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Background: The incidence of breast cancer among young Asian women is increasing, yet they remain underrepresented in global data. We analyzed the epidemiology and outcomes of Asian patients with breast cancer <40 years old across different subtypes to identify their clinical unmet needs., Patients and Methods: Female patients aged ≥20 years diagnosed with early breast cancer were analyzed from the prospective cohort of the Asian Breast Cancer Cooperative Group (ABCCG). For comparison, data from the Surveillance, Epidemiology, and End Results Program (SEER) cancer registry were used. Patients were categorized into three age groups: young (<40 years), alleged premenopausal mid-age (40-49 years), and alleged postmenopausal (aged ≥50 years). Multivariable Cox proportional hazards models for survival were adjusted for subtypes, histologic grade, T stage, nodal status, and study centers., Results: A total of 45 021 patients with breast cancer from Asian study centers, 496 332 SEER-White patients, and 18 279 SEER-Asian patients were included in the analysis. The median age at diagnosis was younger in the Asian cohort (51 years) compared with SEER-Whites (62 years) and SEER-Asians (58 years; P < 0.0001). In the young-age group, hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer was more prevalent among Asians and SEER-Asians compared with SEER-Whites (61.2% and 59.8% versus 54.7%). In the Asian population, young patients with HR+/HER2- breast cancer exhibited significantly inferior overall survival than the mid-age group (6-year overall survival 94.4% versus 96.6%; mid-age to young-age group hazard ratio 0.62; P < 0.001). Similarly, young patients in SEER-Whites showed an earlier decline in survival compared with the mid-age group (89.1% versus 94.0%; P < 0.001)., Conclusion: ABCCG-Asian patients with breast cancer <40 years old with HR+/HER2- subtypes were more likely to have worse survival outcomes than their mid-age counterparts. Our study highlights the poorer prognosis of young patients and underscores the need for a tailored therapeutic approach, such as ovarian function suppression, particularly considering ethnic factors., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The management of the axilla in breast cancer patients with isolated chest wall recurrence (CWR) after mastectomy remains controversial. Although sentinel lymph node biopsy (SLNB) for restaging is feasible, its role is unclear. We aimed to determine if the omission of axillary restaging surgery in female patients with operable presumably isolated CWRs could result in an increased risk of second recurrences., Methods: In this retrospective multicentre study, patients who developed CWRs were reviewed. We excluded patients with suspected or concomitant regional/distant metastases, bilateral cancers and patients without CWR surgery. Patients' demographics, pathological data and subsequent recurrences were collected from a prospective database and were compared between patients with axillary lymph node dissection (ALND) and/or SLNB versus no axillary operation at CWR., Findings: A total of 194 patients with CWRs were eligible. The median age at CWR was 56.0 (IQR 47.0-67.0) years old. At recurrence, 8 (4.1%), 5 (2.6%) and 181 (93.3%) patients had ALND, SLNB and no axillary operation, respectively. Patients with no axillary surgery during CWR were associated with, at primary cancer, a lower incidence of ductal carcinoma in situ as diagnosis ( p = 0.007) and older age ( p = 0.022). Subsequent ipsilateral axillary ( p = 0.768) and second recurrences ( p = 0.061) were not statistically different between patients with and without axillary surgery at CWR on median follow-up of 59.5 (IQR 27.3-105) months., Interpretation: In patients without evidence of concomitant regional or distant metastasis at CWR diagnosis, omission of axillary restaging surgery was not associated with an increased ipsilateral axillary or second recurrences on long-term follow-up.

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 (eQTL HEIDI > 0.05 = 9, mQTL HEIDI > 0.05 = 165). The discriminatory ability of the functional PRS (AUC continuous [95% CI]: 0.540 [0.526 to 0.553]) was found to be lower than that of the GWAS PRS (AUC continuous [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 (AUC continuous , 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.

Background: Although considered a favorable subtype, pure mucinous breast cancer (PMBC) can recur, and evidence for adjuvant therapy is limited. We aimed to compare outcomes of nonmetastatic PMBC with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) to address these uncertainties., Methods: Individual patient-level data from 6 centers on stage I-III hormone receptor-positive and HER2-negative PMBC, IDC, and ILC were used to analyze recurrence-free interval (RFI), recurrence-free survival (RFS), and overall survival (OS), and to identify prognostic factors for PMBC., Results: Data from 20,684 IDC cases, 1,475 ILC cases, and 943 PMBC cases were used. Median follow-up was 6.6 years. Five-year RFI, RFS, and OS for PMBC were 96.1%, 94.9%, and 98.1%, respectively. On multivariable Cox regression, PMBC demonstrated superior RFI (hazard ratio [HR], 0.59; 95% CI, 0.43-0.80), RFS (HR, 0.70; 95% CI, 0.56-0.89), and OS (HR, 0.71; 95% CI, 0.53-0.96) compared with IDC. ILC showed comparable outcomes to IDC. Fewer than half (48.7%) of recurrences in PMBC were distant, which was a lower rate than for IDC (67.3%) and ILC (80.6%). In contrast to RFI, RFS events were driven more by non-breast cancer deaths in older patients. Significant prognostic factors for RFI among PMBC included positive lymph node(s) (HR, 2.42; 95% CI, 1.08-5.40), radiotherapy (HR, 0.44; 95% CI, 0.23-0.85), and endocrine therapy (HR, 0.25; 95% CI, 0.09-0.70). No differential chemotherapy associations with outcomes were detected across PMBC subgroups by nodal stage, tumor size, and age. A separate SEER database analysis also did not find any association of improved survival with adjuvant chemotherapy in these subgroups., Conclusions: Compared with IDC, PMBC demonstrated superior RFI, RFS, and OS. Lymph node negativity, adjuvant radiotherapy, and endocrine therapy were associated with superior RFI. Adjuvant chemotherapy was not associated with better outcomes.

