208 results on '"Broaddus RR"'
Search Results
2. β-catenin mediates glandular formation and dysregulation of β-catenin induces hyperplasia formation in the murine uterus
- Author
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Jeong, J-W, Lee, HS, Franco, HL, Broaddus, RR, Taketo, MM, Tsai, SY, Lydon, JP, and DeMayo, FJ
- Published
- 2009
3. CpG island methylation in aberrant crypt foci of the colorectum
- Author
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Chan, AOO, Broaddus, RR, Houlihan, PS, Issa, JPJ, Hamilton, SR, and Rashid, A
- Subjects
Colorectal Neoplasms - genetics - pathology ,Precancerous Conditions - genetics - pathology ,Colon - metabolism - pathology ,DNA Methylation ,digestive system ,CpG Islands - genetics ,digestive system diseases - Abstract
Aberrant crypt foci (ACF) are postulated to be the earliest precursor lesion in colorectal carcinogenesis, and CpG island methylation has been described as an important molecular pathway. We therefore studied methylation in ACF from patients with familial adenomatous polyposis (FAP) or sporadic colorectal cancer. We assessed methylation status of the p16 tumor suppressor gene, MINT1 (methylated in tumor 1), MINT2, MINT31, O(6)-methylguanine-DNA methyltransferase gene, and hMLH1 mismatch repair gene. We compared methylation to ACF histopathology, K-ras proto-oncogene mutation, loss of heterozygosity at chromosome 1p, and microsatellite instability. Methylation was present in 34% (21 of 61) of ACF, including both FAP and sporadic types, but was more frequent in sporadic ACF [53% (18 of 34) versus 11% (3 of 27), P = 0.002], especially dysplastic sporadic ACF [75% (3 of 4) versus 8% (2 of 24), P = 0.004]. MINT31 was more frequently methylated in heteroplastic ACF than dysplastic ACF [35% (11 of 31) versus 7% (2 of 30), P = 0.01]. Strong associations of ACF methylation with K-ras mutation (P = 0.007) and with loss of chromosome 1p (P = 0.04) were observed, but methylation was the only molecular abnormality identified in 16% (10 of 61) of ACF. Our findings suggest that methylation in ACF is an early event in the pathogenesis of a subset of colorectal carcinomas, and that ACF from FAP patients and patients with sporadic colorectal cancer have distinct epigenetic changes that reflect differences in molecular pathogenesis., published_or_final_version
- Published
- 2002
4. Targeted genetic disruption of peroxisome proliferator-activated receptor-delta and colonic tumorigenesis.
- Author
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Zuo X, Peng Z, Moussalli MJ, Morris JS, Broaddus RR, Fischer SM, Shureiqi I, Zuo, Xiangsheng, Peng, Zhanglong, Moussalli, Micheline J, Morris, Jeffrey S, Broaddus, Russell R, Fischer, Susan M, and Shureiqi, Imad
- Abstract
Peroxisome proliferator-activated receptor-delta (PPAR-delta) is overexpressed in human colon cancer, but its contribution to colonic tumorigenesis is controversial. We generated a mouse model in which PPAR-delta was genetically disrupted in colonic epithelial cells by targeted deletion of exon 4. Elimination of colon-specific PPAR-delta expression was confirmed by real-time reverse transcription-polymerase chain reaction (real-time RT-PCR), immunoblotting, and activity assays. Mice with and without targeted PPAR-delta genetic disruption (10-11 mice per group) were tested for incidence of azoxymethane-induced colon tumors. The effects of targeted PPAR-delta deletion on vascular endothelial growth factor expression were determined by real-time RT-PCR. Targeted PPAR-delta genetic disruption inhibited colonic carcinogenesis: Mice with PPAR-delta((-/-)) colons developed 98.5% fewer tumors than wild-type mice (PPAR-delta((-/-)) vs wild-type, mean = 0.1 tumors per mouse vs 6.6 tumors per mouse, difference = 6.5 tumors per mouse, 95% confidence interval = 4.9 to 8.0 tumors per mouse, P < .001, two-sided test). Increased expression of vascular endothelial growth factor in colon tumors vs normal colon was suppressed by loss of PPAR-delta expression. These findings indicate that PPAR-delta has a crucial role in promoting colonic tumorigenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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5. Prospective determination of prevalence of lynch syndrome in young women with endometrial cancer.
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Lu KH, Schorge JO, Rodabaugh KJ, Daniels MS, Sun CC, Soliman PT, White KG, Luthra R, Gershenson DM, Broaddus RR, Lu, Karen H, Schorge, John O, Rodabaugh, Kerry J, Daniels, Molly S, Sun, Charlotte C, Soliman, Pamela T, White, Kristin G, Luthra, Rajyalakshmi, Gershenson, David M, and Broaddus, Russell R
- Published
- 2007
6. Gynecologic cancer as a 'sentinel cancer' for women with hereditary nonpolyposis colorectal cancer syndrome.
- Author
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Lu KH, Dinh M, Kohlmann W, Watson P, Green J, Syngal S, Bandipalliam P, Chen L, Allen B, Conrad P, Terdiman J, Sun C, Daniels M, Burke T, Gershenson DM, Lynch H, Lynch P, and Broaddus RR
- Published
- 2005
7. The Taylor/Mutch article reviewed.
- Author
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Broaddus RR and Lu KH
- Published
- 2006
8. Current laboratory testing practices for mismatch repair deficiency and microsatellite instability testing: A survey-based review of current laboratory practices.
- Author
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Austin AL, Broaddus RR, Souers RJ, Kane ME, Kolhe R, Miller DV, Moncur JT, Ramkissoon S, Tafe LJ, Trembath DG, and Graham RP
- Abstract
Objectives: To describe mismatch repair (MMR) and microsatellite instability (MSI) testing practices in laboratories using the College of American Pathologists (CAP) MSI/MMR proficiency testing programs prior to the 2022 publication of the MSI/MMR practice guidelines copublished by CAP and the Association of Molecular Pathology (AMP)., Methods: Data from supplemental questionnaires provided with the 2020-B MSI/MMR programs to 542 laboratories across different practice settings were reviewed. Questionnaires contained 21 questions regarding the type of testing performed, specimen/tumor types used for testing, and clinical practices for checkpoint blockade therapy., Results: Domestic laboratories test for MSI/MMR more often than international laboratories (P = .04) and academic hospitals/medical centers test more frequently than nonhospital sites/clinics (P = .03). The most commonly used testing modality is immunohistochemistry, followed by polymerase chain reaction, then next-generation sequencing. Most laboratories (72.6%; 347/478) reported awareness of the use of immune checkpoint inhibitor therapy for patients with high MSI or MMR-deficient results., Conclusions: The results demonstrate the state of MMR and MSI testing in laboratories prior to the publication of the CAP/AMP best practice guidelines, highlighting differences between various laboratory types. The findings indicate the importance of consensus guidelines and provide a baseline for comparison after their implementation., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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9. Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.
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Bowen MB, Melendez B, Zhang Q, Moreno D, Peralta L, Chan WK, Jeter C, Tan L, Zal MA, Lorenzi PL, Dunner K, Yang RK, Broaddus RR, Celestino J, Gokul N, Whitley E, Schmandt R, Lu K, Kim HE, and Yates MS
- Abstract
Lynch syndrome (LS) is defined by inherited mutations in DNA mismatch repair genes, including MSH2, and carries 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, specific mechanisms for LS-associated endometrial carcinogenesis are not well understood. Here, we assessed the effects of MSH2 loss on EC pathogenesis using a novel mouse model (PR-Cre Msh2
flox/flox , abbreviated Msh2KO), primary cell lines established from this model, human tissues, and human EC cell lines with isogenic MSH2 knockdown. Beginning at eight months of age, 30% of Msh2KO mice exhibited endometrial atypical hyperplasia (AH), a precancerous lesion. At 12 to 16 months of age, 47% of Msh2KO mice exhibited either AH or ECs with histologic features similar to human LS-related ECs. Transcriptomic profiling of EC from Msh2KO mice revealed a transcriptomic signature for mitochondrial dysfunction. Studies in vitro and in vivo revealed mitochondrial dysfunction based upon two mechanisms: marked mitochondrial content reduction, along with pronounced disruptions to the integrity of retained mitochondria. Human LS-related ECs also exhibited mitochondrial content reduction compared with non-LS-related ECs. Functional studies revealed metabolic reprogramming of MSH2-deficient EC cells in vitro , including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. We are the first to identify mitochondrial dysfunction and metabolic disruption as a consequence of MSH2 deficiency-related EC. Mitochondrial and metabolic aberrations should be evaluated as novel biomarkers for endometrial carcinogenesis or risk stratification and could serve as targets for cancer interception in women with LS., Significance: This is the first study to report mitochondrial dysfunction contributing to MSH2-deficient endometrial cancer development, identifying a noncanonical pathway for MSH2 deficient carcinogenesis, which also imparts vulnerability to metabolic targeting.- Published
- 2024
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10. Context-dependent environmental associations with endometrial cancer histotype and genotype.
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Nakad Borrego S, Kurnit K, Turner LJ, and Broaddus RR
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- Female, Humans, DNA Methylation, Genotype, DNA Mismatch Repair, MutL Protein Homolog 1 genetics, MutL Protein Homolog 1 metabolism, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, Endometrial Neoplasms pathology
- Abstract
Objective: MLH1 loss due to MLH1 methylation, detected during Lynch syndrome screening, is one of the most common molecular changes in endometrial cancer. It is well established that environmental influences such as nutritional state can impact gene methylation, both in the germline and in a tumor. In colorectal cancer and other cancer types, aging is associated with changes in gene methylation. The objective of this study was to determine if there was an association between aging or body mass index on MLH1 methylation in sporadic endometrial cancer., Methods: A retrospective review of patients with endometrial cancer was performed. Tumors were screened for Lynch syndrome via immunohistochemistry, with MLH1 methylation analysis performed when there was loss of MLH1 expression. Clinical information was abstracted from the medical record., Results: There were 114 patients with mismatch repair deficient tumors associated with MLH1 methylation, and 349 with mismatch repair proficient tumors. Patients with mismatch repair deficient tumors were older than those whose tumors were proficient. Mismatch repair deficient tumors had a higher incidence of lymphatic/vascular space invasion. When stratified by endometrioid grade, associations with body mass index and age became apparent. Patients with endometrioid grades 1 and 2 tumors and somatic mismatch repair deficiency were significantly older, but body mass index was comparable with that of the mismatch repair intact group. For endometrioid grade 3, patient age did not significantly vary between the somatic mismatch repair deficient group and the mismatch repair intact group. In contrast, body mass index was significantly higher in the patients with grade 3 tumors with somatic mismatch repair deficiency., Conclusion: The relationship of MLH1 methylated endometrial cancer with age and body mass index is complex and somewhat dependent on tumor grade. As body mass index is modifiable, it is possible that weight loss induces a 'molecular switch' to alter the histologic characteristics of an endometrial cancer., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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11. Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors.
- Author
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Khlebus E, Vuttaradhi VK, Welte T, Khurana N, Celestino J, Beird HC, Gumbs C, Little L, Legarreta AF, Fellman BM, Nguyen T, Lawson B, Ferri-Borgogno S, Mok SC, Broaddus RR, Gershenson DM, Futreal PA, and Hillman RT
- Subjects
- Adult, Female, Humans, Tumor Microenvironment genetics, Neoplasm Recurrence, Local genetics, Hormones, Granulosa Cell Tumor genetics, Granulosa Cell Tumor pathology
- Abstract
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., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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12. Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of College of American Pathologists Guideline.
