Adherence to hormonal therapy after surgery among older women with ductal carcinoma in situ: Implications for breast cancer-related adverse health events.

BACKGROUND: Evidence from randomized clinical trials (RCTs) shows that receipt of hormonal therapy after surgery for estrogen receptor-positive ductal carcinoma in situ (DCIS) reduces the risk of DCIS and contralateral invasive breast cancer (IBC) but not death from breast cancer. RCTs examined homogeneous samples, and therefore whether this evidence can be generalized to diverse populations is unclear. METHODS: Population-based data from four state cancer registries (California, New Jersey, New York, and Texas) were analyzed on women aged 65 years and older newly diagnosed with DCIS who underwent surgery with or without radiation during the years 2006-2013. Registry records were merged with Medicare enrollment in Parts A and/or B and D (prescription drugs) and associated claims. Whether adherence to hormonal therapy was associated with adverse breast cancer-related health events was analyzed. RESULTS: Achieving excellent adherence did not affect death from breast cancer. In contrast, the risk of developing a subsequent breast tumor was 6.24 percentage points (breast-conserving surgery [BCS] with radiation therapy [RT]) and 10.54 percentage points (BCS alone) lower for women with excellent versus low adherence (p < .00001). For excellent versus good adherence, the reduced risk among women who had BCS with and without RT was approximately 3 and 5 percentage points, respectively. A similar pattern emerged for the risk of IBC among women who achieved excellent versus good or low adherence, whereas good versus low adherence comparisons were not significant. CONCLUSIONS: This analysis of a diverse population-based cohort of women with DCIS demonstrates that achieving excellent adherence to hormonal therapy is critical to minimizing the occurrence of developing subsequent breast tumors. PLAIN LANGUAGE SUMMARY: Our analysis of a diverse population-based cohort of women with ductal carcinoma in situ demonstrates that achieving excellent adherence to hormonal therapy is critical to minimizing the occurrence of developing subsequent breast tumors.

Magnetic lymphatic tracing for omission of sentinel lymph node biopsies in mastectomy patients: a community cancer center experience.

BACKGROUND: Patients with ductal carcinoma in situ (DCIS) and patients undergoing risk reduction mastectomy may undergo sentinel lymph node biopsy (SLNB) at the time of mastectomy to complete axillary staging were an underlying invasive malignancy to be found on final pathology. Among patients with DCIS undergoing mastectomy, 15-29% of patients will have invasive disease on final pathology; therefore, approximately 70-85% of patients may benefit from avoiding SLNB. Superparamagnetic tracers (SPMT) have been proven to be non-inferior to the standard radioisotope and blue dye combination. SPMT remains active for several weeks, allowing a large proportion of DCIS and genetic carrier patients to potentially avoid SLNB in the setting of mastectomy. We hypothesize the use of SPMT will reduce the number of SLNB performed in patients undergoing mastectomy for DCIS and risk reduction, ultimately reducing the number of complications associated with axillary surgery. We seek to report our community cancer center's experience with SPMT and omission of SLNB in the DCIS and prophylactic mastectomy patient population. METHODS: We performed a retrospective review of 52 female patients with DCIS or known genetic predisposition undergoing mastectomy. SPMT (Magtrace®, Endomag Ltd, Cambridge, UK) was injected ipsilateral to DCIS and bilaterally for prophylactic mastectomy patients. Our primary outcome was rate of return to the operating room (OR) for delayed SLNB. Secondary outcomes included post-operative complications within 30 days of surgery and operative time. We compared outcomes to a control group of 28 women undergoing mastectomy for DCIS or for risk reduction who underwent SLNB at their index operation in traditional fashion. Continuous variables were reported using median and interquartile ranges (IQR) and were compared using the Mann-Whitney U test. Categorical data were reported using frequency and percent and were compared using Pearson's Chi-Square or Fisher's Exact test, as appropriate. Alpha was set to 0.05 to determine statistical significance. RESULTS: There was a total of 80 patients (52 SPMT, 28 control). Median age of SPMT patients was 49.5 (IQR 40-60.75) vs. 54.5 (48 - 65) in the traditional tracer group. vs. control group. 57.7% of SPMT patients underwent mastectomy for DCIS vs. 89.3% in the control group. Eight SPMT patients (15.4%) had invasive ductal carcinoma (IDC) on final pathology and seven of those patients underwent delayed SLNB (87.5%). None of the delayed SLNB were positive for metastatic disease. Rates of post-operative complications were similar between the two groups, including hematoma, seroma, and surgical site infection. OR times were also similar with median OR time 202 min (min) for the SPMT group vs. 195 min for the control group. CONCLUSION: Use of SPMT avoided SLNB in 84.6% of our patients. We found no difference in rates of post-operative complications or operative times in patients using SPMT for omission of SLNB at time of mastectomy compared to the control group. Our findings suggest SLNB can be avoided in a majority of patients undergoing mastectomy for DCIS or risk reduction in the setting of genetic predisposition.

