Analysis of ductal carcinoma in situ by self-reported race reveals molecular differences related to outcome.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer (IBC). Studies have indicated differences in DCIS outcome based on race or ethnicity, but molecular differences have not been investigated. METHODS: We examined the molecular profile of DCIS by self-reported race (SRR) and outcome groups in Black (n = 99) and White (n = 191) women in a large DCIS case-control cohort study with longitudinal follow up. RESULTS: Gene expression and pathway analyses suggested that different genes and pathways are involved in diagnosis and ipsilateral breast outcome (DCIS or IBC) after DCIS treatment in White versus Black women. We identified differences in ER and HER2 expression, tumor microenvironment composition, and copy number variations by SRR and outcome groups. CONCLUSIONS: Our results suggest that different molecular mechanisms drive initiation and subsequent ipsilateral breast events in Black versus White women.

Impact of an online decision support tool for ductal carcinoma in situ (DCIS) using a pre-post design (AFT-25).

BACKGROUND: The heterogeneous biology of ductal carcinoma in situ (DCIS), as well as the variable outcomes, in the setting of numerous treatment options have led to prognostic uncertainty. Consequently, making treatment decisions is challenging and necessitates involved communication between patient and provider about the risks and benefits. We developed and investigated an interactive decision support tool (DST) designed to improve communication of treatment options and related long-term risks for individuals diagnosed with DCIS. FINDINGS: The DST was developed for use by individuals aged > 40 years with DCIS and is based on a disease simulation model that integrates empirical data and clinical characteristics to predict patient-specific impacts of six DCIS treatment choices. Personalized risk predictions for each treatment option were communicated using icon arrays and percentages for each outcome. Users of the DST were asked before and after interacting with the DST about: (1) awareness of DCIS treatment options, (2) willingness to consider these options, (3) knowledge of risks associated with DCIS, and (4) helpfulness of the DST. Data were collected from January 2019 to April 2022. Users' median estimated risk of dying from DCIS in 10 years decreased from 9% pre-tool to 3% post-tool (p < 0.0001). 76% (n = 101/132) found the tool helpful. CONCLUSIONS: Information about DCIS treatment options and related risk predictions was effectively communicated, and a large majority participants found the DST to be helpful. Successfully informing patients about their treatment options and how their individual risks affect those options is a critical step in the decision-making process. CLINICALTRIALS: gov Identifier NCT02926911.

Radiological and pathological predictors of post-operative upstaging of breast ductal carcinoma in situ (DCIS) to invasive ductal carcinoma and lymph-nodes metastasis; a potential algorithm for node surgical de-escalation.

BACKGROUND/AIM: Ductal carcinoma in situ is considered a local disease with no metastatic potential, thus sentinel lymph node biopsy (SLNB) may be deemed an overtreatment. SLNB should be reserved for patients with invasive cancer, even though the risk of upstaging rises to 25 %. We aimed to identify clinicopathological predictors of post-operative upstaging in invasive carcinoma. METHODS: We retrospectively analyzed patients with a pre-operative diagnosis of DCIS subjected to breast surgery between January 2017 to December 2021, and evaluated at the Breast Unit of PTV (Policlinico Tor Vergata, Rome). RESULTS: Out of 267 patients diagnosed with DCIS, 33(12.4 %) received a diagnosis upstaging and 9(3.37 %) patients presented with sentinel lymph node (SLN) metastasis. In multivariate analysis, grade 3 tumor (OR 1.9; 95 % CI 1.2-5.6), dense nodule at mammography (OR 1.3; 95 % CI 1.1-2.6) and presence of a solid nodule at ultrasonography (OR 1.5; 95 % CI 1.2-2.6) were independent upstaging predictors. Differently, the independent predictors for SLNB metastasis were: upstaging (OR 2.1.; 95 % CI 1.2-4.6; p = 0.0079) and age between 40 and 60yrs (OR 1.4; 95 % CI 1.4-2.7; p = 0.027). All 9 patients with SLN metastasis received a diagnosis upstaging and were aged between 40 and 60 years old. CONCLUSION: We identified pre-operative independent predictors of upstaging to invasive ductal carcinoma. The combined use of different predictors in an algorithm for surgical treatments of DCIS could reduce the numbers of unnecessary SLNB.

