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Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1–3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.

To investigate the role and mechanism of TNF-inducible protein 3(TNFAIP3) in breast cancer angiogenesis induced by fibroblast growth factor receptor1 (FGFR1) activation.The immunohistochemical assay was used to detect the expression of vascular endothelial cell marker CD31 and CD105 in mice DCIS.COM-iFGFR1 transplanted tumor (previously established by our group). The effects of TNFAIP3 knockout/knockdown breast cancer cell lines on angiogenesis, migration, and invasion of Human Umbilical Vein Endothelial Cells (HUVEC) were detected by the tubulogenesis and Trewells assay. RNA-seq analysis of TNFAIP3 downstreams differential genes after TNFAIP3 knockdown. The expression and secretion of VEGFA after FGFR1 activation in breast cancer cells were detected by qPCR, Western blot, and ELISA.Immunohistochemistry showed that TNFAIP3 knockout inhibited the expression of CD31 and CD105 in DCIS grafted tumors promoted by FGFR1 activation. Tubulogenesis and Trewells experiments showed that TNFAIP3 gene knockout/knockdown inhibited the angiogenesis, migration, and invasion of HUVEC cells promoted by FGFR1 activation. qPCR assay showed that VEGFA mRNA level in the TNFAIP3 knockdown cell line was significantly down-regulated (p 0.05). qPCR, Western blot and ELISA results showed that TNFAIP3 gene knockout/knockdown could inhibit the expression and secretion of VEGFA in breast cancer cells induced by FGFR1 activation.TNFAIP3 promotes breast cancer angiogenesis induced by FGFR1 activation through the expression and secretion of VEGFA.

Ductal carcinoma in-situ (DCIS) accounts for 20-25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite relative mass, hydroxyapatite and whitlockite crystal maturity and, elementally, sodium to calcium ion ratio. A preliminary predictive model for DCIS to invasive cancer progression was developed from these parameters with an AUC of 0.797. These results provide insights into the differing DCIS tissue microenvironments, and how these impact microcalcification formation.

The definition of "no tumor on ink" is generally applied for clear resection margin (RM) after breast-conserving surgery (BCS). However, few studies reported the effect of RM in the setting of neoadjuvant chemotherapy (NAC). We investigated the association between RM status and survival outcomes for those who underwent BCS after NAC for breast cancer.We retrospectively reviewed the data of 2,803 patients who underwent BCS and whole-breast irradiation after NAC between January 2008 and December 2016 from three institutions in South Korea.The 786 patients in the pathologic complete response group (RClear RM of specimen does not have benefit on LRFS after NAC. Additionally, for the patients showing pCR with residual DCIS in the breast, margin involvement also did not affect the risk of local recurrence.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive carcinoma. Multiple studies have shown that DCIS lesions typically possess a driver mutation associated with cancer development. Mutation in the TP53 tumour suppressor gene is present in 15-30% of pure DCIS lesions and in ~30% of invasive breast cancers. Mutations in TP53 are significantly associated with high-grade DCIS, the most likely form of DCIS to progress to invasive carcinoma. In this review, we summarise published evidence on the prevalence of mutant TP53 in DCIS (including all DCIS subtypes), discuss the availability of mouse models for the study of DCIS and highlight the need for functional studies of the role of TP53 in the development of DCIS and progression from DCIS to invasive disease.

MicroRNAs (miRNAs) control diverse biologic processes during tumor progression. This study was conducted to identify miRNAs that are implicated in progression of in situ to invasive breast cancer (IBC) and to evaluate their association with clinicopathological features of ductal carcinoma in situ (DCIS).We performed miRNA microarray analyses to find differentially expressed miRNAs between DCIS and IBC in a test set, and validated expression levels of selected miRNAs using a different set of tumors. Finally, we evaluated the relationship between clinicopathological features and the expression of selected miRNAs in DCIS samples.We found that miR-145-5p, miR-205-5p and miR-451a are significantly down-regulated in IBC compared to DCIS in the whole group, and in the estrogen receptor (ER)-positive and ER-negative subgroups. In a validation set, miR-145, miR-205, and miR-451 also showed lower expression levels in IBC than in DCIS, irrespective of ER status. Moreover, their expression levels were significantly lower in the invasive component compared to the in situ component within same tumors. MiR-145, miR-205 and miR-451 commonly showed lower expression levels in DCIS with positive HER2 status and high Ki-67 proliferation index. Especially, miR-145 and miR-205 showed lower expression levels in DCIS with microinvasion, compared to pure DCIS. In addition, lower miR-205 expression level was associated with high nuclear grade, comedo type necrosis, and hormone receptor negativity.Our study showed that miR-145, miR-205 and miR-451 expression decreased in IBC compared to DCIS, and their expression levels were low in DCIS with high-risk features for progression, implying their contributions in the progression of DCIS to invasive carcinoma as tumor suppressors.

Objective Our purpose is to evaluate the correlation of TILs with clinicopathological characteristics and disease free survival (DFS) in DCIS and DCIS-Mi breast cancer (BC) patients. Methods We retrospectively reviewed the data of 360 DCIS patients and 125 DCIS-Mi patients treated by a single institution from 2016 to 2019. TILs are regarded as continuous variables and are divided into low (≤ 5%), medium (5–40%) and high (≥ 40%) for statistical analysis. Results In DCIS and DCIS-Mi patients, larger tumor size, higher nuclear grade, hormone receptor (HR) negativity and human epidermal growth factor receptor 2(HER2) overexpression are all related to high TILs (P P P = 0.015) and high TILs (P = 0.002) compared with DCIS patients. In the survival analysis, we found that TILs had no effect on the DFS of DCIS (P = 0.938), DCIS-Mi (P = 0.807), and HER2+ (P = 0.379) BC patients. In the univariate and multivariate cox regression analysis, the correlation between TILs and the prognosis of DFS has not been confirmed in the three BC groups (P > 0.05). Conclusion TILs have played an non-negligible role in the progress of DCIS to DCIS-Mi, especially in HER2+ BC. The predictive and prognostic value of TILs still needs further research to confirm.

Background Population breast screening services in England were suspended in March 2020 due to the COVID-19 pandemic. Here, we estimate the number of breast cancers whose detection may be delayed because of the suspension, and the potential impact on cancer deaths over 10 years. Methods We estimated the number and length of screening delays from observed NHS Breast Screening System data. We then estimated additional breast cancer deaths from three routes: asymptomatic tumours progressing to symptomatically diagnosed disease, invasive tumours which remain screen-detected but at a later date, and ductal carcinoma in situ (DCIS) progressing to invasive disease by detection. We took progression rates, prognostic characteristics, and survival rates from published sources. Results We estimated that 1,489,237 women had screening delayed by around 2–7 months between July 2020 and June 2021, leaving 745,277 outstanding screens. Depending on how quickly this backlog is cleared, around 2500–4100 cancers would shift from screen-detected to symptomatic cancers, resulting in 148–452 additional breast cancer deaths. There would be an additional 164–222 screen-detected tumour deaths, and 71–97 deaths from DCIS that progresses to invasive cancer. Conclusions An estimated 148–687 additional breast cancer deaths may occur as a result of the pandemic-related disruptions. The impact depends on how quickly screening services catch up with delays.

