative Breast Cancer.

OBJECTIVE: This study aimed to investigate the associations of CD8+, PARP, and EGFR expressions with two-year survival in patients with triple-negative breast cancer (TNBC). METHODS: A retrospective cohort study was conducted in a national cancer center. All patients aged 18 years diagnosed with TNBC (2013-2017) were included and followed for 24 months or until the patients were deceased. Kaplan-Meier survival function and Cox proportional hazard model were applied for the analyses. RESULTS: The study population was followed for 24 months (2,692 person-months, N = 126). At the end of the follow-up, 27 patients were deceased. The two-year mortality rate was 10 per 1,000 person-month. Kaplan-Meier graphs showed that after approximately one year of follow-up, poorer survival was seen in patients with low CD8+, positive PARP, and positive EGFR. The adjusted analysis found staging as the main predictor of overall survival in TNBC (HR = 7.20, 95% CI= 2.07 - 25.00). CONCLUSIONS: Patients with low CD8+, positive PARP, and positive EGFR expressions seem to be associated with poorer overall survival in TNBC. After approximately one year of follow-up, higher survival was observed in patients with high CD8+, negative PARP, and negative EGFR. Staging remains the main predictor of TNBC survival. Therefore, early detection and treatment of TNBC are essential to improve survival.

What do women want to see in a personalized breast cancer risk report? A qualitative study of Asian women of two countries.

A breast cancer risk assessment tool for Asian populations, incorporating Polygenic Risk Score and Gail Model algorithm, has been established and validated. However, effective methods for delivering personalized risk information remain underexplored. This study aims to identify and develop effective methods for conveying breast cancer risk information to Asian women. Through ten focus group discussions with 32 women in Indonesia and Singapore, we explored preferences for the presentation of risk information. Participants favored comprehensive reports featuring actionable steps, simplified language, non-intimidating visuals, and personalized risk reduction recommendations. Singaporean participants, more aware of breast cancer prevention, showed a lower likelihood of seeking follow-ups upon receiving low-risk results compared to Indonesians. Overall, participants found the reports useful and advocated for similar approaches in other disease assessments. Balancing content and complexity in reports is crucial, highlighting the need for improved patient understanding and engagement with healthcare providers. Future studies could explore physicians' roles in delivering personalized risk assessments for breast cancer prevention.

Volumetric Absorptive Microsampling as a New Biosampling Tool for Monitoring of Tamoxifen, Endoxifen, 4-OH Tamoxifen and N-Desmethyltamoxifen in Breast Cancer Patients.

INTRODUCTION: In this research, we used a volumetric absorptive microsampling (VAMS) technique to collect blood samples from the patients. A rapid and simple sample preparation method and LC-MS.MS assay was then developed and validated for the simultaneous analysis of tamoxifen and its three active metabolites. METHODS: VAMS extraction was performed in methanol by sonication-assisted extraction method for 25 min after 2 hof VAMS drying. Separation was carried out using Acquity UPLC BEH C18 column (2.1 x 100 mm; 1.7 µm), with a flow rate of 0.2 mL/min, and the mobile phase gradient of formic acid 0.1% and formic acid 0.1% in acetonitrile for 5 min. The multiple reaction monitoring (MRM) values were set at m/z 358.31>58.27 for N-desmethyltamoxifen, m/z 372.33>72.28 for tamoxifen, m/z 388.22>72.28 for 4-hydroxytamoxifen, m/z 374.25>58.25 for endoxifen, and m/z 260.26>116.12 for propranolol. RESULTS AND DISCUSSION: The lower limit of quantification value (LLOQ) was 2.50 ng/mL for tamoxifen, 2.50 ng/mL for endoxifen, 1.50 ng/mL for 4-hydroxitamoxifen, and 2.00 ng/mL for N-desmethyltamoxifen. Accuracy (%bias) and precision (%CV) were within 20% for LLOQ and 15% for other concentrations. There were no interference responses >20% of the LLOQ and 5% of the internal standard. The level of ion suppression in all analytes was less than 7%. The preparation system developed in this study successfully extracted more than 90% of analytes from the matrix with precision below 15%. Carryover was shown to be below 6% in all analytes. Stability of analytes in VAMS was demonstrated for up to 30 days, under room temperature storage in a sealed plastic bag with desiccant. This method was successfully applied to analyze tamoxifen and the metabolites level in 30 ER+ breast cancer patients.