Disease-specific survival outcomes for patients after locoregional treatment for ductal carcinoma in situ: observational cohort study.

BACKGROUND: Breast-conserving surgery alone, breast-conserving surgery with adjuvant radiation treatment, and mastectomy are guideline-concordant treatments for ductal carcinoma in situ. The aim of this study was to compare survival outcomes between these treatment options. METHODS: A stratified random sample of patients diagnosed with pure ductal carcinoma in situ between 2008 and 2014 was selected from 1330 sites in the USA. Data on diagnosis, treatment, and follow-up were abstracted by local cancer registrars. Population-averaged marginal estimates of disease-specific survival and overall survival for breast-conserving surgery alone, breast-conserving surgery with radiation treatment, and mastectomy were obtained by combining sampling and overlap weights. RESULTS: A total of 18 442 women were included, with a median follow-up of 67.8 (interquartile range 46.1-93.5) months. A total of 35 women died from breast cancer, at a median age of 62 (interquartile range 50-74) years. Population-averaged 8-year rates of disease-specific survival were 99.6% or higher for all treatment groups, with no significant differences between groups (breast-conserving surgery alone versus breast-conserving surgery with radiation treatment, HR 1.19 (95% c.i. 0.29 to 4.85); and mastectomy versus breast-conserving surgery with radiation treatment, HR 1.74 (95% c.i. 0.53 to 5.72). There was no difference in overall survival between the patients who underwent a mastectomy and the patients who underwent breast-conserving surgery with radiation treatment (HR 1.09 (95% c.i. 0.83 to 1.43)). Patients who underwent breast-conserving surgery alone had lower overall survival compared with the patients who underwent breast-conserving surgery with radiation treatment (HR 1.29 (95% c.i. 1.00 to 1.67)). This survival difference vanished for all but one subgroup, namely patients less than 65 years (HR 1.86 (95% c.i. 1.15 to 3.00)). CONCLUSION: There was no statistically significant difference in disease-specific survival between women operated with breast-conserving surgery alone, breast-conserving surgery with radiation treatment, or mastectomy for ductal carcinoma in situ. Given the low absolute risk of disease-specific mortality, these results provide confidence in offering individualized locoregional treatment without fear of compromising survival.

Adding contrast-enhanced ultrasound can improve the predictive ability of breast conventional ultrasound and mammography for pathological upgrade of biopsy-confirmed ductal carcinoma in situ.

OBJECTIVES: To evaluate the added value of contrast-enhanced ultrasound (CEUS) on top of breast conventional imaging for predicting the upgrading of ductal carcinoma in situ (DCIS) to invasive cancer after surgery. METHODS: This retrospective study enrolled 140 biopsy-proven DCIS lesions in 138 patients and divided them into two groups based on postoperative histopathology: non-upgrade and upgrade groups. Conventional ultrasound (US), mammography (MMG), CEUS and clinicopathological (CL) features were reviewed and compared between the two groups. The predictive performance of different models (with and without CEUS features) for histologic upgrade were compared to calculate the added value of CEUS. RESULTS: Fifty-nine (42.1 %) lesions were histologically upgraded to invasive cancer after surgery. By logistic regression analyses, we found that high-grade DCIS at biopsy (P=0.004), ultrasonographic lesion size > 20 mm (P=0.007), mass-like lesion on US (P=0.030), the presence of suspicious calcification on MMG (P=0.014), the presence of perfusion defect (P=0.005) and the area under TIC>1021.34 ml (P<0.001) on CEUS were six independent factors predicting concomitant invasive components after surgery. The CL+US+MMG model made with the four predictors in the clinicopathologic, US and MMG categories yielded an area under the receiver operating curve (AUROC) value of 0.759 (95 % CI: 0.680-0.828) in predicting histological upgrade. The combination model built by adding the two CEUS predictors to the CL+US+MMG model showed higher predictive efficacy than the CL+US+MMG model (P=0.018), as the AUROC value was improved to 0.861 (95 % CI: 0.793-0.914). CONCLUSIONS: The addition of contrast-enhanced ultrasound to breast conventional imaging could improve the preoperative prediction of an upgrade to invasive cancer from CNB -proven DCIS lesions.

The Use of Sentinel Lymph Node Biopsy in Patients Undergoing Mastectomy for DCIS.