PURPOSE: Patients diagnosed with ductal carcinoma in situ (DCIS) face trade-offs when deciding among different treatments, including surgery, radiation, and endocrine therapy. A less chosen option is active monitoring. While evidence from clinical trials is not yet available, observational studies show comparable results for active monitoring and immediate treatment on cancer outcomes in select subgroups of patients. We developed and tested a web-based decision support tool (DST) to help patients explore current knowledge about DCIS and make an informed choice. METHODS: The DST, an interactive web application, was informed by literature reviews and formative work with patients, breast surgeons, and health communication experts. We conducted iterative interviews to evaluate the DST content among women with and without a history of breast cancer, as well as breast cancer experts. For usability testing, we conducted an online survey among women with and without a history of breast cancer. RESULTS: For content evaluation, 5 women with and 10 women without a history of DCIS were interviewed. The sample included 11 White and 4 non-White women, with a mean age of 64 years. The expert sample consisted of 5 attendings and a physician assistant. The feedback was used to add, clarify, or reorganize information in the DST. For usability testing, 22 participants with a mean age of 61 years were recruited including 15 White and 7 Black women and 6 women with a history of DCIS. The mean usability score was 3.7 out of 5. Most participants (86%) found that the DST provided unbiased information about treatments. To improve usability, we reduced the per-page content and added navigation cues. CONCLUSION: Content and usability evaluation showed that the DST helps patients explore trade-offs of active monitoring and immediate treatment. By adopting a personalized approach, the tool will enable informed decisions aligned with patients’ values and expectations.

PURPOSE: Despite recommendations from national organizations supporting the use of lymph node assessment (LNA) among patients with ductal carcinoma in situ (DCIS) at time of mastectomy, variation in practice patterns across the United States has been observed. However, few studies have evaluated LNA differences and rurality. METHODS: Data from the SEER Patterns of Care (POC) studies were used to identify women who underwent mastectomy for newly diagnosed DCIS during 2000, 2005, 2010, and 2015. Weighted multivariate logistic regression was used to evaluate the association between rural-urban residence and the use of LNA. A subgroup analysis was performed comparing the use of axillary lymph node dissection (ALND) versus sentinel lymph node biopsy (SLNB). RESULTS: Of the 504 patients included in the analysis, approximately 81% underwent LNA at time of mastectomy with lower rates of use observed among rural patients (66%) versus urban patients (82%). In multivariate analysis, LNA increased over time (p

Anatomic extent of ductal carcinoma in situ (DCIS) may be uncertain in spite of clinical, pathologic, and imaging data. Consequently close/positive margins are common with lumpectomy for DCIS and often lead to a challenge in deciding whether to perform a re-excision or mastectomy.From a single health system, we identified cases of lumpectomy for DCIS with close/positive margins who underwent re-excision for the purpose of constructing a nomogram. In total, 289 patients were available for analysis. The patients were randomly divided into two sets allocating 70% to the modeling and 30% to the validation set. A multivariable logistic regression model was used to estimate the probability of overall positive margin status using multiple clinicopathologic predictors. Nomogram validation included internal tenfold cross-validation, internal bootstrap validation, and external validation for which a concordance index was calculated to assess the external validity.Significant predictors of persistent positive margins from regression modeling included necrosis at diagnosis (non-comedo or comedo); DCIS not associated with calcifications on core biopsy; high-grade DCIS; progesterone receptor positivity; and number of positive margins at initial surgery. When subjected to internal validation, the nomogram achieved an uncorrected concordance index of 0.7332, a tenfold cross-validation concordance index of 0.6795, and a bootstrap-corrected concordance index of 0.6881. External validation yielded an estimated concordance index of 0.7095.Using clinical and pathologic variables from initial diagnosis and surgery for DCIS, this nomogram predicts persistent positive margins with margin re-excision, and may be a valuable tool in surgical decision-making.

Preoperative evaluations of the size of ductal carcinoma in situ (DCIS) extension in invasive breast cancer (IBC) are problematic and markers of the actual size of DCIS remain elusive. This study aimed to quantify DCIS on core needle biopsy (CNB) and investigated its association with degree of DCIS extension on paired resection specimens, instead of with presence or absence of an extensive intraductal component or margin status as in earlier studies. This series examined 150 IBCs diagnosed from paired CNB and resection specimens. The DCIS/invasion ratio was calculated using the sum of each element size from CNB. In resection specimens, cases in which the greatest dimension of DCIS extension was longer than the greatest dimension of invasive size were defined as extended DCIS (Ext-DCIS). DCIS/invasion ratio level correlated positively with the degree of Ext-DCIS (P = 0.003). Using receiver operating characteristic curve analysis, setting cases with the subgroup of DCIS extension with greatest dimension 2.5 times that of the invasive size in the resection specimen (Ext-DCIS 2.5) as the positive class provided the best discrimination ability for DCIS/invasion ratio (0.375). In multivariate analysis, DCIS/invasion ratio 0.375 was significantly associated with Ext-DCIS 2.5 (P = 0.033). In conclusion, DCIS/invasion ratio 0.375 in CNB was identified as a predictor of Ext-DCIS 2.5 in resection specimens, suggesting that an approach combining DCIS/invasion ratio from CNB with preoperative staging may better predict the extent of DCIS and facilitate better surgical planning.

Background Surgical delays are associated with invasive cancer for patients with ductal carcinoma in situ (DCIS). During the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pandemic, neoadjuvant endocrine therapy (NET) was used as a bridge until postponed surgeries resumed. This study sought to determine the impact of NET on the rate of invasive cancer for patients with a diagnosis of DCIS who have a surgical delay compared with those not treated with NET. Methods Using the National Cancer Database, the study identified women with hormone receptor-positive (HR+) DCIS. The presence of invasion on final pathology was evaluated after stratifying by receipt of NET and by intervals based on time from diagnosis to surgery (≤30, 31–60, 61–90, 91–120, or 121–365 days). Results Of 109,990 women identified with HR+ DCIS, 276 (0.3%) underwent NET. The mean duration of NET was 74.4 days. The overall unadjusted rate of invasive cancer was similar between those who received NET ((15.6%) and those who did not (12.3%) (p = 0.10). In the multivariable analysis, neither the use nor the duration of NET were independently associated with invasion, but the trend across time-to-surgery categories demonstrated a higher rate of upgrade to invasive cancer in the no-NET group (p < 0.001), but not in the NET group (p = 0.97). Conclusions This analysis of a pre-COVID cohort showed evidence for a protective effect of NET in HR+ DCIS against the development of invasive cancer as the preoperative delay increased, although an appropriately powered prospective trial is needed for a definitive answer. Supplementary Information The online version contains supplementary material available at 10.1245/s10434-021-10883-5.

Purpose The contribution of common genetic variants to pre-cancer progression is understudied due to long follow-up time, rarity of poor outcomes and lack of available germline DNA collection. Alternatively, DNA from diagnostic archival tissue is available, but its somatic nature, limited quantity and suboptimal quality would require an accurate cost-effective genome-wide germline genotyping methodology. Experimental design Blood and tissue DNA from 10 individuals were used to benchmark the accuracy of Single Nucleotide Polymorphisms (SNP) genotypes, Polygenic Risk Scores (PRS) or HLA haplotypes using low-coverage whole-genome sequencing (lc-WGS) and genotype imputation. Tissue-derived PRS were further evaluated for 36 breast cancer patients (11.7 years median follow-up time) diagnosed with DCIS and used to model the risk of Breast Cancer Subsequent Events (BCSE). Results Tissue-derived germline DNA profiling resulted in accurate genotypes at common SNPs (blood correlation r2 > 0.94) and across 22 disease-related polygenic risk scores (PRS, mean correlation r = 0.93). Imputed Class I and II HLA haplotypes were 96.7% and 82.5% concordant with clinical-grade blood HLA haplotypes, respectively. In DCIS patients, tissue-derived PRS was significantly associated with BCSE (HR = 2, 95% CI 1.2–3.8). The top and bottom decile patients had an estimated 28% and 5% chance of BCSE at 10 years, respectively. Conclusions Archival tissue DNA germline profiling using lc-WGS and imputation, represents a cost and resource-effective alternative in the retrospective design of long-term disease genetic studies. Initial results in breast cancer suggest that common risk variants contribute to pre-cancer progression.

