Case report: High grade serous fallopian tube carcinoma with rare gene fusion presenting as widespread peritoneal carcinomatosis.

The discovery of gene fusions involving Neuregulin-1 () within solid tumors has important therapeutic implications, as they are being actively explored as targets for emerging ERBB/ERBB2/ERBB3-directed anti-cancer agents. fusions are very uncommon across all tumor types and are infrequently documented in the medical literature. We report a female patient presenting with widespread peritoneal carcinomatosis diagnosed as high grade serous fallopian tube carcinoma, which harbored a previously undescribed :: fusion.

Analysis of Concordance Between Next-Generation Sequencing Assessment of Microsatellite Instability and Immunohistochemistry-Mismatch Repair From Solid Tumors.

Purpose: The new CAP guideline published in August 2022 recommends using immunohistochemistry (IHC) to test for mismatch repair defects in gastroesophageal (GE), small bowel (SB), or endometrial carcinoma (EC) cancers over next-generation sequencing assessment of microsatellite instability (NGS-MSI) for immune checkpoint inhibitor (ICI) therapy eligibility and states there is a preference to use IHC over NGS-MSI in colorectal carcinoma (CRC).

Methods: We assessed the concordance of NGS-MSI and IHC-MMR from a very large cohort across the spectrum of solid tumors.

Results: Of the over 190,000 samples with both NGS-MSI and IHC-MMR about 1,160 were initially flagged as discordant.

Evidence for Unified Assessment Criteria of HER2 Immunohistochemistry in Colorectal Carcinoma.

Human epidermal growth factor receptor-2 (HER2) expression is an important biomarker for the management of RAS wild-type metastatic colorectal carcinoma (CRC). Immunohistochemistry (IHC) with reflex in situ hybridization (ISH) is accepted as a standard method of assessment, yet there are currently the following 2 sets of criteria used to interpret results: the HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) criteria and the MyPathway criteria. The HER2 Amplification for Colorectal Cancer Enhanced Stratification criteria require ISH confirmation when IHC staining is 3+ in 10% to 49% of cells, whereas the MyPathway criteria mirror those for gastric HER2 assessment and do not recommend ISH confirmation in the previously referenced scenario.

Multiomic Characterization and Molecular Profiling of Nuclear Protein in Testis Carcinoma.

Purpose: Nuclear protein in testis carcinoma (NC) is an underdiagnosed and aggressive squamous/poorly differentiated cancer characterized by rearrangement of the gene on chromosome 15q14. Co-occurring alternations have not been fully characterized.

Methods: We analyzed the genomic and immune landscape of 54 cases of NC that underwent DNA- and RNA-based NGS sequencing (Caris).

Characterizing the genomic landscape through the lens of FOLR1 status in low and high grade serous ovarian carcinoma.

Objective: Targeted therapy in folate receptor alpha (FOLR1)-positive high grade serous ovarian carcinoma (HGSOC) is now a mainstay for platinum-resistant disease. However, the rate of FOLR1-positivity in low grade serous ovarian carcinoma (LGSOC) is not well documented. Less common than HGSOC, LGSOC tends to respond poorly to traditional platinum-based chemotherapeutic regimens, particularly in recurrence.

Genomic and transcriptomic landscape of HER2-low breast cancer.

Background: Novel agents have expanded the traditional HER2 definitions to include HER2-Low (HER2L) Breast Cancer (BC). We sought to evaluate the distinct molecular characteristics of HER2L BC to understand potential clinical/biologic factors driving resistance and clinical outcomes.

Methods: Retrospective analysis was performed on 13,613 BC samples, tested at Caris Life Sciences via NextGen DNA/RNA Sequencing.

Clinical and Genomic Features of Classical and Basal Transcriptional Subtypes in Pancreatic Cancer.

Purpose: Transcriptional profiling of pancreatic cancers has defined two main transcriptional subtypes: classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX and gemcitabine plus nab-paclitaxel by transcriptional subtype.

Experimental Design: We examined 8,743 patients with RNA sequencing from pancreatic cancers performed at Caris Life Sciences.

Molecular profiling METex14+ non-small cell lung cancer (NSCLC): Impact of histology.

Objectives: MET exon 14 skipping alterations (METex14+) represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) with distinct biological and genomic features. We characterized this heterogeneity in a large cohort, integrating genomic and transcriptomic profiling with clinical outcomes, to elucidate the histologic and molecular traits and survival patterns of METex14+ NSCLC.

Materials And Methods: NSCLC tissue samples (n = 28,739) underwent DNA-based next-generation sequencing (592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-sequencing including whole transcriptome sequencing (WTS, NovaSeq), and PD-L1 IHC (Dako 22C3) at Caris Life Sciences.

