Pharmacogenomics and Pharmacogenetics in Osteosarcoma: Translational Studies and Clinical Impact

Abstract

<jats:p>High-grade osteosarcoma (HGOS) is a very aggressive bone tumor which primarily affects adolescents and young adults. Although not advanced as is the case for other cancers, pharmacogenetic and pharmacogenomic studies applied to HGOS have been providing hope for an improved understanding of the biology and the identification of genetic biomarkers, which may impact on clinical care management. Recent developments of pharmacogenetics and pharmacogenomics in HGOS are expected to: i) highlight genetic events that trigger oncogenesis or which may act as drivers of disease; ii) validate research models that best predict clinical behavior; and iii) indicate genetic biomarkers associated with clinical outcome (in terms of treatment response, survival probability and susceptibility to chemotherapy-related toxicities). The generated body of information may be translated to clinical settings, in order to improve both effectiveness and safety of conventional chemotherapy trials as well as to indicate new tailored treatment strategies. Here, we review and summarize the current scientific evidence for each of the aforementioned issues in view of possible clinical applications.</jats:p>

MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

“…In most cases, patients are stratified largely relying on their concrete characteristics such as the clinical manifestations, radiographic features, pathological biopsy, etc. And they are prescribed with a relatively fixed regimen schedule even in those with or without metastases at diagnosis ( 32 ), leading to unsatisfied outcome. Fortunately, the biological biomarkers especially genome feature may conduce to more precise stratification and therapeutic optimization.…”

Resource‐appropriate selection of osteosarcoma treatment protocols in low‐ and middle‐income countries

“…Unique pharmacokinetic and pharmacogenomic factors in MTX metabolism lead to significant inter‐patient and inter‐cycle variability in the serum MTX levels, showing even up to nine‐fold variations (Figure 2A,B). 29–34 Additionally, in osteosarcoma, histological response and survival correlate with the end‐of‐infusion serum MTX level above 700–1000 $$ \umu $$mol/L, or even >1500 $$ \umu $$mol/L 28,30,35–38 . Conversely, very high MTX exposure with delayed MTX clearance and longer exposures may be associated with poorer outcomes and higher toxicity 35 .…”

Recent Insights into Therapy Resistance in Osteosarcoma

“…These still represent a small proportion of patients with osteosarcoma, and no inherited mutations give way to druggable targets [ 16 ]. Whole genomic sequencing approaches can identify druggable targets in certain subsets of patients, but the overall clinical utility of these diagnostic approaches and the subsequent therapies are still under investigation [ 17 , 18 , 19 ].…”