Downregulation of human leukocyte antigen (HLA) class I is one mechanism of escaping anti-tumor immunity by tumor cells. This study was conducted to compare HLA class I expression in ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC) and to evaluate its association with immune cell infiltration of the tumors and clinical outcome of the patients. A total of 830 cases comprising 288 DCIS and 542 IBC were included in this study. Immunohistochemistry for HLA class I expression was performed using HLA-ABC in tissue microarrays and was analyzed in relation to clinicopathologic characteristics of tumors and infiltration of CD4+, CD8+, and FOXP3+ tumor-infiltrating lymphocyte (TIL) subsets and PD-L1+ immune cells. As a whole, there was no difference in HLA class I expression between DCIS and IBC when dichotomized into high or low expression. However, in the HR-negative group, a high level of HLA class I expression was more frequent in IBC than DCIS. On the contrary, in the HR-positive group, a complete loss of HLA class I expression was more frequently observed in IBC than DCIS. High HLA class I expression level was generally associated with aggressive clinicopathologic features of IBC and was associated with high CD4+, CD8+, and FOXP3+ TIL and PD-L1+ immune cell infiltration in both DCIS and IBC. In survival analyses, HLA class I expression was not associated with clinical outcome in DCIS and IBC as a whole; however, low HLA class I expression was associated with poor clinical outcome in HR-negative IBC, especially in triple-negative subtype. In conclusion, this study showed that HLA class I expression increased in association with increased immune cell infiltration during in situ to invasive transition of HR-negative breast cancer, and HLA class I down-regulation had a prognostic value in HR-negative breast cancer.

Ductal carcinoma in situ with microinvasion (DCIS-MI) is a subtype of breast cancer with a good prognosis, for which both breast conserving surgery plus radiotherapy (BCS + RT) and mastectomy are feasible surgical methods, but no clear conclusion has been made on the choice of these treatments. We used the Surveillance, Epidemiology and End Results database to extract 5432 DCIS-MI patients. Participants were divided into the BCS + RT group and the mastectomy group. We compared the overall survival (OS) and breast cancer-specific survival (BCSS) of the two groups using the Kaplan–Meier method and Cox regressions before and after propensity score matching (PSM). Before PSM, both univariate and multivariate analyses showed that BCS + RT group had significantly higher OS and BCSS compared with patients in the mastectomy group (P P P = 0.017). In addition, the subgroup analysis showed that BCS + RT is at least equivalent to mastectomy with respect to OS and BCSS in any subgroup. For patients with DCIS-MI, the prognosis of BCS + RT was superior to mastectomy.

HER2 is an established prognostic and predictive marker for patients with invasive breast cancer. The clinical and biological significance of HER2 overexpression in patients with ductal carcinoma in situ (DCIS) remains poorly defined. DCIS is a heterogeneous disease and some patients with DCIS will not progress to invasive breast cancer. However, clinically significant recurrence rates have been reported after breast-conserving surgery for DCIS and approximately half of these cases will be life-threatening invasive recurrences. Since the incidence of DCIS is rising due to the widespread use of screening mammography, there is robust interest in selecting high-risk DCIS patients that may benefit from adjuvant therapies. Molecular prognostic and predictive models in early invasive breast cancer help clinicians identify patients that will benefit from chemotherapy. Molecular subtyping and profiling could also be useful in treating DCIS patients. According to current practice guidelines, HER2 testing is not recommended in DCIS patients. Nevertheless, evidence suggests that HER2-positive DCIS cases may be associated with adverse clinicopathological parameters and increased recurrence rates. This review summarizes the existing body of evidence linking HER2 expression and ipsilateral breast cancer recurrence in DCIS. HER2, as well as its correlation with other clinicopathological markers might be a useful prognostic and predictive marker, helping clinical decision-making in DCIS patients.

To characterize the clinical, pathological, and imaging features of DCIS occult on conventional imaging diagnosed on MRI-guided biopsy associated with increased risk of invasive disease on surgical excision. All consecutive patients with MRI-detected DCIS occult on conventional imaging between January 2009 and December 2018 were included. Women were divided into two groups based on final pathology: Pure DCIS or DCIS with invasive component. Clinical, imaging, and pathological risk factors for upgrade to invasion were evaluated. Of 50 patients who met the inclusion criteria, 12 (24%) were upgraded to invasive malignancy in the final pathology. The only parameters that showed statistically significant association with upgrade were related to kinetic characteristics: 53% of patients with the combination of fast early upstroke and either plateau or washout curve were upgraded, compared to 12% of women without this combination (p = 0.006). The sensitivity of combined kinetic features for predicting upgrade was 67% (95% CI 35–90%), specificity was 84% (CI 95% 68–94%), positive predictive value was 57% (CI 95% 37–75%), negative predictive value was 89% (CI 95% 77–95%), and OR was 78% (64–88%). Kinetic characteristics show the strongest association with upgrade to invasion in DCIS occult on mammogram and US. Larger studies should be encouraged to consolidate our findings, which may have implication for treatment planning.

Because no prior studies have evaluated the chronological trends of ductal carcinoma in situ (DCIS) despite the increasing number of surgeries performed for DCIS, this study analyzed how the clinical, radiologic, and pathologic characteristics of DCIS changed during a 10-year period. Of 7123 patients who underwent primary breast cancer surgery at a single institution from 2006 to 2015, 792 patients with pure DCIS were included in this study. The chronological trends of age, symptoms, method for detecting either mammography or ultrasonography, tumor size, nuclear grade, comedonecrosis, and molecular markers were calculated using Poisson regression for all patients and asymptomatic patients. During 10 years, DCIS surgery rates significantly increased (p < 0.001). Despite the high percentage of DCIS detected on mammography, the detection rate for DCIS by mammography significantly decreased (97.3% in 2006 to 67.6% in 2015; p = 0.025), whereas the detection rate by ultrasound significantly increased (2.7% to 31.0%; p < 0.001). Conservation surgery rates (odds ratio [OR], 1.058), low-to-intermediate nuclear grade rates (OR, 1.069), and the absence of comedonecrosis (OR, 1.104) significantly increased over time (all p < 0.05). Estrogen receptor (ER) negativity (OR, 0.935) and human epidermal growth factor receptor 2 (HER2) positivity rates (OR, 0.953) significantly decreased (all p < 0.05). The same trends were observed for the 613 asymptomatic patients. The rate of DCIS detected on ultrasound only significantly increased during 10 years. Low-to-intermediate nuclear grade rates significantly increased, whereas ER negativity and HER2 positivity rates significantly decreased during the same period. These findings suggest that DCIS detected on screening ultrasound is less aggressive than DCIS detected on mammography.

