Breast cancer risk stratification using genetic and non-genetic risk assessment tools for 246,142 women in the UK Biobank.

PURPOSE: The benefit of using individual risk prediction tools to identify high-risk individuals for breast cancer (BC) screening is uncertain, despite the personalized approach of risk-based screening. METHODS: We studied the overlap of predicted high-risk individuals among 246,142 women enrolled in the UK Biobank. Risk predictors assessed include the Gail model (Gail), BC family history (FH, binary), BC polygenic risk score (PRS), and presence of loss-of-function (LoF) variants in BC predisposition genes. Youden J-index was used to select optimal thresholds for defining high-risk. RESULTS: In total, 147,399 were considered at high risk for developing BC within the next 2 years by at least 1 of the 4 risk prediction tools examined (Gail2-year > 0.5%: 47%, PRS2-yea r > 0.7%: 30%, FH: 6%, and LoF: 1%); 92,851 (38%) were flagged by only 1 risk predictor. The overlap between individuals flagged as high-risk because of genetic (PRS) and Gail model risk factors was 30%. The best-performing combinatorial model comprises a union of high-risk women identified by PRS, FH, and, LoF (AUC2-year [95% CI]: 62.2 [60.8 to 63.6]). Assigning individual weights to each risk prediction tool increased discriminatory ability. CONCLUSION: Risk-based BC screening may require a multipronged approach that includes PRS, predisposition genes, FH, and other recognized risk factors.

Cost effectiveness analysis of a polygenic risk tailored breast cancer screening programme in Singapore.

BACKGROUND: This study aimed to evaluate the cost-effectiveness of a breast cancer screening programme that incorporates genetic testing using breast cancer associated single nucleotide polymorphisms (SNPs), against the current biennial mammogram-only screening programme to aid in its implementation into the current programme in Singapore. METHODS: A Markov model was used to compare the costs and health outcomes of the current screening programme, against a polygenic risk-tailored screening programme, which can advise a long-term screening strategy depending on the individual's polygenic risk. The model took the perspective of the healthcare system, with a time horizon of 40 years, following women from the age of 35 to 74. Epidemiological and cost data were taken from Asian studies, and an annual discount rate of 3% was used. The model outcome was the incremental cost-effectiveness ratio (ICER), calculated from the difference in costs per quality-adjusted life year (QALY). Scenarios with varying risk thresholds for each polygenic risk group were examined. One-way and probabilistic sensitivity analyses were performed to assess parameter uncertainty. RESULTS: The ICER for a polygenic risk-tailored breast cancer screening programme, compared with the current biennial mammogram-only screening programme, was - 3713.80 SGD/QALY, with incremental costs < 0 and incremental effects > 0. The scenario analysis of different polygenic risk cutoffs showed that the ICERs remain negative, with all ICERs falling within the south-east quadrant of the cost-effectiveness plane, indicating that tailored screening is more cost effective than mammogram-only screening, with lower costs and higher QALYs to be gained. This suggests that a polygenic risk-tailored breast cancer screening programme is cost effective, entailing lower cost than the current mammogram-only programme, while causing no additional harm to women. CONCLUSION: Results from this cost-effectiveness analysis show that polygenic risk-tailored screening is cost effective with an ICER of - 3713.80 SGD/QALY. Tailored screening remains cost effective even across varying percentile cutoffs for each risk group. While the results look promising for incorporating polygenic risk into the current breast cancer screening programme, further studies should be conducted to address various limitations.

Cost-effectiveness Analysis of Breast Cancer Screening Using Mammography in Singapore: A Modeling Study.

