Gene panel identifies residual neuroblastoma metastases



BRUSSELS – In advanced-stage neuroblastoma patients with residual metastases in their bone marrow following two cycles of anti-GD2 immunotherapy, another cycle of this treatment is futile and only causes adverse events, based on a review of 343 stage IV patients treated at one U.S. center.

"Bone marrow minimal residual disease [MRD] measured after two cycles of immunotherapy was the strongest predictor of outcome, irrespective of disease status at the start of immunotherapy," Dr. Nai-Kong V. Cheung said at the Markers in Cancer meeting. "If a patient is positive for MRD after two cycles, don’t continue the treatment."

In the series of 343 patients aged 18 months or older with metastatic, stage IV neuroblastoma that he reviewed, all patients with detectable MRD after two cycles of immunotherapy with GD2 antibody eventually relapsed or died within the next 5 years. In contrast, roughly half of the patients who lacked MRD after the first two cycles of anti-GD2 therapy remained progression free and alive during up to 20 years of follow-up.

Dr. Nai-Kong V. Cheung

The full course of anti-GD2 treatment takes 2 years, has the potential to cause adverse effects, and is painful and expensive. "Why continue and subject patients to a treatment that won’t be beneficial?" Dr. Cheung asked during an interview. "We can use [MRD] as a marker to take patients off of a protocol that will not be useful to them and try a different treatment."

Immunotherapy with anti-GD2 is part of standard treatment for patients with advanced neuroblastoma.

Dr. Cheung, a pediatric oncologist and head of the neuroblastoma program at Memorial Sloan-Kettering Cancer Center in New York, and his associates used a four-marker genetic analysis to find evidence of residual, metastatic neuroblastoma cells in patients’ bone marrow. The four markers they used were:

• GD2 synthase, the gene for an enzyme that helps produce a ganglioside-abundant in neuroblastoma cells;

• PHOX2B, the gene for a transcription factor that promotes nerve cell growth and maturation;

• CCND1, the gene for cyclin D1 protein, an oncogene; and

• ISL 1, the gene for islet 1, a transcription factor involved in cell growth.

The database included 169 patients treated during first remission, 69 treated during second or later remission, and 105 with primary refractory disease. The researchers used the four-test genetic panel to screen for MRD in bone marrow specimens taken from these patients after the first two rounds of anti-GD2 treatment with or without granulocyte-macrophage colony-stimulating factor in a series of four treatment protocols. A patient was considered positive for MRD if at least one of the genetic markers was positive for the presence of neuroblastoma cells in the bone marrow.

In a multivariate analysis, patients negative for MRD had about a fourfold increased rate of progression-free survival and about a threefold increased rate of overall survival, compared with patients positive for MRD; both differences were statistically significant.

Dr. Cheung said that the four-gene panel his group used was developed through a project begun 15 years ago to look for the most discriminating gene signatures of metastatic neuroblastoma cells against the background of normal bone marrow cells, the metastatic destination for at least 90% of advanced neuroblastoma tumors. A similar approach could identify genetic tests for treatment response of other metastatic tumor types, he said.

The meeting was sponsored by the American Society of Clinical Oncology, the European Organisation for Research and Treatment of Cancer, and the National Cancer Institute. Dr. Cheung said that he is a coinventor on patents held by Memorial Sloan-Kettering Cancer Center.

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