◥Neuroblastoma is a childhood cancer with heterogeneous clinical outcomes. To comprehensively assess the impact of telomere maintenance mechanism (TMM) on clinical outcomes in highrisk neuroblastoma, we integrated the C-circle assay [a marker for alternative lengthening of telomeres (ALT)], TERT mRNA expression by RNA-sequencing, whole-genome/exome sequencing, and clinical covariates in 134 neuroblastoma patient samples at diagnosis. In addition, we assessed TMM in neuroblastoma cell lines (n ¼ 104) and patient-derived xenografts (n ¼ 28). ALT was identified in 23.4% of high-risk neuroblastoma tumors and genomic alterations in ATRX were detected in 60% of ALT tumors; 40% of ALT tumors lacked genomic alterations in known ALT-associated genes. Patients with high-risk neuroblastoma were classified into three subgroups (TERT-high, ALT þ , and TERT-low/non-ALT) based on presence of C-circles and TERT mRNA expression (above or below median TERT expression). Event-free survival was similar among TERT-high, ALT þ , or TERT-low/non-ALT patients. However, overall survival (OS) for TERT-low/non-ALT patients was significantly higher relative to TERT-high or ALT patients (log-rank test; P < 0.01) independent of current clinical and molecular prognostic markers. Consistent with the observed higher OS in patients with TERT-low/non-ALT tumors, continuous shortening of telomeres and decreasing viability occurred in low TERT-expressing, non-ALT patient-derived high-risk neuroblastoma cell lines. These findings demonstrate that assaying TMM with TERT mRNA expression and C-circles provides precise stratification of high-risk neuroblastoma into three subgroups with substantially different OS: a previously undescribed TERT-low/non-ALT cohort with superior OS (even after relapse) and two cohorts of patients with poor survival that have distinct molecular therapeutic targets.Significance: These findings assess telomere maintenance mechanisms with TERT mRNA and the ALT DNA biomarker C-circles to stratify neuroblastoma into three groups, with distinct overall survival independent of currently used clinical risk classifiers.
Purpose Prophylactic cranial irradiation (PCI) can improve overall survival (OS) and suppress brain metastases (BM) in patients with limited-stage small cell lung cancer (LS-SCLC) after complete response to primary therapy. However, PCI can be toxic. We sought to identify characteristics of patients who may not benefit from PCI. Methods We identified 658 patients who received chemoradiotherapy at MD Anderson in 1986–2012; 364 received PCI and 294 did not. Median follow-up time was 21.2 months (range 1.2–240.8 months). Cox proportional hazards regression, competing-risk regression, and Kaplan-Meier analyses were used to identify factors influencing OS and BM. Results PCI reduced risks of death [HR 0.73, 95% CI 0.61–0.88, P=0.001] and BM [HR 0.54, 95% CI 0.39–0.76, P<0.001]. Having tumors ≥5 cm increased the risk of BM [HR 1.77, 95% CI 1.22–2.55, P=0.002] but not death [HR 1.16, 95% CI 0.96–1.40, P=0.114]. Among patients ≥70 years with ≥5-cm tumors, PCI did not improve OS [2-year rates 39.4% vs 40.9%, P=0.739]. Conclusions PCI remains standard therapy after complete response to chemoradiotherapy for LS-SCLC. However, older patients may be at risk from comorbidity or extracranial disease. Further work is warranted to identify patients who may not benefit from PCI.
Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere length maintenance mechanism that enables the unlimited proliferation of a subset of cancer cells. Some neuroblastoma (NB) tumors appear to maintain telomere length by activating ALT. Of 40 NB cell lines, we identified four potential ALT cell lines (CHLA-90, SK-N-FI, LA-N-6, and COG-N-291) that were telomerase-negative and had long telomeres (a feature of ALT cells). All four cell lines lacked MYCN amplification and were p53 non-functional upon irradiation. Two of these cell lines (CHLA-90 and SK-N-FI) were positive for C-circles (telomeric DNA circles) and ALT-associated promyelocytic leukemia nuclear bodies, both of which are phenotypic characteristics of ALT. Mutation of ATRX (associated with ALT in tumors) was only found in CHLA-90. Thus, the ALT phenotype in NB may not be limited to tumors with ATRX mutations but is associated with a lack of MYCN amplification and alterations in the p53 pathway.
Cancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ~25% of high-risk neuroblastomas, and progression in patients with ALT neuroblastoma during or after front-line therapy is frequent and often fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma. Patient-derived cell lines and xenografts established from patients with relapsed ALT neuroblastoma demonstrated de novo resistance to temozolomide + irinotecan [SN-38 in vitro, P < 0.05; in vivo mouse event-free survival (EFS), P < 0.0001] vs. telomerase-positive neuroblastomas. We observed that ALT neuroblastoma cells manifested constitutive ataxia-telangiectasia mutated (ATM) activation due to spontaneous telomere dysfunction which was not observed in telomerase-positive neuroblastoma cells. We demonstrated that induction of telomere dysfunction resulted in ATM activation that, in turn, conferred resistance to temozolomide + SN-38 (4.2-fold change in IC50, P < 0.001). ATM knockdown (shRNA) or inhibition using a clinical-stage small-molecule inhibitor (AZD0156) reversed resistance to temozolomide + irinotecan in ALT neuroblastoma cell lines in vitro (P < 0.001) and in four ALT xenografts in vivo (EFS, P < 0.0001). AZD0156 showed modest to no enhancement of temozolomide + irinotecan activity in telomerase-positive neuroblastoma cell lines and xenografts. Ataxia telangiectasia and Rad3 related (ATR) inhibition using AZD6738 did not enhance temozolomide + SN-38 activity in ALT neuroblastoma cells. Thus, ALT neuroblastoma chemotherapy resistance occurs via ATM activation and is reversible with ATM inhibitor AZD0156. Combining AZD0156 with temozolomide + irinotecan warrants clinical testing for neuroblastoma.
Objectives: Comprehensive local consolidative therapy led to improved overall survival in oligometastatic non-small cell lung cancer in a recent phase II trial, yet the role of pulmonary resection in ongoing oligometastatic trials is a matter of controversy. We sought to examine outcomes after pulmonary resection with radiotherapy used as a benchmark comparator.Methods: Patients treated at a single institution (2000-2017) with cT1-3N0-2M1 non-small cell lung cancer, 3 or less synchronous metastases, and performance status 0 to 1, and who received comprehensive local consolidative therapy were analyzed according to local consolidative therapy modality for the primary lesion. Progression was analyzed with death as a competing risk.
Objectives We reviewed our experience treating patients with localized extraskeletal Ewing sarcoma (EES) to determine optimal local management strategies for this rare disease. Methods Sixty patients with localized EES treated at our institution between 1994 and 2018 were reviewed. The Kaplan‐Meier method was used to estimates disease outcomes. Results The median follow‐up time was 74 months (interquartile range [IQR], 17–121). Half the patients (n = 30) received combined‐modality local therapy (CMT) with both surgery and radiation therapy (RT), whereas the other half received single‐modality local therapy (SMT) with either surgery or RT. All patients received chemotherapy. The 5‐year overall survival was 76%. Twenty‐two patients (37%) developed recurrence at a median time of 15 months (IQR, 5–56 months) resulting in 3‐year progression‐free survival (PFS) of 65%. On univariate analysis, the use of both neoadjuvant and adjuvant chemotherapy was associated with improved 5‐year PFS (71% vs. 50%, p = .04) compared with those who received one or the other. Furthermore, 11 patients (18%) developed local recurrences at a median time of 14 months (IQR, 2–19 months), resulting in a 5‐year local control (LC) rate of 77%. Use of CMT was not associated with improved LC (83% vs. 72% SMT, p = .41). Also, use of CMT was the only factor associated with poorer disease‐specific survival (vs. SMT; hazard ratio, 3.4; p = .047; 95% confidence interval, 1.01–11.4). Conclusion For patients with EES, CMT was not associated with a decreased rate of local relapse. These data suggest that SMT alone may be sufficient for LC in select patients. A multi‐institutional collaborative effort should be considered to validate these findings. Implications for Practice Extraskeletal Ewing sarcoma is a rare chemosensitive sarcoma whose clinical course more closely follows Ewing sarcoma of bone rather than that of other soft tissue sarcomas. Based on this study, combined‐modality local therapy did not confer a local control advantage compared with single‐modality local therapy. Therefore, single‐modality local therapy is likely adequate in select patients with favorable disease features, which has the advantage of ensuring prompt administration of systemic therapy. A multi‐institutional collaborative effort is warranted to determine which patients may benefit from de‐escalated local therapy.
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