Thermosensitive Polymeric Nanoparticles for Drug Co-Encapsulation and Breast Cancer Treatment.

Despite advances in breast cancer treatment, there remains a need for local management of noninvasive, low-grade ductal carcinoma in situ (DCIS). These focal lesions are well suited for local intraductal treatment. Intraductal administration supported target site drug retention, improved efficacy, and reduced systemic exposure. Here, we used a poly(N-isopropyl acrylamide, pNIPAM) nanoparticle delivery system loaded with cytotoxic piplartine and an MAPKAP Kinase 2 inhibitor (YARA) for this purpose. For tumor environment targeting, a collagen-binding peptide SILY (RRANAALKAGELYKSILYGSG-hydrazide) was attached to pNIPAM nanoparticles, and the nanoparticle diameter, zeta potential, drug loading, and release were assessed. The system was evaluated for cytotoxicity in a 2D cell culture and 3D spheroids. In vivo efficacy was evaluated using a chemical carcinogenesis model in female Sprague-Dawley rats. Nanoparticle delivery significantly reduced the IC50 of piplartine (4.9 times) compared to the drug in solution. The combination of piplartine and YARA in nanoparticles further reduced the piplartine IC50 (~15 times). Treatment with these nanoparticles decreased the in vivo tumor incidence (5.2 times). Notably, the concentration of piplartine in mammary glands treated with nanoparticles (35.3 ± 22.4 µg/mL) was substantially higher than in plasma (0.7 ± 0.05 µg/mL), demonstrating targeted drug retention. These results indicate that our nanocarrier system effectively reduced tumor development with low systemic exposure.

Predictive factors of invasion in ductal carcinoma in situ diagnosed by core-needle biopsy.

OBJECTIVE: To identify clinical, radiological, and histopathological characteristics that could be predictive factors of microinvasive/invasive breast carcinoma in patients with diagnosis of ductal carcinoma in situ (DCIS) by core-needle biopsy. MATERIAL AND METHODS: This is a retrospective study conducted from 2006-2017, which included women ≥18 years of age with initial DCIS, and who were treated with surgery. Final diagnosis was divided in DCIS and microinvasive/invasive carcinoma. RESULTS: 334 patients were included: 193 (57.8%) with DCIS and 141 (42.2%) with microinvasive/invasive carcinoma (microinvasive 5.1%, invasive 37.1%). Lymph node metastasis occurred in 16.3%. Differences between DCIS and microinvasive/invasive groups included the presence of palpable nodule (36.7% vs. 63.2%), radiological nodule (29% vs. 51%), bigger radiological-tumor size (1.2 cm vs. 1.7 cm), and larger microcalcification extension (2.5 cm vs. 3.1 cm), all of these variables p ≤0.05. Hormonal receptors and HER2 expression were similar. After logistic regression analysis, predictive factor of invasion was the presence of palpable nodule (OR = 4.072, 95%CI = 2.520-6.582, p <0.001) and radiological multicentric disease (OR = 1.677, 95%CI = 1.036-2.716, p = 0.035). CONCLUSIONS: In patients with DCIS, palpable nodule, and radiological multicentric disease, upgrade to microinvasive/invasive is high, and sentinel lymph node is recommended.

OBJETIVO: Identificar características clínicas, radiológicas e histopatológicas como factores predictivos de carcinoma mamario microinvasor/invasor en pacientes con Carcinoma Ductal In Situ (CDIS) diagnosticado mediante aguja de corte. MATERIAL Y MÉTODOS: Estudio retrospectivo de 2006­2017, en mujeres ≥18 años con CDIS diagnosticado con aguja de corte y tratadas con cirugía. Los diagnósticos finales fueron CDIS y carcinoma microinvasor/invasor. RESULTADOS: Se incluyeron 334 pacientes, 193 (57.8%) con CDIS y 141 (42.2%) con carcinoma microinvasor/invasor (microinvasor 5.1%, invasor 37.1%). Hubo 16.3% casos con afección ganglionar. Las diferencias entre el grupo de CDIS y carcinoma microinvasor/invasor fue la presencia de tumor palpable (36.7% vs. 63.2%), nódulo visto por imagen (29% vs. 51%), tumores más grandes (1.2 cm vs. 1.7 cm), y mayor extensión de microcalcificaciones (2.5 cm vs. 3.1 cm), estas variables con p ≤0.05. Los receptores hormonales y HER2 fueron similares. En el análisis de regresión logística, los factores predictivos de invasión fueron tumor palpable (OR = 4.072, IC95% = 2.520­6.582, p <0.001) y multicentricidad radiológica (OR = 1.677, IC95% = 1.036­2.716, p = 0.035). CONCLUSIONES: En CDIS, tumor palpable y enfermedad multicéntrica radiológica, el escalamiento a carcinoma microinvasor/invasor es alto y es recomendable realizar ganglio centinela.

