Measurements of occult tumor cells in bone marrow and peripheral blood, besides providing prognostic impact, are potential sensitive indicators of tumor response in leukemia and metastatic solid tumors. The advent of RT-PCR and novel tumor markers has greatly improved detection sensitivity and enabled retrospective analysis of archived tissue samples. In small cohorts of patients with neuroblastoma and melanoma who were in apparent clinical remission, the presence of GD2 synthase mRNA and cancer/testis antigen GAGE in blood and marrow was found to be strongly prognostic of patient survival. They can potentially be molecular markers of minimal residual disease (MRD), one of the final hurdles to cancer cure. In this grant, we propose to test two hypotheses: (1) immunotherapy is as effective as marrow/stem cell transplant in the adjuvant setting when patients are in apparent clinical remission, and (2) MRD at the end of induction, and at 2 years from diagnosis have the strongest prognostic impact on patient survival.
In aim 1, MRD response will be tested in a large consecutive patient cohort diagnosed with high-risk neuroblastoma undergoing marrow/stem cell transplant (patient N=139), or anti-GD2 monoclonal antibody 3F8 immunotherapy (N=269). MRD response will be correlated with the level of pre-treatment tumor content, as well as clinical/biologic markers known to impact on patient outcome. Host factors that mediate tumor killing by 3F8 will also be tested for correlation with MRD response.
In aim 2, we will test if MRD has an independent prognostic impact on patient survival as adverse tumor biology continues to be neutralized by effective treatment strategy. For this analysis, MRD will be assayed among newly diagnosed stage 4 patients treated by consecutive neuroblastoma protocols (age 1-17 years, N=130) with their marrows obtained at diagnosis, end of induction (right before transplant or 3F8 adjuvant treatment), 12, 18, and 24 months from diagnosis. The relative importance of MRD at these time points will be tested against known prognostic factors. If these two molecular markers of MRD can independently predict patient outcome, they will in the future provide an objective endpoint for stopping further treatment, and serve as sensitive surrogates for evaluating adjuvant therapies. ? ?
|Cheung, Irene Y; Vickers, Andrew; Cheung, Nai-Kong V (2006) Sialyltransferase STX (ST8SiaII): a novel molecular marker of metastatic neuroblastoma. Int J Cancer 119:152-6|
|Cheung, Irene Y; Sahota, Arvind; Cheung, Nai-Kong V (2004) Measuring circulating neuroblastoma cells by quantitative reverse transcriptase-polymerase chain reaction analysis. Cancer 101:2303-8|
|Cheung, Irene Y; Lo Piccolo, M Serena; Kushner, Brian H et al. (2003) Early molecular response of marrow disease to biologic therapy is highly prognostic in neuroblastoma. J Clin Oncol 21:3853-8|
|Cheung, Irene Y; Lo Piccolo, M Serena; Kushner, Brian H et al. (2003) Quantitation of GD2 synthase mRNA by real-time reverse transcriptase polymerase chain reaction: clinical utility in evaluating adjuvant therapy in neuroblastoma. J Clin Oncol 21:1087-93|