Objective To provide a rare case of local recurrent Paget’s disease after nipple-sparing mastectomy (NSM) with immediate breast reconstruction with 10 years of disease-free survival and to analyze the clinical and pathological characteristics. Background Mammary Paget’s disease can be considered a rare type of local recurrence after breast cancer treatment, both in cases of conservative surgery and NSM with immediate breast reconstruction (Lohsiriwat et al, Ann Surg Oncol 19:1850-1855, 2012). Recurrent patients who present with nipple-areolar Paget’s disease usually have unfavorable primary pathological characteristics and different latency periods. However, the recurrent status in patients with favorable primary pathological characteristics and the latency periods after NSM with immediate breast reconstruction are unclear. Methods First, we present a case of local recurrent Paget’s disease in a young patient diagnosed with invasive breast carcinoma at age 30 who underwent NSM with primary silicone reconstruction. Then, the keywords “Paget’s disease” and “nipple-sparing mastectomy” were selected. Articles including the local recurrence of Paget’s disease after NSM were collected from the PubMed, Springer, and OVID databases, and the acquired relevant data were analyzed. We did not restrict our search by study design or publication date. Results Five studies describing 31 cases of local recurrent Paget’s disease after NSM with implant breast reconstruction were included. The mean patient age reported was 45 years, and the average latency period from NSM to the local recurrence of Paget’s disease was 40.2 months. Recurrent tumor histological features were Paget’s disease with ductal carcinoma in situ (DCIS) in 16 patients (50%), Paget’s disease without DCIS in 13 patients (40.6%), and Paget’s disease with ductal intraepithelial neoplasia (DIN) in 3 patients (9.4%). The primary tumor histological feature was estrogen receptor (ER)(−)/progesterone receptor (PR)(−)/human epidermal growth factor receptor (HER-2)(+) in 21 patients (77.8%). Neither locoregional relapse nor metastatic events were found in these recurrent patients who accepted NAC excision after 4–5 years of follow-up. Our reported case showed that the patient experienced pregnancy and lactation after primary adjuvant chemotherapy and endocrine therapy. However, she developed an eczematoid lesion in the NAC 120 months after breast surgery. The histopathological examination was consistent with Paget’s disease of the breast. Complete NAC and breast silicone prosthesis removal were performed. The patient accepted no systematic or local therapy and is currently alive. It is noteworthy that the biological features of the primary tumor were ER(+), PR(+), and HER-2(−); however, the recurrent tumor changed to ER(−), PR(−), and HER-2(+). Conclusions The local recurrence of Paget’s disease after NSM is uncommon; it may develop at a very early age and have a very long time to recurrence, as in our patient, who presented with recurrence 10 years after primary surgery. Surgeons should be wary of local recurrence of the nipple-areola complex after NSM in patients with ER-negative and HER-2-positive primary tumors. However, patients with ER/PR-positive and HER-2-negative tumors should not be neglected; we reported a case of an ER/PR-positive and HER-2-negative primary tumor, and ER-positive recurrent cases have the longest latency period. The local recurrence rate of Paget’s disease after NSM is low, and the prognosis is good in recurrent patients who accept further extensive NAC excision. Further systematic treatment was not considered for this patient.

Whether sentinel lymph node biopsy (SLNB) should be performed in patients with microinvasive breast cancer (MIBC) has been a matter of debate over the last decade. MIBC has a favorable prognosis. Metastasis to the axilla is rare in MIBC, but such axillary mets would impact on treatment recommendations. In this study, we evaluated clinical and histological features in both MIBC and background DCIS including the ER, PR, and HER-2/neu, number of foci of MIBC, and the extent of the DCIS, nuclear grade, presence of comedo necrosis, as well as surgical procedures, adjuvant treatment and follow up, to identify variables which predict disease free survival (DFS), as well as the factors which influence clinical decision making. In the group of 72 patients with MIBC, an average mean patient follow-up time was 32 months. Three patients with MIBC had recurrence, and two deceased, leaving 5 patients in total with poor long-term outcomes and a DFS rate of 91.7%. Performing mastectomy, high nuclear grade, and negativity for ER and HER-2 were found to be associated with the use of SLNB, although none of these variables were found to be associated with DFS. One positive lymph node case was discovered following SLNB in our study. This suggests the use of SLNB may provide diagnostic information to some patients, although these are the anomalies. When comparing patients who had undergone SLNB vs those that had not, there was no difference in DFS; while following multivariate analysis, patients who underwent adjuvant radiation (HR: 0.093, P = 0.04)) were found to have improved DFS. Certainly, the use of SLNB in MIBC is quite the conundrum. It is important to acknowledge that surgical complications have been reported, and traditional metrics used for risk assessment in invasive breast cancer may not necessarily represent risk in the setting of microinvasion.

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.

Funder: Career Development and Innovation Cancer Award, Guys & St Thomas’ Charity and the Cancer Research UK King’s Health Partners Centre at King’s College London., Funder: T32 Translational Genomics Fellowship (NIH), Funder: Single Cell Genomics CPRIT Core Facilities Grant (RP180684)., Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers.

Although intraductal carcinoma (IDC) of the salivary glands was previously called low-grade cribriform cystadenocarcinoma, it was newly categorized in the 4th version of the World Health Organization classification. We report a case of IDC of the upper lip and examined it immunohistochemically and genetically. The patient was a 48-year-old Japanese female, who noticed a tiny nodule on her left upper lip. Histologically, the tumor cells, which had eosinophilic cytoplasm, exhibited papillary and solid growth patterns, and regions of suspected microinvasion or intraductal spread were also seen at the periphery of the tumor. Small necrotic foci were noted. Immunohistochemically, the tumor cells were diffusely positive for the androgen receptor, CK19, CK5/6, EGFR, and SOX10, whereas they were focally positive for GCDFP-15, S-100 protein, and mammaglobin. The tumor nests were surrounded by alpha-smooth muscle actin-p63-/calponin-/CK14-positive myoepithelial cells. The Ki-67 labeling index was 51.2%. Genetic analysis showed no evidence of the TRIM27-RET or NCOA4-RET fusion gene. We finally diagnosed the tumor as a high-grade mixed intercalated duct/apocrine-type IDC of the upper lip. IDC of the minor salivary glands is exceedingly rare. We discuss diagnostic problems associated with minor salivary gland lesions, and the "basal-like" phenotype of this case.

Background We conducted a prospective study with the intention to omit surgery for patients with ductal carcinoma in situ (DCIS) of the breast. We aimed to identify clinicopathological predictors of postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with DCIS. Patients and methods We retrospectively analyzed patients with DCIS diagnosed through biopsy between April 1, 2010 and December 31, 2014, from 16 institutions. Clinical, radiological, and histological variables were collected from medical records. Results We identified 2,293 patients diagnosed with DCIS through biopsy, including 1,663 DCIS (72.5%) cases and 630 IDC (27.5%) cases. In multivariate analysis, the presence of a palpable mass (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.2–2.6), mammography findings (≥ category 4; OR 1.8; 95% CI 1.2–2.6), mass formations on ultrasonography (OR 1.8; 95% CI 1.2–2.5), and tumor size on MRI (> 20 mm; OR 1.7; 95% CI 1.2–2.4) were independent predictors of IDC. Among patients with a tumor size on MRI of ≤ 20 mm, the possibility of postoperative upstaging to IDC was 22.1%. Among the 258 patients with non-palpable mass, nuclear grade 1/2, and positive for estrogen receptor, the possibility was 18.1%, even if the upper limit of the tumor size on MRI was raised to ≤ 40 mm. Conclusion We identified four independent predictive factors of upstaging to IDC after surgery among patients with DCIS diagnosed by biopsy. The combined use of various predictors of IDC reduces the possibility of postoperative upstaging to IDC, even if the tumor size on MRI is larger than 20 mm.

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease in terms of morphological characteristics, protein expression profiles, genetic abnormalities, and potential for progression. Molecular heterogeneity has been extensively studied in DCIS. Yet morphological heterogeneity remains relatively undefined. This study investigated morphological intratumor heterogeneity in a series of 51 large DCIS. Nuclear atypia, DCIS architecture, necrosis, calcifications, stromal architecture, and stromal inflammation were assessed in one biopsy slide and three representative slides from each corresponding resection. For each histopathological feature, a histo-score was determined per slide and compared between the biopsy and the resection, as well as within a single resection. Statistical analysis comprised of Friedman tests, post hoc Wilcoxon tests with Bonferroni corrections, Mann-Whitney U tests, and chi-square tests. Despite substantial morphological heterogeneity in around 50% of DCIS, the histopathological assessment of the biopsy did not statistically significantly differ from the resection. Morphological heterogeneity was not significantly associated with patient age, DCIS size, or type of surgery, except for a weak association between heterogeneous stromal inflammation and smaller DCIS size. At the group level, the degree of heterogeneity did not significantly affect the representativity of a biopsy. At the individual patient level, however, the presence of necrosis, intraductal calcifications, myxoid stromal changes, and high-grade nuclear atypia was underestimated in a minority of DCIS patients. This study confirms the presence of morphological heterogeneity in DCIS for all six evaluated histopathological features. This should be kept in mind when taking biopsy-based treatment decisions for DCIS patients.