Analysis of tamoxifen and its metabolites in dried blood spot and volumetric absorptive microsampling: comparison and clinical application.

This research was conducted to develop the Dried Blood Spot (DBS) and Volumetric Absorptive Microsampling (VAMS) method in the analysis of Tamoxifen (TAM) and its metabolites endoxifen (END), 4-hydroxytamoxifen (4-HT), and N-desmethyltamoxifen (NDT) using Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS). This method was then applied to monitor TAM and its metabolites in breast cancer patients. The UPLC-MS/MS method was developed and validated with propranolol as the internal standard. The recovery and matrix effects on DBS and VAMS were investigated. The validation requirements were fulfilled by the methodology of analysis and sample preparation described in this study. Both VAMS and DBS extraction recoveries were satisfactory, with low variability. Extraction recovery in the VAMS sample was found to be slightly higher than in the DBS sample. Sample stability in DBS and VAMS was demonstrated for up to 2 months. Both of these methods were successfully applied for the analysis of TAM and metabolites in clinical patients. The mean concentrations obtained from the two methods were not significantly different.

Survey data of COVID-19 awareness, knowledge, preparedness and related behaviors among breast cancer patients in Indonesia.

This dataset presents a survey data describing COVID-19 awareness, knowledge, preparedness and related behaviors among breast cancer patients in Indonesia. The data were collected from breast cancer patients through a survey distributed by an online questionnaire, assesing social-demographic characteristics (6 items), COVID-19 awareness (5 items), knowledge (2 items), preparedness (2 items) and related behaviors (2 items), from 20th June until 14th July 2020. The samples were gathered 500 breast cancer patients in Indonesia who were willing to fill an online questionnaire. SPSS version 23.0 was used to analyzed the data by descriptive and inferential statistics and SmartPLS 3 to created the partial least square path modeling. The data will help in preventing the transmission of COVID-19 among breast cancer patients and can support for health education and promotion interventions.

Survey data of multidrug-resistant tuberculosis, Tuberculosis patients characteristics and stress resilience during COVID-19 pandemic in West Sumatera Province, Indonesia.

This set of data presents a survey data describing multidrug-resistant tuberculosis, tuberculosis patients characteristics and stress resilience during COVID-19 pandemic in West Sumatera Province, Indonesia. The data were gathered from multidrug-resistant tuberculosis, tuberculosis patients through a survey distributed by an online questionnaire, assesing patients characteristics (age, sex, level of education, working status, history of close contact to patients with multidrug resistant tuberculosis and tuberculosis, smoking, alcohol consumption, cavitary pulmonary, diabetes mellitus, nutritional status and tuberculosis outside the lung) and stress resilience (3 items), from 15th July until 7th August 2020. The samples were collected 73 multidrug resistant tuberculosis patients and 219 tuberculosis patients in West Sumatera Province, Indonesia who were willing to fill an online questionnaire. SPSS version 23.0 was used to analyzed the data by descriptive and inferential statistics. The data will help to identify mental health problems and potentially as a warning sign that can support for health education interventions among multidrug-resistant tuberculosis and tuberculosis patients during COVID-19 pandemic.

The Application of 1% Methylene Blue Dye As a Single Technique in Breast Cancer Sentinel Node Biopsy.