Competing Interests: None

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 (p paired-samples  = 1.72e-9, p single-timepoint-blood  = 2.03e-15 and p single-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., (© 2023. The Author(s).)

Despite our understanding of the genetic basis of intra-tumoral heterogeneity, the role of stromal heterogeneity arising from an altered tumor microenvironment in affecting tumorigenesis is poorly understood. In particular, extensive study on the peri-tumoral stroma in the morphologically normal tissues surrounding the tumor is lacking. Here, we examine the heterogeneity in tumors and peri-tumoral stroma from 8 ER + /PR + /HER2 - invasive breast carcinomas, through multi-region transcriptomic profiling by microarray. We describe the regional heterogeneity observed at the intrinsic molecular subtype, pathway enrichment, and cell type composition levels within each tumor and its peri-tumoral region, up to 7 cm from the tumor margins. Moreover, we identify a pro-inflammatory adipose-enriched peri-tumoral subtype which was significantly associated with poorer overall survival in breast cancer patients, in contrast to an adaptive immune cell- and myofibroblast-enriched subtype. These data together suggest that peri-tumoral heterogeneity may be an important determinant of the evolution and treatment of breast cancers., (© 2023. Springer Nature Limited.)

This is a case of a tumour that appeared largely unviable after near complete infarction. The lesion presented as a regular shaped mass with cystic appearance lacking definitive malignant radiological signs. Together with the initial non-diagnostic histological result, this could have easily led to a missed diagnosis of cancer., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The COVID-19 pandemic has led to a decrease in cancer screening due to the redeployment of health care resources and public avoidance of health care facilities. Breast cancer is the most common cancer diagnosed in female individuals, with improved survival rates from early detection. An avoidance of screening, resulting in late detection, greatly affects survival and increases health care resource burden and costs., Objective: This study aimed to evaluate if a sustained decrease in public interest in screening occurred and to evaluate other search terms, and hence interest, associated with that., Methods: This study used Google Trends to analyze public interest in breast cancer screening and symptoms. We queried search data for 4 keyword terms ("mammogram," "breast pain," "breast lump," and "nipple discharge") from January 1, 2019, to January 1, 2022. The relative search frequency metric was used to assess interest in these terms, and related queries were retrieved for each keyword to evaluate trends in search patterns., Results: Despite an initial drastic drop in interest in mammography from March to April 2020, this quickly recovered by July 2020. After this period, alongside the recovery of interest in screening, there was a rapid increase in interest for arranging for mammography. Relative search frequencies of perceived breast cancer-related symptoms such as breast lump, nipple discharge, and breast pain remained stable. There was increase public interest in natural and alternative therapy of breast lumps despite the recovery of interest in mammography and breast biopsy. There was a significant correlation between search activity and Breast Cancer Awareness Month in October., Conclusions: Online search interest in breast cancer screening experienced a sharp decline at the beginning of the COVID-19 pandemic, with a subsequent return to baseline interest in arranging for mammography followed this short period of decreased interest., (©Si Ying Tan, Matilda Swee Sun Tang, Chin-Ann Johnny Ong, Veronique Kiak Mien Tan, Nicholas Brian Shannon. Originally published in JMIR Cancer (https://cancer.jmir.org), 06.06.2023.)

Background: Encapsulated papillary carcinoma of the breast is rare, making difficult diagnosis and resulting in patients undergoing excision biopsy before definitive surgery. Evidence-based guidelines are sparse. We would like to further elucidate the clinicopathological, treatment and survival outcomes., Materials and Methods: 54 patients identified, with a median follow up duration of 48 months. Patients' demographics, radiological and clinicopathological characteristics, treatment, adjuvant therapies as well as survival data were analysed., Results: 18 (33.3%) cases were pure EPC, 12 (22.2%) were EPC associated with ductal carcinoma in situ (DCIS) and 24 (44.4%) cases had concurrent invasive ductal carcinoma. EPCs were more likely to present as a solid-cystic mass on sonography (63.8%), regular-shaped (oval or round) (97.9%), lack spiculations (95.7%) and lack suspicious microcalcifications (95.6%). Median tumour size was largest in the EPC with IDC group (18.5 mm). 2 patients developed loco-regional recurrence. Overall survival is good for EPCs of all subtypes., Conclusion: EPC is a rare tumour with excellent prognosis., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Singapore launched a population-based organised mammography screening (MAM) programme in 2002. However, uptake is low. A better understanding of breast cancer (BC) risk factors has generated interest in shifting from a one-size-fits-all to a risk-based screening approach. However, public acceptability of the change is lacking. Focus group discussions (FGD) were conducted with 54 women (median age 37.5 years) with no BC history. Eight online sessions were transcribed, coded, and thematically analysed. Additionally, we surveyed 993 participants in a risk-based MAM study on how they felt in anticipation of receiving their risk profiles. Attitudes towards MAM (e.g., fear, low perceived risk) have remained unchanged for ~25 years. However, FGD participants reported that they would be more likely to attend routine mammography after having their BC risks assessed, despite uncertainty and concerns about risk-based screening. This insight was reinforced by the survey participants reporting more positive than negative feelings before receiving their risk reports. There is enthusiasm in knowing personal disease risk but concerns about the level of support for individuals learning they are at higher risk for breast cancer. Our results support the empowering of Singaporean women with personal health information to improve MAM uptake.

