Alterations to DNA methylation patterns induced by chemotherapy treatment are associated with negative impacts on the olfactory pathway.

BACKGROUND: Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients. METHODS: We performed DNAm analysis in 125 breast cancer patients with blood drawn before and after chemotherapy, using the Illumina MethylationEPIC array. DNAm changes of 588,798 individual CpGs (including 41,207 promoter regions) were evaluated using linear regression models adjusted for monocyte proportion. Gene set enrichment analyses (GSEA) were conducted to identify key Gene Ontology (GO) biological processes or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1273) and not treated (n = 872) by chemotherapy (1808 blood, 337 saliva). RESULTS: A total of 141 differentially methylated CpGs and 11 promoters were significantly associated with chemotherapy after multiple testing corrections in both the paired sample and single time point analyses. GSEA of promoter regions (pre-ranked by test statistics) identified six suppressed biological processes (p < 4.67e-8) related to sensory perception and detection of chemical stimuli, including smell perception (GO:0007606, GO:0007608, GO:0009593, GO:0050906, GO:0050907, and GO:0050911). The same six biological processes were significantly suppressed in the validation dataset (p < 9.02e-14). The KEGG pathway olfactory transduction (hsa04740) was also found to be significantly suppressed (ppaired-samples = 1.72e-9, psingle-timepoint-blood = 2.03e-15 and psingle-timepoint-saliva = 7.52e-56). CONCLUSION: The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy could affect the perception of smell.

Epidemiology and estimated economic impact of musculoskeletal injuries in polytrauma patients in a level one trauma centre in Singapore.

Introduction: Musculoskeletal injuries are the most common reason for surgical intervention in polytrauma patients. Methods: This is a retrospective cohort study of 560 polytrauma patients (injury severity score [ISS] >17) who suffered musculoskeletal injuries (ISS >2) from 2011 to 2015 in National University Hospital, Singapore. Results: 560 patients (444 [79.3%] male and 116 [20.7%] female) were identified. The mean age was 44 (range 3-90) years, with 45.4% aged 21-40 years. 39.3% of the patients were foreign migrant workers. Motorcyclists were involved in 63% of road traffic accidents. The mean length of hospital stay was 18.8 (range 0-273) days and the mean duration of intensive care unit (ICU) stay was 5.7 (range 0-253) days. Patient mortality rate was 19.8%. A Glasgow Coma Scale (GCS) score <12 and need for blood transfusion were predictive of patient mortality (p < 0.05); lower limb injuries, road traffic accidents, GCS score <8 and need for transfusion were predictive of extended hospital stay (p < 0.05); and reduced GCS score, need for blood transfusion and upper limb musculoskeletal injuries were predictive of extended ICU stay. Inpatient costs were significantly higher for foreign workers and greatly exceeded the minimum insurance coverage currently required. Conclusion: Musculoskeletal injuries in polytrauma remain a significant cause of morbidity and mortality, and occur predominantly in economically productive male patients injured in road traffic accidents and falls from height. Increasing insurance coverage for foreign workers in high-risk jobs should be evaluated.

Negative and positive experiences of caregiving among family caregivers of older blunt trauma patients.