In this study, we injected 1% methylene blue dye (MBD) into the subareolar or peritumoral space of the breast. In the case of breast conserving surgery (BCS), a separate incision in the lower axilla hairline was made to find the sentinel nodes (SNs). In mastectomy, the SNs were identified through the same mastectomy incision. The SNs were described as blue nodes or nodes with lymphatic blue channels. An anatomical landmark in the axilla was used to facilitate SNs identification. The SNs metastases were evaluated by intraoperative frozen section analysis and histopathology examination as it is a gold standard. Here, we described the MBD as the lone technique in breast cancer sentinel node biopsy (SNB) which could be useful when radioisotope tracer or patent or isosulfan blue dye (PBD) cannot be provided.

Signaling pathways in early onset sporadic breast cancer of patients in Indonesia.

AIM: to determine signaling pathways in breast cancers from patients aged 35 years old or younger and patients aged more than 35 years old. METHODS: this was a cross-sectional, comparative study of female breast cancer patients who were recruited and divided into two age groups, i.e. 35 years or younger and more than 35 years old. Specimens were obtained by biopsy or surgical removal of the tumors and were confirmed by histopathological examination. The expression of ER, IGF-1R, Her-2, MAPK, and cyclin D1 were measured using immunohistochemistry. RESULTS: ninety-three patients were recruited from September 2004 to December 2005. Forty-three patients were 35 years or younger. More than 90% of the patients within the two groups showed invasive ductal carcinomas and more than half of these tumors were grade 2. Immunohistochemical staining was successfully done in 90 patients. ER-alpha expression was negative in 33 breast cancers (78.6%) from patients less than 35 years old and 32 cancers (66.7%) of older patients. The expressions of IGF-1R, Her-2, MAPK, and cyclin D1 were positive, respectively in 17 (40.5%), 11 (26.2%), 28 (66.7%), and 7 (16.7%) cancers within the group of patients 35 years old or younger, and, respectively in 18 (37.5%), 11 (22.9%), 37 (77.1%), and 9 (18.8%) of cancers from patients more than 35 years old. CONCLUSION: there were no statistically significant differences in the expression of any of the biomarkers between the two groups. In all patients, ER was negative in 72.2% cases and MAPK was positive in 76.7% cases. Patients aged 35 years or younger showed similar ER, IGF-1R, Her-2, MAPK, and cyclin D1 expressions compared to cancers from patients more than 35 years old. These were predominantly ER-negative, suggesting that estrogen does not play a dominant role in their growth. The frequent expression of MAPK in these cancers raises the possibility that growth factors play a dominant role in their growth.

Screening of BRCA1/2 Mutations Using Direct Sequencing in Indonesian Familial Breast Cancer Cases.

Breast cancer has emerged as the most prevalent cancer among women worldwide, including in Indonesia. The contribution of genes associated with high-risk breast-ovarian cancers, BRCA1 and BRCA2, in the Indonesian population is relatively unknown. We have characterized family history of patients with moderate- to high-risk of breast cancer predisposition in 26 unrelated cases from Indonesia for BRCA1/2 mutation analyses using direct sequencing. Known deleterious mutations were not found in either BRCA1 or BRCA2 genes. Seven variants in BRCA2 were documented in 10 of 26 patients (38%). All variants were categorized as unclassified (VUSs). Two synonymous variants, c.3623A>G and c.4035T>C, were found in 5 patients. One variant, c4600T>C, was found in a 38 year old woman with a family history of breast cancer. We have found 4 novel variants in BRCA2 gene including c.6718C>G, c.3281A>G, c.10176C>G, and c4490T>C in 4 unrelated patients, all of them having a positive family history of breast cancer. In accordance to other studies in Asian population, our study showed more frequent variants in BRCA2 compared to BRCA1. Further studies involving larger numbers of hereditary breast cancer patients are required to reveal contribution of BRCA1/2 mutations and/or other predisposing genes among familial breast cancer patients in Indonesia.

Caveolin-1 in Breast Cancer: Single Molecule Regulation of Multiple Key Signaling Pathways.