Ductal carcinoma in situ and cause-specific mortality among younger and older postmenopausal women: the Women's Health Initiative.

BACKGROUND: Whether DCIS is associated with higher breast cancer-specific and all-cause mortality is unclear with few studies in older women. Therefore, we examined DCIS and breast cancer-specific, cardiovascular (CVD)-specific, and all-cause mortality among Women's Health Initiative (WHI) Clinical Trial participants overall and by age (< 70 versus ≥ 70 years). METHODS: Of 68,132 WHI participants, included were 781 postmenopausal women with incident DCIS and 781 matched controls. Serial screening mammography was mandated with high adherence. DCIS cases were confirmed by central medical record review. Adjusted multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Kaplan Meier (KM) plots were used to assess 10-year and 20-year mortality rates. RESULTS: After 20.3 years total, and 13.2 years median post-diagnosis follow-up, compared to controls, DCIS was associated with higher breast cancer-specific mortality (HR 3.29; CI = 1.32-8.22, P = 0.01). The absolute difference in 20-year breast cancer mortality was 1.2% without DCIS and 3.4% after DCIS, log-rank P = 0.026. Findings were similar by age (< 70 versus ≥ 70 years) with no interaction (P interaction = 0.80). Incident DCIS was not associated with CVD-specific mortality (HR 0.77; CI-0.54-1.09, P = 0.14) or with all-cause mortality (HR 0.96; CI = 0.80-1.16, P = 0.68) with similar findings by age. CONCLUSIONS: In postmenopausal women, incident DCIS was associated with over three-fold higher breast cancer-specific mortality, with similar findings in younger and older postmenopausal women. These finding suggest caution in using age to adjust DCIS clinical management or research strategies.

Extracellular Microenvironment Alterations in Ductal Carcinoma In Situ and Invasive Breast Cancer Pathologies by Multiplexed Spatial Proteomics.

Ductal carcinoma in situ (DCIS) is a heterogeneous breast disease that remains challenging to treat due to its unpredictable progression to invasive breast cancer (IBC). Contemporary literature has become increasingly focused on extracellular matrix (ECM) alterations with breast cancer progression. However, the spatial regulation of the ECM proteome in DCIS has yet to be investigated in relation to IBC. We hypothesized that DCIS and IBC present distinct ECM proteomes that could discriminate between these pathologies. Tissue sections of pure DCIS, mixed DCIS-IBC, or pure IBC (n = 22) with detailed pathological annotations were investigated by multiplexed spatial proteomics. Across tissues, 1,005 ECM peptides were detected in pathologically annotated regions and their surrounding extracellular microenvironments. A comparison of DCIS to IBC pathologies demonstrated 43 significantly altered ECM peptides. Notably, eight fibrillar collagen peptides could distinguish with high specificity and sensitivity between DCIS and IBC. Lesion-targeted proteomic imaging revealed heterogeneity of the ECM proteome surrounding individual DCIS lesions. Multiplexed spatial proteomics reported an invasive cancer field effect, in which DCIS lesions in closer proximity to IBC shared a more similar ECM profile to IBC than distal counterparts. Defining the ECM proteomic microenvironment provides novel molecular insights relating to DCIS and IBC.