Purpose To investigate whether radiomics features extracted from magnetic resonance imaging (MRI) of patients with biopsy-proven atypical ductal hyperplasia (ADH) coupled with machine learning can differentiate high-risk lesions that will upgrade to malignancy at surgery from those that will not, and to determine if qualitatively and semi-quantitatively assessed imaging features, clinical factors, and image-guided biopsy technical factors are associated with upgrade rate. Methods This retrospective study included 127 patients with 139 breast lesions yielding ADH at biopsy who were assessed with multiparametric MRI prior to biopsy. Two radiologists assessed all lesions independently and with a third reader in consensus according to the BI-RADS lexicon. Univariate analysis and multivariate modeling were performed to identify significant radiomic features to be included in a machine learning model to discriminate between lesions that upgraded to malignancy on surgery from those that did not. Results Of 139 lesions, 28 were upgraded to malignancy at surgery, while 111 were not upgraded. Diagnostic accuracy was 53.6%, specificity 79.2%, and sensitivity 15.3% for the model developed from pre-contrast features, and 60.7%, 86%, and 22.8% for the model developed from delta radiomics datasets. No significant associations were found between any radiologist-assessed lesion parameters and upgrade status. There was a significant correlation between the number of specimens sampled during biopsy and upgrade status (p = 0.003). Conclusion Radiomics analysis coupled with machine learning did not predict upgrade status of ADH. The only significant result from this analysis is between the number of specimens sampled during biopsy procedure and upgrade status at surgery.

Breast conservation therapy (BCT) is well established for the management of primary operable breast cancer, with oncologic outcomes comparable to those of mastectomy. It remains unclear whether re-conservation therapy (RCT) is suitable for those patients who develop ipsilateral breast tumor recurrence (IBTR), for whom mastectomy is generally recommended. We identified women who underwent BCT for invasive or ductal carcinoma in situ and developed IBTR as a first event, comparing the pattern of subsequent events and survival for those treated by RCT versus mastectomy. Of 16,968 patents who had BCT, 322 (1.9%) developed an isolated IBTR as a first event between 1999 and 2019. 130 (40%) had RCT and 192 (60%) mastectomy. Compared to mastectomy, the RCT patients were older (66 vs 53

Background There is limited knowledge about DCIS cellular composition and relationship with breast cancer events (BCE). Methods Immunofluorescence multiplexing (MxIF) was used to image and quantify 32 cellular biomarkers in FFPE DCIS tissue microarrays. Over 75,000 DCIS cells from 51 patients (median 9 years follow-up for non-BCE cases) were analysed for profiles predictive of BCE. K-means clustering was used to evaluate cellular co-expression of epithelial markers with ER and HER2. Results Only ER, PR and HER2 significantly correlated with BCE. Cluster analysis identified 6 distinct cell groups with different levels of ER, Her2, cMET and SLC7A5. Clusters 1 and 3 were not significant. Clusters 2 and 4 (high ER/low HER2 and SLC7A5/mixed cMET) significantly correlated with low BCE risk (P = 0.001 and P = 0.034), while cluster 6 (high HER2/low ER, cMET and SLC7A5) correlated with increased risk (P = 0.018). Cluster 5 (similar to cluster 6, except high SLC7A5) trended towards significance (P = 0.072). A continuous expression score (Escore) based on these 4 clusters predicted likelihood of BCE (AUC = 0.79, log-rank test P = 5E–05; LOOCV AUC = 0.74, log-rank test P = 0.006). Conclusion Multiplexed spatial analysis of limited tissue is a novel method for biomarker analysis and predicting BCEs. Further validation of Escore is needed in a larger cohort.

The aim of our study was, first, to measure association between radiologists and facilities characteristics and DCIS detection. Second, to assess whether those characteristics affect differently the likelihood of detection of DCIS versus invasive breast cancer. When applicable, we examined whether the identified characteristics were similarly associated with low-grade and high-grade DCIS detection. This retrospective cohort study included 1,750,002 digital screening mammograms (2145 screen-detected DCIS) performed in the Quebec breast cancer screening program between 2007 and 2015 inclusively. The associations between radiologists’ and facilities’ characteristics and (1) the DCIS detection rate, (2) the invasive detection rate, and (3) the odds of DCIS on invasive detection were assess. For statistically significant associations in the latter analysis, analyses stratified by DCIS grade were performed. Multivariable logistic regression with generalized estimating equations estimates to account for correlation among mammograms was used. Compared to radiologists with recall rate between 5.0 and 9.9%, radiologists with recall rate between 15.0–19.9% and ≥ 20% reached a higher DCIS detection rate, with adjusted detection ratios of, respectively, 1.33 (95% confidence interval = 1.15–1.53) and 1.43 (95% confidence interval = 1.13–1.81). Increase in radiologist’ recall rate was statistically significantly associated with an increase in detection of low/intermediate-grade DCIS (P

Ductal carcinoma in situ (DCIS) is considered a non-invasive precursor to breast cancer, and although associated with an increased risk of developing invasive disease, many women with DCIS will never progress beyond their in situ diagnosis. The path from normal duct to invasive ductal carcinoma (IDC) is not well understood, and efforts to do so are hampered by the substantial heterogeneity that exists between patients, and even within patients. Here we show gene expression analysis from > 2,000 individually micro-dissected ductal lesions representing 145 patients. Combining all samples into one continuous trajectory we show there is a progressive loss in basal layer integrity heading towards IDC, coupled with two epithelial to mesenchymal transitions, one early and a second coinciding with the convergence of DCIS and IDC expression profiles. We identify early processes and potential biomarkers, including CAMK2N1, MNX1, ADCY5, HOXC11 and ANKRD22, whose reduced expression is associated with the progression of DCIS to invasive breast cancer.

A preoperative diagnosis of ductal carcinoma in situ (DCIS) is sometimes upstaged to invasive disease postoperatively. Our objective was to clarify the predictive factors of invasive disease using preoperative imaging and to investigate the positive ratio of sentinel lymph nodes (SLN) and the incidence of invasive disease. The subjects were 402 patients with preoperatively diagnosed ductal carcinoma without stromal invasion who underwent breast surgery with concomitant SLN surgery in January 2007 to December 2016. Of the 306 included patients, all 306 patients underwent preoperative MRI and US assessment. Outcomes were analyzed for significance using univariate and multivariate analyses. Of the 306 patients, 115 (37.6%) had invasive disease and 191 (62.4%) had DCIS only. Of the 115 patients with invasive disease, 5 (4.4%) and 4 (3.5%) had macro- and micrometastases in SLN. On the other hand, of the 191 patients with DCIS, only 1 (0.5%) had a micrometastasis. Predictors of invasive disease in the univariate analysis included having a palpable mass, were varied by biopsy method, having a US hypoechoic mass, MRI enhancement, or MRI large enhanced lesion; the size of the mass enhancement ≥ 1.1 cm or a spread of non-mass enhancement ≥ 3.1 cm (P = 0.003). Predictors of invasive disease in the multivariate analysis included US hypoechoic mass and MRI large enhanced lesion. We need to perform SLN biopsy for preoperatively diagnosed DCIS when patients have predictors of invasive disease, but SLN biopsy will no longer be essential for patients when they have no predictors of invasive disease.

