Najat C. Daw

Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma.

Pediatric osteosarcoma is characterized by multiple somatic chromosomal lesions, including structural variations (SVs) and copy number alterations (CNAs). To define the landscape of somatic mutations in pediatric osteosarcoma, we performed whole-genome sequencing of DNA from 20 osteosarcoma tumor samples and matched normal tissue in a discovery cohort, as well as 14 samples in a validation cohort. Single-nucleotide variations (SNVs) exhibited a pattern of localized hypermutation called kataegis in 50% of the tumors. We identified p53 pathway lesions in all tumors in the discovery cohort, nine of which were translocations in the first intron of the TP53 gene. Beyond TP53, the RB1, ATRX, and DLG2 genes showed recurrent somatic alterations in 29%-53% of the tumors. These data highlight the power of whole-genome sequencing for identifying recurrent somatic alterations in cancer genomes that may be missed using other methods.

Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice.

As a single agent the ERBB1 inhibitor, gefitinib (Iressa; ZD1839) showed minimal activity against a panel of 10 pediatric tumor xenografts that do not express the ERBB1 receptor. However, combined with irinotecan (CPT-11), significantly greater than additive activity was observed in four of eight models (P < 0.05), and the combination showed enhanced activity against three additional tumor lines. Breast cancer resistance protein (ABCG2), a transporter that confers resistance to SN-38 (the active metabolite of irinotecan), was readily detected in six of nine xenograft models examined by immunohistochemistry. In vitro gefitinib potently reversed resistance to SN-38 only in a cell line that overexpressed functional ABCG2. However, overexpression of ABCG2 did not decrease accumulation nor increase the rate of efflux of [14C]gefitinib. On the basis of these results and the distribution of Abcg2 in mouse tissues, we assessed the ability of gefitinib to modulate irinotecan pharmacokinetics. Oral gefitinib coadministration resulted in no change in clearance of intravenously administered irinotecan. However, gefitinib treatment dramatically increased the oral bioavailability of irinotecan after simultaneous oral administration. It is concluded that gefitinib may modulate SN-38 activity at the cellular level to reverse tumor resistance mediated by ABCG2 through inhibiting drug efflux and may be used potentially in humans to modulate the oral bioavailability of a poorly absorbed camptothecin such as irinotecan.

Preliminary Efficacy of the Anti-Insulin–Like Growth Factor Type 1 Receptor Antibody Figitumumab in Patients With Refractory Ewing Sarcoma

PURPOSE Patients with Ewing sarcoma (ES) with metastases and those who relapse fare poorly and receive therapies that carry significant toxicity. This phase 1/2 study was conducted to evaluate the efficacy of figitumumab in advanced ES. PATIENTS AND METHODS Patients with sarcoma 10 to 18 years old were enrolled in two dose escalation cohorts (20 and 30 mg/Kg intravenously every 4 weeks) in the phase 1 portion of the study. Patients with ES 10 years old or older were enrolled in the phase 2 portion of the study. The primary phase 2 objective was objective response rate (ORR). RESULTS Thirty-one patients with ES (n = 16), osteosarcoma (n = 11), or other sarcomas (n = 4) were enrolled in the phase 1 portion of the study. Dose escalation proceeded to 30 mg/kg every 4 weeks with no dose-limiting toxicity identified. In the phase 2 portion of the study, 107 patients with ES received figitumumab at 30 mg/kg every 4 weeks for a median of 2 cycles (range, 1 to 16). Sixty three percent of phase 2 patients had received at least three prior treatment regimens. Of 106 evaluable patients, 15 had a partial response (ORR, 14.2%) and 25 had stable disease. Median overall survival was 8.9 months. Importantly, patients with a pretreatment circulating free insulin-like growth factor (IGF) -1 lower than 0.65 ng/mL (n = 14) had a median OS of 3.6 months, whereas those with a baseline free IGF-1 ≥ 0.65 ng/mL (n = 84) had a median OS of 10.4 months (P < .001). CONCLUSION Figitumumab had modest activity as single agent in advanced ES. A strong association between pretreatment serum IGF-1 and survival benefit was identified.

Renal cell carcinoma with novel VCL–ALK fusion: new representative of ALK-associated tumor spectrum

Renal cell carcinoma represents a model for contemporary classification of solid tumors; however, unusual and unclassifiable cases exist and are not rare in children and young adults. The anaplastic lymphoma kinase (ALK) gene has recently been implicated in subsets of pulmonary, esophageal, breast, and colon cancers. These findings strengthen the importance of molecular classification of carcinomas across different organ sites, especially considering the evolving targeted anticancer therapies with ALK inhibitors. In the current study of six pediatric renal cell carcinomas, two cases exhibited structural karyotypic abnormalities involving the ALK locus on chromosomal band 2p23. Fluorescence in situ hybridization (FISH) studies were positive for an ALK rearrangement in one case, and subsequent 5′ rapid amplification of cDNA ends analysis of this tumor revealed that the 3′ portion of the ALK transcript encoding for the kinase domain was fused in frame to the 5′ portion of vinculin (VCL, NM_003373). The new fusion gene is predicted to have an open reading frame of 4122 bp encoding for a 1374-aa oncoprotein; its expression was shown by immunoblotting with anti-VCL and anti-ALK antibodies in tumor tissue lysates. Immunohistochemistry with the same antibodies demonstrated cytoplasmic and subplasmalemmal localization of the oncoprotein determined by its N-terminal VCL portion. FISH with a custom-designed VCL–ALK dual-fusion probe set confirmed the presence of the fusion in neoplastic cells and demonstrated the potential clinical utility of this approach for detecting VCL–ALK in routinely processed tissue. The five remaining pediatric renal cell carcinomas did not show ALK rearrangement by FISH or ALK expression by immunohistochemistry. The data identify the kidney as a new organ site for ALK-associated carcinomas and VCL as a novel ALK fusion partner. The results should prompt further studies to advance the molecular classification of renal cell carcinoma and help to select patients who would benefit from appropriate targeted therapies.

