Pooled Clustering of High-Grade Serous Ovarian Cancer Gene Expression Leads to Novel Consensus Subtypes Associated with Survival and Surgical Outcomes

Abstract

Purpose Here we assess whether molecular subtyping identifies biological features of tumors that correlate with survival and surgical outcomes of high-grade serous ovarian cancer (HGSOC). Experimental Design Consensus clustering of pooled mRNA expression data from over 2,000 HGSOC cases was used to define molecular subtypes of HGSOCs. This de novo classification scheme was then applied to 381 Mayo Clinic HGSOC patients with detailed survival and surgical outcome information. Results Five molecular subtypes of HGSOC were identified. In the pooled dataset, three subtypes were largely concordant with prior studies describing proliferative, mesenchymal, and immunoreactive tumors (concordance > 70%), and the group of tumors previously described as differentiated type was segregated into two new types, one of which (anti-mesenchymal) had down-regulation of genes that were typically upregulated in the mesenchymal subtype. Molecular subtypes were significantly associated with overall survival (p<0.001) and with rate of optimal surgical debulking (≤1 cm, p=1.9E-4) in the pooled dataset. Among stage III-C or IV Mayo Clinic patients, molecular subtypes were also significantly associated with overall survival (p=0.001), as well as rate of complete surgical debulking (no residual disease; 16% in mesenchymal tumors comparing to >28% in other subtypes; p=0.02). Conclusions HGSOC tumors may be categorized into five molecular subtypes that associate with overall survival and the extent of residual disease following debulking surgery. Because mesenchymal tumors may have features that were associated with less favorable surgical outcome, molecular subtyping may have future utility in guiding neoadjuvant treatment decisions for women with HGSOC.

Challenges and Opportunities in Studying the Epidemiology of Ovarian Cancer Subtypes

“…A recent analysis of genotyping accuracy has raised questions about the quality of sequencing-based variant calls in TCGA’s HGSC samples [76] which may affect the findings in Hofree et al [75]. Given the exploratory nature of molecular clustering and limitations of the approaches used, more research is needed about how many underlying molecular subtypes exist [77–79] and if they are consistent across populations [80]. …”

“…A recent study reported that women with the proliferative and mesenchymal subtypes benefit from experimental treatment (Bevacizumab) over standard chemotherapy [93], which raises the possibility that similar subtype-specific variations in response to other actively developing therapeutics for EOC, such as PARP inhibition and immune therapies [94,95] might exist. For example, immunoreactive tumors may be good candidates for immunotherapy [79]; an open-label single-arm Phase II trial has been initiated to evaluate efficacy and safety of pembrolizumab anti-PD-1 monotherapy in these cases [96]. For mesenchymal tumors, TGF-beta inhibition may be considered since the TGF-beta pathway is significantly up-regulated compared to other subtypes, which aligns well with other supervised expression studies reporting worse clinical outcomes associated with this pathway [97–100].…”

Intraperitoneal disease dissemination patterns are associated with residual disease, extent of surgery, and molecular subtypes in advanced ovarian cancer

“…HGSOC molecular subtypes have been independently confirmed by multiple studies [11–13]. Our previous studies [13] demonstrated resectability of disease differs by molecular subtype.…”

“…Our previous studies [13] demonstrated resectability of disease differs by molecular subtype. HGSOC patients with the mesenchymal (mesenchymal) subtype had the lowest RD0 rates and required more complex surgery to achieve RD ≤1 cm compared to patients with other subtypes of tumors.…”

“…HGSOC patients with the mesenchymal (mesenchymal) subtype had the lowest RD0 rates and required more complex surgery to achieve RD ≤1 cm compared to patients with other subtypes of tumors. Patients with mesenchymal subtype had the shortest OS even after adjusting for age, stage, and grade [11, 13]. Despite a significant association between surgical and clinical outcomes across molecular subtypes, it is unclear as to how the molecular subtype affects the behavior of disease.…”