Alexander J. Lazar

Unlucky number 13? Differential effects of KIT exon 13 mutation in gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) represents the majority of soft tissue sarcomas arising from the GI tract. Most GISTs encode activating mutations in the kit gene, an important genetic event in tumorigenesis. Imatinib mesylate (imatinib, Gleevec™; Novartis, Basel, Switzerland) has revolutionized the management of patients with advanced disease by targeting the aberrant kinase activity of Kit.

Role of chemotherapy in dedifferentiated liposarcoma of the retroperitoneum: defining the benefit and challenges of the standard

Benefit from chemotherapy for well-differentiated/de-differentiated (WD/DD) liposarcomas has been reported to be minimal, however traditional response criteria may not adequately capture positive treatment effect. In this study, we evaluate benefit from first-line chemotherapy and characterize imaging response characteristics in patients with retroperitoneal (RP) WD/DD liposarcoma treated at The University of Texas MD Anderson Cancer Center. Response was assessed using RECIST (Response Evaluation Criteria in Solid Tumors) and an exploratory analysis of vascular response was characterized. Among 82 patients evaluable for response to first-line therapy, 31 patients received neoadjuvant chemotherapy for localized/locally advanced disease; 51 received chemotherapy for unresectable recurrent/metastatic disease. Median overall survival from the start of chemotherapy was 29 months (95% CI 24–40 months). Response rates by RECIST: partial response (PR) 21% (17/82), stable disease (SD) 40%, and progression (PD) 39%. All RECIST responses were in patients receiving combination chemotherapy. A qualitative vascular response was seen in 24 patients (31%). Combination chemotherapy yields a response rate of 24% and a clinical benefit rate (CR/PR/SD > 6 months) of 44%, higher than previously reported in DD liposarcoma. A higher percentage of patients experience a vascular response with chemotherapy that is not adequately captured by RECIST in these large heterogeneous tumors.

Soft Tissue Sarcoma of the Head and Neck

Risk Assessment Models The AJCC recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use. Although this is a monumental step toward the goal of precision medicine, this work was published only very recently. Therefore, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine Core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.

Soft Tissue Sarcoma of the Trunk and Extremities

Risk Assessment Models The AJCC has recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use. Although this is a monumental step forward towards the goal of precision medicine, this work was only very recently published. For this reason, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.

Biological Validation of RNA Sequencing Data From Formalin-Fixed Paraffin-Embedded Primary Melanomas

PURPOSE Initiatives such as The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) have generated high-quality, multi-platform molecular data from thousands of frozen tumor samples. While these initiatives have provided invaluable insight into cancer biology, a tremendous potential resource remains largely untapped in formalin-fixed, paraffin-embedded (FFPE) samples that are more readily available, but which can present technical challenges due to crosslinking of fragile molecules such as RNA. MATERIALS AND METHODS We extracted RNA from FFPE primary melanomas and assessed two gene expression platforms -- genome-wide RNA sequencing (RNA-seq) and targeted NanoString -- for their ability to generate coherent biological signals. To do so, we generated an improved approach to quantifying gene expression pathways, in which we refine pathway scores through correlation-guided gene subsetting. We also make comparisons to the TCGA and other publicly available melanoma datasets. RESULTS Comparison of the gene expression patterns to each other, to established biological modules, and to clinical and immunohistochemical data confirmed the fidelity of biological signals from both platforms using FFPE samples to known biology. Moreover, correlations with patient outcome data were consistent with previous frozen-tissue-based studies. CONCLUSION FFPE samples from previously difficult-to-access cancer types - such as small primary melanomas - represents a valuable and previously unexploited source of analyte for RNA-seq and NanoString platforms. This work provides an important step towards the use of such platforms to unlock novel molecular underpinnings and inform future biologically-driven clinical decisions.