BACKGROUND: Current guidelines do not recommend routine sentinel node biopsy (SLNB) for ductal carcinoma in situ (DCIS), except in the setting of mastectomy or microinvasive disease. This study aimed to evaluate national SLNB utilization in women undergoing upfront mastectomy for DCIS, identify predictors of SLNB utilization, and determine the percentage with a positive SLNB. METHODS: A retrospective cohort analysis was performed using the NCDB of women with clinical DCIS who underwent upfront mastectomy between 2012 and 2017. Demographic and clinicopathologic variables were compared between patients who underwent SLNB and those who did not. Multivariate logistic regression models were used to identify factors associated with SLNB utilization and positive SLNB. RESULTS: About 38,973 patients met inclusion criteria: 34,231 (88%) underwent SLNB and 4742 (12%) had no surgical axillary staging. Most patients were age 50-69 (51%), non-Hispanic White (71%), with private insurance (66%). On multivariate analysis, older patients were less likely to receive SLNB (P < .01), while patients with higher grade DCIS were more likely to undergo SLNB (P < .01). In those who underwent SLNB (n = 34,231), only 1,149 (3.4%) had nodal involvement. Non-Hispanic Black patients had increased odds of a positive SLNB (P < .01), while those with estrogen receptor positive disease were less likely to be node positive (OR 0.68, P < .001). CONCLUSIONS: While 88% of patients had a SLNB, only 3.4% were found to be node positive. Given this low rate, it is reasonable to consider SLNB omission in select patients with low grade, hormone receptor positive DCIS undergoing upfront mastectomy.

Application of a Data Quality Framework to Ductal Carcinoma In Situ Using Electronic Health Record Data From the All of Us Research Program.

PURPOSE: The specific aims of this paper are to (1) develop and operationalize an electronic health record (EHR) data quality framework, (2) apply the dimensions of the framework to the phenotype and treatment pathways of ductal carcinoma in situ (DCIS) using All of Us Research Program data, and (3) propose and apply a checklist to evaluate the application of the framework. METHODS: We developed a framework of five data quality dimensions (DQD; completeness, concordance, conformance, plausibility, and temporality). Participants signed a consent and Health Insurance Portability and Accountability Act authorization to share EHR data and responded to demographic questions in the Basics questionnaire. We evaluated the internal characteristics of the data and compared data with external benchmarks with descriptive and inferential statistics. We developed a DQD checklist to evaluate concept selection, internal verification, and external validity for each DQD. The Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) concept ID codes for DCIS were used to select a cohort of 2,209 females 18 years and older. RESULTS: Using the proposed DQD checklist criteria, (1) concepts were selected and internally verified for conformance; (2) concepts were selected and internally verified for completeness; (3) concepts were selected, internally verified, and externally validated for concordance; (4) concepts were selected, internally verified, and externally validated for plausibility; and (5) concepts were selected, internally verified, and externally validated for temporality. CONCLUSION: This assessment and evaluation provided insights into data quality for the DCIS phenotype using EHR data from the All of Us Research Program. The review demonstrates that salient clinical measures can be selected, applied, and operationalized within a conceptual framework and evaluated for fitness for use by applying a proposed checklist.

The SEMA3F-NRP1/NRP2 axis is a key factor in the acquisition of invasive traits in in situ breast ductal carcinoma.

BACKGROUND: A better understanding of ductal carcinoma in situ (DCIS) is urgently needed to identify these preinvasive lesions as distinct clinical entities. Semaphorin 3F (SEMA3F) is a soluble axonal guidance molecule, and its coreceptors Neuropilin 1 (NRP1) and NRP2 are strongly expressed in invasive epithelial BC cells. METHODS: We utilized two cell line models to represent the progression from a healthy state to the mild-aggressive or ductal carcinoma in situ (DCIS) stage and, ultimately, to invasive cell lines. Additionally, we employed in vivo models and conducted analyses on patient databases to ensure the translational relevance of our results. RESULTS: We revealed SEMA3F as a promoter of invasion during the DCIS-to-invasive ductal carcinoma transition in breast cancer (BC) through the action of NRP1 and NRP2. In epithelial cells, SEMA3F activates epithelialmesenchymal transition, whereas it promotes extracellular matrix degradation and basal membrane and myoepithelial cell layer breakdown. CONCLUSIONS: Together with our patient database data, these proof-of-concept results reveal new SEMA3F-mediated mechanisms occurring in the most common preinvasive BC lesion, DCIS, and represent potent and direct activation of its transition to invasion. Moreover, and of clinical and therapeutic relevance, the effects of SEMA3F can be blocked directly through its coreceptors, thus preventing invasion and keeping DCIS lesions in the preinvasive state.