Background: Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry., Methods: A total of 12,901 breast cancer cases and 12,583 controls from 12 case-control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15-55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined., Results: We did not observe associations between any HLA allele and breast cancer risk at P < 5e-8; the smallest p value was observed for HLA-C*12:03 (OR = 1.29, P = 1.08e-3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18)., Conclusions: No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk., (© 2022. The Author(s).)

Objective: Patients with breast cancer who have indeterminate extra-mammary lesions, for example in lung, liver or bone, without other metastatic lesions pose a clinical dilemma regarding subsequent management. This study aimed to investigate the prevalence, characteristics and outcomes of such lesions detected on initial staging imaging, and address the clinical significance of these incidental findings., Materials and Methods: Medical records of patients with newly diagnosed breast cancer who underwent computed tomography scans and bone scintigraphy between January 1, 2015 and June 30, 2021 were reviewed. Patients with indeterminate extra-mammary lesions on imaging were included. Patients with obvious metastatic disease were excluded. Lesion characteristics, breast cancer staging, duration of follow-up and natural history of disease progression were analysed., Results: The study included 52 patients with indeterminate lesions on pre-operative imaging. The median follow-up duration was 14 (range: 6-41) months. The most common site of occurrence of indeterminate lesions was the lung (60.9%) followed by the liver (26.1%). Forty-six had lesions that remained stable (88.5%), while six (11.5%) had progression to metastatic disease. Out of these six, only two (3.8%) developed metastasis in the same site as the original indeterminate lesion, whereas the remaining four developed metastases in other sites., Conclusion: Patients with breast malignancy found to have indeterminate extra-mammary lesions without obvious distant metastasis on initial staging scans are associated with a small risk of subsequently developing metastatic disease. Although most of these lesions remain quiescent, surveillance imaging is recommended because a small but significant proportion of patients with such lesions eventually harbour actual metastatic disease., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (©Copyright 2022 by the the Turkish Federation of Breast Diseases Societies / European Journal of Breast Health published by Galenos Publishing House.)

Purpose: Emerging evidence from animal models suggests that intermittent hypoxia due to obstructive sleep apnea (OSA) is a risk factor for breast cancer. Despite their biological plausibility, human epidemiological studies have reported conflicting results. Therefore, we conducted a meta-analysis to delineate this relationship., Methods: We searched the PubMed, Embase, Scopus, and Cochrane Library databases for eligible studies from inception until June 6, 2021. Two reviewers selected randomized trials or observational studies reporting the association between OSA and breast cancer incidence compared with those without OSA. Two reviewers extracted relevant data and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and Newcastle-Ottawa Scale (NOS). We pooled the maximally covariate-adjusted hazard ratios (HRs) using a random-effects inverse variance-weighted meta-analysis and performed pre-specified subgroup analyses., Results: We included six studies out of 1,707 records, comprising a combined cohort of 5,165,200 patients. All studies used the International Classification of Diseases codes to classify OSA and breast cancer. OSA patients had a 36% increased breast cancer risk (HR, 1.36; 95% confidence interval [CI], 1.03-1.80; N = 6, I² = 96%) compared to those without OSA. Most studies adjusted for confounders, such as age, sex, obesity, diabetes mellitus, alcohol use, and hypertension. Subgroup analyses for studies with (1) multivariate adjustment and (2) at least five years of follow-up yielded HRs of 1.35 (95% CI, 0.98-1.87; N = 5, I² = 96%) and 1.57 (95% CI, 1.14-2.18; N = 4; I² = 90%), respectively. One Mendelian randomization study suggested a causal relationship, with a two-fold increase in the odds of breast cancer in patients with OSA., Conclusion: This meta-analysis suggested that OSA is a risk factor for breast cancer. Future studies should explore the dose-response relationship between OSA and breast cancer, and whether treatment may mitigate breast cancer risk or progression., Competing Interests: The authors declare that they have no competing interests., (© 2022 Korean Breast Cancer Society.)

