Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression.

BACKGROUND: The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on the HER2 molecule decreasing its therapeutic effect. Here, we used mouse models and samples from HER2+ breast cancer patients to unravel MUC4 participation in hindering trastuzumab effect by fostering immune evasion. METHODS: We used a dominant negative TNFα inhibitor (DN) selective for soluble TNFα (sTNFα) together with trastuzumab. Preclinical experiments were performed using two models of conditionally MUC4-silenced tumors to characterize the immune cell infiltration. A cohort of 91 patients treated with trastuzumab was used to correlate tumor MUC4 with tumor-infiltrating lymphocytes. RESULTS: In mice bearing de novo trastuzumab-resistant HER2+ breast tumors, neutralizing sTNFα with DN induced MUC4 downregulation. Using the conditionally MUC4-silenced tumor models, the antitumor effect of trastuzumab was reinstated and the addition of TNFα-blocking agents did not further decrease tumor burden. DN administration with trastuzumab modifies the immunosuppressive tumor milieu through M1-like phenotype macrophage polarization and NK cells degranulation. Depletion experiments revealed a cross-talk between macrophages and NK cells necessary for trastuzumab antitumor effect. In addition, tumor cells treated with DN are more susceptible to trastuzumab-dependent cellular phagocytosis. Finally, MUC4 expression in HER2+ breast cancer is associated with immune desert tumors. CONCLUSIONS: These findings provide rationale to pursue sTNFα blockade combined with trastuzumab or trastuzumab drug conjugates for MUC4+ and HER2+ breast cancer patients to overcome trastuzumab resistance.

Halting ErbB-2 isoforms retrograde transport to the nucleus as a new theragnostic approach for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of receptor tyrosine kinase ErbB-2/HER2. Due to TNBC heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive. We demonstrated that ErbB-2 is localized in the nucleus (NErbB-2) of TNBC cells and primary tumors, from where it drives growth. We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c). Here, we revealed that the inhibitors of the retrograde transport Retro-2 and its cyclic derivative Retro-2.1 evict both WTErbB-2 and ErbB-2c from the nucleus of BC cells and tumors. Using BC cells from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically blocks proliferation of BC cells expressing NErbB-2. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including tumor explants and xenografts. Our mechanistic studies in TNBC cells revealed that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and the plasma membrane, and of ErbB-2c at the Golgi, shedding new light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport, and on the biology of ErbB-2 splicing variants. In addition, we revealed that the presence of a functional signal peptide and a nuclear export signal (NES), both located at the N-terminus of WTErbB-2, and absent in ErbB-2c, accounts for the differential subcellular distribution of ErbB-2 isoforms upon Retro-2 treatment. Our present discoveries provide evidence for the rational repurposing of Retro-2 as a novel therapeutic agent for TNBC.

Nuclear PDCD4 Expression Defines a Subset of Luminal B-Like Breast Cancers with Good Prognosis.

The hormone receptor-positive (estrogen and/or progesterone receptor (PR)-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that includes luminal A-like (LumA-like) and luminal B-like (LumB-like) subtypes. Decreased PR levels is a distinctive biological feature of LumB-like tumors. These tumors also show reduced sensitivity to endocrine therapies and poorer prognosis than LumA-like tumors. Identification of biomarkers to accurately predict disease relapse in these subtypes is crucial in order to select effective therapies. We identified the tumor suppressor PDCD4 (programmed cell death 4), located in the nucleus (NPDCD4), as an independent prognostic factor of good clinical outcome in LumA-like and LumB-like subtypes. NPDCD4-positive LumB-like tumors presented overall and disease-free survival rates comparable to those of NPDCD4-positive LumA-like tumors, indicating that NPDCD4 improves the outcome of LumB-like patients. In contrast, NPDCD4 loss increased the risk of disease recurrence and death in LumB-like compared with LumA-like tumors. This, along with our results showing that LumB-like tumors present lower NPDCD4 positivity than LumA-like tumors, suggests that NPDCD4 loss contributes to endocrine therapy resistance in LumB-like BCs. We also revealed that PR induces PDCD4 transcription in LumB-like BC, providing a mechanistic explanation to the low PDCD4 levels in LumB-like BCs lacking PR. Finally, PDCD4 silencing enhanced BC cell survival in a patient-derived explant model of LumB-like disease. Our discoveries highlight NPDCD4 as a novel biomarker in LumA- and LumB-like subtypes, which could be included in the panel of immunohistochemical markers used in the clinic to accurately predict the prognosis of LumB-like tumors.

Lesiones papilares malignas de la mama: nuestra experiencia / Malignant papillary lesions of the breast: our experience

Objetivo Este trabajo tiene como objetivo evaluar las características de las lesiones papilares malignas diagnosticadas en una obra social durante el período que abarca desde marzo de 2007 hasta agosto de 2015. Material y método Se realizó un análisis retrospectivo descriptivo de corte trasversal donde se incluyeron 56 pacientes con diagnóstico de Carcinoma ductal in situ papilar (cdis papilar), Carcinoma papilar encapsulado y Carcinoma papilar invasor. Se evaluaron las características clínicas, imagenológicas y anatomopatológicas. Conclusiones Las lesiones papilares malignas representan un desafío para el diagnóstico y manejo del equipo tratante dada su baja frecuencia y constante revisión de criterios diagnósticos y de manejo posterior

Objective The aim of the current study is to evaluate the characteristics of malignant papillary lesions diagnosed during march 2007 through agost 2015. Materials and method Retrospective and descriptive analysis has been made incluiding 56 patients with pathological diagnostic of papillary dcis, encapsulated carcinoma and invasive papillary carcinoma. We analyzed clinical characteristics, form of presentation in radiological features and pathological findings. Conclusions Papillary lesions of the breast represent a challenge for diagnostic an clinical management for clinicians involved, due to low frequency and a lack of clinical guidelines

