The epidermal growth factor receptor (EGFR) gene is often amplified and its protein overexpressed in upper gastrointestinal cancers—and overexpression has prognostic value. With the advent of monoclonal antibodies and tyrosine kinase inhibitors against EGFR, we have witnessed a rash of randomized clinical trials in patients with advanced or localized gastroesophageal cancers (squamous cell carcinoma and adenocarcinoma). The results have been uniformly disappointing.
Here, we highlight a recently reported UK trial (COG) in patients with Siewert-type I/II advanced gastroesophageal cancers (adenocarcinoma or squamous cell carcinoma) in the second-line setting.1 The report, by Dutton and colleagues in Lancet Oncology, is summarized in this issue of The ASCO Post.
The COG trial randomly assigned 449 patients to receive gefitinib (Iressa) or placebo. The primary endpoint was overall survival, and secondary endpoints included progression-free survival. The median overall survival was 3.73 months for patients who received gefitinib and 3.63 months for those who received a placebo (hazard ratio [HR] = 0.9, P = .29). There was a minor prolongation of progression-free survival by 0.4 months for patients who received gefitinib (HR = 0.80, P = .02).
Related Trials
Before we speculate as to why gefitinib failed to prolong overall survival in these patients in whom EGFR is often overexpressed and thought to impart resistance to therapy, it is useful to review other studies that have assessed EGFR inhibition in gastroesophageal cancer patients. Equally disappointing results were reported from two EGFR-targeting trials (EXPAND and REAL-3) in patients with metastatic gastric or gastroesophageal cancer.2,3
The EXPAND trial randomly assigned patients to receive capecitabine and cisplatin with or without cetuximab (Erbitux). This study did not achieve its primary endpoint, with the median progression-free survival for capecitabine/cisplatin plus cetuximab being 4.4 months compared to 5.6 months for capecitabine/cisplatin alone (HR = 1.09, 95% confidence interval [CI] = 0.92–1.29, P = .32).2
The REAL-3 study was terminated prematurely because a statistically significantly lower overall survival was noted in patients who received EOC (epirubicin,j oxaliplatin, and capecitabine) and panitumumab (Vectibix). Median overall survival of patients allocated to EOC was 11.3 months (95% CI = 9.6–13.0) compared with 8.8 months (95% CI = 7.7–9.8) in patients allocated to modified EOC and panitumumab (HR =1.37, 95% CI = 1.07–1.76, P = .013). An exploratory molecular analysis of tumors of patients in the trial did not identify any predictive biomarkers for panitumumab.4
A similar strategy of using an anti-EGFR antibody in combination with chemoradiation was evaluated in two randomized trials in patients with localized gastroesophageal cancers. The Radiation Therapy Oncology Group (RTOG) 0436 phase III trial evaluated the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with unresectable esophageal cancer; no prolongation of overall survival was observed with the addition of cetuximab.5
The SCOPE1 study randomized both adenocarcinoma and squamous cell carcinoma patients who were candidates for definitive chemoradiation therapy to cisplatin, capecitabine, and radiation with or without cetuximab. This trial was stopped based on the results of an interim analysis that crossed the bounds for futility. The cetuximab group had a median overall survival of 22.1 months (95% CI = 15.1–24.5) compared to 25.4 months (95% CI = 20.5–37.9) for those who did not get cetuximab (adjusted HR = 1.53, 95% CI = 1.03–2.27, P = .035).6
Driver Mutations
Squamous cell carcinomas seem to overexpress EGFR at a high frequency (60%–70%) and have a fairly high rate of EGFR amplification (28%).7,8 These changes are associated with poor response to chemoradiotherapy and shorter overall survival.9 However in the COG study, squamous cell carcinoma patients formed a minority, and there was a trend for improved overall survival in adenocarcinoma patients, highlighting the fact that overexpression of EGFR may not represent a therapeutic target. In gastric cancer, although EGFR amplification has been low, EGFR expression is similar to that in esophageal cancers, and it is prognostic.10
Exploiting biomarkers in the clinic is very challenging and although there have been a few successes (KRAS, ERRB2, ALK-rearrangement, and BRAF), there are many more failures. It is quite likely that EGFR is not the primary driver in esophageal cancers. The sheer complexity of the genome is staggering, and structural alterations do not necessarily translate into functional/protein aberrations.