Caveolin-1 is a 22-kD trans-membrane protein enriched in particular plasma membrane invaginations known as caveolae. Cav-1 expression is often dysregulated in human breast cancers, being commonly upregulated in cancer cells and downregulated in stromal cells. As an intracellular scaffolding protein, Cav-1, is involved in several vital biological regulations including endocytosis, transcytosis, vesicular transport, and signaling pathways. Several pathways are modulated by Cav-1 including estrogen receptor, EGFR, Her2/neu, TGFß, and mTOR and represent as major drivers in mammary carcinogenesis. Expression and role of Cav-1 in breast carcinogenesis is highly variable depending on the stage of tumor development as well as context of the cell. However, recent data have shown that downregulation of Cav-1 expression in stromal breast tumors is associated with frequent relapse, resistance to therapy, and poor outcome. Modification of Cav-1 expression for translational cancer therapy is particularly challenging since numerous signaling pathways might be affected. This review focuses on present understanding of Cav-1 in breast carcinogenesis and its potential role as a new biomarker for predicting therapeutic response and prognosis as well as new target for therapeutic manipulation.

A pilot genome-wide association study of breast cancer susceptibility loci in Indonesia.

Genome-wide association studies (GWASs) of the entire genome provide a systematic approach for revealing novel genetic susceptibility loci for breast cancer. However, genetic association studies have hitherto been primarily conducted in women of European ancestry. Therefofre we here performed a pilot GWAS with a single nucleotide polymorphism (SNP) array 5.0 platform from Affymetrix® that contains 443,813 SNPs to search for new genetic risk factors in 89 breast cancer cases and 46 healthy women of Indonesian ancestry. The case-control association of the GWAS finding set was evaluated using PLINK. The strengths of allelic and genotypic associations were assessed using logistic regression analysis and reported as odds ratios (ORs) and P values; P values less than 1.00x10(-8) and 5.00x10(-5) were required for significant association and suggestive association, respectively. After analyzing 292,887 SNPs, we recognized 11 chromosome loci that possessed suggestive associations with breast cancer risk. Of these, however, there were only four chromosome loci with identified genes: chromosome 2p.12 with the CTNNA2 gene [Odds ratio (OR)=1.20, 95% confidence interval (CI)=1.13-1.33, P=1.08x10(-7)]; chromosome 18p11.2 with the SOGA2 gene (OR=1.32, 95%CI=1.17-1.44, P=6.88x10(-6)); chromosome 5q14.1 with the SSBP2 gene (OR=1.22, 95%CI=1.11-1.34, P=4.00x10(-5)); and chromosome 9q31.1 with the TEX10 gene (OR=1.24, 95%CI=1.12-1.35, P=4.68x10(-5)). This study identified 11 chromosome loci which exhibited suggestive associations with the risk of breast cancer among Indonesian women.

BRCA1 and BRCA2 germline mutation analysis in the Indonesian population.

Specific mutations in BRCA1 and BRCA2 genes have been identified in specific populations and ethnic groups. However, little is known about the contribution of BRCA1 and BRCA2 mutations to breast cancers in the Indonesian population. One hundred-twenty moderate to high risk breast cancer patients were tested using PCR-DGGE, and any aberrant band was sequenced. Multiplex ligation-dependent probe amplification (MLPA) was performed on all samples to detect large deletions in the two genes. Twenty-three different mutations were detected in 30 individuals, ten were deleterious mutations and 20 were "unclassified variants" with uncertain clinical consequences. Three of seven (c.2784_2875insT, p.Leu1415X and del exon 13-15) and two of four (p.Glu2183X and p.Gln2894X) deleterious mutations that were found in BRCA1 and BRCA2 respectively, are novel. Several novel, pathogenic BRCA1 and BRCA2 germline mutations are found in early onset Indonesian breast cancer patients, these may therefore be specific for the Indonesian population.

Isolated internal mammary sentinel lymph node metastasis in two breast cancer patients.

Lymphatic mapping with sentinel node biopsy may lead to more accurate staging of breast cancer patients. Two patients with sentinel nodes in the internal mammary node chain are described. These nodes were visualized on lymphoscintigraphy images and harvested by the surgeon. They were shown to contain tumor cells in the absence of axillary involvement. This led to upstaging and to a change in the subsequent management.