Prognostic value of tumor-infiltrating lymphocytes in DCIS: a meta-analysis.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) have been shown to be associated with the prognosis of breast ductal carcinoma in situ (DCIS). In this systematic review and meta-analysis, we investigated the role of TILs and TIL subsets in predicting the recurrence risk of DCIS. METHOD: PubMed, Medline, Web of Science, Embase and Cochrane were searched to identify publications investigating the prognostic role of TILs in DCIS. After study screening, data extraction and risk of bias assessment, a meta-analysis was performed to assess the association between TILs (total TILs, CD4+, CD8+, FOXP3+, PD-L1+ TILs) and the risk of DCIS recurrence. RESULTS: A pooled analysis indicated that dense stromal TILs in DCIS were associated with a higher recurrence risk (HR 2.11 (95% CI 1.35-3.28)). Subgroup analysis showed that touching TILs (HR 4.73 (95% CI 2.28-9.80)) was more precise than the TIL ratio (HR 1.49 (95% CI 1.11-1.99)) in estimating DCIS recurrence risk. Moreover, the prognostic value of TILs seemed more suitable for patients who are diagnosed with DCIS and then undergo surgery (HR 2.77, (95% CI 1.26-6.07)) or surgery accompanied by radiotherapy (HR 2.26, (95% CI 1.29-3.95)), than for patients who receive comprehensive adjuvant therapies (HR 1.16, (95% CI 1.35-3.28)). Among subsets of TILs, dense stromal PD-L1+ TILs were valuable in predicting higher recurrence risk of DCIS. CONCLUSION: This systematic review and meta-analysis suggested a non-favorable prognosis of TILs and stromal PD-L1+ TILs in DCIS and indicated an appropriate assessment method for TILs and an eligible population.

Canine and feline in situ mammary carcinoma: A comparative review.

Carcinoma in situ of the breast is a well-known entity in humans. In veterinary medicine, particularly in canine and feline mammary literature, there is no agreement whether the term in situ should be used to indicate a specific carcinoma histotype or the noninvasive status of a carcinoma of any histotype. Moreover, in the most recent histologic classification of mammary tumors published by the Davis-Thompson Foundation, it is suggested to abandon the term carcinoma in situ given the lack of standardized criteria defining this entity, replacing it with epitheliosis or ductal/lobular hyperplasia with severe atypia. This publication presents a critical review of the term in situ in human and veterinary medicine considering the evolution of the term over the years and its heterogeneous use by different authors, including variations in immunohistochemical markers for classification. This review aims to point out the lack of uniformity in the nomenclature and classification issues in veterinary medicine regarding the use of the term in situ, laying the ground for a process of standardization in future publications.

Optical tissue measurements of invasive carcinoma and ductal carcinoma in situ for surgical guidance.

BACKGROUND: Although the incidence of positive resection margins in breast-conserving surgery has decreased, both incomplete resection and unnecessary large resections still occur. This is especially the case in the surgical treatment of ductal carcinoma in situ (DCIS). Diffuse reflectance spectroscopy (DRS), an optical technology based on light tissue interactions, can potentially characterize tissue during surgery thereby guiding the surgeon intraoperatively. DRS has shown to be able to discriminate pure healthy breast tissue from pure invasive carcinoma (IC) but limited research has been done on (1) the actual optical characteristics of DCIS and (2) the ability of DRS to characterize measurements that are a mixture of tissue types. METHODS: In this study, DRS spectra were acquired from 107 breast specimens from 107 patients with proven IC and/or DCIS (1488 measurement locations). With a generalized estimating equation model, the differences between the DRS spectra of locations with DCIS and IC and only healthy tissue were compared to see if there were significant differences between these spectra. Subsequently, different classification models were developed to be able to predict if the DRS spectrum of a measurement location represented a measurement location with "healthy" or "malignant" tissue. In the development and testing of the models, different definitions for "healthy" and "malignant" were used. This allowed varying the level of homogeneity in the train and test data. RESULTS: It was found that the optical characteristics of IC and DCIS were similar. Regarding the classification of tissue with a mixture of tissue types, it was found that using mixed measurement locations in the development of the classification models did not tremendously improve the accuracy of the classification of other measurement locations with a mixture of tissue types. The evaluated classification models were able to classify measurement locations with > 5% malignant cells with a Matthews correlation coefficient of 0.41 or 0.40. Some models showed better sensitivity whereas others had better specificity. CONCLUSION: The results suggest that DRS has the potential to detect malignant tissue, including DCIS, in healthy breast tissue and could thus be helpful for surgical guidance.

Molecular and cellular characterization of two patient-derived ductal carcinoma in situ (DCIS) cell lines, ETCC-006 and ETCC-010.