Surgical treatment of breast precancers - our experience.

INTRODUCTION: Thanks to mammographic screening and the improvement of breast cancer diagnostics, the detection of precancers is also increasing. They are defined as morphological changes of the mammary gland which are more likely to cause cancer. The evaluated precancers are atypical ductal hyperplasia (ADH), lobular carcinoma in situ (LCIS) and radial scar. METHODOLOGY: In the period 1. 1. 2018-31. 12. 2022, we performed 1,302 planned operations for breast disease at the Surgical Clinic of Teaching Hospital Plzen, of which 30 (2%) were precancer operations. ADH was confirmed 11×, LCIS 8×, and a radical scar 11×. The average age of the patients in all three groups was 56 years (27-85). Precancer was diagnosed 8× only by sonography, 3× by mammography and 19× by a combination of both methods. Subsequently, a puncture biopsy was always completed. We performed 28 tumor excisions with intraoperative biopsy and 2 mastectomies. RESULTS: In the case of ADH from puncture biopsy, ADH was confirmed intraoperatively 8×, DCIS was diagnosed 2×, and mucinous carcinoma 1×. In LCIS, no tumor was found by intraoperative biopsy 4×, LCIS was confirmed 1×, lobular invasive carcinoma was diagnosed 1×, mastectomy was performed 2× without intraoperative biopsy. In the radial scar, ADH was diagnosed 3×, sclerosing adenosis 6×, DCIS 1×, invasive carcinoma 1×. After the final histological processing of the samples, there was an increase in diagnosed carcinomas. In ADH, DCIS was confirmed 3×, DIC 2×, and mucinous carcinoma 1×. In LCIS, LIC was diagnosed 3×. In the radial scar, DCIS was confirmed 1×, and invasive carcinoma remain 1×. Thus, carcinoma was diagnosed in 11 patients (37%) thanks to the surgical solution. No patient underwent axillary node surgery. All 11 patients subsequently underwent oncological treatment, always a combination of radiotherapy and hormone therapy. All patients are alive, 10 patients are in complete remission of the disease, one with DCIS experienced a local recurrence after 4 years. CONCLUSION: Surgical treatment of precancers of the breast makes sense, DCIS or even invasive cancer is often hidden in addition to precancer. Thanks to the surgical solution, the cancer was detected in time.

Re-Evaluating the Omission of Radiation Therapy in Low-Risk Patients With Early-Stage Breast Cancer.

Traditionally, management of early-stage breast cancer has required adjuvant radiation therapy following breast conserving surgery, due to decreased local recurrence and breast cancer mortality. However, over the past decade, there has been an increasing emphasis on potential overtreatment of patients with early-stage breast cancer. This has given rise to questions of how to optimize deintensification of treatment in this cohort of patients while maintaining clinical outcomes. A multitude of studies have focused on identification of a subset of patients with invasive breast cancer who were at low risk of local recurrence based on clinicopathologic features and therefore suitable for RT omission. These studies have failed to identify a subset that does not from RT with respect to local control. Several ongoing trials are evaluating alternative approaches to deintensification while focusing on tumor biology. With regards to ductal carcinoma in situ (DCIS), the role of RT has been questioned since breast conservation was utilized. Paralleling invasive disease studies, studies have sought to use clinicopathologic features to identify low risk patients suitable for RT omission but have failed to identify a subset that does not from RT with respect to local control. Use of new assays in patients with DCIS may represent the ideal approach for risk stratification and appropriate deintensification. At this time, when considering deintensification, individualizing treatment decisions with a focus on shared decision making is paramount.

[Isolated intraductal carcinoma of the prostate: a clinicopathological and molecular analysis].

