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. Köbel; J. Madore; S. J. Ramus; B. A. Clarke; P. D.P. Pharoah; S. Deen; D. D. Bowtell; K. Odunsi; U. Menon; C. Morrison; S. Lele; W. Bshara; L. Sucheston; M. W. Beckmann; A. Hein; F. C. Thiel; A. Hartmann; D. L. Wachter; M. S. Anglesio; E. Høgdall; A. Jensen; C. Høgdall; K. R. Kalli; B. L. Fridley; G. L. Keeney; Z. C. Fogarty; R. A. Vierkant; S. Liu; S. Cho; G. Nelson; P. Ghatage; A. Gentry-Maharaj; S. A. Gayther; E. Benjamin; M. Widschwendter; M. P. Intermaggio; B. Rosen; M. Q. Bernardini; H. MacKay; A. Oza; P. Shaw; M. Jimenez-Linan; K. E. Driver; J. Alsop; M. MacK; J. M. Koziak; H. Steed; C. Ewanowich; A. Defazio; G. Chenevix-Trench; S. Fereday; B. Gao; S. E. Johnatty; J. George; L. Galletta; E. L. Goode; S. K. Kjær; D. G. Huntsman; P. A. Fasching; K. B. Moysich; J. D. Brenton; L. E. Kelemen

doi:10.1038/bjc.2014.567

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. Köbel, J. Madore, S. J. Ramus, B. A. Clarke, P. D.P. Pharoah, S. Deen, D. D. Bowtell, K. Odunsi, U. Menon, C. Morrison, S. Lele, W. Bshara, L. Sucheston, M. W. Beckmann, A. Hein, F. C. Thiel, A. Hartmann, D. L. Wachter, M. S. Anglesio, E. HøgdallA. Jensen, C. Høgdall, K. R. Kalli, B. L. Fridley, G. L. Keeney, Z. C. Fogarty, R. A. Vierkant, S. Liu, S. Cho, G. Nelson, P. Ghatage, A. Gentry-Maharaj, S. A. Gayther, E. Benjamin, M. Widschwendter, M. P. Intermaggio, B. Rosen, M. Q. Bernardini, H. MacKay, A. Oza, P. Shaw, M. Jimenez-Linan, K. E. Driver, J. Alsop, M. MacK, J. M. Koziak, H. Steed, C. Ewanowich, A. Defazio, G. Chenevix-Trench, S. Fereday, B. Gao, S. E. Johnatty, J. George, L. Galletta, E. L. Goode, S. K. Kjær, D. G. Huntsman, P. A. Fasching, K. B. Moysich, J. D. Brenton, L. E. Kelemen

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2297-2307
Number of pages	11
Journal	British journal of cancer
Volume	111
Issue number	12
DOIs	https://doi.org/10.1038/bjc.2014.567
State	Published - Dec 9 2014

Keywords

FRA
TCGA
folate receptor alpha
immunohistochemistry
ovarian cancer
prognosis

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1038/bjc.2014.567

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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., ... Kelemen, L. E. (2014). 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, 111(12), 2297-2307. https://doi.org/10.1038/bjc.2014.567

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. / Köbel, M.; Madore, J.; Ramus, S. J. et al.
In: British journal of cancer, Vol. 111, No. 12, 09.12.2014, p. 2297-2307.

Research output: Contribution to journal › Article › peer-review

Köbel, M, Madore, J, Ramus, SJ, Clarke, BA, Pharoah, PDP, Deen, S, Bowtell, DD, Odunsi, K, Menon, U, Morrison, C, Lele, S, Bshara, W, Sucheston, L, Beckmann, MW, Hein, A, Thiel, FC, Hartmann, A, Wachter, DL, Anglesio, MS, Høgdall, E, Jensen, A, Høgdall, C, Kalli, KR, Fridley, BL, Keeney, GL, Fogarty, ZC, Vierkant, RA, Liu, S, Cho, S, Nelson, G, Ghatage, P, Gentry-Maharaj, A, Gayther, SA, Benjamin, E, Widschwendter, M, Intermaggio, MP, Rosen, B, Bernardini, MQ, MacKay, H, Oza, A, Shaw, P, Jimenez-Linan, M, Driver, KE, Alsop, J, MacK, M, Koziak, JM, Steed, H, Ewanowich, C, Defazio, A, Chenevix-Trench, G, Fereday, S, Gao, B, Johnatty, SE, George, J, Galletta, L, Goode, EL, Kjær, SK, Huntsman, DG, Fasching, PA, Moysich, KB, Brenton, JD & Kelemen, LE 2014, '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, vol. 111, no. 12, pp. 2297-2307. https://doi.org/10.1038/bjc.2014.567

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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 = "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",

}

TY - JOUR

T1 - Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma

T2 - Implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study

AU - Köbel, M.

AU - Madore, J.

AU - Ramus, S. J.

AU - Clarke, B. A.

AU - Pharoah, P. D.P.

AU - Deen, S.

AU - Bowtell, D. D.

AU - Odunsi, K.

AU - Menon, U.

AU - Morrison, C.

AU - Lele, S.

AU - Bshara, W.

AU - Sucheston, L.

AU - Beckmann, M. W.

AU - Hein, A.

AU - Thiel, F. C.

AU - Hartmann, A.

AU - Wachter, D. L.

AU - Anglesio, M. S.

AU - Høgdall, E.

AU - Jensen, A.

AU - Høgdall, C.

AU - Kalli, K. R.

AU - Fridley, B. L.

AU - Keeney, G. L.

AU - Fogarty, Z. C.

AU - Vierkant, R. A.

AU - Liu, S.

AU - Cho, S.

AU - Nelson, G.

AU - Ghatage, P.

AU - Gentry-Maharaj, A.

AU - Gayther, S. A.

AU - Benjamin, E.

AU - Widschwendter, M.

AU - Intermaggio, M. P.

AU - Rosen, B.

AU - Bernardini, M. Q.

AU - MacKay, H.

AU - Oza, A.

AU - Shaw, P.

AU - Jimenez-Linan, M.

AU - Driver, K. E.

AU - Alsop, J.

AU - MacK, M.

AU - Koziak, J. M.

AU - Steed, H.

AU - Ewanowich, C.

AU - Defazio, A.

AU - Chenevix-Trench, G.

AU - Fereday, S.

AU - Gao, B.

AU - Johnatty, S. E.

AU - George, J.

AU - Galletta, L.

AU - Goode, E. L.

AU - Kjær, S. K.

AU - Huntsman, D. G.

AU - Fasching, P. A.

AU - Moysich, K. B.

AU - Brenton, J. D.

AU - Kelemen, L. E.

PY - 2014/12/9

Y1 - 2014/12/9

N2 - 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.

AB - 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.

KW - FRA

KW - TCGA

KW - folate receptor alpha

KW - immunohistochemistry

KW - ovarian cancer

KW - prognosis

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U2 - 10.1038/bjc.2014.567

DO - 10.1038/bjc.2014.567

M3 - Article

C2 - 25349970

AN - SCOPUS:84928651145

SN - 0007-0920

VL - 111

SP - 2297

EP - 2307

JO - British journal of cancer

JF - British journal of cancer

IS - 12

ER -

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

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