PURPOSE: To use the National Cancer Database to assess treatment patterns in very young women with ductal carcinoma in situ (DCIS) given their propensity for higher risk features and increased risk of recurrence. METHODS: We used the NCDB to identify female patients who underwent surgery for a first cancer diagnosis of DCIS within three different age groups: ≤30, 31–50, and >50. Demographic information, tumor characteristics, and initial treatment patterns were characterized and compared. Univariable and multivariable logistic regression of individuals with hormone-receptor positive disease who underwent breast conserving surgery (BCS) was conducted to assess for group differences in adjuvant endocrine therapy utilization. Survival analysis was conducted via Kaplan-Meier method and Cox Regression. RESULTS: We identified 236,832 patients meeting inclusion criteria. Individuals in the youngest group were more likely to be a minority, had better Charlson-Deyo scores, lived further from their treatment facility, and were less often insured. This group also had more unfavorable tumor features and were more likely to undergo bilateral mastectomy. In subgroup analysis of patients with hormone-receptor positive disease who underwent BCS, the youngest group was significantly less likely to have received endocrine therapy. There was also a trend towards worse overall survival in the youngest group. CONCLUSION: We report differences in demographics, tumor characteristics, and treatment of very young women with DCIS. Given the known reduction in recurrence with use of adjuvant endocrine therapy, there may be room for increasing therapy rates or otherwise altering guidelines for treatment of young women with hormone-receptor positive DCIS who undergo BCS.

Purpose We performed breast-conserving surgery (BCS) using periareolar incisions for cancers located far from the nipple–areolar complex (NAC) and examined if BCS via a periareolar incision maximized cosmesis and maintained oncologic safety. One of the most important goals of BCS is to improve cosmesis after surgery and quality of life, but the skin incision can affect cosmesis based on the tumor location. Methods Fifty-five patients with breast cancers located far from the NAC underwent BCS via periareolar incisions between January 2017 and April 2018. If a sentinel lymph node biopsy was required, another skin incision was created in the axilla using the conventional technique. Medical records of patients were reviewed retrospectively. Results The mean patient age was 48.1 ± 10.6 years. The mean tumor size was 1.8 ± 1.0 cm (range 0.2–4.5 cm) on preoperative magnetic resonance imaging (MRI); the mean distance from the NAC to the tumor was 5.9 ± 1.9 cm (range 4.0–12.3 cm). Patients with cancers in the subareolar area were excluded even though the distance from the nipple was > 4 cm on MRI. Negative microscopic margins were obtained in all patients. There was no surgical complication such as seroma, bleeding, or infection. Re-operation was not needed. All patients received whole breast radiation therapy. After surgery and radiation therapy, periareolar incision scars were nearly invisible. Conclusion For cancers located far from the NAC, BCS via periareolar incisions is feasible and leads to superior cosmesis in selective patients. Moreover, BCS seems oncologically safe, although long-term outcomes need to be evaluated.

The management of high-risk breast lesions diagnosed on image-guided core biopsy remains controversial. We implemented a high-risk breast conference attended by breast pathologists, imagers, and surgeons to prospectively review all contemporary cases in order to provide a consensus recommendation to either surgically excise or follow on imaging at 6-month intervals for a minimum of 2 years. Between May, 2015 and June, 2019, 127 high-risk lesions were discussed. Of these 127 cases, 116 had concordant radiology–pathology (rad–path) findings. The remaining 11 patients had discordant rad–path findings. Of the 116 concordant cases, 6 were excluded due to lack of the first imaging follow-up until analysis. Of the remaining 110 patients, 43 had atypical ductal hyperplasia (ADH), 12 had lobular carcinoma in situ (LCIS), 19 had atypical lobular hyperplasia (ALH), 33 had radial scar (RS), 2 had flat epithelial atypia (FEA), and 1 had mucocele-like lesion (ML). We recommended excision for ADH if there were > 2 ADH foci or

The aim of this study was to determine the upgrade rate of image-guided core needle biopsy (CNB)-proven benign breast intraductal papillomas (IDPs) without atypia to high-risk benign lesions or malignancy after surgical excision. A retrospective database search at a single institution identified 102 adult female patients with benign breast IDPs without atypia diagnosed on imaging-guided CNBs who subsequently had surgical excisions between 2011 and 2016. Patient characteristics, imaging features, biopsy techniques, and the pathology reports from imaging-guided CNBs and subsequent surgical excisions were reviewed. The upgrade rate to malignancies or high-risk benign lesions was determined at the patient level. The upgrade rate to malignancy was 2.9% (3/102), including two cases of ductal carcinoma in situ (DCIS) and one case of microinvasive (

PURPOSE: Upgrade rates of conventional ADH are reported at 10–30%; however, rates for ADH bordering on DCIS (ADH-BD) are largely unknown. We examined the upgrade rate of ADH-BD and core needle biopsy (CNB) features associated with upgrade. Surgical management in patients with concurrent ipsilateral breast cancer (BC) was also examined. METHODS: From 2000–2018, women with CNB diagnosis of ADH-BD were prospectively identified. Women with pure ADH-BD and concurrent ipsilateral ADH-BD/BC were analyzed separately, and upgrade rates were calculated. CNB features associated with upgrade and type of surgery were examined in women with pure ADH-BD; CNB features and concurrent pathology associated with upgrade were examined in women with ipsilateral BC. RESULTS: 108/236 (46%) patients with pure ADH-BD on CNB had DCIS (40%) or invasive carcinoma (6%) on surgical excision. DCIS or invasive carcinoma was more frequently found on excision of a mass that yielded ADH-BD on biopsy than excision of calcifications (65% vs. 38%; p

Guidelines recommend surgical excision of atypical ductal hyperplasia (ADH) due to the concern of undersampling a potential malignancy on core needle biopsy (CNB). The purpose of this study was to determine clinical, radiological and pathological variables associated with ADH upstaging to cancer and to develop a predictive risk calculator capable of identifying women who have a low oncological risk of upstaging. A prospectively collected database from a tertiary breast referral center was analyzed for women diagnosed with ADH on CNB between January 2013 to December 2017 who underwent surgical excision. CNB and surgical pathology reports were examined to determine rate of upstaging. The association between clinical, radiological and pathological variables were evaluated using regression analysis to determine predictors of ADH upstaging to cancer. Significant variables (p ≤ 0.05) identified on univariate analysis were assigned a score of “1” and were included in the ADH upstaging risk calculator. A total of 1986 patients underwent surgery for a high-risk lesion. We identified 318 (16.0%) patients who had ADH identified on their CNB who underwent surgery—of which 290 were included in our study. The upstage rate was 24.8%. Five variables were associated with upstaging and included in our calculator: (1) lesion > 5 mm on ultrasound; (2) lesion > 5 mm on mammogram; (3) one or more “high-risk” lesion(s) on CNB; (4) pathological suspicion for cancer and; (5) incomplete removal of calcifications on CNB. Patients with a score of 0 had a 2% risk of being upstaged to cancer and were deemed low risk with 17.2% of patients falling within this category. Patients with ADH on CNB can be stratified into a low oncological cohort who have a 2% risk of being upstaged to carcinoma. In the future, these select patients may be counselled and potentially offered observation as an alternative to surgery.

The Japanese Breast Cancer Society Registry started in 1975; it was transferred to the registry platform of the National Clinical Database in 2012. We provide the annual data and an analysis of the Breast Cancer Registry for 2017. Patients’ characteristics and pathological data of the 95,203 registered Japanese breast cancer patients from 1,427 institutes in 2017 were obtained. Trends in age at diagnosis and pathological stage were determined during the most recent 6 years (2012–2017). The mean onset age was 60.2 years with bimodal peaks at 45–49 years and 65–69 years. A short-term trend of the most recent 6 years of data caused the second, older peak. At diagnosis, 32.4% of breast cancer patients were premenopausal. The distribution of stages revealed that the proportion of early stage breast cancer (stage 0–I) increased up to 60%. At the initial diagnosis, 2.2% of patients presented with metastatic disease. Sentinel node biopsy without axillary node dissection was performed without neoadjuvant chemotherapy (NAC) in 68.8%, and with NAC in 31.1%, of patients. For patients without NAC, lymph node metastasis was less than 3% if the tumor size was less than 1 cm. The proportion of node-negativity decreased to 79.5% when tumor size was 2.1–5 cm. This analysis of the registry provides new information for effective treatment in clinical practice, cancer prevention, and the conduct of clinical trials. Further development of the registry and progress in collecting prognostic data will greatly enhance its scientific value.