Objective: To study the clinicopathological features, immunohistochemical phenotypes, molecular changes, differential diagnosis and prognosis of isolated intraductal carcinoma of the prostate (iIDC-P). Methods: Three iIDC-P cases were collected retrospectively from 2016 to 2022 at Ningbo Clinical Pathology Diagnosis Center, Ningbo, China. The clinicopathologic features and immunophenotypic profiles were studied using light microscopy and immunohistochemistry. A targeted next-generation sequencing panel was used to analyze cancer-associated mutations. Follow-up and literature review were also performed. Results: The patients' ages were 61, 67 and 77 years, and their preoperative prostate specific antigen (PSA) levels were 7.99, 7.99 and 4.86 µg/L, respectively. Case 1 and 2 were diagnosed on needle biopsy and radical prostatectomy (RP) specimens, and case 3 was diagnosed on a specimen of transurethral resection of the prostate (TURP). The RP specimen was entirely submitted for histologic examination. In the case 1, iIDC-P was found in one tissue core (involving two ducts) in the biopsy specimen, and in 6 sections (diameter, 0.3-1.1 cm) from the radical prostatectomy specimen, and one section had separate foci of low-grade acinar adenocarcinoma (diameter, 0.05 cm). In the case 2, 6 tissue sections from the biopsy specimens showed iIDC-P, and 13 sections from RP specimen showed iIDC-P (diameter, 0.5-1.6 cm), and the other 3 sections had separate low grade acinar adenocarcinoma (diameter, 0.6 cm). In the case 3, 5 tissue blocks from the TURP specimen showed iIDC-P. The case 1 and 2 showed solid architecture with expansile proliferation of neoplastic cells in native ducts and acini. The case 3 showed dense or loose cribriform pattern, with marked cytological atypia, and frequent mitotic figures. Comedonecrosis was found in solid or dense cribriform glands in the case 2. Immunohistochemically, surrounding basal cells were highlighted using high-molecular-weight cytokeratin (34ßE12 and CK5/6) and p63, while P504s was positive in the tumor cells. The tumor cells were also positive for AR and prostate markers (NKX3.1, PSA and PSAP), and negative for GATA3. The iIDC-P and acinar adenocarcinoma both showed weak PTEN expression and no ERG (nuclear) expression. In case 2 and 3, targeted sequencing revealed activated oncogenic driver mutations in MAPK and PI3K pathway genes (KRAS, MTOR and PTEN). In addition, pathogenic mutation in TP53 and FOXA1 mutation were found in the case 2 and 3, respectively. No case demonstrated TMPRSS2::ERG translocation. All cases were microsatellite stable and had lower tumor mutation burdens (range, 2.1-3.1 muts/Mb). The patients showed no biochemical recurrence or metastasis after follow-up of 16-91 months. Conclusions: iIDC-P is a special type of intraductal carcinoma of the prostate and differs from intraductal carcinoma within high-grade prostate cancer. iIDC-P has unique molecular characteristics and may represent as a molecularly unique in situ tumor of prostate cancer.

Systematic assessment of HER2 status in ductal carcinoma in situ of the breast: a perspective on the potential clinical relevance.

In many countries, hormone receptor status assessment of ductal carcinoma in situ (DCIS) is routinely performed, as hormone receptor-positive DCIS patients are eligible for adjuvant anti-hormonal treatment, aiming to reduce the ipsilateral and contralateral breast cancer risk. Although HER2 gene amplification and its associated HER2 protein overexpression constitute a major prognostic and predictive marker in invasive breast carcinoma, its use in the diagnosis and treatment of DCIS is less straightforward. HER2 immunohistochemistry is not routinely performed yet, as the role of HER2-positivity in DCIS biology is unclear. Nonetheless, recent data challenge this practice. Here, we discuss the value of routine HER2 assessment for DCIS. HER2-positivity correlates strongly with DCIS grade: around four in five HER2-positive DCIS show high grade atypia. As morphological DCIS grading is prone to interobserver variability, HER2 immunohistochemistry could render grading more robust. Several studies showed an association between HER2-positive DCIS and ipsilateral recurrence risk, albeit currently unclear whether this is for overall, in situ or invasive recurrence. HER2-positive DCIS tends to be larger, with a higher risk of involved surgical margins. HER2-positive DCIS patients benefit more from adjuvant radiotherapy: it substantially decreases the local recurrence risk after lumpectomy, without impact on overall survival. HER2-positivity in pure biopsy-diagnosed DCIS is associated with increased upstaging to invasive carcinoma after surgery. HER2 immunohistochemistry on preoperative biopsies might therefore provide useful information to surgeons, favoring wider excisions. The time seems right to consider DCIS subtype-dependent treatment, comprising appropriate local treatment for HER2-positive DCIS patients and de-escalation for hormone receptor-positive, HER2-negative DCIS patients.

