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Article ; Online: Angiogenesis in endometrial carcinoma: Therapies and biomarkers, current options, and future perspectives.

Berger, Amnon A / Dao, Fanny / Levine, Douglas A

2020 Volume 160, Issue 3, Page(s) 844–850

Abstract: Endometrial carcinoma is the most common gynecologic malignancy and the fourth most prevalent cancer in women in the modern world. Despite a relatively high chance of surgical cure, for patients with advanced or recurrent disease there are few ... ...

Abstract	Endometrial carcinoma is the most common gynecologic malignancy and the fourth most prevalent cancer in women in the modern world. Despite a relatively high chance of surgical cure, for patients with advanced or recurrent disease there are few therapeutic options. Angiogenesis has been extensively studied ever since vascular endothelial growth factor (VEGF) was discovered in the 1980s. Several clinical trials of anti-angiogenic therapy in endometrial carcinoma have been conducted, with mixed results, and many researchers have tried to determine prognostic and therapeutic biomarkers. Recent trials, which shed new light on possible treatment biomarkers and efficacious combination therapies, are reviewed in this text. While we are still far from effectively tailoring anti-angiogenic treatment to each patient, these data have provided valuable insight and have put us on track for the discovery of novel opportunities for angiogenesis therapy in endometrial carcinoma.
MeSH term(s)	Biomarkers, Tumor/metabolism ; Endometrial Neoplasms/physiopathology ; Female ; Humans ; Neovascularization, Pathologic/therapy ; Prognosis
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2020-12-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2020.12.016
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Article: CCNE1

Margolis, Benjamin / Dao, Fanny / Licciardi, Michael / Misirlioglu, Selim / Olvera, Narciso / Ramaswami, Sitharam / Levine, Douglas A

Gynecologic oncology reports

2021 Volume 37, Page(s) 100850

Abstract: Objective: We sought to characterize the variability of : Methods: Patients with : Results: Four of 15 patients from an institutional database screened by ddPCR were found to have : Conclusions: ... ...

Abstract	Objective: We sought to characterize the variability of Methods: Patients with Results: Four of 15 patients from an institutional database screened by ddPCR were found to have Conclusions: CCNE1
Language	English
Publishing date	2021-08-21
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2818505-5
ISSN	2352-5789
ISSN	2352-5789
DOI	10.1016/j.gore.2021.100850
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Article ; Online: The role of CTNNB1 mutations and matrix metalloproteinases (MMPs) in anti-angiogenesis treatment of endometrial carcinoma.

Berger, Amnon A / Kawaler, Emily A / Dao, Fanny / Misirlioglu, Selim / Fernandez, Ernesto Arostegui / Olvera, Narciso / Van Oudenhove, Elke / DeLair, Deborah / Levine, Douglas A

Gynecologic oncology

2022 Volume 167, Issue 2, Page(s) 323–333

Abstract: Objective: Treatment options and associated biomarkers for advanced and recurrent disease are limited. Endometrial cancers (ECs) with CTNNB1 exon 3 mutations appear to have preferential response to bevacizumab, an anti-angiogenesis treatment, though the ...

