Association of Antifolate Response Signature Status and Clinical Activity of Pemetrexed-Platinum Chemotherapy in Non-Small Cell Lung Cancer: The Piedmont Study.

Purpose: The Piedmont study is a prospectively designed retrospective evaluation of a new 48-gene antifolate response signature (AF-PRS) in patients with locally advanced/metastatic nonsquamous (NS) non-small cell lung cancer (NSCLC) treated with pemetrexed-containing platinum doublet chemotherapy (PMX-PDC). The study tested the hypothesis that AF-PRS identifies patients with NS-NSCLC who have a higher likelihood of responding positively to PMX-PDC. The goal was to gather clinical evidence supporting AF-PRS as a potential diagnostic test.

Mesenchymal gene expression subtyping analysis for early-stage human papillomavirus-negative head and neck squamous cell carcinoma reveals prognostic and predictive applications.

Patients with oral cavity squamous cell carcinoma (OCSCC) are predominantly human papillomavirus (HPV)(-), and treatment typically involves surgical resection ± neck dissection, followed by radiation ± chemotherapy. We previously described four mRNA expression patterns (classical, atypical, basal, and mesenchymal), each with unique genomic features and prognosis. Here, we examine the clinical utility of gene expression subtyping in head and neck squamous cell carcinoma (HNSCC) and introduce potentially predictive applications in HPV(-) OCSCC.

The pancreatic cancer immune tumor microenvironment is negatively remodeled by gemcitabine while TGF-β receptor plus dual checkpoint inhibition maintains antitumor immune cells.

Pancreatic ductal adenocarcinoma (PDA) tumors have a highly immunosuppressive desmoplastic tumor microenvironment (TME) where immune checkpoint inhibition (ICI) therapy has been exceptionally ineffective. Transforming growth factor-β (TGF-β) receptor activation leads to cancer and immune cell proliferation and phenotype, and cytokine production leading to tumor progression and worse overall survival in PDA patients. We hypothesized that TGF-β receptor inhibition may alter PDA progression and antitumor immunity in the TME.

Mutant - and -Driven Hematopoiesis Populates the Hematopoietic Compartment in Response to Peptide Receptor Radionuclide Therapy.

Purpose: Hematologic toxic effects of peptide receptor radionuclide therapy (PRRT) can be permanent. Patients with underlying clonal hematopoiesis (CH) may be more inclined to develop hematologic toxicity after PRRT. However, this association remains understudied.

Integrative Analysis of miRNAs Identifies Clinically Relevant Epithelial and Stromal Subtypes of Head and Neck Squamous Cell Carcinoma.

Purpose: The objective of this study is to characterize the role of miRNAs in the classification of head and neck squamous cell carcinoma (HNSCC).

Experimental Design: Here, we analyzed 562 HNSCC samples, 88 from a novel cohort and 474 from The Cancer Genome Atlas, using miRNA microarray and miRNA sequencing, respectively. Using an integrative correlations method followed by miRNA expression-based hierarchical clustering, we validated miRNA clusters across cohorts.

Evaluation of pharmacokinetics and safety of cetuximab with cisplatin/carboplatin in patients with advanced solid tumor: Result from phase II studies.

The pharmacokinetics and potential drug-drug interactions between cetuximab and cisplatin or carboplatin from two studies (JXBA and JXBB) were evaluated. These studies were multicenter, open-label phase II trials designed to evaluate the drug-drug interactions between cetuximab (400 mg m initial dose) and cisplatin (JXBA; 100 mg m) or carboplatin (JXBB; area under the curve [AUC] = 5 mg × min mL) with or without 5-fluorouracil (5FU) in patients with advanced solid tumors. Concentrations of cetuximab, cisplatin and carboplatin were determined using analytical methods.

Gene Expression Subtype Predicts Nodal Metastasis and Survival in Human Papillomavirus-Negative Head and Neck Cancer.

Objectives/hypothesis: Gene expression analyses of head and neck cancer have revealed four molecular subtypes: basal (BA), mesenchymal (MS), atypical (AT), and classical (CL). We evaluate whether gene expression subtypes in oral cavity squamous cell carcinoma (OCSCC) and laryngeal squamous cell carcinoma (LSCC) can be used to predict nodal metastasis and prognosticate survival.

Study Design: Retrospective cohort study and genomic analysis.

Induction chemotherapy with carboplatin, nab-paclitaxel and cetuximab for at least N2b nodal status or surgically unresectable squamous cell carcinoma of the head and neck.

Background: Although induction studies of TPF in SCCHN have not improved outcomes compared to chemoradiotherapy alone, phase II studies of weekly carboplatin (CbP), paclitaxel and cetuximab (C225) have shown promising results. Nano-albumin-paclitaxel (nab-paclitaxel) based chemotherapy has demonstrated a higher response rate (RR) than solvent-based paclitaxel in squamous cell carcinoma of the lung with favorable toxicity.

Materials And Methods: Patients with treatment naïve SCCHN of any site with ≥N2b disease or that was unresectable by strict criteria were eligible.