Invasive recurrence after breast conserving treatment of ductal carcinoma in situ of the breast in the Netherlands: time trends and the association with tumour grade.

BACKGROUND: The first aim of this study was to examine trends in the risk of ipsilateral invasive breast cancer (iIBC) after breast-conserving surgery (BCS) of ductal carcinoma in situ (DCIS). A second aim was to analyse the association between DCIS grade and the risk of iIBC following BCS. PATIENTS AND METHODS: In this population-based, retrospective cohort study, the Netherlands Cancer Registry collected information on 25,719 women with DCIS diagnosed in the period 1989-2021 who underwent BCS. Of these 19,034 received adjuvant radiotherapy (RT). Kaplan-Meier analyses and Cox regression models were used. RESULTS: A total of 1135 patients experienced iIBC. Ten-year cumulative incidence rates of iIBC for patients diagnosed in the periods 1989-1998, 1999-2008 and 2009-2021 undergoing BCS without RT, were 12.6%, 9.0% and 5.0% (P < 0.001), respectively. For those undergoing BCS with RT these figures were 5.7%, 3.7% and 2.2%, respectively (P < 0.001). In the multivariable analyses, DCIS grade was not associated with the risk of iIBC. CONCLUSION: Since 1989 the risk of iIBC has decreased substantially and has become even lower than the risk of invasive contralateral breast cancer. No significant association of DCIS grade with iIBC was found, stressing the need for more powerful prognostic factors to guide the treatment of DCIS.

Extramammary breast cancer of the vulva.

A woman in her 70s was seen in the gynaecology outpatient clinic with a swelling on the right side of the vulva. Surgical excision of the lesion revealed unexpectedly an extensive ductal carcinoma in situ with a focus of a grade 2 invasive ductal carcinoma arising in extramammary breast tissue of the vulva. Postoperative staging studies showed normal breasts, with no evidence of disease elsewhere. The patient underwent a wider excision of the right vulva and sentinel node biopsy of the right inguinal region, which revealed no further disease. The patient is currently taking adjuvant hormonal therapy and has remained disease free at 2-year follow-up. This case underscores the importance of considering rare presentations of vulvar malignancies and the necessity for a multidisciplinary approach in managing such cases.

Mapping the cited evidence of ductal carcinoma in situ from the 5th edition of the World Health Organisation classification of tumours of the breast.

AIMS: Ductal carcinoma in situ (DCIS) is recognised by the World Health Organisation (WHO) Classification of Tumours (WCT) as a non-invasive neoplastic epithelial proliferation confined to the mammary ducts and lobules. This report categorises the references cited in the DCIS chapter of the 5th edition of the WCT (Breast Tumours) according to prevailing evidence levels for evidence-based medicine and the Hierarchy of Evidence for Tumour Pathology (HETP), identifying potential gaps that can inform subsequent editions of the WCT for this tumour. METHODS AND RESULTS: We included all citations from the DCIS chapter of the WCT (Breast Tumours, 5th edition). Each citation was appraised according to its study design and evidence level. We developed our map of cited evidence, which is a graphical matrix of tumour type (column) and tumour descriptors (rows). Spheres were used to represent the evidence, with size and colour corresponding to their number and evidence level respectively. Thirty-six publications were retrieved. The cited literature in the DCIS chapter comprised mainly case series and were regarded as low-level. We found an unequal distribution of citations among tumour descriptors. 'Pathogenesis' and 'prognosis and prediction' contained the most references, while 'clinical features', 'aetiology' and 'diagnostic molecular pathology' had only a single citation each. 'Prognosis and prediction' had the greatest proportion of moderate- and high-levels of evidence. CONCLUSION: Our findings align with the disposition for observational studies inherent in the field of pathology. Our map is a springboard for future efforts in mapping all available evidence on DCIS, potentially augmenting the editorial process and future editions of WCTs.