Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.

Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.

Challenges, experiences, and potential supports for East and Southeast Asian mothers in the workforce: a systematic review.

OBJECTIVE: To examine the challenges faced by Asian working mothers with a focus on re-entry to the workplace. In addition, we highlight potential supports that retain women in the workforce. DESIGN: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and registered with PROSPERO database (CRD42022341130). METHODS: Three independent reviewers were involved in the study selection to screen the search results sequentially by title, abstract, and full text using predefined inclusion and exclusion criteria. The methodological quality of each article was assessed via the Critical Appraisal Skills Programme (CASP) tool. RESULTS: We analysed a total of 36 studies conducted across different regions: 30 from the East and 6 from Southeast Asia. Among these studies, 20 were quantitative in nature, 15 were qualitative, and one intervention. The 36 studies cover five themes: 1) policies, 2) external support sources, 3) external pressure, 4) breastfeeding and 5) health status. Within each theme the same factor can have a positive or negative impact on the mother depending on her having a pro-career or pro-family mindset. Companies can take various initiatives to support working mothers, such as providing facilities for expressing breast milk at the workplace, educating staff to promote breastfeeding and accommodate childcare needs, and extending maternity leaves. However, there is a lack of literature that directly addresses the barriers and concrete support available to working mothers in Asia, beyond the scope of breastfeeding. CONCLUSIONS: Our findings underscore several obstacles that can impede a woman's seamless return to work. Pro-family and pro-career mothers have differing needs that cannot be addressed at the same time. There is a lack of comprehensive understanding regarding effective strategies or interventions that can support a positive reintegration into the workforce.

Genomic Insights into Idiopathic Granulomatous Mastitis through Whole-Exome Sequencing: A Case Report of Eight Patients.

Idiopathic granulomatous mastitis (IGM) is a rare condition characterised by chronic inflammation and granuloma formation in the breast. The aetiology of IGM is unclear. By focusing on the protein-coding regions of the genome, where most disease-related mutations often occur, whole-exome sequencing (WES) is a powerful approach for investigating rare and complex conditions, like IGM. We report WES results on paired blood and tissue samples from eight IGM patients. Samples were processed using standard genomic protocols. Somatic variants were called with two analytical pipelines: nf-core/sarek with Strelka2 and GATK4 with Mutect2. Our WES study of eight patients did not find evidence supporting a clear genetic component. The discrepancies between variant calling algorithms, along with the considerable genetic heterogeneity observed amongst the eight IGM cases, indicate that common genetic drivers are not readily identifiable. With only three genes, CHIT1, CEP170, and CTR9, recurrently altering in multiple cases, the genetic basis of IGM remains uncertain. The absence of validation for somatic variants by Sanger sequencing raises further questions about the role of genetic mutations in the disease. Other potential contributors to the disease should be explored.

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.

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.

Profiling Microbial Communities in Idiopathic Granulomatous Mastitis.

Idiopathic granulomatous mastitis (IGM) is a rare and benign inflammatory breast disease with ambiguous aetiology. Contrastingly, lactational mastitis (LM) is commonly diagnosed in breastfeeding women. To investigate IGM aetiology, we profiled the microbial flora of pus and skin in patients with IGM and LM. A total of 26 patients with IGM and 6 patients with LM were included in the study. The 16S rRNA sequencing libraries were constructed from 16S rRNA gene amplified from total DNA extracted from pus and skin swabs in patients with IGM and LM controls. Constructed libraries were multiplexed and paired-end sequenced on HiSeq4000. Metagenomic analysis was conducted using modified microbiome abundance analysis suite customised R-resource for paired pus and skin samples. Microbiome multivariable association analyses were performed using linear models. A total of 21 IGM and 3 LM paired pus and skin samples underwent metagenomic analysis. Bray−Curtis ecological dissimilarity distance showed dissimilarity across four sample types (IGM pus, IGM skin, LM pus, and LM skin; PERMANOVA, p < 0.001). No characteristic dominant genus was observed across the IGM samples. The IGM pus samples were more diverse than corresponding IGM skin samples (Shannon and Simpson index; Wilcoxon paired signed-rank tests, p = 0.022 and p = 0.07). Corynebacterium kroppenstedtii, reportedly associated with IGM in the literature, was higher in IGM pus samples than paired skin samples (Wilcoxon, p = 0.022). Three other species and nineteen genera were statistically significant in paired IGM pus−skin comparison after antibiotic treatment adjustment and multiple comparisons correction. Microbial profiles are unique between patients with IGM and LM. Inter-patient variability and polymicrobial IGM pus samples cannot implicate specific genus or species as an infectious cause for IGM.

