Mutation status affects cisplatin sensitivity in advanced germ cell tumors

TP53 and MDM2 genetic alterations may predict cisplatin resistance and poor outcomes in patients with germ cell tumors, according to study results published in Journal of Clinical Oncology.

Genetic profiling may improve risk stratification and guide the use of targeted therapies when appropriate for patients with cisplatin-resistant tumors.

Germ cell tumors are the most common solid malignancies seen in younger men. These tumors are extremely sensitive to cisplatin chemotherapy, and many men with advanced disease will be cured.

However, as many as 30% of patients will have cisplatin-resistant disease, which requires additional therapies and increases the risk for death.

Darren R. Feldman, MD, genitourinary oncologist at Memorial Sloan Kettering Cancer Center, and colleagues sought to determine whether patients with cisplatin-resistant tumors harbored specific genetic mutations.

Feldman and colleagues performed whole-exome and targeted sequencing on tumors from 180 men (median age, 30.6 years; range, 16-65.1) treated with cisplatin-based chemotherapy.

Patients were considered cisplatin resistant if they experienced an incomplete response to first-line cisplatin chemotherapy, experienced nonteratomatous tumor progression after first-line cisplatin chemotherapy, or had viable nonteratomatous germ cell tumors identified during surgery following chemotherapy.

Nineteen of these patients formed the discovery cohort — 10 of whom were cisplatin resistant and nine cisplatin sensitive. Two patients with cisplatin-resistant tumors harbored TP53 alterations and three patients harbored MDM2 alterations. No patients with cisplatin-sensitive tumors harbored alterations to the TP53/MDM2 pathway (P = .033).

The other 161 patients were in the validation cohort, 94 of whom were cisplatin resistant and 67 cisplatin sensitive.

In this cohort, TP53 mutations only occurred in cisplatin-resistant patients (n = 17). Additionally, seven tumors harbored MDM2 alterations, of which 71.4% (n = 5) were cisplatin resistant.

Alterations to these pathways occurred significantly more often in patients with cisplatin-resistant disease (21.3% vs. 3%; P = .001).

TP53 mutations occurred more frequently in patients with primary mediastinal tumors than in patients with primary testicular tumors (59.1% vs. 2.5%; P < .001). Seventy-four percent of patients with primary mediastinal nonseminomas harbored these mutations.

A multivariate analysis found that patients harboring these mutations had poorer prognoses than those without, regardless of International Germ Cell Cancer Collaborative Group risk categorization (HR = 1.83; 95% CI, 1.12-2.98).

The researchers identified actionable mutations in the RAC1 pathway in nine patients with cisplatin-resistant disease, suggesting a potential for targeted therapies.

“This series provides, to our knowledge, the first evidence of a genomic basis for cisplatin resistance among a significant proportion of patients with advanced germ cell tumors," Feldman and colleagues wrote. “The presence of actionable genomic alterations in nearly half of cisplatin-resistant germ cell tumors suggests novel treatment approaches may be of benefit for patients with refractory germ cell tumors and indicates a potential advantage of prospective genomic characterization of these tumors.” – by Cameron Kelsall

Disclosure: Feldman reports research funding from Novartis and consultant roles with Bayer, Gilead Sciences and Seattle Genetics. Please see the full study for a list of all other researchers’ relevant financial disclosures.