Standard-of-care management of atypical ductal hyperplasia (ADH) is surgical excision. Multiple studies have identified features of ADH in patients at low risk for upgrade who may benefit from omission of surgical excision. Patients with an ipsilateral breast cancer have been excluded from studies investigating observation for the management of ADH. This was a retrospective review of women with both a breast cancer and an ipsilateral separate site of ADH diagnosed on percutaneous biopsy, who underwent excision of both sites from 2008 to 2018. Radiographic and pathologic features of ADH and cancer were analyzed, including imaging size, biopsy modality, distance between sites, cancer subtype, grade, prognostic markers, ADH foci, and presence of necrosis or micropapillary features. Final pathology at the ADH site was used to determine upgrade. Multivariable logistic regression was performed to identify variables significantly associated with ADH upgrade to malignancy. Among 62 women meeting the inclusion criteria, 11 (17.7%) upgraded to malignancy [9 ductal carcinoma in situ (DCIS), 2 invasive cancer] at the site of ADH. Upgrade was significantly higher with ipsilateral DCIS (p = 0.03), ultrasound biopsy at the ADH site (p = 0.01), and ADH with necrosis (p = 0.04). The group at lowest risk for upgrade had stereotactic biopsy and ADH without necrosis (0% upgrade). The presence of breast cancer does not significantly increase the likelihood for upgrade at a separate site of ipsilateral concurrent ADH above contemporary reported upgrade rates of ADH alone (10–30%). When considering breast conservation for breast cancer, omitting excision of the site of ADH can be considered when low-risk features are present.

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. 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. 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

Reoperation rates following breast-conserving surgery (BCS) range from 10 to 40%, with marked surgeon and institutional variation. The aim of this study was to identify factors associated with intraoperative margin re-excision, evaluate for any differences in local recurrence based on margin re-excision and determine reoperation rates with use of intraoperative margin analysis. We analyzed consecutive patients with ductal carcinoma in situ (DCIS) or invasive breast cancer who underwent BCS at our institution between 1 January 2005 and 31 December 2016. Routine intraoperative frozen section margin analysis was performed and positive or close margins were re-excised intraoperatively. Univariate analysis was used to compare margin status and the Kaplan–Meier method was used to compare recurrence. Multivariable logistic regression was utilized to analyze factors associated with re-excision. We identified 3201 patients who underwent BCS—688 for DCIS and 2513 for invasive carcinoma. Overall, 1513 (60.2%) patients with invasive cancer and 434 (63.1%) patients with DCIS had close or positive margins that underwent intraoperative re-excision. Margin re-excision was associated with larger tumor size in both groups. The permanent pathology positive margin rate among all patients was 1.2%, and the 30-day reoperation rate for positive margins was 1.1%. Five-year local recurrence rates were 0.6% and 1.2% for patients with DCIS and invasive cancer, respectively. There was no difference in recurrence between patients with and without intraoperative margin re-excision (p = 0.92). Both DCIS and invasive carcinoma had similar rates of intraoperative margin re-excision. Although intraoperative margin re-excision was common, the reoperation rate was extremely low and there was no difference in recurrence between those with or without intraoperative re-excision.

Objectives MRI is an integral part of breast cancer screening in high-risk patients. We investigated whether the application of the Kaiser score, a clinical decision-support tool, may be used to exclude malignancy in contrast-enhancing lesions classified as BI-RADS 4 on breast MRI screening exams. Methods This retrospective study included 183 consecutive, histologically proven, suspicious (MR BI-RADS 4) lesions detected within our local high-risk screening program. All lesions were evaluated according to the Kaiser score for breast MRI by three readers blinded to the final histopathological diagnosis. The Kaiser score ranges from 1 (lowest, cancer very unlikely) to 11 (highest, cancer very likely) and reflects increasing probabilities of malignancy, with scores greater than 4 requiring biopsy. Receiver operating characteristic (ROC) curve analysis was used to evaluate diagnostic accuracy. Results There were 142 benign and 41 malignant lesions, diagnosed in 159 patients (mean age, 43.6 years). Median Kaiser scores ranged between 2 and 5 in benign and 7 and 8 in malignant lesions. For all lesions, the Kaiser score’s accuracy, represented by the area under the curve (AUC), ranged between 86.5 and 90.2. The sensitivity of the Kaiser score was high, between 95.1 and 97.6% for all lesions, and was best in mass lesions. Application of the Kaiser score threshold for malignancy (≤ 4) could have potentially avoided 64 (45.1%) to 103 (72.5%) unnecessary biopsies in 142 benign lesions previously classified as BI-RADS 4. Conclusions The use of Kaiser score in high-risk MRI screening reliably excludes malignancy in more than 45% of contrast-enhancing lesions classified as BI-RADS 4. Key Points • The Kaiser score shows high diagnostic accuracy in identifying malignancy in contrast-enhancing lesions in patients undergoing high-risk screening for breast cancer. • The application of the Kaiser score may avoid > 45% of unnecessary breast biopsies in high-risk patients. • The Kaiser score aids decision-making in high-risk breast cancer MRI screening programs.

Historically, more than one-third of patients with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS) underwent additional surgery. The SSO-ASTRO guidelines advise 2 mm margins for patients with DCIS having BCS and whole-breast radiation (WBRT). Here we examine guideline impact on additional surgery and factors associated with re-excision. Patients treated with BCS for pure DCIS from August 2015 to January 2018 were identified. Guidelines were adopted on September 1, 2016, and all patients had separately submitted cavity-shave margins. Clinicopathologic characteristics, margin status, and rates of additional surgery were examined. Among 650 patients with DCIS who attempted BCS, 50 (8%) converted to mastectomy. Of 600 who had BCS as final surgery, 336 (56%) received WBRT and comprised our study group. One hundred twenty-eight (38%) were treated pre-guideline and 208 (62%) were treated post-guideline. Characteristics and margin status were similar between groups. The re-excision rate was 38% pre-guideline adoption and 29% post-guideline adoption (p = 0.09), with 91% having only one re-excision. Re-excision for ≥ 2 mm margins was uncommon (6% pre-guideline vs. 5% post-guideline). On multivariate analysis, younger age (OR 0.97, 95% CI 0.94–0.99, p = 0.02) and larger DCIS size (OR 1.43, 95% CI 1.2–1.8, p

Intracystic/encapsulated papillary carcinoma remains a poorly understood disease of the breast with a little amount of reports that describe it. It shares features with DCIS and IDC and predominantly affects postmenopausal women. This study aims to evaluate the clinical presentation, treatment, and outcomes in IPC patients managed at our institution. We retrospectively pooled twenty-eight IPC patients’ medical records at our institution. Descriptive analysis of clinicopathological characteristics, approach, and outcomes was done along with a quantitative statistical analysis. Cases were divided into three groups: isolated IPC, IPC associated with DCIS, and IPC associated with Invasive Carcinoma. Treatment modalities varied according to the IPC type and its associated components. All patients presented with a palpable mass. Immunohistochemical staining revealed that all isolated IPCs were ER and PR positive and HER2 negative. Lymph node dissection proved necessary only in IPC associated invasive carcinoma. Irregular borders and lobulations, among others, were found on non-invasive core biopsies that turned out to be associated with invasion on surgical pathology. All patients were alive after a median follow-up time of 23 months when the study was over with no reports of recurrence. IPC cases and treatment approaches at our institution appear similar to the available literature and confirm the excellent prognosis among IPC. Even more, further studies into the key features such as BMI, family history, and radiological findings are necessary for a potential algorithm that could assess for risk of finding invasion in surgical pathology and subsequently the need for axillary/sentinel lymph node biopsy.

