# Functional Assays to Guide Personalized Oncological Treatment of Patients with Soft-Tissue Sarcomas

## TL;DR

This paper reviews how testing drugs directly on tumor samples can guide personalized treatment for soft-tissue sarcoma patients, potentially improving outcomes.

## Contribution

The paper introduces and evaluates functional assays as a novel approach for personalized treatment of soft-tissue sarcomas.

## Key findings

- Functional assays like organoid cultures and xenografts correlate well with clinical drug responses.
- Xenografts preserve tumor architecture and physiological relevance.
- In vitro drug sensitivity tests using cell suspensions or organoids show strong clinical relevance.

## Abstract

Soft-tissue sarcomas that have spread to the body are often treated with chemotherapy. Such treatment has limited efficacy. In order to improve outcomes, focus has been placed on personalized treatment, where each tumor is analyzed to identify drugs that are most likely to have an effect. This can be done based on information from the genetic material of the tumor cells or direct tests of the drugs on cells or pieces derived from the tumor mass. The latter, known as functional assays, have advantages since they allow for a direct analysis of the effect of each drug. Functional assays have been introduced in the management of soft-tissue sarcomas, and they are reviewed in the present manuscript. Although still at an early stage, this technology has shown promising results, which may improve patient outcomes.

Background/Objectives: Soft tissue sarcomas (STSs) are rare tumors arising from mesenchymal tissues, comprising over 100 distinct histological subtypes with varying biological behaviors, metastatic patterns, and treatment responses Despite advances in multimodal therapy, the overall survival of patients with metastatic STS is poor, mainly due to the weak response to conventional chemotherapy based on doxorubicin and ifosfamide. Methods: This review examines the evolution from traditional one-size-fits-all treatments to personalized medicine strategies, primarily focusing on assays based on patient-derived tumor samples, and it highlights their emerging role in guiding personalized treatment decisions and improving clinical outcomes in STS. These approaches, also known as functional precision oncology, are a step closer to the clinical situation as compared to other personalized therapies that rely on the identification of targetable genomic alterations using high-throughput technologies such as whole-genome sequencing, which have thus far failed to show convincing responses in STS treatment. Results: The main functional precision oncology platforms tested in patients with STS are in vitro cell viability tests, organoid cultures, and patient-derived xenografts. Each has advantages and limitations. In this context, in vitro drug sensitivity using cell suspension or organoids has shown a strong correlation with clinical responses. Furthermore, organoids matched the original tumor histology and microenvironment to a satisfactory degree. Establishment of xenografts proved feasible in the majority of patients; the technique could also preserve the tumor architecture and displayed high physiological relevance to the clinical situation. Conclusions: Although a major clinical study directly comparing conventional chemotherapy to personalized treatment guided by functional assays is yet to be published, this approach has gained popularity given the low efficacy of personalized medicine based on genetic alterations. The results thus far show promise for a better outcome for patients with metastatic STS.