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

British Journal of Cancer, Oct 2014

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.

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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

FULL PAPER British Journal of Cancer (2014) 111, 2297–2307 | doi: 10.1038/bjc.2014.567 Keywords: ovarian cancer; folate receptor alpha; FRA; immunohistochemistry; prognosis; TCGA 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 M Köbel1, J Madore2,3, S J Ramus4, B A Clarke5, P D P Pharoah6,7, S Deen8, D D Bowtell9,10,11, K Odunsi12, U Menon13, C Morrison14, S Lele12,15, W Bshara14, L Sucheston15, M W Beckmann16, A Hein16, F C Thiel16, A Hartmann17, D L Wachter17, M S Anglesio2, E Høgdall18,19, A Jensen18, C Høgdall20, K R Kalli21, B L Fridley22, G L Keeney23, Z C Fogarty24, R A Vierkant24, S Liu25, S Cho1, G Nelson26, P Ghatage26, A Gentry-Maharaj13, S A Gayther4, E Benjamin27, M Widschwendter28, M P Intermaggio4, B Rosen29, M Q Bernardini29, H Mackay30, A Oza29, P Shaw29, M Jimenez-Linan31,32, K E Driver7, J Alsop7, M Mack7, J M Koziak33, H Steed34, C Ewanowich35, A DeFazio36, G Chenevix-Trench37, S Fereday9, B Gao36, S E Johnatty37, J George9, L Galletta9, AOCS Study Group9, E L Goode38, S K Kjær18,20, D G Huntsman2,39, P A Fasching16,40, K B Moysich15, J D Brenton32,41,42,43 and L E Kelemen*,44 1 Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, 1403 29 ST NW, Calgary, AB T2N 2T9, Canada; 2Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC V5E 4E6, Canada; 3Melanoma Institute Australia, University of Sydney, Royal Prince Alfred Hospital, Gloucester House–level 3, Missenden Road, Camperdown, NSW 2050, Australia; 4 Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, Harlyne Norris Research Tower, 1450 Biggy Street, Office 2517G, Los Angeles, CA 90033, USA; 5Department of Laboratory Medicine and Pathobiology, Princess Margaret Cancer Centre, University of Toronto, 610 Univeristy Avenue, M-700, Toronto, ON M5T 2M9, Canada; 6Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK; 7Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK; 8Department of Histopathology, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK; 9Department of Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, Locked Bag I, A’Beckett Street, East Melbourne, VIC 8006, Australia; 10Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Road, Melbourne, VIC 3010, Australia; 11 Sir Peter MacCallum Department of Oncology, University of Melbourne, 30 Flemington Road, Melbourne, VIC 3010, Australia; 12 Department of Gynecological Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA; 13 Gynaecological Cancer Research Centre, Department of Women’s Cancer, Institute for Women’s Health, University College London, Maple House 1st Floor, 149 Tottenham Court Road, London W1T 7DN, UK; 14Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA; 15Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA; 16Department of Gynecology and *Correspondence: Dr LE Kelemen; E-mail: Revised 3 September 2014; accepted 2 October 2014; published online 30 October 2014 & 2014 Cancer Research UK. All rights reserved 0007 – 0920/14 www.bjcancer.com | DOI:10.1038/bjc.2014.567 2297 BRITISH JOURNAL OF CANCER FOLR1 in ovarian cancer Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, Germany; 17Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Krankenhausstrasse 8-10, 91054 Erlangen, Germany; 18Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Ø, Denmark; 19Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2370 Herlev, Denmark; 20The Juliane Marie Center, Department of Obstetrics and Gynecology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Ø, Denmark; 21Department of Medical Oncology, Mayo Clinic, 200 First Street SW, Charlton 6, Rochester, MN 55905, USA; 22Department of Biostatistics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; 23Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, 200 First Street SW, Stabile 13, Rochester, MN 55905, USA; 24Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Charlton 6, Rochester, MN 55905, USA; 25 Anatomic Pathology Research Laboratory, Calgary Laboratory Services, Foothills Medical Center, 1403 29 ST NW, Calgary, AB T2N 2T9, Canada; 26Department of Obstetrics and Gynecology, Division of Oncology, Tom Baker Cancer Centre, University of Calgary, Foothills Medical Center, 1403 29 ST NW, Calgary, AB T2N 2T9, Canada; 27Department of Pathology, Cancer Institute, University College London, Maple House, 149 Tottenham Court Road, London WC1E 6JJ, UK; 28Department of Women’s Cancer, UCL EGA Institute for Womeńs Health, University College London, 74 Huntley Street, London WC1E 6AU, UK; 29Department of Obstetrics and Gynecology, University of Toronto, Princess Margaret Cancer Centre, 610 University Avenue, M-700, Toronto, ON M5T 2M9, Canada; 30Department of Medicine, Division of Medical Oncology, University of Toronto, Princess Margaret Hospital, 610 University Avenue, Toronto, ON M5G 2M9, Canada; 31Department of Pathology, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK; 32National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK; 33Department of Population Health Research, Alberta Health Services-Cancer Care, 2210 2nd Street SW, Calgary, AB, T2S 3C3, Canada; 34Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Royal Alexandra Hospital, 10240 Kingsway Ave, Edmonton, AB T5H 3V9, Canada; 35Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital, 10240 Kingsway Ave, Edmonton, AB T5H 3V9, Canada; 36 Department of Gynaecological Oncology and Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, NSW 2145, Australia; 37Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, 300 Herston Ro (...truncated)


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Köbel, M, Madore, J, Ramus, S J, Clarke, B A, Pharoah, P D P, Deen, S, Bowtell, D D, Odunsi, K, Menon, U, Morrison, C, Lele, S, Bshara, W, Sucheston, L, Beckmann, M W, Hein, A, Thiel, F C, Hartmann, A, Wachter, D L, Anglesio, M S, Høgdall, E, Jensen, A, Høgdall, C, Kalli, K R, Fridley, B L, Keeney, G L, Fogarty, Z C, Vierkant, R A, Liu, S, Cho, S, Nelson, G, Ghatage, P, Gentry-Maharaj, A, Gayther, S A, Benjamin, E, Widschwendter, M, Intermaggio, M P, Rosen, B, Bernardini, M Q, Mackay, H, Oza, A, Shaw, P, Jimenez-Linan, M, Driver, K E, Alsop, J, Mack, M, Koziak, J M, Steed, H, Ewanowich, C, DeFazio, A, Chenevix-Trench, G, Fereday, S, Gao, B, Johnatty, S E, George, J, Galletta, L, Goode, E L, Kjær, S K, Huntsman, D G, Fasching, P A, Moysich, K B, Brenton, J D, Kelemen, L E. 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, British Journal of Cancer, 2014, pp. 2297-2307, Issue: 111, DOI: 10.1038/bjc.2014.567