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.

Calidad de atención y mejora continua en el abordaje integral del cáncer de mama: Evaluación de indicadores en una Unidad de Mastología / Quality of care and continous improvement in a comprehensive approach of breast cancer management: evaluation of indicators in a breast center

Introducción: las Unidades de Mastología son organizaciones que tienen por objetivo abordar la patología mamaria de manera multidisciplinaria e integral. A nivel mundial se han implementado programas para evaluar la calidad de atención a través del cumplimiento de indicadores propuestos por Sociedades Científicas u organismos gubernamentales. Algunos de estos han sido propuestos y revisados por la Sociedad Europea de Mastología (EUSOMA). Objetivo: evaluar la calidad de atención de la Unidad de Mastología del Hospital Juan A. Fernández a través del análisis de una serie de indicadores propuestos por EUSOMA como estándares de calidad de atención en centros de patología mamaria. Material y método: estudio descriptivo retrospectivo analizando la base de datos de las pacientes con cáncer de mama estadios 0 a III operadas entre 2015 y 2019. Se analizaron 25 indicadores de procesos propuestos por EUSOMA en 2017. Se registraron las características de la población, y el porcentaje de pacientes en las cuales se cumple la condición de cada uno de los indicadores. Se registró si el indicador alcanza o supera el mínimo estándar, o si alcanza o supera el valor ideal. Resultados: se evaluaron 284 pacientes. Se observó el cumplimiento de la mayoría de los estándares propuestos (18 de 25), alcanzando o superando en el 25% de los indicadores evaluados el valor ideal. Se lograron alcanzar los estándares de calidad de atención relacionados con el diagnóstico clínico y preoperatorio, caracterización anatomopatológica completa en carcinoma invasor, evaluación multidisciplinaria, tratamiento quirúrgico primario en carcinoma invasor e in situ. Se alcanzaron los objetivos tendientes a evitar el sobretratamiento quirúrgico en carcinoma invasor y en cirugía conservadora en carcinoma in situ. En relación a los tratamientos adyuvantes, se alcanzaron los estándares relacionados con radioterapia post cirugía conservadora y post mastectomía, así como también el tratamiento con hormonoterapia y quimioterapia. El seguimiento de los pacientes se realizó en tiempo en tiempo y forma de acuerdo al indicador establecido. Existen 3 indicadores de calidad obligatorios en los que no se alcanzó el estándar mínimo: se observó la necesidad de mejorar la accesibilidad a los tratamientos antiHer2neu en neoadyuvancia, y de reducir los tiempos de espera al inicio del tratamiento. Conclusiones: se observó el cumplimiento de la mayoría de los estándares propuestos. Dado que existen indicadores obligatorios en los que no se alcanzó el estándar mínimo, los esfuerzos primarios deberán centrarse prioritaria e inicialmente en diseñar una planificación que permita alcanzar estos objetivos, así como también mantener en el tiempo los valores positivos ya alcanzados. Se pone de manifiesto la necesidad de implementar políticas a nivel sanitario nacional que permitan mejorar la accesibilidad a medicación oncológica. A su vez, destacamos la importancia de definir indicadores propios con valores ajustados a las características de nuestro país y mantener una evaluación periódica de la calidad de atención a través de los mismos.

Introduction: Breast Units are organizations that manage Breast Cancer in a comprehensive and multidisciplinary approach. Worlwide, programs have been developed in order to evaluate quality of care through the achievement of certain standards of care that have been proposed by scientific organizations, medical associations or government health departments. Some of these indicators have beeb proposed by the European Society of Breast Cancer Specialist (EUSOMA). Objective: to evaluate quality of care in the Breast Unit at Hospital Juan A Fernández (Buenos Aires, Argentina) through the analysis of a series of indicators described by EUSOMA as standard of care in breast centers. Material and method: we performed a descriptive, retrospective analysis of our database including patients with breast cancer stage 0 to III that wer treated between 2015 and 2019. We studied 25 quality of care process indicators proposed by EUSOMA in 2017. We registered population characteristics and the percentage of patients in which each indicator mínimum requirements were achieved. We also studied whether our results achieved or were beyond the ideal targets for each indicator. Results: a total of 284 patients were evaluated. The mínimum standard of care was achieved in most of the evaluated indicators (18 of 25) and in 25% of these, our results achieved or exce3ded the ideal requirements. The indicators in which the mínimum or ideal standard of care was accomplished were regarding clinical and preoperative diagnosis anatomopathological characterisation in invasive breast cancer, multidisciplinary approach, primary surgical management in invasive and in situ breast cancer, avoidanc of overtreatement in invasive breast cancer and breast conserving therapy in carcinoma in situ. Regarding adjuvant treatment, the standard of care was achieved in radiotherapy after breast conserving surgery and after mastectomy, endocrine therapy and chemotherapy. The follow up timing was according to the indicator. There were 3 mandatory indicators in which the mínimum standards were not achieved and were regarding accesibility to anti Her2neu agents in neoadjuvant setting, and timing form diagnosis to firts treatment. Conclusions: we observed that out Breast Unit achieved most of the quality of care indicators described by EUSOMA. However, there 3 mandatory indicators where the results were below the mínimum. This is why future efforts should be focused on designing and planning new measures that will allow these objectives to be accomplished, as well as maintaining what has already been achived. Our results also show the imperious need to implement national public health pólices that would grant a better accesiblility to oncologic medications. We also analysed the importance of defining our own local quality of care indicators in relation to our health policies and current situation, as well as the importance of a continuous evaluation of quality of care through these indicators.

Canonical ErbB-2 isoform and ErbB-2 variant c located in the nucleus drive triple negative breast cancer growth.

Triple negative breast cancer (TNBC) refers to tumors that do not express clinically significant levels of estrogen and progesterone receptors, and lack membrane overexpression or gene amplification of ErbB-2/HER2, a receptor tyrosine kinase. Transcriptome and proteome heterogeneity of TNBC poses a major challenge to precision medicine. Clinical biomarkers and targeted therapies for this disease remain elusive, so chemotherapy has been the standard of care for early and metastatic TNBC. Our present findings placed ErbB-2 in an unanticipated scenario: the nucleus of TNBC (NErbB-2). Our study on ErbB-2 alternative splicing events, using a PCR-sequencing approach combined with an RNA interference strategy, revealed that TNBC cells express either the canonical (wild-type) ErbB-2, encoded by transcript variant 1, or the non-canonical ErbB-2 isoform c, encoded by alternative variant 3 (RefSeq), or both. These ErbB-2 isoforms function in the nucleus as transcription factors. Evicting both from the nucleus or silencing isoform c only, blocks TN cell and tumor growth. This reveals not only NErbB-2 canonical and alternative isoforms role as targets of therapy in TNBC, but also isoform c dominant oncogenic potential. Furthermore, we validated our findings in the clinic and observed that NErbB-2 correlates with poor prognosis in primary TN tumors, disclosing NErbB-2 as a novel biomarker for TNBC. Our discoveries challenge the present scenario of drug development for personalized BC medicine that focuses on wild-type RefSeq proteins, which conserve the canonical domains and are located in their classical cellular compartments.

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.