Abstract	Objective: Treatment options and associated biomarkers for advanced and recurrent disease are limited. Endometrial cancers (ECs) with CTNNB1 exon 3 mutations appear to have preferential response to bevacizumab, an anti-angiogenesis treatment, though the mechanism of action is unknown. We aim to identify mediators of bevacizumab-responsive endometrial cancers. Methods: We analyzed RNA expression from TCGA and protein expression from CPTAC to identify likely targets for β-catenin overactivity. We then transiently and stably overexpressed β-catenin in EC cells to confirm the results suggested by our in silico analysis. We performed corroborative experiments by silencing CTNNB1 in mutated cell lines to demonstrate functional specificity. We implanted transduced cells into xenograft models to study microvessel density. Results: CTNNB1-mutated ECs were associated with increased β-catenin and MMP7 protein abundance (P < 0.001), but not VEGF-A protein abundance. Overexpressing β-catenin in EC cells did not increase VEGF-A abundance but did increase expression and secretion of MMP7 (P < 0.03). Silencing CTNNB1 in CTNNB1-mutated cells decreased MMP7 gene expression in EC (P < 0.0001). Microvessel density was not increased. Conclusions: These data provide a mechanistic understanding for bevacizumab-response in CTNNB1-mutated ECs demonstrated in GOG-86P. We hypothesize that overexpressed and secreted MMP7 potentially digests VEGFR-1, releasing VEGF-A, and increasing its availability. These activities may drive the formation of permeable vessels, which contributes to tumor progression, metastasis, and immune suppression. This mechanism is unique to EC and advocates for further clinical trials evaluating this treatment-related biomarker.
MeSH term(s)	Female ; Humans ; Angiogenesis Inhibitors/pharmacology ; Angiogenesis Inhibitors/therapeutic use ; beta Catenin/genetics ; beta Catenin/metabolism ; Bevacizumab/pharmacology ; Bevacizumab/therapeutic use ; Endometrial Neoplasms/blood supply ; Endometrial Neoplasms/drug therapy ; Endometrial Neoplasms/genetics ; Endometrial Neoplasms/metabolism ; Matrix Metalloproteinase 7/metabolism ; Mutation ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/metabolism ; Vascular Endothelial Growth Factor A/metabolism
Chemical Substances	Angiogenesis Inhibitors ; beta Catenin ; Bevacizumab (2S9ZZM9Q9V) ; CTNNB1 protein, human ; Matrix Metalloproteinase 7 (EC 3.4.24.23) ; Vascular Endothelial Growth Factor A ; MMP7 protein, human (EC 3.4.24.23)
Language	English
Publishing date	2022-09-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2022.09.013
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Article ; Online: Genetic predisposition to bevacizumab-induced hypertension.

Frey, Melissa K / Dao, Fanny / Olvera, Narciso / Konner, Jason A / Dickler, Maura N / Levine, Douglas A

Gynecologic oncology

2017 Volume 147, Issue 3, Page(s) 621–625

Abstract: Objective: Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. ... ...

Abstract	Objective: Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension (BIH). Methods: Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from six clinical trials. Haplotype-tagging (ht) SNPs for 10 candidate genes associated with hypertension were identified through the International Hapmap Project. Germline DNA was genotyped for 103 htSNPs using mass spectrometry. Bevacizumab toxicities were identified from clinical trial reports. Haplotypes were reconstructed from diploid genotyping data and frequencies were compared using standard two-sided statistical tests. Results: The study included 114 patients with breast, lung, ovarian, or other cancers, of whom 38 developed BIH. WNK1, KLKB1, and GRK4 were found to contain single loci associated with BIH. Haplotype analysis of WNK1, KLKB1, and GRK4 identified risk haplotypes in each gene associated with grade 3/4 BIH. A composite risk model was created based on these haplotypes. Patients with the highest risk score were the most likely to develop grade 3/4 BIH (OR=6.45; P=0.005; 95%CI, 1.86-22.39). Conclusions: We concluded that genetic variation in WNK1, KLKB1, and GRK4 may be associated with BIH. These genes are biologically plausible mediators due to their role in blood pressure control, regulating sodium homeostasis and vascular tone. This preliminary risk model performed better than population-based risk models and when further validated may help risk-stratify patients for BIH prior to initiating therapy.
Language	English
Publishing date	2017-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2017.09.017
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Article ; Online: Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer.

Zhang, Shuang / Iyer, Sonia / Ran, Hao / Dolgalev, Igor / Gu, Shengqing / Wei, Wei / Foster, Connor J R / Loomis, Cynthia A / Olvera, Narciso / Dao, Fanny / Levine, Douglas A / Weinberg, Robert A / Neel, Benjamin G

Cancer discovery

2020 Volume 11, Issue 2, Page(s) 362–383

Abstract: The paucity of genetically informed, immunocompetent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube epithelial organoids using lentiviral gene transduction and/or CRISPR/Cas9 ... ...

