AbstractBackgroundEncapsulated 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 Methods54 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.Results18 (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.ConclusionEPC is a rare tumour with excellent prognosis.

INTRODUCTION Hookwires are commonly deployed under imaging guidance to localise non-palpable breast lesions for excision. However, the use of hookwires has some disadvantages, including patient discomfort, wire migration, damage to surrounding anatomical structures, surgery scheduling inconveniences and limited access to axillary nodes. Novel, alternative, non-radioactive wireless localisation devices using technologies such as radiofrequency identification, magnetic seed and radar have been developed to address these shortcomings.[1,2] While these devices have seen increasing usage in America and Europe, they were introduced to Asia only recently. One of these wireless techniques, the Savi Scout® (SS) surgical guidance system (Cianna Medical, Merit Medical Systems, Inc., South Jordan, UT, USA), was made available in Asia in 2019, and Singapore was the first Asian country to utilise it for breast and axillary localisations. Savi Scout employs radar technology, and it received the United States Food and Drug Administration clearance in 2014. The SS consists of a reflector implant, a needle introducer and an external check console. The reflector is a 12-mm metallic implant [Figure 1] consisting of thin nitinol antennae protruding from either end of a central transistor body. It is inserted percutaneously into the soft tissue via a single-use, preloaded, 16-gauge needle introducer and is deployed by uncovering the overlying sheath at the distal end of the introducer. This passive reflector delivery mechanism prevents damage to the thin antennae. The introducer is unsheathed by first unlocking the release button to either left or right and then retracting it along a sliding track [Figure 1]. Once the reflector is deployed, it cannot be repositioned. A handheld probe connected to the check console is used to locate the deployed reflector by transmitting a radio wave signal (radar), which is received and reflected back by the reflector. The signal capture and reflection mechanism of the reflector is multidirectional and is used to guide direction and distance to the target up to a depth of 6 cm. Unlike hookwires, SS does not have any components protruding from the skin. In addition, there is no placement expiry after deployment and it can be deployed at any time before surgery day, which provides flexibility in procedural scheduling.Figure 1: Photograph shows the parts and functions of the Savi Scout® needle introducer system and the 12-mm-long reflector (inset).Studies from America and Europe have evaluated SS to be a safe and convenient localisation technique for the breast and axilla.[3-8] However, to the best of our knowledge, there have been no published reports evaluating its performance in Asian women, and it is unclear if dense breast tissue, which is more prevalent in Asian women, may affect SS deployment and signal detection. We described our experience in the initial use of SS in Singapore women with the aims of providing an assessment on its performance in Asian women and finding ways to optimise its use. METHODS This was an institutional, review board-approved retrospective review of patients who underwent imaging-guided SS localisations at multiple centres in Singapore from July 2019 to June 2021. Performance was evaluated by 13 users, six of whom were breast imaging-dedicated radiologists and seven were breast surgeons. The ease of reflector deployment, time taken to deploy the reflector, postdeployment signal detection, incidence of reflector damage, incidence of reflector malpositioning, incidence of reflector migration, radiological visibility of the reflector, ease of intraoperative localisation, surgical retrieval rate, complication rate and overall user satisfaction were evaluated. Malpositioning was defined as the centre of reflector sited more than 10 mm from the epicentre of the lesion at deployment. Reflector migration referred to displacement of more than 10 mm from its original deployment site. Deployment time was the duration interval between introducer entry and exit of the skin. Assessments were graded on a 4-point scale of none, low/mild, moderate and high/severe categories, where appropriate. Statistical tests were performed with the online software GraphPad QuickCalcs (https://www.graphpad.com/quickcalcs/). Continuous variables were compared using the Student’s t-test. Comparisons of categorical variables were performed with Fisher’s exact test. The differences were considered statistically significant at P < 0.05. RESULTS Forty-four reflectors were deployed for 31 breast lesions and 13 axillary nodes in 40 female patients. Planned deployments had to be cancelled for five other women with a history of nickel allergy. Thirty-eight (86.4%) reflectors were deployed under ultrasound guidance, while six (13.6%) were performed under mammogram guidance. Four (9.1%) breast placements were inserted before commencement of neoadjuvant chemotherapy, with a mean placement duration of 184 days. There were ten (22.7%) placements