Mammography screening is associated with more favourable breast cancer tumour characteristics and better overall survival: case-only analysis of 3739 Asian breast cancer patients.

BACKGROUND: Early detection of breast cancer (BC) through mammography screening (MAM) is known to reduce mortality. We examined the differential effect that mammography has on BC characteristics and overall survival and the sociodemographic determinants of MAM utilization in a multi-ethnic Asian population. METHODS: This study included 3739 BC patients from the Singapore Breast Cancer Cohort (2010-2018). Self-reported sociodemographic characteristics were collected using a structured questionnaire. Clinical data were obtained through medical records. Patients were classified as screeners (last screening mammogram ≤ 2 years before diagnosis), non-screeners (aware but did not attend or last screen > 2years), and those unaware of MAM. Associations between MAM behaviour (MB) and sociodemographic factors and MB and tumour characteristics were examined using multinomial regression. Ten-year overall survival was modelled using Cox regression. RESULTS: Patients unaware of screening were more likely diagnosed with late stage (ORstage III vs stage I (Ref) [95% CI]: 4.94 [3.45-7.07], p < 0.001), high grade (ORpoorly vs well-differentiated (reference): 1.53 [1.06-2.20], p = 0.022), nodal-positive, large size (OR>5cm vs ≤2cm (reference): 5.06 [3.10-8.25], p < 0.001), and HER2-positive tumours (ORHER2-negative vs HER2-positive (reference): 0.72 [0.53-0.97], p = 0.028). Similar trends were observed between screeners and non-screeners with smaller effect sizes. Overall survival was significantly shorter than screeners in the both groups (HRnon-screeners: 1.89 [1.22-2.94], p = 0.005; HRunaware: 2.90 [1.69-4.98], p < 0.001). Non-screeners and those unaware were less health conscious, older, of Malay ethnicity, less highly educated, of lower socioeconomic status, more frequently ever smokers, and less physically active. Among screeners, there were more reported personal histories of benign breast surgeries or gynaecological conditions and positive family history of breast cancer. CONCLUSIONS: Mammography attendance is associated with more favourable BC characteristics and overall survival. Disparities in the utility of MAM services suggest that different strategies may be needed to improve MAM uptake.

Overlap of high-risk individuals predicted by family history, and genetic and non-genetic breast cancer risk prediction models: implications for risk stratification.

BACKGROUND: Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear. METHODS: In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%. RESULTS: Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history. CONCLUSIONS: Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk.

Polygenic risk scores for prediction of breast cancer risk in Asian populations.

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

DNA methylation and breast cancer-associated variants.

BACKGROUND: A breast cancer polygenic risk score (PRS) comprising 313 common variants reliably predicts disease risk. We examined possible relationships between genetic variation, regulation, and expression to clarify the molecular alterations associated with these variants. METHODS: Genome-wide methylomic variation was quantified (MethylationEPIC) in Asian breast cancer patients (1152 buffy coats from peripheral whole blood). DNA methylation (DNAm) quantitative trait loci (mQTL) mapping was performed for 235 of the 313 variants with minor allele frequencies > 5%. Stability of identified mQTLs (p < 5e-8) across lifetime was examined using a public mQTL database. Identified mQTLs were also mapped to expression quantitative trait loci (eQTLs) in the Genotype-Tissue Expression Project and the eQTLGen Consortium. RESULTS: Breast cancer PRS was not associated with DNAm. A higher proportion of significant cis-mQTLs were observed. Of 822 significant cis-mQTLs (179 unique variants) identified in our dataset, 141 (59 unique variants) were significant (p < 5e-8) in a public mQTL database. Eighty-six percent (121/141) of the matched mQTLs were consistent at multiple time points (birth, childhood, adolescence, pregnancy, middle age, post-diagnosis, or treatment). Ninety-three variants associated with DNAm were also cis-eQTLs (35 variants not genome-wide significant). Multiple loci in the breast cancer PRS are associated with DNAm, contributing to the polygenic nature of the disease. These mQTLs are mostly stable over time. CONCLUSIONS: Consistent results from DNAm and expression data may reveal new candidate genes not previously associated with breast cancer.

