Risk Prediction for Late-Stage Ovarian Cancer by Meta-analysis of 1525 Patient Samples

Riester, Markus; Wei, Wei; Waldron, Levi; Culhane, Aedín C.; Trippa, Lorenzo; Oliva, Esther; Kim, Sung Hoon; Michor, Franziska; Huttenhower, Curtis; Parmigiani, Giovanni; Birrer, Michael J.

doi:10.1093/jnci/dju048

Cited by 187 publications

(176 citation statements)

References 61 publications

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“…Of note, surgical outcome may not be a predictor of survival itself, but rather a reflection of the underlying tumor biology. Indeed, it was recently shown that a specific gene expression signature correlates with surgical outcome in ovarian cancer (20). In our cohort, this may have led to a selection bias for the NACT cohort, because patients were selected for NACT if chance of upfront complete cytoreduction in primary surgery was minimal, thus these patients possibly differ in expression of key genes.…”

Section: Discussionmentioning

confidence: 99%

Treatment Regimen, Surgical Outcome, and T-cell Differentiation Influence Prognostic Benefit of Tumor-Infiltrating Lymphocytes in High-Grade Serous Ovarian Cancer

Wouters

Komdeur

Workel

et al. 2016

Clinical Cancer Research

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Purpose: Tumor-infiltrating lymphocytes (TIL) are associated with a better prognosis in high-grade serous ovarian cancer (HGSC). However, it is largely unknown how this prognostic benefit of TIL relates to current standard treatment of surgical resection and (neo-)adjuvant chemotherapy. To address this outstanding issue, we compared TIL infiltration in a unique cohort of patients with advanced-stage HGSC primarily treated with either surgery or neoadjuvant chemotherapy.Experimental Design: Tissue microarray slides containing samples of 171 patients were analyzed for CD8 þ TIL by IHC.Freshly isolated CD8 þ TIL subsets were characterized by flow cytometry based on differentiation, activation, and exhaustion markers. Relevant T-cell subsets (CD27 þ ) were validated using IHC and immunofluorescence.Results: A prognostic benefit for patients with high intratumoral CD8þ TIL was observed if primary surgery had resulted in a complete cytoreduction (no residual tissue). By contrast, optimal (<1 cm of residual tumor) or incomplete cytoreduction fully abrogated the prognostic effect of CD8 þ TIL. Subsequent analysis of primary TIL by flow cytometry and immunofluorescence identified CD27 as a key marker for a less-differentiated, yet antigen-experienced and potentially tumor-reactive CD8 þ TIL subset. In line with this, CD27 þ TIL were associated with an improved prognosis even in incompletely cytoreduced patients. Neither CD8 þ nor CD27 þ cell infiltration was of prognostic benefit in patients treated with neoadjuvant chemotherapy. Conclusions: Our findings indicate that treatment regimen, surgical result, and the differentiation of TIL should all be taken into account when studying immune factors in HGSC or, by extension, selecting patients for immunotherapy trials. Clin Cancer Res; 22(3); 714-24. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Treatment Regimen, Surgical Outcome, and T-cell Differentiation Influence Prognostic Benefit of Tumor-Infiltrating Lymphocytes in High-Grade Serous Ovarian Cancer

Wouters

Komdeur

Workel

et al. 2016

Clinical Cancer Research

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“…Several previous studies have identified prognostic markers associated with survival (PFS and/ or OS) in EOC (31)(32)(33), including a few recently published studies on POSTN/collagen-remodeling/TGFb-associated stromal signature predicts debulking status or poor survival in ovarian cancer (34)(35)(36). However, none of these studies further characterized the direct role of these potential prognostic markers in modulating chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Periostin and Reactive Stroma Is Associated with Primary Chemoresistance and Predicts Clinical Outcomes in Epithelial Ovarian Cancer

Ryner¹,

Guan²,

Firestein³

et al. 2015

Clinical Cancer Research

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Purpose: Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers.Experimental Design: Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial.Results: We identified a distinct "reactive stroma" gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest-ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy.Conclusions: Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer.

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“…The latter are most likely due to adverse tumor biology. A recent meta-analysis of gene expression analyses has described a combination of biological markers that identified patients with suboptimal debulking [22]. Moreover, patients with BRCA1/2 mutation had a significantly higher risk of developing visceral metastases than matched controls without BRCA1/2 mutations [23].…”

Section: Discussionmentioning

confidence: 99%

Pattern of and reason for postoperative residual disease in patients with advanced ovarian cancer following upfront radical debulking surgery

Heitz

Harter

Alesina

et al. 2016

Gynecologic Oncology

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Risk Prediction for Late-Stage Ovarian Cancer by Meta-analysis of 1525 Patient Samples

Cited by 187 publications

References 61 publications

Treatment Regimen, Surgical Outcome, and T-cell Differentiation Influence Prognostic Benefit of Tumor-Infiltrating Lymphocytes in High-Grade Serous Ovarian Cancer

Treatment Regimen, Surgical Outcome, and T-cell Differentiation Influence Prognostic Benefit of Tumor-Infiltrating Lymphocytes in High-Grade Serous Ovarian Cancer

Upregulation of Periostin and Reactive Stroma Is Associated with Primary Chemoresistance and Predicts Clinical Outcomes in Epithelial Ovarian Cancer

Pattern of and reason for postoperative residual disease in patients with advanced ovarian cancer following upfront radical debulking surgery

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