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BACKGROUND: We sought to identify characteristics of metastatic breast cancer (MBC) patients who may benefit most from primary tumor resection. METHODS: Recursive partitioning analysis (RPA) was used to categorize non-surgical patients with de novo MBC in the NCDB (2010–2015) into 3 groups (I/II/III) based on 3-year overall survival (OS). After bootstrapping (BS), group-level profiles were applied, and the association of surgery with OS was estimated using Cox proportional hazards models. RESULTS: All patients benefitted from surgery (median OS, surgery vs no surgery): 72.7 vs 42.9 months, 47.3 vs 30.4 months, 23.8 vs 14.4 months (all p

Due to widespread adoption of screening mammography, there has been a significant increase in new diagnoses of ductal carcinoma in situ (DCIS). However, DCIS prognosis remains unclear. To address this gap, we developed an in vivo model, Mouse-INtraDuctal (MIND), in which patient-derived DCIS epithelial cells are injected intraductally and allowed to progress naturally in mice. Similar to human DCIS, the cancer cells formed in situ lesions inside the mouse mammary ducts and mimicked all histologic subtypes including micropapillary, papillary, cribriform, solid, and comedo. Among 37 patient samples injected into 202 xenografts, at median duration of 9 months, 20 samples (54%) injected into 95 xenografts showed in vivo invasive progression, while 17 (46%) samples injected into 107 xenografts remained non-invasive. Among the 20 samples that showed invasive progression, nine samples injected into 54 xenografts exhibited a mixed pattern in which some xenografts showed invasive progression while others remained non-invasive. Among the clinically relevant biomarkers, only elevated progesterone receptor expression in patient DCIS and the extent of in vivo growth in xenografts predicted an invasive outcome. The Tempus XT assay was used on 16 patient DCIS formalin-fixed, paraffin-embedded sections including eight DCISs that showed invasive progression, five DCISs that remained non-invasive, and three DCISs that showed a mixed pattern in the xenografts. Analysis of the frequency of cancer-related pathogenic mutations among the groups showed no significant differences (KW: p 0.05). There were also no differences in the frequency of high, moderate, or low severity mutations (KW; p 0.05). These results suggest that genetic changes in the DCIS are not the primary driver for the development of invasive disease. © 2021 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Breast cancer (BC) is the most common malignancy in women. Particular subtypes with aggressive behavior are major contributors to poor outcomes. Triple-negative breast cancer (TNBC) is difficult to treat, pro-inflammatory, and highly metastatic. We demonstrate that TNBC cells express TLR9 and are responsive to TLR9 ligands, and treatment of TNBC cells with chemotherapy increases the release of nucleic-acid-containing damage-associated molecular patterns (NA DAMPs) in cell culture. Such culture-derived and breast cancer patient-derived NA DAMPs increase TLR9 activation and TNBC cell invasion in vitro. Notably, treatment with the polyamidoamine dendrimer generation 3.0 (PAMAM-G3) behaved as a nucleic acid scavenger (NAS) and significantly mitigates such effects. In mice that develop spontaneous BC induced by polyoma middle T oncoprotein (MMTV-PyMT), treatment with PAMAM-G3 significantly reduces lung metastasis. Thus, NAS treatment mitigates cancer-induced inflammation and metastasis and represents a novel therapeutic approach for combating breast cancer., Graphical abstract, Using a nucleic acid scavenger, Eteshola et al. present an innovative way to slow down metastasis following standard-of-care therapy in difficult-to-treat malignancies such as triple-negative breast cancer. By capturing tumor-derived nucleic acid-containing DAMPs in vitro and in a spontaneous transgenic murine model, this strategy lays the groundwork for improving the clinical management of cancer by adding an adjuvant that limits metastatic spread.

PURPOSEThe Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed.METHODSWe conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non–breast cancer deaths and new nonbreast primary cancers from the invasive disease–free survival end point.RESULTSAmong 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low.CONCLUSIONWe recommend an additional end point, invasive breast cancer–free survival, which includes all invasive disease–free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.

Background Radiotherapy (RT) following breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces ipsilateral breast event rates in clinical trials. This study assessed the impact of DCIS treatment on a 20-year risk of ipsilateral DCIS (iDCIS) and ipsilateral invasive breast cancer (iIBC) in a population-based cohort. Methods The cohort comprised all women diagnosed with DCIS in the Netherlands during 1989–2004 with follow-up until 2017. Cumulative incidence of iDCIS and iIBC following BCS and BCS + RT were assessed. Associations of DCIS treatment with iDCIS and iIBC risk were estimated in multivariable Cox models. Results The 20-year cumulative incidence of any ipsilateral breast event was 30.6% (95% confidence interval (CI): 28.9–32.6) after BCS compared to 18.2% (95% CI 16.3–20.3) following BCS + RT. Women treated with BCS compared to BCS + RT had higher risk of developing iDCIS and iIBC within 5 years after DCIS diagnosis (for iDCIS: hazard ratio (HR)age 3.2 (95% CI 1.6–6.6); HRage ≥ 50 3.6 (95% CI 2.6–4.8) and for iIBC: HRage 2.1 (95% CI 1.4–3.2); HRage ≥ 50 4.3 (95% CI 3.0–6.0)). After 10 years, the risk of iDCIS and iIBC no longer differed for BCS versus BCS + RT (for iDCIS: HRage 0.7 (95% CI 0.3–1.5); HRage ≥ 50 0.7 (95% CI 0.4–1.3) and for iIBC: HRage 0.6 (95% CI 0.4–0.9); HRage ≥ 50 1.2 (95% CI 0.9–1.6)). Conclusion RT is associated with lower iDCIS and iIBC risk up to 10 years after BCS, but this effect wanes thereafter.

BACKGROUND. Contralateral axillary nodal metastases (CAM) is classified as stage IV disease, although many centers treat CAM with curative intent. We hypothesized that patients with CAM, treated with multimodality therapy, would have improved overall survival (OS) versus patients with distant metastatic disease (M1) and similar OS to those with locally advanced breast cancer (LABC). METHODS. Using the NCDB (2004–2016), we categorized adult patients with node-positive breast cancer into three study groups: LABC, CAM, and M1. Kaplan-Meier curves were used to visualize the unadjusted OS. Cox proportional hazards models were used to estimate the association of study group with OS. RESULTS. A total of 94,487 patients were identified: 122 with CAM, 12,325 with LABC, and 82,040 with M1 (median follow-up 63.6 months). LABC and CAM patients had similar histology and rates of chemotherapy and endocrine therapy receipt. However, the CAM group had significantly larger tumors, more estrogen-receptor expression, higher T-stage, and more mastectomies than the LABC group. Compared with M1 patients, CAM patients were more likely to have grade 3 and cT4 tumors. Patients with CAM and LABC had similar 5-year unadjusted OS and significantly improved OS vs M1 patients. After adjustment, LABC and CAM patients continued to have similar OS and better OS vs M1 patients. CONCLUSIONS. CAM patients who receive multi-modal therapy with curative intent may have OS more comparable to LABC patients than M1 patients. Out data support a reevaluation of whether CAM should remain classified as M1, as N3 may better reflect disease prognosis and treatment goals.

BACKGROUND. Although metastatic breast cancer (MBC) remains incurable, advances in therapies have improved survival. Using a contemporary dataset of de novo MBC patients, we explore how overall (OS) and cancer-specific survival (CSS) changed over time. METHODS. All patients with de novo MBC from 1988 to 2016 were selected from Surveillance, Epidemiology, and End Results (SEER) 18. Unadjusted OS and CSS were estimated by Kaplan–Meier method and stratified by disease characteristics. Cox proportional hazards models determined factors associated with survival. RESULTS. 47,034 patients were included, with median OS of 25 months and CSS of 27 months. Survival steadily improved over time (1988: 1-year OS 62%, CSS 65%; 2015: 1-year OS 72%, CSS 74%). Patients with triple-negative breast cancer (TNBC) had the worst prognosis and were most likely to die from MBC [versus human epidermal growth factor receptor 2 (HER2)+ and hormone receptor (HR)+/HER2−]. Those with ≥ 4 sites of metastatic disease were also more likely to die from MBC with nearly identical OS and CSS (5-year OS 9%, CSS 9%), when compared with those with 1 site (5-year OS 31%, CSS 35%). After adjustment, improved CSS was associated with bone-only disease [hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.83–0.94], while TNBC (versus HER2+: HR 3.12, 95% CI 2.89–3.36) and > 3 sites of metastatic disease (versus 1 site: HR 3.24, 95% CI 2.68–3.91) were associated with worse CSS (all p < 0.001). CONCLUSIONS. Accurate prognostic estimates are essential for patient care. As treatments for patients with MBC have expanded, OS and CSS have improved, and more patients, particularly with limited distant disease or favorable tumor subtypes, are also dying from non-MBC causes.

