RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER- ) from four independent cohorts. RANK protein expression was more frequent in ER- tumors, where it associated with poor outcome and poor response to chemotherapy. In ER- breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER- breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER- tumors after menopause.

Immune Checkpoint Inhibitors and Novel Immunotherapy Approaches for Breast Cancer.

PURPOSE OF REVIEW: To critically review the existing evidence on immune checkpoint inhibitors (ICIs) in early-stage and metastatic breast cancer and discuss emerging strategies in the different breast cancer subtypes. RECENT FINDINGS: Immunotherapy has become one of the major milestones in contemporary oncology, revolutionizing the treatment of multiple solid tumors. ICI agents combined with chemotherapy have demonstrated significant efficacy in both early-stage and metastatic triple-negative breast cancer. However, only a subgroup of patients responds to those agents and some associated toxicities, although infrequent, can be life-disabling. Emerging data from immunotherapy studies in advanced hormone receptor-positive (HR +) breast cancer as well as HER2-positive disease are arising with mixed results. Although breast cancer has not classically been considered a hot tumor, ICIs have proven to be effective in a subset of breast cancer patients. However, much remains to be learned, and the identification of new biomarkers beyond PD-L1 expression is essential not only to improve the efficacy of ICI but also to identify patients who can avoid them, together with their toxicities and costs.

Genomic characterization and tumor evolution in paired samples of metaplastic breast carcinoma.

Metaplastic breast carcinomas are a rare and heterogeneous group of tumors (0.5-2%). They are mainly triple negative tumors but they present poorer chemotherapy responses and worse prognosis than other triple negative tumors. The aim of our study was to characterize the molecular profile and tumor evolution in matched (primary-relapse) tumor samples from patients with early-stage metaplastic breast carcinomas who had disease recurrence/progression. We performed genomic profiling of tumor biopsies at least from two different time points of their tumor evolution. Tumor samples were analyzed by DNA-Next Generation Sequencing (Illumina 2 x 75bp) using the Action OncoKitDX panel (Imegen-Health in Code group), which includes point mutations in 50 genes, CNVs, and fusion genes. Only pathogenic and likely pathogenic variants were considered for analysis and they were categorized following the ComPerMed criteria. We analyzed 21 matched tumor samples (8 primary and 13 relapse/progression samples). Genomic profiling of matched tumor samples revealed that mutations present in primary tumors are generally maintained in the relapse/disease progression. We did not find a significant increase in point mutations between primary and relapse/progression samples, although gene amplifications were found more frequently in relapse/progression samples. Tumor samples harbored high frequency of TP53 (100%) and TERT promoter (29%) mutations, and of MYC amplifications (80% of which in relapse/progression samples). No PI3KCA mutations were found, but PTEN variations were enriched in 38% of samples (10% mutations and 28% deletions). FGFR1 amplifications were identified in 13% of samples (primary tumor only). Neither ERBB2 nor EGFR gene amplifications were detected. The most frequent pathogenic alterations occurred in cycle regulation's genes, including TP53 and TERT promoter mutations, and MYC amplifications. Relapse/progression samples were highly enriched for MYC amplification. Larger studies are required to better characterize these tumors, and identify new strategies to improve the prognosis of these patients.

Predictive factors for omitting lymphadenectomy in patients with node-positive breast cancer treated with neo-adjuvant systemic therapy.

A pathologic complete response (pCR) in the axilla occurs in 30%-40% of patients with initially node-positive breast cancer after neo-adjuvant chemotherapy (NACT). Debate persists about whether to perform systematic axillary lymphadenectomy (ALND) in patients with initial node-positive disease and clinical complete response after NACT. We aimed to identify predictive factors of axillary pCR (ypN0) after NACT. This retrospective study analyzed data for all patients with initial biopsy-proven node-positive disease who underwent ALND after NACT between June 2008 and December 2016 at our institution. Clinical and pathologic features, recurrence and specific mortality rates were compared between patients who achieved an axillary pCR and those who did not (ypN0 vs ypN+, respectively). A total of 331 patients were included, of whom 128 (38.7%) became ypN0 after NACT. Among patients with >2 suspicious axillary lymph nodes before treatment, 54 (38%) achieved ypN0 status. The independent predictors of ypN0 were Ki-67 > 30 (OR 1.98; 95% CI, 1.146-3.381), HER2 positivity (OR 2.6; 95% CI, 1.354-5.108), nonluminal molecular-like subtype (OR 4.15; 95% CI, 2.068-5.108), and clinical complete response, defined as negative clinical and ultrasonographic findings (OR 2.8; 95% CI, 1.110-7.081). After a mean follow-up of 61 months, distant disease-free and overall survival rates were higher in patients with ypN0 disease (HR 4.14; 95% CI, 2.03-8.43) than ypN+ patients. Complete clinical response and the presence of nonluminal molecular-like subtypes independently predicted ypN0. Patients meeting these criteria might be suitable form omitting ALND and just performing targeted axillary procedures to patients meeting these criteria.

Embolismo por polimetil-metacrilato posterior a inyección subcutánea en región glútea: a propósito de un caso / Polymethyl-methacrylate embolism after subcutaneous injection in gluteal region: report of a case

El polimetil-metacrilato es un polímero de alta resistencia al impacto, ampliamente utilizado en diferentes campos de la medicina, sin embargo, aún no está clara su indicación como relleno glúteo. A pesar de su aparente inocuidad, se han presentado complicaciones durante su uso como granulomas y nódulos palpables. Se han reportado casos de embolismo pulmonar por polimetil-metacrilato posterior a vertebroplastias. Sin embargo, no se encontró reporte bibliográfico de casos de embolismo pulmonar con su uso en procedimientos estéticos. Presentamos caso de paciente femenino de 31 años de edad, quien 4 horas luego de la inyección de 500 cm3 de polimetil-metacrilato en cada región glútea, presenta disnea en reposo de aparición súbita con tos seca y palpitaciones, disminución de agudeza visual y petequias generalizadas. Se diagnostica probable embolismo pulmonar por polimetil-metacrilato y retinopatía de Purtscher. Existe similitud clínica e imaginología del caso en estudio con embolismo por silicone, y las imágenes del fondo de ojo semejan la obstrucción de pequeñas arteriolas retinianas compatibles con este diagnóstico. Se sugieren nuevas investigaciones en el uso de polimetil-metacrilato como procedimiento estético en pro de la seguridad y en beneficio de los pacientes

Polymethyl-methacrylate is a high impact resistant polymer, widely used in different medicine fields, however its indication in buttock implants is still not clear. Even though its apparent innocuity, it has presented complications like granulomas and palpable nodules. There have been reported cases of pulmonary embolism caused by polimetil-metacrilato secondary to vertebroplasties. However, there have been no bibliographic cases of pulmonary embolism due to its use in aesthetic procedures. We present a case of a woman patient of 31 years old, who 4 hours after 500 cc injection of polymethyl- Methacrylate in each buttock, presents rest dyspnea with abrupt dry cough and palpitations, reduction in visual acuity and generalized petechiae. It is diagnosed probable pulmonary embolism by polimetil-metacrilato and Purtscher retinopathy. There is a clinical and imaginological similitude between this case and silicone embolism and the images of fondoscopy are similar to those of small retinian arteriole obstruction compatible with the diagnosis. Thereby, it is suggested new investigations in the use of polymethyl-methacrylate as esthetic procedure in favor of the patient’s security and benefit