Introduction: Male breast cancer (MBC) is rare, representing <1% of all breast cancers. Treatment recommendations have been extrapolated from trial data of female breast cancer patients. This study aims to report our institutional experience of MBC across a 20 year period, analyse the survival outcome and prognosis of this group against female breast cancer patients treated at the same centre., Methods: Clinical, histopathological, treatment and survival data of male and female breast cancer patients treated between Jan 1999 and July 2019 at Singapore General Hospital and National Cancer Centre Singapore were identified and analysed., Results: Fifty-seven male patients were identified. The median age at diagnosis was 63 years. Majority had invasive ductal carcinoma (86%) and presented at an early disease stage: 70.2% presented as Tis/T1/T2 and 49.1% had no axillary nodal involvement. 84.2% had a simple mastectomy with either a sentinel lymph node biopsy or axillary clearance. The median follow up was 5.69 years for males and 5.83 years for females. The median survival was 11.86 years for males and 16.3 years for females. At 5 years, overall survival (OS) was 69.9% (52.3-82.1%) and disease free survival (DFS) was 62.9% (44.9-76.5%) for males compared with OS 83.8% (83.21-84.39%) and DFS 74.5% (73.91-75.09%) for females., Conclusion: MBC remains understudied. Our institutional data indicates that good long term survival in South-East Asian patients can be achieved with treatment protocols that are similar to female breast cancer. More prospective studies are required., (© 2022 Royal Australasian College of Surgeons.)

Background: The hypothesis that breast cancer (BC) susceptibility variants are linked to chemotherapy-induced toxicity has been previously explored. Here, we investigated the association between a validated 313-marker-based BC polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever and febrile neutropenia (FNc) in Asian BC patients., Methods: This observational case-control study of Asian BC patients treated with chemotherapy included 161 FNc patients, 219 neutropenia patients, and 936 patients who did not develop neutropenia. A continuous PRS was calculated by summing weighted risk alleles associated with overall, estrogen receptor- (ER-) positive, and ER-negative BC risk. PRS distributions neutropenia or FNc cases were compared to controls who did not develop neutropenia using two-sample t -tests. Odds ratios (OR) and corresponding 95% confidence intervals were estimated for the associations between PRS (quartiles and per standard deviation (SD) increase) and neutropenia-related outcomes compared to controls., Results: PRS distributions were not significantly different in any of the comparisons. Higher PRS overall quartiles were negatively correlated with neutropenia or FNc. However, the associations were not statistically significant (PRS per SD increase OR neutropenia: 0.91 [0.79-1.06]; FNc: 0.87 [0.73-1.03]). No dose-dependent trend was observed for the ER-positive weighted PRS (PRS ER-pos ) and ER-negative weighted PRS (PRS ER-neg )., Conclusion: BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.

Purpose: With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women., Methods: In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 gene, using germline BRCA genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration., Results: Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow P value = .614) and discriminated well between BRCA and non- BRCA pathogenic variant carriers (area under receiver operating curve, 0.80; 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% ( P value = .003), thereby improving the overall efficacy., Conclusion: Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients., Competing Interests: Andrew LeeEmployment: IlluminaPatents, Royalties, Other Intellectual Property: I am an inventor of the BOADICEA model that is licensed to Cambridge Enterprise (part of the University of Cambridge) for commercialization. I have received royalties from Cambridge Enterprise Nur Aishah Mohd TaibConsulting or Advisory Role: Roche, AstraZeneca, MSD Veronique K.M. TanHonoraria: AstraZeneca (Inst), Roche (Inst)Consulting or Advisory Role: Bertis (Inst) Douglas F. EastonPatents, Royalties, Other Intellectual Property: Royalties from Boadicea risk prediction tool (Inst) Antonis C. AntoniouPatents, Royalties, Other Intellectual Property: Inventor of the BOADICEA model, which has been licensed to Cambridge Enterprise for commercialization. I may receive royalties if commercialization is realized (Inst) Soo Hwang TeoSpeakers' Bureau: AstraZeneca, Pfizer, RocheNo other potential conflicts of interest were reported.

