Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine.
BACKGROUND
Despite advances in molecular medicine over recent decades, there has been little advancement in the treatment of osteosarcoma. We performed comprehensive molecular profiling in two cases of metastatic and chemotherapy-refractory osteosarcoma to guide molecularly targeted therapy.


METHODS
Hybridization capture of >300 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from tumor samples from two patients with recurrent, metastatic osteosarcoma. The DNA from each sample was sequenced to high, uniform coverage. Immunohistochemical probes and morphoproteomics analysis were performed, in addition to fluorescence in situ hybridization. All analyses were performed in CLIA-certified laboratories. Molecularly targeted therapy based on the resulting profiles was offered to the patients. Biomedical analytics were performed using QIAGEN's Ingenuity® Pathway Analysis.


RESULTS
In Patient #1, comprehensive next-generation exome sequencing showed MET amplification, PIK3CA mutation, CCNE1 amplification, and PTPRD mutation. Immunohistochemistry-based morphoproteomic analysis revealed c-Met expression [(p)-c-Met (Tyr1234/1235)] and activation of mTOR/AKT pathway [IGF-1R (Tyr1165/1166), p-mTOR [Ser2448], p-Akt (Ser473)] and expression of SPARC and COX2. Targeted therapy was administered to match the P1K3CA, c-MET, and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib. In Patient #2, aberrations included NF2 loss in exons 2-16, PDGFRα amplification, and TP53 mutation. This patient was enrolled on a clinical trial combining targeted agents temsirolimus, sorafenib and bevacizumab, to match NF2, PDGFRα and TP53 aberrations. Both the patients did not benefit from matched therapy.


CONCLUSIONS
Relapsed osteosarcoma is characterized by complex signaling and drug resistance pathways. Comprehensive molecular profiling holds great promise for tailoring personalized therapies for cancer. Methods for such profiling are evolving and need to be refined to better assist clinicians in making treatment decisions based on the large amount of data that results from this type of testing. Further research in this area is warranted.
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Vivek
V
Subbiah
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Michael J
MJ
Wagner
Department of Pathology & Laboratory Medicine, The University of Texas-Houston Medical School, Houston, TX 77030, USA.
Mary F
MF
McGuire
Department of Internal Medicine, The University of Texas-Houston Medical School, Houston, TX 77030, USA.
Nawid M
NM
Sarwari
Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Eswaran
E
Devarajan
Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Valerae O
VO
Lewis
Division of Gynecological Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Shanon
S
Westin
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Shumei
S
Kato
Department of Pathology & Laboratory Medicine, The University of Texas-Houston Medical School, Houston, TX 77030, USA.
Robert E
RE
Brown
Department of of Pediatric Hematology/Oncology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Pete
P
Anderson
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D058990:Molecular Targeted Therapy; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D057285:Precision Medicine; D040901:Proteomics; D055815:Young Adult
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
molecular profiling; osteosarcoma; personalized medicine; precision medicine; targeted therapy