Irene Cheung, ScD

Associate Member and Attending, Pediatrics

Minimal Residual Disease

Many patients with high-risk neuroblastoma, despite being in clinical remission after completing induction chemotherapy, are often left with minimal residual disease (MRD), i.e. the presence of microscopic levels of tumor cells not detectable by conventional clinicopathological methods. Unfortunately, the presence of MRD is likely to contribute to the patient's eventual relapse and death. Immunotherapy and biologic therapy directed against MRD have been shown to improve outcome. Therefore, the ability to measure MRD is critical for gauging the success of these targeting strategies, especially in the key metastatic compartments of bone marrow and peripheral blood. With the emergence of central nervous system relapse, cerebrospinal fluid is another crucial site for MRD monitoring. Detection of MRD can help develop accurate prognostic profiles for patients at diagnosis and during treatment, such that more appropriate therapy can be delivered to the individual patients. Accurate MRD measurement will also help identify the optimal time for autologous stem cell collection prior to transplant. The ultimate utility of MRD detection is to determine the clinical significance of these occult tumor cells in relations to patient relapse, survival, and even cure, using progression-free and overall survival as the clinical endpoints.

Molecular detection of MRD has progressed in the past decade to not only detect but also to quantify the target gene transcription level by real-time quantitative RT-PCR technology with high sensitivity and specificity. Because neuroblastoma cells express catecholamines, tyrosine hydroxylase, which is the rate-limiting enzyme in the catecholamine synthesis pathway, has proven to be a useful molecular marker for MRD detection. Our laboratory has demonstrated that GD2 synthase, the key enzyme for the synthesis of GD2- a ubiquitous and abundant antigen on neuroblastoma, is a clinically relevant molecular marker. We have also identified 2 additional markers for metastatic neuroblastoma, namely sialyltransferase STX and cyclin D1.

However, no single MRD marker will be adequate because neuroblastoma, like other cancers, is heterogeneous. Using gene expression array analysis on stage 4 neuroblastomas and remission bone marrows, 34 potential MRD markers from 16,000 genes were selected. Sensitivity and specificity studies further narrowed the list to 8 top-ranking candidates.Using well-annotated bone marrow samples collected from the same phase of an immunotherapy protocol, we identified 6 novel markers based on their prognostic impact on clinical outcome. We believe these novel markers will augment the precision in measuring MRD in metastatic neuroblastoma.

Parallel studies using gene expression analysis on solid tumors have also yielded selective MRD markers for other human cancers. One example was our work in identifying new subclinical markers of Ewing sarcoma. Using the same strategy, MRD markers for melanoma and small cell lung cancer are currently being identified. We believe that having clinically relevant markers is crucial in the overall clinical management of cancer patients.

Publications

Cheung IY, Feng Y, Danis K, Shukla N, Meyers P, Ladanyi M, Cheung NK. Novel markers of subclinical disease for Ewing family tumors from gene expression profiling. Clinical Cancer Research 13:6978-6983, 2007. [PubMed Abstract]

Cheung IY, Feng Y, Gerald W, Cheung NK. Exploiting gene expression profiling to identify novel minimal residual disease markers of neuroblastoma. Clinical Cancer Research, 14:7020-7027, 2008. [PubMed Abstract]