Background: Neoadjuvant chemotherapy (NAC) plays an important role in the management of locally advanced breast cancer. It allows for downstaging of tumors, potentially allowing for breast conservation. NAC also allows for in-vivo testing of the tumors' response to chemotherapy and provides important prognostic information. There are currently no clearly defined clinical models that incorporate imaging with clinical data to predict response to NAC. Thus, the aim of this work is to develop a predictive AI model based on routine CT imaging and clinical parameters to predict response to NAC., Methods: The CT scans of 324 patients with NAC from multiple centers in Singapore were used in this study. Four different radiomics models were built for predicting pathological complete response (pCR): first two were based on textural features extracted from peri-tumoral and tumoral regions, the third model based on novel space-resolved radiomics which extract feature maps using voxel-based radiomics and the fourth model based on deep learning (DL). Clinical parameters were included to build a final prognostic model., Results: The best performing models were based on space-resolved and DL approaches. Space-resolved radiomics improves the clinical AUCs of pCR prediction from 0.743 (0.650 to 0.831) to 0.775 (0.685 to 0.860) and our DL model improved it from 0.743 (0.650 to 0.831) to 0.772 (0.685 to 0.853). The tumoral radiomics model performs the worst with no improvement of the AUC from the clinical model. The peri-tumoral combined model gives moderate performance with an AUC of 0.765 (0.671 to 0.855)., Conclusions: Radiomics features extracted from diagnostic CT augment the predictive ability of pCR when combined with clinical features. The novel space-resolved radiomics and DL radiomics approaches outperformed conventional radiomics techniques., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Advances in adjuvant therapy have led to increased survival rates after cancer prognosis. Herceptin, a targeted therapy, had first been introduced to Singapore in 2006. We aimed to assess whether subsidies for Herceptin from 2012 will lead to changes in uptake among HER2-positive patients by socioeconomic groups., Methods: Random-intercept logistic regression was used to model diagnostic test and Herceptin uptake using the Singapore Breast Cancer Cohort from 2006 to 2018, adjusting for covariates such as education, housing type, and marital status before and after subsidies. Interrupted time series analysis was used to evaluate the impact of Herceptin subsidy on treatment uptake. Concentration index was also computed by ethnicity and education to measure inequality in uptake., Results: We found that the odds of diagnostic testing were not associated with socioeconomic factors. Nevertheless, before subsidies, highest education attained (odds ratio 4.57; 95% confidence interval 1.90-11.02; P<.01) significantly increased the odds of Herceptin uptake. These odds were leveled after the introduction of subsidies to Herceptin treatment from 2012. After subsidy, we also found that Herceptin uptake increased significantly by 11.4% (95% confidence interval 3.47-19.4; P=.016). In addition, inequality of Herceptin use decreased especially among the Indians, where at least 40% were used in the higher educated group before subsidy., Conclusions: Subsidies have lowered the barriers to Herceptin uptake for marginalized individuals. Having targeted subsidies for socioeconomically disadvantaged groups may work more efficiently in providing ease of access than a blanket subsidy in Herceptin., (Copyright © 2021 ISPOR--The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s).)

Background: HER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC)., Methods: Patients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) (n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH-) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH- status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort (n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS., Results: ABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82-0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76-0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85-0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79-0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83-0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78-0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH- and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59-0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found., Conclusions: HER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC., (© 2022. The Author(s).)

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., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.)

Purpose: This study identified factors predicting malignant upgrade for atypical ductal hyperplasia (ADH) diagnosed on core-needle biopsy (CNB) and developed a nomogram to facilitate evidence-based decision making., Methods: This retrospective analysis included women diagnosed with ADH at the National Cancer Centre Singapore (NCCS) in 2010-2015. Cox proportional hazards regression was used to identify clinical, radiological, and histological factors associated with malignant upgrade. A nomogram was constructed using variables with the strongest associations in multivariate analysis. Multivariable logistic regression coefficients were used to estimate the predicted probability of upgrade for each factor combination., Results: Between 2010 and 2015, 238,122 women underwent mammographic screening under the National Breast Cancer Screening Program. Among 29,564 women recalled, 5,971 CNBs were performed. Of these, 2,876 underwent CNBs at NCCS, with 88 patients (90 lesions) diagnosed with ADH and 26 lesions upgraded to breast malignancy on excision biopsy. In univariate analysis, factors associated with malignant upgrade were the presence of a mass on ultrasound ( p = 0.018) or mammography ( p = 0.026), microcalcifications ( p = 0.047), diffuse microcalcification distribution ( p = 0.034), mammographic parenchymal density ( p = 0.008). and ≥ 3 separate ADH foci found on biopsy ( p = 0.024). Mammographic parenchymal density (hazard ratio [HR], 0.04; 95% confidence interval [CI], 0.005-0.35; p = 0.014), presence of a mass on ultrasound (HR, 10.50; 95% CI, 9.21-25.2; p = 0.010), and number of ADH foci (HR, 1.877; 95% CI, 1.831-1.920; p = 0.002) remained significant in multivariate analysis and were included in the nomogram., Conclusion: Our model provided good discrimination of breast cancer risk prediction (C-statistic of 0.81; 95% CI, 0.74-0.88) and selected for a subset of women at low risk (2.1%) of malignant upgrade, who may avoid surgical excision following a CNB diagnosis of ADH., Competing Interests: The authors declare that they have no competing interests., (© 2022 Korean Breast Cancer Society.)

Background: Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent., Methods: Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease., Results: PTV 9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV 25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV 25genes carriership, but not PTV 9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28])., Conclusions: PTV 9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions., (© 2021. The Author(s).)