Analysis of prognostic factors in ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital studies.

Advances in systemic and local therapies have improved outcomes for patients with the Ewing sarcoma family of tumors (ESFT). As new treatments are developed, a critical review of data from past treatment eras is needed to identify clinically relevant risk groups.

Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma

The combination of gemcitabine and docetaxel has demonstrated promise in sarcomas diagnosed in adults. In the current study, the toxicity and efficacy of this combination were evaluated in pediatric sarcomas.

Improved survival for patients with recurrent Wilms tumor: The experience at St. Jude Children's Research Hospital

Background Reported estimates of survival for patients with recurrent Wilms tumor are 24% to 43%. Because published survival data are more than a decade old and do not reflect advances in therapy, the authors reviewed their experience in treating recurrent Wilms tumor to determine whether the probability of survival has increased. Patients and Methods The authors reviewed the cases of 54 patients with recurrent Wilms tumor who were treated on one of six consecutive clinical trials at St. Jude Childrens Research Hospital between 1969 and 2000. Results Five-year overall survival estimates after relapse were 63.6 ± 15.7% for patients treated during or after 1984 (n = 20) and 20.6 ± 6.5% for patients treated before 1984 (n = 34) (P = 0.002). When the analysis was restricted to patients with high-risk clinical features, 5-year overall survival estimates were 47.6 ± 15.7% for those treated in the modern era (n = 16) and 11.1 ± 5.2% for those treated in the earlier era (n = 25) (P = 0.005). Only three patients received high-dose chemotherapy with autologous stem cell rescue; one survived. No patients with recurrent anaplastic histology disease survived. Conclusions Significant progress has been achieved in the treatment of recurrent favorable-histology Wilms tumor using multimodality salvage regimens with conventional doses of chemotherapy. Novel therapeutic strategies will be necessary to cure patients with recurrent anaplastic Wilms tumor.

High-dose methotrexate pharmacokinetics and outcome of children and young adults with osteosarcoma

High‐dose methotrexate (HDMTX) is used frequently in combination regimens that include nephrotoxic chemotherapy. The authors evaluated the impact of factors such as age and prior nephrotoxic agents on MTX pharmacokinetics in children and young adults with osteosarcoma and examined whether MTX pharmacokinetic parameters were associated with outcome.

Telomerase Expression Predicts Unfavorable Outcome in Osteosarcoma

PURPOSE Osteosarcoma is distinct from most cancers in that the majority of osteosarcomas lack telomerase expression and use the alternative lengthening of telomeres (ALT) mechanism to maintain telomeres. Laboratory studies suggest that compared with ALT, telomerase expression is associated with increased tumor aggressiveness. We evaluated the clinical significance of telomerase expression in human osteosarcoma. PATIENTS AND METHODS Fifty-six osteosarcomas from 51 patients treated at St Jude Childrens Research Hospital between 1982 and 2003 were evaluated for telomerase enzyme activity, mRNA expression of the catalytic component of telomerase (TERT), and presence of the ALT pathway. RESULTS Outcome analysis was based on TERT mRNA expression in the primary tumor samples from 44 patients. Fourteen primary tumors expressed TERT mRNA (32%; eight TERT only, six TERT and ALT) and 30 did not express TERT mRNA (68%; 29 ALT, one no ALT). Progression-free survival (PFS) was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 21.4% +/- 9.5% v 63.7% +/- 11.1%; P =.014). Likewise, overall survival was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 42.9% +/- 12.2% v 70.0% +/- 9.9%; P =.031). Among 31 patients with nonmetastatic disease at diagnosis, PFS was lower in the TERT-positive group compared with the TERT-negative group (3-year estimates, 33.3% +/- 13.6% v 72.0% +/- 11.5%; P =.092). CONCLUSION Telomerase expression in primary tumor samples is associated with decreased PFS and OS in patients with osteosarcoma. Additional studies are warranted to better define the clinical utility of this molecular marker.

Copy number gains in EGFR and copy number losses in PTEN are common events in osteosarcoma tumors

Osteosarcoma cell lines and tumors have been shown to express epidermal growth factor receptor (EGFR) and harbor amplifications at the EGFR locus. In this study, the authors further analyzed the genomic features of EGFR in osteosarcoma tumors and investigated whether they correlate with phosphatase and tensin homolog (PTEN) expression and copy number status.