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Background: Adjuvant radiotherapy (RT) after breast-conserving surgery for DCIS lowers the relative local recurrence risk by half. To identify a low-risk group with the minimal benefit of RT could avoid side effects and spare costs. In this study, the outcome was compared for different RT-strategies using data from the randomized SweDCIS trial., Material and Methods: Five strategies were compared in a Swedish setting: RT-to-none or all, RT to high-risk women defined by DCISionRT, modified Radiation Therapy Oncology Group (RTOG) 9804 criteria, and Swedish Guidelines. Ten-year recurrence risks and cost including adjuvant RT and local recurrence treatment cost were calculated., Results: The mean age at recurrence was 64.4 years (36-90) and the mean cost for treating a recurrence was $21,104. In the SweDCIS cohort ( n  = 504), 59 women developed DCIS, and 31 invasive recurrence. Ten-year absolute local recurrence risk (invasive and DCIS) according to different strategies varied between 18.6% (12.5-23.6%) and 7.8% (5.0-12.6%) for RT-to-none or to-all, with an additional cost of $2614 US dollars per women and $24,201 per prevented recurrence for RT-to-all. The risk differences between other strategies were not statistically significant, but the larger proportion receiving RT, the fewer recurrences. DCISionRT spared 48% from RT with 8.1% less recurrences compared to RT-to-none, and a cost of $10,534 per prevented recurrence with additional cost depending on the price of the test. RTOG 9804 spared 39% from RT, with 9.7% less recurrences, $9525 per prevented recurrence and Swedish Guidelines spared 13% from RT, with 10.0% less recurrences, and $21,521 per prevented recurrence., Conclusion: It seems reasonable to omit RT in pre-specified low-risk groups with minimal effect on recurrence risk. Costs per prevented recurrence varied more than two-fold but which strategy that could be considered most cost-effective needs to be further evaluated, including the DCISionRT-test price.

Purpose: Mammography (MG) is the standard imaging in surveillance of women with a personal history of breast cancer or DCIS (PHBC), supplemented with ultrasound. Contrast Enhanced Mammography (CEM) has higher sensitivity than MG and US. We report the performance of CEM compared with MG ± US., Methods: A retrospective study of patients undergoing their first surveillance CEM in an Australian hospital setting between June 2006 and October 2020. Cases where a patient was recalled for assessment were identified, recording radiology, pathology and treatment details. Blinded re-reading of recalled cases was performed to determine the contribution of contrast. Use of surveillance US across the board was assessed for the period., Results: 73/1191 (6.1%) patients were recalled. 35 (48%) were true positives (TP), with 26 invasive cancers and 9 cases of DCIS, while 38 (52%) were false positive (FP) with a positive predictive value (PPV) 47.9%. 32/73 were recalled due to MG findings, while 41/73 were only recalled due to Contrast. 14/73 had 'minimal signs' with a lesion identifiable on MG with knowledge of the contrast finding, while 27/73 were visible only with contrast. 41% (17/41) recalled due to contrast were TP. Contrast-only TPs were found with low and high mammographic density (MD). Screening breast US reduced by 55% in the year after CEM was implemented., Conclusion: Compared to MG, CEM as a single surveillance modality for those with PHBC has higher sensitivity and comparable specificity, identifying additional malignant lesions that are clinically significant. Investigation of interval cancer and subsequent round outcomes is warranted., (© 2023. The Author(s).)

