Subclonal Somatic Copy-Number Alterations Emerge and Dominate in Recurrent Osteosarcoma.

Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease. SIGNIFICANCE: The chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.

Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma.

Multiple large-scale tumor genomic profiling efforts have been undertaken in osteosarcoma, however, little is known about the spatial and temporal intratumor heterogeneity and how it may drive treatment resistance. We performed whole-genome sequencing of 37 tumor samples from eight patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. We identified subclonal copy number alterations in all but one patient. We observed that in five patients, a subclonal copy number clone from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clone in 6 out of 7 patients with more than one clone. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy number clones. Our study sheds light on intratumor heterogeneity and the potential drivers of treatment resistance in osteosarcoma.

Survey of Paediatric Oncologists and Pathologists regarding Their Views and Experiences with Variant Translocations in Ewing and Ewing-Like Sarcoma: A Report of the Children's Oncology Group.

Advances in molecular diagnostics have identified subsets of Ewing and Ewing-like sarcomas driven by variant translocations with unique biology. It is likely that patients with these tumours will have different clinical features and therapeutic outcomes. Nevertheless, the management of these patients both locally and within cooperative group trials depends on the local pathological diagnosis. It is not known what molecular diagnostic approaches are employed by local pathologists or if the exact translocation is commonly determined. In addition, it is not known what therapeutic approaches are employed for these patients or what cooperative trials are deemed appropriate for these patients by expert consensus. To answer these questions, we performed an international survey of oncologists and pathologists to better understand the diagnostic approaches used to identify variant translocations and the influence the findings have on therapy and clinical trial eligibility. An online survey was distributed to oncologists and pathologists primarily in North America. A total of 141 surveys were completed, representing a 28% response rate. The majority of respondents considered EWSR1-ETS gene family translocations (range 61-96%) to be Ewing sarcoma and would include them on the primary arm of a Ewing sarcoma clinical trial. There was a lack of consensus on how to classify and stratify BCOR-CCNB3, CIC-DUX4, and EWSR1+ with non-ETS partner fusions. Most respondents were either unsure how their institution tested, or their institution did not perform the test. In cases with atypical Ewing morphology, most respondents favoured additional fusion transcript testing. There is a lack of consensus regarding the classification and stratification of rare molecular subtypes in Ewing sarcoma. It is not clear how these alternative translocations have impacted outcomes for past clinical studies. This suggests a need for molecular confirmation of diagnoses and centralized or minimum standardization of testing for future trial enrolment.

Central nervous system relapse of rhabdomyosarcoma.

PURPOSE: The optimal management of central nervous system (CNS) relapse of rhabdomyosarcoma (RMS) is unclear. We examined diagnosis, management, and outcomes of patients with RMS developing CNS relapse. METHODS: Records of 23 patients diagnosed with CNS relapse between 1999 and 2016 were reviewed. Median age at presentation of CNS relapse was 15 years (range, 1-34 years). High-risk features at initial presentation were as follows: 16 alveolar patients, 13 Stage IV, and 13 with primary tumor in parameningeal locations. RESULTS: CNS relapse occurred at a median 12 months (range, 1-23 months) from diagnosis and most common presenting symptoms were headache (n = 9), nausea/vomiting (n = 8), visual difficulty (n = 5), and none (n = 5). Leptomeningeal metastases were detected in 21 patients while only 2 developed parenchymal metastases without leptomeningeal involvement. Fifteen patients received CNS-directed radiation therapy (RT), including craniospinal irradiation to a median 36 Gy (range, 18-36 Gy) and/or whole brain radiotherapy to a median 30 Gy (range, 6-41.4 Gy). Three patients received concurrent chemotherapy. Follow-up magnetic resonance imaging was conducted in 13 patients after RT initiation with 8 demonstrating improvement, 2 with stable disease, and 3 with progression. Twelve patients were tested for reactivity to I-131-labeled monoclonal antibody 8H9, and three tested positive and received at least one intra-Ommaya dose; all three lived >12 months post-CNS relapse. Twenty­two patients died of CNS disease and one of treatment complications, with metastatic disease at other sites. Median survival post-CNS relapse was 5 months (range, 0.1-49 months). CONCLUSIONS: The prognosis for patients with RMS developing CNS relapse remains poor. Treatment including CNS-directed RT should be considered and investigation into preventative therapies is warranted.

