Publications by authors named "Russell R Broaddus"

174 Publications

Low grade endometrioid endometrial cancer: complexities beyond p53abn.

Int J Gynecol Cancer 2021 09 28;31(9):1312. Epub 2021 Jul 28.

Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/ijgc-2021-002941DOI Listing
September 2021

Clinical and Functional Characterization of Atypical / Mutations in Metastatic Colorectal Cancer.

Clin Cancer Res 2021 Aug 11;27(16):4587-4598. Epub 2021 Jun 11.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Mutations in () predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all 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 variants. Using an cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and xenograft models of transduced isogenic clones, we assessed signaling changes across mutations.

Results: exon 2, extended , and atypical mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no codon 117/146 and only one codon 59 mutation was noted. Atypical mutations had worse overall survival than wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24-6.80; = 0.014). We functionally characterized 114 variants with the FACT assay. All exon 2 and extended mutations appeared activating. Of 57 atypical 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 variants are identified. L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included variants and functionally relevant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-0180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364867PMC
August 2021

Inactivating Mutations of the Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy.

Cancers (Basel) 2021 May 20;13(10). Epub 2021 May 20.

Department of Cancer Biology, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13102487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160817PMC
May 2021

Clinical and Financial Implications of Second-Opinion Surgical Pathology Review.

Am J Clin Pathol 2021 Sep;156(4):559-568

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqaa263DOI Listing
September 2021

Long-term Patterns of Excess Mortality among Endometrial Cancer Survivors.

Cancer Epidemiol Biomarkers Prev 2021 06 18;30(6):1079-1088. Epub 2021 Mar 18.

Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.

Background: We investigated excess mortality after endometrial cancer using conditional relative survival estimates and standardized mortality ratios (SMR).

Methods: Women diagnosed with endometrial cancer during 2000-2017 ( = 183,153) were identified in the Surveillance Epidemiology and End Results database. SMRs were calculated as observed deaths among endometrial cancer survivors over expected deaths among demographically similar women in the general U.S.

Population: Five-year relative survival was estimated at diagnosis and each additional year survived up to 12 years post-diagnosis, conditional on survival up to that year.

Results: For the full cohort, 5-year relative survival was 87.7%, 96.2%, and 97.1% at 1, 5, and 10 years post-diagnosis, respectively. Conditional 5-year relative survival first exceeded 95%, reflecting minimal excess mortality compared with the general population, at 4 years post-diagnosis overall. However, in subgroup analyses, conditional relative survival remained lower for Black women (vs. White) and for those with regional/distant stage disease (vs. localized) throughout the study period. The overall SMR for all-cause mortality decreased from 5.90 [95% confidence interval (CI), 5.81-5.99] in the first year after diagnosis to 1.16 (95% CI, 1.13-1.19) at 10+ years; SMRs were consistently higher for non-White women and for those with higher stage or grade disease.

Conclusions: Overall, endometrial cancer survivors had only a small survival deficit beyond 4 years post-diagnosis. However, excess mortality was greater in magnitude and persisted longer into survivorship for Black women and for those with more advanced disease.

Impact: Strategies to mitigate disparities in mortality after endometrial cancer will be needed as the number of survivors continues to increase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-20-1631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172460PMC
June 2021

Loss of CD73 shifts transforming growth factor-β1 (TGF-β1) from tumor suppressor to promoter in endometrial cancer.

Cancer Lett 2021 05 17;505:75-86. Epub 2021 Feb 17.

Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

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/CCND1 expression associated with poor tumor differentiation, increased myometrial and lymphatic/vascular space invasion, and patient death. Further loss of CD73 in CD73 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2021.01.030DOI Listing
May 2021

Endometrial Cancer. Reply.

N Engl J Med 2021 02;384(6):586

University of North Carolina, Chapel Hill, NC.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc2035378DOI Listing
February 2021

Evaluating Mismatch Repair/Microsatellite Instability Status Using Cytology Effusion Specimens to Determine Eligibility for Immunotherapy.

