Breaking paradigms: Long non-coding RNAs forming gene fusions with potential implications in cancer.

Long non-coding RNAs (lncRNAs) are non-coding RNAs longer than 200 nucleotides with dynamic regulatory functions. They interact with a wide range of molecules such as DNA, RNA, and proteins to modulate diverse cellular functions through several mechanisms and, if deregulated, they can lead to cancer development and progression. Recently, it has been described that lncRNAs are susceptible to form gene fusions with mRNAs or other lncRNAs, breaking the paradigm of gene fusions consisting mainly of protein-coding genes. However, their biological significance in the tumor phenotype is still uncertain. Therefore, their recent identification opens a new line of research to study their biological role in tumorigenesis, and their potential as biomarkers with clinical relevance or as therapeutic targets. The present study aimed to review the lncRNA fusions identified so far and to know which of them have been associated with a potential function. We address the current challenges to deepen their study as well as the reasons why they represent a future therapeutic window in cancer.

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.

Comprehensive Genomic Profile of Heterogeneous Long Follow-Up Triple-Negative Breast Cancer and Its Clinical Characteristics Shows DNA Repair Deficiency Has Better Prognostic.

Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which promotes a clinical heterogeneity that further complicates treatment. We performed a detailed whole exome sequencing profile of 29 Mexican patients with long follow-up TNBC to identify genomic alterations associated with overall survival (OS), disease-free survival (DFS), and pathologic complete response (PCR), with the aim to define their role as molecular predictive factors of treatment response and prognosis. We detected 31 driver genes with pathogenic mutations in TP53 (53%), BRCA1/2 (27%), CDKN1B (9%), PIK3CA (9%), and PTEN (9%), and 16 operative mutational signatures. Moreover, tumors with mutations in BRCA1/2 showed a trend of sensitivity to platinum salts. We found an association between deficiency in DNA repair and surveillance genes and DFS. Across all analyzed tumors we consistently found a heterogeneous molecular complexity in terms of allelic composition and operative mutational processes, which hampered the definition of molecular traits with clinical utility. This work contributes to the elucidation of the global molecular alterations of TNBC by providing accurate genomic data that may help forthcoming studies to improve treatment and survival. This is the first study that integrates genomic alterations with a long follow-up of clinical variables in a Latin American population that is an underrepresented ethnicity in most of the genomic studies.

Identification of miRNA Master Regulators in Breast Cancer.

Breast cancer is the neoplasm with the highest number of deaths in women. Although the molecular mechanisms associated with the development of this tumor have been widely described, metastatic disease has a high mortality rate. In recent years, several studies show that microRNAs or miRNAs regulate complex processes in different biological systems including cancer. In the present work, we describe a group of 61 miRNAs consistently over-expressed in breast cancer (BC) samples that regulate the breast cancer transcriptome. By means of data mining from TCGA, miRNA and mRNA sequencing data corresponding to 1091 BC patients and 110 normal adjacent tissues were downloaded and a miRNA-mRNA network was inferred. Calculations of their oncogenic activity demonstrated that they were involved in the regulation of classical cancer pathways such as cell cycle, PI3K-AKT, DNA repair, and k-Ras signaling. Using univariate and multivariate analysis, we found that five of these miRNAs could be used as biomarkers for the prognosis of overall survival. Furthermore, we confirmed the over-expression of two of them in 56 locally advanced BC samples obtained from the histopathological archive of the National Cancer Institute of Mexico, showing concordance with our previous bioinformatic analysis.

miRNA profile obtained by next­generation sequencing in metastatic breast cancer patients is able to predict the response to systemic treatments.

Metastatic breast cancer (MBC) is a challenge for oncologists, and public efforts should focus on identifying additional molecular markers and therapeutic management to improve clinical outcomes. Among all diagnosed cases of breast cancer (BC; approximately 10%) involve metastatic disease; notably, approximately 40% of patients with early­stage BC develop metastasis within 5 years. The management of MBC consists of systemic therapy. Despite different treatment options, the 5­year survival rate is <20%, which may be due to a lack of response with de novo or acquired resistance. MicroRNAs (miRNAs or miRs) are promising biomarkers as they are readily detectable and have a broad spectrum and potential clinical applications. The aim of this study was to identify a miRNA profile for distinguishing patients with MBC who respond to systemic treatment. Patients with MBC were treated according to the National Comprehensive Cancer Network guidelines. We performed miRNA­Seq on 9 primary tumors using the Thermo Fisher Scientific Ion S5 system. To obtain global miRNA profiles, we carried out differentially expressed gene elimination strategy (DEGES) analysis between the responsive and non­responsive patients. The results identified a profile of 12 miRNAs associated with the response to systemic treatment. The data were validated in an independent cohort (TCGA database). Based on the results, the upregulation of miR­342­3p and miR­187­3p was associated with the response to systemic treatment, and with an increased progression­free survival (PFS) and overall survival (OS); by contrast, the downregulation of miR­301a­3p was associated with a higher PFS and OS. On the whole, the findings of this study indicate that these miRNAs may serve as biomarkers for the response to systemic treatment or the prognosis of patients with MBC. However, these data should be validated experimentally in other robust cohorts and using different specimens before implementing these miRNAs as biomarkers in clinical practice to benefit this group of patients.

