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Computational pathology is a rapidly expanding area for research due to the current global transformation of histopathology through the adoption of digital workflows. Survival prediction of breast cancer patients is an important task that currently depends on histopathology assessment of cancer morphological features, immunohistochemical biomarker expression and patient clinical findings. To facilitate the manual process of survival risk prediction, we developed a computational pathology framework for survival prediction using digitally scanned haematoxylin and eosin-stained tissue microarray images of clinically aggressive triple negative breast cancer. Our results show that the model can produce an average concordance index of 0.616. Our model predictions are analysed for independent prognostic significance in univariate analysis (hazard ratio = 3.12, 95% confidence interval [1.69,5.75], p < 0.005) and multivariate analysis using clinicopathological data (hazard ratio = 2.68, 95% confidence interval [1.44,4.99], p < 0.005). Through qualitative analysis of heatmaps generated from our model, an expert pathologist is able to associate tissue features highlighted in the attention heatmaps of high-risk predictions with morphological features associated with more aggressive behaviour such as low levels of tumour infiltrating lymphocytes, stroma rich tissues and high-grade invasive carcinoma, providing explainability of our method for triple negative breast cancer., (© 2022. The Author(s).)

Background: Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS., Methods: The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236)., Findings: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; p<0·001). The boost group had higher rates of grade 2 or higher breast pain (10% [8-12%] vs 14% [12-17%], p=0·003) and induration (6% [5-8%] vs 14% [11-16%], p<0·001)., Interpretation: In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results., Funding: National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group., Competing Interests: Declaration of interests BHC reports research grants from National Health and Medical Research Council, Susan G Komen for the Cure, Breast Cancer Now, and OncoSuisse Swiss Federation Against Cancer to support the submitted work at Trans-Tasman Oncology Group (Newcastle, NSW, Australia), Centre for Biostatistics and Clinical Trials of Peter MacCallum Cancer Centre (Melbourne, VIC, Australia), and participating cooperative trials groups and sites; and in kind support from Veracyte and NanoString for biomarker testing, outside the submitted work. IHK and AHW report research grants to support the submitted work at the UK Trial Centre, University of Edinburgh (Breast Cancer Now); and research funding from the Dutch Cancer Society to support the submitted work in the Netherlands. TJW reports research funding and non-direct financial support for biomarker testing from Exact Sciences and Genomic Health for ongoing studies. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: To assess the cosmetic impact of breast conserving surgery (BCS), whole breast irradiation (WBI) fractionation and tumour bed boost (TBB) use in a phase III trial for women with ductal carcinoma in situ (DCIS) of the breast., Materials and Methods: Baseline and 3-year cosmesis were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Cosmetic Rating System and digital images in a randomised trial of non-low risk DCIS treated with postoperative WBI +/- TBB. Baseline cosmesis was assessed for four geographic clusters of treating centres. Cosmetic failure was a global score of fair or poor. Cosmetic deterioration was a score change from excellent or good at baseline to fair or poor at three years. Odds ratios for cosmetic deterioration by WBI dose-fractionation and TBB use were calculated for both scoring systems., Results: 1608 women were enrolled from 11 countries between 2007 and 2014. 85-90% had excellent or good baseline cosmesis independent of geography or assessment method. TBB (16 Gy in 8 fractions) was associated with a >2-fold risk of cosmetic deterioration (p < 0.001). Hypofractionated WBI (42.5 Gy in 16 fractions) achieved statistically similar 3-year cosmesis compared to conventional WBI (50 Gy in 25 fractions) (p ≥ 0.18). The adverse impact of a TBB was not significantly associated with WBI fractionation (interaction p ≥ 0.30)., Conclusions: Cosmetic failure from BCS was similar across international jurisdictions. A TBB of 16 Gy increased the rate of cosmetic deterioration. Hypofractionated WBI achieved similar 3-year cosmesis as conventional WBI in women treated with BCS for DCIS., Competing Interests: Declaration of Competing Interest All authors declare no commercial conflicts of interests other than per capita or grant funding to their institutions for patient accrual. The funding bodies had no role in the analysis or reporting of results and did not review or edit the text of the manuscript., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Radiotherapy is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both in vitro and in vivo , resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage, and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome in radiotherapy-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant breast cancer xenografts highly amenable to sensitization by cotreatment with a miR-139-5p mimetic. Significance: The microRNA described in this study offers a potentially useful predictive biomarker of radiosensitivity in solid tumors and a generally applicable druggable target for tumor radiosensitization. Cancer Res; 78(2); 501-15. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Introduction: Breast cancer is a complex heterogeneous disease and is a leading cause of death in women. Early diagnosis and monitoring progression of breast cancer are important for improving prognosis. The aim of this study was to identify protein biomarkers in urine for early screening detection and monitoring invasive breast cancer progression., Method: We performed a comparative proteomic analysis using ion count relative quantification label free LC-MS/MS analysis of urine from breast cancer patients (n = 20) and healthy control women (n = 20)., Results: Unbiased label free LC-MS/MS-based proteomics was used to provide a profile of abundant proteins in the biological system of breast cancer patients. Data analysis revealed 59 urinary proteins that were significantly different in breast cancer patients compared to the normal control subjects (p<0.05, fold change >3). Thirty-six urinary proteins were exclusively found in specific breast cancer stages, with 24 increasing and 12 decreasing in their abundance. Amongst the 59 significant urinary proteins identified, a list of 13 novel up-regulated proteins were revealed that may be used to detect breast cancer. These include stage specific markers associated with pre-invasive breast cancer in the ductal carcinoma in-situ (DCIS) samples (Leucine LRC36, MAST4 and Uncharacterized protein CI131), early invasive breast cancer (DYH8, HBA, PEPA, uncharacterized protein C4orf14 (CD014), filaggrin and MMRN2) and metastatic breast cancer (AGRIN, NEGR1, FIBA and Keratin KIC10). Preliminary validation of 3 potential markers (ECM1, MAST4 and filaggrin) identified was performed in breast cancer cell lines by Western blotting. One potential marker MAST4 was further validated in human breast cancer tissues as well as individual human breast cancer urine samples with immunohistochemistry and Western blotting, respectively., Conclusions: Our results indicate that urine is a useful non-invasive source of biomarkers and the profile patterns (biomarkers) identified, have potential for clinical use in the detection of BC. Validation with a larger independent cohort of patients is required in the following study.

