@article{ff9a2468c0bc4e27a238b9451313cb79,
title = "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 (P interaction =0.01, N=1422) and TCGA (P interaction =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.",
keywords = "FRA, TCGA, folate receptor alpha, immunohistochemistry, ovarian cancer, prognosis",
author = "M. K{\"o}bel and J. Madore and Ramus, {S. J.} and Clarke, {B. A.} and Pharoah, {P. D.P.} and S. Deen and Bowtell, {D. D.} and K. Odunsi and U. Menon and C. Morrison and S. Lele and W. Bshara and L. Sucheston and Beckmann, {M. W.} and A. Hein and Thiel, {F. C.} and A. Hartmann and Wachter, {D. L.} and Anglesio, {M. S.} and E. H{\o}gdall and A. Jensen and C. H{\o}gdall and Kalli, {K. R.} and Fridley, {B. L.} and Keeney, {G. L.} and Fogarty, {Z. C.} and Vierkant, {R. A.} and S. Liu and S. Cho and G. Nelson and P. Ghatage and A. Gentry-Maharaj and Gayther, {S. A.} and E. Benjamin and M. Widschwendter and Intermaggio, {M. P.} and B. Rosen and Bernardini, {M. Q.} and H. MacKay and A. Oza and P. Shaw and M. Jimenez-Linan and Driver, {K. E.} and J. Alsop and M. MacK and Koziak, {J. M.} and H. Steed and C. Ewanowich and A. Defazio and G. Chenevix-Trench and S. Fereday and B. Gao and Johnatty, {S. E.} and J. George and L. Galletta and Goode, {E. L.} and Kj{\ae}r, {S. K.} and Huntsman, {D. G.} and Fasching, {P. A.} and Moysich, {K. B.} and Brenton, {J. D.} and Kelemen, {L. E.}",
note = "Funding Information: We wish to thank all of the patients, study centers and personnel who participated in this study. We gratefully acknowledge the contributions of the AOCS Group (http://www.aocstudy.org) (AOC); Mie Konno, Michelle Darago, Faye Chambers, the Tom Baker Cancer Centre Translational Laboratories (AOV); Karin Goodman, Ashley Pitzer, Mayo Clinic Medical Genome Facility (MAY, MAC); Kristy Angell, SEARCH team, the Human Research Tissue Bank at Addenbrooke{\textquoteright}s Hospital that is supported by the NIHR Cambridge Biomedical Research Centre (SEA); Ian Jacobs, Eva Wozniak, Andy Ryan, Jeremy Ford, Nayala Balogun (UKO); and the Cheryl Brown Ovarian Cancer Outcomes Unit (VAN). The results published here are in part based upon data generated by The Cancer Genome Atlas Project established by the National Cancer Institute and National Human Genome Research Institute. Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at http:// cancergenome.nih.gov/. This manuscript is dedicated to the memory of Barton A Kamen for his pioneering work in folate-binding proteins and anti-folate pharmacology. This work was supported by the US Department of Defense (DAMD17-01-1-0729), Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, Cancer Foundation of Western Australia, Cancer Council Tasmania and National Health and Medical Research Council of Australia (NHMRC, Grants 400413 and 400281) (AOC); the Canadian Institutes for Health Research (MOP-86727) (AOV); Calgary Laboratory Services (RS10-533) (CAL); the National Institutes of Health (R01CA61107), Danish Cancer Society (research grant 94 222 52) and Mermaid I project (MAL); National Institutes of Health (R01CA122443, P50CA136393), Mayo Foundation and Fred C. and Katherine B. Andersen Foundation (MAY, MAC); Cancer Research UK (C490/A10119, C490/A10124), National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre (SEA); Eve Appeal (Oak Foundation), and NIHR University College London Hospitals Biomedical Research Centre (UKO); British Columbia Cancer Foundation, the Carraressi Foundation through donations to the Vancouver General Hospital and University of British Columbia Hospital Foundation (VAN). BG was supported by NHMRC and the Cancer Institute of NSW (CINSW), AdeF was supported by the University of Sydney Cancer Research Fund, and CINSW through the Sydney-West Translational Cancer Research Centre. LEK was supported by a Canadian Institutes for Health Research Investigator award MSH-87734. Publisher Copyright: {\textcopyright} 2014 Cancer Research UK.",
year = "2014",
month = dec,
day = "9",
doi = "10.1038/bjc.2014.567",
language = "English (US)",
volume = "111",
pages = "2297--2307",
journal = "British journal of cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "12",
}