Ductal Carcinoma in situ: Underestimation of Percutaneous Biopsy and Positivity of Sentinel Lymph Node Biopsy in a Brazilian Public Hospital.

BACKGROUND: Mammography screening has become widely spread and provided a marked increase in ductal carcinoma in situ (DCIS) diagnosis. In DCIS, the ductal epithelium proliferates without invasion through the basal cell membrane. However, histologic underestimation can happen in some cases. OBJECTIVE: To analyze the rate of histologic underestimation (histopathologic results upgraded to invasive carcinoma after surgery) and the rate of positive results of sentinel lymph node biopsy (SLNB) in patients diagnosed with DCIS in a Brazilian public hospital. METHODS: We reviewed medical records of all consecutive patients admitted between 2009 and 2013 whose initial diagnosis was DCIS through core needle biopsy. DCIS cases with a high risk of invasion underwent SLNB. We excluded cases with invasion or micro-invasion components in the first biopsy. RESULTS: A total of 86 women were included, most with microcalcifications as the primary radiological lesion (73.2%), and underwent preoperative biopsy, with an invasive component in 21 (24.4%) in the final pathology report. Most had invasive carcinoma of no special type (NST): 52.3% (n = 11) and microinvasive tumors (7 cases, 33.3%). The main factors associated with histologic underestimation were nodular lesion (61.9%, p<0.001) and an ultra-sonography-guided biopsy (71.4%, p=0.0005). The positivity rate of SLNB was 4.3%. All these patients underwent mastectomy, and the initial histologic pattern was solid DCIS. CONCLUSION: The "histologic underestimation" rate among patients with DCIS was not low, and less than 5% of patients who underwent SLNB had axillary positivity. This result suggests that patients who have DCIS and a high risk of invasion and undergoing mastectomy should have SLNB. As to the patients who will undergo lumpectomy, SLNB could be omitted and could be performed if patients have upgraded to invasive breast cancer.

Indicators of a pro-tumor immune response are evident at early stages of breast cancer.

With advances in checkpoint inhibitor and CAR T-cell therapies, among other advances in immunotherapy, this is an exciting time to be a tumor immunologist. We are witnessing the transition of decades of work at the bench leading to substantial success in the clinic. While work continues developing new and improving existing immunotherapies, there remains a great deal of basic tumor immunology still to learn, information that can only lead to greater success in the clinic. One area in need of more attention is understanding the immune response at early stages of breast cancer. While there is no question that early diagnosis and treatment save lives, a greater understanding about the immune response during early stages of breast cancer may reveal information that could assist in monitoring individuals at risk of breast cancer, and could have implications for patients diagnosed at early stages of disease, and may provide important information about the origins of an immune-suppressive environment. Here, we review studies that have looked at the very early immune response to breast cancer focusing on patients with DCIS, before invasion in spontaneous transgenic murine mammary carcinoma models, and before transplantable or orthotopic murine mammary carcinoma models become palpable. The findings revealed that indicators of a pro-tumor immune response are already present at early stages of disease.

Potential biomarkers of ductal carcinoma in situ progression.

BACKGROUND: Ductal carcinoma in situ is a non-obligate precursor of invasive breast carcinoma and presents a potential risk of over or undertreatment. Finding molecular biomarkers of disease progression could allow for more adequate patient treatment. We aimed to identify potential biomarkers that can predict invasiveness risk. METHODS: In this epithelial cell-based study archival formalin-fixed paraffin-embedded blocks from six patients diagnosed with invasive lesions (pure invasive ductal carcinoma), six with in-situ lesions (pure ductal carcinoma in situ), six with synchronous lesions (invasive ductal carcinoma with an in-situ component) and three non-neoplastic breast epithelium tissues were analyzed by gene expression profiling of 770 genes, using the nCounter® PanCancer Pathways panel of NanoString Technologies. RESULTS: The results showed that in comparison with non-neoplastic tissue the pure ductal carcinoma in situ was one with the most altered gene expression profile. Comparing pure ductal carcinoma in situ and in-situ component six differentially expressed genes were found, three of them (FGF2, GAS1, and SFRP1), play a role in cell invasiveness. Importantly, these genes were also differentially expressed between invasive and noninvasive groups and were negatively regulated in later stages of carcinogenesis. CONCLUSIONS: We propose these three genes (FGF2, GAS1, and SFRP1) as potential biomarkers of ductal carcinoma in situ progression, suggesting that their downregulation may be involved in the transition of stationary to migrating invasive epithelial cells.

