Prediction of genetic biomarkers, e.g., microsatellite instability and BRAF in colorectal cancer is crucial for clinical decision making. In this paper, we propose a whole slide image (WSI) based genetic biomarker prediction method via prompting techniques. Our work aims at addressing the following challenges: (1) extracting foreground instances related to genetic biomarkers from gigapixel WSIs, and (2) the interaction among the fine-grained pathological components in WSIs. Specifically, we leverage large language models to generate medical prompts that serve as prior knowledge in extracting instances associated with genetic biomarkers. We adopt a coarse-to-fine approach to mine biomarker information within the tumor microenvironment. This involves extracting instances related to genetic biomarkers using coarse medical prior knowledge, grouping pathology instances into fine-grained pathological components and mining their interactions. Experimental results on two colorectal cancer datasets show the superiority of our method, achieving 91.49% in AUC for MSI classification. The analysis further shows the clinical interpretability of our method.

Deep Learning (DL) can predict biomarkers directly from digitized cancer histology in a weakly-supervised setting. Recently, the prediction of continuous biomarkers through regression-based DL has seen an increasing interest. Nonetheless, clinical decision making often requires a categorical outcome. Consequently, we developed a weakly-supervised joint multi-task Transformer architecture which has been trained and evaluated on four public patient cohorts for the prediction of two key predictive biomarkers, microsatellite instability (MSI) and homologous recombination deficiency (HRD), trained with auxiliary regression tasks related to the tumor microenvironment. Moreover, we perform a comprehensive benchmark of 16 approaches of task balancing for weakly-supervised joint multi-task learning in computational pathology. Using our novel approach, we improve over the state-of-the-art area under the receiver operating characteristic by +7.7% and +4.1%, as well as yielding better clustering of latent embeddings by +8% and +5% for the prediction of MSI and HRD in external cohorts, respectively.

High-throughput screening technology has facilitated the generation of large-scale drug responses across hundreds of cancer cell lines. However, there exists significant discrepancy between in vitro cell lines and actual tumors in vivo in terms of their response to drug treatments, because of tumors comprise of complex cellular compositions and histopathology structure, known as tumor microenvironment (TME), which greatly influences the drug cytotoxicity against tumor cells. To date, no study has focused on modeling the impact of the TME on clinical drug response. This paper proposed a domain adaptation network for feature disentanglement to separate representations of cancer cells and TME of a tumor in patients. Two denoising autoencoders were separately used to extract features from cell lines (source domain) and tumors (target domain) for partial domain alignment and feature decoupling. The specific encoder was enforced to extract information only about TME. Moreover, to ensure generalizability to novel drugs, we applied a graph attention network to learn the latent representation of drugs, allowing us to linearly model the drug perturbation on cellular state in latent space. We calibrated our model on a benchmark dataset and demonstrated its superior performance in predicting clinical drug response and dissecting the influence of the TME on drug efficacy.

A disease capable of decimating and killing those affected, cancer involves cells in a specific part of the body growing and reproducing uncontrollably in a process known as proliferation. In a recent breakthrough, the tumor microenvironment (TME) has been established as a key driver for cancer progression, promoting resistance to therapeutics all the while enabling the disease to evade the immune system. Specifically, myeloid-derived suppressor cells (MDSCs) have been shown to play a central role in maintaining the TME through the suppression of host immunity, the establishment of new vasculature, and the remodeling of connective tissue to support tumor growth. Therefore, it is imperative to develop cancer immunotherapies able to promote the anti-oncological activity of the immune system with the dual ability to combat the highly detrimental effects of the TME. However, while it is straightforward to assess the effect of new therapies on cancer cells, estimating the effectiveness of these novel therapies on the TME is challenging.