BACKGROUND: Currently it is unclear how in situ breast cancer progresses to invasive disease; therefore, a better understanding of the events that occur during the transition to invasive carcinoma is warranted. Here we have conducted a detailed molecular and cellular characterization of two, patient-derived, ductal carcinoma in situ (DCIS) cell lines, ETCC-006 and ETCC-010. METHODS: Human DCIS cell lines, ETCC-006 and ETCC-010, were compared against a panel of cell lines including the immortalized, breast epithelial cell line, MCF10A, breast cancer cell lines, MCF7 and MDA-MB-231, and another DCIS line, MCF10DCIS.com. Cell morphology, hormone and HER2/ERBB2 receptor status, cell proliferation, survival, migration, anchorage-independent growth, indicators of EMT, cell signalling pathways and cell cycle proteins were examined using immunostaining, immunoblots, and quantitative, reverse transcriptase PCR (qRT-PCR), along with clonogenic, wound-closure and soft agar assays. RNA sequencing (RNAseq) was used to provide a transcriptomic profile. RESULTS: ETCC-006 and ETCC-010 cells displayed notable differences to another DCIS cell line, MCF10DCIS.com, in terms of morphology, steroid-receptor/HER status and markers of EMT. The ETCC cell lines lack ER/PR and HER, form colonies in clonogenic assays, have migratory capacity and are capable of anchorage-independent growth. Despite being isogenic, less than 30% of differentially expressed transcripts overlapped between the two lines, with enrichment in pathways involving receptor tyrosine kinases and DNA replication/cell cycle programs and in gene sets responsible for extracellular matrix organisation and ion transport. CONCLUSIONS: For the first time, we provide a molecular and cellular characterization of two, patient-derived DCIS cell lines, ETCC-006 and ETCC-010, facilitating future investigations into the molecular basis of DCIS to invasive ductal carcinoma transition.

Long noncoding RNA BHLHE40-AS1 promotes early breast cancer progression through modulating IL-6/STAT3 signaling.

Ductal carcinoma in situ (DCIS) is a nonobligate precursor to invasive breast cancer. Only a small percentage of DCIS cases are predicted to progress; however, there is no method to determine which DCIS lesions will remain innocuous from those that will become invasive disease. Therefore, DCIS is treated aggressively creating a current state of overdiagnosis and overtreatment. There is a critical need to identify functional determinants of progression of DCIS to invasive ductal carcinoma (IDC). Interrogating biopsies from five patients with contiguous DCIS and IDC lesions, we have shown that expression of the long noncoding RNA BHLHE40-AS1 increases with disease progression. BHLHE40-AS1 expression supports DCIS cell proliferation, motility, and invasive potential. Mechanistically, BHLHE40-AS1 modulates interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) activity and a proinflammatory cytokine signature, in part through interaction with interleukin enhancer-binding factor 3. These data suggest that BHLHE40-AS1 supports early breast cancer progression by engaging STAT3 signaling, creating an immune-permissive microenvironment.

CDH2/N-cadherin and early diagnosis of invasion in patients with ductal carcinoma in situ.

PURPOSE: This proof-of-concept study investigates gene expression in core needle biopsies (CNB) to predict whether individuals diagnosed with ductal carcinoma in situ (DCIS) on CNB were affected by invasion at the time of diagnosis. METHODS: Using a QuantiGene Plex 2.0 assay, 14 gene expression profiling was performed in 303 breast tissue samples. Preoperative diagnostic performance of a gene was measured by area under receiver-operating characteristic curve (AUC) with 95% confidence interval (CI). The gene mRNA positivity cutoff was computed using Gaussian mixture model (GMM); protein expression was measured by immunohistochemistry; DNA methylation was evaluated by targeted bisulfite sequencing. RESULTS: mRNA from 69% (34/49) mammoplasties, 72% (75/104) CNB DCIS, and 89% (133/150) invasive breast cancers (IBC) were analyzed. Based on pre-and post-surgery DCIS chart reviews, 21 cases were categorized as DCIS synchronous with invasion and 54 DCIS were pure DCIS without pathologic evidence of invasive disease. The ectopic expression of neuronal cadherin CDH2 was probable in 0% mammoplasties, 6% pure DCIS, 29% synchronous DCIS, and 26% IBC. The CDH2 mRNA positivity in preoperative biopsies showing pure DCIS was predictive of a final diagnosis of invasion (AUC = 0.67; 95% CI 0.53-0.80; P = 0.029). Site-specific methylation of the CDH2 promoter (AUC = 0.76; 95% CI 0.54-0.97; P = 0.04) and measurements of N-cadherin, a pro-invasive cell-cell adhesion receptor encoded by CDH2 (AUC = 0.8; 95% CI 0.66-0.99; P < 0.005) had a discriminating power allowing for discernment of CDH2-positive biopsy. CONCLUSIONS: Evidence of CDH2/N-cadherin expression, predictive of invasion synchronous with DCIS, may help to clarify a diagnosis and direct the course of therapy earlier in a patient's care.

