Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy

doi:10.1007/s11523-015-0369-6

Clinical Trial

. 2015 Dec;10(4):583-96.

doi: 10.1007/s11523-015-0369-6.

Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy

Evelyn Despierre¹, Ignace Vergote², Ryan Anderson³, Corneel Coens⁴, Dionyssios Katsaros⁵, Fred R Hirsch³, Bram Boeckx^{6

7}, Marileila Varella-Garcia³, Annamaria Ferrero⁸, Isabelle Ray-Coquard⁹, Els M J J Berns¹⁰, Antonio Casado¹¹, Diether Lambrechts^{6

7}, Antonio Jimeno³; European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG); Groupe d’Investigateurs Nationaux pour les Etudes des Cancers de l’Ovaire (GINECO); Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie (A-AGO); National Cancer Research Institute (NCRI); Australia New Zealand Gynaecological Oncology Group (ANZGOG); Mario Negri Gynecologic Oncology group (MaNGO)

Collaborators, Affiliations

Collaborators

C Abraham, Le Chesnay, F Amant, R Anderson, A Azzedine, C Benedetto, G Bertelli, P Berteloot, D Berton-Rigaud, N Biglia, N Bonichon-Lamichhane, P Bougnoux, E Bourbouloux, C Bourcier, M Buck, M Campone, E M Canuto, A Casado Herraez, I Cauvin, L Chauvenet, A Chevalier-Place, P -H Cottu, J Cretin, I Cumin, H Curé, F Dalenc, S Danese, A Davis, P Debruyne, G Delplanque, R Delva, V D'Hondt, D Dramais, X Durando, C El Kouri, C Esteban, M Fabbro, C Falandry, B Filleul, A Floquet, P Fumoleau, M Garcia-Varella, C Garnier, E Gilby, L Gladieff, F Goffin, M -C Gouttebel, J A Green, J -P Guastalla, A -C Hardy-Bessard, F Hirsch, A Hughes, D Jaubert, M -C Kaminsky, D Katsaros, R Largillier, D Lebrun- Jezekova, B Leduc, M Leheurteur, A Lesoin, K Leunen, N Levasseur, C Leyronnas, J -F Llory, A Lortholary, F Mayer, D Mayeur, C Mendiola, L Mignot, J Morgan, M -A Mouret-Reynier, P Neven, T Petit, E Picardo, J Plaza, M Pluvio-Coronado, F Priou, E Pujade-Lauraine, I Ray Coquard, N Reed, I Rigault de la Longrais, S Scholl, I Sillet-Bach, C Steer, J Summers, V Trillet-Lenoir, P Van Dam, M E L Van Der Burg, E Vanlerenberghe, J -M Vannetzel, I Vergote, J A Vidart Aragon, J Waters, B Weber, G Yazbek, P Zola

Affiliations

¹ Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. evelyndespierre@gmail.com.
² Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
³ University of Colorado Cancer Center, Aurora, Colorado, USA.
⁴ EORTC Headquarters, Brussels, Belgium.
⁵ Azienda Ospedaliera, Presidio Santa Anna, SCDO 3 Ginecologia Oncologica, Università di Torino, Turin, Italy.
⁶ Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
⁷ Vesalius Research Center (VRC), VIB, Leuven, Belgium.
⁸ Academic Division of Gynecological Oncology, Mauriziano Hospital, Turin, Italy.
⁹ Département d'Oncologie Médicale Adulte, Centre Leon Bérard, Lyon, France.
¹⁰ Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
¹¹ Hospital Universitario Clínico San Carlos, Servicio de Oncologia Medica, Madrid, Spain.

PMID: 26004768
PMCID: PMC4661131
DOI: 10.1007/s11523-015-0369-6

Clinical Trial

Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy

Evelyn Despierre et al. Target Oncol. 2015 Dec.

. 2015 Dec;10(4):583-96.

doi: 10.1007/s11523-015-0369-6.