This study aimed to analyze our 11-year experience using NSM with immediate breast reconstruction in breast cancer. Between January 2007 and December 2015, 251 NSMs were performed on 251 women with breast cancer for therapeutic purpose at Pusan National University Hospital. The clinical and pathologic mean tumor size was 3.1 cm. Based on preoperative imaging, mean distance between tumor and nipple was 2.5 cm. Among 251 tumors, 119 cases (47.4%) and 69 cases (27.5%) with a distances ≤ 2 cm and ≤ 1 cm, respectively, were detected. There were 11 patients (4.4%) with locoregional recurrences during the mean follow-up period of 68.0 months. Of these 11 cases, one (0.4%) had local recurrence in the retained NAC, and the others had recurrence in the chest wall or skin. Unless clinical and histological evidence of nipple involvement, NSM can be an oncologically safe surgical option for breast cancer, even if the tumor is located close to the nipple.

We explored the impact of the relative volume of a tumor versus the entire breast on outcomes in patients undergoing breast conservation therapy (BCT) versus mastectomy and reconstruction (M + R). We hypothesized that there would be a threshold tumor:breast ratio (TBR) below which patient-reported outcomes (PRO) would favor BCT and above which would favor M + R. We conducted a prospective cohort study of patients with ductal carcinoma in situ (DCIS) or invasive breast cancers undergoing BCT or M + R. A prerequisite for inclusion, analysis of tumor and breast volumes was conducted from three-dimensional magnetic resonance imaging reconstructions to calculate the TBR. Three-dimensional photography was utilized to calculate pre- and postoperative volumes and assess symmetry. Oncologic, surgical, and patient-reported outcome data were obtained from relevant BREAST-Q modules administered pre- and postoperatively. The BCT cohort had significantly smaller tumor volumes (p = 0.001) and lower TBRs (p = 0.001) than patients undergoing M + R overall. The M + R group, however, comprised a broader range of TBRs, characterized at lower values by patients opting for contralateral prophylactic mastectomy. Postoperative satisfaction with breasts, psychosocial, and sexual well-being scores were significantly higher in the BCT cohort, while physical well-being significantly favored the M + R cohort 480.2 ± 286.3 and 453.1 ± 392.7 days later, respectively. Relative to BCT, M + R was used to manage a broad range of TBRs. The relative importance of oncologic and surgical risk reduction, symmetry, and number of procedures can vary considerably and may limit the utility of TBR as a guide for deciding between BCT and M + R. Clinical Trial StatementThis study was registered with clinicaltrials.gov as “A Prospective Trial to Assess Tumor:Breast Ratio and Patient Satisfaction Following Lumpectomy Versus Mastectomy With Reconstruction”, Identifier: NCT02216136.

To report early toxicity and 5‑year clinical outcomes of adjuvant breast inversely planned intensity-modulated radiotherapy with simultaneously integrated boost (IMRT-SIB) after breast-conserving surgery for early stage breast cancer patients. In all, 467 patients including 406 invasive breast cancer and 61 ductal carcinoma in situ (DCIS) were enrolled in a single institutional phase II trial. All patients underwent IMRT-SIB treatment to irradiate the whole breast and the tumor bed. Doses to whole breast and surgical bed were 45 and 60 Gy, respectively, delivered in 25 fractions over 5 weeks. The grade of maximum acute skin toxicity during treatment was recorded. Lung toxicity was noted within 6 months and patient-reported cosmetic outcomes were recorded at the 12 month follow-up after the end of radiotherapy. Clinical outcomes were assessed during follow-up. Median follow-up time was 5.46 years. Median age was 46 years old (range 22–70 years old). No patient with DCIS had a local recurrence or distant metastasis. Among 406 patients with invasive breast cancer, the unadjusted 5‑year actuarial rate of locoregional control was 98.7% (95% confidence interval [CI] 97.5–100), and distant metastasis-free survival 98.7% (95% CI 97.4–100), respectively. Acute skin toxicity was recorded at grade 0–1 in 76.5% of patients, and grade 2 in 23.5% of patients. None of these patients had grade 3 or more than grade 3 skin toxicity. Grade 1 pneumonitis was found in 25.3% of patients. Assessment of patient reported cosmetic outcomes at the 12 month follow-up showed good or excellent outcome in 86.5% of cases. The use of inversely planned IMRT-SIB as part of breast-conserving therapy results in optimal 5‑year tumor control and minor early toxicities.

To evaluate the diagnostic performance of dynamic contrast-enhanced (DCE)–MRI in predicting malignancy after percutaneous biopsy diagnosis of atypical ductal hyperplasia (ADH). In this retrospective study, 68 lesions (66 women) with percutaneous biopsy diagnosis of ADH and pre-operative breast DCE-MRI performed between January 2016 and December 2017 were included. Two radiologists reviewed in consensus mammography, ultrasound, and MR images. The final diagnosis after surgical excision was used as standard of reference. Clinical and imaging features were compared in patients with and without upgrade to malignancy after surgery. The diagnostic performance of DCE-MRI in predicting malignant upgrade was evaluated. A 9-gauge vacuum-assisted biopsy was performed in 40 (58.8%) cases and a 14-gauge core needle biopsy in 28 (41.2%) cases. Upgrade to malignancy was observed in 17/68 (25%) lesions, including 4/17 (23.5%) cases of invasive cancer and 13/17 (76.5%) cases of ductal carcinoma in situ (DCIS). In 16/17 (94.1%) malignant and 20/51 (39.2%) benign lesions, a suspicious enhancement could be recognized in DCE-MRI. The malignant lesion without suspicious enhancement was a low-grade DCIS (4 mm size). Sensitivity, specificity, positive predictive value, and negative predictive value of DCE-MRI on predicting malignancy were respectively 94.1%, 60.7%, 44.4%, and 96.8%. No other clinical or imaging features were significantly different in patients with and without upgrade to malignancy. After a percutaneous biopsy diagnosis of ADH, malignancy can be ruled out in most of the cases, if no suspicious enhancement is present in the biopsy area at DCE-MRI. Breast DCE-MRI may be used to avoid surgery in more than half of the patients with final benign diagnosis. • Breast DCE-MRI can safely rule out malignancy if no suspicious enhancement is present in the biopsy area after a percutaneous biopsy diagnosis of ADH. • All cases of upgrade to high-grade DCIS and invasive cancers can be identified at breast DCE-MRI after a percutaneous biopsy diagnosis of ADH. • Breast DCE-MRI may be used to avoid surgery in more than half of the patients with final benign diagnosis.

To comprehensively describe the tumor and clinical characteristics of breast cancer in a cohort of male patients and to assess the factors that affect survival. Much of the standard care of male breast cancer is based on the diagnosis and treatment strategies of female breast cancer. However, important clinical differences between the two have been elucidated, which suggests the need for unique attention to male breast cancer. We evaluated the records of male patients who were diagnosed with breast cancer between 2004 and 2015 using the National Cancer Database (NCDB). Data obtained were demographic characteristics, clinical and tumor data, type of therapy, as well as survival data. We used descriptive statistics to characterize our study population. We then performed a survival and Cox proportional hazards analysis. We identified 16,498 patients (median age: 63 years). Several treatment modalities were used, of which surgery was the most common (14,882 [90.4%]). The total follow-up time was 13 years (156 months). Five-year survival was 77.7% (95% CI 76.9–78.4) and 10-year survival was 60.7%. In a Cox proportional hazards model, mastectomy was associated with the greatest survival (hazard ratio [HR] 0.49; p