Vogelstein et al recently suggested that the whole idea of eradicating cancer by targeting metastatic disease seems improbable.11 The carcinogenesis takes decades to transform a normal (stem) cell into cancer. Cancer cells use approximately 12 pathways for survival. Driver mutations are difficult to decipher, and the cure of cancer is unlikely to come from focusing on advanced cancer; the advantage might come from focusing on early detection (eg, blood biomarker testing).
Multiple Mechanisms
One possibility for the findings in studies in this area is that the EGFR pathway is upregulated through multiple mechanisms, and therefore the direct blockage of the EGFR pathway alone would be expected to be ineffective or insufficient, as appears to be borne out by these trials. The Hippo signaling pathway regulates organ size and cell proliferation. YAP1 is a key downstream effector of the Hippo signaling pathway and is tightly regulated by a number of upstream kinases and their adaptors—eg, Mst1/2, Sav1, and Lats1/2, which are tumor suppressors in several tumor types.12
Conditional deletion of these genes in mice led to a dramatic increase in organ size and tumor formation in a process largely dependent on YAP1.12 In transgenic mice, tissue-specific expression of YAP results in tissue overgrowth and tumor formation.13 EGFR activation occurs frequently in Hippo pathway–defective mouse liver tumors.14 A recent study from Reddy et al demonstrated that the EGFR-RAS-MAPK branch of EGFR signaling activates YAP1 by promoting phosphorylation of the Ajuba family protein WTIP and enhancing WTIP binding to Lats1/2.15
Therefore, it may be that a therapeutic combination to inhibit one or more pathways would be advantageous. The trials we discussed have not selected patients based on EGFR or other biomarkers; however, a predictive biomarker for a given inhibitor is difficult to figure out. It is entirely possible that YAP1 is upregulating EGFR and that YAP1 should be inhibited in EGFR-overexpressing tumors.
In summary, we believe that in-depth functional and structural studies of the gastroesophageal cancer genome are needed. Simultaneously, we should be harnessing the prowess of the immune system, through vaccines, antibodies, cell therapy, and/or programmed cell death inhibitors. ■
Disclosure: Drs. Elimova and Song reported no potential conflicts of interest. Dr. Ajani has received research grants from Amgen, Genentech, BMS, Taiho, Novartis, and DFP, and is a paid consultant for Lilly and Celgene.
References
1. Dutton SJ, Ferry DR, Blazeby JM, et al: Gefitinib for oesophageal cancer progressing after chemotherapy (COG): A phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol 15:894-904, 2014.
2. Lordick F, Kang YK, Chung HC, et al: Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open-label phase 3 trial. Lancet Oncol 14:490-499, 2013.
3. Waddell T, Chau I, Cunningham D, et al: Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. Lancet Oncol 14:481-489, 2013.
4. Okines AF, Gonzalez de Castro D, Cunningham D, et al: Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials. Eur J Cancer 49:2116-2125, 2013.
5. Suntharalingam M, Winter K, Ilson DH, et al: The initial report of RTOG 0436: A phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with esophageal cancer treated without surgery. J Clin Oncol 32(3 suppl):Abstract LBA6, 2014.
6. Crosby T, Hurt CN, Falk S, et al: Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): A multicentre, phase 2/3 randomised trial. Lancet Oncol 14:627-637, 2013.
7. Hanawa M, Suzuki S, Dobashi Y, et al: EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus. Int J Cancer 118:1173-1180, 2006.
8. Gibault L, Metges JP, Conan-Charlet V, et al: Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer. Br J Cancer 93:107-115, 2005.
9. Wang KL, Wu TT, Choi IS, et al: Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: Association with poor outcome. Cancer 109:658-667, 2007.
10. Galizia G, Lieto E, Orditura M, et al: Epidermal growth factor receptor (EGFR) expression is associated with a worse prognosis in gastric cancer patients undergoing curative surgery. World J Surg 31:1458-1468, 2007.
11. Vogelstein B, Papadopoulos N, Velculescu VE, et al: Cancer genome landscapes. Science 339:1546-1558, 2013.
12. Lu L, Li Y, Kim SM, et al: Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci USA 107:1437-1442, 2010.
13. Camargo FD, Gokhale S, Johnnidis JB, et al: YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol 17:2054-2060, 2007.
14. Bard-Chapeau EA, Nguyen AT1, Rust AG, et al: Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model. Nat Genet 46:24-32, 2014.
15. Reddy BV, Irvine KD: Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev Cell 24:459-471, 2013.
Drs. Elimova, Song, and Ajani are in the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
