Reply to B. Royer-Pokora et al
Authors: Elizabeth J. Perlman, Paul E. Grundy, Daniel M. Green, Jeffrey S. Dome, Robert C. Shamberger, E. Cristy Ruteshouser, Vicki Huff
Journal: Journal of Clinical Oncology (2011)

We thank Royer-Pokora and Graf 1 for their thoughtful comments and for the opportunity to clarify the characteristics of the patients that were examined in our recent study. 2 The majority of the comments concern patients with constitutional WT1 mutations.Royer-Pokora and Graf 1 point out the lack of analysis for constitutional WT1 mutation in our study.They suggest that the relapses in our study may reflect metachronous tumor development within patients with unrecognized constitutional WT1 mutation.While DNA from normal kidney or blood was indeed available for the loss of heterozygosity studies, these studies were carried out approximately 10 years ago.Unfortunately, in the intervening years, these samples have either been depleted or degraded and thus were either not available or not conducive for the recent WT1 mutational analyses, although these analyses were attempted.However, in our opinion the reservations expressed do not bias our study, for reasons provided below.First, patients with synchronous bilateral disease were not eligible for the National Wilms Tumor Study (NWTS)-5 very low risk Wilms tumor (VLRWT) treatment arm and were therefore effectively excluded from our study.Secondly, although metachronous contralateral tumor development was counted as an event in the disease-free survival analysis in the previous clinical reports, 3,4 patients with metachronous tumors were not classified as relapse in our study because we were interested in true relapses and not new primary tumors.Furthermore, if a metachronous contralateral tumor developed, the patient commonly received chemotherapy for this second tumor.At that point, the outcome of the first tumor in the absence of chemotherapy could not be evaluated, which was the point of our study.Because all patients who received chemotherapy were excluded from our study, patients with metachronous tumor development were also effectively excluded.In summary, our study did not include patients with bilateral disease or patients who developed metachronous contralateral tumors.Patients with constititutional WT1 mutations often have bilateral disease and/or develop metachronous contralateral tumors.While patients with constitutional WT1 mutations were not explicitly excluded from the NWTS5-VLRWT treatment arm, for practical reasons (including those mentioned above) such patients were infrequently registered.During NWTS-5, comprehensive information regarding the presence or absence of specific physical findings was obtained for all patients registered; this effort was one of the goals of NWTS-5.We have obtained this information for all patients whose tumors carried WT1 mutations in this study.One patient (who developed lung metastasis) demonstrated hemihypertrophy, hypospadias, and undescended testes (patient 1) and one patient (who did not relapse) had bilateral undescended testes (patient 2).Of the 56 patients in our study, these represent two of the three patients who displayed constitutional isodisomy for multiple loci on 11p15; both patients also had two copies of 11p13 with the same WT1 mutation.The remaining seven patients with WT1-mutant tumors showed no physical abnormalities.Therefore, there is some evidence to suggest that our study