- Author
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Vikas P, Messersmith H, Compton C, Sholl L, Broaddus RR, Davis A, Estevez-Diz M, Garje R, Konstantinopoulos PA, Leiser A, Mills AM, Norquist B, Overman MJ, Sohal D, Turkington RC, and Johnson T
- Subjects
- Humans, DNA Mismatch Repair, Microsatellite Instability, Pathologists, Immune Checkpoint Inhibitors, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics
- Abstract
Purpose: The College of American Pathologists (CAP) has developed a guideline on testing for mismatch repair (MMR) and microsatellite instability (MSI) for patients considered for immune checkpoint inhibitor therapy. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations., Methods: The CAP guideline was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations., Results: The ASCO Endorsement Panel determined that the recommendations from the CAP guideline, published on August 3, 2022, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer ., Recommendations: Within the guideline, MMR immunohistochemistry (IHC), MSI polymerase chain reaction, and MSI next-generation sequencing are all recommended testing options for colorectal cancer, MMR-IHC and MSI-polymerase chain reaction for gastroesophageal and small bowel cancer, and only MMR-IHC for endometrial cancer. No recommendation in favor of any testing method over another could be made for any other cancer. Tumor mutational burden was not recommended as a surrogate for DNA MMR deficiency. If MMR deficiency consistent with Lynch syndrome is detected, it should be communicated to the treating physician.Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines.
- Published
- 2023
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13. MIG-6 Is Critical for Progesterone Responsiveness in Human Complex Atypical Hyperplasia and Early-Stage Endometrial Cancer.
- Author
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Jeong O, Broaddus RR, Lessey BA, Risinger JI, Hunter MI, and Kim TH
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- Female, Humans, Endometrium metabolism, Hyperplasia metabolism, Intracellular Signaling Peptides and Proteins metabolism, Receptors, Progesterone metabolism, Tumor Suppressor Proteins metabolism, Carcinoma, Endometrioid pathology, Endometrial Neoplasms drug therapy, Endometrial Neoplasms genetics, Endometrial Neoplasms metabolism, Progesterone metabolism, Adaptor Proteins, Signal Transducing metabolism
- Abstract
Women with complex atypical hyperplasia (CAH) or early-stage endometrioid endometrial cancer (EEC) are candidates for fertility preservation. The most common approach is progesterone (P4) therapy and deferral of hysterectomy until after completion of childbearing. However, P4 therapy response rates vary, and molecular mechanisms behind P4 resistance are poorly understood. One potential molecular cause of P4 resistance is a loss or attenuation of PGR expression. Mitogen-inducible gene 6 (MIG-6) is critical for P4 responsiveness. MIG-6 protein expression in the endometrial epithelial and stromal cells from women with CAH and EEC was significantly lower compared to women without CAH or EEC. The P4-responsive women (10/15) exhibited an increase of MIG-6 expression in epithelial and stromal cells compared to P4-resistant women (5/15). In addition, immunohistochemical analysis for PGR results showed that stromal PGR levels are significantly higher in P4-responsive women compared to P4-resistant women, whereas epithelial PGR expression was not different. A reverse correlation of MIG-6 and pAKT levels was observed in early-stage EEC patients. Studies strongly suggest that loss of MIG-6 and PGR and activation of pAKT lead to P4 resistance in CAH and EEC. These results will help to elucidate the molecular mechanism leading to P4 resistance in CAH and EEC.
- Published
- 2022
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14. Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer.
- Author
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Bartley AN, Mills AM, Konnick E, Overman M, Ventura CB, Souter L, Colasacco C, Stadler ZK, Kerr S, Howitt BE, Hampel H, Adams SF, Johnson W, Magi-Galluzzi C, Sepulveda AR, and Broaddus RR
- Subjects
- Female, Humans, DNA Mismatch Repair genetics, Immune Checkpoint Inhibitors, Pathologists, Pathology, Molecular methods, Systematic Reviews as Topic, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Microsatellite Instability
- Abstract
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., Competing Interests: Authors' disclosures of potential conflicts of interest and author contributions are found in the Appendix at the end of this article.
- Published
- 2022
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15. Mechanisms of mutant β-catenin in endometrial cancer progression.
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Parrish ML, Broaddus RR, and Gladden AB
- Abstract
Endometrial carcinoma (EC) is the most diagnosed gynecological malignancy in Western countries. Both incidence and mortality rates of EC have steadily risen in recent years. Despite generally favorable prognoses for patients with the endometrioid type of EC, a subset of patients has been identified with decreased progression-free survival. Patients in this group are distinguished from other endometrioid EC patients by the presence of exon 3 hotspot mutations in CTNNB1 , the gene encoding for the β-catenin protein. β-catenin is an evolutionarily conserved protein with critical functions in both adherens junctions and Wnt-signaling. The exact mechanism by which exon 3 CTNNB1 mutations drive EC progression is not well understood. Further, the potential contribution of mutant β-catenin to adherens junctions' integrity is not known. Additionally, the magnitude of worsened progression-free survival in patients with CTNNB1 mutations is context dependent, and therefore the importance of this subset of patients can be obscured by improper categorization. This review will examine the history and functions of β-catenin, how these functions may change and drive EC progression in CTNNB1 mutant patients, and the importance of this patient group in the broader context of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Parrish, Broaddus and Gladden.)
- Published
- 2022
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16. DNA Damage Repair Classifier Defines Distinct Groups in Hepatocellular Carcinoma.
- Author
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Smith MA, Van Alsten SC, Walens A, Damrauer JS, Maduekwe UN, Broaddus RR, Love MI, Troester MA, and Hoadley KA
- Abstract
DNA repair pathways have been associated with variability in hepatocellular carcinoma (HCC) clinical outcomes, but the mechanism through which DNA repair varies as a function of liver regeneration and other HCC characteristics is poorly understood. We curated a panel of 199 genes representing 15 DNA repair pathways to identify DNA repair expression classes and evaluate their associations with liver features and clinicopathologic variables in The Cancer Genome Atlas (TCGA) HCC study. We identified two groups in HCC, defined by low or high expression across all DNA repair pathways. The low-repair group had lower grade and retained the expression of classical liver markers, whereas the high-repair group had more clinically aggressive features, increased p53 mutant-like gene expression, and high liver regenerative gene expression. These pronounced features overshadowed the variation in the low-repair subset, but when considered separately, the low-repair samples included three subgroups: L1, L2, and L3. L3 had high DNA repair expression with worse progression-free (HR 1.24, 95% CI 0.81-1.91) and overall (HR 1.63, 95% CI 0.98-2.71) survival. High-repair outcomes were also significantly worse compared with the L1 and L2 groups. HCCs vary in DNA repair expression, and a subset of tumors with high regeneration profoundly disrupts liver biology and poor prognosis.
- Published
- 2022
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17. Adjuvant treatment in early-stage endometrial cancer: context-dependent impact of somatic CTNNB1 mutation on recurrence-free survival.
- Author
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Kurnit KC, Fellman BM, Mills GB, Bowser JL, Xie S, and Broaddus RR
- Subjects
- Female, Humans, Mutation, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Radiotherapy, Adjuvant, Retrospective Studies, beta Catenin genetics, Carcinoma, Endometrioid drug therapy, Carcinoma, Endometrioid therapy, Endometrial Neoplasms drug therapy, Endometrial Neoplasms therapy
- Abstract
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 ., Competing Interests: Competing interests: KK: travel support from GOG Foundation; advisory board participation for LEAP Therapeutics (through GOG Foundation). BMF: grant support from NIH Cancer Center support grant CA016672. GM: licenses for HRD assay to Myriad Genetics; consulting fees for AstraZeneca, Chrysallis Biotechnology, Ellipses Pharma, ImmunoMet, Infinity, Ionis, Lilly, Medacorp, Nanostring, PDX Pharmaceuticals, SignalChem Lifesciences, Tarveda, Turbine, Zentalis Pharmaceuticals; patents for DSP Nanostring; stock for Catena Pharmaceuticals, ImmunoMET, SignalChem, Tarveda, Turbine. JB: None. SX: grant funding with NIH SPORE in Uterine Cancer NIH P50 CA098258. RRB: grant funding with NIH SPORE in Uterine Cancer P50 CA098258., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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18. A phase II study of MK-2206, an AKT inhibitor, in uterine serous carcinoma.
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Stover EH, Xiong N, Myers AP, Tayob N, Engvold V, Polak M, Broaddus RR, Makker V, Drapkin R, Liu JF, Horowitz NS, Meric-Bernstam F, Aghajanian C, Coleman RL, Mills GB, Cantley LC, Matulonis UA, Westin SN, and Konstantinopoulos PA
- Abstract
Uterine serous carcinoma (USC) is an uncommon subtype of endometrial cancer with a poor prognosis. USCs have genomic alterations in the PI3K pathway. A prior phase II study of AKT inhibitor MK-2206 (an allosteric AKT inhibitor, primarily affecting AKT1 and AKT2) in endometrial cancers resulted in progression-free survival (PFS) of ≥6 months in five out of seven patients with USC. To further assess the activity of MK-2206 in USC, we designed a phase II, single-stage assessment of MK-2206 in patients with advanced or recurrent high-grade serous endometrial cancer, who had received up to two lines of prior therapy. MK-2206 (135 mg) was administered orally once per week, in continuous 28-day cycles. Fourteen patients received treatment. The most common treatment-related adverse events were diarrhea (36%), acneiform rash (36%), nausea (29%), fatigue (29%), and hyperglycemia (21%); most events were grade 1-2. One confirmed partial response was observed in a patient who was also alive and progression-free at 6 months. One additional patient was alive and progression-free at 6 months. The clinical benefit rate was 14.3% (95% CI: 1.8 to 42.8). Five patients had stable disease (35.7%) and seven had progressive disease (50%); one was unevaluable. Median PFS was 2 months (95% CI: 1.6 to 4.4) and median overall survival was 6.4 months (95% CI: 5.1 to not reached). In summary, MK-2206 had limited activity in USC, although a few patients achieved sustained progression-free intervals in this study and in the previously reported phase II trial of MK-2206. Further investigations are needed to identify features associated with response., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that they have no competing interests relevant to this study. For completeness, the following conflicts of interest disclosure is provided: A.P.M. is a full-time employee of Novartis. V.M. has participated in advisory boards for Novartis, Iteos, Eisai, Merck, Karyopharm, Clovis, and GSK. R.D. has been a consultant for Repare Therapeutics and Mersana Therapeutics, and is a founding member and has a financial interest in VOC Health. J.F.L. has received institutional funding for clinical trials from 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro, and Vigeo Therapeutics; and has participated in advisory boards for AstraZeneca, Clovis, Eisai, EpsilaBio, Genentech, GSK/Tesaro, and Regeneron Pharmaceuticals. F. M.-B. has received research support from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., and Taiho Pharmaceutical Co.,; has been a consultant for AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, and Zymeworks; has received honoraria from Chugai Biopharmaceuticals; and has participated in advisory boards for Black Diamond, Biovica, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis. C.A. has received institutional funding for clinical trials from Abbvie, Clovis, Genentech, and AstraZeneca; has been a consultant for Eisai/Merck, Mersana Therapeutics, Roche/Genentech, Abbvie, AstraZeneca, Merck, and Repare Therapeutics; and has served on an advisory board for Blueprint Medicines. R.C. has received research support from AstraZeneca, Merck, Clovis, Genmab, Roche/Genentech, Janssen, Immunogen, and Genelux; and has been a consultant for AstraZeneca, GSK, Clovis, Genmab, Roche/Genentech, Janssen, Agenus, Regeneron, OncoQuest, Immunogen, Genelux, Onxerna, Onxeo, Deciphera, and Alkermes. G.B.M. has received funding for clinical trials from AstraZeneca, Genentech, GSK,and Eli Lilly; has been a consultant and/or advisory board member for Amphista, AstraZeneca, Chrysallis Biotechnology, GSK, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, Turbine, and Zentalis Pharmaceuticals; and has a financial interest in Catena Pharmaceuticals, ImmunoMet, SignalChem, and Tarveda. L.C.C. has been a consultant for Novartis. U.A.M. has been a consultant for Merck, Novartis, and Astrazeneca; and has served on an advisory board for Symphogen. S.N.W. has received research funding from AstraZeneca, Bayer, Bio-Path, Clovis Oncology, GSK, Mereo, Novartis, OncXerna, Roche/Genentech, Zentalis; and has been a consultant for Agenus, AstraZeneca, Clovis Oncology, Eisai, ERQX, GSK, ImmunoGen, Merck, Mereo, Novartis, Pfizer, Roche/Genentech, Vincerx, and Zentalis. P.A.K. has been a consultant for Alkermes, AstraZeneca, Bayer, GSK, Merck, Pfizer, Tesaro, Mersana, Repare Therapeutics, and Kadmon., (© 2022 The Authors.)