Improved Tumor Purity Metrics in Next-generation Sequencing for Clinical Practice: The Integrated Interpretation of Neoplastic Cellularity and Sequencing Results (IINCaSe) Approach.

Neoplastic cellularity contributes to the analytic sensitivity of most present technologies for mutation detection, such that they underperform when stroma and inflammatory cells dilute a cancer specimen's variant fraction. Thus, tumor purity assessment by light microscopy is used to determine sample adequacy before sequencing and to interpret the significance of negative results and mutant allele fraction afterwards. However, pathologist estimates of tumor purity are imprecise and have limited reproducibility.

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors.

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC.

The association between copy number aberration, DNA methylation and gene expression in tumor samples.

We systematically studied the association between somatic copy number aberration (SCNA), DNA methylation and gene expression using -omic data from The Cancer Genome Atlas (TCGA) on six cancer types: breast cancer, colon cancer, glioblastoma, leukemia, lower-grade glioma and prostate cancer. A major challenge for such integrated study is that the association between DNA methylation and gene expression is severely confounded by tumor purity and cell type composition, which are often unobserved and difficult to estimate. To overcome this challenge, we developed a method to remove confounding effects by calculating the principal components that span the space of the latent factors.

Statistical significance for hierarchical clustering.

Cluster analysis has proved to be an invaluable tool for the exploratory and unsupervised analysis of high-dimensional datasets. Among methods for clustering, hierarchical approaches have enjoyed substantial popularity in genomics and other fields for their ability to simultaneously uncover multiple layers of clustering structure. A critical and challenging question in cluster analysis is whether the identified clusters represent important underlying structure or are artifacts of natural sampling variation.

Capecitabine and lapatinib for the first-line treatment of metastatic/recurrent head and neck squamous cell carcinoma.

Background: The combination of cisplatin, 5-fluorouracil, and cetuximab is a standard treatment for patients with recurrent/metastatic head and neck cancer, with a high rate of toxicity. Identifying less toxic, equally effective regimens is imperative. Therefore, in the current study, the authors investigated first-line treatment with an all-oral regimen of capecitabine and lapatinib.

Using the galactose-α-1,3-galactose enzyme-linked immunosorbent assay to predict anaphylaxis in response to cetuximab.

Background: Cetuximab is a monoclonal antibody against epidermal growth factor receptor with activity against head and neck cancer and colorectal cancer. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States with a grade 3/4 infusion reaction rate of 14%. Previous retrospective data have suggested that the presence of preformed immunoglobulin E antibodies against galactose-α-1,3-galactose in serum can predict anaphylaxis in response to cetuximab.

Identification of Human Papillomavirus Infection in Cancer Tissue by Targeted Next-generation Sequencing.

Human papillomaviruses (HPV) are oncogenic DNA viruses implicated in squamous cell carcinomas of several anatomic sites, as well as endocervical adenocarcinomas. Identification of HPV is an actionable finding in some carcinomas, potentially influencing tumor classification, prognosis, and management. We incorporated capture probes for oncogenic HPV strains 16 and 18 into a broader next-generation sequencing (NGS) panel designed to identify actionable mutations in solid malignancies.

Comparison of RNA-Seq by poly (A) capture, ribosomal RNA depletion, and DNA microarray for expression profiling.

Background: RNA sequencing (RNA-Seq) is often used for transcriptome profiling as well as the identification of novel transcripts and alternative splicing events. Typically, RNA-Seq libraries are prepared from total RNA using poly(A) enrichment of the mRNA (mRNA-Seq) to remove ribosomal RNA (rRNA), however, this method fails to capture non-poly(A) transcripts or partially degraded mRNAs. Hence, a mRNA-Seq protocol will not be compatible for use with RNAs coming from Formalin-Fixed and Paraffin-Embedded (FFPE) samples.

Classifying squamous cell carcinoma of the head and neck: prognosis, prediction and implications for therapy.

Traditionally, squamous cell cancers of the head and neck (SCCHN) have been classified by their anatomic location and stage. This system has been unsatisfactory in that it leaves substantial heterogeneity in prognosis and inadequate definition of optimal therapy. The most promising novel marker for superior prognosis in SCCHN is human papillomavirus (HPV).

Emerging technologies for improved stratification of cancer patients: a review of opportunities, challenges, and tools.

Cancer is a heterogeneous collection of diseases with wild variation in etiology, pathogenesis, response to therapy, and prognosis. Sources of variation are frequently obscure. Current practice attempts to classify tumors by tissue of origin and extent of disease through staging such that more risky tumors can be managed with more aggressive treatments.

Molecular biology of head and neck cancer: risks and pathways.

Patients present with a differential baseline risk of cancer based on normal and expected variations in genes associated with cancer. The baseline risk of developing cancer is acted on throughout life as the genome of different cells interacts with the environment in the form of exposures (eg, toxins, infections). As genetic damage is incurred throughout a lifetime (directly to DNA sequences or to the epigenome), events are set in motion to progressively disrupt normal cellular pathways toward tumorigenesis.