David Rimm

BackgroundDesmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies.MethodsWe assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and …

PurposeThe prognostic and predictive significance of pathologist-read tumor infiltrating lymphocytes (TILs) in head and neck cancers have been demonstrated through multiple studies over the years. TILs have not been broadly adopted clinically, perhaps due to substantial inter-observer variability. In this study, we developed a machine-based algorithm for TIL evaluation in head and neck cancers and validated its prognostic value in independent cohorts.Experimental designA network classifier called NN3-17 was trained to identify and calculate tumor cells, lymphocytes, fibroblasts and “other” cells on hematoxylin-eosin stained sections using the QuPath software. These measurements were used to construct three predefined TIL variables. A retrospective collection of 154 head and neck squamous cell cancer cases was used as the discovery set to identify optimal association of TIL variables and survival. Two …

Background: trastuzumab deruxtecan (T-DXd) is a standard treatment for patients (pts) with HER2-positive (HER2+) and HER2-low metastatic breast cancer (MBC). HER2-low expression has been shown to be a highly unstable biomarker, and no data exists on the activity of T-DXd among pts with changes in HER2 status over time. Furthermore, limited data exists on the performance of regimens administered after progression on T-DXd. Methods: We analyzed data for pts with MBC receiving T-DXd at Dana-Farber Cancer Institute between 7/2017 - 2/2023 and at Duke Cancer Center between 3/2020 - 4/2022. The disease was categorized HER2+ if IHC 3+ or ISH-amplified at any time point; HER2-negative cases were categorized as HER2-low (IHC 2+/ISH- or IHC 1+) or HER2-0 (IHC 0) based on the last biopsy before T-DXd; the HER2 status for the primary tumor and at first metastatic diagnosis …

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by negative immunohistochemistry staining for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Treatment options for TNBCs are limited due to lack of tumor-specific targeted therapies, resulting in poor prognosis and patient survival. This is exacerbated by lack of prognostic markers of response. While current studies suggest tumor immune interactions are important, current immune activity quantifications, such as scores quantifying abundance of tumor-infiltrating lymphocytes (TILs), are not sufficient to define tumor immune status. We used imaging mass cytometry (IMC) to measure 33 markers on primary tumors of 100 patients undergone chemotherapy with long-term follow-up to explore the tumor immune microenvironment of TNBCs. Concordant with previous …

Spatially resolved transcriptomics or proteomics data have the potential to contribute fundamental insights into the mechanisms underlying physiologic and pathological processes. However, analysis of these data capable of relating spatial information, multiplexed markers, and their observed phenotypes remains technically challenging. To analyze these relationships, we developed SORBET, a deep learning framework that leverages recent advances in graph neural networks (GNN). We apply SORBET to predict tissue phenotypes, such as response to immunotherapy, across different disease processes and different technologies including both spatial proteomics and transcriptomics methods. Our results show that SORBET accurately learns biologically meaningful relationships across distinct tissue structures and data acquisition methods. Furthermore, we demonstrate that SORBET facilitates understanding of the spatially-resolved biological mechanisms underlying the inferred phenotypes. In sum, our method facilitates mapping between the rich spatial and marker information acquired from spatial `omics technologies to emergent biological phenotypes. Moreover, we provide novel techniques for identifying the biological processes that comprise the predicted phenotypes.

Purpose: Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to anti-PD-1 blockade. Rates of occult sentinel lymph node positivity vary drastically between its two distinct histological subtypes, pure and mixed, underscoring the need for better prognostic biomarkers to inform therapeutic strategies.Methods: Here, we assembled a tissue microarray comprising various sections of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM from 1989 to 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the Nanostring GeoMx platform and quantified regions by three tissue compartments defined by fluorescence colocalization [tumor (S100+/PMEL+), leukocytes (CD45+), and nonimmune stroma (S100-/PMEL-/CD45-/SYTO …

T-DXd has been approved by the FDA to treat patients with metastatic HER2-low and -positive breast cancer. The utility of current HER2 immunohistochemistry (IHC) assays in evaluating HER2-low tumors is not clear. A simple and objective method to evaluate HER2 expression in breast cancer is urgently needed. RNAScope can detect HER2 RNA levels by in situ hybridization using one regular unstained FFPE slide and processed using the Leica BOND-III autostainer that is readily available in many clinical laboratories. RNA level detected by RNAScope can be quantified by dots/cell using publicly available software. Therefore, RNAScope is a practical assay and could be a promising alternative to IHC to quantify HER2 levels in breast cancer. We evaluated HER2 levels in 605 breast cancer tissue microarray cores using RNAScope and the two most commonly used FDA approved HER2 IHC assays: Ventana …

Trastuzumab deruxtecan (T-DXd) has been approved by the US Food and Drug Administration (FDA) to treat patients with metastatic HER2-positive and HER2-low breast cancer, and clinical trials are examining its efficacy against early-stage breast cancer. Current HER2 immunohistochemical (IHC) assays are suboptimal in evaluating HER2-low breast cancers and identifying which patients would benefit from T-DXd. HER2 expression in 526 breast cancer tissue microarray (TMA) cores was measured using the FDA-approved PATHWAY and HercepTest IHC assays, and the corresponding RNA levels were evaluated by RNAscope. HER2 protein levels by regression analysis using a quantitative immunofluorescence score against cell line arrays with known HER2 protein levels determined by mass spectrometry were available in 48 of the cores. RNAscope was also performed in 32 metastatic biopsies from 23 …