PURPOSETo develop guideline recommendations concerning optimal neoadjuvant therapy for breast cancer.METHODSASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy for breast cancer and provide recommended care options.RESULTSA total of 41 articles met eligibility criteria and form the evidentiary basis for the guideline recommendations.RECOMMENDATIONSPatients undergoing neoadjuvant therapy should be managed by a multidisciplinary care team. Appropriate candidates for neoadjuvant therapy include patients with inflammatory breast cancer and those in whom residual disease may prompt a change in therapy. Neoadjuvant therapy can also be used to reduce the extent of local therapy or reduce delays in initiating therapy. Although tumor histology, grade, stage, and estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) expression should routinely be used to guide clinical decisions, there is insufficient evidence to support the use of other markers or genomic profiles. Patients with triple-negative breast cancer (TNBC) who have clinically node-positive and/or at least T1c disease should be offered an anthracycline- and taxane-containing regimen; those with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy. Carboplatin may be offered to patients with TNBC to increase pathologic complete response. There is currently insufficient evidence to support adding immune checkpoint inhibitors to standard chemotherapy. In patients with hormone receptor (HR)-positive (HR-positive), HER2-negative tumors, neoadjuvant chemotherapy can be used when a treatment decision can be made without surgical information. Among postmenopausal patients with HR-positive, HER2-negative disease, hormone therapy can be used to downstage disease. Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy in combination with anti-HER2-positive therapy. Patients with T1aN0 and T1bN0, HER2-positive disease should not be routinely offered neoadjuvant therapy. Additional information is available at www.asco.org/breast-cancer-guidelines .

Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal stiffening in tumours should identify biomarkers to stratify patients for therapy and interventions to improve outcome. We profiled lysyl hydroxylase-mediated and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in aggressive human breast cancer subtypes with the stiffest stroma. These tissues harbour the highest number of tumour-associated macrophages, whose therapeutic ablation in experimental models reduced metastasis, and decreased collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme, lysyl oxidase, had no impact on collagen crosslinking in PyMT mammary tumours, whereas stromal cell targeting did. Stromal cells in microdissected human tumours expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of biopsies from a cohort of patients with breast cancer revealed that stromal expression of lysyl hydroxylase 2, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening, correlated significantly with disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumour aggression and identify lysyl hydroxylase 2 as a stromal biomarker.

BACKGROUND: We examined whether the National Comprehensive Cancer Network distress thermometer (DT), a patient-reported outcome measure, could be used to identify levels and causes of distress associated with racial/ethnic disparities in time to care among patients with breast cancer. METHODS: We identified women aged ≥18 years with stage O-IV breast cancer who were diagnosed in a single health system between January 2014 and July 2016. The baseline visit was defined as the first postdiagnosis, pretreatment clinical evaluation. Zero-inflated negative binomial (ZINB) regression (modeling non-zero DT scores and DT scores = 0) and logistic regression (modeling DT score ≥ 4, threshold for social services referral) were used to examine associations between baseline score (0 = none to 10 = extreme) and types of stressors (emotional, familial, practical, physical, spiritual) after adjustment for race/ethnicity and other characteristics. Linear regression with log transformation was used to identify predictors of time to evaluation and time to treatment. RESULTS: A total of 1029 women were included (median baseline DT score = 4). Emotional, physical, and practical stressors were associated with distress in both the ZINB and logistic models (all P < .05). Black patients (n = 258) were more likely to report no distress than Whites (n = 675; ZINB zero model odds ratio, 2.72; 95% CI, 1.68-4.40; P < .001) despite reporting a similar number of stressors (P = .07). Higher DT scores were associated with shorter time to evaluation and time to treatment while being Black and having physical or practical stressors were associated with delays in both (all P < .05). CONCLUSIONS: Patient-reported stressors predicted delays in time to care, but patient-reported levels of distress did not, with Black patients having delayed time to care despite reporting low levels of distress. We describe anticipatory, culturally responsive strategies for using patient-reported outcomes to address observed disparities.

Rationale and Objectives The purpose of this study is to quantify breast radiologists’ performance at predicting occult invasive disease when ductal carcinoma in situ (DCIS) presents as calcifications on mammography and to identify imaging and histopathological features that are associated with radiologists’ performance. Materials and Methods Mammographically detected calcifications that were initially diagnosed as DCIS on core biopsy and underwent definitive surgical excision between 2010 and 2015 were identified. Thirty cases of suspicious calcifications upstaged to invasive ductal carcinoma and 120 cases of DCIS confirmed at the time of definitive surgery were randomly selected. Nuclear grade, estrogen and progesterone receptor status, patient age, calcification long axis length, and breast density were collected. Ten breast radiologists who were blinded to all clinical and pathology data independently reviewed all cases and estimated the likelihood that the DCIS would be upstaged to invasive disease at surgical excision. Subgroup analysis was performed based on nuclear grade, long axis length, breast density and after exclusion of microinvasive disease. Results Reader performance to predict upstaging ranged from an area under the receiver operating characteristic curve (AUC) of 0.541–0.684 with a mean AUC of 0.620 (95%CI: 0.489–0.751). Performances improved for lesions smaller than 2 cm (AUC: 0.676 vs 0.500; p = 0.002). The exclusion of microinvasive cases also improved performance (AUC: 0.651 vs 0.620; p = 0.005). There was no difference in performance based on breast density (p = 0.850) or nuclear grade (p = 0.270) Conclusion Radiologists were able to predict invasive disease better than chance, particularly for smaller DCIS lesions (

BACKGROUND: Elderly women with clinically node-positive (cN+) breast cancer (BC) often have comorbidities that limit life expectancy and complicate treatment. We sought to determine whether the number of lymph nodes (LNs) retrieved among older women with node-positive breast cancer was associated with overall survival (OS). METHODS: Using the National Cancer Database (2010–2015), women 70–90y with cN+ BC and ≥1 LN removed were categorized by treatment sequence: upfront surgery or neoadjuvant chemotherapy (NAC). Multivariable Cox proportional hazards models with restricted cubic splines characterized the functional association of LN retrieval with OS; threshold values of LN retrieval were estimated. Cox proportional hazards models were used to estimate the association of LN retrieval groups with OS. RESULTS: In the upfront surgery cohort, a non-linear association was identified between LNs retrieved and OS. In the NAC cohort, no association was identified. For the upfront surgery cohort, the optimal threshold value of LN retrieval was 21 LN (90% CI 18–23). Based on this estimate, LN retrieval groups were created: 23 LNs. After adjustment, retrieval of

BACKGROUND: The goal of this study was to assess the impact of trastuzumab on locoregional failure. METHODS: The analysis included 2763 patients with HER2-positive (HER2+) breast cancer who were randomly assigned to adjuvant doxorubicin (A), cyclophosphamide (C), paclitaxel (T) and trastuzumab (H) (arm A, AC→T [n = 922]; arm B, AC→T→H [n = 988]; arm C, AC→T+H→H [n = 853]). Radiotherapy was given after AC→T concurrently with H. Radiotherapy was given after lumpectomy (L) or after mastectomy (M) with ≥4 positive lymph nodes but was optional for 1 to 3 positive lymph nodes. Locoregional failures at 10 years (LFR10) as first events were compared using competing risk analysis. RESULTS: The median follow-up was 13.0 years. The first site of failure was local-only in 96 cases, locoregional in 16 cases, regional in 32 cases, and not specified in 2 cases; LFR10 was 4.8% (95% CI 4.1%–5.7%). LFR10 was 5.5% (95% CI 4.3%–7.2%), 4.9% (95% CI 3.7%–6.4%), and 2.8% (95% CI 1.9%–4.1%) in arms A, B, and C (B vs A: hazard ratio [HR] 0.91, P = .62; C vs A: HR 0.72, P = .12). For estrogen receptor–positive patients, LFR10 was 3.7% (95% CI 2.8%–4.8%) and for estrogen receptor–negative patients, it was 6.1% (95% CI 5.0%–7.4%; HR 0.61, P = .004). Local treatment included L+RT (n = 1044 [38%]), M+RT (n = 1025 [37%]), and M (n = 694 [25%]). LFR10 was 6.% (95% CI 5.0%–7.8%), 3.0% (95% CI 2.1%–4.3%), and 5.5% (95% CI 4.0%–7.4%) for L+RT, M+RT, and M, respectively (M+RT vs L+RT: HR 0.43, P < .001; M vs L+RT: HR 0.88, P = .57). For 1 to 3 positive lymph nodes, LFR10 was 6.5% (95% CI 4.8%–8.9%), 4.1% (95% CI 2.4%–7.0%), and 4.3% (95% CI 2.9%–6.5%) in L+RT, M+RT, and M, respectively (M vs L+RT: HR 0.68, P = .14; M vs M+RT: HR 1.2, P = .6). CONCLUSION: Low 10-year LFRs were seen regardless of trastuzumab use. Differences in local therapy in patients with 1 to 3 positive lymph nodes did not appear to improve local control. Local therapy studies for HER2+ and other tumor characteristics are important as the role of local therapies continues to evolve.

