TP53 Mutations Linked With Improved Survival in Soft-Tissue Sarcoma

The presence of a TP53 mutation was associated with improved survival in patients with advanced soft-tissue sarcoma (STS) who were treated with vascular endothelial growth factor receptor (VEGFR) inhibition with pazopanib or other drugs, according to a new study.

Trials have shown some benefit in advanced STS with pazopanib. “Recently, there has been a convergence of evidence to suggest that STSs with mutations in the TP53 gene may respond better to VEGFR inhibition than TP53 wild-type,” wrote study authors led by James L. Chen, MD, of Ohio State University in Columbus. In preclinical work, loss of function p53 mutant cells produced substantially more VEGF, and this contributes directly to angiogenesis and thus tumor growth.

The study was a retrospective review of 19 patients with advanced STS who were treated with either pazopanib (18 patients) or sunitinib (1 patient) and who had next-generation sequencing performed on their tumor. Of the total cohort, 11 patients had received prior doxorubicin-based therapy. The results were published in Annals of Oncology.

In total, the researchers observed 233 total mutations in these patients. TP53 mutations were the most common, occurring in 10 of the 19 patients (53%). The only other mutation present in more than 20% of the cases was in Rb1, which occurred in 6 of 19 patients (32%).

Patients with the TP53 mutations had better progression-free survival (PFS) than TP53 wild-type patients, with a median PFS of 208 days vs 136 days. This yielded a hazard ratio for progression of 0.38 (95% confidence interval [CI], 0.09–0.83; P = .036). The authors noted that, contrary to hypothesis, Rb1 mutants tended to fare worse than others, though this was not statistically significant.

The study did have some clear limitations, including its retrospective nature and small sample size. “Despite this, we observed a significant increase in the PFS of patients with advanced STS and TP53 mutations that is hypothesis-generating and supported by the emerging relevance of targeting the p53-VEGF axis as a therapeutic modality in cancer patients,” they concluded. “Larger correlative studies should be performed to confirm these results in the future.”