TP53, MDM2 Alterations Linked to Cisplatin Resistance in Testicular Cancer

TP53 and MDM2 alterations are associated with resistance to cisplatin and inferior progression-free survival among patients with metastatic germ cell tumors, regardless of risk category, according to a study published in the Journal of Clinical Oncology.¹

Although the majority of patients with advanced germ cell tumors are cured with cisplatin-based chemotherapy, up to 30% of patients demonstrate resistance to cisplatin, necessitating intensive salvage therapy associated with a higher risk of cancer-specific mortality. Researchers attempted to identify recurrent genetic alterations that increase the risk for developing cisplatin resistance.

Investigators performed whole-exome sequencing on 19 tumor samples from men with advanced germ cell tumor of any primary site who received standard first-line cisplatin-based chemotherapy at Memorial Sloan Kettering Cancer Center in New York, New York, and on a prospective cohort of 161 patients.

TP53 alterations were observed exclusively in tumor samples from patients with cisplatin-resistant disease and 7 additional tumors with MDM2 amplifications. Alterations within TP53 and MDM2 were more common among patients with cisplatin-resistant, in contrast with those with cisplatin-sensitive germ cell tumors (21.3% versus 3%; P = .001).

TP53 mutations/deletions alone and in combination with MDM2 amplifications were significantly more common in resistant versus in sensitive tumors (P < .001).

Median follow-up was 38.8 months; patients with TP53/MDM2 pathway alterations had significantly shorter progression-free survival than those without these alterations.

This is the first genomic evaluation to establish a genetic basis for cisplatin resistance among patients with germ cell tumors.

Reference

1. Bagrodia A, Lee BH, Lee W, et al. Genetic determinants of cisplatin resistance in patients with advanced germ cell tumors. J Clin Oncol. 2016 Sep 19. doi: 10.1200/JCO.2016.68.7798 [Epub ahead of print]