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).
RELATED: Twins Study Suggests Strong Familial Risk for Testicular Cancer
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.
- 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]