in metastatic nodes that were inserted before neoadjuvant chemotherapy for subsequent targeted axillary dissection (TAD), with a mean placement period of 148 days. Twenty-one (47.7%) reflectors were inserted on the same day as surgery and another nine (20.5%) were non-same day deployments within 2 weeks of surgery. All users expressed overall satisfaction with SS use and there were no major complications. On specific technical aspects of deployment, there was no significant resistance when advancing the introducer in dense breast tissue. The introducer’s release button was highlighted to be mechanically stiff in 12 (27.3%) instances, with four (9.1%) encountering mild resistance and eight (18.2%) encountering significant resistance. Mean deployment times were 3 min and 9 s and 1 min and 53 s (P = 0.037) for insertions performed under ultrasound and mammogram guidance, respectively. There were no cases of reflector damage, malpositioning or migration [Tables 1 and 2].Table 1: Deployment outcomes by lesion and deployment types.Table 2: Surgical technical performance of deployments (N=44).On the surgical technical aspect, five of seven breast surgeons (71.4%) felt that SS provided greater flexibility in incision placement. Intraoperatively, the reflector was easily and accurately located with the use of the check console, apart from a few cases that encountered signal detection difficulty. Specimen radiographs confirmed that the reflectors were all fully retrieved with no evidence of damage. Failed signal detection on immediate postdeployment was encountered in three (6.8%) cases. In two of these cases, the reflector was inserted into a metastatic axillary node before commencement of neoadjuvant chemotherapy for the purpose of TAD. In both instances, core needle biopsy of the nodes was performed just before reflector deployment and postbiopsy haematomas were the likely cause of signal impedance. Signal was detected for both reflectors during a signal check a week later. At surgery 5 months later, signal was detected intraoperatively for one of the cases, but was absent in the other (2.3%). In this case of the absent intraoperative signal, the targeted node and the reflector were successfully retrieved after surgical exploration with the aid of intraoperative ultrasound. Subsequent investigations showed no malfunction of the reflector and check console, with no definite cause found for the signal failure. The third case of signal failure was related to a mammogram-guided deployment on surgery day, targeting a postbiopsy clip. There was a residual moderate-sized, postbiopsy haematoma next to the clip, which was likely impeding the signal. The clip was subsequently localised with a hookwire as an additional measure, but there was intermittent signal detected intraoperatively, which was sufficient to guide excision without difficulty. There was also one (2.3%) case of intermittent signal in a case of ultrasound-guided deployment adjacent to a moderate-sized, post-core needle biopsy haematoma. There was mild difficulty locating the reflector intraoperatively, but excision was successful. Signal loss triggered by diathermy contact was encountered in two cases (4.5%) that involved wide local excision for breast cancer. In both instances, the reflector tip was visible in the dissection plane at the time of signal loss, and the reflectors and tumours were excised with clear margins. The reflector was well visualised on ultrasound in 30 out of 31 cases (96.8%) and poorly visualised in one case (3.2%). The reflector was distinctively visualised on all postdeployment mammograms that were performed (30/30) [Figure 2]. In the six cases that had breast magnetic resonance imaging (MRI), the reflector was well seen in all of them and was best visualised in the T1-weighted, non-subtracted, postcontrast sequences with fat saturation. The reflector was seen as a small blooming artefact on MRI.Figure 2: Radiological appearance of reflectors (arrows) in a patient. (a) Mammogram shows the reflectors inserted before neoadjuvant chemotherapy embedded within the breast tumour and metastatic axillary node. (b) Sonogram shows the echogenic linear reflector within the enlarged node.DISCUSSION Our multicentre early experience demonstrated the utility of SS in a variety of clinical settings with good outcomes in Asian women. There was no signal inhibition in dense breast tissue and the introducer was able to advance into dense breasts without difficulty. Unlike hookwires, the small reflector posed little risk of injuring adjacent structures and was a useful alternative to hookwires for difficult-to-access sites such as lesions close to the chest wall or axillary nodes close to vital anatomical structures. Flexibility in scheduling deployments was a welcomed benefit. The implant also had the advantage of causing minimal MRI artefacts, which did not significantly obscure MRI assessment. There were, however, a few drawbacks encountered. Rare instances of intermittent or absent reflector signal were documented, mostly related to signal impedance by an adjacent haematoma, which is well documented as a cause of signal failure.[6,7] To reduce the risk of signal failure, the reflector is best placed superficial to the haematoma if present. True reflector malfunction is extremely rare, but it has been documented before.