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Br J Cancer. 2014 Dec 9;111(12):2297-307. doi: 10.1038/bjc.2014.567. Epub 2014 Oct 30.

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.

Author information

1
Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, 1403 29 ST NW, Calgary, AB T2N 2T9, Canada.
2
1] Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC V5E 4E6, Canada [2] Melanoma Institute Australia, University of Sydney, Royal Prince Alfred Hospital, Gloucester House-level 3, Missenden Road, Camperdown, NSW 2050, Australia.
3
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.
4
Department of Laboratory Medicine and Pathobiology, Princess Margaret Cancer Centre, University of Toronto, 610 Univeristy Avenue, M-700, Toronto, ON M5T 2M9, Canada.
5
1] Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK [2] Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
6
Department of Histopathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, UK.
7
1] Department of Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, Locked Bag I, A'Beckett Street, East Melbourne, VIC 8006, Australia [2] Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Flemington Road, Melbourne, VIC 3010, Australia [3] Sir Peter MacCallum Department of Oncology, University of Melbourne, 30 Flemington Road, Melbourne, VIC 3010, Australia.
8
Department of Gynecological Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
9
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.
10
Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
11
1] Department of Gynecological Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA [2] Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
12
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
13
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, Germany.
14
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Krankenhausstrasse 8-10, 91054 Erlangen, Germany.
15
Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC V5E 4E6, Canada.
16
1] Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Ø, Denmark [2] Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2370 Herlev, Denmark.
17
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Ø, Denmark.
18
The Juliane Marie Center, Department of Obstetrics and Gynecology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Ø, Denmark.
19
Department of Medical Oncology, Mayo Clinic, 200 First Street SW, Charlton 6, Rochester, MN 55905, USA.
20
Department of Biostatistics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
21
Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, 200 First Street SW, Stabile 13, Rochester, MN 55905, USA.
22
Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Charlton 6, Rochester, MN 55905, USA.
23
Anatomic Pathology Research Laboratory, Calgary Laboratory Services, Foothills Medical Center, 1403 29 ST NW, Calgary, AB T2N 2T9, Canada.
24
Department 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.
25
Department of Pathology, Cancer Institute, University College London, Maple House, 149 Tottenham Court Road, London WC1E 6JJ, UK.
26
Department of Women's Cancer, UCL EGA Institute for Women's Health, University College London, 74 Huntley Street, London WC1E 6AU, UK.
27
Department of Obstetrics and Gynecology, University of Toronto, Princess Margaret Cancer Centre, 610 University Avenue, M-700, Toronto, ON M5T 2M9, Canada.
28
Department of Medicine, Division of Medical Oncology, University of Toronto, Princess Margaret Hospital, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
29
1] Department of Pathology, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK [2] National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK.
30
Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
31
Department of Population Health Research, Alberta Health Services-Cancer Care, 2210 2nd Street SW, Calgary, AB, T2S 3C3, Canada.
32
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Royal Alexandra Hospital, 10240 Kingsway Ave, Edmonton, AB T5H 3V9, Canada.
33
Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital, 10240 Kingsway Ave, Edmonton, AB T5H 3V9, Canada.
34
Department of Gynaecological Oncology and Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, NSW 2145, Australia.
35
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD,4006, Australia.
36
Department of Cancer Genomics and Genetics, Peter MacCallum Cancer Centre, Locked Bag I, A'Beckett Street, East Melbourne, VIC 8006, Australia.
37
Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, 200 First Street SW Charlton 6, Rochester, MN 55905, USA.
38
1] Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Ø, Denmark [2] The Juliane Marie Center, Department of Obstetrics and Gynecology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Ø, Denmark.
39
1] Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC V5E 4E6, Canada [2] Centre For Translational and Applied Genomics, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada.
40
1] Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, Germany [2] Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
41
1] National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 2QQ, UK [2] Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK [3] Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK [4] Cambridge Experimental Cancer Medicine Centre, Cambridge CB2 0RE, UK.
42
Department of Public Health Sciences, Medical University of South Carolina and Hollings Cancer Center, 135 Cannon Street, Charleston, SC 29425, USA.

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.

PMID:
25349970
PMCID:
PMC4264456
DOI:
10.1038/bjc.2014.567
[Indexed for MEDLINE]
Free PMC Article

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