Therapeutically exploitable genetic aberrations in intimal sarcomas
Imatinib and olaratumab might prove to be therapeutic approaches for some patients with intimal sarcomas, based on a retrospective evaluation of genetic aberrations in 11 patients with intimal sarcomas, Jason Roszik, PhD, MBA, reported at the meeting.
Dr. Roszik and his colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed information on 11 patients with intimal sarcomas in the American Association for Cancer Research (AACR) project, Genomics Evidence Neoplasia Information Exchange (GENIE). Sampling was taken from the primary tumor in 8 patients and from the metastatic site in the other 3.
MDM2 amplifications were seen in 8 of 10 patients with available copy number alterations. Amplifications in the CDK pathway were present in 5, PDGFRA gain was seen in 4, and CDKN2A copy number loss was present in 3. Mutations that could be targeted with drugs included ALK, ATM/ATR, PTCH1 and PDGFRB, he said.
Unique genomic rearrangement events included PDE4DIP-NOTCH2 and MRPS30-ARID2 fusions. Co-occurring alterations included a NOTCH2 copy number gain in the PDE4DIP-NOTCH2 fusion tumor, and PDGFRB mutations in both fusion-positive cases.
The researchers also drew on the published findings of whole-exome sequencing and array-comparative genomic hybridization from an autopsy case of cardiac intimal sarcoma (Virchows Arch. 2017 Sep;471(3):423-428). That study identified concurrent PDGFRA amplification and PDGFRB mutation.
The researchers additionally examined clinical trial enrollments and could find no patient with intimal sarcoma among 406 sarcoma enrolled patients. Intimal sarcomas were not eligible for any clinical trial given the location of the tumors in major blood vessels.
“The somatic mutations and DNA copy number alterations in the PDGFR pathway relevant to the pathogenesis and potential targeted therapy of cardiac intimal sarcoma may be targeted by imatinib or olaratumab. Inclusion of such rare tumors in targeted therapy basket trials with a waiver for inclusion criteria is warranted,” Dr. Roszik and his colleagues concluded in the abstract of their presentation.
The promise of combination therapy
The “largest experience using multimodality therapy with proton based local therapy” for sarcomas involving the pericardium, myocardium, valves, pulmonary veins, or pulmonary arteries was reported by Yen-Lin E. Chen, MD, and her colleagues at Massachusetts General Hospital, Boston.
They examined an institutional sarcoma data repository of 13,950 patients and found 37 patients with sarcomas arising from the pericardium, myocardium, valves, pulmonary veins, or pulmonary arteries. These included 9 with unclassified pleomorphic sarcoma/malignant fibrous histiocytoma, 8 with angiosarcoma, 4 with spindle cell sarcoma, 4 with sarcoma not otherwise specified, 3 with leiomyosarcoma, 2 with osteosarcoma, 2 with Ewing sarcoma, and 1 each with chondrosarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, and intimal sarcoma.
Two-thirds of the patients had induction chemotherapy with or without maintenance therapy. Adriamycin, ifosfamide, and taxol therapies were most common. Two-thirds received proton based radiotherapy. Of the 23 patients who underwent resection, 11 were R2 (macroscopic positive margins), 3 were R1 (microscopic positive margins), and 9 were R0 (clear margins).
The 1-year overall survival rate was 64%, which fell to 37% at 3 years and to 28% at 5 years. Median survival was 28 months, twice that typically seen in the literature, Dr. Chen said.
For patients receiving proton based radiotherapy to a median dose of 64.8 GyRBE (range 63-72 GyRBE, 3 with additional intraoperative electrons), local failure free survivals were 80%, 64%, and 52% at 1, 3, and 5 years, respectively. For patients who did not receive radiotherapy, local failure free survival rates were 13%, 10%, 10%, respectively.
Overall, the 1, 3, and 5 year metastatic free survival rates were 25%, 14%, and 14%.
Survival rate was significantly better for patients with tumors smaller than 5 cm ( P =0.036), those over 40 years old ( P =0.028), those able to have surgery ( P =0.011), and those with non-angiosarcoma histologies ( P = 0.002).