Massive Malignant Epithelioid Angiomyolipoma of the Kidney

Renal angiomyolipomas (AMLs) are a subset of perivascular epithelioid cell neoplasms (PEComas) that are associated with tuberous sclerosis complex (TSC). Epithelioid angiomyolipomas (EAMLs) are a rare variant of AML with more aggressive propensities. EAMLs with malignant potential can be difficult to distinguish from relatively benign AMLs and other renal tumors. Although there are no established criteria for predicting EAML malignancy, there are proposed histologic parameters that are associated with higher tumor risk. EAML can be treated with surgical resection as well as mTOR inhibitors. Here, we present a unique case of a patient with a 36-cm renal EAML metastatic to the lungs that was treated with complete surgical resection of the primary lesion and mTOR inhibition

Unique Aberrations in Intimal Sarcoma Identified by Next-Generation Sequencing as Potential Therapy Targets

Intimal sarcomas are rare and histologically heterogeneous tumors, commonly arising from the pulmonary arteries. They have remained challenging to treat. Few studies in the literature study the genomics of this cancer. Identifying targetable alterations is an important step in advancing the treatment of intimal sarcomas. Using data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR GENIE) database, we cataloged genetic alterations and assessed their clinical utility from thirteen patients with intimal sarcoma. Notable copy number alterations included amplification in MDM2, CDK4, PDGFRA, and NOTCH2, as well as copy number losses in CDKN2A and CDKN2B. Actionable alterations included mutations in ATM/ATR, PTCH1, and PDGFRB. Moreover, genomic rearrangement events, specifically PDE4DIP-NOTCH2 and MRPS30-ARID2 fusions were identified. Co-occurring alterations included a NOTCH2 copy number gain in the PDE4DIP-NOTCH2 fusion positive tumor and PDGFRB mutations in both fusion-positive cases. Our study suggests that PDGFRB may be relevant in the tumorigenesis process. Including genomic profiling in the management of intimal sarcoma and potential enrollment in targeted therapy trials is warranted

Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials

Abstract Background Immunotherapies, specifically those based on immune checkpoint inhibitors, have shown promising activity in multiple tumor types. Other than mifamurtide (MEPACT®) for osteosarcoma approved by European Medicines Agency, there are no approved immunotherapies for sarcomas. Methods We analyzed medical records of patients with advanced sarcoma who were referred to Phase 1 clinic at MD Anderson and received an immunotherapy (checkpoint inhibitors, vaccines, or cytokine based therapies). Clinical parameters including demographics, clinical history, toxicity, and response were abstracted. Results Among 50 patients enrolled in immunotherapy trials (Bone 10; Soft-tissue 40) we found 14 different subtypes of sarcomas. Royal Marsden Hospital (RMH) prognostic score was <2 (86%). Performance status (PS) was 0–1 in 48 patients (96%); median number of prior therapies was 3 (0–12). Immunotherapy consisted of checkpoint inhibitors (82%: PD1 = 7, PD-L1 = 11, CTLA4 = 22, other = 1) of which 42% were combinations, as well as vaccines (14%), and cytokines (4%). Median overall survival (OS) was 13.4 months (11.2 months: not reached). Median progression free survival (PFS) was 2.4 months (95% CI = 1.9–3.2 months). Best response was partial response (PR) in 2 patients with alveolar soft part sarcoma (ASPS) and stable disease (SD) in 11 patients (3 GIST, 3 liposarcomas (2 DDLS, 1 WDLS), 2 ASPS, 2 leiomyo, 1 osteo). PFS was 34% (23%, at 50%) at 3 months, 16% (8%, 30%) at 6 months, and 6% (2%, 20%) at 1 year. Pseudo-progression followed by stable disease was observed in 2 patients (4%). Grade 3/4 adverse events included rash (10%), fever (6%), fatigue (6%), and nausea/vomiting (6%). Conclusion Immunotherapies were well tolerated in advanced sarcoma patients enrolled in trials. All four ASPS patients had clinical benefit with checkpoint inhibitors and this was the only subtype experiencing partial response. Further evaluation of checkpoint inhibitors in ASPS is warranted

Deciphering the molecular landscape and the tumor microenvironment of perivascular epitheloid cell neoplasma (PEComa)