Background: Patients with breast cancer have an increased risk of developing subsequent breast cancers. It is important to distinguish whether these tumours are de novo or recurrences of the primary tumour in order to guide the appropriate therapy. Our aim was to investigate the use of DNA methylation profiling and array comparative genomic hybridization (aCGH) to determine whether the second tumour is clonally related to the first tumour., Methods: Methylation-sensitive high-resolution melting was used to screen promoter methylation in a panel of 13 genes reported as methylated in breast cancer (RASSF1A, TWIST1, APC, WIF1, MGMT, MAL, CDH13, RARβ, BRCA1, CDH1, CDKN2A, TP73, and GSTP1) in 29 tumour pairs (16 ipsilateral and 13 contralateral). Using the methylation profile of these genes, we employed a Bayesian and an empirical statistical approach to estimate clonal relationship. Copy number alterations were analysed using aCGH on the same set of tumour pairs., Results: There is a higher probability of the second tumour being recurrent in ipsilateral tumours compared with contralateral tumours (38 % versus 8 %; p <0.05) based on the methylation profile. Using previously reported recurrence rates as Bayesian prior probabilities, we classified 69 % of ipsilateral and 15 % of contralateral tumours as recurrent. The inferred clonal relationship results of the tumour pairs were generally concordant between methylation profiling and aCGH., Conclusion: Our results show that DNA methylation profiling as well as aCGH have potential as diagnostic tools in improving the clinical decisions to differentiate recurrences from a second de novo tumour.

Introduction: The purpose of this study was to evaluate the cardiac dosimetry delivered before and after routine 3D CT whole-breast radiotherapy planning, including cardiac contouring and the relevance of a 15-mm maximum myocardial depth (MMD) planning tolerance threshold., Methods: The PULp FICTion study permitted cardiac dosimetry comparisons for 140 patients (70 in the 'before-contouring era' (BC) and 70 in the 'post-contouring era' (PC) ). Comparisons were made of MMD and dosimetry for whole heart, anterior myocardium and left anterior descending (LAD)/coronary artery (overall, superior and inferior) by contouring era., Results: The MMD mean was 15.6 mm (range 1-40). If the internal mammary chain (IMC) was treated, the MMD increased from 15 to 27.7 mm (P < 0.0001). Excluding IMC patients revealed no difference in MMD between conservation and mastectomy (14.9 vs 17.4, P = 0.3), boost and no boost (14.5 vs 15.5, P = 0.41) or BC and PC (15.7 vs 14.5. P = 0.33) and no differences related to treating clinician, anthracycline use or age. Only in potentially low-risk patients defined as not requiring IMC or boost treatment was there a difference in MMD by era, with 17.7 mm (1-40) in the BC era and 13.9 mm (1-31) mm in the PC era (P = 0.013). Inferior LAD mean doses increased from 49% to 84% of the prescribed breast dose when MMD was >15 mm, and the proportion of patients with a mean dose <40% of the prescribed breast dose fell from 48% to 8%., Conclusion: Changes in cardiac dosimetry associated with routine cardiac contouring have initially been minor and restricted to low-risk patients. A 15-mm MMD reasonably represents a transition from low mean distal LAD doses to substantial doses., (© 2014 The Royal Australian and New Zealand College of Radiologists.)