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- 2022
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19. The Changing Landscape of Gynecologic Cancer Mortality in the United States.
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Giaquinto AN, Broaddus RR, Jemal A, and Siegel RL
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- Female, Humans, United States epidemiology, Health Status Disparities, Ovarian Neoplasms ethnology, Ovarian Neoplasms mortality, Uterine Neoplasms ethnology, Uterine Neoplasms mortality
- Abstract
Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest.
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- 2022
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20. Clinical and Financial Implications of Second-Opinion Surgical Pathology Review.
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Johnson SM, Samulski TD, O'Connor SM, Smith SV, Funkhouser WK, Broaddus RR, and Calhoun BC
- Subjects
- Clinical Coding, Cost Savings, Diagnostic Errors economics, Humans, Insurance, Health, Reimbursement, Pathology, Surgical organization & administration, Referral and Consultation organization & administration, Retrospective Studies, Diagnostic Errors prevention & control, Pathology, Surgical economics, Referral and Consultation economics
- Abstract
Objectives: Second-opinion pathology review identifies clinically significant diagnostic discrepancies for some patients. Discrepancy rates and laboratory-specific costs in a single health care system for patients referred from regional affiliates to a comprehensive cancer center ("main campus") have not been reported., Methods: Main campus second-opinion pathology cases for 740 patients from eight affiliated hospitals during 2016 to 2018 were reviewed. Chart review was performed to identify changes in care due to pathology review. To assess costs of pathology interpretation, reimbursement rates for consultation Current Procedural Terminology billing codes were compared with codes that would have been used had the cases originated at the main campus., Results: Diagnostic discrepancies were identified in 104 (14.1%) patients, 30 (4.1%) of which resulted in a change in care. In aggregate, reimbursement for affiliate cases was 65.6% of the reimbursement for the same cases had they originated at the main campus. High-volume organ systems with low relative consultation reimbursement included gynecologic, breast, and thoracic., Conclusions: Preventable diagnostic errors are reduced by pathology review for patients referred within a single health care system. Although the resulting changes in care potentially lead to overall cost savings, the financial value of referral pathology review could be improved., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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21. Low grade endometrioid endometrial cancer: complexities beyond p53abn.
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Broaddus RR and Kurnit KC
- Subjects
- Female, Humans, Carcinoma, Endometrioid, Endometrial Neoplasms
- Abstract
Competing Interests: Competing interests: None declared.
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- 2021
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22. Clinical and Functional Characterization of Atypical KRAS / NRAS Mutations in Metastatic Colorectal Cancer.
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Loree JM, Wang Y, Syed MA, Sorokin AV, Coker O, Xiu J, Weinberg BA, Vanderwalde AM, Tesfaye A, Raymond VM, Miron B, Tarcic G, Zelichov O, Broaddus RR, Ng PKS, Jeong KJ, Tsang YH, Mills GB, Overman MJ, Grothey A, Marshall JL, and Kopetz S
- Subjects
- Aged, Colorectal Neoplasms pathology, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Colorectal Neoplasms genetics, GTP Phosphohydrolases genetics, Membrane Proteins genetics, Mutation, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
Purpose: Mutations in KRAS/NRAS ( RAS ) predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all RAS mutations have similar impact, and atypical mutations beyond those in standard guidelines exist., Experimental Design: We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical RAS variants. Using an in vitro cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and in vivo xenograft models of transduced isogenic clones, we assessed signaling changes across mutations., Results: KRAS exon 2, extended RAS , and atypical RAS mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, KRAS L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no NRAS codon 117/146 and only one NRAS codon 59 mutation was noted. Atypical RAS mutations had worse overall survival than RAS/BRAF wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24-6.80; P = 0.014). We functionally characterized 114 variants with the FACT assay. All KRAS exon 2 and extended RAS mutations appeared activating. Of 57 atypical RAS variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results, and activating atypical variants were those that occurred at highest prevalence in clinical cohorts., Conclusions: We provide best available evidence to guide treatment when atypical RAS variants are identified. KRAS L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included RAS variants and functionally relevant., (©2021 American Association for Cancer Research.)
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- 2021
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23. Inactivating Mutations of the IK Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy.
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Gao C, Jin G, Forbes E, Mangala LS, Wang Y, Rodriguez-Aguayo C, Amero P, Bayraktar E, Yan Y, Lopez-Berestein G, Broaddus RR, Sood AK, Xue F, and Zhang W
- Abstract
IK is a mitotic factor that promotes cell cycle progression. Our previous investigation of 271 endometrial cancer (EC) samples from the Cancer Genome Atlas (TCGA) dataset showed IK somatic mutations were enriched in a cluster of patients with high-grade and high-stage cancers, and this group had longer survival. This study provides insight into how IK somatic mutations contribute to EC pathophysiology. We analyzed the somatic mutational landscape of IK gene in 547 EC patients using expanded TCGA dataset. Co-immunoprecipitation and mass spectrometry were used to identify protein interactions. In vitro and in vivo experiments were used to evaluate IK's role in EC. The patients with IK-inactivating mutations had longer survival during 10-year follow-up. Frameshift and stop-gain were common mutations and were associated with decreased IK expression. IK knockdown led to enrichment of G2/M phase cells, inactivation of DNA repair signaling mediated by heterodimerization of Ku80 and Ku70, and sensitization of EC cells to cisplatin treatment. IK/Ku80 mutations were accompanied by higher mutation rates and associated with significantly better overall survival. Inactivating mutations of IK gene and loss of IK protein expression were associated with weakened Ku80/Ku70-mediated DNA repair, increased mutation burden, and better response to chemotherapy in patients with EC.
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- 2021
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24. Utilization of cytology smears improves success rates of RNA-based next-generation sequencing gene fusion assays for clinically relevant predictive biomarkers.
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Ramani NS, Chen H, Broaddus RR, Lazar AJ, Luthra R, Medeiros LJ, Patel KP, Rashid A, Routbort MJ, Stewart J, Tang Z, Bassett R, Manekia J, Barkoh BA, Dang H, and Roy-Chowdhuri S
- Subjects
- Adult, Aged, Aged, 80 and over, Biopsy, Fine-Needle, Female, Humans, Male, Middle Aged, Neoplasms genetics, Retrospective Studies, Biomarkers, Tumor genetics, Cytodiagnosis methods, Cytological Techniques methods, Gene Fusion, High-Throughput Nucleotide Sequencing methods, Neoplasms diagnosis
- Abstract
Background: The use of RNA-based next-generation sequencing (NGS) assays to detect gene fusions for targeted therapy has rapidly become an essential component of comprehensive molecular profiling. For cytology specimens, the cell block (CB) is most commonly used for fusion testing; however, insufficient cellularity and/or suboptimal RNA quality are often limiting factors. In the current study, the authors evaluated the factors affecting RNA fusion testing in cytology and the added value of smears in cases with a suboptimal or inadequate CB., Methods: A 12-month retrospective review was performed to identify cytology cases that were evaluated by a targeted RNA-based NGS assay. Samples were sequenced by targeted amplicon-based NGS for 51 clinically relevant genes on a proprietary platform. Preanalytic factors and NGS quality parameters were correlated with the results of RNA fusion testing., Results: The overall success rate of RNA fusion testing was 92%. Of the 146 cases successfully sequenced, 14% had a clinically relevant fusion detected. NGS testing success positively correlated with RNA yield (P = .03) but was independent of the tumor fraction, the tumor size, or the number of slides used for extraction. CB preparations were adequate for testing in 45% cases, but the inclusion of direct smears increased the adequacy rate to 92%. There was no significant difference in testing success rates between smears and CB preparations., Conclusions: The success of RNA-based NGS fusion testing depends on the quality and quantity of RNA extracted. The use of direct smears significantly improves the adequacy of cytologic samples for RNA fusion testing for predictive biomarkers., (© 2020 American Cancer Society.)
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- 2021
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25. Loss of CD73 shifts transforming growth factor-β1 (TGF-β1) from tumor suppressor to promoter in endometrial cancer.
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Kurnit KC, Draisey A, Kazen RC, Chung C, Phan LH, Harvey JB, Feng J, Xie S, Broaddus RR, and Bowser JL
- Subjects
- Adenosine physiology, Adult, Aged, Animals, Cell Differentiation, Cell Line, Tumor, Female, GPI-Linked Proteins physiology, Humans, Mice, Mice, Inbred C57BL, Middle Aged, Neoplasm Staging, 5'-Nucleotidase physiology, Endometrial Neoplasms pathology, Transforming Growth Factor beta1 physiology, Tumor Suppressor Proteins physiology
- Abstract
In many tumors, CD73 (NT5E), a rate-limiting enzyme in adenosine biosynthesis, is upregulated by TGF-β and drives tumor progression. Conversely, CD73 is downregulated in endometrial carcinomas (EC) despite a TGF-β-rich environment. Through gene expression analyses of normal endometrium samples of the uterine cancer TCGA data set and genetic and pharmacological studies, we discovered CD73 loss shifts TGF-β1 from tumor suppressor to promoter in EC. TGF-β1 upregulated CD73 and epithelial integrity in vivo in the normal endometrium and in vitro in early stage EC cells. With loss of CD73, TGF-β1-mediated epithelial integrity was abrogated. EC cells developed TGF-β1-mediated stress fibers and macromolecule permeability, migration, and invasion increased. In human tumors, CD73 is downregulated in deeply invasive stage I EC. Consistent with shifting TGF-β1 activity, CD73 loss increased TGF-β1-mediated canonical signaling and upregulated cyclin D1 (CCND1) and downregulated p21 expression. This shift was clinically relevant, as CD73
Low /CCND1High expression associated with poor tumor differentiation, increased myometrial and lymphatic/vascular space invasion, and patient death. Further loss of CD73 in CD73Low expressing advanced stage EC cells increased TGF-β-mediated stress fibers, signaling, and invasiveness, whereby adenosine A1 receptor agonist, CPA, dampened TGF-β-mediated invasion. These data identify CD73 loss as essential for shifting TGF-β activity in EC., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2021
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26. Endometrial biomarkers in premenopausal women with obesity: an at-risk cohort.
