Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor-positive Breast Cancer.

Estrogen receptor-positive (ER+) breast cancer is not considered immunogenic and, to date, has been proven resistant to immunotherapy. Endocrine therapy remains the cornerstone of treatment for ER+ breast cancers. However, constitutively activating mutations in the estrogen receptor alpha (ESR1) gene can emerge during treatment, rendering tumors resistant to endocrine therapy. Although these mutations represent a pathway of resistance, they also represent a potential source of neoepitopes that can be targeted by immunotherapy. In this study, we investigated ESR1 mutations as novel targets for breast cancer immunotherapy. Using machine learning algorithms, we identified ESR1-derived peptides predicted to form stable complexes with HLA-A*0201. We then validated the binding affinity and stability of the top predicted peptides through in vitro binding and dissociation assays and showed that these peptides bind HLA-A*0201 with high affinity and stability. Using tetramer assays, we confirmed the presence and expansion potential of antigen-specific CTLs from healthy female donors. Finally, using in vitro cytotoxicity assays, we showed the lysis of peptide-pulsed targets and breast cancer cells expressing common ESR1 mutations by expanded antigen-specific CTLs. Ultimately, we identified five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides, which were the most immunogenic. Overall, these data confirm the immunogenicity of epitopes derived from ESR1 and highlight the potential of these peptides to be targeted by novel immunotherapy strategies. SIGNIFICANCE: Estrogen receptor (ESR1) mutations have emerged as a key factor in endocrine therapy resistance. We identified and validated five novel, immunogenic ESR1-derived peptides that could be targeted through vaccine-based immunotherapy.

Association between frailty and overall survival among older adults with hepatocellular carcinoma.

INTRODUCTION: Older adults undergoing cancer treatment often experience more treatment-related toxicities and increased risk of mortality compared to younger patients. The role of frailty among older individuals as a predictor of outcomes has gained growing significance. We evaluated the association between frailty and overall survival (OS) in patients with hepatocellular carcinoma (HCC) ≥60 years. MATERIALS AND METHODS: Older adults ≥60 years with HCC enrolled in a prospective single-institution registry underwent a patient-reported geriatric assessment (GA) covering multiple health domains related to prior to their initial medical oncology appointment. Frailty was measured using a 44-item deficit accumulation frailty index. We categorized patients as robust, pre-frail, and frail using standard cutpoints. The primary outcome was overall survival (OS). Univariable and multivariable models were built to evaluate the association between frailty and OS after adjusting for potential confounders. RESULTS: Total of 116 older adults with HCC with a median age of 67 years were enrolled; 82% male, 27% Black, and 78% with stage III/IV disease. Overall, 19 (16.3%) were robust, 39 (33.6%) pre-frail, and 58 (50.1%) frail. There were 76 patients receiving liver directed therapy. Of these, 13 (17%) were robust, 26 (34%) were pre-frail, and 37 (49%) were frail. Over a median follow up of 0.9 years, 53 patients died. After adjusting for age, stage, etiology, and Child-Pugh class, being frail (vs. robust) was associated with worse OS (hazard ratio (HR) 2.6 [95% CI 1.03-6.56]; p = 0.04). DISCUSSION: Half of the participants in this study were frail, which was independently associated with worse survival in adults ≥60 years of age with HCC. Identification of pre-treatment frailty may allow opportunities to guide treatment decisions and prognostication.

Unidad de Microcirugía: 30 años de experiencia clínica, entrenamiento continuo e investigación / Microsurgery unit: 30 years of clinical experience, continuous training and research

Se describen 30 años de actividades clínicas, entrenamiento e investigación en dos Unidades de Microcirugía. El Servicio de Cirugía Experimental del Centro Médico Nacional (CMN) ''20 de Noviembre'' del ISSSTE y el Departamento de Cirugía de la Facultad de Medicina de la UNAM, ambos de la Ciudad de México; participando en 121 casos clínicos resueltos con técnicas microquirúrgicas en 7 diferentes especialidades. En el ISSSTE, de 1977 a 2007, se han impartido 104 cursos de ''Microcirugía vascular'' y entrenado a 453 cirujanos y residentes de especialidades quirúrgicas. En la UNAM, de 1984 a 2007 se han entrenado 364 alumnos en 67 cursos. Desde 1979 hemos estudiado experimentalmente microprótesis vasculares de origen biológico o sintético de 1 y 2 mm de diámetro, en sustitución de segmentos de aorta y vena cava en rata, generando seis publicaciones. Desde 1996 estamos trabajando el fenómeno de ''angiogénesis'' como tratamiento de miembros inferiores con isquemia crítica. Con base en los trabajos previos, el Comité de Investigación y Ética del CMN aprobó un protocolo de investigación en pacientes con dicha patología, acumulando a la fecha 26 extremidades con trasplante de células endoteliales progenitoras, derivadas de la médula ósea, aplicadas por inyección intramuscular y por vía venosa distal a nivel de vena safena. Del 2004 al 2009 se han amputado 5 extremidades y salvamento de 21; los resultados del estudio se encuentran en evaluación para su publicación. Los hospitales con programas de formación de residentes en especialidades quirúrgicas, deben contar con laboratorio de microcirugía para entrenamiento básico, continuo y diseño de protocolos de investigación, ofreciendo a los pacientes soluciones con técnicas microquirúrgicas.

We describe 30 years of clinical, training and research activities in two Microsurgery Units. The Experimental Surgery Service of the National Medical Center ''20 de Noviembre'' from the ISSSTE (Mexican Health and Welfare Institute for government employees) and the Department of Surgery of the School of Medicine, UNAM (National Autonomous University of Mexico), both located in Mexico City, participating in 121 clinical cases resolved with microsurgical techniques in seven different specialties. At the ISSSTE, from 1977 to 2007, 104 courses on ''Vascular Microsurgery'' have been given and 453 surgeons and residents have been trained in surgical techniques. At the UNAM, from 1984 to 2007, 364 students have been trained in 67 courses. Since 1979, we have experimentally studied vascular microprostheses of biological or synthetic origin of 1 to 2 mm in diameter in substitution of aorta and cava vein segments in rats, giving rise to six publications. Since 1996, we have been studying the ''angiogenesis'' phenomenon as treatment for lower extremities with critical ischemia. Based on previous studies, the Ethics and Research Committee of the ISSSTE-Medical Center approved a research protocol in patients with that pathology, accumulating, until this date, 26 extremities with bone marrow-derived stem cells, applied through intramuscular injection and through distal venous route at the level of the saphenous vein. From 2004 to 2009, five extremities have been amputated and 21 have been saved; the results of the study are being evaluated for publication. Hospitals with programs for the training of residents in surgical specialties must have a laboratory of microsurgery for the basic and continuous training and for the design of research protocols, to be able to offer solutions to the patients with microsurgical techniques.