Arch Pathol Lab Med 2021 01;145(1):46-54

The Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2019-0398-OADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529913PMC
January 2021

Endometrial Cancer.

N Engl J Med 2020 11;383(21):2053-2064

From the Department of Gynecologic Oncology and Reproductive Medicine, the University of Texas M.D. Anderson Cancer Center, Houston (K.H.L.); and the Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill (R.R.B.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMra1514010DOI Listing
November 2020

Pathologic distribution at the time of interval tumor reductive surgery informs personalized surgery for high-grade ovarian cancer.

Int J Gynecol Cancer 2021 02 29;31(2):232-237. Epub 2020 Oct 29.

Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/ijgc-2020-001597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263077PMC
February 2021

Utilization of cytology smears improves success rates of RNA-based next-generation sequencing gene fusion assays for clinically relevant predictive biomarkers.

Cancer Cytopathol 2021 05 29;129(5):374-382. Epub 2020 Oct 29.

Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncy.22381DOI Listing
May 2021

Pten and Dicer1 loss in the mouse uterus causes poorly differentiated endometrial adenocarcinoma.

Oncogene 2020 10 25;39(40):6286-6299. Epub 2020 Aug 25.

Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-020-01434-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541676PMC
October 2020

Endometrial biomarkers in premenopausal women with obesity: an at-risk cohort.

Am J Obstet Gynecol 2021 03 21;224(3):278.e1-278.e14. Epub 2020 Aug 21.

Departments of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

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 (n=97) or a body mass index of ≤25 kg/m (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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2020.08.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897335PMC
March 2021

Prospective phase II trial of levonorgestrel intrauterine device: nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer.

Am J Obstet Gynecol 2021 02 15;224(2):191.e1-191.e15. Epub 2020 Aug 15.

Departments of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

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. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2020.08.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855308PMC
February 2021

Identification of biomarkers of immune checkpoint blockade efficacy in recurrent or refractory solid tumor malignancies.

Oncotarget 2020 Feb 11;11(6):600-618. Epub 2020 Feb 11.

Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

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 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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021232PMC
February 2020

Long-term overall survival and prognostic score predicting survival: the IMPACT study in precision medicine.

J Hematol Oncol 2019 12 30;12(1):145. Epub 2019 Dec 30.

Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13045-019-0835-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937824PMC
December 2019

Variable Expression of MSH6 in Endometrial Carcinomas With Intact Mismatch Repair and With MLH1 Loss Due to MLH1 Methylation.

Int J Gynecol Pathol 2020 Nov;39(6):507-513

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PGP.0000000000000655DOI Listing
November 2020

Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer.

Int J Cancer 2020 07 13;147(2):413-422. Epub 2019 Dec 13.

Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX.

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).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214201PMC
July 2020

Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study.

Clin Cancer Res 2020 02 18;26(3):581-587. Epub 2019 Oct 18.

Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.

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%, = 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..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-0471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002216PMC
February 2020

G-protein coupled receptor 64 (GPR64) acts as a tumor suppressor in endometrial cancer.

BMC Cancer 2019 Aug 14;19(1):810. Epub 2019 Aug 14.

Department of Obstetrics and Gynecology & Reproductive Biology, College of Human Medicine, Michigan State University, 400 Monroe Avenue NW, Grand Rapids, MI, 49503, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-5998-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694613PMC
August 2019

Fasting Reduces Intestinal Radiotoxicity, Enabling Dose-Escalated Radiation Therapy for Pancreatic Cancer.

Int J Radiat Oncol Biol Phys 2019 11 2;105(3):537-547. Epub 2019 Jul 2.

Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2019.06.2533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754784PMC
November 2019

Adjuvant combined-modality therapy for stage IIIC endometrioid and non-endometrioid endometrial cancer.