Abstract	The paucity of genetically informed, immunocompetent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube epithelial organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high-grade serous tubo-ovarian cancer (HGSC) models exhibiting mutational combinations seen in patients with HGSC. Detailed analysis of homologous recombination (HR)-proficient (
MeSH term(s)	Animals ; Cystadenocarcinoma, Serous/drug therapy ; Cystadenocarcinoma, Serous/genetics ; Disease Models, Animal ; Fallopian Tube Neoplasms/drug therapy ; Fallopian Tube Neoplasms/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Tumor Microenvironment
Language	English
Publishing date	2020-11-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-20-0455
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Article ; Online: Noninvasive ovarian cancer biomarker detection via an optical nanosensor implant.

Williams, Ryan M / Lee, Christopher / Galassi, Thomas V / Harvey, Jackson D / Leicher, Rachel / Sirenko, Maria / Dorso, Madeline A / Shah, Janki / Olvera, Narciso / Dao, Fanny / Levine, Douglas A / Heller, Daniel A

Science advances

2018 Volume 4, Issue 4, Page(s) eaaq1090

Abstract: Patients with high-grade serous ovarian carcinoma (HGSC) exhibit poor 5-year survival rates, which may be significantly improved by early-stage detection. The U.S. Food and Drug Administration-approved biomarkers for HGSC-CA-125 (cancer antigen 125) and ... ...

Abstract	Patients with high-grade serous ovarian carcinoma (HGSC) exhibit poor 5-year survival rates, which may be significantly improved by early-stage detection. The U.S. Food and Drug Administration-approved biomarkers for HGSC-CA-125 (cancer antigen 125) and HE4 (human epididymis protein 4)-do not generally appear at detectable levels in the serum until advanced stages of the disease. An implantable device placed proximal to disease sites, such as in or near the fallopian tube, ovary, uterine cavity, or peritoneal cavity, may constitute a feasible strategy to improve detection of HGSC. We engineered a prototype optical sensor composed of an antibody-functionalized carbon nanotube complex, which responds quantitatively to HE4 via modulation of the nanotube optical bandgap. The complexes measured HE4 with nanomolar sensitivity to differentiate disease from benign patient biofluids. The sensors were implanted into four models of ovarian cancer, within a semipermeable membrane, enabling the optical detection of HE4 within the live animals. We present the first in vivo optical nanosensor capable of noninvasive cancer biomarker detection in orthotopic models of disease.
MeSH term(s)	Animals ; Biomarkers, Tumor ; Biosensing Techniques ; Cystadenocarcinoma, Serous/blood ; Cystadenocarcinoma, Serous/diagnosis ; Cystadenocarcinoma, Serous/metabolism ; Disease Models, Animal ; Female ; Humans ; Mice ; Nanotechnology ; Neoplasm Grading ; Neoplasm Staging ; Optical Devices ; Ovarian Neoplasms/blood ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/metabolism
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2018-04-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.aaq1090
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Article ; Online: Massively parallel sequencing analysis of mucinous ovarian carcinomas: genomic profiling and differential diagnoses.

Mueller, Jennifer J / Schlappe, Brooke A / Kumar, Rahul / Olvera, Narciso / Dao, Fanny / Abu-Rustum, Nadeem / Aghajanian, Carol / DeLair, Deborah / Hussein, Yaser R / Soslow, Robert A / Levine, Douglas A / Weigelt, Britta

Gynecologic oncology

2018 Volume 150, Issue 1, Page(s) 127–135

Abstract: Objective: Mucinous ovarian cancer (MOC) is a rare type of epithelial ovarian cancer resistant to standard chemotherapy regimens. We sought to characterize the repertoire of somatic mutations in MOCs and to define the contribution of massively parallel ... ...

