Search

Background and Purpose: Conventional magnetic resonance imaging (MRI) poses challenges in quantitative analysis because voxel intensity values lack physical meaning. While intensity standardization methods exist, their effects on head and neck MRI have not been investigated. We developed a workflow based on healthy tissue region of interest (ROI) analysis to determine intensity consistency within a patient cohort. Through this workflow, we systematically evaluated intensity standardization methods for MRI of head and neck cancer (HNC) patients. Materials and Methods: Two HNC cohorts (30 patients total) were retrospectively analyzed. One cohort was imaged with heterogenous acquisition parameters (HET cohort), whereas the other was imaged with homogenous acquisition parameters (HOM cohort). The standard deviation of cohort-level normalized mean intensity (SD NMIc), a metric of intensity consistency, was calculated across ROIs to determine the effect of five intensity standardization methods on T2-weighted images. For each cohort, a Friedman test followed by a post-hoc Bonferroni-corrected Wilcoxon signed-rank test was conducted to compare SD NMIc among methods. Results: Consistency (SD NMIc across ROIs) between unstandardized images was substantially more impaired in the HET cohort (0.29 ± 0.08) than in the HOM cohort (0.15 ± 0.03). Consequently, corrected p-values for intensity standardization methods with lower SD NMIc compared to unstandardized images were significant in the HET cohort (p 0.05). In both cohorts, differences between methods were often minimal and nonsignificant. Conclusions: Our findings stress the importance of intensity standardization, either through the utilization of uniform acquisition parameters or specific intensity standardization methods, and the need for testing intensity consistency before performing quantitative analysis of HNC MRI.

While there has been an overall decline of tobacco and alcohol-related head and neck cancer in recent decades, there has been an increased incidence of HPV-associated oropharyngeal cancer (OPC). Recent research studies and clinical trials have revealed that the cancer biology and clinical progression of HPV-positive OPC is unique relative to its HPV-negative counterparts. HPV-positive OPC is associated with higher rates of disease control following definitive treatment when compared to HPV-negative OPC. Thus, these conditions should be considered unique diseases with regards to treatment strategies and survival. In order to sufficiently characterize HPV-positive OPC and guide treatment strategies, there has been a considerable effort to diagnose, prognose, and track the treatment response of HPV-associated OPC through advanced imaging research. Furthermore, HPV-positive OPC patients are prime candidates for radiation de-escalation protocols, which will ideally reduce toxicities associated with radiation therapy and has prompted additional imaging research to detect radiation-induced changes in organs at risk. This manuscript reviews the various imaging modalities and current strategies for tackling these challenges as well as provides commentary on the potential successes and suggested improvements for the optimal treatment of these tumors.

Summary: Monoclonal antibodies (mAbs) targeting the oncogenic receptor tyrosine kinase ERBB2/HER2, such as Trastuzumab, are the standard of care therapy for breast cancers driven by ERBB2 overexpression and activation. However, a substantial proportion of patients exhibit de novo resistance. Here, by comparing matched Trastuzumab-naive and post-treatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me3, a repressive histone modification catalyzed by polycomb repressor complex 2 (PRC2). In ErbB2+ breast cancer models, PRC2 silences endogenous retroviruses (ERVs) to suppress anti-tumor type-I interferon (IFN) responses. In patients, elevated H3K27me3 in tumor cells following Trastuzumab treatment correlates with suppression of interferon-driven viral defense gene expression signatures and poor response. Using an immunocompetent model, we provide evidence that EZH2 inhibitors promote interferon-driven immune responses that enhance the efficacy of anti-ErbB2 mAbs, suggesting the potential clinical benefit of epigenomic reprogramming by H3K27me3 depletion in Trastuzumab-resistant disease. : Hirukawa et al. link Trastuzumab resistance in ErbB2+ breast cancers with activity of the methyltransferase EZH2, a key epigenetic regulator. By silencing retrotransposons, EZH2 suppresses type-I interferon signaling to limit immune surveillance. Retrotransposon de-repression following EZH2 inhibition triggers interferon responses and sensitizes immunocompetent in vivo models to ErbB2 antibody therapy. Keywords: ErbB2/HER2, breast cancer, Polycomb Repressor Complex 2, PRC2, epigenetics, Trastuzumab resistance, endogenous retroviruses, immune surveillance, type I interferon signaling, transcriptional silencing

