Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study

Abstract

Background:Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.Methods:Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.Results:FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20–0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10–3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25–0.94).Conclusions:FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

“…Patients were followed from enrollment in an IRB-approved protocol until death from any cause (eTable 1). 24–26 Tumors were obtained at initial debulking surgery, formalin-fixed, paraffin embedded, and arrayed on tissue microarrays (TMAs). Clinical covariates and vital status underwent standardized quality control measures.…”

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

“…Most of these patients also participated in previous OTTA studies 18, 19, 20, and all studies received ethics board approval for tumor profiling. TMAs were constructed containing 1–6 cores of 0.6–1.0 mm in diameter from formalin‐fixed paraffin embedded tissue representing tumor from each patient.…”

Predictors of pretreatment CA125 at ovarian cancer diagnosis: a pooled analysis in the Ovarian Cancer Association Consortium

“…Studies included in this analysis were the Alberta Ovarian Tumor Types Study (AOV) (18, 19), Australian Ovarian Cancer Study (AUS)(20), Belgium Ovarian Cancer Study (BEL)(21), Hawaii Ovarian Cancer Study (HAW)(22, 23), Dr. Horst Schmidt Kliniken (HSK)(24, 25), Hospital-based Epidemiological research Program at Aichi Cancer Center (JPN)(26), Women’s Cancer Program at the Samuel Oschin Comprehensive cancer Institute (LAX)(27), Malignant Ovarian cancer Study (MAL)(28), Mayo Clinic Ovarian Cancer Case-Control Study (MAY)(29, 30), New England Case Control Study (NEC) (31), Oregon Ovarian Cancer Registry (ORE)(32, 33), Danish Pelvic Mass Study (PVD)(34), and Scottish Randomized Trial in Ovarian Cancer (SRO)(35, 36). In total, there were 5,538 women with preoperative CA125 values in OCAC.…”