OBJECTIVES: Family caregivers play a fundamental role in the care of the older blunt trauma patient. We aim to identify risk factors for negative and positive experiences of caregiving among family caregivers. DESIGN: Prospective, nationwide, multi-center cohort study. SETTING AND PARTICIPANTS: 110 family caregivers of Singaporeans aged≥55 admitted for unintentional blunt trauma with an Injury Severity Score (ISS) or New Injury Severity Score (NISS)≥10 were assessed for caregiving-related negative (disturbed schedule and poor health, lack of family support, lack of finances) and positive (esteem) experiences using the modified-Caregiver Reaction Assessment (m-CRA) three months post-injury. METHODS: The association between caregiver and patient factors, and the four m-CRA domains were evaluated via linear regression. RESULTS: Caregivers of retired patients and caregivers of functionally dependent patients (post-injury Barthel score <80) reported a worse experience in terms of disturbed schedule and poor health (ß-coefficient 0.42 [95% Confidence Interval 0.10, 0.75], p = .01; 0.77 [0.33, 1.21], p = .001), while male caregivers and caregivers who had more people in the household reported a better experience (-0.39 [-0.73, -0.06], p = .02; -0.16 [-0.25, -0.07], p = .001). Caregivers of male patients, retired patients, and patients living in lower socioeconomic housing were more likely to experience lack of family support (0.28, [0.03, -0.53], p = .03; 0.26, [0.01, 0.52], p = .05; 0.34, [0.05, -0.66], p = .02). In the context of lack of finances, caregivers of male patients and caregivers of functionally dependent patients reported higher financial strain (0.74 [0.31, 1.17], p = .001; 0.84 [0.26, 1.43], p = .01). Finally, caregivers of male patients reported higher caregiver esteem (0.36 [0.15, 0.57], p = .001). CONCLUSIONS AND IMPLICATIONS: Negative and positive experiences of caregiving among caregivers of older blunt trauma patients are associated with pre-injury disability and certain patient and caregiver demographics. These factors should be considered when planning the post-discharge support of older blunt trauma patients.

BREAst screening Tailored for HEr (BREATHE)-A study protocol on personalised risk-based breast cancer screening programme.

Routine mammography screening is currently the standard tool for finding cancers at an early stage, when treatment is most successful. Current breast screening programmes are one-size-fits-all which all women above a certain age threshold are encouraged to participate. However, breast cancer risk varies by individual. The BREAst screening Tailored for HEr (BREATHE) study aims to assess acceptability of a comprehensive risk-based personalised breast screening in Singapore. Advancing beyond the current age-based screening paradigm, BREATHE integrates both genetic and non-genetic breast cancer risk prediction tools to personalise screening recommendations. BREATHE is a cohort study targeting to recruit ~3,500 women. The first recruitment visit will include questionnaires and a buccal cheek swab. After receiving a tailored breast cancer risk report, participants will attend an in-person risk review, followed by a final session assessing the acceptability of our risk stratification programme. Risk prediction is based on: a) Gail model (non-genetic), b) mammographic density and recall, c) BOADICEA predictions (breast cancer predisposition genes), and d) breast cancer polygenic risk score. For national implementation of personalised risk-based breast screening, exploration of the acceptability within the target populace is critical, in addition to validated predication tools. To our knowledge, this is the first study to implement a comprehensive risk-based mammography screening programme in Asia. The BREATHE study will provide essential data for policy implementation which will transform the health system to deliver a better health and healthcare outcomes.

Health Services Use and Functional Recovery Following Blunt Trauma in Older Persons - A National Multicentre Prospective Cohort Study.

OBJECTIVE: Frailty is associated with morbidity and mortality in older injured patients. However, for older blunt-trauma patients, increased frailty may not manifest in longer length of stay at index admission. We hypothesized that owing to time spent in hospital from readmissions, frailty would be associated with less total time at home in the 1-year postinjury period. DESIGN: Prospective, nationwide, multicenter cohort study. SETTING AND PARTICIPANTS: All Singaporean residents aged ≥55 years admitted for blunt trauma with an Injury Severity Score (ISS) or New Injury Severity Score (NISS) ≥10 from March 2016 to July 2018. METHODS: Frailty (by modified Fried criteria) was assessed at index admission, based on questions on preinjury weight loss, slowness, exhaustion, physical activity, and grip strength at the time of recruitment. Low time at home was defined as >14 hospitalized days within 1 year postinjury. The contribution of planned and unplanned readmission to time at home postinjury was explored. Functional trajectory (by Barthel Index) over 1 year was compared by frailty. RESULTS: Of the 218 patients recruited, 125 (57.3%) were male, median age was 72 years, and 48 (22.0%) were frail. On univariate analysis, frailty [relative to nonfrail: odds ratio (OR) 3.45, 95% confidence interval (CI) 1.33-8.97, P = .01] was associated with low time at home. On multivariable analysis, after inclusion of age, gender, ISS, intensive care unit admission, and surgery at index admission, frailty (OR 5.21, 95% CI 1.77-15.34, P < .01) remained significantly associated with low time at home in the 1-year postinjury period. Unplanned readmissions were the main reason for frail participants having low time at home. Frail participants had poorer function in the 1-year postinjury period. CONCLUSIONS AND IMPLICATIONS: In the year following blunt trauma, frail older patients experience lower time at home compared to patients who were not frail at baseline. Screening for frailty should be considered in all older blunt-trauma patients, with a view to being prioritized for postdischarge support.