Role of boost radiotherapy for local control of pure ductal carcinoma in situ after breast-conserving surgery: a multicenter, retrospective study of 622 patients.

PURPOSE: To evaluate the effect of boost radiotherapy on ipsilateral breast tumor recurrence (IBTR) for ductal carcinoma in situ (DCIS) after breast-conserving surgery and whole breast radiotherapy (WBRT) with or without boost. METHODS AND MATERIALS: Retrospective, multicentre study of 622 patients (624 tumors) diagnosed with pure DCIS from 1993-2011. RESULTS: Most tumors (377/624; 60.4%) received a boost. At a median follow-up of 8.8 years, IBTR occurred in 64 cases (10.3%). A higher percentage of patients with risk factors for IBTR received a boost (p < 0.05). Boost was not associated with lower rates of IBTR than WBRT alone (HR 0.75, 95% CI 0.42-1.35). On the univariate analyses, IBTR was significantly associated with tumor size (11-20 mm, HR 2.32, 95% CI 1.27-4.24; and > 20 mm, HR 2.10, 95% CI 1.14-3.88), re-excision (HR 1.76, 95% CI 1.04-2.96), and tamoxifen (HR 2.03, 95% CI 1.12-3.70). Boost dose > 16 Gy had a protective effect (HR 0.39, 95% CI 0.187-0.824). Multivariate analyses confirmed the independent associations between IBTR and 11-20 mm (p = 0.02) and > 20 mm (p = 0.009) tumours, and re-excision (p = 0.006). On the margin-stratified multivariate analysis, tamoxifen was a poor prognostic factor in the close/positive margin subgroup (HR 4.28 95% CI 1.23-14.88), while the highest boost dose ( > 16 Gy) had a significant positive effect (HR 0.34, 95% CI 0.13-0.86) in the negative margin subgroup. CONCLUSIONS: Radiotherapy boost did not improve the risk of IBTR. Boost radiotherapy was more common in patients with high-risk disease. Tumor size and re-excision were significant independent prognostic factors.

Adherencia a hormonoterapia en pacientes con carcinoma ductal in situ de mama / Adherence to hormonal therapy in patients with ductal carcinoma in situ of the breast

Introducción Las pacientes con Carcinoma Ductal in Situ de mama (cdis) tienen mayor riesgo de desarrollar carcinoma invasor. Aquellas con receptores hormonales positivos se beneficiarían con hormonoterapia. El largo período de tratamiento y los efectos adversos asociados al mismo hacen dificultosa la adherencia. Objetivos El objetivo del presente trabajo es analizar la adherencia a la hormonoterapia en pacientes operadas por Carcinoma Ductal in Situ en el Hospital Universitario Austral. Material y método Es un estudio observacional, analítico, de corte transversal. Se incluyeron pacientes con diagnóstico de Carcinoma Ductal in Situ que fueron intervenidas quirúrgicamente en el Hospital Universitario Austral en el período comprendido entre el 24 de julio de 2000 y el 5 de julio de 2017. Los datos fueron recopilados a través de una encuesta. Resultados Se obtuvieron 100 encuestas. La adherencia fue del 82%. La misma no se modificó según edad, conocimiento de riesgos y beneficios del tratamiento, tipo y número de cirugías, radioterapia y número de consultas. Las reacciones adversas a la medicación fueron la causa más frecuente de abandono al tratamiento. Conclusiones El tratamiento multidisciplinario podría asegurar un óptimo nivel de adherencia

Introduction Patients with Ductal Carcinoma in Situ of the breast (dcis) have a higher risk of developing invasive carcinoma. Those with hormone receptor-positive would benefit from hormonal therapy. The long period of treatment and the associated adverse events make adherence difficult. Objectives The aim of this study is to analyze the adherence of hormonal therapy in operated patients with Ductal Carcinoma in Situ at Hospital Universitario Austral. Materials and method It is an observational, analytical and cross-sectional study. Patients diagnosed with Ductal Carcinoma in Situ who underwent surgery at Hospital Universitario Austral in the period between 07/24/2000 and 07/05/2017 were included. The data was collected through a survey. Results 100 surveys were obtained. The adherence was 82%. It was not modified according to age, knowledge of risks and benefits of the treatment, type and number of surgeries, radiotherapy and number of consultations. Adverse events were the most frequent cause of discontinue of treatment. Conclusions Multidisciplinary treatment could ensure an optimal level of adherence