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Dottino JA, Zhang Q, Loose DS, Fellman B, Melendez BD, Borthwick MS, McKenzie LJ, Yuan Y, Yang RK, Broaddus RR, Lu KH, Soliman PT, and Yates MS
- Subjects
- Adult, Biomarkers blood, Cohort Studies, Cross-Sectional Studies, Endometrial Neoplasms epidemiology, Endometrial Neoplasms etiology, Endometrium metabolism, Endometrium pathology, Estrogens biosynthesis, Female, Humans, Obesity complications, Risk Factors, Estrogens blood, Obesity blood, Premenopause blood
- Abstract
Background: Obesity is a well-known risk factor for endometrial cancer, but the mechanisms of obesity-related carcinogenesis are not well defined, particularly for premenopausal women. With the continuing obesity epidemic, increases in the incidence of endometrial cancer and a younger age of diagnosis are often attributed to a hyperestrogenic state created by hormone production in adipose tissue, but significant knowledge gaps remain. The balance of estrogen-responsive signals has not been defined in the endometrium of premenopausal women with obesity, where obesity may not create hyperestrogenism in the context of ovaries being the primary source of estrogen production. Obesity is associated with a state of low-grade, chronic inflammation that can promote tumorigenesis, and it is also known that hormonal changes alter the immune microenvironment of the endometrium. However, limited research has been conducted on endometrial immune-response changes in women who have an increased risk for cancer due to obesity., Objective: Endometrial estrogen-regulated biomarkers, previously shown to be dysregulated in endometrial cancer, were evaluated in a cohort of premenopausal women to determine if obesity is associated with differences in the biomarker expression levels, which might reflect an altered risk of developing cancer. The expression of a multiplexed panel of immune-related genes was also evaluated for expression differences related to obesity., Study Design: Premenopausal women with a body mass index of ≥30 kg/m
2 (n=97) or a body mass index of ≤25 kg/m2 (n=33) were prospectively enrolled in this cross-sectional study, which included the assessment of serum metabolic markers and a timed endometrial biopsy for pathologic evaluation, hormone-regulated biomarker analysis, and immune response gene expression analysis. Medical and gynecologic histories were obtained. Endometrial gene expression markers were also compared across the body mass index groups in a previous cohort of premenopausal women with an inherited cancer risk (Lynch syndrome)., Results: In addition to known systemic metabolic differences, histologically normal endometria from women with obesity showed a decrease in gene expression of progesterone receptor (P=.0027) and the estrogen-induced genes retinaldehyde dehydrogenase 2 (P=.008), insulin-like growth factor 1 (P=.016), and survivin (P=.042) when compared with women without obesity. The endometrial biomarkers insulin-like growth factor 1, survivin, and progesterone receptor remained statistically significant in multivariate linear regression models. In contrast, women with obesity and Lynch syndrome had an increased expression of insulin-like growth factor 1 (P=.017). There were no differences in endometrial proliferation, and limited endometrial immune differences were observed., Conclusion: When comparing premenopausal women with and without obesity in the absence of endometrial pathology or an inherited cancer risk, the expression of the endometrial biomarkers does not reflect a local hyperestrogenic environment, but it instead reflects a decreased cancer risk profile that may be indicative of a compensated state. In describing premenopausal endometrial cancer risk, it may be insufficient to attribute a high-risk state to obesity alone; further studies are warranted to evaluate individualized biomarker profiles for differences in the hormone-responsive signals or immune response. In patients with Lynch syndrome, the endometrial biomarker profile suggests that obesity further increases the risk of developing cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2021
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27. Endometrial Cancer. Reply.
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Lu KH and Broaddus RR
- Subjects
- Female, Humans, Endometrial Neoplasms
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- 2021
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28. Pathologic distribution at the time of interval tumor reductive surgery informs personalized surgery for high-grade ovarian cancer.
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Bailey CD, Previs R, Fellman BM, Zaid T, Huang M, Brown A, Enbaya A, Balakrishnan N, Broaddus RR, Bodurka DC, Soliman P, Fleming ND, Nick A, Sood AK, and Westin SN
- Subjects
- Adolescent, Adult, Carcinoma, Ovarian Epithelial pathology, Female, Humans, Middle Aged, Neoadjuvant Therapy methods, Ovarian Neoplasms pathology, Peritoneal Neoplasms pathology, Time Factors, Young Adult, Carcinoma, Ovarian Epithelial surgery, Cytoreduction Surgical Procedures methods, Ovarian Neoplasms surgery, Peritoneal Neoplasms surgery
- Abstract
Introduction: The surgical approach for interval debulking surgery after neoadjuvant chemotherapy has been extrapolated from primary tumor reductive surgery for high-grade ovarian cancer. The study objective was to compare pathologic distribution of malignancy at interval debulking surgery versus primary tumor reductive surgery., Methods: Patients with a diagnosis of high-grade serous or mixed, non-mucinous, epithelial ovarian, fallopian tube or primary peritoneal cancer who underwent neoadjuvant chemotherapy or primary tumor reductive surgery and had at least 6 months of follow-up were identified through tumor registry at a single institution from January 1995 to April 2016. Pathologic involvement of organs was categorized as macroscopic, microscopic, or no tumor. Statistical analyses included Mann-Whitney and Fisher's exact tests., Results: Of 918 patients identified, 366 (39.9%) patients underwent interval debulking surgery and 552 (60.1%) patients underwent primary tumor reductive surgery. Median age was 62.3 years (range 25.3-92.5). The majority of patients in the interval debulking surgery group were unstaged (261, 71.5%). In the patients who had a primary tumor reductive surgery, 406 (74.6%) had stage III disease. In both groups, the majority of patients had serous histology: 325 (90%) and 435 (78.8%) in the interval debulking and primary tumor reductive surgery groups, respectively. There was a statistically significant difference between disease distribution on the uterus between the groups; 31.4% of the patients undergoing interval debulking surgery had no evidence of uterine disease compared with 22.1% of primary tumor reductive surgery specimens (p<0.001). In the adnexa, there was macroscopic disease present in 253 (69.2%) and 482 (87.4%) of cases in the interval vs primary surgery groups, respectively (p<0.001). Within the omentum, no tumor was present in the omentum in 52 (14.2%) in the interval surgery group versus 91 (16.5%) in the primary surgery group (p<0.001). In the interval surgery group, there was no tumor involving the small and large bowel in 49 (13.4%) and 28 (7.7%) pathologic specimens, respectively. This was statistically significantly different from the small and large bowel in the primary surgery group, of which there was no tumor in 20 (3.6%, p<0.001) and 16 (2.9%, p<0.001) of cases, respectively., Conclusion: In patients undergoing interval debulking surgery, there was less macroscopic involvement of tumor in the uterus, adnexa and bowel compared with patients undergoing primary cytoreductive surgery., Competing Interests: Competing interests: RP receives research support from Myriad. AKS is a consultant for Merck, and Kiyatec. AKS receives research funding (M-Trap); and is a shareholder (BioPath). SNW is a consultant for AstraZeneca, Circulogene, Clovis Oncology, Eisai, GSK/Tesaro, Merck, Novartis, Pfizer, and Roche/Genentech. SNW receives research support from ArQule, AstraZeneca, Bayer, Clovis Oncology, Cotinga Pharmaceuticals, Novartis, Roche/Genentech, and GSK/Tesaro. All conflicts of interest are not related to the current work., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2021
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29. Prospective phase II trial of levonorgestrel intrauterine device: nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer.
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Westin SN, Fellman B, Sun CC, Broaddus RR, Woodall ML, Pal N, Urbauer DL, Ramondetta LM, Schmeler KM, Soliman PT, Fleming ND, Burzawa JK, Nick AM, Milbourne AM, Yuan Y, Lu KH, Bodurka DC, Coleman RL, and Yates MS
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Adult, Aged, Aged, 80 and over, Aldehyde Dehydrogenase 1 Family genetics, Aldehyde Dehydrogenase 1 Family metabolism, Biomarkers metabolism, Biomarkers, Tumor metabolism, Body Mass Index, Carcinoma, Endometrioid metabolism, Carcinoma, Endometrioid pathology, Endometrial Hyperplasia metabolism, Endometrial Hyperplasia pathology, Endometrial Neoplasms metabolism, Endometrial Neoplasms pathology, Female, Gene Expression, Humans, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Ki-67 Antigen genetics, Ki-67 Antigen metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Middle Aged, Neoplasm Grading, Neoplasm Staging, Quality of Life, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism, Retinal Dehydrogenase genetics, Retinal Dehydrogenase metabolism, Treatment Outcome, Wnt Signaling Pathway genetics, Young Adult, Carcinoma, Endometrioid drug therapy, Contraceptive Agents, Hormonal administration & dosage, Endometrial Hyperplasia drug therapy, Endometrial Neoplasms drug therapy, Intrauterine Devices, Medicated, Levonorgestrel administration & dosage
- Abstract
Background: The incidence of complex atypical hyperplasia and early-stage endometrioid endometrial cancer is increasing, in part owing to the epidemic of obesity, which is a risk factor tightly linked to the development of endometrial hyperplasia and cancer. The standard upfront treatment for complex atypical hyperplasia and early-stage endometrial cancer is hysterectomy. However, nonsurgical treatment of early-stage endometrial neoplasia may be necessary owing to medical comorbidities precluding surgery or desired future fertility., Objective: This study aimed to evaluate the efficacy of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and grade 1 endometrioid endometrial carcinoma., Study Design: A single-institution, single-arm, phase II study of the levonorgestrel intrauterine device (52 mg levonorgestrel, Mirena) was conducted in patients with complex atypical hyperplasia or grade 1 endometrioid endometrial cancer. The primary endpoint was pathologic response rate at 12 months, including complete or partial response. Quality of life and toxicity were assessed. Molecular analyses for proliferation markers, hormone-regulated genes, and wingless-related integration site pathway activation were performed at baseline and 3 months., Results: A total of 57 patients were treated (21 endometrial cancer, 36 complex atypical hyperplasia). The median age was 48.0 years, and the median body mass index was 45.5 kg/m
2 . Of the 47 evaluable patients, 12-month response rate was 83% (90% credible interval, 72.7-90.3)-37 were complete responders (8 endometrial cancer; 29 complex atypical hyperplasia), 2 were partial responders (2 endometrial cancer), 3 had stable disease (2 endometrial cancer; 1 complex atypical hyperplasia), and 5 had progressive disease (3 endometrial cancer; 2 complex atypical hyperplasia). After stratification for histology, the response rate was 90.6% for complex atypical hyperplasia and 66.7% for grade 1 endometrioid endometrial cancer. Notably, 4 patients (9.5%) experienced relapse after the initial response. Adverse events were mild, primarily irregular bleeding and cramping. Quality of life was not negatively affected. At 3 months, exogenous progesterone effect was present in 96.9% of responders (31 of 32) vs 25% of nonresponders (2 of 8) (P=.001). Nonresponders had higher baseline proliferation (Ki67) and lower dickkopf homolog 3 gene expression than responders (P=.023 and P=.030). Nonresponders had significantly different changes in secreted frizzled-related protein 1, frizzled class receptor 8, and retinaldehyde dehydrogenase 2 compared with responders., Conclusion: The levonorgestrel intrauterine device has a substantial activity in complex atypical hyperplasia and grade 1 endometrioid endometrial cancer, with a modest proportion demonstrating upfront progesterone resistance. Potential biomarkers were identified that may correlate with resistance to therapy; further exploration is warranted., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2021
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30. Evaluating Mismatch Repair/Microsatellite Instability Status Using Cytology Effusion Specimens to Determine Eligibility for Immunotherapy.