[3,6,8] We recommend performing a signal check just before surgery, so that alternative means of localisation can still be arranged before surgery in the rare event of signal failure. Another intraoperative pitfall was reflector deactivation after electrocautery contact. To avoid this, there is a need to carry out dissections with greater care when nearing the reflector and use the check console to guide proximity distance from the reflector frequently. Even with reflector deactivation, we did not feel it was a significant problem because it would indicate that the targeted site has been reached and the reflector together with the lesion will be identified in the dissection plane by then. In our series, the two cases of reflector deactivation did not adversely affect surgical outcomes. In the event that the reflector cannot be detected and located during surgery, it can be localised with the aid of intraoperative imaging. Being easily seen on sonography and X-ray examinations, the reflector may be located with the help of intraoperative ultrasound or fluoroscopy, as in one of our cases. The introducer’s delivery mechanism was slightly cumbersome. The needle tip had to be advanced a further 6 mm, so that the reflector would be centred well upon deployment. For ultrasound deployments, the proceduralist may take a few adjustments to achieve this optimal needle position, whereas this additional advancement can be precalibrated into the mammogram machine settings, removing the need for manual adjustments in mammogram-guided localisations. This was reflected in the longer procedural times for ultrasound-guided deployments compared to mammogram-guided ones. Notably, there was unexpected difficulty in retracting the introducer’s release button during reflector deployment. A few cases required extreme effort to fully retract the button and the procedure took longer to complete. It was not an isolated batch problem and there were also no such reports in other studies for reference. To troubleshoot this, our users found it easier to retract after switching the button to the opposite sliding track. The needle position may also unintentionally shift during the physical struggle to retract the release button, especially when performing under ultrasound guidance. We suggest checking the needle position when the release button is retracted halfway. If there is a need to reposition, the release button may be reversed to resheath and protect the reflector before proceeding to reposition the needle. We found that the reflector was not damaged with this manoeuvre. On the surgical technical aspect, most of the breast surgeons felt that SS allowed greater flexibility in incision placement. The accurate localisation facilitated a more targeted resection, which can help reduce excessive tissue resection, and skin incisions could be confidently placed directly over the lesion or cosmetically placed far from the lesion. Finally, SS use was limited by nickel allergy and cost considerations. The nitinol antennae contain small amount of nickel and, out of caution, we did not proceed with SS insertion for a few women who had nickel allergy.[4,5] Nickel allergy, however, is fairly prevalent and clinicians should routinely ask patients about this, so that they can plan in advance for alternative localisation methods, if necessary. Cost-wise locally, the reflector can be up to nine times more expensive than a hookwire. A significant capital outlay would also be necessary for procurement of the console. Unlike the findings from several American and European studies, many local clinicians felt that SS was too expensive for routine localisations despite its perceived benefits, which largely explained the low usage during the study period. However, we found that the most cost-effective utility in our local setting was the upfront deployment of SS in patients undergoing neoadjuvant chemotherapy before a planned breast conservation surgery or TAD. This group of patients will fully benefit from the dual functionality of SS acting as both a tumour clip and a localisation guide for subsequent surgical excision, eliminating the need for another localisation on surgery day, which will save procedural costs. One of the limitations of this paper is not evaluating the patients’ experience. However, none of the patients explicitly expressed dissatisfaction or discomfort with the reflector deployed in them. Cosmetic outcomes were also not evaluated. These are important points that can be explored in future. In summary, SS worked well in Asian women with some clinical benefits, but users need to be aware of its limitations. We have suggested ways on how to troubleshoot and optimise its use, and we hope our early experience will help other institutions in Asia to implement SS or other wireless localisation devices in their clinical practice and to navigate potential challenges. Acknowledgement We would like to thank Dr Permeen Akhtar bt Mohamed Yusoff from Research Office, Singapore General Hospital, Singapore, for assistance in editing and formatting of the manuscript. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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.