Frailty and length of stay in older adults with blunt injury in a national multicentre prospective cohort study.

BACKGROUND: Patients suffering moderate or severe injury after low falls have higher readmission and long-term mortality rates compared to patients injured by high-velocity mechanisms such as motor vehicle accidents. We hypothesize that this is due to higher pre-injury frailty in low-fall patients, and present baseline patient and frailty demographics of a prospective cohort of moderate and severely injured older patients. Our second hypothesis was that frailty was associated with longer length of stay (LOS) at index admission. METHODS: This is a prospective, nation-wide, multi-center cohort study of Singaporean residents aged ≥55 years admitted for ≥48 hours after blunt injury with an injury severity score or new injury severity score ≥10, or an Organ Injury Scale ≥3, in public hospitals from 2016-2018. Demographics, mechanism of injury and frailty were recorded and analysed by Chi-square, or Kruskal-Wallis as appropriate. RESULTS: 218 participants met criteria and survived the index admission. Low fall patients had the highest proportion of frailty (44, 27.3%), followed by higher level fallers (3, 21.4%) and motor vehicle accidents (1, 2.3%) (p < .01). Injury severity, extreme age, and surgery were independently associated with longer LOS. Frail patients were paradoxically noted to have shorter LOS (p < .05). CONCLUSION: Patients sustaining moderate or severe injury after low falls are more likely to be frail compared to patients injured after higher-velocity mechanisms. However, this did not translate into longer adjusted LOS in hospital at index admission.

Cohort profile: The Singapore Breast Cancer Cohort (SGBCC), a multi-center breast cancer cohort for evaluation of phenotypic risk factors and genetic markers.

This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers.

Definitive Surgery Is Safe in Borderline Patients Who Respond to Resuscitation.

OBJECTIVES: We hypothesize that in adequately resuscitated borderline polytrauma patients with long bone fractures (femur and tibia) or pelvic fractures, early (within 4 days) definitive stabilization (EDS) can be performed without an increase in postoperative ventilation and postoperative complications. DESIGN: Retrospective cohort study. SETTING: Level 1 trauma center. PATIENTS: In total, 103 patients were included in this study; of whom, 18 (17.5%) were female and 85 (82.5%) were male. These patients were borderline trauma patients who had the following parameters before definitive surgery, normal coagulation profile, lactate of <2.5 mmol/L, pH of ≥7.25, and base excess of ≥5.5. INTERVENTION: These patients were treated according to Early Total Care, definitive surgery on day of admission, or Damage Control Orthopaedics principles, temporizing external fixation followed by definitive surgery at a later date. Timing of definitive surgical fixation was recorded as EDS or late definitive surgical fixation (>4 days). MAIN OUTCOME MEASURES: Primary outcome measured was the duration of ventilation more than 3 days post definitive surgery and presence of postoperative complications. RESULTS: Thirty-five patients (34.0%) received Early Total Care, whereas 68 (66.0%) patients were treated with Damage Control Orthopaedics. In total, 51 (49.5%) of all patients had late definitive surgery, whereas 52 patients (50.5%) had EDS. On logistic regression, the following factors were found to be predictive of higher rates of postoperative ventilation ≥ 3 days, units of blood transfused, and time to definitive surgery > 4 days. Increased age, head abbreviated injury score of 3 or more and time to definitive surgery were found to be associated with an increased risk of postoperative complications. CONCLUSIONS: Borderline polytrauma patients with no severe soft tissue injuries, such as chest or head injuries, may be treated with EDS if adequately resuscitated with no increase in need for postoperative ventilation and complications. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A rare case report of recurrent metastatic breast cancer mimicking primary pancreatic cancer.