Abstract	Objective: Mucinous ovarian cancer (MOC) is a rare type of epithelial ovarian cancer resistant to standard chemotherapy regimens. We sought to characterize the repertoire of somatic mutations in MOCs and to define the contribution of massively parallel sequencing to the classification of tumors diagnosed as primary MOCs. Methods: Following gynecologic pathology and chart review, DNA samples obtained from primary MOCs and matched normal tissues/blood were subjected to whole-exome (n = 9) or massively parallel sequencing targeting 341 cancer genes (n = 15). Immunohistochemical analysis of estrogen receptor, progesterone receptor, PTEN, ARID1A/BAF250a, and the DNA mismatch (MMR) proteins MSH6 and PMS2 was performed for all cases. Mutational frequencies of MOCs were compared to those of high-grade serous ovarian cancers (HGSOCs) and mucinous tumors from other sites. Results: MOCs were heterogeneous at the genetic level, frequently harboring TP53 (75%) mutations, KRAS (71%) mutations and/or CDKN2A/B homozygous deletions/mutations (33%). Although established criteria for diagnosis were employed, four cases harbored mutational and immunohistochemical profiles similar to those of endometrioid carcinomas, and one case for colorectal or endometrioid carcinoma. Significant differences in the frequencies of KRAS, TP53, CDKN2A, FBXW7, PIK3CA and/or APC mutations between the confirmed primary MOCs (n = 19) and HGSOCs, mucinous gastric and/or mucinous colorectal carcinomas were found, whereas no differences in the 341 genes studied between MOCs and mucinous pancreatic carcinomas were identified. Conclusions: Our findings suggest that the assessment of mutations affecting TP53, KRAS, PIK3CA, ARID1A and POLE, and DNA MMR protein expression may be used to further aid the diagnosis and treatment decision-making of primary MOC.
MeSH term(s)	Diagnosis, Differential ; Female ; Genomics/methods ; Humans ; Immunohistochemistry/methods ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/pathology
Language	English
Publishing date	2018-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2018.05.008
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Article ; Online: Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma.

Ducie, Jennifer / Dao, Fanny / Considine, Michael / Olvera, Narciso / Shaw, Patricia A / Kurman, Robert J / Shih, Ie-Ming / Soslow, Robert A / Cope, Leslie / Levine, Douglas A

Nature communications

2017 Volume 8, Issue 1, Page(s) 990

Abstract: Many high-grade serous carcinomas (HGSCs) of the pelvis are thought to originate in the distal portion of the fallopian tube. Serous tubal intra-epithelial carcinoma (STIC) lesions are the putative precursor to HGSC and identifiable in ~ 50% of advanced ... ...

Abstract	Many high-grade serous carcinomas (HGSCs) of the pelvis are thought to originate in the distal portion of the fallopian tube. Serous tubal intra-epithelial carcinoma (STIC) lesions are the putative precursor to HGSC and identifiable in ~ 50% of advanced stage cases. To better understand the molecular etiology of HGSCs, we report a multi-center integrated genomic analysis of advanced stage tumors with and without STIC lesions and normal tissues. The most significant focal DNA SCNAs were shared between cases with and without STIC lesions. The RNA sequence and the miRNA data did not identify any clear separation between cases with and without STIC lesions. HGSCs had molecular profiles more similar to normal fallopian tube epithelium than ovarian surface epithelium or peritoneum. The data suggest that the molecular features of HGSCs with and without associated STIC lesions are mostly shared, indicating a common biologic origin, likely to be the distal fallopian tube among all cases.High-grade serous carcinomas (HGSCs) are associated with precursor lesions (STICs) in the fallopian epithelium in only half of the cases. Here the authors report the molecular analysis of HGSCs with and without associated STICs and show similar profiles supporting a common origin for all HGSCs.
MeSH term(s)	Adenocarcinoma in Situ/genetics ; Adenocarcinoma in Situ/pathology ; Adult ; Aged ; Case-Control Studies ; Fallopian Tube Neoplasms/genetics ; Fallopian Tube Neoplasms/pathology ; Female ; Humans ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Neoplasms, Cystic, Mucinous, and Serous/genetics ; Neoplasms, Cystic, Mucinous, and Serous/pathology ; Neoplasms, Multiple Primary/genetics ; Neoplasms, Multiple Primary/pathology ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Peritoneal Neoplasms/genetics ; Peritoneal Neoplasms/pathology ; RNA, Messenger/metabolism ; Transcriptome
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2017-10-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2041-1723
ISSN (online)	2041-1723
DOI	10.1038/s41467-017-01217-9
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Article ; Online: A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer.

Aghajanian, Carol / Filiaci, Virginia / Dizon, Don S / Carlson, Jay W / Powell, Matthew A / Secord, Angeles Alvarez / Tewari, Krishnansu S / Bender, David P / O'Malley, David M / Stuckey, Ashley / Gao, JianJiong / Dao, Fanny / Soslow, Robert A / Lankes, Heather A / Moore, Kathleen / Levine, Douglas A

Gynecologic oncology

2018 Volume 150, Issue 2, Page(s) 274–281

Abstract: Objective: Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy.: Methods: In this randomized phase II trial, ...