Patrón de recurrencia local en el carcinoma ductal in situ de mama según su inmunofenotipo / Pattern of local recurrence in ductal carcinoma in situ according to the inmunophenotype

Introducción En el carcinoma intraductal o carcinoma ductal in situ (cdis), la sobreexpresión del her2 neu (her2 neu+), alcanza un 60 a 70% de los casos y se asocia con la presencia de alto grado nuclear, comedo-necrosis y baja expresión de receptores hormonales. La asociación entre la sobreexpresión de her2 neu, receptor de estrógeno negativo (re) y alta expresión de factor de proliferación Ki67 (>14%) en pacientes con cdis tendría mayor riesgo de recurrencia local. Objetivos Determinar la frecuencia de sobreexpresión del factor de membrana epidérmico her2 neu en los carcinomas ductales in situ de mama y su relación con la recurrencia local de la enfermedad. Asimismo, determinar la relación entre la sobreexpresión del her2 neu y la supervivencia libre de enfermedad (sle), la supervivencia global (sg), los receptores hormonales y Ki67, y el tipo de recurrencia. Material y método Estudio retrospectivo que incluye pacientes con diagnóstico de cdis de mama en el Servicio de Mastología del Hospital Británico de Buenos Aires operadas entre enero de 2006 y diciembre de 2014. Las variables analizadas fueron la edad, el estado menopáusico, la forma de presentación, el tratamiento quirúrgico y adyuvante, el diagnóstico anátomo-patológico y la inmunohistoquímica, la supervivencia libre de enfermedad y la supervivencia global. Resultados Se incluyeron en el estudio 252 pacientes que cumplían con los criterios de inclusión, agrupándolas según la sobreexpresión o no del receptor de membrana her2 neu en el resultado anátomo-patológico de la pieza operatoria. Sobreexpresaron el receptor de membrana her2 neu (her2 neu+) 86 pacientes (34,1%), mientras que 166 pacientes (65,9%) fueron her2 neu negativo (her2 neu­). Se observó menor número de re negativo en el grupo her2 neu­ (8,4%) vs las pacientes del grupo her2 neu+ (39,5%) (p<0,001). Se registraron 24 recurrencias locales (9,52%), 8 de ellas del grupo her2 neu­ (4,8%) y las 16 restantes del grupo her2 neu+ (18,6%). Se halló una asociación estadísticamente significativa entre la recurrencia local y la sobreexpresión de her2 neu: p=0,04. Conclusiones Se encontró que la sobreexpresión del her2 neu se asoció a una mayor tasa de recurrencia local del carcinoma ductal in situ, con una menor sle en este grupo. También hubo un mayor número de tumores con receptores hormonales negativos en el grupo her2 neu+. En cuanto a la sg, no encontramos diferencias entre ambos grupos

Introduction The incidence of human epidermal growth factor 2 (her2 neu) overexpression or amplification in ductal carcinoma in situ (dcis) is between 60 to 70%, and is associated with the presence of high nuclear grade, comedonecrosis, and low expression of hormonal receptors. There is a higher risk of local recurrence in patients with dcis that overexpress her2 neu, have negative estrogen receptor and high Ki67 (>14%). Objectives Identify patients diagnosed with dcis that overexpressed her2 neu, and its association with local recurrence. Likewise, determine the relationship between her2 neu amplification and disease free survival (dfs), overall survival (os), and expression of hormonal receptors, Ki67 and the type of recurrence. Materials and method Retrospective study, that included patients with dcis diagnosed and surgically treated in the Breast Service of Hospital Britanico de Buenos Aires between January 2006 and December 2014. Demographic information analyzed included age, menopausal status, type of presentation, surgery and adjuvant therapy, histopathological analysis and immunohistochemistry (ihc), dfs and os. Results 252 patients were included and divided in two groups according to the her2 neu expression in the histopathologic result after surgery. The overexpression of her2 neu (her2 neu positive/her2 neu+) was found in 86 patients (34.1%) and 166 patients (65,9%) were her2 neu negative (her2 neu­). In the her2 neu­ group we found less negative estrogen receptor (8.4%) than in the her2 neu+ group (39.5%) (p<0.001). There were 24 local recurrence (9.52%): 8 were her2 neu­ (4.8%) and 16 were her2 neu+ (18.6%). The association between local recurrence and her2 neu overexpression was statistically significant in our analysis: p=0.04. Conclusions The her2 neu overexpression was related with a higher recurrence rate, less dfs. There was also a higher number of tumors with negative estrogen receptor that overexpressed her2 neu. No difference was found in the os between groups

Granulomatous lobular mastitis associated with ductal carcinoma in situ of the breast.