INTRODUCTION: Secondary pancreatic tumors are rare, of which a breast cancer primary is extremely uncommon. To our knowledge, we present the 14th case reported worldwide and first from Singapore of lobular breast cancer metastasizing to the pancreas. PRESENTATION OF CASE: A 53-year-old woman presented with painless obstructive jaundice, weight loss over 1.5 months and a 2 cm right breast mass. She had left breast Invasive Lobular Carcinoma (ILC) treated 5 years prior with wide local excision, adjuvant radiotherapy and hormonal therapy. She had elevated bilirubin, liver enzymes and Cancer Antigen (CA) 19-9. Imaging found 3 right breast nodules, left axillary lymphadenopathy, biliary dilatation with an ampullary mass, and bone metastases. Breast nodule biopsies confirmed ILC but ampullary mass cytopathology was inconclusive. Frozen section of the mass during exploratory laparotomy showed metastatic ILC; a triple bypass surgery was done and chemo-endocrine therapy commenced. DISCUSSION: ILC is the commonest type of breast carcinoma in cases with pancreatic metastases, usually recurring after long disease-free intervals, and widely metastatic at presentation. Imaging characteristics help differentiate secondary from primary pancreatic tumors. Radiological features and history of an extra-pancreatic cancer suffice in suspecting pancreatic metastases. Despite limited surgical experience, it is well accepted that pancreatic metastasectomy offers reasonably good long-term survival rates, quality of life and can even be curative in highly selected cases. CONCLUSION: This case is an interesting case because it highlights the diagnostic dilemma involved in the rare entity of breast cancer metastatic to the pancreas, and summarizes its diagnosis and management.

Ultrasound Guided Optoacoustic Tomography in Assessment of Tumor Margins for Lumpectomies.

PURPOSE: To determine the accuracy of a handheld ultrasound-guided optoacoustic tomography (US-OT) probe developed for human deep-tissue imaging in ex vivo assessment of tumor margins postlumpectomy. METHODS: A custom-built two-dimensional (2D) US-OT-handheld probe was used to scan 15 lumpectomy breast specimens. Optoacoustic signals acquired at multiple wavelengths between 700 and 1100 nm were reconstructed using model linear algorithm, followed by spectral unmixing for lipid and deoxyhemoglobin (Hb). Distribution maps of lipid and Hb on the anterior, posterior, superior, inferior, medial, and lateral margins of the specimens were inspected for margin involvement, and results were correlated with histopathologic findings. The agreement in tumor margin assessment between US-OT and histopathology was determined using the Bland-Altman plot. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of margin assessment using US-OT were calculated. RESULTS: Ninety margins (6 × 15 specimens) were assessed. The US-OT probe resolved blood vessels and lipid up to a depth of 6 mm. Negative and positive margins were discriminated by marked differences in the distribution patterns of lipid and Hb. US-OT assessments were concordant with histopathologic findings in 87 of 89 margins assessed (one margin was uninterpretable and excluded), with diagnostic accuracy of 97.9% (kappa = 0.79). The sensitivity, specificity, PPV, and NPV were 100% (4/4), 97.6% (83/85), 66.7% (4/6), and 100% (83/83), respectively. CONCLUSION: US-OT was capable of providing distribution maps of lipid and Hb in lumpectomy specimens that predicted tumor margins with high sensitivity and specificity, making it a potential tool for intraoperative tumor margin assessment.

Accelerated partial breast irradiation in an Asian population: dosimetric findings and preliminary results of a multicatheter interstitial program.

