Context.—: The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status. Objective.—: To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy. Design.—: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. Using the National Academy of Medicine–endorsed Grading of Recommendations Assessment, Development and Evaluation approach, the recommendations were derived from available evidence, strength of that evidence, open comment feedback, and expert panel consensus. Mismatch repair immunohistochemistry, microsatellite instability derived from both polymerase chain reaction and next-generation sequencing, and tumor mutation burden derived from large panel next-generation sequencing were within scope. Results.—: Six recommendations and 3 good practice statements were developed. More evidence and evidence of higher quality were identified for colorectal cancer and other cancers of the gastrointestinal (GI) tract than for cancers arising outside the GI tract. Conclusions.—: An optimal assay depends on cancer type. For most cancer types outside of the GI tract and the endometrium, there was insufficient published evidence to recommend a specific clinical assay. Absent published evidence, immunohistochemistry is an acceptable approach readily available in most clinical laboratories.

Black women suffer a higher mortality from endometrial cancer (EC) than White women. Potential biological causes for this disparity include a higher prevalence of obesity and more lethal histologic/molecular subtypes. We hypothesize that another biological factor driving this racial disparity could be the EC microbiome. Banked tumor specimens of postmenopausal, Black and White women undergoing hysterectomy for early stage endometrioid EC were identified. The microbiota of the tumors were characterized by bacterial 16S rRNA sequencing. The microbial component of endometrioid ECs in The Cancer Genome Atlas (TCGA) database were assessed for comparison. 95 early stage ECs were evaluated: 23 Black (24%) and 72 White (76%). Microbial diversity was increased (p<0.001), and Firmicutes, Cyanobacteria and OD1 phyla abundance was higher in tumors from Black versus White women (p<0.001). Genus level abundance of Dietzia and Geobacillus were found to be lower in tumors of obese Black versus obese White women (p<0.001). Analysis of early stage ECs in TCGA found that microbial diversity was higher in ECs from Black versus White women (p<0.05). When comparing ECs from obese Black versus obese White women, 5 bacteria distributions were distinct, with higher abundance of Lactobacillus acidophilus in ECs from Black women being the most striking difference. Similarly in TCGA, Dietzia and Geobacillus were more common in ECs from White women compared to Black. Increased microbial diversity and the distinct microbial profiles between ECs of obese Black versus obese White women suggests that intra-tumoral bacteria may contribute to EC disparities and pathogenesis.

Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few effective treatments for recurrent disease. The objective of this study was to characterize the tumor microenvironment (TME) of primary and recurrent aGCTs and to identify correlates of disease recurrence. Total RNA sequencing (RNA-seq) was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors. After read alignment and quality-control filtering, DESeq2 was used to identify differentially expressed genes (DEG) between primary and recurrent tumors. Functional enrichment pathway analysis and gene set enrichment analysis was performed using “clusterProfiler” and “GSVA” R packages. TME composition was investigated through the analysis and integration of multiple published RNA-seq deconvolution algorithms. TME analysis results were externally validated using data from independent previously published RNA-seq datasets. A total of 31 DEGs were identified between primary and recurrent aGCTs. These included genes with known function in hormone signaling such as LHCGR and INSL3 (more abundant in primary tumors) and CYP19A1 (more abundant in recurrent tumors). Gene set enrichment analysis revealed that primarily immune-related and hormone-regulated gene sets expression was increased in recurrent tumors. Integrative TME analysis demonstrated statistically significant depletion of cancer-associated fibroblasts in recurrent tumors. This finding was confirmed in multiple independent datasets. Implications: Recurrent aGCTs exhibit alterations in hormone pathway gene expression as well as decreased infiltration of cancer-associated fibroblasts, suggesting dual roles for hormonal signaling and TME remodeling underpinning disease relapse.

Https://doi.org/10.18632/oncotarget.27466 Richard K. Yang, Yun Qing, Fatima Zahra Jelloul, Mark J. Routbort, Peng Wang, Kenna Shaw, Jiexin Zhang, Jack Lee, L. Jeffrey Medeiros, Scott Kopetz, Michael...

Objective The primary objective of this study was to determine whether women whose tumors harbor a somatic CTNNB1 mutation have longer recurrence-free survival if they receive traditional adjuvant therapy strategies compared with those who do not. Methods A retrospective, stage I endometrial cancer cohort from MD Anderson Cancer Center was assessed. Clinical and pathological characteristics and type of adjuvant therapy (cuff brachytherapy, pelvic radiation, chemotherapy) were obtained by review of medical records. CTNNB1 exon 3 sequencing was performed. Summary statistics were calculated, and recurrence-free survival was measured using the Kaplan-Meier product-limit estimator. Results The analysis included 253 patients, 245 with information regarding adjuvant therapy. Most patients had tumors of endometrioid histology (210/253, 83%) with superficial myometrial invasion (197/250, 79%) and no lymphatic/vascular space invasion (168/247, 68%). Tumor CTNNB1 mutations were present in 45 (18%) patients. Patients receiving adjuvant therapy were more likely to have higher-grade tumors, non-endometrioid histology, deep myometrial invasion, and lymphatic/vascular invasion. For patients with low-risk features not receiving adjuvant therapy, the presence of CTNNB1 mutation did not significantly impact recurrence-free survival (11.3 years wild-type vs 8.1 years mutant, p=0.65). The cohort was then limited to intermediate-risk tumors, defined as endometrioid histology of any grade with deep myometrial invasion and/or lymphatic/vascular space invasion. When recurrence-free survival was stratified by CTNNB1 mutation status and adjuvant therapy, patients with CTNNB1 mutations and no adjuvant therapy had the shortest recurrence-free survival at 1.6 years, followed by patients with CTNNB1 mutations who received adjuvant therapy (4.0 years), and wild-type CTNNB1 with and without adjuvant therapy (8.5 and 7.2 years, respectively) (comparison for all four groups, p=0.01). Conclusion In patients with intermediate-risk endometrioid endometrial cancers, the use of adjuvant therapy was associated with an improvement in recurrence-free survival for patients with tumor mutations in CTNNB1.