Therapeutic Implication of Genomic Landscape of Adult Metastatic Sarcoma.

PURPOSE: This study investigated therapeutic potential of integrated genome and transcriptome profiling of metastatic sarcoma, a rare but extremely heterogeneous group of aggressive mesenchymal malignancies with few systemic therapeutic options. METHODS: Forty-three adult patients with advanced or metastatic non-GI stromal tumor sarcomas of various histology subtypes who were enrolled in the Personalized OncoGenomics program at BC Cancer were included in this study. Fresh tumor tissues along with blood samples underwent whole-genome and transcriptome sequencing. RESULTS: The most frequent genomic alterations in this cohort are large-scale structural variation and somatic copy number variation. Outlier RNA expression as well as somatic copy number variations, structural variations, and small mutations together suggest the presence of one or more potential therapeutic targets in the majority of patients in our cohort. Point mutations or deletions in known targetable cancer genes are rare; for example, tuberous sclerosis complex 2 provides a rationale for targeting the mammalian target of rapamycin pathway, resulting in a few patients with exceptional clinical benefit from everolimus. In addition, we observed recurrent 17p11-12 amplifications, which seem to be a sarcoma-specific event. This may suggest that this region harbors an oncogene(s) that is significant for sarcoma tumorigenesis. Furthermore, some sarcoma tumors carrying a distinct mutational signature suggestive of homologous recombination deficiency seem to demonstrate sensitivity to double-strand DNA-damaging agents. CONCLUSION: Integrated large-scale genomic analysis may provide insights into potential therapeutic targets as well as novel biologic features of metastatic sarcomas that could fuel future experimental and clinical research and help design biomarker-driven basket clinical trials for novel therapeutic strategies.

Diagnostic value of next-generation sequencing in an unusual sphenoid tumor.

Extraordinary advancements in sequencing technology have made what was once a decade-long multi-institutional endeavor into a methodology with the potential for practical use in a clinical setting. We therefore set out to examine the clinical value of next-generation sequencing by enrolling patients with incurable or ambiguous tumors into the Personalized OncoGenomics initiative at the British Columbia Cancer Agency whereby whole genome and transcriptome analyses of tumor/normal tissue pairs are completed with the ultimate goal of directing therapeutics. First, we established that the sequencing, analysis, and communication with oncologists could be completed in less than 5 weeks. Second, we found that cancer diagnostics is an area that can greatly benefit from the comprehensiveness of a whole genome analysis. Here, we present a scenario in which a metastasized sphenoid mass, which was initially thought of as an undifferentiated squamous cell carcinoma, was rediagnosed as an SMARCB1-negative rhabdoid tumor based on the newly acquired finding of homozygous SMARCB1 deletion. The new diagnosis led to a change in chemotherapy and a complete nodal response in the patient. This study also provides additional insight into the mutational landscape of an adult SMARCB1-negative tumor that has not been explored at a whole genome and transcriptome level.

Acute saddle pulmonary embolism in Ewing sarcoma.

Two young adults had similar presentations of Ewing sarcoma, with spinal cord involvement and significant neurologic deficits. Shortly after workup, stabilization, and initiation of chemotherapy, both developed acute saddle pulmonary embolism, despite prophylactic anticoagulation. In both cases, prompt intravenous thrombolysis and therapeutic anticoagulation successfully managed this complication. Review of the presentation, treatment options, and most current guidelines for acute saddle pulmonary embolism follow the case presentations.

Patterns of relapse in breast cancer: changes over time.

Adjuvant systemic treatment for breast cancer has evolved resulting in improved outcomes. A relevant question is whether these advances have changed the pattern of distant relapse. Women diagnosed with stage I-III breast cancer were divided into three time cohorts according to changes in adjuvant therapy; A: 1989-1991-CMF chemotherapy in premenopausal and tamoxifen for postmenopausal women; B: 1992-1997-anthracycline chemotherapy and tamoxifen for pre/postmenopausal women; C: 1998-2001-broader use of anthracyclines. The primary endpoint was 5-year cumulative incidence of bone metastasis (BM) as first site of metastasis (FSOM) versus non-bone metastasis (NBM). The ratios NBM/BM in each period were calculated. The eligibility criteria were met by 21,415 cases; Cohorts A: 1989-1991 (n = 3,915), B: 1992-1997 (n = 9,229) and C: 1998-2001 (n = 8,271). Between 1989 and 2001, the percentage of patients receiving adjuvant chemotherapy increased from 23.1 to 34.4%. A decline in cumulative 5-year incidence rates for BM and NBM as FSOM was seen comparing cohort A to C, P < 0.0001. The ratio NBM/BM was significantly increased from 1.53 in the early cohort to 2.00 in the later one, P = 0.0083. The most prominent increase (84%) was in the ER-negative group, chemotherapy treated, P = 0.0272. A significant decline in 5-year cumulative incidence of metastases and an increase in the proportion of NBM as first site of metastasis were observed between earlier and later cohorts. This may reflect the need for more successful adjuvant treatment options for aggressive breast cancer subtypes which are more likely to present with early spread to visceral organs. Understanding patterns of relapse may help design new adjuvant strategies.

Verification of imatinib cost-effectiveness in advanced gastrointestinal stromal tumor in British Columbia (VINCE-BC study).

BACKGROUND: This cost-effectiveness analysis of imatinib in British Columbia Cancer Agency (BCCA) patients with advanced gastrointestinal stromal tumors (GIST) was performed to justify funding. PATIENTS AND METHODS: A pragmatic, retrospective review identified BCCA patients with advanced GIST who received imatinib or historical treatment during successive, pre-specified time periods. Primary outcome was the cost-effectiveness (CE) of imatinib based on median overall survival (MOS). Secondary outcomes were cost-effectiveness based on median progression-free survival (PFS) and comparison to literature efficacy. This study took the BCCA perspective. Sensitivity analyses varying effectiveness over the 95% confidence interval (CI), cost to its extremes, discounting level at 0, 3, and 5%, and substituting life expectancy for MOS were performed. RESULTS: Forty-six and 47 patients in the imatinib and historical groups respectively showed MOS with imatinib to be 66.7 months (95%CI 61.7- infinity) compared to 7.7 (95%CI 6.0-12.6) in the historical group. Median-PFS were 45.3 months (95%CI 24.4-infinity) and 5.6 (95%CI 3.5-8.5) respectively. Imatinib effectiveness was similar to literature reports. The annual incremental CE ratio for imatinib was $15,882 CDN per median life year gained and $23,603 CDN per median year of PFS. CONCLUSIONS: Imatinib for advanced GIST seems cost-effective in BC. RESULT: were robust across a range of sensitivity analyses.