TBX3 promotes progression of pre-invasive breast cancer cells by inducing EMT and directly up-regulating SLUG.

The acquisition of cellular invasiveness by breast epithelial cells and subsequent transition from ductal carcinoma in situ (DCIS) to invasive breast cancer is a critical step in breast cancer progression. Little is known about the molecular dynamics governing this transition. We have previously shown that overexpression of the transcriptional regulator TBX3 in DCIS-like cells increases survival, growth, and invasiveness. To explore this mechanism further and assess direct transcriptional targets of TBX3 in a high-resolution, isoform-specific context, we conducted genome-wide chromatin-immunoprecipitation (ChIP) arrays coupled with transcriptomic analysis. We show that TBX3 regulates several epithelial-mesenchymal transition (EMT)-related genes, including SLUG and TWIST1. Importantly, we demonstrate that TBX3 is a direct regulator of SLUG expression, and SLUG expression is required for TBX3-induced migration and invasion. Assessing TBX3 by immunohistochemistry in early-stage (stage 0 and stage I) breast cancers revealed high expression in low-grade lesions. Within a second independent early-stage non-high-grade cohort, we observed an association between TBX3 level in the DCIS and size of the invasive focus. Additionally, there was a positive correlation between TBX3 and SLUG, and TBX3 and TWIST1 in the invasive carcinoma. Pathway analysis revealed altered expression of several proteases and their inhibitors, consistent with the ability to degrade basement membrane in vivo. These findings strongly suggest the involvement of TBX3 in the promotion of invasiveness and progression of early-stage pre-invasive breast cancer to invasive carcinoma through the low-grade molecular pathway. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

An Emerging Model for Cancer Development from a Tumor Microenvironment Perspective in Mice and Humans.

In the past, cancer development was studied in terms of genetic mutations acquired in cancer cells at each stage of the development. We present an emerging model for cancer development in which the tumor microenvironment (TME) plays an integral part. In this model, the tumor development is initiated by a slowly growing nearly homogeneous colony of cancer cells that can evade detection by the cell's innate mechanism of immunity such as natural killer (NK) cells (first stage; colonization). Subsequently, the colony develops into a tumor filled with lymphocytes and stromal cells, releasing pro-inflammatory cytokines, growth factors, and chemokines (second stage; lymphocyte infiltration). Cancer progression proceeds to a well-vesiculated silent tumor releasing no inflammatory signal, being nearly devoid of lymphocytes (third stage; silenced). Eventually some cancer cells within a tumor undertake epithelial-to-mesenchymal transition (EMT), which leads to cancer metastasis (fourth stage; EMT). If a circulating metastasized cancer cell finds a niche in a new tissue and evades detection by NK cells, it can establish a new colony in which very few stromal cells are present (fifth stage; metastasis), which is much like a colony at the first stage of development. At every stage, cancer cells influence their own TME, and in turn, the TME influences the cancer cells contained within, either by direct interaction between cancer cells and stromal cells or through exchange of cytokines. In this article, we examine clinical findings and animal experiments pertaining to this paradigm-shifting model and consider if, indeed, some aspects of cancer development are governed solely by the TME.

Ectopic expression of PLC-ß2 in non-invasive breast tumor cells plays a protective role against malignant progression and is correlated with the deregulation of miR-146a.

Cells in non-invasive breast lesions are widely believed to possess molecular alterations that render them either susceptible or refractory to the acquisition of invasive capability. One such alteration could be the ectopic expression of the ß2 isoform of phosphoinositide-dependent phospholipase C (PLC-ß2), known to counteract the effects of hypoxia in low-invasive breast tumor-derived cells. Here, we studied the correlation between PLC-ß2 levels and the propensity of non-invasive breast tumor cells to acquire malignant features. Using archival FFPE samples and DCIS-derived cells, we demonstrate that PLC-ß2 is up-regulated in DCIS and that its forced down-modulation induces an epithelial-to-mesenchymal shift, expression of the cancer stem cell marker CD133, and the acquisition of invasive properties. The ectopic expression of PLC-ß2 in non-transformed and DCIS-derived cells is, to some extent, dependent on the de-regulation of miR-146a, a tumor suppressor miRNA in invasive breast cancer. Interestingly, an inverse relationship between the two molecules, indicative of a role of miR-146a in targeting PLC-ß2, was not detected in primary DCIS from patients who developed a second invasive breast neoplasia. This suggests that alterations of the PLC-ß2/miR-146a relationship in DCIS may constitute a molecular risk factor for the appearance of new breast lesions. Since neither traditional classification systems nor molecular characterizations are able to predict the malignant potential of DCIS, as is possible for invasive ductal carcinoma (IDC), we propose that the assessment of the PLC-ß2/miR-146a levels at diagnosis could be beneficial for identifying whether DCIS patients may have either a low or high propensity for invasive recurrence.