- Author
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Jacobi EM, Landon G, Broaddus RR, and Roy-Chowdhuri S
- Subjects
- Adult, Aged, Aged, 80 and over, Ascitic Fluid pathology, Biomarkers, Tumor analysis, Female, Humans, Immunotherapy, Male, Middle Aged, Patient Selection, Pericardial Effusion pathology, Brain Neoplasms diagnosis, Colorectal Neoplasms diagnosis, Cytodiagnosis methods, Endometrial Neoplasms, Microsatellite Instability, Neoplastic Syndromes, Hereditary diagnosis
- Abstract
Context.—: The approval of pembrolizumab for treatment of patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) advanced cancers has led to increased requests for MSI and/or MMR immunoperoxidase (IPOX) testing. Diagnoses for patients with advanced-stage cancer are frequently made from cytology specimens., Objective.—: To investigate the feasibility of using cell block (CB) preparations of effusions for MMR IPOX evaluation., Design.—: Surgical pathology cases of colorectal and endometrial carcinomas with known MMR/MSI status and matched effusions with available CBs were identified. Cell block sections were evaluated for adequacy and stained with MMR IPOX (MSH2, MSH6, MLH1, and PMS2). The CBs were reviewed, the number of tumor cells quantified, and MMR IPOX was interpreted as retained, lost, suboptimal, or noncontributory., Results.—: We identified 748 cases with MMR/MSI testing on surgical specimens having matched effusions. Of these, 131 cases (17.5%) had an available CB and 53 were deemed adequate for MMR IPOX staining. MMR IPOX results between effusion CBs and surgical pathology specimens were concordant in 45 of 53 (85%), inconclusive in 6 of 53 (11%), and discordant in 2 of 53 (4%) cases., Conclusions.—: There was high concordance of MMR IPOX testing between cytologic and surgical specimens, with no false-positive and 2 false-negative CB results. Limited tumor cells, staining in cells indefinite as tumor, tumor staining heterogeneity, and lack of internal control staining were problematic in some cases. Our findings indicate that cytologic effusion specimens may be suitable substrates for MMR IPOX biomarker testing; however, inconclusive cases need to be interpreted with caution., (© 2021 College of American Pathologists.)
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- 2021
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31. Endometrial Cancer.
- Author
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Lu KH and Broaddus RR
- Subjects
- Age of Onset, Body Mass Index, Combined Modality Therapy, Endometrial Neoplasms epidemiology, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Female, Humans, Neoplasm Staging, Uterine Neoplasms ethnology, Colorectal Neoplasms, Hereditary Nonpolyposis complications, Endometrial Neoplasms therapy, Hysterectomy methods, Obesity complications
- Published
- 2020
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32. Variable Expression of MSH6 in Endometrial Carcinomas With Intact Mismatch Repair and With MLH1 Loss Due to MLH1 Methylation.
- Author
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Tandon N, Hudgens C, Fellman B, Tetzlaff MT, and Broaddus RR
- Subjects
- Aged, Carcinoma, Endometrioid genetics, Carcinoma, Endometrioid pathology, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA-Binding Proteins analysis, Endometrial Neoplasms chemistry, Endometrial Neoplasms pathology, Female, Gene Expression Regulation, Neoplastic genetics, Humans, Middle Aged, MutS Homolog 2 Protein analysis, MutS Homolog 2 Protein chemistry, MutS Homolog 2 Protein genetics, DNA Methylation genetics, DNA Mismatch Repair genetics, DNA-Binding Proteins genetics, Endometrial Neoplasms genetics, MutL Protein Homolog 1 genetics
- Abstract
Immunohistochemistry for mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 is an effective screen to detect individuals at risk for Lynch syndrome. College of American Pathologists guidelines stipulate that protein expression should be reported as present versus absent, as most patients with germline mutations in a mismatch repair gene have complete loss of protein expression in tumor cells. A similar approach is employed to screen for cancer patients eligible for immune checkpoint blockade. This "all or none" interpretive approach ignores substantial evidence that mismatch repair may be more finely regulated by other mechanisms. We have observed clinically that MSH6 expression is variable, even in carcinomas that are overall considered positive for MSH6 expression. A proof-of-principle study was therefore designed to more rigorously quantify the protein expression of MSH6 and its binding partner, MSH2, using image analysis applied to age-matched endometrioid grade 2 subsets that were either mismatch repair intact or MLH1-deficient due to MLH1 gene methylation. In both endometrioid groups, MSH6 expression was significantly lower than MSH2 expression. MSH6 expression increased in higher grade, mismatch repair intact serous carcinomas, but it was still significantly lower than that for MSH2. MSH2 expression was consistently high across the 3 different tumor groups. These results suggest that MSH6 expression is subject to wide fluctuations in expression, even when overall its expression is considered intact. While such fluctuations are likely not relevant for Lynch syndrome screening, they may be more impactful when considering patients eligible for immune checkpoint blockade.
- Published
- 2020
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33. Pten and Dicer1 loss in the mouse uterus causes poorly differentiated endometrial adenocarcinoma.
- Author
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Wang X, Wendel JRH, Emerson RE, Broaddus RR, Creighton CJ, Rusch DB, Buechlein A, DeMayo FJ, Lydon JP, and Hawkins SM
- Subjects
- Adenocarcinoma, Clear Cell genetics, Animals, Cell Line, Tumor, DEAD-box RNA Helicases metabolism, Disease Models, Animal, Endometrial Neoplasms genetics, Endometrium pathology, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Gene Knockout Techniques, Humans, Lim Kinases genetics, Mice, Mice, Transgenic, MicroRNAs metabolism, PTEN Phosphohydrolase metabolism, RNA-Seq, Ribonuclease III metabolism, Adenocarcinoma, Clear Cell pathology, Cell Differentiation genetics, DEAD-box RNA Helicases genetics, Endometrial Neoplasms pathology, PTEN Phosphohydrolase genetics, Ribonuclease III genetics
- Abstract
Endometrial cancer remains the most common gynecological malignancy in the United States. While the loss of the tumor suppressor, PTEN (phosphatase and tensin homolog), is well studied in endometrial cancer, recent studies suggest that DICER1, the endoribonuclease responsible for miRNA genesis, also plays a significant role in endometrial adenocarcinoma. Conditional uterine deletion of Dicer1 and Pten in mice resulted in poorly differentiated endometrial adenocarcinomas, which expressed Napsin A and HNF1B (hepatocyte nuclear factor 1 homeobox B), markers of clear-cell adenocarcinoma. Adenocarcinomas were hormone-independent. Treatment with progesterone did not mitigate poorly differentiated adenocarcinoma, nor did it affect adnexal metastasis. Transcriptomic analyses of DICER1 deleted uteri or Ishikawa cells revealed unique transcriptomic profiles and global miRNA downregulation. Computational integration of miRNA with mRNA targets revealed deregulated let-7 and miR-16 target genes, similar to published human DICER1-mutant endometrial cancers from TCGA (The Cancer Genome Atlas). Similar to human endometrial cancers, tumors exhibited dysregulation of ephrin-receptor signaling and transforming growth factor-beta signaling pathways. LIM kinase 2 (LIMK2), an essential molecule in p21 signal transduction, was significantly upregulated and represents a novel mechanism for hormone-independent pathogenesis of endometrial adenocarcinoma. This preclinical mouse model represents the first genetically engineered mouse model of poorly differentiated endometrial adenocarcinoma.
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- 2020
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34. Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer.
- Author
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Myers AP, Konstantinopoulos PA, Barry WT, Luo W, Broaddus RR, Makker V, Drapkin R, Liu J, Doyle A, Horowitz NS, Meric-Bernstam F, Birrer M, Aghajanian C, Coleman RL, Mills GB, Cantley LC, Matulonis UA, and Westin SN
- Subjects
- Adult, Aged, Drug Administration Schedule, Endometrial Neoplasms genetics, Female, Heterocyclic Compounds, 3-Ring adverse effects, Humans, Middle Aged, Neoplasm Recurrence, Local genetics, Precision Medicine, Treatment Outcome, Class I Phosphatidylinositol 3-Kinases genetics, Endometrial Neoplasms drug therapy, Heterocyclic Compounds, 3-Ring administration & dosage, Mutation, Neoplasm Recurrence, Local drug therapy
- Abstract
Endometrial cancers have high rates of phosphoinositide 3-kinase (PI3K) pathway alterations. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized patients with tumors harboring PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. A Phase II study was performed in patients with recurrent endometrial cancer; all histologies except carcinosarcoma were eligible. Up to two prior chemotherapy lines were permitted, excluding prior treatment with PI3K pathway inhibitors. The first 18 patients were treated with MK-2206 200 mg weekly. Due to unacceptable toxicity, dose was reduced to 135 mg. Co-primary endpoints were objective response rate (ORR) and progression-free survival at 6 months (6moPFS). Thirty-seven patients were enrolled (one ineligible). By somatic PIK3CA mutation analysis, nine patients were mutant (MT) [one with partial response (PR)/6moPFS, two with 6moPFS]. Twenty-seven patients were wild-type (WT) (one PR and four 6moPFS). Most common toxicities were rash (44%), fatigue (41%), nausea (42%) and hyperglycemia (31%). Grade 3 and 4 toxicities occurred in 25 and 17% of patients, respectively. Exploratory analysis found serous histology had greater 6moPFS as compared to all other histologies (5/8 vs. 2/28, p = 0.003). PTEN expression was associated with median time to progression (p = 0.04). No other significant associations with PI3K pathway alterations were identified. There is limited single agent activity of MK-2206 in PIK3CA MT and PIK3CA WT endometrial cancer populations. Activity was detected in patients with serous histology and due to their poor outcomes warrants further study (NCT01307631)., (© 2019 UICC.)
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- 2020
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35. Identification of biomarkers of immune checkpoint blockade efficacy in recurrent or refractory solid tumor malignancies.
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Yang RK, Qing Y, Jelloul FZ, Routbort MJ, Wang P, Shaw K, Zhang J, Lee J, Medeiros LJ, Kopetz S, Tetzlaff MT, and Broaddus RR
- Abstract
Patients with advanced solid malignancies recurrent or resistant to standard therapy have limited treatment options. The role of molecular biomarkers for predicting immune checkpoint blockade (ICB) efficacy are not well characterized in these patients. Tumor mutational profiles of 490 patients with a variety of advanced solid tumors enrolled in a prospective protocol were analyzed to identify prognostic and predictive biomarkers. ICB therapy was defined as treatment with any CTLA-4, PD-1, and/or PD-L1 monoclonal antibody. ICB treatment was associated with significantly improved overall survival compared to non-ICB therapy. Multivariate regression analysis including the two variables of tumor mutation burden (TMB) and ICB, and their interaction term, showed favorable survival associated with ICB, unfavorable survival associated with TMB without ICB treatment, and improved outcome with increasing TMB in ICB treated patients. Tumor TP53 mutation was associated with worse survival, but these patients still benefitted from ICB. A more comprehensive multivariate analysis including cancer type, specific gene mutations, and TMB revealed that ICB treatment was an independent predictor of improved overall survival. Therefore, ICB-based therapeutic trials are beneficial in patients with advanced solid malignancies, but the most benefit may be restricted to patients with the right combination of TMB and specific tumor histology and genotype., Competing Interests: CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. Scott Kopetz: Stock and Other Ownership Interests: MolecularMatch, Navire Consulting or Advisory Role: Roche, Genentech, EMD Serono, Merck, Karyopharm Therapeutics, Amal Therapeutics, Navire Pharma, Symphogen, Holy Stone, Biocartis, Amgen, Novartis, Lilly, Boehringer Ingelheim, Boston Medical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre; Research Funding: Amgen (Inst), Sanofi (Inst), Biocartis (Inst), Guardant Health (Inst), Array BioPharma (Inst), Genentech (Inst), EMD Serono (Inst), MedImmune (Inst), Novartis (Inst) J. Jack Lee: Consulting or Advisory Role: AbbVie The authors do not have any other relevant financial relationships to disclose., (Copyright: © 2020 Yang et al.)
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- 2020
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36. Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study.