Introduction: The nipple-areolar complex (NAC) has special histological properties with higher melanocyte concentration than breast skin. To date, there are no data describing the late effects on the NAC following breast-conserving therapy (BCT). This study evaluated colour changes in the NAC in patients treated with breast-conserving surgery and adjuvant radiotherapy after 5 years., Methods: Digital photographs obtained at 5 years following breast irradiation from the St. George and Wollongong (SGW) trial (NCT00138814) were evaluated by five experts using an iPad® (Apple Inc., Cupertino, CA, USA) application specifically created for this study. The SGW trial randomised 688 patients with Tis-2, N0-1, M0 carcinoma to the control arm of 50 Gy in 25 fractions and boost arm of 45 Gy in 25 fractions and 16 Gy in 8 fractions electron boost., Results: A total of 141/372 (38%) patients had altered NAC (86% lighter, 10% darker). Patients with Celtic skin type had increased likelihood of having an altered NAC (odds ratio (OR), 1.75 (CI 1.1-2.7, P = 0.011)). On subgroup analysis, those with Celtic skin type receiving biologically equivalent dose (BED) Gy3 ≥ 80 Gy had OR of 3.03 (95% CI 1.2-7.5, P = 0.016) for having altered colour. There was a dose response with more profound changes seen in the NAC compared with irradiated breast skin if BED Gy3 ≥ 80 Gy with OR of 2.42 (95% CI 1.1-5.6, P = 0.036)., Conclusion: In this Caucasian BCT population, over 30% of patients developed lighter NAC and more commonly in women with Celtic skin type. The degree of this effect increased with higher radiation dose., (© 2014 The Royal Australian and New Zealand College of Radiologists.)

Although the survival of breast cancer (BC) patients has increased over the last two decades due to improved screening programs and postoperative adjuvant systemic therapies, many patients die from metastatic relapse. Current biomarkers used in the clinic are not useful for the early detection of BC, or monitoring its progression, and have limited value in predicting response to treatment. The development of proteomic techniques has sparked new searches for novel protein markers for many diseases including BC. Proteomic techniques allow for a high-throughput analysis of samples with the visualization and quantification of thousands of potential protein and peptide markers. Human urine is one of the most interesting and useful biofluids for routine testing and provides an excellent resource for the discovery of novel biomarkers, with the advantage over tissue biopsy samples due to the ease and less invasive nature of collection. In this review, we summarize the results from studies where urine was used as a source for BC biomarker research and discuss urine sample preparation, its advantage, challenges, and limitation. We focus on the gel-based proteomic approaches as well as the recent development of quantitative techniques in BC urine biomarker detection. Finally, the future use of modern proteomic techniques in BC biomarker identification will be discussed.

The aims of this study were to evaluate the impact of cosmetic and functional outcomes after breast-conserving surgery (BCS) and radiation on quality of life (QOL). In this exploratory analysis; baseline, 5 and 10 years data of patient's assessment of breast cosmesis, arm swelling/pain, limitation of movement, loss of feeling in fingers and breast sensitivity/tenderness were dichotomized and their impact on QOL (QLQ-C30) were assessed. Multivariable modelling was also performed to assess associations with QOL. The St. George and Wollongong randomized trial randomized 688 patients into the boost and no boost arms. 609, 580, and 428 patients had baseline, 5 and 10 years cosmetic data available, respectively. Similar numbers had the various functional assessments in the corresponding period. By univariate analysis, cosmesis and a number of functional outcomes were highly associated with QOL. Adjusted multivariate modelling showed that cosmesis remained associated with QOL at 5 and 10 years. Breast sensitivity, arm pain, breast separation, age and any distant cancer event were also associated with QOL on multivariate modelling at 10 years. This study highlights the importance of maintaining favorable cosmetic and functional outcomes following BCS. In addition, the clinically and statistically significant relationship between functional outcomes and QOL shows the importance for clinicians and allied health professionals in identifying, discussing, managing, and limiting these effects in women with breast cancer in order to maintain QOL.