Advanced-stage renal cell carcinoma treated by radical nephrectomy and adjacent organ or structure resection.

OBJECTIVE: To examine the effect of radical nephrectomy (RN) with adjacent organ and structure resection on survival, as invasion of adjacent organs in patients with renal cell carcinoma (RCC) is rare. PATIENTS AND METHODS: After institutional review board approval, we reviewed our database and statistically analysed of patients with pathological stage T3 or T4 RCC who had RN and resection of a contiguous organ or structure. RESULTS: We identified 38 patients of 2464 (1.5%) who had RN with adjacent organ or structure resection. The median (interquartile range) size of the mass was 11 (8-14) cm, and the follow-up 13 (5-33) months. Most patients (68%) were pT4 stage and had conventional clear cell carcinoma (95%). Fourteen patients (37%) had positive surgical margins. The liver (10) was the most commonly resected adjacent organ or structure. Only one patient remains alive with no evidence of disease at 5 years, while three are currently alive with disease. Overall, 34 of 38 patients (90%) ultimately died from disease at a median (range) of 11.7 (5.4-29.2) months after surgical resection. The surgical margin status was the only statistically significant factor for recurrence and death (P = 0.006). CONCLUSIONS: The prognosis for patients with advanced RCC and adjacent organ or structure involvement is extremely poor and similar to that of patients with metastatic disease. These patients should be thoroughly counselled about the impact of surgical management and considered for entry into neoadjuvant or adjuvant clinical trials with new targeted systemic agents.

Prostate volume and pathologic prostate cancer outcomes after radical prostatectomy.

OBJECTIVES: To more clearly elucidate the relationship between prostate volume (PV) and prostate cancer parameters. METHODS: The Urologic Oncology Database was reviewed. A total of 3460 patients had undergone radical prostatectomy from 1988 to 2006. Of these, 2600 with complete data were included in the study and were stratified by the PV: normal (0 to 40 cm(3)), moderate (40 to 80 cm(3)), or large (greater than 80 cm(3)). The prostate cancer variables were evaluated using analysis of variance. Regression models were used to determine the role of PV in Gleason sum discordance (greater than 1 unit) controlling for prostate-specific antigen level and clinical and pathologic stage. RESULTS: Of the 2600 patients, 1453 (55.2%) had a normal, 1035 (39.8%) a moderate, and 130 (5.0%) a large PV. Patients with a normal PV were more likely to have a Gleason sum greater than 6 at biopsy (46.2%) and radical retropubic prostatectomy (68.4%) compared with patients with a moderate (39.0% and 58.9%, respectively) or a large (41.5% and 57.7%, respectively) PV (P = 0.005 and P = 0.001, respectively). Patients with a normal PV had greater rates of extraprostatic extension (32.3%) and positive margins (28.2%) compared with those with a moderate (25.5% and 22.4%, respectively) or a large (23.3% and 20.3%, respectively) PV (P = 0.002 and P = 0.005, respectively). Of all 2600 patients, 55.9% had no change between the biopsy and pathologic Gleason sum, 255 (9.8%) were downgraded, and 890 (34.3%) were upgraded. Patients with a large PV had a greater rate of downgrading (16.2%) than those with a normal (8.7%) or moderate (10.5%) PV (P = 0.01). Patients upgraded had the greatest rate of pathologically advanced disease (35.3% with Stage T3 or greater, P <0.001). On multivariate regression analysis, PV (odds ratio 0.99, P = 0.005), prostate-specific antigen level (odds ratio 1.03, P <0.001), and age (odds ratio 1.03, P <0.001) were predictors of Gleason discordance +/-2. CONCLUSIONS: The results of our study have shown that patients with a large PV (greater than 80 cm(3)) are more likely to have a lower Gleason sum, locally confined and less-aggressive pathologic disease, and were more often downgraded.