BACKGROUND: Limited research is available on the cost-effectiveness of breast cancer screening programs in Asian countries. We evaluated the cost-effectiveness of Singapore's national mammography screening program, implemented in 2002, recommending annual screening between ages 40 and 49 and biennial screening between ages 50 and 69, and alternative screening scenarios taking into account important country-specific factors. METHODS: We used national data from Singapore in the MIcrosimulation SCreening ANalysis-Fatal diameter (MISCAN-Fadia) model to simulate 302 screening scenarios for 10 million women born between 1910 and 1969. Screening scenarios varied by starting and ending age, screening interval, and attendance. Outcome measures included life-years gained (LYG), breast cancer deaths averted, false positives, overdiagnosis, quality-adjusted life years (QALY), costs (in 2002 Singapore dollars; S$), and incremental cost-effectiveness ratios (ICER). Costs and effects were calculated and discounted with 3% using a health care provider's perspective. RESULTS: Singapore's current screening program at observed attendance levels required 54,158 mammograms per 100,000 women, yielded 1,054 LYG, and averted 57 breast cancer deaths. At attendance rates ≥50%, the current program was near the efficiency frontier. Most scenarios on the efficiency frontier started screening at age 40. The ICERs of the scenarios on the efficiency frontiers ranged between S$10,186 and S$56,306/QALY, which is considered cost-effective at a willingness-to-pay threshold of S$70,000/QALY gained. CONCLUSIONS: Singapore's current screening program lies near the efficiency frontier, and starting screening at age 40 or 45 is cost-effective. Furthermore, enhancing screening attendance rates would increase benefits while maintaining cost-effectiveness. IMPACT: Screening all women at age 40 or 45 is cost-efficient in Singapore, and a policy change may be considered.

Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population.

OBJECTIVE: An unmet need exists for a non-invasive biomarker assay to aid gastric cancer diagnosis. We aimed to develop a serum microRNA (miRNA) panel for identifying patients with all stages of gastric cancer from a high-risk population. DESIGN: We conducted a three-phase, multicentre study comprising 5248 subjects from Singapore and Korea. Biomarker discovery and verification phases were done through comprehensive serum miRNA profiling and multivariant analysis of 578 miRNA candidates in retrospective cohorts of 682 subjects. A clinical assay was developed and validated in a prospective cohort of 4566 symptomatic subjects who underwent endoscopy. Assay performance was confirmed with histological diagnosis and compared with Helicobacter pylori (HP) serology, serum pepsinogens (PGs), 'ABC' method, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). Cost-effectiveness was analysed using a Markov decision model. RESULTS: We developed a clinical assay for detection of gastric cancer based on a 12-miRNA biomarker panel. The 12-miRNA panel had area under the curve (AUC)=0.93 (95% CI 0.90 to 0.95) and AUC=0.92 (95% CI 0.88 to 0.96) in the discovery and verification cohorts, respectively. In the prospective study, overall sensitivity was 87.0% (95% CI 79.4% to 92.5%) at specificity of 68.4% (95% CI 67.0% to 69.8%). AUC was 0.848 (95% CI 0.81 to 0.88), higher than HP serology (0.635), PG 1/2 ratio (0.641), PG index (0.576), ABC method (0.647), CEA (0.576) and CA19-9 (0.595). The number needed to screen is 489 annually. It is cost-effective for mass screening relative to current practice (incremental cost-effectiveness ratio=US$44 531/quality-of-life year). CONCLUSION: We developed and validated a serum 12-miRNA biomarker assay, which may be a cost-effective risk assessment for gastric cancer. TRIAL REGISTRATION NUMBER: This study is registered with ClinicalTrials.gov (Registration number: NCT04329299).

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.

Factors associated with false-positive mammography at first screen in an Asian population.

INTRODUCTION: False-positive recall is an issue in national screening programmes. The aim of this study is to investigate the recall rate at first screen and to identify potential predictors of false-positive recall in a multi-ethnic Asian population-based breast cancer screening programme. METHODS: Women aged 50-64 years attending screening mammography for the first time (n = 25,318) were included in this study. The associations between potential predictors (sociodemographic, lifestyle and reproductive) and false-positive recall were evaluated using multivariable logistic regression models. RESULTS: The recall rate was 7.6% (n = 1,923), of which with 93.8% were false-positive. Factors independently associated with higher false-positive recall included Indian ethnicity (odds ratio [95% confidence interval]: 1.52 [1.25 to 1.84]), premenopause (1.23 [1.04 to 1.44]), nulliparity (1.85 [1.57 to 2.17]), recent breast symptoms (1.72 [1.31 to 2.23]) and history of breast lump excision (1.87 [1.53 to 2.26]). Factors associated with lower risk of false-positive recall included older age at screen (0.84 [0.73 to 0.97]) and use of oral contraceptives (0.87 [0.78 to 0.97]). After further adjustment of percent mammographic density, associations with older age at screening (0.97 [0.84 to 1.11]) and menopausal status (1.12 [0.95 to 1.32]) were attenuated and no longer significant. CONCLUSION: For every breast cancer identified, 15 women without cancer were subjected to further testing. Efforts to educate Asian women on what it means to be recalled will be useful in reducing unnecessary stress and anxiety.

