Emerging predictive biomarkers in the management of bone and soft tissue sarcomas

ABSTRACT

Introduction

Soft tissue and bone sarcomas are a heterogeneous group of malignancies, each with a unique biology and clinical course. As our understanding of individual sarcoma subtypes and their molecular landscapes increases, predictive biomarkers are emerging to improve patient selection for chemotherapies, targeted therapies, and immunotherapy approaches.

Areas covered

This review highlights predictive biomarkers rooted in molecular mechanisms of sarcoma biology, focusing on cell cycle regulation, DNA damage repair, and immune microenvironment interactions. We review CDK4/6 inhibitor predictive biomarkers, including CDKN2A loss, ATRX status, MDM2 levels, and Rb1 status. We discuss homologous recombination deficiency (HRD) biomarkers that predict vulnerability to DNA damage repair (DDR) pathway inhibitors, such as molecular signatures and functional HRD markers. We describe tertiary lymphoid structures and suppressive myeloid cells in the sarcoma immune microenvironment that may influence immunotherapy efficacy.

Expert opinion

While predictive biomarkers are not routinely used in sarcoma clinical practice currently, emerging biomarkers are being developed alongside clinical advancements. Novel therapies and predictive biomarkers will be essential for individualizing future approaches to sarcoma management and improving patient outcomes.

KEYWORDS:

• Cell cycle control
• DNA damage repair
• homologous recombination
• immune microenvironment
• predictive biomarkers
• sarcoma

Article highlights

• ATRX status and MDM2 levels may predict response to CDK4/6 inhibitors in well-differentiated and dedifferentiated liposarcomas

• Patients with tumors harboring CDKN2A loss and intact Rb may be more likely to benefit from CDK4/6 inhibitors

• Molecular profiling identified sarcoma immune class (SIC) E characterized by the presence of tertiary lymphoid structures (TLS), a potential predictive biomarker associated with an increased response rate to PD-1 inhibition

• Sarcomas are infiltrated by immunosuppressive myeloid cells, including M2-like macrophages, that may predict response to chemotherapy/immune checkpoint inhibitor combinations

Declaration of interest

R Riedel’s spouse has co-ownership in Limbguard, LLC, has received institutional clinical research support from AADi, AROG, Ayala, BioAtla, Blueprint, Cogent, Daiichi-Sankyo, Deciphera, GlaxoSmithKline, InhibRx, NanoCarrier, Oncternal, PTC Therapeutics, SARC, SpringWorks, Tracon, Trillium and has served as a Consultant/Advisor for AADi, Adaptimmune, Blueprint, Daiichi-Sankyo, Deciphera, NanoCarrier, SpringWorks.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received no funding.