INTRODUCTION: Accelerated partial breast irradiation (APBI) using the multicatheter method has excellent cosmesis and low rates of long-term toxicity. However, there are few studies looking at the feasibility of this procedure and the outcomes in an Asian population. This study aims to look at outcomes at our hospital. METHODS: We identified 121 patients treated with APBI at our center between 2008 and 2014. The median follow-up for our patient group was 30 months (range 3.7-66.5). The prescribed dose per fraction was 3.4 Gy in 10 fractions. In this study population, 71% of the patients were Chinese while 15% (n=19) were of other Asian ethnicity. RESULTS: In this study, the median breast volume was 850 cc (range 216-2,108) with 59.5% (n=72) patients with a breast volume of <1,000 cc. The average planning target volume was 134 cc (range 28-324). The number of catheters used ranged from 8 to 25 with an average of 18 catheters used per patient. We achieved an average dose homogeneity index of 0.76 in our patients. The average D90(%) was 105% and the average D90(Gy) was 3.6 Gy per fraction. The median volume receiving 100% of the prescribed dose (V100) was 161.7 cc (range 33.9-330.1), 150% of the prescribed dose (V150) and 200% of the prescribed dose (V200) was 39.4 cc (range 14.6-69.6) and 14.72 cc (range 6.48-22.25), respectively. Our dosimetric outcomes were excellent even in patients with breast volume under 1,000 cc. There were no cases of grade 3 skin toxicity or acute pneumonitis. Two patients had a postoperative infection and two patients had fat necrosis postprocedure. CONCLUSION: Multicatheter high dose rate APBI is a safe and feasible procedure that can be carried out with minimal toxicity in Asian patients with breast volumes under 1,000 cc.

Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer.

BACKGROUND: Prolonged anti-angiogenic therapy destroys tumor vasculature, whereas vascular-normalizing doses may enhance intra-tumoral drug delivery. We hypothesize that low-dose, short-course sunitinib normalizes vasculature, enhancing chemotherapy efficacy. PATIENTS AND METHODS: In phase Ib, treatment-naïve breast cancer patients received four cycles of pre-operative doxorubicin/cyclophosphamide, with sunitinib before each cycle. The optimal dose of sunitinib leading to tumor vessel normalization on immunohistochemistry was identified. In phase II, subjects were randomized to chemotherapy alone or chemotherapy plus sunitinib at the recommended phase II dose (RP2D). Primary endpoint was pathological complete response (pCR) rate. Tumor and functional imaging biomarkers were evaluated serially. RESULTS: In phase Ib (n=9), sunitinib 12.5 mg daily for 7 days before each chemotherapy was established as RP2D. In phase II, patients receiving chemotherapy plus sunitinib (n=24) had similar pCR rates (5.0% versus 4.3%, p=1.00), but a higher incidence of chemotherapy dose delays (33.3% versus 8.7%, p=0.04), compared to those receiving chemotherapy alone (n=25). The addition of sunitinib to chemotherapy significantly increased vascular normalization index (VNI) and decreased lymphatic vessel density (D2-40) on immunohistochemistry [VNI:25.50±27.94% versus 49.29±31.84%, p=0.034; D2-40:3.29±2.70 versus 1.29±1.54, p=0.014, baseline versus post-cycle 1], and improved perfusion on DCE-MRI (Ktrans:12.6±9.6 mL/100 g/min versus 16.3±10.7 mL/100 g/min, baseline versus post-cycle 1, p=0.015). Conversely, immunohistochemical and DCE-MRI parameters were not significantly altered by chemotherapy alone. CONCLUSION: Low-dose, short-course sunitinib prior to anthracycline-based chemotherapy in breast cancer patients did not improve pCR and increased chemotherapy dose delays. However, the addition of sunitinib induced compelling pharmacodynamic evidence of vascular normalization. Further studies with alternative cytotoxic regimens should be explored.

High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer.

