Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials

A F C Okines; D Gonzalez de Castro; D Cunningham; I Chau; R. E. Langley; L. C. Thompson; S P Stenning; C Saffery; Y Barbachano; F Coxon; G Middleton; D Ferry; T Crosby; S Madhusudan; J Wadsley; J Waters; M Hall; D Swinson; A Robinson; D Smith; J S Reis-Filho; T S Waddell; L Puckey; S Hulkki Wilson; Z Eltahir; M Band; A Wotherspoon

doi:10.1016/j.ejca.2013.02.007

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials

A F C Okines, D Gonzalez de Castro, D Cunningham, I Chau, R. E. Langley, L. C. Thompson, S P Stenning, C Saffery, Y Barbachano, F Coxon, G Middleton, D Ferry, T Crosby, S Madhusudan, J Wadsley, J Waters, M Hall, D Swinson, A Robinson, D SmithJ S Reis-Filho, T S Waddell, L Puckey, S Hulkki Wilson, Z Eltahir, M Band, A Wotherspoon

Cancer and Genomic Sciences

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

36 Citations (Scopus)

Abstract

BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma.

PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect.

RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival.

CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

Original language	English
Pages (from-to)	2116-2125
Number of pages	10
Journal	European Journal of Cancer
Volume	49
Issue number	9
Early online date	4 Mar 2013
DOIs	https://doi.org/10.1016/j.ejca.2013.02.007
Publication status	Published - Jun 2013

Bibliographical note

Keywords

Adenocarcinoma
Antineoplastic Combined Chemotherapy Protocols
Esophageal Neoplasms
Genetic Markers
Humans
Mutation
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases
Prognosis
Proto-Oncogene Proteins
Proto-Oncogene Proteins B-raf
Stomach Neoplasms
Survival Analysis
ras Proteins

UN SDGs

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

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Cite this

Okines, A. F. C., Gonzalez de Castro, D., Cunningham, D., Chau, I., Langley, R. E., Thompson, L. C., Stenning, S. P., Saffery, C., Barbachano, Y., Coxon, F., Middleton, G., Ferry, D., Crosby, T., Madhusudan, S., Wadsley, J., Waters, J., Hall, M., Swinson, D., Robinson, A., ... Wotherspoon, A. (2013). Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials. European Journal of Cancer, 49(9), 2116-2125. Advance online publication. https://doi.org/10.1016/j.ejca.2013.02.007

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title = "Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials",

abstract = "BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma.PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect.RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival.CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.",

keywords = "Adenocarcinoma, Antineoplastic Combined Chemotherapy Protocols, Esophageal Neoplasms, Genetic Markers, Humans, Mutation, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Prognosis, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Stomach Neoplasms, Survival Analysis, ras Proteins",

author = "Okines, {A F C} and {Gonzalez de Castro}, D and D Cunningham and I Chau and Langley, {R. E.} and Thompson, {L. C.} and Stenning, {S P} and C Saffery and Y Barbachano and F Coxon and G Middleton and D Ferry and T Crosby and S Madhusudan and J Wadsley and J Waters and M Hall and D Swinson and A Robinson and D Smith and Reis-Filho, {J S} and Waddell, {T S} and L Puckey and {Hulkki Wilson}, S and Z Eltahir and M Band and A Wotherspoon",

year = "2013",

month = jun,

doi = "10.1016/j.ejca.2013.02.007",

language = "English",

volume = "49",

pages = "2116--2125",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier",

number = "9",

}

Okines, AFC, Gonzalez de Castro, D, Cunningham, D, Chau, I, Langley, RE, Thompson, LC, Stenning, SP, Saffery, C, Barbachano, Y, Coxon, F, Middleton, G, Ferry, D, Crosby, T, Madhusudan, S, Wadsley, J, Waters, J, Hall, M, Swinson, D, Robinson, A, Smith, D, Reis-Filho, JS, Waddell, TS, Puckey, L, Hulkki Wilson, S, Eltahir, Z, Band, M & Wotherspoon, A 2013, 'Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials', European Journal of Cancer, vol. 49, no. 9, pp. 2116-2125. https://doi.org/10.1016/j.ejca.2013.02.007

TY - JOUR

T1 - Biomarker analysis in oesophagogastric cancer

T2 - Results from the REAL3 and TransMAGIC trials

AU - Okines, A F C

AU - Gonzalez de Castro, D

AU - Cunningham, D

AU - Chau, I

AU - Langley, R. E.

AU - Thompson, L. C.

AU - Stenning, S P

AU - Saffery, C

AU - Barbachano, Y

AU - Coxon, F

AU - Middleton, G

AU - Ferry, D

AU - Crosby, T

AU - Madhusudan, S

AU - Wadsley, J

AU - Waters, J

AU - Hall, M

AU - Swinson, D

AU - Robinson, A

AU - Smith, D

AU - Reis-Filho, J S

AU - Waddell, T S

AU - Puckey, L

AU - Hulkki Wilson, S

AU - Eltahir, Z

AU - Band, M

AU - Wotherspoon, A

PY - 2013/6

Y1 - 2013/6

N2 - BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma.PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect.RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival.CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

AB - BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma.PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect.RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival.CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

KW - Adenocarcinoma

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Esophageal Neoplasms

KW - Genetic Markers

KW - Humans

KW - Mutation

KW - PTEN Phosphohydrolase

KW - Phosphatidylinositol 3-Kinases

KW - Prognosis

KW - Proto-Oncogene Proteins

KW - Proto-Oncogene Proteins B-raf

KW - Stomach Neoplasms

KW - Survival Analysis

KW - ras Proteins

U2 - 10.1016/j.ejca.2013.02.007

DO - 10.1016/j.ejca.2013.02.007

M3 - Article

C2 - 23481512

SN - 0959-8049

VL - 49

SP - 2116

EP - 2125

JO - European Journal of Cancer

JF - European Journal of Cancer

IS - 9

ER -

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials

Abstract

Bibliographical note

Keywords

UN SDGs

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