OBJECTIVE: We aim to identify prognostic groups within a de novo metastatic cohort, incorporating both anatomic and biologic factors. BACKGROUND: Staging for breast cancer now includes anatomic and biologic factors, although the guidelines for stage IV disease do not account for how these factors may influence outcomes. METHODS: Adults with de novo metastatic breast cancer were selected from the National Cancer DataBase (2010–2013). Recursive partitioning analysis was used to group patients with similar overall survival (OS) based on clinical T/N stage, tumor grade, ER, PR, HER2, number of metastatic sites, and presence of bone-only metastases. Categories were created by amalgamating homogeneous groups based on 3-year OS rates (stage IVA: >50%, stage IVB: 30%–50%, stage IVC: 1) as the first stratification point, and ER status as the second stratification point for both resulting groups. Additional divisions were made based on HER2 status, PR status, cT stage, tumor grade, and presence of bone-only metastases. After bootstrapping, significant differences in 3-year OS were noted between the 3 groups [stage IVB vs IVA: HR 1.58 (95% confidence interval 1.50–1.67), stage IVC vs IVA: HR 3.54 (95% confidence interval 3.33–3.77)]. CONCLUSIONS: Both anatomic and biologic factors yielded reliable and reproducible prognostic estimates among patients with metastatic disease. These findings support formal stratification of de novo stage IV breast cancer into 3 distinct prognosis groups.

Background The COVID-19 pandemic has posed extraordinary demands from patients, providers, and health care systems. Despite this, surgical oncologists must maintain focus on providing high-quality, empathetic care for the almost 2 million patients nationally who will be diagnosed with operable cancer this year. The focus of hospitals is transitioning from initial COVID-19 preparedness activities to a more sustained approach to cancer care. Methods Editorial Board members provided observations of the implications of the pandemic on providing care to surgical oncology patients. Results Strategies are presented that have allowed institutions to successfully prepare for cancer care during COVID-19, as well as other strategies that will help hospitals and surgical oncologists manage anticipated challenges in the near term. Perspectives are provided on: (1) maintaining a safe environment for surgical oncology care; (2) redirecting the multidisciplinary model to guide surgical decisions; (3) harnessing telemedicine to accommodate requisite physical distancing; (4) understanding interactions between SARS CoV-2 and cancer therapy; (5) considering the ethical impact of professional guidelines for surgery prioritization; and (6) advocating for our patients who require oncologic surgery in the midst of the COVID-19 pandemic. Conclusions Until an effective vaccine becomes available for widespread use, it is imperative that surgical oncologists remain focused on providing optimal care for our cancer patients while managing the demands that the COVID-19 pandemic will continue to impose on all of us.

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

Intra-tumoral heterogeneity (ITH) could represent clonal evolution where subclones with greater fitness confer more malignant phenotypes and invasion constitutes an evolutionary bottleneck. Alternatively, ITH could represent branching evolution with invasion of multiple subclones. The two models respectively predict a hierarchy of subclones arranged by phenotype, or multiple subclones with shared phenotypes. We delineate these modes of invasion by merging ancestral, topographic, and phenotypic information from 12 human colorectal tumors (11 carcinomas, 1 adenoma) obtained through saturation microdissection of 325 small tumor regions. The majority of subclones (29/46, 60%) share superficial and invasive phenotypes. Of 11 carcinomas, 9 show evidence of multiclonal invasion, and invasive and metastatic subclones arise early along the ancestral trees. Early multiclonal invasion in the majority of these tumors indicates the expansion of co-evolving subclones with similar malignant potential in absence of late bottlenecks and suggests that barriers to invasion are minimal during colorectal cancer growth., Invasion is a critical step in tumor development. Here, in colorectal cancer, the authors show that multiclonal invasion of the muscularis mucosae is pervasive, suggesting that invasive capacity is not a significant bottleneck in the evolution of the disease.

Background: Guideline-concordant care (GCC) for DCIS includes surgery, radiation, and endocrine treatment. Active surveillance (AS) is a strategy under study for management of low risk DCIS. The PORTAL Study was designed to evaluate patient reported outcomes (PROs) after GCC for DCIS compared to women who received AS for DCIS combined with women with a history of other atypical lesions (atypical ductal hyperplasia (ADH), or atypical lobular hyperplasia/lobular carcinoma in situ (LN), as proxies for AS-managed DCIS. Methods: The PORTAL Study invited women age≥ 18, diagnosed with DCIS, ADH, or LN between 2012-2017 from 4 academic centers to complete a one-time, cross-sectional survey. Clinical, pathological, and treatment information was obtained from medical record review. The primary outcome was breast/chest wall pain assessed with the Breast Cancer Pain Questionnaire (BCPQ) including severity (10-point scale, ≥3=clinically relevant), a Pain Burden Index (PBI), which is a composite of severity, frequency, and location (breast, arm, side, axilla) and assessments of sensory disturbances, and impact of pain on emotional and physical functioning. Additional PROs included measures of generalized pain (Brief Pain Inventory), anxiety (STAI-Short Form), depression (CES-D), and QOL (Quality of Life in Adult Cancer Survivors). Pain, psychosocial, and QOL outcomes were compared between the GCC vs. AS groups using Wilcoxon Rank Sum and Chi-Square tests. Results: Of 1565 patients invited and sent a survey, 927 (59%) responded to the survey with evaluable pain outcome data. Median time from diagnosis was 3.8 years. Median age at survey completion was 58 (range: 26-94) years; 13% identified as non-White; 4% Hispanic. Among those with DCIS (n=554), 97% had GCC (62%, lumpectomy, 38%, mastectomy; 48%, radiation), representing 58% of participants vs 42% representing AS. The prevalence of clinically relevant pain was higher in the GCC vs. AS group (16.5% vs 9%, p=.0009). Median BCPQ-PBI, sensory disturbance, physical, and emotional impact scores were all higher (p BCPQ Scores, GCC vs. ASGCCASMean (range)Median (IQR)Mean (range)Median (IQR)p*PBI6.4 (0-80)0 (0-9)2.9 (0-64)0 (0-0) Citation Format: Shoshana M Rosenberg, Laura H Hendrix, Kristin L Schreiber, Alastair M Thompson, Isabelle Bedrosian, Kevin S Hughes, Thomas Lynch, Desiree Basila, Deborah E Collyar, Elizabeth S Frank, Sonja Darai, Conor Lanahan, Jeffrey R Marks, Jennifer K Plichta, Terry Hyslop, Ann H Partridge, E. Shelley Hwang. The Patient-reported Outcomes after Routine Treatment of Atypical Lesions (PORTAL) study: Pain, psychosocial wellbeing, and quality of life among women undergoing guideline concordant care for DCIS vs. active surveillance for in situ and atypical lesions [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-21-07.