Purpose: Studies that report equivalent oncologic outcomes of sentinel lymph node biopsy (SLNB) alone versus axillary lymph node dissection (ALND) for T1-2N1mi breast cancers are heavily weighted with patients who received breast-conserving surgery (BCS). The impact of omitting ALND in N1mi patients treated with mastectomy is not well studied. It is also unknown if these patients would benefit from post-mastectomy radiotherapy (PMRT). This study reports the outcomes of patients with T1-2N1mi breast cancer treated by mastectomy without axillary therapy., Methods: Patients who had T1-2N1mi breast cancer and underwent mastectomy from January 1998 to December 2018 were identified from our multi-institutional prospective database. Axillary recurrence rate (ARR), disease-free survival (DFS), and overall survival (OS) are reported., Results: 260 patients with pT1-2N1mi breast cancer who had mastectomy were identified. They had either SLNB (35.4%) or ALND (64.6%). Majority of these patients received adjuvant systemic therapy (93.8%). 77 (29.6%) patients received radiotherapy, 31 after SLNB and 46 after ALND. At median follow-up of 61 months, ARR was 1.1% (n = 1) in the SLNB only group, vs. 0.6% (n = 1) in the ALND group (p = 0.752). DFS and OS were not significantly different between patients with SLNB alone versus ALND (p = 0.40 and p = 0.27, respectively). Among 92 patients who had SLNB only, no DFS or OS difference was observed with the use of PMRT., Conclusion: In T1-2N1mi patients with mastectomy and SLNB, axillary recurrences were rare. No statistically significant differences were noted between patients with SLNB, ALND, or PMRT. Our findings suggest that these patients may be safely treated without axillary therapy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Breast fibroepithelial lesions are biphasic tumors which comprise the common benign fibroadenomas (FAs) and the rarer phyllodes tumors (PTs). This study analyzed 262 (42%) conventional FAs, 45 (7%) cellular FAs, and 321 (51%) benign PTs contributed by the International Fibroepithelial Consortium, using a previously curated 16 gene panel. Benign PTs were found to possess a higher number of mutations, and higher rates of cancer driver gene alterations than both groups of FAs, in particular MED12, TERT promoter, RARA, FLNA, SETD2, RB1, and EGFR. Cases with MED12 mutations were also more likely to have TERT promoter, RARA, SETD2, and EGFR. There were no significant differences detected between conventional FAs and cellular FAs, except for PIK3CA and MAP3K1. TERT promoter alterations were most optimal in discriminating between FAs and benign PTs. Our study affirms the role of sequencing and key mutations that may assist in refining diagnoses of these lesions.

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., Competing Interests: The authors have declared that no competing interests exist.

Background: Socioeconomic status (SES) is likely to affect survival in breast cancer patients. Housing value is a reasonable surrogate for SES in Singapore where most residents own their own homes, which could be public (subsidised) or private housing. We evaluated effects of housing value and enhanced medical subsidies on patients' presentation, treatment choices, compliance and survival in a setting of good access to healthcare., Methods: A retrospective analysis of breast cancer patients treated in a tertiary hospital cluster from 2000 to 2016 was performed. Individual-level Housing value Index (HI) was derived from each patient's address and then grouped into 3 tiers: HI(high)(minimal subsidy), HI(med)(medium subsidy) and HI(low)(high subsidy). Cox regression was performed to evaluate the associations between overall survival (OS) and cancer-specific survival (CSS) with HI and various factors., Findings: We studied a multiracial cohort of 15,532 Stage 0-IV breast cancer patients. Median age was 53.7 years and median follow-up was 7.7 years. Patients with lower HI presented with more advanced disease and had lower treatment compliance. On multivariable analysis, compared to HI(high) patients, HI(med) patients had decreased OS (HR=1.14, 95% CI 1.05-1.23) and CSS (HR=1.15, 95% CI 1.03-1.27), and HI(low) patients demonstrated reduced OS (HR=1.16, 95% CI 1.01-1.33). Ten-year non-cancer mortality was higher in lower HI-strata. Enhanced medical subsidy approximately halved treatment noncompliance rates but its receipt was not an independent prognostic factor for survival., Interpretation: Despite good healthcare access, lower-HI patients have poorer survival from both cancer and non-cancer causes, possibly due to delayed health-seeking and poorer treatment compliance. Enhanced subsidies may mitigate socioeconomic disadvantages., Funding: None., Competing Interests: We declare no competing interests., (© 2020 The Author(s). Published by Elsevier Ltd.)

Background: Cancer-related fatigue (CRF) is a debilitating condition which commonly affects cancer survivors. The management of CRF remains a challenge due to the lack of effective pharmacological interventions. Traditional Chinese medicine (TCM) could be a potential therapeutic option for CRF. The modified Xiang Bei Yang Rong Tang (XBYRT) is a TCM herbal decoction, formulated to improve fatigue symptoms in cancer survivors. This clinical trial aims to evaluate the efficacy and safety of XBYRT in improving CRF and quality of life (QOL) of cancer survivors., Methods: This is a single centre, randomized, double-blind, placebo-controlled, parallel trial. Eighty cancer survivors will be recruited and randomized to receive the XBYRT or placebo decoction, in a ratio of 1:1. Participants will consume the XBYRT/placebo decoction daily for 8 weeks and undergo assessments at baseline and 4, 8 and 10 weeks after baseline. The participants will be assessed for patient-reported outcomes (PRO), blood biomarkers and adverse events at each time point. The primary outcome is the overall health and QOL status, at 8 weeks follow-up. The secondary outcomes are the effects of XBYRT on fatigue levels, cancer-related cognitive impairment and QOL, as assessed by PRO. The incidence of adverse events and the effects of the XBYRT decoction on blood biomarkers associated with CRF will also be evaluated., Discussion: Efficacy and safety outcomes from this trial will provide important clinical data to guide future large-scale randomized controlled trials, and the evaluation of the objective blood biomarkers can help to delineate the biological mechanisms of CRF., Trial Registration Number: ClinicalTrials.gov NCT04104113 . Registered on 26 September 2019.