Purpose: To evaluate comprehensively the effect of a radiotherapy boost on breast cosmetic outcomes after 5 years in patients treated with breast-conserving surgery., Methods: The St. George and Wollongong trial (NCT00138814) randomized 688 patients with histologically proven Tis-2, N 0-1, M0 carcinoma to the control arm of 50 Gy in 25 fractions (342 patients) and the boost arm of 45 Gy in 25 fractions to the whole breast followed by a 16 Gy in 8 fraction electron boost (346 patients). Five-year cosmetic outcomes were assessed by a panel subjectively in 385 patients and objectively using pBRA (relative breast retraction assessment). A subset of patients also had absolute BRA measurements. Clinician assessment and patient self-assessment of overall cosmetic and specific items as well as computer BCCT.core analysis were also performed., Results: The boost arm had improved cosmetic overall outcomes as scored by the panel and BCCT.core software with 79% (p = 0.016) and 81% (p = 0.004) excellent/good cosmesis respectively compared with 68% in no-boost arm. The boost arm also had lower pBRA and BRA values with a mean difference of 0.60 and 1.82 mm, respectively, but was not statistically significant. There was a very high proportion of overall excellent/good cosmetic outcome in 95% and 93% in the boost and no-boost arms using patient self-assessment. However, no difference in overall and specific items scored by clinician assessment and patient self-assessment was found., Conclusion: The results show the negative cosmetic effect of a 16-Gy boost is offset by a lower whole-breast dose of 45 Gy., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study is to determine whether immunohistochemical (IHC) assessment of Ki67 and p53 improves prognostication of oestrogen receptor-positive (ER+) breast cancer after breast-conserving therapy (BCT). In all, 498 patients with invasive breast cancer from a randomised trial of BCT with or without tumour bed radiation boost were assessed using IHC., Methods: The ER+ tumours were classified as 'luminal A' (LA): ER+ and/or PR+, Ki-67 low, p53-, HER2- or 'luminal B' (LB): ER+ and/or PR+and/or Ki-67 high and/or p53+ and/or HER2+. Kaplan-Meier and Cox proportional hazards methodology were used to ascertain relationships to ispilateral breast tumour recurrence (IBTR), locoregional recurrence (LRR), distant metastasis-free survival (DMFS) and breast cancer-specific survival (BCSS)., Results: In all, 73 patients previously LA were re-classified as LB: a greater than four-fold increase (4.6-19.3%) compared with ER, PR, HER2 alone. In multivariate analysis, the LB signature independently predicted LRR (hazard ratio (HR) 3.612, 95% CI 1.555-8.340, P=0.003), DMFS (HR 3.023, 95% CI 1.501-6.087, P=0.002) and BCSS (HR 3.617, 95% CI 1.629-8.031, P=0.002) but not IBTR., Conclusion: The prognostic evaluation of ER+ breast cancer is improved using a marker panel, which includes Ki-67 and p53. This may help better define a group of poor prognosis ER+ patients with a greater probability of failure with endocrine therapy.

Proscription of antiperspirant or deodorant use during adjuvant breast radiotherapy is common. The investigators were seeking an information base to facilitate design of an appropriate controlled trial of the use of deodorants during radiotherapy. The first component consisted of a survey of women after adjuvant breast radiotherapy seeking information about routine deodorant use and potential concern if deodorants were not permitted during radiotherapy. The second component comprised a literature search for any existing controlled evidence regarding harm from deodorant use during radiotherapy. Four hundred fourteen women completed surveys. Two hundred eighty recalled advice against deodorants. Two hundred ninety-nine women routinely used deodorants, 70% of whom used roll-on products. Forty-five continued deodorant use during radiation, 20 of these despite recalling advice not to wear a deodorant. Of the 233 women who routinely wore a deodorant but abstained during radiotherapy, 19% expressed a lot of concern about body odour and 45% were slightly concerned. Three controlled studies totalling 310 patients report specific deodorants versus no deodorant use which did not show statistically significantly increased skin reactions, but had only a small subset with axillary irradiation. The proscription of deodorant use during radiotherapy is of unproven benefit and causes body odour concern to the majority of women who are usual deodorant users. The next most appropriate trial would compare use of the usual deodorant versus no deodorant, would encompass a significant number of women with radiotherapy to the axilla or application of deodorant to irradiated skin areas, and include endpoints other than skin reaction alone.