Background: Side effects of and adherence to aromatase inhibitors in women with ductal carcinoma in situ are not well described. Methods: Postmenopausal women in a prospective phase II study of neoadjuvant letrozole for estrogen receptor positive DCIS completed questionnaires on side effects [Menopause Specific Quality of Life Questionnaire (MENQOL), Brief Pain Inventory-short form (BPI-SF), Arthritis Impact Measurement Scales (AIMS2)], well-being (FACT-G), and adherence [Medication-Taking questionnaire] at baseline, 1, 3 and 6 months (mo), and study completion. We used descriptive statistics and paired t-tests to compare 1, 3 and 6 mo results to baseline. Hierarchical linear mixed modeling, controlling for baseline symptom or well-being level, was used to examine effect of symptoms and well-being on intentional and nonintentional nonadherence, based on the Medication-Taking Questionnaire. Results: Included were 84 women, mean age 63 (39-83) years. In univariate analyses, compared to baseline, menopausal symptoms increased [physical (p=0.001 at 3, p0.05). Lower emotional (p=0.049) and functional (p=0.002) well-being by FACT-G and higher joint pain (p=0.03) by AIMS2 were associated with higher nonintentional nonadherence; higher physical side effects of menopause (p=0.001) by MENQOL were associated with lower intentional nonadherence. Conclusions: Among women taking letrozole for DCIS, menopausal symptoms and joint pain/stiffness increased over time with most differences noted at 3 and 6 mo. Lower well-being and higher symptom levels were associated with higher nonintentional nonadherence. NCT01439711.U10CA180821, U10CA180882, UG1CA189823, Breast Cancer Research Foundation, https://acknowledgments.alliancefound.org. Citation Format: Gretchen Kimmick, Amylou C Dueck, Rebecca Shelby, Michelle Naughton, Abigail Caudle, Briant Fruth, E. Shelley Hwang. Musculoskeletal side effects over time and association with adherence in women taking neoadjuvant letrozole for estrogen receptor positive DCIS: CALGB 40903 (Alliance) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-17.

Pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is associated with improved overall survival (OS) in patients with breast cancer, but it is unclear how post-NACT response influences radiation therapy administration in patients presenting with node-positive disease. We sought to determine whether nodal pCR is associated with likelihood of receiving nodal radiation and whether radiation therapy among patients experiencing nodal pCR is associated with improved OS.Clinical N1 (cN1) female breast cancer patients diagnosed during 2010 to 2015 who were ypN0 (ie, nodal pCR; n = 12,341) or ypN1 (ie, residual disease; n = 13,668) after NACT were identified in the National Cancer Database. Multivariate logistic regression was used to identify factors associated with receiving radiation therapy. Cox proportional hazards modeling was used to estimate the association between radiation therapy and adjusted OS.The study included 26,009 patients; 43.9% (n = 5423) of ypN0 and 55.3% (n = 7556) of ypN1 patients received nodal radiation. Rates of nodal radiation remained the same over time among ypN0 patients (trend test, P = .29) but increased among ypN1 patients from 49% in 2010 to 59% in 2015 (trend test, P.001). After adjusting for covariates, nodal pCR (vs no stage change) was associated with decreased likelihood of nodal radiation after mastectomy (∼20% decrease) and lumpectomy (∼30% decrease; both P.01). After mastectomy, nodal (vs no) radiation conferred no significant survival benefit in ypN0 patients, but it approached significance for ypN1 patients (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.69-0.99, P = .04; overall P = .11). After lumpectomy, nodal radiation was associated with improved adjusted OS for ypN0 (HR, 0.38; 95% CI, 0.22-0.66) and ypN1 patients (HR, 0.44; 95% CI, 0.30-0.66; both P.001), but this improvement was not significantly greater than that associated with breast-only radiation.ypN0 patients were less likely to receive nodal radiation than ypN1 patients were, suggesting that selective omission already occurs and, in the context of limited survival data, could potentially be appropriate for select patients.

BACKGROUND: Given presumed differences in disease severity between young (≤ 45 years) and elderly (≥ 75 years) women with breast cancer, we sought to compare tumor histopathology, stage at presentation, patterns of care, and survival at the extremes of age. METHODS: Adults with stages 0–IV breast cancer in the National Cancer Database (2004–2015) were categorized by age (18–45 years, 46–74 years, ≥ 75 years) and compared. Kaplan–Meier curves were used to visualize unadjusted overall survival (OS). A Cox proportional-hazards model was used to estimate the effect of age group, including adjustment for tumor subtype [hormone receptor [HR]+/HER2−, HER2+, triple-negative (TN)]. RESULTS: Of the 1,201,252 patients identified, 13% were ≤ 45 years and 17.5% were ≥ 75 years. Women ≤ 45 years were more likely to have higher pT/N stages and grade 3 disease compared to older patients; however, rates of de novo cM1 disease were comparable (3.7% vs 3.5%). HER2+ and TN tumors were more common in those ≤ 45 years (HER2+ : 18.6% vs 9.2%; TN: 14.9% vs 8.2%), while HR+/HER2− tumors were more likely in women ≥ 75 years (69.3% vs 51.3%) (all p < 0.001). Younger patients were more likely to undergo mastectomy vs lumpectomy (56% vs 34%), and receive chemotherapy (65.8% vs 10.2%) and radiation (56.2% vs 39.5%). After adjustment, OS was worse in older patients (older HR 2.94, CI 2.86–3.03). CONCLUSIONS: High-risk tumor subtypes and comprehensive multimodal treatment remain significantly more common among younger women (≤ 45 years) with breast cancer, yet, elderly women are similarly diagnosed with incurable de novo metastatic disease. Tailored screening and treatment strategies are critical to prevent age-related disparities in breast cancer care.

PURPOSE: Inflammatory breast cancer (IBC) is an aggressive variant for which axillary lymph node dissection following neoadjuvant chemotherapy (NACT) remains standard of care. But with increasingly effective systemic therapy, it is unclear whether more limited axillary surgery may be appropriate in some IBC patients. We sought to examine whether extent of axillary lymph node (LN) surgery was associated with overall survival (OS) for IBC. METHODS: Female breast cancer patients with non-metastatic IBC (cT4d) diagnosed 2010–2014 were identified in the National Cancer Data Base. Cox proportional hazards modeling was used to estimate the association between extent of axillary surgery (≤9 vs ≥10 LNs removed) and OS after adjusting for covariates, including post-NACT nodal status (ypN0 vs ypN1–3) and radiotherapy receipt (yes/no). RESULTS: 3,471 patients were included: 597 (17.2%) had cN0 disease, 1,833 (52.8%) had cN1 disease, and 1,041 (30%) had cN2–3 disease. 49.9% of cN0 patients were confirmed to be ypN0 on post-NACT surgical pathology. Being ypN0 (vs ypN1–3) was associated with improved adjusted OS for all patients. Radiotherapy was associated with improved adjusted OS for cN1 and cN2–3 patients but not for cN0 patients. Regardless of ypN status, there was a trend towards improved adjusted OS with having ≥10 (vs ≤9) LNs removed for cN2–3 patients (HR 0.78, 95% CI 0.60–1.01, p=0.06) but not for cN0 patients (p=0.83). CONCLUSIONS: A majority of IBC patients in our study presented with node-positive disease, and for those presenting with cN2–3 disease, more extensive axillary surgery is potentially associated with improved survival. For cN0 patients, however, more extensive axillary surgery was not associated with a survival benefit, suggesting an opportunity for more personalized care.

Graphical abstract, Highlights • Abnormalities in cell nuclear morphology is a hallmark of cancer. • Changes in nuclear morphology are utilized by pathologists in tumor grading. • Heterogeneity in DCIS grade may influence invasive progression. • Current pathological assessment of DCIS does not incorporate heterogeneity. • I mage analysis is a supplemental tool for pathologists to quantitatively grade DCIS., Abnormalities in cell nuclear morphology are a hallmark of cancer. Histological assessment of cell nuclear morphology is frequently used by pathologists to grade ductal carcinoma in situ (DCIS). Objective methods that allow standardization and reproducibility of cell nuclear morphology assessment have potential to improve the criteria needed to predict DCIS progression and recurrence. Aggressive cancers are highly heterogeneous. We asked whether cell nuclear morphology heterogeneity could be incorporated into a metric to classify DCIS. We developed a nuclear heterogeneity image index to objectively, and quantitatively grade DCIS. A whole-tissue cell nuclear morphological analysis, that classified tumors by the worst ten percent in a duct-by-duct manner, identified nuclear size ranges associated with each DCIS grade. Digital image analysis further revealed increasing heterogeneity within ducts or between ducts in tissues of worsening DCIS grade. The findings illustrate how digital image analysis comprises a supplemental tool for pathologists to objectively classify DCIS and in the future, may provide a method to predict patient outcome through analysis of nuclear heterogeneity.

