Study Identifies Molecular Targets in Chemo-Resistant Germ Cell Tumors

A sequencing study found that about half of advanced germ cell tumor (GCT) patients with platinum-resistant or -refractory disease harbor potentially actionable mutations. Results of this study were presented at the 2016 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held January 7–9 in San Francisco (abstract 473).

Most patients with metastatic GCTs will be cured with platinum-based chemotherapy, but about 20% to 30% will have refractory or resistant disease requiring salvage chemotherapy and additional surgery. Mortality in these patients approaches 50%.

“This provides an opportunity to fulfill an unmet need and incorporate biology into the treatment of these patients, and identify novel therapies for patients with resistant or refractory disease,” said Aditya Bagrodia, MD, of Memorial Sloan Kettering Cancer Center in New York, who presented the new study.

The researchers used whole-exome sequencing and another sequencing protocol known as the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK IMPACT) on a total of 120 patients; Bagrodia focused on the 76 patients with resistant disease. The mean age of these patients was 29.44 years; most (84%) had non-seminoma GCTs, and most tumor samples (65.8%) were collected after chemotherapy administration.

Resistant patients had a much higher rate of nonsynonymous mutations; 47% had at least one potentially actionable alteration.

TP53/MDM2 alterations were found only in the resistant patients, in approximately 50%. Patients with wild-type TP53 had significantly longer progression-free survival than those with mutated TP53 (P < .001).

MDM2 amplifications were seen in 9.2% of the resistant patients; MDM2 functionally inactivates p53, Bagrodia said, and noted that there are currently seven MDM2 inhibitors in clinical trials.

MYCN amplification was found in 5.3% of the patients, which is associated with poor prognosis in neuroblastoma. KIT mutations also occurred in 5.3% of patients, which activates multiple tumor-associated pathways, including PI3K/AKT, RAS/MAPK, and JAK/STAT.

KRAS mutations were found in 12% of patients, NRAS mutations in 4%, and BRAF mutations in 4%. The study also reported six novel RAC1 mutations that have not previously been characterized.

“We have identified actionable mutations in a significant proportion of these patients with platinum-resistant GCTs, which may lead to individualized therapeutic options for these patients,” Bagrodia concluded.

The discussant for the session, Christian K. Kollmannsberger, MD, of the British Columbia Cancer Agency in Vancouver, said that this is one of the first reports looking in detail into potential targets for this relatively small population of refractory GCT patients.

“We know very little about molecular targets in GCTs,” he said. “We have a very high cure rate in GCTs, which is hindering broad drug development because the bar is very high. The ultimate expectation in GCT is still cure, something which most of the targeted therapies out there today are unlikely to achieve, and we may need to rethink our approach to refractory disease.”