Suboptimal cytoreduction in ovarian carcinoma is associated with molecular pathways characteristic of increased stromal activation.
OBJECTIVE
Suboptimal cytoreductive surgery in advanced epithelial ovarian cancer (EOC) is associated with poor survival but it is unknown if poor outcome is due to the intrinsic biology of unresectable tumors or insufficient surgical effort resulting in residual tumor-sustaining clones. Our objective was to identify the potential molecular pathway(s) and cell type(s) that may be responsible for suboptimal surgical resection.


METHODS
By comparing gene expression in optimally and suboptimally cytoreduced patients, we identified a gene network associated with suboptimal cytoreduction and explored the biological processes and cell types associated with this gene network.


RESULTS
We show that primary tumors from suboptimally cytoreduced patients express molecular signatures that are typically present in a distinct molecular subtype of EOC characterized by increased stromal activation and lymphovascular invasion. Similar molecular pathways are present in EOC metastases, suggesting that primary tumors in suboptimally cytoreduced patients are biologically similar to metastatic tumors. We demonstrate that the suboptimal cytoreduction network genes are enriched in reactive tumor stroma cells rather than malignant tumor cells.


CONCLUSIONS
Our data suggest that the success of cytoreductive surgery is dictated by tumor biology, such as extensive stromal reaction and increased invasiveness, which may hinder surgical resection and ultimately lead to poor survival.
Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Zhenqiu
Z
Liu
Graduate Program in Biomedical Science and Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Jessica A
JA
Beach
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Hasmik
H
Agadjanian
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Dongyu
D
Jia
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Paul-Joseph
PJ
Aspuria
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
Beth Y
BY
Karlan
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA. Electronic address: Sandra.Orsulic@cshs.org.
Sandra
S
Orsulic
D019540:Area Under Curve; D001808:Blood Vessels / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000556:secondary / Q000601:surgery*; D065426:Cytoreduction Surgical Procedures; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D042601:Lymphatic Vessels / Q000473:pathology; D009361:Neoplasm Invasiveness; D018365:Neoplasm, Residual; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D011237:Predictive Value of Tests; D012372:ROC Curve; D017154:Stromal Cells
Cancer-associated stroma; Cytoreductive surgery; Debulking; Desmoplasia; Epithelial–mesenchymal transition; Invasion; Metastasis; Ovarian cancer