Purpose: There is an unmet need to identify women diagnosed with ductal carcinoma in situ (DCIS) with a low risk of in-breast recurrence (IBR) after breast conserving surgery (BCS), which could omit radiation therapy (RT), and also to identify those with elevated IBR risk remaining after BCS plus RT. We evaluated a novel biosignature for a residual risk subtype (RRt) to help identify patients with elevated IBR risk after BCS plus RT., Methods and Materials: Women with DCIS treated with BCS with or without RT at centers in the US, Australia, and Sweden (n = 926) were evaluated. Patients were classified into 3 biosignature risk groups using the decision score (DS) and the RRt category: (1) Low Risk (DS ≤2.8 without RRt), (2) Elevated Risk (DS >2.8 without RRt), and (3) Residual Risk (DS >2.8 with RRt). Total and invasive IBR rates were assessed by risk group and treatment., Results: In patients at low risk, there was no significant difference in IBR rates with or without RT (total, P = .8; invasive IBR, P = .7), and there were low overall 10-year rates (total, 5.1%; invasive, 2.7%). In patients with elevated risk, IBR rates were decreased with RT (total: hazard ratio [HR], 0.25; P < .001; invasive: HR, 0.28; P = .005); 10-year rates were 20.6% versus 4.9% (total) and 10.9% versus 3.1% (invasive). In patients with residual risk, although IBR rates decreased with RT after BCS (total: HR, 0.21; P < .001; invasive: HR, 0.29; P = .028), IBR rates remained significantly higher after RT compared with patients with elevated risk (HR, 2.5; 95% CI, 1.2-5.4; P = .018), with 10-year rates of 42.1% versus 14.7% (total) and 18.3% versus 6.5% (invasive)., Conclusions: The novel biosignature identified patients with 3 distinct risk profiles: Low Risk patients with a low recurrence risk with or without adjuvant RT, Elevated Risk patients with excellent outcomes after BCS plus RT, and Residual Risk patients with an elevated recurrence risk remaining after BCS plus RT, warranting potential intensified or alternative treatment approaches., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Whilst some of the diversity in management of women with ductal carcinoma in situ (DCIS) may be explained by tumour characteristics, the role of patient preference and the factors underlying those preferences have been less frequently examined. We have used a descriptive qualitative study to explore treatment decisions for a group of Australian women diagnosed with DCIS through mammographic screening. Semi-structured telephone interviews were performed with 16 women diagnosed with DCIS between January 2012 and December 2018, recruited through the LifePool dataset (a subset of BreastScreen participants who have agreed to participate in research). Content analysis using deductive coding identified three themes: participants did not have a clear understanding of their diagnosis or prognosis; reported involvement in decision making about management varied; specific factors including the psychosexual impact of mastectomy and perceptions of radiotherapy, could act as barriers or facilitators to specific decisions about treatment. The treatment the women received was not simply determined by the characteristics of their disease. Interaction with the managing clinician was pivotal, however many other factors played a part in individual decisions. Recognising that decisions are not purely a function of disease characteristics is important for both women with DCIS and the clinicians who care for them., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The impact of MRI on improving surgical outcomes in DCIS is debated. Here, we explore the utility of MRI in the investigation and management of DCIS in three key areas. Firstly, we highlight that MRI is likely to be a more accurate predictor of actual tumour size than conventional imaging. Secondly, we examine mastectomy rates and reoperation rates across the literature and suggest that surgical outcomes do not differ between pre-operative MRI and conventional imaging groups, despite improved size estimation on MRI. Finally, we examine the rapidly developing field of oncoplastic breast surgery and highlight a paucity of data in determining the usefulness of pre-operative MRI in this field, despite this being an oncologically safe alternative with improved patient outcomes and satisfaction., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine the government and out-of-pocket community costs (out-of-hospital medical services and prescription medicines) associated with screen-detected and community-detected cancers (i.e. cancers detected outside of Australia's organised screening program [BreastScreen])., Methods: We analyse administrative data on government-subsidised medical services and prescription medicines for 568 Victorian women diagnosed with breast cancer or ductal carcinoma in situ (DCIS). Using multivariable regression analysis, we estimate the government and out-of-pocket community costs incurred in the three years after diagnosis for screen-detected cancers and community-detected cancers. Additionally, we estimate the government costs associated with diagnosis within and outside of BreastScreen., Results: Average government costs for breast cancer diagnosis were similar within and outside of BreastScreen [$808 (lower limit 676; upper limit 940) vs $837 (95%CI 671; 1,003) respectively]; however, women with community-detected cancers incurred an additional $254 (95%CI 175; 332) out-of-pocket. Controlling for differences in known cancer characteristics, compared to screen-detected cancers, community-detected breast cancers were associated with an additional $2,622 (95%CI 644; 4,776) in government expenditure in the three years following diagnosis. Adverse cancer characteristics that were more prevalent in community-detected cancers (high grade, lymph node involvement, HER2 positive receptor status) were associated with increased government and out-of-pocket costs., Conclusions: Community-detected breast cancers were associated with increased government and out-of-pocket costs. Implications for public health: These costs should be considered when evaluating current and alternative breast cancer screening strategies., (© 2020 The Authors.)

Background: Mammographic screening reduces breast cancer mortality but may lead to the overdiagnosis and overtreatment of low-risk breast cancers. Conservative management may reduce the potential harm of overtreatment, yet little is known about the impact upon quality of life., Objectives: To quantify women's preferences for managing low-risk screen detected ductal carcinoma in situ (DCIS), including the acceptability of active monitoring as an alternative treatment., Methods: Utilities (cardinal measures of quality of life) were elicited from 172 women using visual analogue scales (VASs), standard gambles, and the Euro-Qol-5D-5L questionnaire for seven health states describing treatments for low-risk DCIS. Sociodemographics and breast cancer history were examined as predictors of utility., Results: Both patients and non-patients valued active monitoring more favourably on average than conventional treatment. Utilities were lowest for DCIS treated with mastectomy (VAS: 0.454) or breast conserving surgery (BCS) with adjuvant radiotherapy (VAS: 0.575). The utility of active monitoring was comparable to BCS alone but was rated more favourably as progression risk was reduced from 40% to 10%. Disutility for active monitoring was likely driven by anxiety around progression, whereas conventional management impacted other dimensions of quality of life. The heterogeneity between individual preferences could not be explained by sociodemographic variables, suggesting that the factors influencing women's preferences are complex., Conclusions: Active monitoring of low-risk DCIS is likely to be an acceptable alternative for reducing the impact of overdiagnosis and overtreatment in terms of quality of life. Further research is required to determine subgroups more likely to opt for conservative management., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The current model for breast cancer progression proposes independent 'low grade (LG)-like' and 'high grade (HG)-like' pathways but lacks a known precursor to HG cancer. We applied low-coverage whole-genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. Fourteen out of twenty isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG-like CNA than LG DCIS (e.g. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent 'low grade-like' and 'high grade-like' pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH cases could be more clinically significant than LG DCIS, requiring biomarkers for personalising management. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P=0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P=0.005), including a significant positive association with amplification or gain of ERBB2 (P<0.05). The association between TP53 mutation and ERBB2 amplification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P=0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer and a frequent mammographic finding requiring treatment. Up to 25% of DCIS can recur and half of recurrences are invasive, but there are no reliable biomarkers for recurrence. We hypothesised that copy number aberrations could predict likelihood of recurrence. We analysed a cohort of pure DCIS cases treated only with wide local excision for genome-wide copy number and loss of heterozygosity using Affymetrix OncoScan MIP arrays. Cases included those without recurrence within 7 years (n = 25) and with recurrence between 1 and 5 years after diagnosis (n = 15). Pure DCIS were broadly similar in copy number changes compared with invasive breast cancer, with the consistent exception of a greater frequency of ERBB2 amplification in DCIS. There were no significant differences in age or ER status between the cases with a recurrence vs those without. Overall, the DCIS cases with recurrence had more copy number events than the DCIS without recurrence. The increased copy number appeared non-random with several genomic regions showing an increase in frequency in recurrent cases, including 20 q gain, ERBB2 amplification and 15q loss. Copy number changes may provide prognostic information for DCIS recurrence, but validation in additional cohorts is required.

