A pan-cancer clinical platform to predict immunotherapy outcomes and prioritize immuno-oncology combinations in early-phase trials.

Background: Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing.

Methods: We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types.

Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients.

MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors.

RAGE/SNAIL1 signaling drives epithelial-mesenchymal plasticity in metastatic triple-negative breast cancer.

Epithelial/Mesenchymal (E/M) plasticity plays a fundamental role both in embryogenesis and during tumorigenesis. The receptor for advanced glycation end products (RAGE) is a driver of cell plasticity in fibrotic diseases; however, its role and molecular mechanism in triple-negative breast cancer (TNBC) remains unclear. Here, we demonstrate that RAGE signaling maintains the mesenchymal phenotype of aggressive TNBC cells by enforcing the expression of SNAIL1.

A Comprehensive Biomarker Analysis of Microsatellite Unstable/Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy.

The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (: 9 patients) or IT-resistant group (: 7 patients), respectively.

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAF metastatic colorectal cancer.

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAF colorectal cancer (mCRC). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRC treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors.

Performance of 16S Metagenomic Profiling in Formalin-Fixed Paraffin-Embedded versus Fresh-Frozen Colorectal Cancer Tissues.

Formalin-fixed, paraffin-embedded (FFPE) tissues represent the most widely available clinical material to study colorectal cancer (CRC). However, the accuracy and clinical validity of FFPE microbiome profiling in CRC is uncertain. Here, we compared the microbial composition of 10 paired fresh-frozen (FF) and FFPE CRC tissues using 16S rRNA sequencing and RNA-ISH.

The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers.

The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples).

A CT-based Radiomics Signature Is Associated with Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors.

Background Reliable predictive imaging markers of response to immune checkpoint inhibitors are needed. Purpose To develop and validate a pretreatment CT-based radiomics signature to predict response to immune checkpoint inhibitors in advanced solid tumors. Materials and Methods In this retrospective study, a radiomics signature was developed in patients with advanced solid tumors (including breast, cervix, gastrointestinal) treated with anti-programmed cell death-1 or programmed cell death ligand-1 monotherapy from August 2012 to May 2018 (cohort 1).

Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer.

Novel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification).

Evolving Landscape of Molecular Prescreening Strategies for Oncology Early Clinical Trials.

Most academic precision oncology programs have been designed to facilitate enrollment of patients in early clinical trials with matched targeted agents. Over the last decade, major changes were seen both in the targetable molecular alteration landscape and in drug development trends. In this article, we describe how the Vall d'Hebron Institute of Oncology molecular prescreening program adapted to a dynamic model of biomarker-drug codevelopment.

Sequential immunohistochemistry and virtual image reconstruction using a single slide for quantitative KI67 measurement in breast cancer.

Objective: Ki67 is a prognostic and predictive marker in breast cancer (BC). However, manual scoring (MS) by visual assessment suffers from high inter-observer variability which limits its clinical use. Here, we developed a new digital image analysis (DIA) workflow, named KiQuant for automated scoring of Ki67 and investigated its equivalence with standard pathologist's assessment.

Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer.

Protein biomarkers are widely used in cancer diagnosis, prognosis, and prediction of treatment response. Here we introduce the use of targeted multiplex proteomics (TMP) as a tool to simultaneously measure a panel of 54 proteins involved in oncogenic, tumour suppression, drug metabolism and resistance, in patients with metastatic colorectal cancer (mCRC). TMP provided valuable diagnostic information by unmasking an occult neuroendocrine differentiation and identifying a misclassified case based on abnormal proteins phenotype.

HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade.

Background: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.

Methods: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090).

p95HER2-T cell bispecific antibody for breast cancer treatment.

T cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the T cell receptor and to tumor-associated or tumor-specific antigens. The receptor tyrosine kinase HER2 is a tumor-associated antigen in ~25% of breast cancers. TCBs targeting HER2 may result in severe toxicities, likely due to the expression of HER2 in normal epithelia.