We studied the changes of intratumoral stromal proteins including THBS1, TNC, FN, SPARC and α-SMA, following neoadjuvant chemotherapy. The underlying mechanisms by which THBS1 and TNC regulated resistance to docetaxel were further studied using functional studies. 100 patients with newly diagnosed breast cancer were treated with alternating sequential doxorubicin and docetaxel. Immunohistochemistry (IHC) staining for stromal proteins was performed on pre- and post-treatment core biopsies respectively. THBS1 and TNC were further validated with IHC in an independent cohort of 31 patients. A high baseline combined expression score of the 5 stromal proteins predicted independently for poor progression-free (HRadjusted 2.22, 95% CI 1.06-4.64) and overall survival (HRadjusted 5.94, 95% CI 2.25-15.71). After 1-2 cycles of chemotherapy, increased expression of THBS1, TNC, FN, SPARC and α-SMA was seen in patients with subsequent pathological lymph node involvement at surgery. Increased expression of THBS1 and TNC compared to baseline was also seen in intrinsically resistant tumors, but not in sensitive ones. Both THBS1 and TNC-associated chemoresistance were confirmed in an independent validation cohort. Exogenous THBS1 and TNC protected MCF-7 cells against proliferation inhibition induced by docetaxel through activating integrin ß1/mTOR pathway. Thus, up-regulation of THBS1, TNC, FN, SPARC and α-SMA following neoadjuvant chemotherapy was associated with chemotherapy resistance in breast cancer patients. Functional studies showed THBS1 and TNC to mediate chemoresistance through the integrin ß1/mTOR pathway, suggesting that therapies targeting integrin ß1/mTOR pathway may be a promising strategy to overcome chemotherapy resistance.

Current Status of the Management of Hereditary Breast and Ovarian Cancer in Asia: First Report by the Asian BRCA Consortium.

BACKGROUND: BRCA1/BRCA2 mutations are associated with an increased lifetime risk for hereditary breast and ovarian cancer (HBOC). Compared with the Western developed countries, genetic testing and risk assessment for HBOC in Asia are less available, thus prohibiting the appropriate surveillance, clinical strategies and cancer management. METHODS: The current status of HBOC management in 14 Asian countries, including genetic counselling/testing uptakes and clinical management options, was reviewed. We analysed how economic factors, healthcare and legal frameworks, and cultural issues affect the genetic service availability in Asia. RESULTS: In 2012, only an estimated 4,000 breast cancer cases from 14 Asian countries have benefited from genetic services. Genetic testing costs and the absence of their adoption into national healthcare systems are the main economic barriers for approaching genetic services. Training programmes, regional accredited laboratories and healthcare professionals are not readily available in most of the studied countries. A lack of legal frameworks against genetic discrimination and a lack of public awareness of cancer risk assessment also provide challenges to HBOC management in Asia. CONCLUSIONS: The Asian BRCA Consortium reports the current disparities in genetic services for HBOC in Asia and urges the policy makers, healthcare sectors and researchers to address the limitations in HBOC management.

High-Throughput Mutation Profiling Changes before and 3 Weeks after Chemotherapy in Newly Diagnosed Breast Cancer Patients.

BACKGROUND: Changes in tumor DNA mutation status during chemotherapy can provide insights into tumor biology and drug resistance. The purpose of this study is to analyse the presence or absence of mutations in cancer-related genes using baseline breast tumor samples and those obtained after exposure to one cycle of chemotherapy to determine if any differences exist, and to correlate these differences with clinical and pathological features. METHODS: Paired breast tumor core biopsies obtained pre- and post-first cycle doxorubicin (n = 18) or docetaxel (n = 22) in treatment-naïve breast cancer patients were analysed for 238 mutations in 19 cancer-related genes by the Sequenom Oncocarta assay. RESULTS: Median age of patients was 48 years (range 32-64); 55% had estrogen receptor-positive tumors, and 60% had tumor reduction ≥25% after cycle 1. Mutations were detected in 10/40 (25%) pre-treatment and 11/40 (28%) post-treatment samples. Four mutation pattern categories were identified based on tumor mutation status pre- → post-treatment: wildtype (WT)→WT, n = 24; mutant (MT)→MT, n = 5; MT→WT, n = 5; WT→MT, n = 6. Overall, the majority of tumors were WT at baseline (30/40, 75%), of which 6/30 (20%) acquired new mutations after chemotherapy. Pre-treatment mutations were predominantly in PIK3CA (8/10, 80%), while post-treatment mutations were distributed in PIK3CA, EGFR, PDGFRA, ABL1 and MET. All 6 WT→MT cases were treated with docetaxel. Higher mutant allele frequency in baseline MT tumors (n = 10; PIK3CA mutations n = 8) correlated with less tumor reduction after cycle 1 chemotherapy (R = -0.667, p = 0.035). No other associations were observed between mutation pattern category with treatment, clinicopathological features, and tumor response or survival. CONCLUSION: Tumor mutational profiles can change as quickly as after one cycle of chemotherapy in breast cancer. Understanding of these changes can provide insights on potential therapeutic options in residual resistant tumors. TRIAL REGISTRATION: ClinicalTrials.gov NCT00212082.