Abstract	Objective: Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy. Methods: In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety. Results: Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63-1.02), 1.22 (0.96-1.55) and 0.87 (0.68-1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p < 0.039) but not in Arms 2 and 3; the HRs (92% CIs) were 0.71 (0.55-0.91), 0.99 (0.78-1.26), and 0.97 (0.77-1.23), respectively. No new safety signals were identified. Common mutations and rates of mismatch repair protein loss are described by histotype. Potential predictive biomarkers for temsirolimus and bevacizumab were identified. Conclusion: PFS was not significantly increased in any experimental arm compared to historical controls. NRG Oncology/Gynecologic Oncology Group Study GOG-86P.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bevacizumab/administration & dosage ; Carboplatin/administration & dosage ; Endometrial Neoplasms/drug therapy ; Epothilones/administration & dosage ; Female ; Humans ; Middle Aged ; Neoplasm Recurrence, Local/drug therapy ; Paclitaxel/administration & dosage ; Sirolimus/administration & dosage ; Sirolimus/analogs & derivatives
Chemical Substances	Epothilones ; Bevacizumab (2S9ZZM9Q9V) ; temsirolimus (624KN6GM2T) ; Carboplatin (BG3F62OND5) ; ixabepilone (K27005NP0A) ; Paclitaxel (P88XT4IS4D) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2018-05-24
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2018.05.018
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Article ; Online: Validated gene targets associated with curatively treated advanced serous ovarian carcinoma.

Barlin, Joyce N / Jelinic, Petar / Olvera, Narciso / Bogomolniy, Faina / Bisogna, Maria / Dao, Fanny / Barakat, Richard R / Chi, Dennis S / Levine, Douglas A

Gynecologic oncology

2013 Volume 128, Issue 3, Page(s) 512–517

Abstract: Objectives: High-grade serous ovarian cancer (HGSOC) mostly presents at an advanced stage and has a low overall survival rate. However, a subgroup of patients are seemingly cured after standard initial therapy. We hypothesize that the molecular profiles ...

Abstract	Objectives: High-grade serous ovarian cancer (HGSOC) mostly presents at an advanced stage and has a low overall survival rate. However, a subgroup of patients are seemingly cured after standard initial therapy. We hypothesize that the molecular profiles of these patients vary from long-term survivors who recur. Methods: Patients with advanced HGSOC who underwent primary cytoreductive surgery and platinum-based chemotherapy were identified from The Cancer Genome Atlas (TCGA) and institutional (MSKCC) samples. A curative-intent group was defined by recurrence-free survival of >5years. A long-term recurrent group was composed of patients who recurred but survived >5years. RNA was hybridized to Affymetrix U133A transcription microarrays. The NanoString nCounter gene expression system was used for validation in an independent patient population. Results: In 30 curative and 84 recurrent patients, class comparison identified twice as many differentially expressed probes between the groups than expected by chance alone. TCGA and MSKCC data sets had 19 overlapping genes. Pathway analyses identified over-represented networks that included nuclear factor kappa B (NFkB) transcription and extracellular signal-regulated kinase (ERK) signaling. External validation was performed in an independent population of 28 curative and 38 recurrent patients. Three genes (CYP4B1, CEPT1, CHMP4A) in common between our original data sets remained differentially expressed in the external validation data. Conclusions: There are distinct transcriptional elements in HGSOC from patients likely to be cured by standard primary therapy. Three genes have withstood rigorous validation and are plausible targets for further study, which may provide insight into molecular features associated with long-term survival and chemotherapy resistance mechanisms.
MeSH term(s)	Adult ; Aged ; Cystadenocarcinoma, Serous/drug therapy ; Cystadenocarcinoma, Serous/genetics ; Cystadenocarcinoma, Serous/pathology ; Cystadenocarcinoma, Serous/surgery ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Middle Aged ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/pathology ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Ovarian Neoplasms/surgery ; Survivors ; Treatment Outcome
Language	English
Publishing date	2013-03
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2012.11.018
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