Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer

E. F. Smit; M. A. Socinski; B. P. Mullaney; S. P. Myrand; G. V. Scagliotti; P. Lorigan; M. Reck; T. Ciuleanu; J. Von pawel; N. A. Karaseva; A. Szczesna; D. Ohannesian; E. Powell; R. R. Hozak; S. Hong; S. C. Guba; N. Thatcher

doi:10.1093/annonc/mdr563

Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer

E. F. Smit, M. A. Socinski, B. P. Mullaney, S. P. Myrand, G. V. Scagliotti, P. Lorigan, M. Reck, T. Ciuleanu, J. Von pawel, N. A. Karaseva, A. Szczesna, D. Ohannesian, E. Powell, R. R. Hozak, S. Hong, S. C. Guba, N. Thatcher

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

Abstract

Background: Clinical results of a randomized phase III trial comparing pemetrexed-carboplatin (PC) with etoposide-carboplatin (EC) in chemonaive patients with extensive-stage disease small-cell lung cancer (ED-SCLC) resulted in trial closure for futility; biomarker analyses using immunohistochemistry (IHC) and single-nucleotide polymorphisms (SNPs) are described herein. Patients and Methods: Thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyltransferase (GARFT), and folylpolyglutamate synthetase (FPGS) were investigated using IHC (n = 395). SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), folate receptor-α FR-α, and solute carrier 19A1 (SLC19A1; n = 611). Results: None of the IHC biomarkers (folate pathway or ERCC1) were found to be predictive or prognostic in this setting. rs2838952 (adjacent to SLC19A1) had significant treatment-independent association with overall survival (OS; hazard ratio 0.590, P = 0.01). Nine GGH-associated SNPs interacted with rs3788205 (SLC19A1) for OS on the PC arm. rs12379987 (FPGS) interacted with treatment for OS (interaction P = 0.036). Conclusion: Potential ERCC1 and folate pathway IHC biomarkers failed to predict outcome in either study arm in ED-SCLC. SNPs in regions including FPGS and SLC19A1 and interacting SNPs in GGH and SLC19A1 were associated with differences in OS; however, none of these SNPs predicted for greater survival with PC over EC. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Original language	English
Article number	mdr563
Pages (from-to)	1723-1729
Number of pages	6
Journal	Annals of Oncology
Volume	23
Issue number	7
DOIs	https://doi.org/10.1093/annonc/mdr563
Publication status	Published - Jul 2012

Keywords

Biomarkers
Carboplatin
Etoposide
Pemetrexed
Small-cell lung cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Smit, E. F., Socinski, M. A., Mullaney, B. P., Myrand, S. P., Scagliotti, G. V., Lorigan, P., Reck, M., Ciuleanu, T., Von pawel, J., Karaseva, N. A., Szczesna, A., Ohannesian, D., Powell, E., Hozak, R. R., Hong, S., Guba, S. C., & Thatcher, N. (2012). Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer. Annals of Oncology, 23(7), 1723-1729. Article mdr563. https://doi.org/10.1093/annonc/mdr563

@article{ec7ecad839b04e8192bdf3e13a664a1c,

title = "Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer",

abstract = "Background: Clinical results of a randomized phase III trial comparing pemetrexed-carboplatin (PC) with etoposide-carboplatin (EC) in chemonaive patients with extensive-stage disease small-cell lung cancer (ED-SCLC) resulted in trial closure for futility; biomarker analyses using immunohistochemistry (IHC) and single-nucleotide polymorphisms (SNPs) are described herein. Patients and Methods: Thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyltransferase (GARFT), and folylpolyglutamate synthetase (FPGS) were investigated using IHC (n = 395). SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), folate receptor-α FR-α, and solute carrier 19A1 (SLC19A1; n = 611). Results: None of the IHC biomarkers (folate pathway or ERCC1) were found to be predictive or prognostic in this setting. rs2838952 (adjacent to SLC19A1) had significant treatment-independent association with overall survival (OS; hazard ratio 0.590, P = 0.01). Nine GGH-associated SNPs interacted with rs3788205 (SLC19A1) for OS on the PC arm. rs12379987 (FPGS) interacted with treatment for OS (interaction P = 0.036). Conclusion: Potential ERCC1 and folate pathway IHC biomarkers failed to predict outcome in either study arm in ED-SCLC. SNPs in regions including FPGS and SLC19A1 and interacting SNPs in GGH and SLC19A1 were associated with differences in OS; however, none of these SNPs predicted for greater survival with PC over EC. {\textcopyright} The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.",

keywords = "Biomarkers, Carboplatin, Etoposide, Pemetrexed, Small-cell lung cancer",