Qualitative Radiogenomics: Association Between BI-RADS Calcification Descriptors and Recurrence Risk as Assessed by the Oncotype DX Ductal Carcinoma In Situ Score.

OBJECTIVE: Treatment of ductal carcinoma in situ (DCIS) is controversial given the variable recurrence and progression to invasive carcinoma. Identifying women who would benefit from adjuvant radiation therapy on the basis of their recurrence risk may allow more individualized management strategies. The Oncotype DX Breast DCIS Score-which we refer to here as the "DCIS score"-is a validated surrogate marker of local recurrence. This study evaluated the association between BI-RADS mammographic calcification descriptors and the DCIS score. MATERIALS AND METHODS: Fifty-eight women diagnosed with DCIS presenting with calcifications who had Oncotype DX Breast DCIS assay results were identified. Pretreatment BI-RADS mammographic calcification features were collected including morphology, distribution, and maximum span. The association between calcification descriptors and DCIS score was assessed with logistic regression modeling. Mean DCIS scores were calculated for calcification features significantly associated with DCIS score. All analyses were adjusted for patient age, DCIS grade, and progesterone receptor status. RESULTS: Of the suspicious calcifications that proved to represent DCIS, 19.0% were amorphous; 25.9%, coarse heterogeneous; 39.7%, fine pleomorphic; and 15.5%, fine linear or fine linear branching in morphology. The mean DCIS scores by calcification morphology were 22.3, 35.5, 36.7, and 44.1, respectively. Amorphous calcification morphology had a significantly lower adjusted mean DCIS score compared with fine pleomorphic morphology (p = 0.01) and fine linear or fine linear branching morphology (p = 0.02). The adjusted odds ratio (OR) of intermediate or high risk of recurrence (defined as a DCIS score ≥ 39) was significantly higher for women with fine pleomorphic calcifications (OR = 53.1, p = 0.01) and for those with fine linear or fine linear branching calcifications (OR = 24.0, p = 0.04) than for women with amorphous calcifications. CONCLUSION: Women with amorphous calcification morphology had the lowest DCIS scores compared with women with fine pleomorphic and fine linear or fine linear branching morphologies. Both fine pleomorphic and fine linear or fine linear branching morphologies were associated with higher odds of intermediate or high risk of recurrence. These findings suggest mammographic features are potential biomarkers of DCIS recurrence and could help individualize treatment decisions.

Intratumoral Heterogeneity in Ductal Carcinoma In Situ: Chaos and Consequence.

Ductal carcinoma in situ (DCIS) is a non-invasive proliferative growth in the breast that serves as a non-obligate precursor to invasive ductal carcinoma. The widespread adoption of screening mammography has led to a steep increase in the detection of DCIS, which now comprises approximately 20% of new breast cancer diagnoses in the United States. Interestingly, the intratumoral heterogeneity (ITH) that has been observed in invasive breast cancers may have been established early in tumorigenesis, given the vast and varied ITH that has been detected in DCIS. This review will discuss the intratumoral heterogeneity of DCIS, focusing on the phenotypic and genomic heterogeneity of tumor cells, as well as the compositional heterogeneity of the tumor microenvironment. In addition, we will assess the spatial heterogeneity that is now being appreciated in these lesions, and summarize new approaches to evaluate heterogeneity of tumor and stromal cells in the context of their spatial organization. Importantly, we will discuss how a growing understanding of ITH has led to a more holistic appreciation of the complex biology of DCIS, specifically its evolution and natural history. Finally, we will consider ways in which our knowledge of DCIS ITH might be translated in the future to guide clinical care for DCIS patients.

Trends in breast cancer mortality by stage at diagnosis among young women in the United States.

