Investigating the Pathogenicity of Uncommon KRAS Mutations and Their Association with Clinicopathologic Characteristics in Patients with Colorectal Cancer.

Kirsten rat sarcoma viral oncogene homolog (KRAS) somatic mutations occur in 30% to 40% of patients with colorectal cancer (CRC). These were thought to equally affect prognosis and resistance to anti-epidermal growth factor receptor agents; however, recent data show the activity of KRAS-G12C and pan-RAS inhibitors. The effects of uncommon KRAS (uKRAS) variants are largely unexplored.

Deep learning algorithm on H&E whole slide images to characterize alterations frequency and spatial distribution in breast cancer.

The tumor suppressor is frequently mutated in hormone receptor-negative, HER2-positive breast cancer (BC), contributing to tumor aggressiveness. Traditional ancillary methods like immunohistochemistry (IHC) to assess functionality face pre- and post-analytical challenges. This proof-of-concept study employed a deep learning (DL) algorithm to predict mutational status from H&E-stained whole slide images (WSIs) of BC tissue.

Detecting BRAF mutations in colorectal cancer in clinical practice: An Italian experts' position paper.

BRAF p.V600E exon 15 hotspot mutation can identify a molecular subgroup of metastatic colorectal cancer (mCRC) patients exhibiting poor prognosis under the conventional chemotherapy regimen. Recently, the chemotherapy-free combination of encorafenib and cetuximab has been approved as the standard of care for previously treated BRAF p.

Molecular tumor board in patients with metastatic breast cancer.

Purpose: Comprehensive genomic profiling is becoming increasingly important in the management of patients with metastatic breast cancer (mBC). Real-world clinical outcomes from applying molecular tumor boards (MTBs) recommendations in this context remain limited. Accordingly, we conducted a retrospective, single-institution analysis to evaluate the clinical impact of discussing patients affected by mBC at the MTB.

Co-Occurring Driver Genomic Alterations in Advanced Non-Small-Cell Lung Cancer (NSCLC): A Retrospective Analysis.

Actionable driver mutations account for 40-50% of NSCLC cases, and their identification clearly affects treatment choices and outcomes. Conversely, non-actionable mutations are genetic alterations that do not currently have established treatment implications. Among co-occurring alterations, the identification of concurrent actionable genomic alterations is a rare event, potentially impacting prognosis and treatment outcomes.

Concurrent presence of primary hemangioma and breast cancer metastasis within a lymph node: a case report inspired by the legacy of Professor Juan Rosai.

Secondary neoplastic lesions in lymph nodes are predominantly metastases from solid tumors, whereas primary lymph node hemangiomas are exceptionally uncommon, with only 24 well-documented cases in the literature. Histologically, they are characterized by endothelial cells that may appear flattened or enlarged, with variable vascular density, and the presence of stromal elements. Notably, the concurrent presence of a primary hemangioma and a metastasis from breast cancer - the latter being the most prevalent secondary lesion in axillary lymph nodes - represents an unprecedented observation.

Standardized molecular pathology workflow for ctDNA-based ESR1 testing in HR+/HER2- metastatic breast cancer.

Mutations in the estrogen receptor alpha gene (ESR1) can lead to resistance to endocrine therapy (ET) in hormone receptor-positive (HR+)/ HER2- metastatic breast cancer (MBC). ESR1 mutations can be detected in up to 40 % of patients pretreated with ET in circulating tumor DNA (ctDNA). Data from prospective randomized trials highlight those patients with HR+/HER2- MBC with detectable ESR1 mutations experience better outcomes when receiving novel selective estrogen receptor degraders (SERDs).

Invasive lobular breast cancer: Focus on prevention, genetics, diagnosis, and treatment.

Invasive lobular cancer (ILC) is the most common of the breast cancer special types, accounting for up to 15% of all breast malignancies. The distinctive biological features of ILC include the loss of the cell adhesion molecule E-cadherin, which drives the tumor's peculiar discohesive growth pattern, with cells arranged in single file and dispersed throughout the stroma. Typically, such tumors originate in the lobules, are more commonly bilateral compared to invasive ductal cancer (IDC) and require a more accurate diagnostic examination through imaging.

Early Breast Cancer Risk Assessment: Integrating Histopathology with Artificial Intelligence.

Effective risk assessment in early breast cancer is essential for informed clinical decision-making, yet consensus on defining risk categories remains challenging. This paper explores evolving approaches in risk stratification, encompassing histopathological, immunohistochemical, and molecular biomarkers alongside cutting-edge artificial intelligence (AI) techniques. Leveraging machine learning, deep learning, and convolutional neural networks, AI is reshaping predictive algorithms for recurrence risk, thereby revolutionizing diagnostic accuracy and treatment planning.

Deleterious alterations in homologous recombination repair genes and efficacy of platinum-based chemotherapy in biliary tract cancers.

Background: Platinum-based chemotherapy represents the standard first-line treatment for biliary tract cancers (BTC). Deficits in genes involved in the homologous recombination (HR) and DNA damage response (DDR) may confer higher sensitivity to platinum agents.

Methods: We retrospectively included patients affected by BTC from 2 Italian institutions.

Clinical actionability of BRCA2 alterations in uterine leiomyosarcoma: a molecular tumor board case report and a cBioPortal comprehensive analysis.

Background: Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors.

Methods: To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies.