Asian women with breast cancer are often studied in aggregate, belying significant intragroup diversity. The authors sought to examine differences in breast cancer characteristics and outcomes among Asian women.Asian, non-Hispanic Black, Hispanic, and non-Hispanic White women aged 18 years and older who were diagnosed with breast cancer from 1990 to 2016 were identified in the Surveillance, Epidemiology, and End Results 18 database. Asian patients were subclassified as Chinese, Japanese, Korean, Filipino, Vietnamese, South Asian (Asian Indian or Pakistani), Southeast Asian (SEA, i.e., Cambodian, Laotian, Hmong, or Thai), or other Asian. Unadjusted overall survival (OS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Cox proportional hazards models were used to estimate adjusted OS and CSS.In total, 910,415 women were included (Asian, n = 63,405; Black, n = 92,226; Hispanic, n = 84,451; White, n = 670,333). Asian women had higher rates of human epidermal growth factor receptor 2 (HER2)-positive disease compared with White women (18.7% vs 13.8%) and had the highest 10-year unadjusted OS and CSS among all racial/ethnic groups (all P.001). SEA women had the highest rates of stage IV disease at presentation, whereas Japanese women had the lowest rates (5.9% vs 2.7%; P.001). Japanese women had the highest 10-year unadjusted CSS (89.4%; 95% confidence interval, 88.7%-90.1%) of any distinct Asian group, whereas SEA women had the worst unadjusted CSS (78%; 95% confidence interval, 74.1%-81.3%; P.001). After adjustment, SEA women had the worst OS of any Asian group and were the only Asian group without improved OS compared with White women (reference category; P = .08).Breast cancer characteristics and outcomes vary significantly among Asian women. Future research should consider disaggregation by country or region of origin to identify subgroups that are at risk for worse outcomes than aggregated data may suggest.Asian women with breast cancer are frequently studied as a single entity. However, Asian ethnic groups differ greatly by country of origin, genetic ancestry, disease frequency, socioeconomic status, patterns of immigration, as well as dietary and cultural practices. Women of different Asian ethnicities vary significantly with regard to cancer characteristics, such as mortality and tumor subtype. Future research should disaggregate these populations to better understand, treat, and counsel Asian patients with breast cancer.

Simple Summary In breast cancer, there is a high degree of variability in tumors and the surrounding tissue called the tumor microenvironment (TME). To better understand tumor biology and metastasis, as well as to predict response to cancer treatments or the course of the disease, it is important to characterize molecular diversity in the breast TME. The GeoMx Digital Spatial Profiler (DSP) enables researchers to spatially analyze proteins and RNA transcripts in tumors and surrounding tissues from patients or preclinical models. Using the GeoMx DSP, protein expression and RNA transcripts in the distinct regions of a tumor can be quantified up to and including the whole transcriptome level. Herein, the GeoMx Breast Cancer Consortium presents best practices for GeoMx spatial profiling of tumors to promote the collection of high-quality data, optimization of data analysis and integration of datasets to accelerate biomarker discovery. These best practices can also be applied to any tumor type to provide information about the tumor and the TME. Abstract Breast cancer is a heterogenous disease with variability in tumor cells and in the surrounding tumor microenvironment (TME). Understanding the molecular diversity in breast cancer is critical for improving prediction of therapeutic response and prognostication. High-plex spatial profiling of tumors enables characterization of heterogeneity in the breast TME, which can holistically illuminate the biology of tumor growth, dissemination and, ultimately, response to therapy. The GeoMx Digital Spatial Profiler (DSP) enables researchers to spatially resolve and quantify proteins and RNA transcripts from tissue sections. The platform is compatible with both formalin-fixed paraffin-embedded and frozen tissues. RNA profiling was developed at the whole transcriptome level for human and mouse samples and protein profiling of 100-plex for human samples. Tissue can be optically segmented for analysis of regions of interest or cell populations to study biology-directed tissue characterization. The GeoMx Breast Cancer Consortium (GBCC) is composed of breast cancer researchers who are developing innovative approaches for spatial profiling to accelerate biomarker discovery. Here, the GBCC presents best practices for GeoMx profiling to promote the collection of high-quality data, optimization of data analysis and integration of datasets to advance collaboration and meta-analyses. Although the capabilities of the platform are presented in the context of breast cancer research, they can be generalized to a variety of other tumor types that are characterized by high heterogeneity.

SUMMARYDuctal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes by analyzing 677 DCIS samples from 481 patients with 7.1 years median follow-up from the Translational Breast Cancer Research Consortium (TBCRC) 038 study and the Resource of Archival Breast Tissue (RAHBT) cohorts. We identified 812 genes associated with ipsilateral recurrence within 5 years from treatment and developed a classifier that was predictive of DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions were identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.HIGHLIGHTS⍰ Development of a new classifier for DCIS recurrence or progression⍰ Outcome associated pathways identified across multiple data types and compartments⍰ Four stroma-specific signatures identified⍰ CNAs characterize DCIS subgroups associated with high risk invasive cancers

Most tissue collections of neoplasms are composed of formalin-fixed and paraffin-embedded (FFPE) excised tumor samples used for routine diagnostics. DNA sequencing is becoming increasingly important in cancer research and clinical management; however, it is difficult to accurately sequence DNA from FFPE samples. We developed and validated a new bioinformatic algorithm to robustly identify somatic single nucleotide variants (SNVs) from whole exome sequencing using small amounts of DNA extracted from archival FFPE samples of breast cancers. We optimized this strategy using 28 pairs of technical replicates. After optimization, the mean similarity between replicates increased 5-fold, reaching 88% (range 0-100%), with a mean of 21.4 SNVs (range 1-68) per sample, representing a markedly superior performance to existing algorithms. We found that the SNV-identification accuracy declined when there was less than 40ng of DNA available and that insertion-deletion variant calls are less reliable than single base substitutions. As the first application of the new algorithm, we compared samples of ductal carcinoma in situ (DCIS) of the breast to their adjacent invasive ductal carcinoma (IDC) samples. We observed an increased number of mutations (paired-samples sign test, pKey PointsThe sequencing of reduced quantities of DNA extracted from FFPE samples leads to substantial sequencing errors that require correction in order to obtain accurate detection of somatic mutations.We developed and validated a new bioinformatic algorithm to robustly identify somatic single nucleotide variants using small amounts of DNA extracted from archival FFPE samples of breast cancers.Variant calling software packages need to be optimized to reduce the impact of sequencing errors. Our bioinformatics pipeline represents a significant methodological advance compared to the currently available bioinformatic tools used for the analysis of small FFPE samples.

Background We aim to determine clinical and pathological stage discordance rates and to evaluate factors associated with discordance. Methods Adults with clinical stages I-III breast cancer were identified from the National Cancer Data Base. Concordance was defined as cTN = pTN (discordance: cTN≠pTN). Multivariate logistic regression was used to identify factors associated with discordance. Results Comparing clinical and pathological stage, 23.1% were downstaged and 8.7% were upstaged. After adjustment, factors associated with downstaging (vs concordance) included grade 3 (OR 10.56, vs grade 1) and HER2-negative (OR 3.79). Factors associated with upstaging (vs concordance) were grade 3 (OR 10.56, vs grade 1), HER2-negative (OR 1.25), and lobular histology (OR 2.47, vs ductal). ER-negative status was associated with stage concordance (vs downstaged or upstaged, OR 0.52 and 0.87). Conclusions Among breast cancer patients, nearly one-third exhibit clinical-pathological stage discordance. This high likelihood of discordance is important to consider for counseling and treatment planning.

Active surveillance trials for low-risk ductal carcinoma in situ (DCIS) are in progress in the United States and Europe. In some of these trials, the presence of comedo necrosis in the DCIS has been an exclusion criterion for trial entry. However, the minimum amount of necrosis required by pathologists for a diagnosis of comedo necrosis is not well-defined. We surveyed 35 experienced breast pathologists to assess their diagnostic threshold for comedo necrosis. Pink circles representing necrosis ranging in extent from 10 to 80% of the duct diameter were superimposed on eight replicate histologic images of a single duct involved by low nuclear grade, solid pattern DCIS. These images were circulated by e-mail to the participating pathologists who were asked to select the image that represents the minimum amount of necrosis that they require for a diagnosis of comedo necrosis. Among the 35 participants, the minimum extent of the duct diameter required for a diagnosis of comedo necrosis was 10% for 4 pathologists, 20% for 5, 30% for 11, 40% for 7, 50% for 6, 60% for 1 and 70% for 1. There was no single threshold about which more than one-third of the pathologists agreed met the minimal criteria for comedo necrosis. We conclude that even among experienced breast pathologists, the threshold for comedo necrosis is highly variable. Our findings highlight the need for a standardized definition of comedo necrosis as a trial criterion, and more generally where it may be used as a marker of increased risk of recurrence for therapeutic decision making.