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Soliman PT, Westin SN, Iglesias DA, Fellman BM, Yuan Y, Zhang Q, Yates MS, Broaddus RR, Slomovitz BM, Lu KH, and Coleman RL
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- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Everolimus, Female, Humans, Letrozole, Middle Aged, Progression-Free Survival, Carcinoma, Endometrioid, Metformin
- Abstract
Purpose: Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second-line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent EEC., Patients and Methods: A Simon two-stage design was employed. Women with ≤2 prior chemotherapy regimens for recurrence were eligible. Pretreatment biopsy was required, followed by everolimus 10 mg orally, letrozole 2.5 mg orally, and metformin 500 mg orally twice a day on a 4-week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity., Results: Sixty-two patients were enrolled. Median age was 62 years (40-77) with 401 cycles completed, median of 6 cycles (1-31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received >12 cycles. Median follow-up was 17.9 months (2-47). Median progression-free survival was 5.7 [95% confidence interval (CI), 3.0-8.1] and OS was 19.6 months (95% CI, 14.2-26.3). Positive progesterone receptor expression was associated with CB (89.5% vs. 27.3%, P = 0.001)., Conclusions: Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor-positive tumors may have better response; validation studies are needed. See related commentary by Madariaga et al., p. 523 ., (©2019 American Association for Cancer Research.)
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- 2020
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37. Long-term overall survival and prognostic score predicting survival: the IMPACT study in precision medicine.
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Tsimberidou AM, Hong DS, Wheler JJ, Falchook GS, Janku F, Naing A, Fu S, Piha-Paul S, Cartwright C, Broaddus RR, Nogueras Gonzalez GM, Hwu P, and Kurzrock R
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor antagonists & inhibitors, Case-Control Studies, Clinical Trials, Phase I as Topic, Female, Follow-Up Studies, Humans, Liver Neoplasms drug therapy, Liver Neoplasms secondary, Male, Middle Aged, Neoplasms drug therapy, Neoplasms pathology, Prognosis, Protein Kinases chemistry, Response Evaluation Criteria in Solid Tumors, Survival Rate, Young Adult, Biomarkers, Tumor genetics, Liver Neoplasms mortality, Molecular Targeted Therapy, Neoplasms mortality, Precision Medicine methods, Protein Kinase Inhibitors therapeutic use, Protein Kinases genetics
- Abstract
Background: In 2007, we initiated IMPACT, a precision medicine program for patients referred for participation in early-phase clinical trials. We assessed the correlation of factors, including genomically matched therapy, with overall survival (OS)., Patients and Methods: We performed molecular profiling (Clinical Laboratory Improvement Amendments) (genes ≤ 182) for patients with lethal/refractory advanced cancers referred to the Phase 1 Clinical Trials Program. Matched therapy, if available, was selected on the basis of genomics. Clinical trials varied over time and included investigational drugs against various targets (single agents or combinations). Patients were followed up for up to 10 years., Results: Of 3487 patients who underwent tumor molecular profiling, 1307 (37.5%) had ≥ 1 alteration and received therapy (matched, 711; unmatched, 596; median age, 57 years; 39% men). Most common tumors were gastrointestinal, gynecologic, breast, melanoma, and lung. Objective response rates were: matched 16.4%, unmatched 5.4% (p < .0001); objective response plus stable disease ≥ 6 months rates were: matched 35.3% and unmatched 20.3%, (p < .001). Respective median progression-free survival: 4.0 and 2.8 months (p < .0001); OS, 9.3 and 7.3 months; 3-year, 15% versus 7%; 10-year, 6% vs. 1% (p < .0001). Independent factors associated with shorter OS (multivariate analysis) were performance status > 1 (p < .001), liver metastases (p < .001), lactate dehydrogenase levels > upper limit of normal (p < .001), PI3K/AKT/mTOR pathway alterations (p < .001), and non-matched therapy (p < .001). The five independent factors predicting shorter OS were used to design a prognostic score., Conclusions: Matched targeted therapy was an independent factor predicting longer OS. A score to predict an individual patient's risk of death is proposed., Trial Registration: ClinicalTrials.gov, NCT00851032, date of registration February 25, 2009.
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- 2019
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38. Fasting Reduces Intestinal Radiotoxicity, Enabling Dose-Escalated Radiation Therapy for Pancreatic Cancer.
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de la Cruz Bonilla M, Stemler KM, Jeter-Jones S, Fujimoto TN, Molkentine J, Asencio Torres GM, Zhang X, Broaddus RR, Taniguchi CM, and Piwnica-Worms H
- Subjects
- Abdomen radiation effects, Animals, Apoptosis, Cell Line, Tumor, DNA Breaks, Double-Stranded, Female, Histones metabolism, Intestine, Small cytology, Intestine, Small radiation effects, Male, Maximum Tolerated Dose, Mice, Mice, Inbred C57BL, Organs at Risk radiation effects, Pancreatic Neoplasms mortality, Proof of Concept Study, Radiation Injuries mortality, Radiation Injuries prevention & control, Radiotherapy Dosage, Random Allocation, Regeneration, Stem Cells physiology, Time Factors, Tumor Stem Cell Assay methods, Duodenum radiation effects, Fasting, Organ Sparing Treatments, Pancreatic Neoplasms radiotherapy, Radiation Tolerance, Stem Cells radiation effects
- Abstract
Purpose: Chemotherapy combined with radiation therapy is the most commonly used approach for treating locally advanced pancreatic cancer. The use of curative doses of radiation in this disease setting is constrained because of the close proximity of the head of the pancreas to the duodenum. The purpose of this study was to determine whether fasting protects the duodenum from high-dose radiation, thereby enabling dose escalation for efficient killing of pancreatic tumor cells., Methods and Materials: C57BL/6J mice were either fed or fasted for 24 hours and then exposed to total abdominal radiation at 11.5 Gy. Food intake, body weight, overall health, and survival were monitored. Small intestines were harvested at various time points after radiation, and villi length, crypt depth, and number of crypts per millimeter of intestine were determined. Immunohistochemistry was performed to assess apoptosis and double-strand DNA breaks, and microcolony assays were performed to determine intestinal stem cell regeneration capacity. A syngeneic KPC model of pancreatic cancer was used to determine the effects of fasting on the radiation responses of both pancreatic cancer and host intestinal tissues., Results: We demonstrated that a 24-hour fast in mice improved intestinal stem cell regeneration, as revealed by microcolony assay, and improved host survival of lethal doses of total abdominal irradiation compared with fed controls. Fasting also improved survival of mice with orthotopic pancreatic tumors subjected to lethal abdominal radiation compared with controls with free access to food. Furthermore, fasting did not affect tumor cell killing by radiation therapy and enhanced γ-H2AX staining after radiation therapy, suggesting an additional mild radiosensitizing effect., Conclusions: These results establish proof of concept for fasting as a dose-escalation strategy, enabling ablative radiation in the treatment of unresectable pancreatic cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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39. G-protein coupled receptor 64 (GPR64) acts as a tumor suppressor in endometrial cancer.
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Ahn JI, Yoo JY, Kim TH, Kim YI, Broaddus RR, Ahn JY, Lim JM, and Jeong JW
- Subjects
- AMP-Activated Protein Kinases metabolism, Carcinoma, Endometrioid genetics, Carcinoma, Endometrioid metabolism, Cell Line, Tumor, Cell Movement, Cell Proliferation, Connexin 43 metabolism, Endometrial Neoplasms genetics, Endometrial Neoplasms metabolism, Female, Gene Expression Regulation, Neoplastic, Humans, Neoplasm Invasiveness, Phosphorylation, RNA, Small Interfering, Receptors, G-Protein-Coupled antagonists & inhibitors, Receptors, G-Protein-Coupled genetics, Carcinoma, Endometrioid pathology, Endometrial Neoplasms pathology, Receptors, G-Protein-Coupled metabolism
- Abstract
Background: Endometrial cancer is the most common gynecological cancer. G-protein coupled receptor 64 (GPR64) belongs to a family of adhesion GPCRs and plays an important role in male fertility. However, the function of GPR64 has not been studied in endometrial cancer. Our objective is to investigate the role of GPR64 in endometrial cancer., Methods: We examined the levels of GPR64 in human endometrioid endometrial carcinoma by immunohistochemistry analysis. To determine a tumor suppressor role of GPR64 in endometrial cancer, we used a siRNA loss of function approach in human endometrial adenocarcinoma cell lines., Results: GPR64 levels were remarkably lower in 10 of 21 (47.62%) of endometrial carcinoma samples compared to control. Depletion of GPR64 by siRNA transfection revealed an increase of colony formation ability, cell proliferation, cell migration, and invasion activity in Ishikawa and HEC1A cells. The expression of Connexin 43 (Cx43), a member of the large family of gap junction proteins, was reduced through activation of AMP-activated protein kinase (AMPK) in Ishikawa cells with GPR64-deficicy., Conclusions: These results suggest that GPR64 plays an important tumor suppressor role in endometrial cancer.
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- 2019
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40. Adjuvant combined-modality therapy for stage IIIC endometrioid and non-endometrioid endometrial cancer.
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Chapman BV, Swanick CW, Ning MS, Allen PK, Soliman PT, Westin SN, Pardeshi V, Broaddus RR, Lu KH, Jhingran A, Eifel PJ, and Klopp AH
- Subjects
- Adult, Aged, Aged, 80 and over, Carboplatin administration & dosage, Carcinoma, Endometrioid pathology, Chemoradiotherapy, Adjuvant, Endometrial Neoplasms pathology, Female, Humans, Lymphatic Metastasis, Middle Aged, Neoplasm Staging, Paclitaxel administration & dosage, Prognosis, Retrospective Studies, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Endometrioid therapy, Cisplatin therapeutic use, Endometrial Neoplasms therapy
- Abstract
Objective: To identify the optimal adjuvant treatment regimen for patients with endometrioid and non-endometrioid node-positive endometrial cancer., Methods: We retrospectively identified 249 women with FIGO 2009 stage IIIC endometrial cancer at our institution who underwent surgical staging from 1985 to 2015 followed by external beam radiotherapy (RT), chemotherapy (CT), or a combination of CT + RT. Survival rates were calculated using the Kaplan-Meier method., Results: The 5-year disease-specific survival (DSS) rate for all patients was 65%. Adjuvant CT + RT conferred higher rates of 5-year DSS as compared to CT alone in patients with grade 3 endometrioid and non-endometrioid tumors (61% vs. 27%, P = 0.04 and 67% vs. 38%, P = 0.02, respectively). Among patients with non-endometrioid tumors, treatment with concurrent chemoradiotherapy followed by additional sequential chemotherapy had higher 5-year DSS rates than with concurrent chemoradiotherapy alone (74% vs. 50%, P = 0.02). The 3-year pelvic recurrence rate was 5% with RT ± CT and 35% with CT alone (P < 0.001) for all patients. No paraaortic nodal failures were observed following extended-field RT, but 14% of patients who received pelvic-only RT or CT alone developed recurrences in the paraaortic nodes (P < 0.001)., Conclusions: Combined-modality therapy including adjuvant external beam pelvic radiotherapy yields excellent outcomes for patients with all subtypes of node-positive endometrial cancer. The most pronounced DSS advantage from adjuvant chemoradiotherapy was evident in women with non-endometrioid endometrial cancer., (Copyright © 2019. Published by Elsevier Inc.)
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- 2019
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41. Microsatellite Instability Occurs in a Subset of Follicular Thyroid Cancers.