Background :Neoadjuvant chemotherapy (NAC) plays an important role in the management of locally advanced breast cancer. It allows for downstaging of tumours, potentially allowing for breast conservation. NAC also allows for in-vivo testing of the tumours’ 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 deep learning 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 augments the predictive ability of pathological complete response when combined with clinical features. The novel space-resolved radiomics and deep learning radiomics approaches outperformed conventional radiomics techniques.

Primary breast carcinomas often present as ill-defined, infiltrative lesions which may contain calcifications, whereas metastatic cancers from non-mammary sites are often more well-circumscribed, sharply demarcated from the adjacent breast tissue and are usually not associated with calcifications, although there are exceptions. We report an atypical case of a lady with lung adenocarcinoma with pleural involvement, who presented with diffuse breast swelling with calcifications on imaging from metastatic lung adenocarcinoma, the first of its kind in the literature. We postulate that the pathophysiology of this was due to lymphatic spread of the tumour from the pleura resulting in retrograde lymphovascular congestion of the breast, resulting in swelling and dystrophic calcification.

Purpose: Atypical ductal hyperplasia (ADH) is a high risk lesion with an increased risk of developing breast cancer. This study aims to identify factors predictive of malignant upgrade for ADH diagnosed on core needle biopsy (CNB) and to develop a nomogram to facilitate evidence-based decision making.Methods: Retrospective analysis of women with CNB diagnosed ADH at the National Cancer Centre Singapore between 2010 and 2015 was performed. Cox proportional hazards regression was used to identify independent clinical, radiological and histological factors associated with malignant upgrade. A nomogram was constructed and multivariable logistic regression coefficients were used to estimate the predicted probability of upgrade for each factor combination. Combinations with the lowest predicted probabilities (≤5%) were identified as low risk. Model sensitivity, specificity, positive and negative predictive values were assessed.Results: From 2010-2015, 238,122 women underwent screening under the national breast cancer screening programme. 29,564 women were recalled and 5742 CNBs were performed, of which 2686 were performed at NCCS. 88 patients (90 lesions) were diagnosed with ADH. 26 lesions were upgraded to a breast malignancy on excision biopsy. On univariate analysis, presence of a mass on either ultrasound (p= 0.018) or mammogram (p=0.026), presence of mammographic microcalcifications (p=0.047), diffuse microcalcification distribution (p=0.034), mammographic parenchymal density (p=0.008), presence of microcalcifications on biopsy (p=0.037) and three or more separate foci of ADH found on biopsy (p=0.024) were associated with malignant upgrade. Mammographic parenchymal density (Hazard ratio= 0.04, 95% CI 0.005-0.35, p=0.014), presence of a mass on ultrasound (Hazard ratio= 10.50, 95% CI 9.21-25.2, p=0.010) and number of foci of ADH (Hazard ratio = 1.877, 95% CI 1.831-1.920, p=0.002) remained significant on multivariate analysis and were included in the normogram which demonstrated good discrimination with C-statistic of 0.81 [95% CI, 0.74 to 0.88].Conclusion: Our model provides good discrimination of breast cancer risk prediction in patients with ADH on CNB. A subset of women at low risk (<5%) of upgrade to cancer may avoid surgical excision following a core-needle biopsy diagnosis of ADH.

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 PRSoverall 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 (PRSER-pos) and ER-negative weighted PRS (PRSER-neg). Conclusion: BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.