The ensuing COVID-19 pandemic poses unprecedented and daunting challenges to the routine delivery of oncological and supportive care to patients with breast cancer. Considerations include the infective risk of patients who are inherently immunosuppressed from their malignancy and therapies, long-term oncological outcomes from the treatment decisions undertaken during this extraordinary period, and diverted healthcare resources to support a coordinated whole-of-society outbreak response. In this review, we chronicle the repercussions of the COVID-19 outbreak on breast cancer management in Singapore and describe our approach to triaging and prioritising care of breast tumours. We further propose adaptations to established clinical processes and practices across the different specialties involved in breast oncology, with references to the relevant evidence base or expert consensus guidelines. These recommendations have been developed within the unique context of Singapore's public healthcare sector. They can serve as a resource to guide breast cancer management for future contingencies in this city-state, while certain elements therein may be extrapolatable to other medical systems during this global public health emergency.

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease which is increasingly diagnosed through improved screening measures. Multiple prognostic scores have been devised to predict the risk of local recurrence (LR), and the optimal adjuvant management for DCIS is still debated. Hence, the aim of this analysis is to investigate the factors contributing to the prognosis of DCIS, in particular the role of its hormonal status. From 2005 to 2016, a total of 1221 female patients diagnosed with DCIS at the National Cancer Centre Singapore and Singapore General Hospital were studied. The mean age of diagnosis was 54 years of age (sd = 11.0), with estrogen receptor (ER)-positive DCIS tumors presenting earlier (mean age 54 vs 57 years of age; P < .001). DCIS with negative hormonal status (HS) correlates significantly with a larger size (mean 23.5mm vs 13.0 mm, P < .001) and higher grade of tumor (P < .001). Patients with positive HS were more likely to undergo breast conservation surgery over a mastectomy, in contrast to patients with negative HS (P < .001). Patients with negative HS had a poorer prognosis, with a shorter time of overall survival time (HR = 26.3, P = .020). In conclusion, our study shows that the hormonal status, age of diagnosis, and positive margins are important prognostic factors for DCIS, at least in our Asian population., (© 2019 Wiley Periodicals, Inc.)

Fibroepithelial lesions (FELs) are a heterogeneous group of tumours comprising fibroadenomas (FAs) and phyllodes tumours (PTs). Here we used a 16-gene panel that was previously discovered to be implicated in pathogenesis and progression, to characterise a large international cohort of FELs via targeted sequencing. The study comprised 303 (38%) FAs and 493 (62%) PTs which were contributed by the International Fibroepithelial Consortium. There were 659 (83%) Asian and 109 (14%) non-Asian FELs, while the ethnicity of the rest was unknown. Genetic aberrations were significantly associated with increasing grade of PTs, and were detected more in PTs than FAs for MED12, TERT promoter, RARA, FLNA, SETD2, TP53, RB1, EGFR, and IGF1R. Most borderline and malignant PTs possessed ≥ 2 mutations, while there were more cases of FAs with ≤ 1 mutation compared to PTs. FELs with MED12 mutations had significantly higher rates of TERT promoter, RARA, SETD2, EGFR, ERBB4, MAP3K1, and IGF1R aberrations. However, FELs with wild-type MED12 were more likely to express TP53 and PIK3CA mutations. There were no significant differences observed between the mutational profiles of recurrent FAs, FAs with a history of subsequent ipsilateral recurrence or contralateral occurrence, and FAs without a history of subsequent events. We identified recurrent mutations which were more frequent in PTs than FAs, with borderline and malignant PTs harbouring cancer driver gene and multiple mutations. This study affirms the role of a set of genes in FELs, including its potential utility in classification based on mutational profiles. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: Known collectively as breast fibroepithelial lesions (FELs), the common fibroadenomas (FAs) and the rarer phyllodes tumors (PTs) are a heterogenous group of biphasic neoplasms. Owing to limited tissue availability, inter-observer variability, overlapping histological features and heterogeneity of these lesions, diagnosing them accurately on core biopsies is challenging. As the choice management option depends on the histological diagnosis; a novel 16-gene panel assay was developed to improve the accuracy of preoperative diagnosis on core biopsy specimens., Methods: Using this 16-gene panel, targeted amplicon-based sequencing was performed on 275 formalin-fixed, paraffin-embedded (FFPE) breast FEL specimens, archived at the Singapore General Hospital, from 2008 to 2012., Results: In total, 167 FAs, 24 benign, 14 borderline and 6 malignant PTs, were profiled. Compared to FAs, PTs had significantly higher mutation rates in the TERT promoter (p <  0.001), RARA (p <  0.001), FLNA, RB1 and TP53 (p = 0.002, 0.020 and 0.018, respectively). In addition to a higher mutational count (p <  0.001), TERT promoter (p <  0.001), frameshift, nonsense and splice site (p = 0.001, < 0.001 and 0.043, respectively) mutations were also frequently observed in PTs. A multivariate logistic regression model was built using these as variables and a predictive scoring system was developed. It classifies a FEL at low or high risk (score <  1 and ≥ 1, respectively) of being a PT. This scoring system has good discrimination (ROC area = 0.773, 95% CI: 0.70 to 0.85), calibration (p = 0.945) and is significant in predicting PTs (p <  0.001)., Conclusion: This novel study demonstrates the ability to extract DNA of sufficient quality and quantity for targeted sequencing from FFPE breast core biopsy specimens, along with their successful characterization and profiling using our customized 16-gene panel. Prospective work includes validating the utility of this promising 16-gene panel assay as an adjunctive diagnostic tool in clinical practice.