Gynecol Oncol 2019 07 17;154(1):22-28. Epub 2019 May 17.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2019.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523189PMC
July 2019

Use of a Targeted Exome Next-Generation Sequencing Panel Offers Therapeutic Opportunity and Clinical Benefit in a Subset of Patients With Advanced Cancers.

JCO Precis Oncol 2019 8;3. Epub 2019 Mar 8.

University of Texas MD Anderson Cancer Center, Houston, TX.

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 ( = .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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.18.00213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446317PMC
March 2019

Microsatellite Instability Occurs in a Subset of Follicular Thyroid Cancers.

Thyroid 2019 04 27;29(4):523-529. Epub 2019 Mar 27.

1 Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2018.0655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457885PMC
April 2019

Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion.

Cancer Res 2019 03 24;79(5):954-969. Epub 2019 Jan 24.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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 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 mutation ( ) 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 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 mutation-dependent colorectal tumorigenesis by showing PPARD activation enhances mutation-dependent tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-1790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397663PMC
March 2019

Targeted next-generation sequencing of endometrial cancer and matched circulating tumor DNA: identification of plasma-based, tumor-associated mutations in early stage patients.

Mod Pathol 2019 03 12;32(3):405-414. Epub 2018 Oct 12.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-018-0158-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395490PMC
March 2019

The ERM family member Merlin is required for endometrial gland morphogenesis.

Dev Biol 2018 10 15;442(2):301-314. Epub 2018 Aug 15.

Department of Genetics, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Program of Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ydbio.2018.08.006DOI Listing
October 2018

KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary.

Nat Commun 2018 06 27;9(1):2496. Epub 2018 Jun 27.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-04950-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021426PMC
June 2018

MIG-6 suppresses endometrial epithelial cell proliferation by inhibiting phospho-AKT.

BMC Cancer 2018 May 29;18(1):605. Epub 2018 May 29.

Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA.

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 Mig-6 ). We examined P4 effect and regulation of AKT signaling in the endometrium of mutant mice.

Results: Sprr2f Mig-6 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-018-4502-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975686PMC
May 2018

Predicting high-risk endometrioid carcinomas using proteins.

Oncotarget 2018 Apr 13;9(28):19704-19715. Epub 2018 Apr 13.

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: The lethality of endometrioid endometrial cancer (EEC) is primarily attributable to advanced-stage diseases. We sought to develop a biomarker model that predicts EEC surgical stage at the time of clinical diagnosis.

Results: PSES was significantly correlated with surgical stage in the TCGA cohort ( < 0.0001) and in the validation cohort ( = 0.0003). Even among grade 1 or 2 tumors, PSES was significantly higher in advanced than in early stage tumors in both the TCGA ( = 0.005) and MD Anderson Cancer Center (MDACC) ( = 0.006) cohorts. Patients with positive PSES score had significantly shorter progression-free survival than those with negative PSES in the TCGA (hazard ratio [HR], 2.033; 95% CI, 1.031 to 3.809; = 0.04) and validation (HR, 3.306; 95% CI, 1.836 to 9.436; = 0.0007) cohorts. The ErbB signaling pathway was most significantly enriched in the PSES proteins and downregulated in advanced stage tumors.

Methods: Using reverse-phase protein array expression profiles of 170 antibodies for 210 EEC cases from TCGA, we constructed a Protein Scoring of EEC Staging (PSES) scheme comprising 6 proteins (3 of them phosphorylated) for surgical stage prediction. We validated and evaluated its diagnostic potential in an independent cohort of 184 EEC cases obtained at MDACC using receiver operating characteristic curve analyses. Kaplan-Meier survival analysis was used to examine the association of PSES score with patient outcome, and Ingenuity pathway analysis was used to identify relevant signaling pathways. Two-sided statistical tests were used.

Conclusions: PSES may provide clinically useful prediction of high-risk tumors and offer new insights into tumor biology in EEC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.24803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929419PMC
April 2018
-->