Purpose: To determine the clinical utility of intrinsic molecular phenotype after breast-conserving therapy (BCT) with lumpectomy and whole-breast irradiation with or without a cavity boost., Patients and Methods: Four hundred ninety-eight patients with invasive breast cancer were enrolled into a randomized trial of BCT with or without a tumor bed radiation boost. Tumors were classified by intrinsic molecular phenotype as luminal A or B, HER-2, basal-like, or unclassified using a five-biomarker panel: estrogen receptor, progesterone receptor, HER-2, CK5/6, and epidermal growth factor receptor. Kaplan-Meier and Cox proportional hazards methodology were used to ascertain relationships to ipsilateral breast tumor recurrence (IBTR), locoregional recurrence (LRR), distant disease-free survival (DDFS), and death from breast cancer., Results: Median follow-up was 84 months. Three hundred ninety-four patients were classified as luminal A, 23 were luminal B, 52 were basal, 13 were HER-2, and 16 were unclassified. There were 24 IBTR (4.8%), 35 LRR (7%), 47 distant metastases (9.4%), and 37 breast cancer deaths (7.4%). The overall 5-year disease-free rates for the whole cohort were: IBTR 97.4%, LRR 95.6%, DDFS 92.9%, and breast cancer-specific death 96.3%. A significant difference was observed for survival between subtypes for LRR (P = .012), DDFS (P = .0035), and breast cancer-specific death (P = .0482), but not for IBTR (P = .346)., Conclusion: The 5-year and 10-year survival rates varied according to molecular subtype. Although this approach provides additional information to predict time to IBTR, LRR, DDFS, and death from breast cancer, its predictive power is less than that of traditional pathologic indices. This information may be useful in discussing outcomes and planning management with patients after BCT.

Malignant myoepithelioma of the breast (MMB) is a rare and often aggressive disease with poor prognosis. Little is known regarding its optimal treatment and progression. We describe the clinical history of a woman following excision of a benign adenomyoepithelioma which recurred years later as a radioresistant malignant myoepithelioma with high levels of ataxia telangiectasia mutated protein and mutant p53 (Cys135Phe). MMB requires close follow-up and aggressive treatment. If adjuvant radiotherapy is adopted to improve local control, minimal postoperative delay and higher doses than for standard post-mastectomy radiation are recommended.

Anastrozole is a third-generation aromatase inhibitor with an extensive evidence base to preferentially support its use in multiple scenarios in endocrine-responsive breast cancer. These include neoadjuvant treatment, immediate and delayed adjuvant treatment, salvage treatment and first-line treatment of advanced breast cancer. Compared to tamoxifen, it offers superior efficacy and a different side effect profile that results in better tolerance and compliance. Anastrozole is considered cost effective compared with tamoxifen in a variety of healthcare systems. Anastrozole has been applied to the management of a number of endocrine conditions other than breast cancer. The major future areas of interest are in breast cancer prevention, integration with surgery, radiotherapy and other systemic targeted therapies.

Using whole sections of formalin-fixed paraffin-embedded material the expression of p27(KIP-1), cyclin A and cyclin D1 was examined in 60 cases of ductal carcinoma in situ (DCIS) using routine immunohistochemistry with a median follow up of 95 months (range 10-139 months) to identify any association with disease recurrence. Fifty-six patients were treated by local excision and radiotherapy and four by mastectomy without radiotherapy. There was a highly significant positive association between p27(KIP-1) and estrogen receptor/progesterone receptor (ER/PR) status (P = 0.002, P = 0.02) and with p27(KIP-1) and cyclin D1 expression (P = 0.002). A trend between cyclin A and PR status (P = 0.08) was also identified. These findings mirror those described in invasive ductal carcinoma, but there were no associations of any biomarker with histological parameters such as nuclear grade or with local recurrence on univariate analysis, which was present in four of the 56 locally excised group (7.1%). Further examination of a larger cohort may be worthwhile to explore the possible role as adjunctive predictive markers to aid clinical decision making.