IntroductionStatins, HMG-CoA reductase inhibitors, are commonly used cholesterol-lowering medications which are also increasingly recognized to have anti-cancer properties for various cancers, including breast cancer. Most clinical evidence supports a protective effect of statin on reducing breast cancer recurrence, particularly in hormone-receptor positive breast cancers.This study seeks to study the impact of statin use on breast cancer recurrence in an Asian population.MethodsThis is a retrospective study of patients diagnosed with breast cancer at the National Cancer Centre and Singapore General Hospital from 2005-2015. Statin use was defined as use after surgery. Associations between statin use, breast cancer recurrence and overall survival were estimated using Cox proportional hazards regression with adjustment for age, TNM stage, grade, ER/HER2 status, and co-morbidities. Associations between statin-use and disease-specific survival were estimated using competing risks regression.ResultsA total of 7858 females with breast cancer were studied, 1353(17.2%) were statin users, 6505(82.8%) were non-statin users, with a median follow-up of 8.67 years. Distribution of cancer stage, histology, molecular subtypes and grades were similar in both groups. Estrogen receptor(ER) positive (HR 0.57,95%CI 0.43-0.76,p<0.001) and HER2 negative (HR 0.74,95%CI 0.57-0.96,p=0.026) invasive cancers had a lower risk of recurrence in statin users. Statin users trended towards a long term recurrence-risk reduction (all subtypes,HR 0.48,p=0.002; ER-, HR 0.34,p=0.036; HER2+,HR 0.10,p=0.002). The risk-reduction benefit is not appreciated in statin users with DCIS, possibly due to small recurrence event numbers. Disease-specific survival benefit was seen in statin users with ER+ cancers (adjusted SHR 0.71,95%CI 0.53-0.96,p=0.027), especially ER+ invasive cancers (adjusted SHR 0.72, 95%CI 0.53-0.97,p=0.028), but with no statistically significant benefit in overall survival for statin users (all subtypes).ConclusionThis is the first known retrospective study on the effect of statin use and breast cancer recurrence in an Asian population. Similar to previous international studies, statin use is associated with a risk reduction in breast cancer recurrence. This is especially beneficial in patients who have ER+ and HER2- invasive breast cancer. Statin use is also associated with a reduced risk of breast cancer recurrence in all subtypes of breast cancer in the long term (>6 years post diagnosis).

Mammography is extensively used for breast cancer screening but has high false-positive rates. Here, prospectively collected blood samples were used to identify circulating microRNA (miRNA) biomarkers to discriminate between malignant and benign breast lesions among women with abnormal mammograms. The Discovery cohort comprised 72 patients with breast cancer and 197 patients with benign breast lesions, while the Validation cohort had 73 and 196 cancer and benign cases, respectively. Absolute expression levels of 324 miRNAs were determined using RT-qPCR. miRNA biomarker panels were identified by: (1) determining differential expression between malignant and benign breast lesions, (2) focusing on top differentially expressed miRNAs, and (3) building panels from an unbiased search among all expressed miRNAs. Two-fold cross-validation incorporating a feature selection algorithm and logistic regression was performed. A six-miRNA biomarker panel identified by the third strategy, had an area under the curve (AUC) of 0.785 and 0.774 in the Discovery and Validation cohorts, respectively, and an AUC of 0.881 when differentiating between cases versus those with benign lesions or healthy individuals with normal mammograms. Biomarker panel scores increased with tumor size, stage and number of lymph nodes involved. Our work demonstrates that circulating miRNA signatures can potentially be used with mammography to differentiate between patients with malignant and benign breast 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.

Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states.

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.

BackgroundSocioeconomic 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.MethodsA 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.FindingsWe 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.InterpretationDespite 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.FundingNone.

Background: Sentinel lymph node biopsy (SLNB) has become standard of care as a staging procedure in patients with early stage breast cancer. Patients with nodal micrometastasis (N1mi) on SLNB are likely to have low nodal disease burden. Therefore, in this retrospective study we aim to review the outcome of our patients with pN1mi treated with SLNB versus axillary lymph node dissection (ALND).

Abstract 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.

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.

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.