Genomic profiling of dedifferentiated liposarcoma compared to matched well-differentiated liposarcoma reveals higher genomic complexity and a common origin

Well-differentiated (WD) liposarcoma is a low-grade mesenchymal tumor with features of mature adipocytes and high propensity for local recurrence. Often, WD patients present with or later progress to a higher-grade nonlipogenic form known as dedifferentiated (DD) liposarcoma. These DD tumors behave more aggressively and can metastasize. Both WD and DD liposarcomas harbor neochromosomes formed from amplifications and rearrangements of Chr 12q that encode oncogenes (MDM2, CDK4, and YEATS2) and adipocytic differentiation factors (HMGA2 and CPM). However, genomic changes associated with progression from WD to DD have not been well-defined. Therefore, we selected patients with matched WD and DD tumors for extensive genomic profiling in order to understand their clonal relationships and to delineate any defining alterations for each entity. Exome and transcriptomic sequencing was performed for 17 patients with both WD and DD diagnoses. Somatic point and copy-number alterations were integrated with transcriptional analyses to determine subtype-associated genomic features and pathways. The results were, on average, that only 8.3% of somatic mutations in WD liposarcoma were shared with their cognate DD component. DD tumors had higher numbers of somatic copy-number losses, amplifications involving Chr 12q, and fusion transcripts than WD tumors. HMGA2 and CPM rearrangements occur more frequently in DD components. The shared somatic mutations indicate a clonal origin for matched WD and DD tumors and show early divergence with ongoing genomic instability due to continual generation and selection of neochromosomes. Stochastic generation and subsequent expression of fusion transcripts from the neochromosome that involve adipogenesis genes such as HMGA2 and CPM may influence the differentiation state of the subsequent tumor.

Soft Tissue Sarcoma of the Abdomen and Thoracic Visceral Organs

Risk Assessment Models The AJCC has recently established guidelines that will be used to evaluate published statistical prediction models for the purpose of granting endorsement for clinical use. Although this is a monumental step forward towards the goal of precision medicine, this work was only very recently published. For this reason, the existing models that have been published or may be in clinical use have not yet been evaluated for this cancer site by the Precision Medicine core of the AJCC. In the future, the statistical prediction models for this cancer site will be evaluated, and those that meet all AJCC criteria will be endorsed.

Soft Tissue Sarcoma – Unusual Histologies and Sites

Emerging Prognostic Factors for Clinical Care The Cancer Genome Atlas and other efforts have genomically characterized several sarcomas. These data, however, do not yet have an impact on prognosis or definitive predictive value for response to treatment to date. For example, it is recognized that mutations in TP53 and CDKN2A are common in aneuploid tumors, but the data regarding these alterations and their impact on staging and treatment remain too sparse to form any recommendations.

Abstract 2286: Targeting the notch pathway: A potential therapeutic approach for desmoid tumors

Desmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF-03084014, a potent γ-secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/β-catenin pathway. Consequently, Notch pathway inhibition by PF-03084014 might be a promising approach for DT treatment. The expression of Notch pathway components was analyzed in DT tissues and cell strains with immunohistochemistry and Western blotting, respectively. A panel of DT cell strains was exposed to PF-03084014 and evaluated for cell proliferation. Antitumor effects were assessed via cell cycle, apoptosis, and migration and invasion analysis. Cells treated with PF-03084014 were characterized with a gene array analysis combined with Ingenuity Pathway Analysis. The results showed that Notch pathway components were expressed at different levels in DTs. Hes1 (Hes Family BHLH Transcription Factor 1) was overexpressed in DT tumors versus dermal scar tissue, and PF-03084014 caused significant decreases in Notch intracellular domain and Hes1 expression in DT cell strains. PF-03084014 decreased DT cell migration and invasion and also caused cell growth inhibition in DT cell strains, most likely through cell cycle arrest. Gene array analysis combined with Ingenuity Pathway Analysis showed that Wnt1-inducible signaling pathway protein 2 possibly regulated Notch and WNT pathways after treatment with PF-03084014 through integrin. Our findings suggest that the Notch pathway is an important DT therapeutic target. Furthermore, PF-03084014 has significant antitumor activity against DTs, and it may be an alternative strategy for DT treatment. Citation Format: Danielle Braggio, Hui Shang, Ya-Jung Lee, Ghadah A. Al-Sannaa, Chad J. Creighton, Svetlana Bolshakov, Alexander JF Lazar, Dina Lev, Raphael E. Pollock. Targeting the notch pathway: A potential therapeutic approach for desmoid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2286.