author = "Smit, {E. F.} and Socinski, {M. A.} and Mullaney, {B. P.} and Myrand, {S. P.} and Scagliotti, {G. V.} and P. Lorigan and M. Reck and T. Ciuleanu and {Von pawel}, J. and Karaseva, {N. A.} and A. Szczesna and D. Ohannesian and E. Powell and Hozak, {R. R.} and S. Hong and Guba, {S. C.} and N. Thatcher",

year = "2012",

month = jul,

doi = "10.1093/annonc/mdr563",

language = "English",

volume = "23",

pages = "1723--1729",

journal = "Annals of Oncology",

issn = "1569-8041",

publisher = "Oxford University Press",

number = "7",

}

Smit, EF, Socinski, MA, Mullaney, BP, Myrand, SP, Scagliotti, GV, Lorigan, P, Reck, M, Ciuleanu, T, Von pawel, J, Karaseva, NA, Szczesna, A, Ohannesian, D, Powell, E, Hozak, RR, Hong, S, Guba, SC & Thatcher, N 2012, 'Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer', Annals of Oncology, vol. 23, no. 7, mdr563, pp. 1723-1729. https://doi.org/10.1093/annonc/mdr563

TY - JOUR

T1 - Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer

AU - Smit, E. F.

AU - Socinski, M. A.

AU - Mullaney, B. P.

AU - Myrand, S. P.

AU - Scagliotti, G. V.

AU - Lorigan, P.

AU - Reck, M.

AU - Ciuleanu, T.

AU - Von pawel, J.

AU - Karaseva, N. A.

AU - Szczesna, A.

AU - Ohannesian, D.

AU - Powell, E.

AU - Hozak, R. R.

AU - Hong, S.

AU - Guba, S. C.

AU - Thatcher, N.

PY - 2012/7

Y1 - 2012/7

N2 - Background: Clinical results of a randomized phase III trial comparing pemetrexed-carboplatin (PC) with etoposide-carboplatin (EC) in chemonaive patients with extensive-stage disease small-cell lung cancer (ED-SCLC) resulted in trial closure for futility; biomarker analyses using immunohistochemistry (IHC) and single-nucleotide polymorphisms (SNPs) are described herein. Patients and Methods: Thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyltransferase (GARFT), and folylpolyglutamate synthetase (FPGS) were investigated using IHC (n = 395). SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), folate receptor-α FR-α, and solute carrier 19A1 (SLC19A1; n = 611). Results: None of the IHC biomarkers (folate pathway or ERCC1) were found to be predictive or prognostic in this setting. rs2838952 (adjacent to SLC19A1) had significant treatment-independent association with overall survival (OS; hazard ratio 0.590, P = 0.01). Nine GGH-associated SNPs interacted with rs3788205 (SLC19A1) for OS on the PC arm. rs12379987 (FPGS) interacted with treatment for OS (interaction P = 0.036). Conclusion: Potential ERCC1 and folate pathway IHC biomarkers failed to predict outcome in either study arm in ED-SCLC. SNPs in regions including FPGS and SLC19A1 and interacting SNPs in GGH and SLC19A1 were associated with differences in OS; however, none of these SNPs predicted for greater survival with PC over EC. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

AB - Background: Clinical results of a randomized phase III trial comparing pemetrexed-carboplatin (PC) with etoposide-carboplatin (EC) in chemonaive patients with extensive-stage disease small-cell lung cancer (ED-SCLC) resulted in trial closure for futility; biomarker analyses using immunohistochemistry (IHC) and single-nucleotide polymorphisms (SNPs) are described herein. Patients and Methods: Thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyltransferase (GARFT), and folylpolyglutamate synthetase (FPGS) were investigated using IHC (n = 395). SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), folate receptor-α FR-α, and solute carrier 19A1 (SLC19A1; n = 611). Results: None of the IHC biomarkers (folate pathway or ERCC1) were found to be predictive or prognostic in this setting. rs2838952 (adjacent to SLC19A1) had significant treatment-independent association with overall survival (OS; hazard ratio 0.590, P = 0.01). Nine GGH-associated SNPs interacted with rs3788205 (SLC19A1) for OS on the PC arm. rs12379987 (FPGS) interacted with treatment for OS (interaction P = 0.036). Conclusion: Potential ERCC1 and folate pathway IHC biomarkers failed to predict outcome in either study arm in ED-SCLC. SNPs in regions including FPGS and SLC19A1 and interacting SNPs in GGH and SLC19A1 were associated with differences in OS; however, none of these SNPs predicted for greater survival with PC over EC. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

KW - Biomarkers

KW - Carboplatin

KW - Etoposide

KW - Pemetrexed

KW - Small-cell lung cancer

U2 - 10.1093/annonc/mdr563

DO - 10.1093/annonc/mdr563

M3 - Article

C2 - 22186609

SN - 1569-8041

VL - 23

SP - 1723

EP - 1729

JO - Annals of Oncology

JF - Annals of Oncology

IS - 7

M1 - mdr563

ER -

Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer

Abstract

Keywords

UN SDGs

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