Predicting Tumor Metastasis by Employing a Target Organ/Primary Lesion Fusion Radiomics Model: a Prospective Observational Trial

Metastasis is an important biological feature of malignant tumors, and it is also the main factor affecting the outcome of cancer patients. The direct death of most cancer patients is the mass effect of metastatic lesions or the loss of metastatic target organ function. Therefore, it has become one of the urgent and arduous tasks in the field of oncology to explore the pathophysiological mechanism of malignant tumor metastasis and find new targets to form new methods for the early diagnosis and treatment of tumor metastasis.

Tumor metastasis is a continuous and gradual process. Tumor cells in the primary tumor proliferated, tumor cells shed from the primary tumor, invaded the basement membrane, invaded blood vessels, lymphatic vessels or body cavity, and migrated to another site or organ with the blood flow and lymph flow. Tumor cells adhered to the capillaries of the target organ, penetrated the blood vessels to form micrometastases, cell proliferation and produced new blood vessels, and formed secondary tumors of the same type as the primary tumor. They can invade and metastasize again. In the process of metastasis, gene mutations and subsequent changes in the immunogenicity of tumor cells promote the formation of local tumor tissue inhibitory microenvironment, which suppresses the host immune system and leads to tumor metastasis.

Previous studies have found that tumor metastasis has Organ specificity, called "Organ-tropism". That is, different types of tumors tend to metastasize to different organs. For example, lung cancer often metastasizes to the brain, colorectal cancer and pancreatic cancer commonly metastasize to the liver, breast cancer and prostate cancer commonly metastasize to the bone, and so on. Therefore, Stephen Paget, a British pathologist, put forward and elaborated his "seed and soil theory" more than a hundred years ago, advocating that metastasis requires the spread of tumor cells, that is, "seeds", and the ideal environment for receiving organs, that is, "fertile soil". He proposed in this theory that successful metastasis to distant organs requires not only tumor cells with metastatic potential (seeds) but also a suitable host organ (soil). During tumor progression, the composition and phenotypic types of immune cells in the tumor microenvironment are shaped by both malignant cells and the niche of adjacent tissues. Metastatic tumors (seeds) will retain genetic characteristics when they are transferred to different organ-specific tissue environments (soil). It is not enough for tumor cells to reach a certain organ tissue, but also requires the coordination between tumor cells (seeds) and organ microenvironment (soil) to plant and grow in a suitable environment (soil) and become metastatic foci. In the "seed and soil theory", the intrinsic characteristics of seeds have been proved to affect various key transfer processes. On the other hand, few studies have focused on the relationship between the intrinsic characteristics of soil (target organ) and the formation of malignant tumor metastasis, one of the main reasons is that it is often not ethical to conduct invasive research on the target organ of patients without metastasis.

Radiomics is an emerging field, which develops new biomarkers through quantitative analysis of imaging examination images of patients, which can study and analyze the potential pathophysiological characteristics of regions of interest in a non-invasive way. Previous studies have shown that radiomics studies of seeds (primary tumors) can predict metastasis of many malignant tumors, which establishes radiomics evidence for the "seed and soil" theory from the perspective of seeds. However, radiomics studies from the perspective of soil (the target organ for metastasis) are rare. Taking the brain metastases of lung cancer as an example, most existing radiomics studies using brain imaging information only evaluate the regions where brain metastases have occurred. Considering that radiomics can also extract biological features from target organs that have not yet metastasized, our group has found that radiomics analysis of pretreatment brain MRI images of lung cancer patients without baseline brain metastasis can effectively predict the probability of brain metastasis in a certain period of time. This study also revealed for the first time that the target organ without metastasis (soil) also plays a key role in the occurrence of malignant tumor metastasis.

The results of this study also suggest that the malignancy prediction model derived from radiomics could be a promising tool for screening patients at high risk of tumor metastasis. Integrated risk prediction models that take into account seed and soil characteristics may help guide clinical practice (e.g., more rigorous monitoring of high-risk patients or the use of more intensive systemic treatment).