Robust estimation of the effect of an exposure on the change in a continuous outcome.

BACKGROUND: The change in two measurements of a continuous outcome can be modelled directly with a linear regression model, or indirectly with a random effects model (REM) of the individual measurements. These methods are susceptible to model misspecifications, which are commonly addressed by applying monotonic transformations (e.g., Box-Cox transformation) to the outcomes. However, transforming the outcomes complicates the data analysis, especially when variable selection is involved. We propose a robust alternative through a novel application of the conditional probit (cprobit) model. METHODS: The cprobit model analyzes the ordered outcomes within each subject, making the estimate invariant to monotonic transformation on the outcome. By scaling the estimate from the cprobit model, we obtain the exposure effect on the change in the observed or Box-Cox transformed outcome, pending the adequacy of the normality assumption on the raw or transformed scale. RESULTS: Using simulated data, we demonstrated a similar good performance of the cprobit model and REM with and without transformation, except for some bias from both methods when the Box-Cox transformation was applied to scenarios with small sample size and strong effects. Only the cprobit model was robust to skewed subject-specific intercept terms when a Box-Cox transformation was used. Using two real datasets from the breast cancer and inpatient glycemic variability studies which utilize electronic medical records, we illustrated the application of our proposed robust approach as a seamless three-step workflow that facilitates the use of Box-Cox transformation to address non-normality with a common underlying model. CONCLUSIONS: The cprobit model provides a seamless and robust inference on the change in continuous outcomes, and its three-step workflow is implemented in an R package for easy accessibility.

Associations between workability and patient-reported physical, psychological and social outcomes in breast cancer survivors: a cross-sectional study.

PURPOSE: Workability is of increasing importance especially in Asia given the increasing incidence rates and young age of onset of breast cancer. This study explores the determinants of employment and suboptimal workability. And evaluate the association between workability and patient-reported physical, psychological, and social outcomes. METHODS: In a hospital-based cross-sectional study, 327 breast cancer survivors, < 65 years of age and > 1 year post-diagnosis were recruited. Employed survivors filled out the workability index, which measures a person's capacity to meet work demands in relation to current health status. The EORTC-QLQ-C30, EORTC-QLQ-BR23, hospital anxiety and depression scale, multidimensional fatigue inventory, and brief pain index were administered. Fisher's exact test and Kruskal-Wallis test were used to test for associations of workability and employment status with demographic, clinical characteristics, and patient-reported outcomes. Linear models with standardised scores for patient-reported outcomes were fitted to study the associations of workability with patient-reported outcomes. RESULTS: Of the 327 survivors, < 65 years of age (working age), 140 (43%) were in full-time and 34 (10%) in part-time employment. Employed survivors were younger at time of diagnosis and at time of survey. Employment status was not associated with time since diagnosis, ethnicity, or clinical characteristics. Suboptimal workability was present in 37% of employed survivors of the working age, and more common in jobs that include physical work activities. Higher level of depression, financial difficulty and physical fatigue, more breast symptoms, and poorer global health status were independently associated with poorer workability. CONCLUSIONS: Lower employment and reduced workability in breast cancer survivors is common, and reduced workability is associated with higher levels of depression, financial difficulty and physical fatigue, more breast symptoms, and poorer global health status. Longitudinal research on psychosocial support with workability in Asia may find tailored approach to improve or maintain workability in employed breast cancer patients.

A meta-analysis of idiopathic granulomatous mastitis treatments for remission and recurrence prevention.