Authors

Collaborators

C Abraham, Le Chesnay, F Amant, R Anderson, A Azzedine, C Benedetto, G Bertelli, P Berteloot, D Berton-Rigaud, N Biglia, N Bonichon-Lamichhane, P Bougnoux, E Bourbouloux, C Bourcier, M Buck, M Campone, E M Canuto, A Casado Herraez, I Cauvin, L Chauvenet, A Chevalier-Place, P -H Cottu, J Cretin, I Cumin, H Curé, F Dalenc, S Danese, A Davis, P Debruyne, G Delplanque, R Delva, V D'Hondt, D Dramais, X Durando, C El Kouri, C Esteban, M Fabbro, C Falandry, B Filleul, A Floquet, P Fumoleau, M Garcia-Varella, C Garnier, E Gilby, L Gladieff, F Goffin, M -C Gouttebel, J A Green, J -P Guastalla, A -C Hardy-Bessard, F Hirsch, A Hughes, D Jaubert, M -C Kaminsky, D Katsaros, R Largillier, D Lebrun- Jezekova, B Leduc, M Leheurteur, A Lesoin, K Leunen, N Levasseur, C Leyronnas, J -F Llory, A Lortholary, F Mayer, D Mayeur, C Mendiola, L Mignot, J Morgan, M -A Mouret-Reynier, P Neven, T Petit, E Picardo, J Plaza, M Pluvio-Coronado, F Priou, E Pujade-Lauraine, I Ray Coquard, N Reed, I Rigault de la Longrais, S Scholl, I Sillet-Bach, C Steer, J Summers, V Trillet-Lenoir, P Van Dam, M E L Van Der Burg, E Vanlerenberghe, J -M Vannetzel, I Vergote, J A Vidart Aragon, J Waters, B Weber, G Yazbek, P Zola

Affiliations

¹ Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. evelyndespierre@gmail.com.
² Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
³ University of Colorado Cancer Center, Aurora, Colorado, USA.
⁴ EORTC Headquarters, Brussels, Belgium.
⁵ Azienda Ospedaliera, Presidio Santa Anna, SCDO 3 Ginecologia Oncologica, Università di Torino, Turin, Italy.
⁶ Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
⁷ Vesalius Research Center (VRC), VIB, Leuven, Belgium.
⁸ Academic Division of Gynecological Oncology, Mauriziano Hospital, Turin, Italy.
⁹ Département d'Oncologie Médicale Adulte, Centre Leon Bérard, Lyon, France.
¹⁰ Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
¹¹ Hospital Universitario Clínico San Carlos, Servicio de Oncologia Medica, Madrid, Spain.

PMID: 26004768
PMCID: PMC4661131
DOI: 10.1007/s11523-015-0369-6

Erratum in

Erratum to: Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy.
Despierre E, Vergote I, Anderson R, Coens C, Katsaros D, Hirsch FR, Boeckx B, Varella-Garcia M, Ferrero A, Ray-Coquard I, Green JA, Steer C, Berns EM, Casado A, Lambrechts D, Jimeno A. Despierre E, et al. Target Oncol. 2016 Jun;11(3):429. doi: 10.1007/s11523-016-0433-x. Target Oncol. 2016. PMID: 27056749 No abstract available.

Abstract

Background: In this work, we aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in patients with ovarian cancer who were treated within the phase III randomized European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) 55041 study comparing erlotinib with observation in patients with no evidence of disease progression after first-line platinum-based chemotherapy.

Methods: Somatic mutations in KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN were determined in 318 (38 %) and expression of EGFR, pAkt, pMAPK, E-cadherin and Vimentin, and EGFR and HER2 gene copy numbers in 218 (26 %) of a total of 835 randomized patients. Biomarker data were correlated with progression-free survival (PFS) and overall survival (OS).

Results: Only 28 mutations were observed among KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN (in 7.5 % of patients), of which the most frequent were in KRAS and PIK3CA. EGFR mutations occurred in only three patients. When all mutations were pooled, patients with at least one mutation in KRAS, NRAS, BRAF, PIK3CA, or EGFR had longer PFS (33.1 versus 12.3 months; HR 0.57; 95 % CI 0.33 to 0.99; P = 0.042) compared to those with wild-type tumors. EGFR overexpression was detected in 93 of 218 patients (42.7 %), and 66 of 180 patients (36.7 %) had EGFR gene amplification or high levels of copy number gain. Fifty-eight of 128 patients had positive pMAPK expression (45.3 %), which was associated with inferior OS (38.9 versus 67.0 months; HR 1.81; 95 % CI 1.11 to 2.97; P = 0.016). Patients with positive EGFR fluorescence in situ hybridization (FISH) status had worse OS (46.1 months) than those with negative status (67.0 months; HR 1.56; 95 % CI 1.01 to 2.40; P = 0.044) and shorter PFS (9.6 versus 16.1 months; HR 1.57; 95 % CI 1.11 to 2.22; P = 0.010). None of the investigated biomarkers correlated with responsiveness to erlotinib.

Conclusions: In this phase III study, increased EGFR gene copy number was associated with worse OS and PFS in patients with ovarian cancer. It remains to be determined whether this association is purely prognostic or is also predictive.