Genomic landscapes of breast fibroepithelial tumors.

Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications.

HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population.

Histone deacetylases (HDACs) are enzymes involved in transcriptional repression. We aimed to examine the significance of HDAC1 and HDAC2 gene expression in the prediction of recurrence and survival in 156 patients with hepatocellular carcinoma (HCC) among a South East Asian population who underwent curative surgical resection in Singapore. We found that HDAC1 and HDAC2 were upregulated in the majority of HCC tissues. The presence of HDAC1 in tumor tissues was correlated with poor tumor differentiation. Notably, HDAC1 expression in adjacent non-tumor hepatic tissues was correlated with the presence of satellite nodules and multiple lesions, suggesting that HDAC1 upregulation within the field of HCC may contribute to tumor spread. Using competing risk regression analysis, we found that increased cancer-specific mortality was significantly associated with HDAC2 expression. Mortality was also increased with high HDAC1 expression. In the liver cancer cell lines, HEP3B, HEPG2, PLC5, and a colorectal cancer cell line, HCT116, the combined knockdown of HDAC1 and HDAC2 increased cell death and reduced cell proliferation as well as colony formation. In contrast, knockdown of either HDAC1 or HDAC2 alone had minimal effects on cell death and proliferation. Taken together, our study suggests that both HDAC1 and HDAC2 exert pro-survival effects in HCC cells, and the combination of isoform-specific HDAC inhibitors against both HDACs may be effective in targeting HCC to reduce mortality.

Breast cancer in South East Asia: comparison of presentation and outcome between a middle income and a high income country.

BACKGROUND: There are large differences in socio-economic growth within the region of South East Asia, leading to sharp contrasts in health-systems development between countries. This study compares breast cancer presentation and outcome between patients from a high income country (Singapore) and a middle income country (Malaysia) in South East Asia. METHODS: Within the Singapore Malaysia Breast Cancer Registry we identified all consecutive patients diagnosed with breast cancer between 1993 and 2007 at the National University Hospital in Singapore (high income country, n=2,141) and the University of Malaya Medical Center in Kuala Lumpur, Malaysia (middle income country, n=3,320). We compared demographics, tumor characteristics, treatment patterns, and survival between patients from both countries. RESULTS: In Malaysia, patients were less often diagnosed with in situ breast cancer (adjusted odds ratio [ORadj] 0.2; 95% confidence interval [95% CI] 0.1-0.3), more likely to be diagnosed with late stage (III and IV) disease (ORadj for stage III 1.6; 95% CI 1.3-2.0; ORadj for stage IV 1.2; 95% CI 1.1-1.4) as compared to patients from Singapore. Univariate analysis showed that Malaysian patients were at a 72% increased risk of death as compared to Singaporeans. After adjusting for other prognostic factors, the risk decreased by only 5% (ORadj 1.67, 95% CI 1.44-1.92). CONCLUSIONS: Differences in way of presentation (except stage and tumor size) and treatment of breast cancer patients from the two countries are small. The overall survival of breast cancer patients from Malaysia is much lower than that of Singaporean patients.