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Genutis LK, Tomsic J, Bundschuh RA, Brock PL, Williams MD, Roychowdhury S, Reeser JW, Frankel WL, Alsomali M, Routbort MJ, Broaddus RR, Wakely PE Jr, Phay JE, Walker CJ, and de la Chapelle A
- Subjects
- Adenocarcinoma, Follicular pathology, Genetic Predisposition to Disease, Hemizygote, Humans, Loss of Heterozygosity, Mutation, Phenotype, Risk Factors, Thyroid Neoplasms pathology, Adenocarcinoma, Follicular genetics, Biomarkers, Tumor genetics, DNA Mismatch Repair, Microsatellite Instability, MutS Homolog 2 Protein genetics, Thyroid Neoplasms genetics
- Abstract
Background: Inactivation of DNA mismatch repair (MMR) and the resulting microsatellite instability (MSI) are frequently observed in endometrial, stomach, and colorectal cancers, as well as more rarely in other solid tumor types. The prevalence of MSI in thyroid cancer has not been explored in depth, although recent studies utilizing data from large cancer sequencing efforts such as The Cancer Genome Atlas indicate that MSI is absent or at least very rare in the most common and most well studied histologic subtype, papillary thyroid carcinoma. This study aimed to determine the prevalence of MSI in thyroid cancer by using a large series comprising all major histological subtypes., Methods: A total of 485 thyroid cancer patients were screened for MSI/MMR deficiency, including all major histologic subtypes (195 papillary thyroid carcinoma, 156 follicular thyroid carcinoma [FTC], 50 anaplastic thyroid carcinoma, 65 medullary thyroid carcinoma, and 17 poorly differentiated thyroid carcinomas) by using a combination of polymerase chain reaction-based detection, immunohistochemistry, and next-generation sequencing., Results: A total of four tumors were MSI-high and had loss of MMR protein expression, all of which were from FTC patients. Whole-exome sequencing was performed on two MSI-high FTCs and revealed a hemizygous loss of function mutation in MSH2 in one tumor., Conclusions: Based on these data, it is estimated that the overall prevalence of MSI in FTC is 2.5%, and MSI is either entirely absent or rare in other histology subtypes of thyroid carcinoma. These findings highlight the importance of testing for MSI in FTC.
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- 2019
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42. Use of a Targeted Exome Next-Generation Sequencing Panel Offers Therapeutic Opportunity and Clinical Benefit in a Subset of Patients With Advanced Cancers.
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Kopetz S, Mills Shaw KR, Lee JJ, Zhang J, Litzenburger B, Holla V, Kinyua W, Broaddus E, Daniels MS, Meric-Bernstam F, and Broaddus RR
- Abstract
Purpose: Smaller hotspot-based next-generation sequencing (NGS) panels have emerged to support standard of care therapy for patients with cancer. When standard treatments fail, it is unknown whether additional testing using an expanded panel of genes provides any benefit. The purpose of this study was to determine if larger sequencing panels that capture additional actionable genes, coupled with decision support, translates into treatment with matched therapy after frontline therapy has failed., Patients and Methods: A prospective protocol accrued 521 patients with a wide variety of refractory cancers. NGS testing using a 46- or 50-gene hotspot assay, then a 409-gene whole-exome assay, was sequentially performed in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. A decision-support team annotated somatic alterations in clinically actionable genes for function and facilitated therapeutic matching. Survival and the impact of matched therapy use were determined by Kaplan-Meier estimate, log-rank test, and Cox proportional hazards regression., Results: The larger NGS panel identified at least one alteration in an actionable gene not previously identified in the smaller sequencing panel in 214 (41%) of 521 of enrolled patients. After the application of decision support, 41% of the alterations in actionable genes were considered to affect the function of the gene and were deemed actionable. Forty patients (40 of 214 [19%]) were subsequently treated with matched therapy. Treatment with matched therapy was associated with significantly improved overall survival compared with treatment with nonmatched therapy ( P = .017)., Conclusion: Combining decision support with larger NGS panels that incorporate genes beyond those recommended in current treatment guidelines helped to identify patients who were eligible for matched therapy while improving overall treatment selection and survival. This survival benefit was restricted to a small subset of patients., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc. Scott KopetzStock and Other Ownership Interests: MolecularMatch, Navire Consulting or Advisory Role: Roche, Genentech, EMD Serono, Merck, Karyopharm Therapeutics, Amal Therapeutics, Navire Pharma, Symphogen, Holy Stone, Biocartis, Amgen, Novartis Research Funding: Amgen (Inst), Sanofi (Inst), Biocartis (Inst), Guardant Health (Inst), Array BioPharma (Inst), Genentech (Inst), EMD Serono (Inst), MedImmune (Inst), Novartis (Inst)J. Jack LeeConsulting or Advisory Role: AbbVieBeate LitzenburgerEmployment: QiagenFunda Meric-BernstamHonoraria: Sumitomo Group, Dialectica Consulting or Advisory Role: Genentech, Inflection Biosciences, Pieris Pharmaceuticals, Clearlight Diagnostics, Darwin Health, Samsung Bioepis, Spectrum Pharmaceuticals, Aduro Biotech, Origimed, Xencor, Debiopharm Group Research Funding: Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, Puma Biotechnology, CytomX Therapeutics, Jounce Therapeutics, Zymeworks, Curis, Pfizer, eFFECTOR Therapeutics, AbbVie, Boehringer Ingelheim (I), Guardant Health (Inst) No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)
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- 2019
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43. Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion.
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Liu Y, Deguchi Y, Tian R, Wei D, Wu L, Chen W, Xu W, Xu M, Liu F, Gao S, Jaoude JC, Chrieki SP, Moussalli MJ, Gagea M, Morris J, Broaddus RR, Zuo X, and Shureiqi I
- Subjects
- Animals, Benzamides pharmacology, Carcinogenesis, Cell Line, Tumor, Colorectal Neoplasms genetics, Disease Progression, HCT116 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Invasiveness, PPAR delta biosynthesis, PPAR delta genetics, Receptors, Cytoplasmic and Nuclear biosynthesis, Receptors, Cytoplasmic and Nuclear genetics, Sulfones pharmacology, Thiazoles pharmacology, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, PPAR delta metabolism, Receptors, Cytoplasmic and Nuclear metabolism
- Abstract
APC mutations activate aberrant β-catenin signaling to drive initiation of colorectal cancer; however, colorectal cancer progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of β-catenin, is upregulated in colorectal cancer. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apc
min mice has raised questions about the effects of PPARD on aberrant β-catenin activation and colorectal cancer. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation ( ApcΔ580 ) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in colorectal cancer. Overexpression or deletion of PPARD in IEC augmented or suppressed β-catenin activation via up- or downregulation of BMP7/TAK1 signaling and strongly promoted or suppressed colorectal cancer, respectively. Depletion of PPARD in human colorectal cancer organoid cells inhibited BMP7/β-catenin signaling and suppressed organoid self-renewal. Treatment with PPARD agonist GW501516 enhanced colorectal cancer tumorigenesis in ApcΔ580 mice, whereas treatment with PPARD antagonist GSK3787 suppressed tumorigenesis. PPARD expression was significantly higher in human colorectal cancer-invasive fronts versus their paired tumor centers and adenomas. Reverse-phase protein microarray and validation studies identified PPARD-mediated upregulation of other proinvasive pathways: connexin 43, PDGFRβ, AKT1, EIF4G1, and CDK1. Our data demonstrate that PPARD strongly potentiates multiple tumorigenic pathways to promote colorectal cancer progression and invasiveness. SIGNIFICANCE: These findings address long-standing, important, and unresolved questions related to the potential role of PPARD in APC mutation-dependent colorectal tumorigenesis by showing PPARD activation enhances APC mutation-dependent tumorigenesis., (©2019 American Association for Cancer Research.)- Published
- 2019
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44. Targeted next-generation sequencing of endometrial cancer and matched circulating tumor DNA: identification of plasma-based, tumor-associated mutations in early stage patients.
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Bolivar AM, Luthra R, Mehrotra M, Chen W, Barkoh BA, Hu P, Zhang W, and Broaddus RR
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- Adult, Aged, Aged, 80 and over, Carcinoma, Endometrioid blood, Carcinoma, Endometrioid diagnosis, Circulating Tumor DNA blood, Endometrial Neoplasms blood, Endometrial Neoplasms diagnosis, Female, High-Throughput Nucleotide Sequencing, Humans, Middle Aged, Mutation, Neoplasm Recurrence, Local diagnosis, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Carcinoma, Endometrioid genetics, Circulating Tumor DNA genetics, Endometrial Neoplasms genetics
- Abstract
There is currently no blood-based marker in routine use for endometrial cancer patients. Such a marker could potentially be used for early detection, but it could also help to track tumor recurrence following hysterectomy. This is important, as extra-vaginal recurrence of endometrial endometrioid adenocarcinoma is usually incurable. This proof-of-principle study was designed to determine if tumor-associated mutations could be detected in cell-free DNA from the peripheral blood of early and late stage endometrial endometrioid carcinoma patients. Approximately 90% of endometrioid carcinomas have at least one mutation in the genes CTNNB1, KRAS, PTEN, or PIK3CA. Using a custom panel targeting 30 hotspot amplicons in these four genes, next-generation sequencing was performed on cell-free DNA extracted from plasma obtained from a peripheral blood draw at the time of hysterectomy and the matching tumor DNA from 48 patients with endometrioid endometrial carcinomas. At least one mutation in the tumor was detected in 45/48 (94%) of patients. Fifteen of 45 patients (33%) had a mutation in the plasma that matched a mutation in the tumor. These same mutations were not detected in the matched negative control buffy coat. Presence of a plasma mutation was significantly associated with advanced stage at hysterectomy, deep myometrial invasion, lymphatic/vascular invasion, and primary tumor size. Detecting a plasma-based mutation was independent of the amount of cell-free DNA isolated from the plasma. Overall, 18% of early stage patients had a mutation detected in the plasma. These results demonstrate that mutations in genes relevant to endometrial cancer can be identified in the peripheral blood of patients at the time of surgery. Future studies can help to determine the post-operative time course of mutation clearance from the peripheral blood and if mutation re-emergence is predictive of recurrence.
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- 2019
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45. Molecular Modifiers of Hormone Receptor Action: Decreased Androgen Receptor Expression in Mismatch Repair Deficient Endometrial Endometrioid Adenocarcinoma.
- Author
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Gan Q, Crumley S, and Broaddus RR
- Subjects
- Aged, Brain Neoplasms metabolism, Carcinoma, Endometrioid metabolism, Case-Control Studies, Cohort Studies, Colorectal Neoplasms metabolism, DNA Methylation, DNA Mismatch Repair genetics, Endometrial Neoplasms metabolism, Female, Humans, Immunohistochemistry, MutL Protein Homolog 1 metabolism, Neoplastic Syndromes, Hereditary metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Androgens metabolism, Brain Neoplasms pathology, Carcinoma, Endometrioid pathology, Colorectal Neoplasms pathology, Endometrial Neoplasms pathology, NF-kappa B metabolism, Neoplastic Syndromes, Hereditary pathology, Receptors, Androgen metabolism
- Abstract
Endometrial endometrioid carcinoma is related to estrogen excess and expression of estrogen and progesterone receptors. Epidemiological evidence suggests that exposure to elevated androgens, as in polycystic ovarian syndrome, increases the risk of endometrial cancer. Factors impacting androgen receptor (AR) expression are not well studied. Mismatch repair (MMR) deficiency due to MLH1 gene methylation is one of the most common molecular alterations in endometrial cancer, occurring in 15% to 20% of cases. MLH1 methylation can be associated with decreased expression of other genes, so we examined the effect of MMR status on AR expression. As NF-κB is known to induce AR, this transcription factor was also examined. Three hundred forty-four unselected endometrial carcinomas were evaluated for DNA MMR. Loss of expression of MLH1 with MLH1 methylation was defined as MMR deficient, and positive expression of MMR proteins was defined as MMR intact. A case-control cohort of 96 grade 2 endometrioid carcinomas was studied from this set (47 MMR deficient, 49 MMR intact). Cases were matched for histotype, grade, and age. AR and NF-κB immunohistochemical expression were evaluated by 2 different scoring systems (CAP/ASCO and Allred) used for estrogen receptor. Despite higher levels of NF-κB, MMR deficiency was associated with a significantly lower mean percentage of AR expression. The MMR deficient group had more variable AR expression, with more cases scoring on the lower end of the spectrum. These findings have implications for clinical trials of AR antagonists in gynecologic cancers.