BackgroundConventional MRI poses unique challenges in quantitative analysis due to a lack of specific physical meaning for voxel intensity values. In recent years, intensity standardization methods to optimize MRI signal consistency have been developed to address this problem. However, the effects of standardization methods on the head and neck region have not been previously investigated.PurposeThis study proposes a workflow based on healthy tissue region of interest (ROI) analysis to determine intensity consistency within a patient cohort. Through this workflow, we systematically evaluate different intensity standardization methods for T2-weighted MRI of the head and neck region.MethodsTwo image cohorts of five head and neck cancer patients, one with heterogeneous acquisition parameters (median age 59 years [range, 53-61]), and another with homogeneous acquisition parameters from a clinical trial (NCT04265430) (median age 61 years [range, 54-77]) were retrospectively analyzed. The standard deviation of cohort-level normalized mean intensity (SD NMIc), a metric of intensity consistency, was calculated across ROIs to determine the effect of five intensity standardization methods on T2-weighted images. For each cohort, the Friedman test with a subsequent post-hoc Bonferroni-corrected Wilcoxon signed-rank test was conducted to compare SD NMIc among methods.ResultsConsistency (SD NMIc across ROIs) between T2-weighted images is substantially more impaired in the cohort with heterogeneous acquisition parameters (0.28 ± 0.04) than in the cohort with homogeneous acquisition parameters (0.15 ± 0.05). Consequently, intensity standardization methods more significantly improve consistency in the cohort with heterogeneous acquisition parameters (corrected p < 0.005 for all methods compared to no standardization) than in the cohort with homogeneous acquisition parameters (corrected p > 0.5 for all methods compared to no standardization).ConclusionsOur findings stress the importance of image acquisition parameter standardization, together with the need for testing intensity consistency before performing quantitative analysis of MRI.

IMPACT: This work will standardize necessary image pre-processing for diagnostic and prognostic clinical workflows dependent on quantitative analysis of conventional magnetic resonance imaging. OBJECTIVES/GOALS: Conventional magnetic resonance imaging (MRI) poses challenges for quantitative analysis due to a lack of uniform inter-scanner voxel intensity values. Head and neck cancer (HNC) applications in particular have not been well investigated. This project aims to systematically evaluate voxel intensity standardization (VIS) methods for HNC MRI. METHODS/STUDY POPULATION: We utilize two separate cohorts of HNC patients, where T2-weighted (T2-w) MRI sequences were acquired before beginning radiotherapy for five patients in each cohort. The first cohort corresponds to patients with images taken at various institutions with a variety of non-uniform acquisition scanners and parameters. The second cohort corresponds to patients from a prospective clinical trial with uniformity in both scanner and acquisition parameters. Regions of interest from a variety of healthy tissues assumed to have minimal interpatient variation were manually contoured for each image and used to compare differences between a variety of VIS methods for each cohort. Towards this end, we implement a new metric for cohort intensity distributional overlap to compare region of interest similarity in a given cohort. RESULTS/ANTICIPATED RESULTS: Using a simple and interpretable metric, we have systematically investigated the effects of various commonly implementable VIS methods on T2-w sequences for two independent cohorts of HNC patients based on region of interest intensity similarity. We demonstrate VIS has a substantial effect on T2-w images where non-uniform acquisition parameters and scanners are utilized. Oppositely, it has a modest to minimal impact on T2-w images generated from the same scanner with the same acquisition parameters. Moreover, with a few notable exceptions, there does not seem to be a clear advantage or disadvantage to using one VIS method over another for T2-w images with non-uniform acquisition parameters. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our results inform which VIS methods should be favored in HNC MRI and may indicate VIS is not a critical factor to consider in circumstances where similar acquisition parameters can be utilized. Moreover, our results can help guide downstream quantitative imaging tasks that may one day be implemented in clinical workflows.

SUMMARY The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this “proteogenomics” approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases.Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy., In Brief Breast cancer is a highly heterogeneous disease with variable outcomes and subtype-driven treatment approaches, making precision medicine a considerable challenge. Proteogenomic analyses of 122 primary breast cancers provide insights into clinically relevant biology, including cell cycle dysregulation, tumor immunogenicity, aberrant metabolism, and heterogeneity in therapeutic target expression., Graphical Abstract

Cancer cells explore a broad mutational landscape, bringing the possibility that tumor-specific somatic mutations could fall in the same codons as germline SNVs and leverage their presence to produce substitutions with a larger impact on protein function. While multiple, temporally consecutive mutations to the same codon have in the past been detected in the germline, this phenomenon has not yet been explored in the context of germline-somatic variant co-occurrences during cancer development. We examined germline context at somatic mutation sites for 1395 patients across four cancer cohorts (breast, skin, colon, and head and neck) and found 392 codon-level co-occurrences between germline and somatic variants, including over a dozen in well-known cancer genes. We found that for the majority of these co-occurrence events, traditional somatic calling led to an inaccurate representation of the protein site and a significantly lower predicted impact on protein fitness. We conclude that these events often lead to imprecise annotation of somatic variants but do not appear to be a frequent source of driver events during cancer development.