Aims: Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease that has risen to prominence and more recently controversy, with the advent of screening mammography. Debate concerning the true biological potential of low nuclear grade DCIS continues to challenge therapeutic considerations. In this study, we carried out a comprehensive literature review of the behaviour, outcomes and current management trials of low-grade DCIS, as well as a retrospective study of a large single institutional series of low-grade DCIS diagnosed at our hospital., Methods and Results: The study cohort comprised 195 cases of low-grade DCIS diagnosed at the Singapore General Hospital from 1994 to 2010. Clinicopathological parameters and follow-up data were retrieved and compared between screen-detected and symptomatic low-grade DCIS. Immunohistochemistry was performed for ER, PR and HER2. Among 195 cases, 123 (63.1%) were screen-detected, while 72 (36.9%) were symptomatic. Screen-detected cases had frequent calcifications (P < 0.001) and were smaller (P = 0.018) than symptomatic cases. All cases were ER-positive and rate of PR expression was high. No HER2 overexpression was observed. Mean and median follow-up periods were 107.8 and 109.6 months, respectively. Six patients recurred ipsilaterally, and one patient developed direct distant metastasis. One breast cancer-related death was recorded. Positive surgical margins (P = 0.023) were significantly associated with a higher risk of ipsilateral recurrences, as well as poorer disease-free survivals (P = 0.010)., Conclusion: Our data indicate that low-grade DCIS may be followed by invasive recurrences and even metastatic disease, requiring more study before being regarded as innocuous and indolent., (© 2019 John Wiley & Sons Ltd.)

Background: Despite similar survival rates, breast-conserving therapy (BCT) remains a distant second choice after simple mastectomy for patients with early-stage breast cancer in Singapore. Uptake of reconstruction after mastectomy is also low (18 per cent). The aim of this study was to explore the factors influencing a patient's choice for mastectomy when eligible for BCT, and why patients decline reconstruction after mastectomy., Methods: Patients from the National Cancer Centre Singapore, who were eligible for BCT but chose mastectomy without reconstruction, between December 2014 and December 2015 were included. An interviewer-administered questionnaire focusing on patients' reasons for choosing mastectomy over BCT and not opting for immediate breast reconstruction after mastectomy was used. Tumour characteristics were retrieved from medical records. Spearman's rank correlation coefficient, Mann-Whitney U and Kruskal-Wallis tests were used to analyse the correlation between the patient's self-rated influential factors and variables. Statistical significance was taken as P  < 0·050., Results: Ninety-one patients were included (90·1 per cent response rate). The main reasons for choosing mastectomy over BCT were: fear of cancer recurrence (considered very important in 74 per cent), the perception that health outweighs breast retention (49 per cent) and the possibility of second surgery for margins (40 per cent). Key factors for rejecting immediate reconstruction after mastectomy were: patient-perceived 'old age' (very important in 53 per cent), concern about two sites of surgery (42 per cent) and financial cost (29 per cent). Given a second chance, 19·8 per cent of patients would undergo BCT instead of mastectomy., Conclusion: This study has identified the considerations that women in Singapore have when deciding on breast cancer surgery. Some perceptions need to be addressed for women to make a fully informed decision, especially as one-fifth regret their initial choice.

Background: Women with unilateral breast cancer have an increased risk of developing bilateral breast cancer (BBC). Patients with metachronous BBC (mBBC) usually have an earlier age of onset, and their prognoses have been shown to be either similar or poorer than those with synchronous BBC (sBBC). Given the differing presentation and characteristics of breast cancers in the Asian population and the West, this study aims to characterize Asian patients with BBC., Methods: All patients who had oncological breast surgery between 2001 and 2010 at the Singapore General Hospital and National Cancer Centre Singapore were reviewed. Patients with BBC were identified and studied., Results: A total of 5520 Singaporean women had oncological breast surgery, 155 women (2.8%) had BBC. Of those with BBC, 47.1% (n = 73) were synchronous and 52.9% (n = 82) metachronous (mean interval of 39.4 months), and there was no difference in median age in both groups (54 years of age). Patients with sBBC were more likely to have a positive family history and had asymptomatic contralateral tumours. Although patients with sBBCs were more likely to have ER/PR positive and Her2 negative tumours, they had a lower 5-year overall survival than those with mBBC (P = 0.022)., Conclusion: Our study shows that Asian women with BBC have different characteristics to their Western counterparts. In particular, women with sBBC tended to have a lower 5-year overall survival compared to those with mBBC, despite having seemingly biologically favourable tumours, which suggest that there may be more underlying their tumour biology and genetics., (© 2018 Royal Australasian College of Surgeons.)