Purpose: The major aim of our meta-analysis was to review the effectiveness of various treatment modalities for achieving successful remission and preventing recurrence for women with idiopathic granulomatous mastitis (IGM). This knowledge is instrumental in developing evidence-based guidelines for clinicians to improve management strategies and outcomes for patients with IGM. Methods: A systematic literature search was performed on MEDLINE (Ovid), Embase (Elsevier), PubMed, Cochrane Library, Web of Science, and Google Scholar; studies published to 19 January 2022 were included. A meta-analysis of 57 observational studies was performed. The results of two randomized controlled trials were also examined. Results: There were 3,035 IGM patients across the observational and randomised studies. Overall recurrence and remission rates across all treatment strategies in 59 studies are 87.9% (2,667/3035) and 13.5% (359/2667), respectively. The studies reported 19 different treatment strategies, comprising observation, medical monotherapies, surgery, and combinations involving medical therapies, with and without surgery. Among monotherapy treatment, surgical management had the highest pooled remission rate (0.99 [95% confidence interval (CI) = 0.97-1.00]); among combination therapy, this was steroids and surgery (0.99 [0.94-1.00]). Antibiotic monotherapy had the lowest remission rate (0.72 [0.37-0.96]). The highest recurrence rates belonged to treatments that combined antibiotics and surgery (0.54 [0.02-1.00]), and antibiotics, steroids, and surgery (0.57 [0.00-1.00]). Most successful for preventing recurrence were observation (0.03 [0.00-0.10]), methotrexate (0.08 [0.00-0.24]), and steroids and surgery (0.05 [0.01-0.12]). There is a significant association between longer follow-up duration and recurrence rate reported, p = 0.002. Conclusion: Combination therapies, especially those incorporating antibiotics, steroids, and surgery, have demonstrated higher remission rates, challenging the use of antibiotic monotherapy. There is an increased emphasis on the need for personalised, multi-pronged approach for preventing IGM recurrence, with longer follow-up care. More prospective future work in IGM research, with standardised diagnostic criteria, treatment protocols, and reporting guidelines will be important for developing treatment protocols and guidelines clinicians can adhere to in the clinical management of IGM patients.Systematic review registration: PROSPERO (CRD42022301386).

Current approaches to diagnosing and treating idiopathic granulomatous mastitis: A summary from in-depth clinician interviews.

Background: Idiopathic granulomatous mastitis (IGM) is a rare, chronic inflammatory breast condition primarily affecting women of reproductive age. Its diagnosis is challenging due to similarities with other breast disorders, necessitating exclusion of other granulomatous diseases. The management of IGM remains inconsistent and unclear, with high recurrence rates and varying practices. Methods: This qualitative study involved semi-structured interviews with nine clinicians from Singapore, Malaysia, and Egypt to examine current diagnostic and therapeutic approaches for IGM. Transcripts were analysed using NVivo software for coding and summarisation. Findings: Clinicians predominantly used imaging and histopathology for diagnosis. Treatment commonly involved corticosteroids, though dosages and tapering regimens varied widely. Methotrexate was used sparingly for refractory cases due to associated risks. Surgical interventions were infrequent, reflecting a preference for medical management. There was a consensus on the need for randomised controlled trials (RCTs) to establish standardised treatment protocols. Interpretation: This study reveals the complex nature of IGM diagnosis and treatment from clinicians in Singapore, Malaysia and Egypt. This underscores the need for more specific and definitive diagnostic tests, rather than relying on exclusionary methods, and standardised treatment guidelines. Multi-centre RCTs are essential for developing evidence-based protocols to improve patient outcomes and address regional differences effectively.

Characterizing the Relationship between Expression Quantitative Trait Loci (eQTLs), DNA Methylation Quantitative Trait Loci (mQTLs), and Breast Cancer Risk Variants.

PURPOSE: To assess the association of a polygenic risk score (PRS) for functional genetic variants with the risk of developing breast cancer. METHODS: Summary data-based Mendelian randomization (SMR) and heterogeneity in dependent instruments (HEIDI) were used to identify breast cancer risk variants associated with gene expression and DNA methylation levels. A new SMR-based PRS was computed from the identified variants (functional PRS) and compared to an established 313-variant breast cancer PRS (GWAS PRS). The two scores were evaluated in 3560 breast cancer cases and 3383 non-cancer controls and also in a prospective study (n = 10,213) comprising 418 cases. RESULTS: We identified 149 variants showing pleiotropic association with breast cancer risk (eQTLHEIDI > 0.05 = 9, mQTLHEIDI > 0.05 = 165). The discriminatory ability of the functional PRS (AUCcontinuous [95% CI]: 0.540 [0.526 to 0.553]) was found to be lower than that of the GWAS PRS (AUCcontinuous [95% CI]: 0.609 [0.596 to 0.622]). Even when utilizing 457 distinct variants from both the functional and GWAS PRS, the combined discriminatory performance remained below that of the GWAS PRS (AUCcontinuous, combined [95% CI]: 0.561 [0.548 to 0.575]). A binary high/low-risk classification based on the 80th centile PRS in controls revealed a 6% increase in cases using the GWAS PRS compared to the functional PRS. The functional PRS identified an additional 12% of high-risk cases but also led to a 13% increase in high-risk classification among controls. Similar findings were observed in the SCHS prospective cohort, where the GWAS PRS outperformed the functional PRS, and the highest-performing PRS, a combined model, did not significantly improve over the GWAS PRS. CONCLUSIONS: While this study identified potentially functional variants associated with breast cancer risk, their inclusion did not substantially enhance the predictive accuracy of the GWAS PRS.