Diferencias en el diagnóstico de cáncer de mama en menores de 40 años en tres sectores del sistema de salud / Difference at the time of diagnosis of breast cancer under age 40 between three sectors of the health system

Introducción El cáncer de mama en mujeres menores de 40 años es una patología que, aunque poco frecuente ­alrededor del 5 al 7% de los cánceres­, presenta una mortalidad del 47%. Se diagnostica en estadios más avanzados y es de peor pronóstico, siendo la edad el principal factor pronóstico desfavorable. El programa nacional de detección de cáncer de mama del Instituto Nacional del Cáncer (inc) recomienda solicitar la primera mamografía de screening a los 35 años y con una perioricidad anual a partir de los 40 años. Objetivo Con este estudio, se pretende identificar si existe diferencias al momento del diagnóstico de cáncer de mama en menores de 40 años entre tres sectores del sistema de salud en nuestro país. Material y método Se trata de un estudio descriptivo, de corte transversal. Se enfoca el estudio desde tres áreas: el sector público (Hospital Parmenio Piñero), el sector de obras sociales (Obra Social de Empleados de Comercio ­osecac­) y el sector privado (consultorio del Dr. Gerardo Müller Perrier). Se realizó una revisión de historias clínicas de las pacientes que fueron atendidas entre los años 2005 y 2015 en los tres sectores mencionados. La población abarcó a 1.761 pacientes, y la muestra final quedó conformada por 89 pacientes: 29 del sector público, 31 del sector de obras sociales y 29 de consultorio privado. Bases de datos utilizadas: Pubmed, md Consult, rima. Años de búsqueda: 2005-2015. Resultados La incidencia hallada fue del 5%, siendo la más alta la del sector de la obra social: 7,2%. La franja etaria más frecuente fue la comprendida entre los 36 y 39 años, con el 51%. El 67% de las pacientes no tenían antecedentes familiares. El motivo de consulta más frecuente ­69%­ fue el nódulo palpable. En el sector privado, el 42% consultó por control. Habia realizado mamografía de screening solo el 24% en la serie general pero el 42% en el sector privado. El 21% tenía ecografía de screening pero complementaria a la mamografía. El tipo histológico más frecuente ­78%­ fue¨el Carcinoma Ductal Invasor (cdi). El Carcinoma Ductal In Situ (cdis ) fue del 24% en el sector privado y de menos del 10% en los otros dos sectores. El Triple Negativo (tn) se presentó en el 32% de la serie general, seguido del Luminal A (la) en el 30%. En cuanto a estadios avanzados al diagnóstico, el resultado fue del 50% entre EIIB-IIIA, mientras que el Estadio O fue más frecuente en el sector privado: 17%. Encontramos una sobrevida global de 104 meses (ic 95% 89-119); y comparando los tres grupos, el tiempo de sobrevida fue mayor para el sector privado (p < 0,001). Pero cuando analizamos la sobrevida según el método de screening, no encontramos diferencias. Conclusiones Los distintos estilos de vida en los diferentes sectores de nuestro estudio generan conductas diferentes en cuanto a participar de estudios de screening y de prevención secundaria para el cáncer de mama, circunstancia que atribuimos a la disparidad en la información y en el conocimiento respecto del tema. Recomendamos que el examen clínico y el autoexamen sean impulsados por los profesionales de la salud a partir de edades precoces como herramientas útiles en la detección temprana, especialmente en esta población.

Introduction The breast cancer in women under 40 years old is a rare pathology, about 5 to 7%, with a mortality rate of 47%. It is diagnosed at more advanced stages and it´s of worse prognosis. The age is main factor unfavorable prognosis. The national breast cancer screening program recommends to request the first screening mammogram at age 35 and annually starting at age 40. Objectives This study aims to identify if there is difference at the time of diagnosis of breast cancer under age 40 between three sectors of the health system. Materials and method This is a descriptive, cross-sectional study. This study focuses in three areas: public sector (Hospital Parmenio Piñero), social security sector (osecac) and the private sector (clinic of Dr. Gerardo Müller Perrier). By reviewing the medical records of patients who were treated between 2005-2015 in the three sectors mentioned, the population was formed by 1.761 and the final sample was conformed by 89 patients: 29 of public sector, 31 of social security sector and 29 of private clinics. Results The incidence found was of 5%, the more high in the sector of the work social: 7.2%. Strip age more common were 36 to 39 years with 51%. 67% of the patients did not have a family history of cancer. Frequently the reason of medical visit was nodule palpable (69%); in the private sector, 42% looked for control. Only 24% had mammography in screening in the series general, but 42% in the sector private. 21% had ultrasound for screening but always with the mammography. cdi was the commonest histological type: 78%; dcis was 24% in private sector and less than 10% in the other two sectors. tn was present in 32% of the overall series, followed by la with the 30%. Advanced stage to the diagnostics was 50% between EIIB-IIIA, while Stage O was 17% more frequent in the private sector. We found a global survival of 104 months (95% ci 89-119); comparing the three groups, the survival time was higher for the private sector (p < 0.001). But when we analyzed the survival according to the screening method, we found no differences. Conclusions The different lifestyles in the different sectors of our study generate a different way to participate in studies of screening and secondary prevention of breast cancer; we attribute this to the disparity between the information and the knowledge in this regard. We recommend that clinical examination and self-examination shut driven for professionals in health, from the early ages, as an useful early detection tools, particularly in this population.