The association of granulomatous lobular mastitis and carcinoma of the breast is very infrequent. We present the case of a 44-year-old woman with concurrent granulomatous lobular mastitis with coryneform bacteria and ductal carcinoma in situ in the same breast.

Is it possible to predict underestimation in ductal carcinoma in situ of the breast? Yes, using a simple score!

BACKGROUND: Approximately 30% of patients with an initial diagnosis of ductal carcinoma ductal in situ (DCIS) present stromal invasion in the final surgical specimen. This study aimed to describe the prevalence of upstaging in women with an initial diagnosis of pure DCIS and identify predictive factors of invasion. METHODS: This is a cross-sectional study including patients with an initial unilateral DCIS diagnosed through needle core or vacuum-assisted biopsy. All patients were submitted to surgical excision. Clinical, radiological and histological variables were retrospectively collected from our medical records. RESULTS: A total of 169 biopsies diagnosed with DCIS were included in this study. 53 patients presented upstaging for invasive carcinoma (31.4%). In the univariate analysis the following variables were significantly associated with invasive breast carcinoma (IBC) at final diagnosis: age < 46 years, the presence of a palpable mass, type of biopsy, nuclear grade, and comedonecrosis. The frequency of upstaging did not vary according to the tumor size or menopausal status. In the multivariate analysis, only the type of biopsy and the presence of comedonecrosis remained as independent predictors of invasion. Our score attributed specific points according to the type of biopsy and the presence of comedonecrosis, ranging from 0 to 2.5, showing a very good predictive ability. CONCLUSIONS: We were able to identify that the type of biopsy and comedonecrosis are predictive factors of stromal invasion among women with DCIS. The proposed score has shown a good predictive ability and its utilization in the clinical practice can improve therapeutic planning.

Mortality of women with ductal carcinoma in situ of the breast: a population-based study from the Girona province, Spain (1994-2013).

PURPOSE: We aim to comprehensively describe the incidence and mortality trends of ductal carcinoma in situ (DCIS) in the Girona province, Spain (1994-2013) and to estimate the all-cause mortality excess risk of diagnosed women. METHODS: Age-standardized rates of DCIS were estimated between 1994 and 2013. Standard mortality ratios (SMR) and absolute excess mortality were calculated overall and by tumor and patient characteristics. A sensitivity analysis was conducted excluding cases with a subsequent invasive breast cancer (sIBC). RESULTS: Of the 641 women included, 56 died (follow-up time: 8.4 person-years). Between 1994 and 2013, a significant increase in incidence and decrease in mortality was identified among women aged between 50 and 69 years old. Neoplasms and circulatory system disease were the most common causes of death. No excess risk of death was found overall, except for women aged < 50 years (SMR = 3.44, 95% CI 1.85; 6.40) and those with a sIBC (SMR = 2.51, 95% CI 1.26; 5.02), risk that lessened when cases with sIBC were excluded. Patients with sIBC also showed an excess risk (SMR = 2.29, 95% CI 1.03; 5.10). CONCLUSIONS: Among women aged 50-69 years old, incidence of DCIS has significantly increased yet mortality has decreased. Overall, the all-cause mortality risk of women diagnosed with DCIS remains similar to that of the general population except for women diagnosed before age 50 and those with sIBC, who showed a significant increased risk. Differential management of these patients should be considered.

Radiotherapy in breast ductal carcinoma in situ / Radioterapia em carcinoma ductal in situ de mama

Breast ductal carcinoma in situ (DCIS) comprises a heterogeneous group of lesions with different forms of clinical and pathological presentation. Postoperative radiotherapy is usually performed in DCIS patients who underwent conservative breast surgery. The objective of the present study was to describe indications and clinical evidences of radiotherapy for breast DCIS patients

O carcinoma ductal in situ (CDIS) de mama compreende um grupo heterogêneo de lesões com diferentes formas de apresentação clínica e patológica. A radioterapia pós-operatória é normalmente realizada nas pacientes com CDIS submetidas à cirurgia conservadora de mama. O presente estudo teve o objetivo de apresentar as indicações e as evidências para a utilização da radioterapia na abordagem do CDIS de mama.