A Case Series of Breast Metastases from Different Extramammary Malignancies and Their Literature Review.

Metastasis to the breast from all other primary sites is unusual. Twelve patients were diagnosed between 2007 and 2017 at National Cancer Institute, Mexico. Solitary or multiple masses, round or oval, and hypoechoic and solid lesions with posterior acoustic shadowing were patterns commonly reported in these patients; other arrangements include diffuse involvement of the breast simulating an inflammatory carcinoma. The development of a breast metastasis is revealed, in our experience, as a negative prognostic factor. Thus, the radiologist should know about the varied appearance of metastatic breast lesions and provide radiopathological correlations when available.

Ki67 Changes Identify Worse Outcomes in Residual Breast Cancer Tumors After Neoadjuvant Chemotherapy.

BACKGROUND: Several breast cancer (BC) trials have adopted pathological complete response (pCR) as a surrogate marker of long-term treatment efficacy. In patients with luminal subtype, pCR seems less important for outcome prediction. BC is a heterogeneous disease, which is evident in residual tumors after neoadjuvant-chemotherapy (NAC). This study evaluates changes in Ki67 in relation to disease-free survival (DFS) and overall survival (OS) in patients without pCR. SUBJECTS, MATERIALS, AND METHODS: Four hundred thirty-five patients with stage IIA-IIIC BC without pCR after standard NAC with anthracycline and paclitaxel were analyzed. We analyzed the decrease or lack of decrease in the percentage of Ki67-positive cells between core biopsy samples and surgical specimens and correlated this value with outcome. RESULTS: Twenty-five percent of patients presented with luminal A-like tumors, 45% had luminal B-like tumors, 14% had triple-negative BC, 5% had HER2-positive BC, and 11% had triple-positive BC. Patients were predominantly diagnosed with stage III disease (52%) and high-grade tumors (46%). Median Ki67 level was 20% before NAC, which decreased to a median of 10% after NAC. Fifty-seven percent of patients had a decrease in Ki67 percentage. Ki67 decrease significantly correlated with better DFS and OS compared with no decrease, particularly in the luminal B subgroup. Multivariate analysis showed that nonreduction of Ki67 significantly increased the hazard ratio of recurrence and death by 3.39 (95% confidence interval [CI] 1.8-6.37) and 7.03 (95% CI 2.6-18.7), respectively. CONCLUSION: Patients without a decrease in Ki67 in residual tumors after NAC have poor prognosis. This warrants the introduction of new therapeutic strategies in this setting. IMPLICATIONS FOR PRACTICE: This study evaluates the change in Ki67 percentage before and after neoadjuvant chemotherapy (NAC) and its relationship with survival outcomes in patients with breast cancer who did not achieve complete pathological response (pCR). These patients, a heterogeneous group with diverse prognoses that cannot be treated using a single algorithm, pose a challenge to clinicians. This study identified a subgroup of these patients with a poor prognosis, those with luminal B-like tumors without a Ki67 decrease after NAC, thus justifying the introduction of new therapeutic strategies for patients who already present a favorable prognosis (luminal B-like with Ki67 decrease).

68Ga-DTPA Anti-HER2 positron emission tomography/CT successfully predicts the overexpression of human epidermal growth factor receptor in lung metastases from breast cancer.

Molecular identification of a metastatic tumour without the inconvenience of a biopsy and the time required for pathological characterization is possible using molecular imaging. Here, we present the case of a patient with breast cancer in whom 68Ga-diethylenetriamine pentaacetic acid anti-human epidermal growth factor receptor 2 positron emission tomography-CT was successfully employed to characterize the expression of human epidermal growth factor receptor 2 in metastatic sites.

An Uncommon Case of Bilateral Breast Enlargement Diagnosed as Tumoral Pseudoangiomatous Stromal Hyperplasia: Imaging and Pathological Findings.

The incidence of reported pseudoangiomatous stromal hyperplasia (PASH), as well as the variability and severity of clinical presentations, is increasing in the literature. In parallel, several authors posit the need for an improved classification of PASH to avoid possible variables associated with this diagnosis. Here, we present a 25-year-old woman with PASH accompanied by severe bilateral and symmetrical breasts enlargement, highlighting an uncommon clinical presentation of PASH as much as the careful interdisciplinary review and correlation of histology and all available imaging studies to confirm the definitive diagnosis.