Background: A sound understanding of the benefits of different treatment options and their health-related quality of life (HRQoL) impacts is required for optimal breast cancer care., Methods: A cross-sectional cohort study was conducted to determine the prevalence and severity of persistent functional decrements and symptoms and identify demographic, clinical and treatment variables associated with poorer outcomes. Four hundred English-speaking women treated for ductal carcinoma-in-situ or stage I to III breast cancer between 1999 and 2009, at least 12 months after surgery and currently disease free, were randomly selected and invited to complete (1) the Breast Cancer Treatment Outcome Scale and (2) the EORTC core Quality of Life Questionnaire, version 3., Results: The response rate was 85.60 %. Many participants reported moderate to severe decrements in a number of HRQoL domains, including functional well-being (15 %), cosmetic status (32 %) and overall quality of life (21 %). There were significant associations (p < .05) between younger age and poorer HRQoL but none between time since surgery and morbidity (p > .05). Different treatments were associated with different HRQoL impacts. Poorer functional status was predicted by axillary dissection (p = .011), and adjuvant radiotherapy was a significant predictor of breast-specific pain (p < .05)., Conclusions: Many breast cancer survivors report long-term morbidity that is unaffected by time since surgery. The significant associations between the extent of locoregional therapies and poorer HRQoL outcomes emphasize the importance of the safe tailoring of these treatments.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive ductal carcinoma (IDC). Annotation of the genetic differences between the two lesions may assist in the identification of genes that promote the invasive phenotype. Synchronous DCIS and IDC cells were microdissected from FFPE tissue and analysed by molecular inversion probe (MIP) copy number arrays. Matched IDC and DCIS showed highly similar copy number profiles (average of 83% of the genome shared) indicating a common clonal origin although there is evidence that the DCIS continues to evolve in parallel with the co-existing IDC. Four chromosomal regions of loss (3q, 6q, 8p and 11q) and four regions of gain (5q, 16p, 19q and 20) were recurrently affected in IDC but not in DCIS. CCND1 and MYC showed increased amplitude of gain in IDC. One region of loss (17p11.2) was specific to DCIS. IDC-specific regions include genes with previous links to breast cancer progression and potential therapeutic targets such as AXL, SPHK1 and PLAUR.

Background: Ductal carcinoma in situ (DCIS) is commonly identified on screening mammography. Standard treatment for localized DCIS is wide local excision (WLE) and adjuvant radiotherapy. This approach represents overtreatment in many cases, where the DCIS would never have become clinically significant, or where less intensive treatment would have been satisfactory. We reviewed the medium-term outcome of a cohort of screen detected DCIS patients treated mainly with WLE without radiotherapy., Methods: All patients diagnosed with DCIS at NorthWestern BreastScreen between January 1994 and December 2005 were identified from a prospective database. Demographic, pathological, treatment, and outcome data were collected and analyzed. Survival and local recurrence (LR) rates were determined, and associations between various factors and recurrence were analyzed., Results: A total of 422 patients were diagnosed with DCIS. There were 400 patients treated with WLE, and 27 of these received adjuvant radiotherapy. The 5- and 8-year overall and breast cancer specific survival rates were 96.1 and 91.3%, and 99.6 and 99.3%, respectively. The local recurrence rate was 15.4 and 17.1% at 5 and 8 years. Of 56 local recurrences, 34 had WLE after recurrence, 16 of which had adjuvant radiotherapy. No single factor was statistically significantly associated with local recurrence, although combining factors revealed groups where the LR rate was less than 5%., Conclusions: Breast cancer specific mortality was very low in this cohort of older patients with screen-detected DCIS. There was a moderate rate of local recurrence that could usually be salvaged with breast conservation. Decisions regarding adjuvant radiotherapy should take these findings into account.