Actualidad para el diagnóstico del carcinoma ductal in situ: correlación radiopatológica / Current issues in the diagnosis of ductal carcinoma in situ: a radiopathological correlation

El carcinoma ductal in situ (CDIS) se encuentra en un grupo heterogéneo de tumores, cuyo diagnóstico se ha visto incrementado con el uso de la mamografía como método de cribado. El sistema de clasificación de Van Nuys, que se basa principalmente en el grado nuclear histológico y la presencia de necrosis, es el sistema más reproducible para la clasificación histopatológica. La anomalía más común que se observa en la mamografía son las microcalcificaciones, coexistiendo con otras lesiones como masas y distorsión arquitectural, que representan lesiones de bajo grado. El diagnóstico inicial debe realizarse mediante anamnesis y examen físico detallado que permita realizar una aproximación a las características morfoestructurales de la lesión, para posteriormente llegar a un acercamiento imagenológico y dinámico mediante resonancia magnética (RM), complementada con técnicas de inmunohistoquímica que caractericen el tumor. La presencia de distribución segmentaria morfológica es típico de malignidad (CDIS). La cinética de las lesiones en el estudio dinámico de la RM varía, siendo patognomónico de CDIS el patrón de washout en la fase de reforzamiento tardío. Sin embargo, el patrón dinámico parece estar correlacionado con los hallazgos mamográficos. Los hallazgos de RM y TC multidetector pueden ser útiles en combinación con la RM de mama para el mapeo preoperatorio. Sin embargo, existen técnicas complementarias como la espectroscopía y la difusión ponderada que mejoran la especificidad de la RM y tienen utilidad en la predicción de respuesta a la quimioterapia adyuvante. Estas aplicaciones futuras podrán mejorar la capacidad de diagnóstico oportuno y opciones de tratamiento.

Ductal carcinoma in situ (DCIS) falls into a heterogeneous group of tumors, whose diagnosis has increased with the use of mammography as screening method. The Van Nuys Prognostic Index, mainly based on histological nuclear grade and presence of necrosis, is the most reproducible histopathological classification system. The most common abnormality observed during a mammography are microcalcifications, which coexist with other lesions such as masses and architectural distortion, and represent low-grade lesions. The initial diagnosis should be performed by anamnesis and a detailed physical examination to help determine the morphostructural characteristics of the lesion. Then an imaging and dynamic approach should be achieved by magnetic resonance imaging (MRI) complemented by immunohistochemistry to characterize the tumor. The presence of morphological segmental distribution is typical of malignancy (DCIS). The kinetics of the lesions using a dynamic MRI varies, with the washout and late enhancement pattern being pathognomonic for DCIS. However, the dynamic pattern seems to be correlated with mammographic findings. Multidetector CT and MRI findings may be useful in combination with breast MRI for preoperative mapping. Nevertheless, there are complementary techniques such as spectroscopy and weighted diffusion that improve the specificity of the MRI and are useful in predicting response to adjuvant chemotherapy. These future applications will improve the ability for early diagnosis and treatment options.

Epithelial cells captured from ductal carcinoma in situ reveal a gene expression signature associated with progression to invasive breast cancer.

Breast cancer biomarkers that can precisely predict the risk of progression of non-invasive ductal carcinoma in situ (DCIS) lesions to invasive disease are lacking. The identification of molecular alterations that occur during the invasion process is crucial for the discovery of drivers of transition to invasive disease and, consequently, biomarkers with clinical utility. In this study, we explored differences in gene expression in mammary epithelial cells before and after the morphological manifestation of invasion, i.e., early and late stages, respectively. In the early stage, epithelial cells were captured from both pre-invasive lesions with distinct malignant potential [pure DCIS as well as the in situ component that co-exists with invasive breast carcinoma lesions (DCIS-IBC)]; in the late stage, epithelial cells were captured from the two distinct morphological components of the same sample (in situ and invasive components). Candidate genes were identified using cDNA microarray and rapid subtractive hybridization (RaSH) cDNA libraries and validated by RT-qPCR assay using new samples from each group. These analyses revealed 26 genes, including 20 from the early and 6 from the late stage. The expression profile based on the 20 genes, marked by a preferential decrease in expression level towards invasive phenotype, discriminated the majority of DCIS samples. Thus, this study revealed a gene expression signature with the potential to predict DCIS progression and, consequently, provides opportunities to tailor treatments for DCIS patients.

Enfermedad de Paget mamaria: Presentacion de dos casos / Mammary Paget's disease: Report of two cases

La Enfermedad de Paget Mamaria (EPM), es una neoplasia infrecuente del complejo pezón/areola, que se presenta como expresión de un carcinoma intraductal adyacente. Presentamos dos casos de pacientes atendidas en nuestro servicio.

Mammary Paget's disease is a rare neoplasm of the nipple/areola area, which is presented as an expression of an adjacent intraductal carcinoma. We report two cases of patients treated in our service.

Morphologic, molecular and microenvironment factors associated with stromal invasion in breast ductal carcinoma in situ: Role of myoepithelial cells.