Consensus molecular subtyping of metastatic colorectal cancer expands biomarker-directed therapeutic benefit for patients with CMS1 and CMS2 tumors.

Background: We developed a whole transcriptome sequencing (WTS)-based Consensus Molecular Subtypes (CMS) classifier using FFPE tissue and investigated its prognostic and predictive utility in a large clinico-genomic database of CRC patients (n = 24,939).

Methods: The classifier was trained against the original CMS datasets using an SVM model and validated in an independent blinded TCGA dataset (88.0% accuracy).

Detection of human papillomavirus (HPV) in malignant melanoma.

The most common type of melanoma is cutaneous melanoma (CM). The predominant mutational signature is that of ultraviolet radiation (UVR) exposure. The Cancer Genome Atlas (TCGA) molecular classification includes four major subtypes of CM based on common genetic alterations involving the following genes: BRAF, NRAS, and NF1, with a small fraction being "triple" wild-type.

Multiomic Characterization Reveals a Distinct Molecular Landscape in Young-Onset Pancreatic Cancer.

Purpose: Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between patients with young-onset pancreatic cancer (YOPC; younger than 50 years) and patients with average-onset pancreatic cancer (AOPC; 70 years and older).

Methods: We analyzed matched whole-transcriptome and DNA sequencing data from 2,430 patient samples (YOPC, n = 292; AOPC, n = 2,138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline.

Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 "Lynch-like" mismatch repair gene mutation.

Objectives: To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated ("Lynch-like") endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes.

Methods: 1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter.

Opposing Roles of Mutations in Human Prostate and Endometrial Cancers.

Purpose: Recurrent gene mutations in speckle-type POZ protein (), the substrate-binding component of E3 ubiquitin ligase, are associated with tumor progression in prostate and endometrial cancers. Here, we characterized mutations in these cancers and explored their association with molecular and immune signatures and patient outcomes.

Methods: There were 7,398 prostate cancer and 19,188 endometrial cancer samples analyzed for clinical and molecular profiles at Caris Life Sciences.

The Genomic Landscape of Vulvar Squamous Cell Carcinoma.

Vulvar squamous cell cancer (VSC) accounts for 90% of vulvar cancers. Next-generation sequencing studies of VSC imply human papillomavirus (HPV) and p53 status play separate roles in carcinogenesis and prognosis. We sought to describe the genomic landscape and analyze the immunologic profiles of VSC with respect to HPV and p53 status.

Multi-omic characterization reveals a distinct molecular landscape in young-onset pancreatic cancer.

Purpose: Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; <50-yrs.) and average-onset pancreatic cancer (AOPC; ≥70-yrs.) patients.

HER2+ endometrioid endometrial cancer possesses distinct molecular and immunologic features associated with a more active immune microenvironment and worse prognosis.

Objective: HER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies.

Methods: 2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ).

Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells.

Unlabelled: The rarity of malignant Hodgkin and Reed Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL) limits the ability to study the genomics of cHL. To circumvent this, our group has previously optimized fluorescence-activated cell sorting to purify HRS cells. Using this approach, we now report the whole-genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events leading to cHL.

Mutational analysis of microsatellite-stable gastrointestinal cancer with high tumour mutational burden: a retrospective cohort study.

Background: Genomic signatures contributing to high tumour mutational burden (TMB-H) independent from mismatch-repair deficiency (dMMR) or microsatellite instability-high (MSI-H) status are not well studied. We aimed to characterise molecular features of microsatellite stable (MSS) TMB-H gastrointestinal tumours.

Methods: Molecular alterations of 48 606 gastrointestinal tumours from Caris Life Sciences (CARIS) identified with next-generation sequencing were compared among MSS-TMB-H, dMMR/MSI-H, and MSS-TMB-low (L) tumours, using χ or Fisher's exact tests.

Proceedings From the ASCO/College of American Pathologists Immune Checkpoint Inhibitor Predictive Biomarker Summit.

Purpose: Immune checkpoint inhibition (ICI) therapy represents one of the great advances in the field of oncology, highlighted by the Nobel Prize in 2018. Multiple predictive biomarkers for ICI benefit have been proposed. These include assessment of programmed death ligand-1 expression by immunohistochemistry, and determination of mutational genotype (microsatellite instability or mismatch repair deficiency or tumor mutational burden) as a reflection of neoantigen expression.

Molecular characterization of ESR1 variants in breast cancer.

Purpose: Estrogen receptor 1 (ESR1) mutations and fusions typically arise in patients with hormone receptor-positive breast cancer after aromatase inhibitor therapy, whereby ESR1 is constitutively activated in a ligand-independent manner. These variants can impact treatment response. Herein, we characterize ESR1 variants among molecularly profiled advanced breast cancers.