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Figures

**Fig. 1**
EGFR immunohistochemical staining. A hybrid (H)-score was generated based on the fraction of staining cells in each intensity category [0 (no staining), 1+ (weak), 2+ (moderate), 3+ (strong)]. The H-score was calculated by completing the formula (% cells of 0 intensity × 0)+(% of 1+ intensity × 1)+(% of 2+ intensity × 2)+(% of 3+ intensity × 3), with the overall score ranging from 0 to 300. Panels illustrate specimens graded with score 0 (a), score 80 (low expression, b), score 170 (moderate expression, c) and score 280 (high expression, d) (image magnification 40x)

**Fig. 2**
*EGFR* determined by fluorescence in situ hybridization. FISH was performed with the EGFR (red)/CEP7 (green) probe (Abbott Molecular, Des Plaines, IL, USA). Panels illustrate specimens representing low gain in gene copy number per cell (*EGFR* FISH-negative) (a), high (high polysomy=b; gene amplification=c) gain in gene copy number per cell (EGFR FISH-positive)

**Fig. 3**
Kaplan-Meier curves for overall survival and progression-free survival. Data were analyzed according to presence of mutations (top), pMAPK immunohistochemistry (middle), and EGFR gene copy number (bottom)

**Fig. 4**
Kaplan-Meier curves for overall survival and progression-free survival according to treatment allocation. Data were analyzed according to presence of mutations (top), pMAPK immunohistochemistry (middle), and EGFR gene copy number (bottom)

See this image and copyright information in PMC

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References

1. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358(11):1160–74. doi:10.1056/NEJMra0707704. - PubMed
1. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37. - PubMed
1. Skirnisdóttir I, Sorbe B, Seidal T. The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early stage (FIGO I-II) epithelial ovarian carcinoma. Int J Gynecol Cancer. 2001;11(2):119–29. - PubMed
1. Fischer-Colbrie J, Witt A, Heinzl H, Speiser P, Czerwenka K, Sevelda P, Zeillinger R. EGFR and steroid receptors in ovarian carcinoma: comparison with prognostic parameters and outcome of patients. Anticancer Res. 1997;17(1B):613–9. - PubMed
1. Berchuck A, Rodriguez GC, Kamel A, Dodge RK, Soper JT, Clarke-Pearson DL, Bast RC., Jr Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. I. Correlation of receptor expression with prognostic factors in patients with ovarian cancer. Am J Obstet Gynecol. 1991;164(2):669–74. - PubMed

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[1] Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358(11):1160–74. doi:10.1056/NEJMra0707704. - PubMed

[2] Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358(11):1160–74. doi:10.1056/NEJMra0707704. - PubMed

[3] Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37. - PubMed

[4] Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37. - PubMed

[5] Skirnisdóttir I, Sorbe B, Seidal T. The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early stage (FIGO I-II) epithelial ovarian carcinoma. Int J Gynecol Cancer. 2001;11(2):119–29. - PubMed

[6] Skirnisdóttir I, Sorbe B, Seidal T. The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early stage (FIGO I-II) epithelial ovarian carcinoma. Int J Gynecol Cancer. 2001;11(2):119–29. - PubMed

[7] Fischer-Colbrie J, Witt A, Heinzl H, Speiser P, Czerwenka K, Sevelda P, Zeillinger R. EGFR and steroid receptors in ovarian carcinoma: comparison with prognostic parameters and outcome of patients. Anticancer Res. 1997;17(1B):613–9. - PubMed

[8] Fischer-Colbrie J, Witt A, Heinzl H, Speiser P, Czerwenka K, Sevelda P, Zeillinger R. EGFR and steroid receptors in ovarian carcinoma: comparison with prognostic parameters and outcome of patients. Anticancer Res. 1997;17(1B):613–9. - PubMed

[9] Berchuck A, Rodriguez GC, Kamel A, Dodge RK, Soper JT, Clarke-Pearson DL, Bast RC., Jr Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. I. Correlation of receptor expression with prognostic factors in patients with ovarian cancer. Am J Obstet Gynecol. 1991;164(2):669–74. - PubMed

[10] Berchuck A, Rodriguez GC, Kamel A, Dodge RK, Soper JT, Clarke-Pearson DL, Bast RC., Jr Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. I. Correlation of receptor expression with prognostic factors in patients with ovarian cancer. Am J Obstet Gynecol. 1991;164(2):669–74. - PubMed

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Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy

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Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy

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