Feasibility of monitoring Global Breast Cancer Initiative Framework key performance indicators in 21 Asian National Cancer Centers Alliance member countries.

Background: The Global Breast Cancer Initiative (GBCI) Framework, launched by the World Health Organisation (WHO) in 2023, emphasises assessing, strengthening, and scaling up services for the early detection and management of breast cancer. This study aims to determine the feasibility of monitoring the status of breast cancer control in the 21 Asian National Cancer Centers Alliance (ANCCA) countries based on the three GBCI Framework key performance indicators (KPIs): stage at diagnosis, time to diagnosis, and treatment completion. Methods: We reviewed published literature on breast cancer control among 21 ANCCA countries from May to July 2023 to establish data availability and compiled the latest descriptive statistics and sources of the indicators using a standardised data collection form. We performed bivariate Pearson's correlation analysis to measure the strength of correlation between stage at diagnosis, mortality and survival rates, and universal health coverage. Findings: Only 12 (57%) ANCCA member countries published national cancer registry reports on breast cancer age-standardised incidence rate (ASIR) and age-standardised mortality rate (ASMR). Indonesia, Myanmar, and Nepal had provincial data and others relied on WHO's Global Cancer Observatory (GLOBOCAN) estimates. GLOBOCAN data differed from the reported national statistics by 5-10% in Bhutan, Indonesia, Iran, the Republic of Korea, Singapore, and Thailand and >10% in China, India, Malaysia, Mongolia, and Sri Lanka. The proportion of patients diagnosed in stages I and II strongly correlated with the five-year survival rate and with the universal health coverage (UHC) index. Three countries (14%) reported national data with >60% of invasive breast cancer patients diagnosed at stages I and II, and a five-year survival rate of >80%. Over 60% of the ANCCA countries had no published national data on breast cancer staging, the time interval from presentation to diagnosis, and diagnosis to treatment. Five (24%) countries reported data on treatment completion. The definition of delayed diagnosis and treatment completion varied across countries. Interpretation: GBCI's Pillar 1 KPI correlates strongly with five-year survival rate and with the UHC index. Most ANCCA countries lacked national data on cancer staging, timely diagnosis, and treatment completion KPIs. While institutional-level data were available in some countries, they may not represent the nationwide status. Strengthening cancer surveillance is crucial for effective breast cancer control. The GBCI Framework indicators warrant more detailed definitions for standardised data collection. Surrogate indicators which are measurable and manageable in country-specific settings, could be considered for monitoring GBCI indicators. Ensuring UHC and addressing health inequalities are essential to early diagnosis and treatment of breast cancer. Funding: Funding for this research article's processing fee (APC) will be provided by the affiliated institution to support the open-access publication of this work. The funding body is not involved in the study design; collection, management, analysis and interpretation of data; or the decision to submit for publication. The funding body will be informed of any planned publications, and documentation provided.

Age-specific breast and ovarian cancer risks associated with germline BRCA1 or BRCA2 pathogenic variants - an Asian study of 572 families.