Background: In absence of definitive molecular risk markers, clinical management of patients diagnosed with ductal carcinoma in situ (DCIS) remains largely guided by patient and tumor characteristics. In this study, we analyzed recent trends in DCIS incidence and compared them against trends in mammography use. Methods: The Surveillance, Epidemiology, and End Results registry was queried for patients diagnosed with DCIS from 2000 to 2014 (18 registries). Joinpoint regression analyses were used to compute age- and race-stratified trends in age-adjusted incidence of DCIS. The patterns of DCIS incidence were compared against mammography utilization data from the National Health Interview Survey. Results: Between 2000 and 2014, overall DCIS incidence in the U.S. population was stable (P = 0.24). Among age groups 20 to 44 years and 45 to 55 years, DCIS incidence increased by 1.3% (P = 0.001) and 0.6% (P = 0.02) per year, respectively. Although stable among white women, DCIS incidence increased among black women and women of other races by 1.6% (P < 0.001) and 1.0% (P = 0.002) per year, respectively. Mammography uptake correlated well with DCIS incidence, with the exception of women ages 40 to 49 years and black women who experienced an increase in DCIS incidence despite stagnating and decreasing mammography uptake, respectively. Conclusions: Overall DCIS incidence rates have remained stable between 2000 and 2014. However, subgroup analyses revealed an increase in incidence among both younger women and black women. Impact: DCIS incidence trends did not correlate with the mammography uptake patterns, suggesting that etiologic factors other than screening may be leading to an increased DCIS incidence in these groups.

Cancer treatment costs are not routinely addressed in shared decisions for breast cancer surgery. Thus, we sought to characterize cost awareness and communication among surgeons treating breast cancer. We conducted a self-administered, confidential electronic survey among members of the American Society of Breast Surgeons from 1 July to 15 September 2018. Questions were based on previously published or validated survey items, and assessed surgeon demographics, cost sensitivity, and communication. Descriptive summaries and cross-tabulations with Chi-square statistics were used, with exact tests where warranted, to assess findings. Of those surveyed (N = 2293), 598 (25%) responded. Surgeons reported that ‘risk of recurrence’ (70%), ‘appearance of the breast’ (50%), and ‘risks of surgery’ (47%) were the most influential on patients’ decisions for breast cancer surgery; 6% cited out-of-pocket costs as significant. Over half (53%) of the surgeons agreed that doctors should consider patient costs when choosing cancer treatment, yet the majority of surgeons (58%) reported ‘infrequently’ (43%) or ‘never’ (15%) considering patient costs in medical recommendations. The overwhelming majority (87%) of surgeons believed that patients should have access to the costs of their treatment before making medical decisions. Surgeons treating a higher percentage of Medicaid or uninsured patients were more likely to consistently consider costs (p

Standard treatment for ductal carcinoma in situ (DCIS) is similar to that of invasive carcinoma. However, there is significant controversy regarding the true clinical implications of DCIS, and thus, the best management strategy. The aim of this review is to highlight relevant biology, diagnostic considerations, treatment options, and recent clinical trials. Outcomes are generally excellent with low recurrence rates and exceptional disease-specific survival. Outcomes can be predicted using various prognostic indicators and/or nomograms to guide treatment decisions. Ongoing clinical trials of active surveillance are based upon the argument that ipsilateral invasive recurrence is the most clinically meaningful endpoint. These trials seek to compare ipsilateral invasive cancer diagnoses between standard of care and close monitoring. Recent trials have revealed the marked heterogeneity in the biology of DCIS, offering an opportunity to de-escalate therapy for women at lowest risk for progression. DCIS also presents an ideal setting in which to test novel prevention agents. Future care of patients with DCIS will include biomarker-based risk assessment in order to better individualize treatment to biologic risk of invasive progression.

BACKGROUND. Breast surgery carries a low risk of postoperative mortality. For older patients with multiple comorbidities, even low-risk procedures can confer some increased perioperative risk. We sought to identify factors associated with postoperative mortality in breast cancer patients ≥70 years to create a nomogram for predicting risk of death within 90 days. METHODS. Patients diagnosed with nonmetastatic invasive breast cancer (2010–2016) were selected from the National Cancer Database. Unadjusted OS was estimated using the Kaplan–Meier method. Multivariate logistic regression was used to estimate the association of age and surgery with 90-day mortality and to build a predictive nomogram. RESULTS. Among surgical patients ≥70 years, unadjusted 90-day mortality increased with increasing age (70–74 = 0.4% vs. ≥85 = 1.6%), comorbidity score (0 = 0.5% vs. ≥3 = 2.7%), and disease stage (I = 0.4% vs. III = 2.7%; all p < 0.001). After adjustment, death within 90 days of surgery was associated with higher age (≥85 vs. 70–74: odds ratio [OR] 3.16, 95% confidence interval [CI] 2.74–3.65), comorbidity score (≥3 vs. 0: OR 4.79, 95% CI 3.89–5.89), and disease stage (III vs. I: OR 4.30, 95% CI 3.69–5.00). Based on these findings, seven variables (age, gender, comorbidity score, facility type, facility location, clinical stage, and surgery type) were selected to build a nomogram; estimates of risk of death within 90 days ranged from 30%. CONCLUSIONS. Breast operations remain relatively low-risk procedures for older patients with breast cancer, but select factors can be used to estimate the risk of postoperative mortality to guide surgical decision-making among older women.

Soft extracellular matrix protects breast cancer cells from apoptosis and reduces the efficacy of chemo- and radiation therapies through enhanced NF-κB signaling and diminished proapoptotic JNK activity. Therapeutic targeting of the NF-κB–JNK axis may thwart treatment resistance in breast cancer., Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.

Background The North Carolina Breast and Cervical Cancer Control Program (NC BCCCP) provides breast cancer screening services to underserved women to mitigate disparities in access to care. The authors sought to characterize this understudied population. Methods Women 21 years old or older who underwent their first breast cancer screen through NC BCCCP from 2008 to 2018 were included. Demographic factors associated with the timeline of care and odds of a breast cancer diagnosis were identified with negative binomial and logistic regression, respectively. Results Of the 88,893 women identified, 45.5% were non-Hispanic (NH) White, 30.9% were NH Black, 19.6% were Hispanic, 1.7% were American Indian, and 1.1% were Asian. Breast cancer was diagnosed in 2.5% of the women (n = 2255). Hispanic women were the least likely to be diagnosed with breast cancer (odds ratio vs NH White women, 0.40; 95% confidence interval [CI], 0.34-0.47). Among patients with breast pathology, the median time to diagnosis was 19 days (interquartile range [IQR], 10-33 days), and the time to treatment was 33 days (IQR, 19-54 days). After adjustments, a longer time to diagnosis was significantly associated with age (incidence rate ratio [IRR], 1.01; 95% CI, 1.01-1.02) and being NH Black (vs NH White; IRR, 1.17; 95% CI, 1.06-1.29). A longer time to treatment was significantly associated with age (IRR, 1.01; 95% CI, 1.01-1.01), being NH Black (vs NH White; IRR, 1.20; 95% CI, 1.10-1.31), and being Hispanic (vs NH White; IRR, 1.22; 95% CI, 1.05-1.41). Conclusions NC BCCCP participants with breast cancer received treatment within approximately 1 month of presentation, and this finding aligns with quality care benchmarks. Nevertheless, racial/ethnic disparities in timeliness of care persist, and this suggests opportunities for improvement. Lay summary This review of approximately 90,000 participants in a breast cancer screening program for uninsured and underinsured women highlights the importance of safety net programs in providing timely care to underserved patients. The authors found that the North Carolina Breast and Cervical Cancer Control Program met timeliness benchmarks from the Centers for Disease Control and Prevention across all racial/ethnic groups. However, non-Hispanic Black women experienced relative delays in the time to diagnosis, and both non-Hispanic Black women and Hispanic women experienced relative delays in the time to treatment. These findings demonstrate how racial/ethnic disparities in the timeliness of care can persist even within a program intended to reduce barriers to access.