Analysis of persistence and antibiotic response in colorectal cancer.

Colorectal cancers comprise a complex mixture of malignant cells, nontransformed cells, and microorganisms. is among the most prevalent bacterial species in colorectal cancer tissues. Here we show that colonization of human colorectal cancers with and its associated microbiome-including , , and species-is maintained in distal metastases, demonstrating microbiome stability between paired primary and metastatic tumors.

MRI features of cotyledonoid dissecting leiomyoma of the uterus.

Imaging evaluation of uterine masses is important to assess the type of lesion and to target surgery, if surgical excision is necessary. This can be decisive in fertile women with benign masses resembling malignancies, in order to avoid overtreatment. In this study, the magnetic resonance imaging (MRI) appearance of cotyledonoid dissecting leiomyoma of the uterus, a rare benign variant of leiomyoma mimicking malignancy, is presented.

The differential role of L1 in ovarian carcinoma and normal ovarian surface epithelium.

Epithelial ovarian carcinoma (EOC) arises from the ovarian surface epithelium (OSE), a monolayer of poorly differentiated epithelial cells that lines the ovary. The molecular mechanisms underlying EOC invasion into the surrounding stroma and dissemination to the peritoneum and to retroperitoneal lymph nodes are still unclear. Here, we analyzed the expression and the functional role of the cell adhesion molecule L1 during EOC development.

Measurement by multidetector CT scan of the volume of hypopharyngeal and laryngeal tumours: accuracy and reproducibility.

The purpose of this study was to register the accuracy and reproducibility of the multidetector computed tomography (MDCT) estimate of hypopharyngeal and laryngeal tumor volumes. Eighteen consecutive patients with larynx or hypopharynx squamous cell carcinoma were enrolled in this prospective trial, scheduled for surgery and examined by MDCT. A total of 72 tumor volume measurements were reported by two different operators, one of them in three different sessions, using the sum-of-areas method.

Metaplastic carcinoma of the breast, an unusual disease with worse prognosis: the experience of the European Institute of Oncology and review of the literature.

Background: Metaplastic carcinoma of the breast is a rare form of breast cancer and has an uncertain prognostic significance. The purpose of the present study was to compare the clinical course, and prognosis, between this type of tumor and poorly differentiated ductal carcinoma.

Patients And Methods: We analyzed 37 cases of metaplastic carcinoma of the breast treated at our institution (European Institute of Oncology in Milan, Italy) between 1997 and 2004, comparing them with 72 cases (control group) of poorly differentiated ductal carcinoma.

The transactivating isoforms of p63 are overexpressed in high-grade follicular lymphomas independent of the occurrence of p63 gene amplification.

p63 is a p53-related gene mapping to 3q28 that codes for multiple mRNA transcripts with (TA-p63) or without (DeltaN-p63) transactivating effects on genes that promote cell differentiation and apoptosis. We analysed p63 alterations by immunohistochemistry, quantitative real-time RT-PCR and FISH in a series of 45 follicular lymphomas (FL). None of the tumours showed immunoreactivity for the p40 antibody, which recognizes only the truncated isoforms of p63, or DeltaN-p63 mRNA expression.

Immunoreactivity for cyclin D3 is frequently detectable in high-grade primary gastric lymphomas in the absence of the t(6;14)(p21.1;q32.3) chromosomal translocation.

Cyclin D3 plays a pivotal role in controlling the physiological progression from the G1 to the S phase of the cell cycle. Recent data suggest that cyclin D3 may be deregulated in extranodal non-Hodgkin's lymphomas (NHLs) as a consequence of the t(6;14)(p21.1;q32.

Molecular and immunohistochemical analysis of HER2/neu oncogene in synovial sarcoma.

Amplification and/or overexpression of HER2/neu have been documented in many types of epithelial tumor and recently has been reported in sarcomas, particularly in osteosarcomas. But the role of HER2/neu alterations in soft tissue tumors remains poorly understood. Thus the present study investigates the expression of HER2/neu in 13 patients with synovial sarcoma (SS).