Health-related quality of life in Asian patients with breast cancer: a systematic review.

OBJECTIVE: To summarise the evidence on determinants of health-related quality of life (HRQL) in Asian patients with breast cancer. DESIGN: Systematic review conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and registered with PROSPERO (CRD42015032468). METHODS: According to the PRISMA guidelines, databases of MEDLINE (PubMed), Embase and PsycINFO were systematically searched using the following terms and synonyms: breast cancer, quality of life and Asia. Articles reporting on HRQL using EORTC-QLQ-C30, EORTC-QLQ-BR23, FACT-G and FACT-B questionnaires in Asian patients with breast cancer were eligible for inclusion. The methodological quality of each article was assessed using the quality assessment scale for cross-sectional studies or the Newcastle-Ottawa Quality Assessment Scale for cohort studies. RESULTS: Fifty-seven articles were selected for this qualitative synthesis, of which 43 (75%) were cross-sectional and 14 (25%) were longitudinal studies. Over 75 different determinants of HRQL were studied with either the EORTC or FACT questionnaires. Patients with comorbidities, treated with chemotherapy, with less social support and with more unmet needs have poorer HRQL. HRQL improves over time. Discordant results in studies were found in the association of age, marital status, household income, type of surgery, radiotherapy and hormone therapy and unmet sexuality needs with poor global health status or overall well-being. CONCLUSIONS: In Asia, patients with breast cancer, in particular those with other comorbidities and those treated with chemotherapy, with less social support and with more unmet needs, have poorer HRQL. Appropriate social support and meeting the needs of patients may improve patients' HRQL.

Breast cancer risk assessment using genetic variants and risk factors in a Singapore Chinese population.

INTRODUCTION: Genetic variants for breast cancer risk identified in genome-wide association studies (GWAS) in Western populations require further testing in Asian populations. A risk assessment model incorporating both validated genetic variants and established risk factors may improve its performance in risk prediction of Asian women. METHODS: A nested case-control study of female breast cancer (411 cases and 1,212 controls) within the Singapore Chinese Health Study was conducted to investigate the effects of 51 genetic variants identified in previous GWAS on breast cancer risk. The independent effect of these genetic variants was assessed by creating a summed genetic risk score (GRS) after adjustment for body mass index and the Gail model risk factors for breast cancer. RESULTS: The GRS was an independent predictor of breast cancer risk in Chinese women. The multivariate-adjusted odds ratios (95% confidence intervals) of breast cancer for the second, third, and fourth quartiles of the GRS were 1.26 (0.90 to 1.76), 1.47 (1.06 to 2.04) and 1.75 (1.27 to 2.41) respectively (P for trend<0.001). In addition to established risk factors, the GRS improved the classification of 6.2% of women for their absolute risk of breast cancer in the next five years. CONCLUSIONS: Genetic variants on top of conventional risk factors can improve the risk prediction of breast cancer in Chinese women.

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.

Molecular epidemiology and its current clinical use in cancer management.

The revelation of the entire human DNA sequence in 2001, and the launching of the international haplotype map (HapMap) project, made the identification of common markers of disease possible, dramatically transforming molecular epidemiology. In recent years, the development of, and discoveries within, human genome research have been rapid, highlighted by the current explosion of genome-wide association studies (GWAS). GWAS aim at finding germline changes that increase cancer risk. An equally important and rapid development had been seen in cancer genomics, with great strides being made in our understanding of somatic mutations that allow and accompany cancer development. In this review we discuss whether it is currently possible to use these new discoveries to aid the reduction of cancer mortality by reducing risk of disease, improving prognosis, and keeping complications due to treatment to a minimum. Findings from GWAS have mostly been used to predict risk, but there is the potential to use them for prognostication and even treatment prediction. Expression arrays have identified prognostic patterns for breast cancer, but few reliable patterns are available for treatment prediction. More importantly, virtually no genetic signatures are available to predict morbidity from treatment. Thus, there is a need to bring different biological techniques together and integrate them with existing clinical oncological care for a simultaneous risk and outcome assessment.