BACKGROUND: Ductal carcinoma in situ is the last step preceding invasive ductal carcinoma in breast carcinogenesis. OBJECTIVE: We investigated the role of myoepithelial cells and epithelium characteristics as predictors of the risk of stromal invasion. METHODS: We selected 236 cases with initial diagnosis of DCIS followed by surgical ressection distributed in groups 1 (without invasion) and 2 (with invasive carcinoma). RESULTS: The risk of stromal invasion after a DCIS diagnosis in biopsy was associated to triple-negative profile and loss of CD10 expression by myoepithelial cells, and inversely associated with CK5/6 expression by neoplastic cells and high expression of Smooth Muscle Myosin Heavy Chain (SMMHC) by myoepithelial cells. CONCLUSIONS: A combination of characteristics of epithelial and myoepithelial cells in DCIS in biopsy specimens is related to the risk of stromal invasion.

[Sentinel lymph node metastasis in patients with ductal breast carcinoma in situ]. / Metástasis a ganglio centinela de pacientes con carcinoma ductal in situ de la mama.

BACKGROUND: Sentinel lymph node biopsy in patients with ductal carcinoma in situ still controversial, with positive lymph node in range of 1.4-12.5% due occult invasive breast carcinoma in surgical specimen. OBJECTIVE: To know the frequency of sentimel node metastases in patients with ductal carcinoma in situ, identify differences between positive and negative cases. METHODS: Retrospective study of patients with ductal carcinoma in situ treated with sentinel lymph node biopsy because mastectomy indication, palpable tumor, radiological lesion = 5 cm, non-favorable breast-tumor relation and/or patients whom surgery could affect lymphatic flow drainage. RESULTS: Of 168 in situ carcinomas, 50 cases with ductal carcinoma in situ and sentinel lymph node biopsy were included, with a mean age of 51.6 years, 30 (60%) asymptomatic. The most common symptoms were palpable nodule (18%), nipple discharge (12%), or both (8%). Microcalcifications were common (72%), comedonecrosis pattern (62%), grade-2 histology (44%), and 28% negative hormonal receptors. Four (8%) cases had intra-operatory positive sentinel lymph node and one patient at final histo-pathological study (60% micrometastases, 40% macrometastases), all with invasive carcinoma in surgical specimen. Patients with intra-operatory positive sentinel lymph node where younger (44.5 vs 51 years), with more palpable tumors (50% vs 23.1%), and bigger (3.5 vs 2 cm), more comedonecrosis pattern (75% vs 60.8%), more indifferent tumors (75% vs 39.1%), and less cases with hormonal receptors (50% vs 73.9%), compared with negative sentinel lymph node cases, all these differences without statistic significance. CONCLUSIONS: One of each 12 patients with ductal carcinoma in situ had affection in sentinel lymph node, so we recommend continue doing this procedure to avoid second surgeries due the presence of occult invasive carcinoma.

Antecedentes: en pacientes con carcinoma ductal in situ la biopsia de ganglio centinela es motivo de controversia porque se reportan ganglios positivos en 1.4-12.5% debido al carcinoma invasor oculto en la pieza quirúrgica. Objetivo: conocer la frecuencia de metástasis en ganglio centinela en pacientes con carcinoma ductal in situ e identificar las diferencias entre los casos positivos y negativos. Material y métodos: estudio retrospectivo, transversal, analítico de pacientes con carcinoma ductal in situ a quienes se realizó una biopsia de ganglio centinela por requerir mastectomía, tener un tumor palpable, lesión radiológica = 5 cm, inadecuada relación mama-tumor o porque la escisión pudiera afectar el flujo linfático. Resultados: de 168 carcinomas in situ, se incluyeron 50 casos con carcinoma ductal in situ y biopsia de ganglio centinela, de pacientes con edad promedio de 51.6 años, 30 (60%) de ellas asintomáticas. Los signos reportados fueron: nódulo palpable (18%), secreción por el pezón (12%) o ambos (8%). Predominaron las microcalcificaciones (72%), comedonecrosis (62%) y grado histológico -2 (44%) con 28% de receptores hormonales negativos. En el estudio transoperatorio 4 (8%) pacientes tuvieron ganglio centinela positivo y un caso en estudio histopatológico definitivo (60% micrometástasis, 40% macrometástasis), todos con carcinoma invasor en la pieza quirúrgica. Las pacientes con ganglio centinela transoperatorio positivo eran más jóvenes (44.5 vs 51 años), con más tumores palpables (50 vs 23.1%), más grandes (3.5 vs 2 cm), más comedonecrosis (75 vs 60.8%), más indiferenciados (75% vs 39.1%) y menos receptores hormonales (50 vs 73.9%), que las que tenían ganglio centinela negativo, sin que estas diferencias tuvieran significación estadística. Conclusiones: puesto que 1 de cada 12 pacientes con carcinoma ductal in situ tiene afectación ganglionar en el ganglio centinela, se recomienda seguir tomando la biopsia para evitar segundas cirugías por un carcinoma invasor oculto.