Background: Clinical management of Asian BRCA1 and BRCA2 pathogenic variants (PV) carriers remains challenging due to imprecise age-specific breast (BC) and ovarian cancer (OC) risks estimates. We aimed to refine these estimates using six multi-ethnic studies in Asia. Methods: Data were collected on 271 BRCA1 and 301 BRCA2 families from Malaysia and Singapore, ascertained through population/hospital-based case-series (88%) and genetic clinics (12%). Age-specific cancer risks were estimated using a modified segregation analysis method, adjusted for ascertainment. Findings: BC and OC relative risks (RRs) varied across age groups for both BRCA1 and BRCA2. The age-specific RR estimates were similar across ethnicities and country of residence. For BRCA1 carriers of Malay, Indian and Chinese ancestry born between 1950 and 1959 in Malaysia, the cumulative risk (95% CI) of BC by age 80 was 40% (36%-44%), 49% (44%-53%) and 55% (51%-60%), respectively. The corresponding estimates for BRCA2 were 29% (26-32%), 36% (33%-40%) and 42% (38%-45%). The corresponding cumulative BC risks for Singapore residents from the same birth cohort, where the underlying population cancer incidences are higher compared to Malaysia, were higher, varying by ancestry group between 57 and 61% for BRCA1, and between 43 and 47% for BRCA2 carriers. The cumulative risk of OC by age 80 was 31% (27-36%) for BRCA1 and 12% (10%-15%) for BRCA2 carriers in Malaysia born between 1950 and 1959; and 42% (34-50%) for BRCA1 and 20% (14-27%) for BRCA2 carriers of the same birth cohort in Singapore. There was evidence of increased BC and OC risks for women from >1960 birth cohorts (p-value = 3.6 × 10-5 for BRCA1 and 0.018 for BRCA2). Interpretation: The absolute age-specific cancer risks of Asian carriers vary depending on the underlying population-specific cancer incidences, and hence should be customised to allow for more accurate cancer risk management. Funding: Wellcome Trust [grant no: v203477/Z/16/Z]; CRUK (PPRPGM-Nov20∖100002).

Polygenic risk scores for the prediction of common cancers in East Asians: A population-based prospective cohort study.

Background: To evaluate the utility of polygenic risk scores (PRSs) in identifying high-risk individuals, different publicly available PRSs for breast (n=85), prostate (n=37), colorectal (n=22), and lung cancers (n=11) were examined in a prospective study of 21,694 Chinese adults. Methods: We constructed PRS using weights curated in the online PGS Catalog. PRS performance was evaluated by distribution, discrimination, predictive ability, and calibration. Hazard ratios (HR) and corresponding confidence intervals (CI) of the common cancers after 20 years of follow-up were estimated using Cox proportional hazard models for different levels of PRS. Results: A total of 495 breast, 308 prostate, 332 female-colorectal, 409 male-colorectal, 181 female-lung, and 381 male-lung incident cancers were identified. The area under receiver operating characteristic curve for the best-performing site-specific PRS were 0.61 (PGS000873, breast), 0.70 (PGS00662, prostate), 0.65 (PGS000055, female-colorectal), 0.60 (PGS000734, male-colorectal), 0.56 (PGS000721, female-lung), and 0.58 (PGS000070, male-lung), respectively. Compared to the middle quintile, individuals in the highest cancer-specific PRS quintile were 64% more likely to develop cancers of the breast, prostate, and colorectal. For lung cancer, the lowest cancer-specific PRS quintile was associated with 28-34% decreased risk compared to the middle quintile. In contrast, the HR observed for quintiles 4 (female-lung: 0.95 [0.61-1.47]; male-lung: 1.14 [0.82-1.57]) and 5 (female-lung: 0.95 [0.61-1.47]) were not significantly different from that for the middle quintile. Conclusions: Site-specific PRSs can stratify the risk of developing breast, prostate, and colorectal cancers in this East Asian population. Appropriate correction factors may be required to improve calibration. Funding: This work is supported by the National Research Foundation Singapore (NRF-NRFF2017-02), PRECISION Health Research, Singapore (PRECISE) and the Agency for Science, Technology and Research (A*STAR). WP Koh was supported by National Medical Research Council, Singapore (NMRC/CSA/0055/2013). CC Khor was supported by National Research Foundation Singapore (NRF-NRFI2018-01). Rajkumar Dorajoo received a grant from the Agency for Science, Technology and Research Career Development Award (A*STAR CDA - 202D8090), and from Ministry of Health Healthy Longevity Catalyst Award (HLCA20Jan-0022).The Singapore Chinese Health Study was supported by grants from the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016) and the U.S. National Institutes of Health (NIH) (R01 CA144034 and UM1 CA182876).

