Genomic Profiling of Rare Undifferentiated Sarcomatoid Subtypes of Pancreatic Carcinomas: In Search of Therapeutic Targets.

PURPOSE: The highly aggressive undifferentiated sarcomatoid carcinoma (USC) subtype of pancreatic ductal adenocarcinoma (PDAC) remains poorly characterized because of its rarity. Previous case reports suggest that immune checkpoint inhibitors could be a promising treatment strategy, but the prevalence of established predictive biomarkers of response is largely unknown. The objective of this study was to leverage comprehensive genomic profiling of USC PDAC tumors to determine the prevalence of biomarkers associated with potential response to targeted therapies. METHODS: USC tumors (n = 20) underwent central pathology review by a board-certified gastrointestinal pathologist to confirm the diagnosis. These samples were compared with non-USC PDAC tumors (N = 5,562). Retrospective analysis of DNA and RNA next-generation sequencing data was performed. RESULTS: USC PDACs were more frequently PD-L1+ by immunohistochemistry than non-USC PDAC (63% v 16%, respectively, P < .001). Furthermore, USC PDAC had an increase in neutrophils (8.99% v 5.55%, P = .005) and dendritic cells (1.08% v 0.00%, q = 0.022) and an increased expression of PDCD1LG2 (4.6% v 1.3%, q = 0.001), PDCD1 (2.0% v 0.8%, q = 0.060), and HAVCR2 (45.9% v 21.7%, q = 0.107) than non-USC PDAC. Similar to non-USC PDAC, KRAS was the most commonly mutated gene (86% v 90%, respectively, P = 1). CONCLUSION: To our knowledge, this work represents the largest molecular analysis of USC tumors to date and showed an increased expression of immune checkpoint genes in USC tumors. These findings provide evidence for further investigation into immune checkpoint inhibitors in USC tumors.

The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors.

Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16-2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design.

Molecular Characterization of TFE3-Rearranged Renal Cell Carcinoma: A Comparative Study With Papillary and Clear Cell Renal Cell Carcinomas.

TFE3-rearranged renal cell carcinoma (rRCC) is a rare subtype of renal cell carcinomas belonging to the MiT family translocation RCC. To further elucidate the co-alterations that occur along with TFE3 fusions in rRCC, we characterized the genomic, transcriptional, and immune landscapes in comparison to clear cell (ccRCC) and papillary renal cell carcinoma (pRCC). Next-generation sequencing of RNA (whole transcriptome) and DNA (592-gene panel or whole exome) for rRCC (N = 20), pRCC (N = 20), and ccRCC samples (N = 392) was performed. Patients with rRCC were significantly younger and more frequently female (median 44.5 years, 75.0% female) as compared with patients with pRCC (68.5 years, 25.0% female; P < .05) and ccRCC (62.0 years, 27.8% female; P < .05). A total of 8 unique fusion partners were observed, including a novel fusion with SRRM2::TFE3 in 2 patients. ccRCC exhibited significantly higher mutation rates of VHL (0% rRCC, 0% pRCC, 78.7% ccRCC; P < .05) and PBMR1 (0% rRCC, 5.0% pRCC, 49.4% ccRCC; P < .05). The genomic landscapes of rRCC were sparse with no mutations occurring with a prevalence higher than 10% other than pTERT (18.2% rRCC, 0% pRCC, 9.2% ccRCC). rRCC were associated with significantly less M1 macrophages (0.8%) as compared with pRCC (1.4%) and ccRCC (2.7%) (P < .05), suggesting a cold tumor-immune microenvironment. However, rRCC were more commonly PD-L1+ (rRCC 50%, pRCC 19.0%, ccRCC 12.2%; P < .05). Gene set enrichment analysis showed that rRCC are enriched in genes related to oxidative phosphorylation when compared with both ccRCC and pRCC. Despite having a colder tumor-immune microenvironment than pRCC and ccRCC, increased PDL1+ rates in rRCC suggest a potential benefit from immune checkpoint inhibitor therapy.

The Genomic Landscape of Urothelial Carcinoma with High and Low ERBB2 Expression.

BACKGROUND: Recent data suggests that HER2-targeted treatment is efficacious in urothelial carcinoma (UC). We investigated the genomic, transcriptomic, and immune landscapes and clinical outcomes in UC segmented by ERBB2 expression. METHODS: NextGen DNA/RNA sequencing was performed for 4743 UC tumors. A total of 3% (124/4125) of tumors had HER2 IHC and whole transcriptome sequencing (WTS) data. ERRB2-high and -low tumors were defined by ≥75th and <25th percentiles of ERBB2 expression, respectively. PD-L1 (SP142) positive staining was defined as ≥2+ and ≥5%. HER2 (4B5) positive staining was defined as ≥3+ and >10% or 2+ and >10% with positive HER2 in situ hybridization (ISH). RESULTS: Of the patients who were ERBB2-high, 79% (61/77) were HER2 positive via IHC. Tumors from lower tract UC had higher ERBB2 expression compared to upper tract UC (50 v 40 median TPM (mTPM), p < 0.001). ERBB2 expression was similar between primary and metastatic tumors (47 v 47 mTPM, p = 0.95). ERBB2-high tumors had a higher prevalence of pathogenic mutations in pTERT, ERBB2, and ELF3 versus ERBB2-low tumors, p < 0.001. ERBB2-high tumors had higher expressions of ADC target genes NECTIN4 (12 v 8 mTPM) and TACSTD2 (366 v 74 mTPM) versus ERBB2-low (p < 0.001), as well as better overall survival from time of tissue sampling than ERBB2-low (HR 1.71, p < 0.001). CONCLUSION: Our study demonstrated a high concordance between HER2 expression by IHC and ERBB2 gene expression by WTS in UC. Differences in ADC target expression between ERBB2-high vs. ERBB2-low UC may provide a rationale for combination treatment strategies with HER2-ADC. The association between high ERBB2 expression and survival advantage warrants further investigation.

Alternatively-Activated Macrophages Upregulate Mesothelial Expression of P-Selectin to Enhance Adhesion of Ovarian Cancer Cells.

Peritoneal metastasis of high-grade serous ovarian cancer (HGSOC) occurs when tumor cells suspended in ascites adhere to mesothelial cells. Despite the strong relationship between metastatic burden and prognosis in HGSOC, there are currently no therapies specifically targeting the metastatic process. We utilized a coculture model and multivariate analysis to examine how interactions between tumor cells, mesothelial cells, and alternatively-activated macrophages (AAM) influence the adhesion of tumor cells to mesothelial cells. We found that AAM-secreted MIP-1ß activates CCR5/PI3K signaling in mesothelial cells, resulting in expression of P-selectin on the mesothelial cell surface. Tumor cells attached to this de novo P-selectin through CD24, resulting in increased tumor cell adhesion in static conditions and rolling underflow. C57/BL6 mice treated with MIP-1ß exhibited increased P-selectin expression on mesothelial cells lining peritoneal tissues, which enhanced CaOV3 adhesion ex vivo and ID8 adhesion in vivo Analysis of samples from patients with HGSOC confirmed increased MIP-1ß and P-selectin, suggesting that this novel multicellular mechanism could be targeted to slow or stop metastasis in HGSOC by repurposing anti-CCR5 and P-selectin therapies developed for other indications.Significance: This study reports novel insights on the peritoneal dissemination occurring during progression of ovarian cancer and has potential for therapeutic intervention.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3560/F1.large.jpg Cancer Res; 78(13); 3560-73. ©2018 AACR.