BACKGROUND: De-escalation of axillary surgery after neoadjuvant chemotherapy (NAC) requires careful patient selection. We sought to determine predictors of nodal pathologic complete response (ypN0) among patients treated on CALGB 40601 or 40603, which tested NAC regimens in HER2+ and triple-negative breast cancer (TNBC), respectively. METHODS: 760 patients with stage II-III HER2+ or TNBC were analyzed. Those who had axillary surgery before NAC (n=122), or who had missing pre-treatment clinical nodal status (cN) (n=58) or ypN status (n=41) were excluded. The proportion of patients with ypN0 disease was estimated for those with and without breast pathologic complete response (pCR) according to pre-treatment nodal status. RESULTS: In 539 patients, the overall ypN0 rate was 76.3% (411/539) – 93.2% (245/263) in patients with breast pCR and 60.1% (166/276) with residual breast disease (RD) (P

Pure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of pure DCIS and their subsequent events using a combination of whole exome, targeted and copy number sequencing, supplemented by single cell analysis. Unexpectedly, 18% of all invasive events after DCIS were clonally unrelated to the primary DCIS. Single cell sequencing of selected pairs confirmed our findings. In contrast, synchronous DCIS and invasive disease (n=44) were almost always (93%) clonally related. This challenges the dogma that almost all invasive events after DCIS represent invasive transformation of the initial DCIS and suggests that DCIS could be an independent risk factor for developing invasive disease as well as a precursor lesion. Our findings support a paradigm shift that confirms a more complex role for DCIS than previously recognized, and that the future management of DCIS should take into account both the precursor and risk factor implications of this diagnosis.

PURPOSE: Ductal carcinoma in situ (DCIS), a nonobligate precursor of breast cancer, is often aggressively managed with multimodal therapy. However, there is limited research on patients' preferences for trade-offs among treatment-related outcomes such as breast appearance, side effects, and future cancer risk. We sought to investigate whether women consider treatment features aside from cancer risk when making treatment choices for ductal carcinoma in situ and if so, to what degree other features influence these decisions. METHODS: A discrete choice experiment was administered to participants in a comprehensive cancer screening mammography clinic. The experimental design was used to generate constructed health profiles resulting from different management strategies. Health profiles were defined by breast appearance, severity of infection within the first year, chronic pain, hot flashes, and risk of developing or dying from breast cancer within 10 years. RESULTS: One hundred ninety-four women without a personal history of breast cancer completed the choice task. Across 10 choice questions, 29% always selected the health profile with a lower risk of invasive breast cancer (ie, dominated on cancer risk), regardless of the effects of treatment. For nonrisk dominators, breast cancer risk remained the most important factor but was closely followed by chronic pain (24% [95% CI, 20 to 28]) and infection (22% [95% CI, 18 to 25]). Depending on treatment outcomes, the tolerable increase in breast cancer risk was as high as 3.4%. CONCLUSION: Most women were willing to make some trade-offs between invasive cancer risk and treatment-related outcomes. Our findings highlight the importance of shared decision-making weighing risks and benefits between patient and provider management of low-risk disease.

Despite increasing evidence supporting the clinical relevance of tumour infiltrating lymphocytes (TILs) in invasive breast cancer, TIL spatial variability within ductal carcinoma in situ (DCIS) samples and its association with progression are not well understood. To characterise tissue spatial architecture and the microenvironment of DCIS, we designed and validated a new deep learning pipeline, UNMaSk. Following automated detection of individual DCIS ducts using a new method IM-Net, we applied spatial tessellation to create virtual boundaries for each duct. To study local TIL infiltration for each duct, DRDIN was developed for mapping the distribution of TILs. In a dataset comprising grade 2–3 pure DCIS and DCIS adjacent to invasive cancer (adjacent DCIS), we found that pure DCIS cases had more TILs compared to adjacent DCIS. However, the colocalisation of TILs with DCIS ducts was significantly lower in pure DCIS compared to adjacent DCIS, which may suggest a more inflamed tissue ecology local to DCIS ducts in adjacent DCIS cases. Our study demonstrates that technological developments in deep convolutional neural networks and digital pathology can enable an automated morphological and microenvironmental analysis of DCIS, providing a new way to study differential immune ecology for individual ducts and identify new markers of progression.

Ductal carcinomain situ(DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand how the tumor microenvironment (TME) changes with transition to IBC, we used Multiplexed Ion Beam Imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to analyze 140 clinically annotated surgical resections covering the full spectrum of breast cancer progression. We compared normal, DCIS, and IBC tissues using machine learning tools for multiplexed cell segmentation, pixel-based clustering, and object morphometrics. Transition from DCIS to IBC was found to occur along a trajectory marked by coordinated shifts in location and function of myoepithelium, fibroblasts, and infiltrating immune cells in the surrounding stroma. Taken together, this comprehensive study within the HTAN Breast PreCancer Atlas offers insight into the etiologies of DCIS, its transition to IBC, and emphasizes the importance of the TME stroma in promoting these processes.

Ductal carcinoma in situ (DCIS) is the most commonly diagnosed precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes to identify predictors of subsequent ipsilateral breast events. We analyzed 677 DCIS samples from 481 patients with 7.1 years median follow-up from two independent cohorts. We made observations on DNA, RNA, and protein expression, and generated a de novo clustering scheme for DCIS that represents the fundamental transcriptomic organization at this early stage of breast neoplasia. Distinct DCIS stromal expression patterns and immune cell compositions were identified. We also found RNA expression patterns that correlate with later events in both cohorts. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

Management of breast cancer in limited-resource settings is hindered by a lack of low-cost, logistically sustainable approaches toward molecular and cellular diagnostic pathology services that are needed to guide therapy. To address these limitations, we have developed a multimodal cellphone-based platform—the EpiView-D4—that can evaluate both cellular morphology and molecular expression of clinically relevant biomarkers directly from fine-needle aspiration (FNA) of breast tissue specimens within 1 h. The EpiView-D4 is comprised of two components: (1) an immunodiagnostic chip built upon a “non-fouling” polymer brush-coating (the “D4”) which quantifies expression of protein biomarkers directly from crude cell lysates, and (2) a custom cellphone-based optical microscope (“EpiView”) designed for imaging cytology preparations and D4 assay readout. As a proof-of-concept, we used the EpiView-D4 for assessment of human epidermal growth factor receptor-2 (HER2) expression and validated the performance using cancer cell lines, animal models, and human tissue specimens. We found that FNA cytology specimens (prepared in less than 5 min with rapid staining kits) imaged by the EpiView-D4 were adequate for assessment of lesional cellularity and tumor content. We also found our device could reliably distinguish between HER2 expression levels across multiple different cell lines and animal xenografts. In a pilot study with human tissue (n = 19), we were able to accurately categorize HER2-negative and HER2-positve tumors from FNA specimens. Taken together, the EpiView-D4 offers a promising alternative to invasive—and often unavailable—pathology services and may enable the democratization of effective breast cancer management in limited-resource settings.

Women with dense breasts have an increased lifetime risk of malignancy that has been attributed to a higher epithelial density. Quantitative proteomics, collagen analysis, and mechanical measurements in normal tissue revealed that stroma in the high-density breast contains more oriented, fibrillar collagen that is stiffer and correlates with higher epithelial cell density. microRNA (miR) profiling of breast tissue identified miR-203 as a matrix stiffness-repressed transcript that is downregulated by collagen density and reduced in the breast epithelium of women with high mammographic density. Culture studies demonstrated that ZNF217 mediates a matrix stiffness- and collagen density-induced increase in Akt activity and mammary epithelial cell proliferation. Manipulation of the epithelium in a mouse model of mammographic density supported a causal relationship between stromal stiffness, reduced miR-203, higher levels of the murine homolog Zfp217, and increased Akt activity and mammary epithelial proliferation. ZNF217 was also increased in the normal breast epithelium of women with high mammographic density, correlated positively with epithelial proliferation and density, and inversely with miR-203. The findings identify ZNF217 as a potential target toward which preexisting therapies, such as the Akt inhibitor triciribine, could be used as a chemopreventive agent to reduce cancer risk in women with high mammographic density.