CDH1 Genotype Exploration in Women With Hereditary Lobular Breast Cancer Phenotype.

Importance: Pathogenic or likely pathogenic (P/LP) germline CDH1 variants are associated with risk for diffuse gastric cancer and lobular breast cancer (LBC) in the so-called hereditary diffuse gastric cancer (HDGC) syndrome. However, in some circumstances, LBC can be the first manifestation of this syndrome in the absence of diffuse gastric cancer manifestation.

Objectives: To evaluate the frequency of germline CDH1 variants in women with the hereditary LBC (HLBC) phenotype, somatic CDH1 gene inactivation in germline CDH1 variant carriers' tumor samples, and the association of genetic profiles with clinical-pathological data and survival.

Expression of immune-related genes and breast cancer recurrence in women with ductal carcinoma in situ.

Background And Aim: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer with highly variable clinical behavior, but risk stratification is still challenging. We sought to identify immune-related gene expression signatures of pure DCIS associated with different risks of breast cancer recurrence.

Methods: A retrospective nested case-control study of 143 pure DCIS was performed including 70 women with subsequent ipsilateral breast event (IBE, in situ or invasive; cases) and 73 DCIS women with no IBE and matched for age, tumor size, treatment, hormone receptors/HER2 status, and follow-up time (controls).

Digital counting of tissue cells for molecular analysis: the QuANTUM pipeline.

The estimation of tumor cellular fraction (TCF) is a crucial step in predictive molecular pathology, representing an entry adequacy criterion also in the next-generation sequencing (NGS) era. However, heterogeneity of quantification practices and inter-pathologist variability hamper the robustness of its evaluation, stressing the need for more reliable results. Here, 121 routine histological samples from non-small cell lung cancer (NSCLC) cases with complete NGS profiling were used to evaluate TCF interobserver variability among three different pathologists (pTCF), developing a computational tool (cTCF) and assessing its reliability vs ground truth (GT) tumor cellularity and potential impact on the final molecular results.

Cancers of Unknown Primary Origin: Real-World Clinical Outcomes and Genomic Analysis at the European Institute of Oncology.

Background: Cancer of unknown primary origin (CUP) poses a significant challenge due to poor clinical outcomes and limited treatment options. As such, further definition of clinicopathological factors and genomic profile to better adapt treatment strategies is required.

Methods: Medical records were interrogated to retrospectively include CUP with available clinical and genomics data at the European Institute of Oncology.

testing in hormone receptor-positive/HER2-negative metastatic breast cancer: real-world data from Italian molecular pathology laboratories.

gene mutations occur in approximately 40% of hormone receptor-positive/HER2-negative (HR/HER2) metastatic breast cancers (MBCs), electing them to targeted therapy. Testing status is complex due to selection of biological specimen and testing method. This work investigates real-life experience on testing in HR/HER2 MBC.

PD-L1 testing in metastatic triple-negative breast cancer: Interobserver and interplatform reproducibility of CE-IVD assays for CPS and IC scores.

PD-L1 test is recommended in different types of tumors to select patients eligible for immune checkpoint inhibitors (ICI) therapy. Several factors make this test challenging in metastatic triple-negative breast cancer (mTNBC). Different assays and platforms are available, each associated with distinct scoring systems and threshold values specific to the ICI compound used, i.

Real-world use of multigene signatures in early breast cancer: differences to clinical trials.

Purpose: In Italy, Lombardy was the first region to reimburse multigene assays (MGAs) for patients otherwise candidates for chemotherapy. This is a real-world experience of MGAs usage in six referral cancer centers in Lombardy.

Methods: Among MGAs, Oncotype DX (RS) was used in 97% of cases.

Non-Small Cell Lung Cancer Testing on Reference Specimens: An Italian Multicenter Experience.

Introduction: Biomarker testing is mandatory for the clinical management of patients with advanced non-small cell lung cancer (NSCLC). Myriads of technical platforms are now available for biomarker analysis with differences in terms of multiplexing capability, analytical sensitivity, and turnaround time (TAT). We evaluated the technical performance of the diagnostic workflows of 24 representative Italian institutions performing molecular tests on a series of artificial reference specimens built to mimic routine diagnostic samples.

Clinicopathological characteristics of multiple-classifier endometrial cancers: a cohort study and systematic review.

Background: Endometrial cancers with more than one molecular feature- mutations (POLEmut), mismatch repair protein deficiency (MMRd), p53 abnormality (p53abn)-are called 'multiple classifiers'.

Objective: To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them.

Methods: Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included.

Standardized and simplified reporting of next-generation sequencing results in advanced non-small-cell lung cancer: Practical indications from an Italian multidisciplinary group.

Molecular biomarker testing is increasingly becoming standard of care for advanced non-small cell lung cancer (NSCLC). Tissue and liquid biopsy-based next-generation sequencing (NGS) is now highly recommended and has become an integral part of the routine management of advanced NSCLC patients. This highly sensitive approach can simultaneously and efficiently detect multiple biomarkers even in scant samples.

Advances in Early Breast Cancer Risk Profiling: From Histopathology to Molecular Technologies.

Early breast cancer (BC) is the definition applied to breast-confined tumors with or without limited involvement of locoregional lymph nodes. While risk stratification is essential for guiding clinical decisions, it can be a complex endeavor in these patients due to the absence of comprehensive guidelines. Histopathological analysis and biomarker assessment play a pivotal role in defining patient outcomes.