Although humans contain the same genes, the sequence within these DNA sites can vary from person to person. These small variations, also known as genetic variants, can increase the risk of developing certain diseases. While each variant will only have a weak effect, if multiple variations are present the odds of developing the disease becomes significantly higher. To determine which variants are linked to a disease, researchers carry out genome-wide association studies which involve analyzing the genomes of individuals with and without the condition and comparing their genetic codes. This data is then used to calculate how different combinations of variants impact a person's chance of getting the disease, also known as a polygenic risk score. Currently, most genome-wide association studies only incorporate genetic data from people with European ancestry. Consequently, polygenic risk scores performed using this information may not accurately predict the risk of developing the disease for individuals with other ethnicities, such as people with Asian ancestry. Here, Ho et al. evaluated how well previously calculated polygenic risk scores for the four most common cancers (breast, colorectal, prostate and lung) worked on individuals of East Asian descent. The scores were tested on a dataset containing the genetic sequence, medical history, diet and activity levels of over 21,000 people living in Singapore in the 1990s. Ho et al. found that the polygenic risk scores for breast, prostate and colorectal cancer were able to predict disease risk. However, the score for lung cancer did not perform as well. The polygenic risk score for breast cancer was the most accurate, and was able to stratify individuals into distinct risk bands at an earlier age than other scores. These findings shed light on which existing polygenic risk scores will be effective at assessing cancer risk in individuals with East Asian ancestry. Indeed, Ho et al. have already incorporated the polygenic risk score for breast cancer into a pilot study screening individuals in a comparable population in Singapore. However, the polygenic risk scores tested still performed better on individuals with European ancestry, highlighting the need to address the lack of Asian representation in genome-wide association studies.

Will Absolute Risk Estimation for Time to Next Screen Work for an Asian Mammography Screening Population?

Personalized breast cancer risk profiling has the potential to promote shared decision-making and improve compliance with routine screening. We assessed the Gail model's performance in predicting the short-term (2- and 5-year) and the long-term (10- and 15-year) absolute risks in 28,234 asymptomatic Asian women. Absolute risks were calculated using different relative risk estimates and Breast cancer incidence and mortality rates (White, Asian-American, or the Singapore Asian population). Using linear models, we tested the association of absolute risk and age at breast cancer occurrence. Model discrimination was moderate (AUC range: 0.580-0.628). Calibration was better for longer-term prediction horizons (E/Olong-term ranges: 0.86-1.71; E/Oshort-term ranges:1.24-3.36). Subgroup analyses show that the model underestimates risk in women with breast cancer family history, positive recall status, and prior breast biopsy, and overestimates risk in underweight women. The Gail model absolute risk does not predict the age of breast cancer occurrence. Breast cancer risk prediction tools performed better with population-specific parameters. Two-year absolute risk estimation is attractive for breast cancer screening programs, but the models tested are not suitable for identifying Asian women at increased risk within this short interval.

How Asian Breast Cancer Patients Experience Unequal Incidence of Chemotherapy Side Effects: A Look at Ethnic Disparities in Febrile Neutropenia Rates.

The majority of published findings on chemotherapy-induced febrile neutropenia (FN) are restricted to three ethnic groups: Asians, Caucasians, and African Americans. In this two-part study, we examined FN incidence and risk factors in Chinese, Malay, and Indian chemotherapy-treated breast cancer (BC) patients. Hospital records or ICD codes were used to identify patients with FN. In both the Singapore Breast Cancer Cohort (SGBCC) and the Joint Breast Cancer Registry (JBCR), the time of the first FN from the start of chemotherapy was estimated using Cox regression. Multinomial regression was used to evaluate differences in various characteristics across ethnicities. FN was observed in 170 of 1014 patients in SGBCC. The Cox model showed that non-Chinese were at higher risk of developing FN (HRMalay [95% CI]:2.04 [1.44-2.88], p < 0.001; HRIndian:1.88 [1.11-3.18], p = 0.018). In JBCR, FN was observed in 965 of 7449 patients. Univariable Cox models identified ethnicity, a lower baseline absolute neutrophil count, non-luminal A proxy subtypes, and anthracycline-containing regimens as risk factors. Disparities across ethnicities' risk (HRMalay:1.29 [1.07-1.54], p = 0.006; HRIndian:1.50 [1.19-1.88], p < 0.001) remained significant even after further adjustments. Finally, an age-adjusted multinomial model showed that Malays (p = 0.006) and Indians (p = 0.009) were significantly more likely to develop multiple episodes of FN during treatment. Ethnic differences in chemotherapy-induced FN among BC patients exist. Further studies can focus on investigating pharmacogenetic differences across ethnicities.