Over 97% of individuals diagnosed with ductal carcinoma in situ (DCIS) will choose to receive guideline concordant care (GCC), which was originally designed to treat invasive cancers and is associated with treatment related morbidity. An alternative to GCC is active surveillance (AS) where therapy is delayed until medically necessary. Differences in mortality risk between the two approaches in women age 65+ are analyzed in this study. SEER and Medicare information on treatment during the first year after diagnosis was used to identify three cohorts based on treatment type and timing: GCC (N = 21,772; immediate consent for treatment), AS1 (N = 431; delayed treatment within 365 days), and AS2 (N = 205; no treatment/ongoing AS). A propensity score-based approach provided pseudorandomization between GCC and AS groups and survival was then compared. Strong influence of comorbidities on the treatment received was observed for all age-groups, with the greatest burden observed in the AS2 group. All-cause and breast-cancer-specific mortality hazard ratios (HR) for AS1 were not statistically different from the GCC group; AS2 was associated with notably higher risk for both all-cause (HR:3.54; CI:3.29, 3.82) and breast-cancer-specific (HR:10.73; CI:8.63,13.35) mortality. Cumulative mortality was substantially higher from other causes than from breast cancer, regardless of treatment group. Women managed with AS for DCIS had higher all-cause and breast-cancer-specific mortality. This effect declined after accounting for baseline comorbidities. Delays of up to 12 months in initiation of GCC did not underperform immediate surgery.

PURPOSE: We sought to examine tumor subtype, stage at diagnosis, time to surgery (TTS), and overall survival (OS) among Hispanic patients of different races and among Hispanic and non-Hispanic (NH) women of the same race. METHODS: Women 18 years of age or older who had been diagnosed with stage 0-IV breast cancer and who had undergone lumpectomy or mastectomy were identified in the National Cancer Database (2004-2014). Tumor subtype and stage at diagnosis were compared by race/ethnicity. Multivariable linear regression and Cox proportional hazards modeling were used to estimate associations between race/ethnicity and adjusted TTS and OS, respectively. RESULTS: A total of 44,374 Hispanic (American Indian [AI]: 79 [0.2%]; Black: 1,011 [2.3%]; White: 41,126 [92.7%]; Other: 2,158 [4.9%]) and 858,634 NH women (AI: 2,319 [0.3%]; Black: 97,206 [11.3%]; White: 727,270 [84.7%]; Other: 31,839 [3.7%]) were included. Hispanic Black women had lower rates of triple-negative disease (16.2%) than did NH Black women (23.5%) but higher rates than did Hispanic White women (13.9%; P < .001). Hispanic White women had higher rates of node-positive disease (23.2%) versus NH White women (14.4%) but slightly lower rates than Hispanic (24.6%) and NH Black women (24.5%; P < .001). Hispanic White women had longer TTS versus NH White women regardless of treatment sequence (adjusted means: adjuvant chemotherapy, 42.71 v 38.60 days; neoadjuvant chemotherapy, 208.55 v 201.14 days; both P < .001), but there were no significant racial differences in TTS among Hispanic patients. After adjustment, Hispanic White women (hazard ratio, 0.77 [95% CI, 0.74 to 0.81]) and Black women (hazard ratio, 0.75 [95% CI, 0.58 to 0.96]) had improved OS versus NH White women (reference) and Black women (hazard ratio, 1.15 [95% CI, 1.12 to 1.18]; all P < .05). CONCLUSION: Hispanic women had improved OS versus NH women, but racial differences in tumor subtype and nodal stage among Hispanic women highlight the importance of disaggregating racial/ethnic data in breast cancer research.

BACKGROUND. In 2002, breast cancer patients with supraclavicular nodal metastases (cN3c) were downstaged from AJCC stage IV to IIIc, prompting management with locoregional treatment. We sought to estimate the impact of multimodal therapy on overall survival (OS) in a contemporary cohort of cN3c patients. METHODS. Women ≥ 18 years with cT1-T4c/cN3c invasive breast cancer who underwent systemic therapy were identified from the 2004–2016 National Cancer Database. We compared three patient cohorts: (a) cN3c + multimodal therapy (systemic therapy, surgery, and radiation); (b) cN3c + non-standard therapy; and, (c) cM1. Logistic regression identified factors associated with receipt of multimodal therapy and Kaplan–Meier was used to estimate unadjusted OS. The Cox proportional hazards model estimated effects of diagnosis and treatment on OS after adjustment. RESULTS. Overall, 1827 (3.7%) patients with cN3c disease and 46,919 (96.3%) cM1 patients were identified. Of cN3c patients, 74.5% (n = 1362) received multimodal therapy and 25.5% (n = 465) received non-standard therapy; receipt of multimodal therapy was associated with improved 5-year OS (multimodal: 59% vs. M1: 28% vs. non-standard: 28%, log-rank p < 0.001). Adjusting for covariates, non-standard therapy was associated with an increased risk of death compared with receipt of multimodal therapy (HR 2.20, 95% CI 1.71–2.83, p < 0.001). Private insurance was the only patient characteristic associated with a greater likelihood of receiving multimodal therapy (OR 2.81; 95% CI, 1.64–4.82; p < 0.001). CONCLUSION. Women with cN3c breast cancer who received multimodal therapy demonstrated improved overall survival when compared with patients undergoing non-standard therapy and those with metastatic (M1) disease. Although selection bias may contribute to worse overall survival among cN3c patients undergoing non-standard therapy, national guidelines should encourage locoregional treatment in carefully selected patients.

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PURPOSE: Increasing health care costs, longer life expectancy, improved breast cancer (BC) survival, and higher levels of complex comorbidities have important implications for future Medicare expenditures. METHODS: Data from the SEER program linked to Medicare claims records were used. Women with BC (cases) were categorized into 3 groups on the basis of their year of diagnosis (1998, 2003, or 2008) and were propensity score matched to women without a BC diagnosis (controls). All stage and stage-specific longitudinal changes in survival, morbidity levels using the Elixhauser index, and Medicare expenditures in 2018 dollars were calculated and compared. RESULTS: More than 15% of BC cases were diagnosed in patients over the age of 85 years. The prevalence of most comorbidities increased over time. Costs among cases increased between 1998 and 2008. Spending directly correlated with the stage of disease at diagnosis, with the lowest per-patient costs in the ductal carcinoma in situ (DCIS) subgroup ($14,792 in 1998 and $19,652 in 2008) and the highest in those with distant cancer ($37,667 in 1998 and $43,675 in 2008). Assuming no significant changes in the distribution of BC stage or age at diagnosis, the total annual costs of caring for patients with BC in women 65 years of age or older at diagnosis increased by at least $1.1 billion between 1998 and 2008. CONCLUSION: Improvements in BC survivorship are associated with intensive use of health care resources and substantially higher downstream costs among Medicare beneficiaries. Appropriate planning, in both the fiscal and the oncology care infrastructure, is required to prepare the health system for these emerging health care trends.

Background The clinical behavior of breast cancer varies by racial and ethnic makeup (REM), but the impact of REM on the clinical outcomes of breast atypia remains understudied. We examined the impact of REM on risk of underlying or subsequent carcinoma following a diagnosis of breast atypia. Methods In this retrospective, single-institution chart review, adult women diagnosed with breast atypia (atypical ductal hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in situ) were stratified by REM. Regression modeling was used to estimate risk of underlying or subsequent carcinoma. Results We identified 539 patients with breast atypia, including 15 Hispanic (2.8%), 127 non-Hispanic black (23.6%), and 397 non-Hispanic white women (73.7%). Diagnoses included 75.1% atypical ductal hyperplasia (n = 405), 4.6% atypical lobular hyperplasia (n = 25), and 20.2% lobular carcinoma in situ (n = 109). Rates for each type of atypia did not vary by REM (P = 0.33). Of those with atypia on needle biopsy, the rate of underlying carcinoma at excision was 17.3%. After adjustment, REM was not associated with greater risk for carcinoma at excision (P = 0.41). Of those with atypia alone on surgical excision, the rate of a subsequent carcinoma diagnosis was 15.4% (median follow-up 49 mo). REM was not associated with a long-term risk for carcinoma (P = 0.37) or differences in time to subsequent carcinoma (log-rank P = 0.52). Chemoprevention uptake rates were low (10.6%), especially among Hispanic (0%) and non-Hispanic black (3.8%) patients (P = 0.01). Conclusions Among patients with atypia, REM does not appear to influence type of histologic atypia, risk for carcinoma, or clinical outcome, despite differences in chemoprevention rates.