Ductal carcinoma in situ of the breast: morphological and molecular features implicated in progression.

The spread of mammographic screening programmes around the world, including in developing countries, has substantially contributed to the diagnosis of small non-palpable lesions, which has increased the detection rate of DCIS (ductal carcinoma in situ). DCIS is heterogeneous in several ways, such as its clinical presentation, morphology and genomic profile. Excellent outcomes have been reported; however, many questions remain unanswered. For example, which patients groups are overtreated and could instead benefit from minimal intervention and which patient groups require a more traditional multidisciplinary approach. The development of a comprehensive integrated analysis that includes the radiological, morphological and genetic aspects of DCIS is necessary to answer these questions. This review focuses on discussing the significant findings about the morphological and molecular features of DCIS and its progression that have helped to uncover the biological and genetic heterogeneity of this disease. The knowledge gained in recent years might allow the development of tailored clinical management for women with DCIS in the future.

Immunohistochemical profile of high-grade ductal carcinoma in situ of the breast

OBJECTIVE: To determine the frequency of the immunohistochemical profiles of a series of high-grade ductal carcinoma in situ of the breast. METHODS: One hundred and twenty-one cases of high-grade ductal carcinoma in situ, pure or associated with invasive mammary carcinoma, were identified from 2003 to 2008 and examined with immunohistochemistry for estrogen receptor, human epidermal growth factor receptor 2, cytokeratin 5, and epidermal growth factor receptor. The tumors were placed into five subgroups: luminal A, luminal B, HER2, basal-like, and “not classified”. RESULTS: The frequencies of the immunophenotypes of pure ductal carcinoma in situ were the following: luminal A (24/42 cases; 57.1%), luminal B (05/42 cases; 11.9%), HER2 (07/42 cases; 16.7%), basal-like phenotype (00/42 cases; 0%), and “not classified” (06/42 cases; 14.3%). The immunophenotypes of ductal carcinoma in situ associated with invasive carcinoma were the following: luminal A (46/79 cases; 58.2%), luminal B (10/79 cases; 12.7%), HER2 (06/79 cases; 7.6%), basal-like (06/79 cases; 7.6%), and “not classified” (11/79 cases; 13.9%). There was no significant difference in the immunophenotype frequencies between pure ductal carcinoma in situ and ductal carcinoma in situ associated with invasive carcinoma (p>0.05). High agreement was observed in immunophenotypes between both components (kappa=0.867). CONCLUSION: The most common immunophenotype of pure ductal carcinoma in situ was luminal A, followed by HER2. The basal-like phenotype was observed only in ductal carcinoma in situ associated with invasive carcinoma, which had a similar phenotype. .

Basal cytokeratin as a potential marker of low risk of invasion in ductal carcinoma in situ

OBJECTIVES: Biological markers that predict the development of invasive breast cancer are needed to improve personalized therapy for patients diagnosed with ductal carcinoma in situ. We investigated the role of basal cytokeratin 5/6 in the risk of invasion in breast ductal carcinoma in situ. METHODS: We constructed tissue microarrays using 236 ductal carcinoma in situ samples: 90 pure samples (group 1) and 146 samples associated with invasive carcinoma (group 2). Both groups had similar nuclear grades and were obtained from patients of similar ages. The groups were compared in terms of estrogen (ER) and progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) expression, cytokeratin 5/6 immunostaining, human epidermal growth factor receptor 1 (EGFR) membrane staining and molecular subtype, as indicated by their immunohistochemistry profiles. RESULTS: ER/PR-negative status was predictive of invasion, whereas HER2 superexpression and cytokeratin 5/6-positive status were negatively associated with invasion. Among the high-grade ductal carcinoma in situ cases, a triple-positive profile (positive for estrogen receptor, progesterone receptor, and HER2) and cytokeratin 5/6 expression by neoplastic cells were negatively associated with invasion. In the low-grade ductal carcinoma in situ subgroup, only cytokeratin 5/6 expression exhibited a negative association with the probability of invasion. CONCLUSION: The immunohistochemical expression of cytokeratin 5/6 by ductal carcinoma in situ epithelial cells may provide clinically useful information regarding the risk of progression to invasive disease. .