BACKGROUND: Assessing trends in breast cancer survival among young women who are largely unaffected by breast cancer screening will provide important information regarding improvements in the effectiveness of cancer care for breast cancer in the last few decades. METHODS: The cohort for this study consisted of women who were diagnosed with breast cancer between ages 20 and 39 years from the Surveillance, Epidemiology, and End Results program's 9-registry areas from 1975 to 2015. Trends in the breast cancer incidence rate and survival were assessed among young women. RESULTS: Among women aged 20 to 39 years, breast cancer incidence increased from 24.6 per 100,000 in 1975 to 31.7 per 100,000 in 2015 (annual percent change, 0.5; 95% confidence interval [CI], 0.4-0.6). Among women with breast cancer, 5-year breast-cancer-specific survival increased significantly from 74.0% during 1975 to 1979 to 88.5% during 2010 to 2015 (hazard ratio for dying from breast cancer for 2010-2015 vs 1975-1979, 0.37; 95% CI, 0.32-0.41). The increase in cancer-specific survival reached a plateau in 2005; however, among young women with metastatic breast cancer, it continued to increase after 2005, from 45.6% during 2005 to 2009 to 56.5% during 2010 to 2015 (hazard ratio for dying from breast cancer for 2010-2015 vs 2005-2009, 0.74; 95% CI, 0.60-0.92). Similar patterns also were observed for 5-year overall survival and among women aged 20 to 29 years and those aged 30 to 39 years. CONCLUSIONS: There were substantial improvements in the effectiveness of breast cancer treatment on overall and cancer-specific survival from 1975 to 2015. However, improvements appeared to have reached a plateau after 2005, except among young women with metastatic breast cancer, in whom survival continued to improve throughout the period.

Development and validation of algorithms to differentiate ductal carcinoma in situ from invasive breast cancer within administrative claims data.

BACKGROUND: Overtreatment is a common concern for patients with ductal carcinoma in situ (DCIS), but this entity is difficult to distinguish from invasive breast cancers in administrative claims data sets because DCIS often is coded as invasive breast cancer. Therefore, the authors developed and validated algorithms to select DCIS cases from administrative claims data to enable outcomes research in this type of data. METHODS: This retrospective cohort using invasive breast cancer and DCIS cases included women aged 66 to 70 years in the 2004 through 2011 Texas Cancer Registry (TCR) data linked to Medicare administrative claims data. TCR records were used as "gold" standards to evaluate the sensitivity, specificity, and positive predictive value (PPV) of 2 algorithms. Women with a biopsy enrolled in Medicare parts A and B at 12 months before and 6 months after their first biopsy without a second incident diagnosis of DCIS or invasive breast cancer within 12 months in the TCR were included. Women in 2010 Medicare data were selected to test the algorithms in a general sample. RESULTS: In the TCR data set, a total of 6907 cases met inclusion criteria, with 1244 DCIS cases. The first algorithm had a sensitivity of 79%, a specificity of 89%, and a PPV of 62%. The second algorithm had a sensitivity of 50%, a specificity of 97%. and a PPV of 77%. Among women in the general sample, the specificity was high and the sensitivity was similar for both algorithms. However, the PPV was approximately 6% to 7% lower. CONCLUSIONS: DCIS frequently is miscoded as invasive breast cancer, and thus the proposed algorithms are useful to examine DCIS outcomes using data sets not linked to cancer registries. Cancer 2018;124:2815-2823. © 2018 American Cancer Society.

Initiation of and adherence to tamoxifen and aromatase inhibitor therapy among elderly women with ductal carcinoma in situ.

BACKGROUND: The National Surgical Adjuvant Breast and Bowel Project B35 and International Breast Cancer Intervention Studies II Ductal Carcinoma In Situ trials showed similar treatment effects of anastrozole and tamoxifen in reducing cancer recurrence risk among ductal carcinoma in situ (DCIS) patients. Studies have shown low levels of hormone therapy drug initiation for DCIS patients, but the current body of literature lacks information on the 5-year adherence rates for these drugs from population-based studies. METHODS: This study evaluated the initiation and 5-year adherence levels for women aged 66 to 85 years who had been diagnosed with estrogen receptor (ER)-positive DCIS between 2007 and 2011 according to the Surveillance, Epidemiology, and End Results and Texas Cancer Registry databases linked to Medicare claims. Chi-square tests, trend tests, and logistic regression were used to identify factors associated with treatment initiation. RESULTS: There were 2871 women with ER-positive DCIS, and approximately 45% began treatment with tamoxifen or aromatase inhibitors (AIs) within 1 year of their DCIS diagnosis. The median age was 73 years for the users and 75 years for the nonusers. Women aged 66 to 70 years who underwent lumpectomy and radiation therapy were significantly more likely to initiate hormone therapy. The initiation of therapy was also significantly associated with patients' geographic location, education, marital status, diagnosis year, and race/ethnicity. Among users, adherence decreased from 67% in the first year to 30% in the fifth year. CONCLUSIONS: Initiation and adherence levels for tamoxifen or AIs among older women with ER-positive DCIS are low. Future studies should develop methods to ensure that informed discussions take place between health care providers and patients regarding hormonal therapy for cancer prevention. Cancer 2017;123:940-47. © 2016 American Cancer Society.