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- 2019
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46. The ERM family member Merlin is required for endometrial gland morphogenesis.
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Lopez EW, Vue Z, Broaddus RR, Behringer RR, and Gladden AB
- Subjects
- Animals, Cell Adhesion physiology, Cell Polarity physiology, DNA-Binding Proteins metabolism, DNA-Binding Proteins physiology, Endometrium cytology, Endometrium metabolism, Endometrium pathology, Epithelial Cells metabolism, Female, In Situ Hybridization, Infertility, Female, Mice, Mice, Inbred C57BL, Morphogenesis physiology, Neurofibromin 2 deficiency, Neurofibromin 2 genetics, Neurofibromin 2 metabolism, Signal Transduction, Transcription Factors metabolism, Transcription Factors physiology, Endometrium growth & development, Neurofibromin 2 physiology
- Abstract
Disruption of endometrial gland formation or function can cause female infertility. Formation of endometrial glands via tubulogenesis of luminal epithelial cells requires the establishment and maintenance of cell polarity and cell adhesion. The FERM domain-containing protein Merlin coordinates epithelial cell polarity and cell adhesion and is critical for epithelial tissue function in the skin and kidney. We now demonstrate a requirement for Merlin in endometrial gland development. Conditional deletion of Merlin in the endometrium results in female infertility caused by the absence of gland formation. Interestingly, we observed glandular epithelial markers within discrete groups of cells in the Merlin-deficient luminal epithelium. Wnt signaling, a pathway necessary for endometrial gland development is maintained in Merlin-deficient endometrium, suggesting the glandular fate program is active. Instead, we observe increased levels of apical actin and markers indicative of high membrane tension on the basal surface of the Merlin-deficient luminal epithelium. These findings suggest that the structural integrity of the luminal epithelium during gland formation is required for appropriate endometrial tubulogenesis and tissue function. Moreover, our work implicates Merlin-dependent regulation of mechanical tension in the proper formation of endometrial gland architecture and function., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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47. Prospective Randomized Biomarker Study of Metformin and Lifestyle Intervention for Prevention in Obese Women at Increased Risk for Endometrial Cancer.
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Yates MS, Coletta AM, Zhang Q, Schmandt RE, Medepalli M, Nebgen D, Soletsky B, Milbourne A, Levy E, Fellman B, Urbauer D, Yuan Y, Broaddus RR, Basen-Engquist K, and Lu K
- Subjects
- Adiposity drug effects, Adiposity physiology, Biomarkers blood, Body Composition drug effects, Body Composition physiology, Body Mass Index, Endometrial Neoplasms etiology, Endometrium drug effects, Endometrium physiology, Female, Humans, Middle Aged, Obesity blood, Obesity drug therapy, Obesity rehabilitation, Prospective Studies, Treatment Outcome, Weight Loss drug effects, Weight Loss physiology, Endometrial Neoplasms prevention & control, Healthy Lifestyle physiology, Metformin administration & dosage, Obesity complications, Weight Reduction Programs methods
- Abstract
Obesity increases risk of endometrial cancer through dysregulation of estrogen and insulin signaling. The primary aim of this study was to evaluate the impact of metformin or lifestyle intervention on endometrial proliferation in postmenopausal obese women. Secondary aims included evaluating obesity-related biomarkers and adverse events experienced. Obese, postmenopausal women with prediabetes were randomized into four groups for a 16-week intervention using a 2 (metformin 1700 mg/day vs. placebo) × 2 (lifestyle intervention vs. no lifestyle intervention) factorial design. Pre- and postintervention endometrial proliferation, anthropometrics, body composition, and serum biomarkers (sex hormones, sex hormone binding globulin, IGF-I, adiponectin, omentin, insulin, glucose, and others) were assessed. Data were analyzed with linear regression models and false-discovery rate correction. Of 576 women approached for the study, 52 attended initial screening, 29 were eligible and randomized, and 26 completed the study. Lifestyle intervention resulted in significant loss of weight (-4.23 kg, P = 0.006) and total fat mass (-3.23 kg, P < 0.001). Participants receiving metformin lost 3.43 kg of weight ( P = 0.023), but this was not statistically significant after multiple comparisons adjustment controlling false-discovery rate to 10%. Endometrial proliferation was low at baseline (mean 7.1%) and remained unchanged by 16 weeks, but included substantial variability. Metformin and lifestyle intervention produced minor changes to serum biomarkers. Lifestyle intervention produced the most significant changes in weight and body composition. While it is known that obese postmenopausal women are at increased risk for endometrial cancer, improved biomarkers are needed to stratify risk and test prevention strategies, particularly at the endometrial tissue level. Cancer Prev Res; 11(8); 477-90. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
- Full Text
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48. Molecular Profile of Advanced Thyroid Carcinomas by Next-Generation Sequencing: Characterizing Tumors Beyond Diagnosis for Targeted Therapy.
- Author
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Chen H, Luthra R, Routbort MJ, Patel KP, Cabanillas ME, Broaddus RR, and Williams MD
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cell Line, Tumor, Child, DNA Mutational Analysis, Female, Gene Expression Regulation, Neoplastic genetics, High-Throughput Nucleotide Sequencing, Humans, MAP Kinase Kinase 1 genetics, Male, Middle Aged, Neoplasm Staging, Proto-Oncogene Proteins B-raf genetics, Signal Transduction, Thyroid Neoplasms pathology, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Proteins, Young Adult, Molecular Targeted Therapy, Mutation genetics, Neoplasm Proteins genetics, Thyroid Neoplasms genetics
- Abstract
Next-generation sequencing (NGS) for molecular diagnostics allows simultaneous testing of activating oncogenes and tumor suppressor mutations in multiple signal pathways. Extended mutational profiling of advanced thyroid cancers may enhance considerations for targeted therapies. We analyzed clinically derived molecular profiling of 216 patients with advanced thyroid carcinoma using NGS (Ion Torrent Personal Genome Machine) from April 2012 to February 2014. We examined substitutions and small indels in 46 or 50 cancer-related genes using Ampliseq Cancer Hotspot panel in respect to tumor diagnosis and clinical correlations.Mutations were common in advanced thyroid carcinomas 154 (71%) predominately in targetable MAPK pathway (146/216, 68%), and several PI3K/AKT pathway (8, 4%; six as comutations). BRAF V600E mutation associated with papillary (94/139, 68%), poorly differentiated (4/39, 10%), and anaplastic (3/12, 25%) carcinomas. NRAS mutations occurred in follicular (5/12, 42%) and poorly differentiated thyroid carcinoma (12/39, 31%). Tumor suppressor mutations (16, 7%) occurred predominantly in TP53 in Hurthle cell (2/5, 40%, the only mutation), in anaplastic (3/12, 25%) and poorly differentiated thyroid carcinoma (4/39, 10%) some as comutations and in papillary thyroid carcinoma (5/139, 4%) always a comutation. Kaplan-Meier analysis of patients with poorly differentiated thyroid carcinoma containing activating mutations who received targeted therapeutics showed improved survival compared to similarly treated patients without mutations in targetable pathways ( P = 0.02). In conclusion, MAPK pathway is the predominant target for therapy in advance thyroid carcinomas; adding NGS enables the identification of comutations associated with resistance ( PI3K/AKT ). Within poorly differentiated thyroid carcinoma, the molecular profile may hold prognostic value in the era of targeted therapy. Mol Cancer Ther; 17(7); 1575-84. ©2018 AACR ., (©2018 American Association for Cancer Research.)
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- 2018
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49. KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary.
- Author
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Hillman RT, Celestino J, Terranova C, Beird HC, Gumbs C, Little L, Nguyen T, Thornton R, Tippen S, Zhang J, Lu KH, Gershenson DM, Rai K, Broaddus RR, and Futreal PA
- Subjects
- Adult, Aged, Alleles, Cell Nucleus metabolism, DNA-Binding Proteins metabolism, Female, Granulosa Cell Tumor pathology, Humans, Middle Aged, Mutation, Neoplasm Proteins metabolism, Neoplasm Recurrence, Local pathology, Ovarian Neoplasms pathology, Ovary cytology, Ovary pathology, Retrospective Studies, Exome Sequencing, DNA-Binding Proteins genetics, Granulosa Cell Tumor genetics, Neoplasm Proteins genetics, Neoplasm Recurrence, Local genetics, Ovarian Neoplasms genetics
- Abstract
Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2) is a recurrent somatic event in aGCT. Mono-allelic KMT2D-truncating mutations are more frequent in recurrent (10/44, 23%) compared with primary (1/35, 3%) aGCTs (p = 0.02, two-sided Fisher's exact test). IHC detects additional non-KMT2D-mutated aGCTs with loss of nuclear KMT2D expression, suggesting that non-genetic KMT2D inactivation may occur in this tumor type. These findings identify KMT2D inactivation as a novel driver event in aGCTs and suggest that mutation of this gene may increase the risk of disease recurrence.
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- 2018
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50. MIG-6 suppresses endometrial epithelial cell proliferation by inhibiting phospho-AKT.
- Author
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Yoo JY, Kang HB, Broaddus RR, Risinger JI, Choi KC, and Kim TH
- Subjects
- Animals, Cell Proliferation, Cornified Envelope Proline-Rich Proteins genetics, Endometrium cytology, Endometrium metabolism, Endometrium pathology, Epithelial Cells metabolism, Epithelial Cells pathology, Estrogen Receptor alpha metabolism, Female, Humans, Intracellular Signaling Peptides and Proteins genetics, Mice, Mice, Knockout, Models, Animal, Phosphorylation, Receptors, Progesterone metabolism, Signal Transduction, Adaptor Proteins, Signal Transducing metabolism, Endometrial Neoplasms pathology, Intracellular Signaling Peptides and Proteins metabolism, Progesterone metabolism, Proto-Oncogene Proteins c-akt metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Background: Aberrant hyperactivation of epithelial proliferation, AKT signaling, and association with unopposed estrogen (E2) exposure is the most common endometrial cancer dysfunction. In the normal uterus, progesterone (P4) inhibits proliferation by coordinating stromal-epithelial cross-talk, which we previously showed is mediated by the function of Mitogen-inducible gene 6 (Mig-6). Despite their attractive characteristics, non-surgical conservative therapies based on progesterone alone have not been universally successful. One barrier to this success has been the lack of understanding of the P4 effect on endometrial cells., Method: To further understand the role of Mig-6 and P4 in controlling uterine proliferation, we developed a Sprr2f-cre driven mouse model where Mig-6 is specifically ablated only in the epithelial cells of the uterus (Sprr2f
cre+ Mig-6f/f ). We examined P4 effect and regulation of AKT signaling in the endometrium of mutant mice., Results: Sprr2fcre+ Mig-6f/f mice developed endometrial hyperplasia. P4 treatment abated the development of endometrial hyperplasia and restored morphological and histological characteristics of the uterus. P4 treatment reduced cell proliferation which was accompanied by decreased AKT signaling and the restoration of stromal PGR and ESR1 expression. Furthermore, our in vitro studies revealed an inhibitory effect of MIG-6 on AKT phosphorylation as well as MIG-6 and AKT protein interactions., Conclusions: These data suggest that endometrial epithelial cell proliferation is regulated by P4 mediated Mig-6 inhibition of AKT phosphorylation, uncovering new mechanisms of P4 action. This information may help guide more effective non-surgical interventions in the future.- Published
- 2018
- Full Text
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