The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes

In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemotherapy achieve a pathological complete response after treatment and more than 90% die due to metastasis formation. The diverse clinical responses and metastatic developments are attributed to extensive intrapatient genetic heterogeneity and tumor evolution acting on this neoplasm. In this work, we aimed to evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease. We sequenced the whole exome of 16 lesions from four patients who did not respond to therapy, and took several follow-up samples, including samples from tumors before and after treatment, as well as from the lymph nodes and skin metastases. We found substantial intrapatient genetic heterogeneity, with a variable tumor mutational composition. Early truncal events were MCL1 amplifications. Metastatic lesions had deletions in RB1 and PTEN, along with TERT, AKT2, and CCNE1 amplifications. Mutational signatures 06 and 12 were mainly detected in skin metastases and lymph nodes. According to phylogenetic analysis, the lymph node metastases occurred at an early stage of TNBC development. Finally, each patient had three to eight candidate driving mutations for targeted treatments. This study delves into the genomic complexity and the phylogenetic and evolutionary development of aggressive TNBC, supporting early metastatic development, and identifies specific genetic alterations associated with a response to targeted therapies.

Skin Nodules as a First Presentation of Synchronous Bilateral Invasive Lobular Breast Carcinoma: A Case Report

The most common cause of skin metastases in adult women is primary breast carcinoma, which comprises about 70% of cases [1]. Skin metastases have non-specific clinical appearances, making it challenging to differentiate them from other benign conditions [1]. We present a case of a 52-year-old female with type II diabetes and a three-month history of refractory skin lesions who did not respond to anti-inflammatory treatment. The patient subsequently complained of a right breast lump, evaluation of which led to the diagnosis of bilateral synchronous invasive lobular carcinoma.

OTME-17. Single cell characterization of the immune microenvironment of melanoma brain and leptomeningeal metastases

Melanoma brain metastases (MBM) and leptomeningeal metastases (LMM) are two manifestations of melanoma dissemination to the CNS with vastly different survival outcomes. Analysis of single cell RNA-Seq data from 43 clinical specimens has uncovered a distinct, immune-suppressed T cell landscape in the LMM microenvironment that is distinct to those of the brain and skin metastases. An LMM patient with an extraordinarily long survival and documented response to therapy demonstrated an immune repertoire that was distinct from those of typical poor survivors and more similar to CSF from non-LMM donors. Analysis of serial specimens over the course of therapy demonstrated reductions in melanoma cells and macrophages, coupled with increased levels of T cells and dendritic cells in the CSF of the extraordinary responder, whereas poor survivors showed no improvement in T cell responses. In MBM patients, targeted therapy and immunotherapy was associated with increased immune infiltrate, with similar T cell transcriptional diversity noted between skin metastases and MBM - suggestive of immune cell trafficking into the brain. Treatment with targeted therapy was associated with an enrichment of CD8 T cells. Immunotherapy was associated with a more diverse lymphocyte landscape and higher numbers of antibody-producing cells. These findings were confirmed by multiplexed staining of patient specimens and using an immune-competent mouse model of MBM. Correlation analysis across the entire immune landscape identified the presence of a rare, novel population of dendritic cells (DC3s) to be correlated with increased overall survival, regardless of disease site/treatment. The presence of DC3s positively regulated the immune environment of both patient samples and preclinical melanoma models through modulation of activated T cells and MHC expression in the tumor. Our study provides the first comprehensive atlas of two distinct sites of melanoma CNS metastases and identifies rare populations of cells that underlie the biology of this devastating disease.

Gastric Cancer Case with Skin Metastases and Scleroderma-like Paraneoplastic Rheumatic Syndrome

In this case report, we will describe a gastric cancer case, which presented with rare manifestation of skin metastases and unrelated to the mechanical impact of distant metastases scleroderma-like paraneoplastic rheumatic syndrome. 72-year-old woman was referred to hospital with complaints gradual during the time period of one year. Skin changes included - thickening, dermal induration mostly seen on her upper body – arms, neck, face, chest and abdominal wall, causing contracture and limited movements. In the area of her upper arms, neck and upper part of her chest multiple small, painless, hard subcutaneous nodules were present and hyperpigmentation in the neck area. There were no signs of Raynaud’s phenomenon, telangiectasia, alopecia, hypopigmentation or muscle weakness and pain. Upon further examination and multiple biopsies (gastric and skin nodules) poorly differentiated gastric carcinoma was confirmed with peritoneal dissemination, ascites, cutaneous, subcutaneous metastasis and scleroderma-like paraneoplastic syndrome. After systemic treatment for gastric cancer patient showed improvement of paraneoplastic syndrome manifestations, quality of life and radiologically stable disease.