Trends in adjuvant therapies after breast-conserving surgery for hormone receptor-positive ductal carcinoma in situ: findings from the National Cancer Database, 2004-2013.

PURPOSE: Breast-conserving surgery (BCS) followed by radiotherapy (RT) with or without endocrine therapy (ET) is a standard treatment option for ductal carcinoma in situ (DCIS). We sought to investigate national patterns in the use of adjuvant therapy after BCS for hormone receptor (HR)-positive DCIS over time. PATIENTS AND METHODS: Using data from the National Cancer Data Base, we identified patients diagnosed with DCIS and treated with BCS between 2004 and 2013. Multivariable logistic regression was used to estimate the odds of adjuvant therapy use controlling for clinicopathologic demographic and facility-level characteristics. RESULTS: We identified 66,079 patients who underwent BCS for DCIS. Overall, 21% received no adjuvant treatment, 71% received RT, 48% received ET, and 38% received the combination therapy. In adjusted analyses among the patients with HR-positive DCIS (n = 50,147), the administration of RT decreased (odds ratio [OR] 0.86, 95% CI 0.77-0.97), while the use of ET increased (OR 1.5, 95% CI 1.4-1.6) in 2013 compared to 2004. Young patients, elderly patients, positive margin status, and Medicare insurance were associated with lower use of both RT and ET. We observed both clinicopathologic and geographic variation in the use of adjuvant therapies. In the lowest risk subgroup, the use of RT decreased from 57% in 2004 to 48% in 2013 (OR 0.64, 95% CI 0.45-0.89). CONCLUSION: Our study suggests a shift in patterns of care for DCIS that is impacted by both clinicopathologic and demographic factors, with the use of RT decreasing and the use of ET increasing in HR-positive DCIS patients. Current trials are designed to address the possible over-treatment of low-risk DCIS.

Non-mass breast lesions on ultrasound: final outcomes and predictors of malignancy.

Background Breast cancer can present as non-mass lesions (NMLs) on ultrasound. However, knowledge of and understanding about NMLs are scarce. Purpose To retrospectively investigate the final outcomes of sonographic breast NMLs and determine the clinical and radiologic variables associated with malignancy Material and Methods In our radiologic database of breast ultrasound examinations between 2011 and 2014, we found 119 women with 121 NMLs with available histopathologic or sonographic follow-up (over 2 years) data. We collected the clinical variables (patient's age, symptoms, and mammographic density) and histopathologic data as well as radiologic variables (mammographic and ultrasound findings) after retrospective review by two radiologists, the authors of the current paper, in consensus. We classified the ultrasound findings according to distribution (focal, linear or segmental, and regional) and associated features (calcification, architectural distortion, and ductal changes) and analyzed the associations between variables and malignancy using the t test and χ2 test. Results Of the 121 NMLs, 88 (72.7%) were benign and 33 (27.3%) were malignant. Ductal carcinoma in situ (DCIS) (17/33, 51.5%) and invasive ductal cancer with or without DCIS (13/33, 39.4%) comprised the main malignancies, and malignancy was significantly associated with palpability ( P = 0.000). Mammographic findings and sonographic distribution and associated features were significantly different between benign and malignant lesions ( P = 0.000, P = 0.004, and P = 0.001, respectively). Malignant lesions showed more frequent calcifications combined with asymmetry ( P = 0.000) on mammography and linear-segmental distributions ( P = 0.001) and associated calcifications ( P = 0.019) or architectural distortions ( P = 0.015) on ultrasound. Conclusion Breast NMLs on ultrasound showed high risk of malignancy. Symptoms and mammographic and ultrasound findings can be possible predictors of malignancy in NMLs.