11539 Background: PEComa is a rare mesenchymal neoplasm composed of perivascular epithelioid cells. Due to its rarity, diagnosis is challenging and no standardized treatment guidelines have been established. A subgroup of PEComas are characterized by a loss of function mutation in TSC1/2 that activates the PIK3-Akt-mTOR pathway. In the majority of patients, however, the molecular landscape and the composition of the tumor microenvironment (TME) remain largely unclear. Thus, we conducted this study to elucidate the genetic landscape of PEComas. A comparative analysis was performed with melanoma as a representative immunogenic tumor type. Methods: Thirty-five PEComa specimens were centrally analysed at the Caris Life Sciences laboratory. NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome-sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ) were performed. Gene expression profiling (GEP) was performed by unsupervised hierarchical clustering. RNA deconvolution analysis was performed using the Microenvironment Cell Populations (MCP)-counter method to quantify immune cell populations (Becht 2016, Genome Biology). Results: The most common mutations detected in this cohort were TP53 (47%), ATRX (32%), TSC1/2 (11%/29%) and MSH3 (17%). Interestingly, TP53 mutations occurred less frequently (25 vs 60%, p = 0.055) in TSC1/2-mutated ( TSC1/2-mt) compared to TSC1/2-wildtype ( TSC1/2-wt) tumors, whereas MSH3 (25%, n = 1/4) and ERCC2 (14%, n = 2/14) mutations were exclusively observed in TSC1/2-mt cases. TSC1/2 mutations and other mTOR signalling pathway alterations, including two TFE gene fusion transcripts, were mutually exclusive. Of note, we found that 33.3% (n = 2) of TSC2-mt tumors were associated with high PIK3-Akt-mTOR pathway expression, while 100% (n = 3) of TSC1-mt tumors demonstrated lower expression. Deficient mismatch repair/microsatellite instability-high and high tumor mutational burden were rare (2.9%, n = 1 each) and observed concurrently in absence of PD-L1 expression. Overall, PD-L1 expression was observed in 21.9% (n = 7) of patients. An exploratory comparison with melanoma revealed that PEComa TMEs were characterized by a significant increase of NK cells and fibroblasts, as well as a relevant decrease of CD8 + T cells and B cells. Conclusions: Within this study we discovered a heterogeneous molecular landscape with a high prevalence of TSC1/2 mutations that were in part associated with transcriptional up-regulation of the PIK3-Akt-mTOR pathway. Furthermore, the relatively immune-cold TME compared to melanoma suggests increased lymphocyte infiltration may be required to increase the efficacy of immune checkpoint inhibitors for PEComa

Phase I study of sapanisertib with carboplatin and paclitaxel in mTOR pathway altered solid malignancies

Abstract Pre-clinically, the mTORC1/2 inhibitor sapanisertib restored sensitivity to platinums and enhanced paclitaxel-induced cancer cell killing. NCT03430882 enrolled patients with mTOR pathway aberrant tumors to receive sapanisertib, carboplatin and paclitaxel. Primary objective was safety and secondary objectives were clinical response and survival. One patient had a dose-limiting toxicity at dose level 4. There were no unanticipated toxicities. Grade 3–4 treatment-related adverse events included anemia (21%), neutropenia (21%), thrombocytopenia (10.5%), and transaminitis (5%). Of 17 patients evaluable for response, 2 and 11 patients achieved partial response and stable disease, respectively. Responders included a patient with unclassified renal cell carcinoma harboring EWSR1-POU5F1 fusion and a patient with castrate resistant prostate cancer harboring PTEN loss. Median progression free survival was 3.84 months. Sapanisertib in combination with carboplatin plus paclitaxel demonstrated a manageable safety profile, with preliminary antitumor activity observed in advanced malignancies harboring mTOR pathway alterations

Multiomic analysis to reveal distinct molecular profiles of uterine and nonuterine leiomyosarcoma.

11555Background: Leiomyosarcoma (LMS) is a rare group of mesenchymal malignancies found in the uterus, retroperitoneum, skin, or other soft-tissue sites. Treatment for LMS is extrapolated from tria..

Large scale multiomic analysis suggests mechanisms of resistance to immunotherapy in leiomyosarcoma.

11512Background: Leiomyosarcomas (LMS) have been reported to have immunohistochemical (IHC) and gene expression signatures suggestive of an immune-responsive tumor microenvironment. Despite this, i..