Targeted Therapy: an Evolving Concept in Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) affects approximately 11,000 persons per year in the United States, is increasing in incidence, and is associated with an exceptionally high mortality rate.[1-4] In this issue of ONCOLOGY, Krasna reviews the role of multimodality therapy in the treatment of EAC. Poor outcome in patients with EAC is reflective of both deficiencies in early detection and the inadequacy of available therapies across stages.

Alterations in the types and schedules of conventional cytotoxic regimens has failed to improve outcome substantially. This has led to a change of focus, with greater emphasis on targeted therapies. The increasing availability of potential agents and a better understanding of the biology of the cancer have further facilitated this approach. Various agents are already in clinical trials, and a number of others are in early phases of development, with promising preclinical data.

Targets Currently Under Clinical Investigation

Epidermal Growth Factor Receptor (EGFR) Pathway
The EGFR signaling pathway influences the expression and activation of a variety of key regulators of cell growth, cell proliferation, nutrient uptake, cell survival, invasion, angiogenesis, and metastasis.[5,6] EGFR activation and expression is implicated in the progression of Barrett metaplasia, and a high level of expression is reported in EAC.[7,8]

Upregulation of EGFR has been reported as a poor prognostic factor in EAC; in particular, it correlates with lymph node metastasis, higher stage, and poorer outcome.[9,10] Based on its extensive association with EAC, this pathway has been targeted by using both monoclonal antibodies and small molecule tyrosine kinase inhibitors. EGFR-targeting monoclonal antibodies used in this context include cetuximab (Erbitux), matuzumab (NCT00215644, NCT00113581), and panitumumab (ACOSOG Z4051). Cetuximab has been used in many cooperative group and single-institution clinical trials. These include a Southwest Oncology Group (SWOG) trial of cetuximab as second-line therapy in patients with metastatic EAC. In this study, the primary end-point was 6-month overall survival (OS). In 55 patients who were given single-agent cetuximab therapy, the 6-month OS rate was 36%.[11] Preclinical and similar early clinical studies suggest potential activity and minimal toxicities with EGFR antibodies for esophageal cancer.[12]

Various trials are investigating the role of small molecules, including erlotinib (Tarceva), gefitinib (Iressa), lapatinib (Tykerb), and multikinase inhibitors sunitinib (Sutent) and sorafinib (Nexavar).

HER2
HER2 is another member of the EGFR family that is associated with cell proliferation, migration, and differentiation.[13] HER2 over-expression and/or amplification has been reported in EAC,[14] along with some evidence supporting a prognostic utility.[15] Various phase I and II trials have reported a possible benefit for HER2 blockade.[16] Data from these trials served as the basis for a recent prospective phase III trial (ToGA) that evaluated the therapeutic benefit of blocking this target in a randomized fashion.[17]

In the ToGA study, more than 594 patients with HER2-positive gastric and gastroesophageal junction (GEJ) tumors were randomly assigned to receive cisplatin and a fluoropyrimidine either with or without trastuzumab (Herceptin). This trial showed a significant improvement in survival (13.5 months vs 11.1 months) with the addition of trastuzumab, thus establishing the addition of trastuzumab to chemotherapy as a new standard of care.

Vascular Endothelial Growth Factor (VEGF)
Inhibition of angiogenesis by bevacizumab (Avastin)-mediated blockade of the VEGF pathway is known to have a survival benefit in non–small-cell lung cancer and colorectal cancer,[18] among others. Various preclinical and clinical studies have suggested a possible role of this pathway in EAC.[19,20] In a phase II trial carried out by Memorial Sloan-Kettering Cancer Center (MSKCC), the addition of bevacizumab to combination irinotecan (Camptosar)/cisplatin chemotherapy was evaluated in patients with metastatic or unresectable esophagogastric cancer. There seemed to be a significant improvement in time to progression as well as OS compared with historical controls.[21]

In order to validate the MSKCC study, a phase III trial (AVAGAST) was undertaken and recently completed.[22] This randomized, placebo-controlled study compared chemotherapy with bevacizumab to chemotherapy without bevacizumab; it failed to show a significant improvement in OS in patients with gastric and GEJ tumors.

Hepatocyte Growth Factor (HGF) Receptor/c-Met
The HGF receptor c-Met is a transmembrane protein tyrosine kinase receptor that regulates various signal transducers, including phosphatidylinositol 3-kinase (PI3K) and extracellular regulated kinase (ERK), ultimately resulting in growth, survival, motility, and invasion.[23] Preclinical studies show overexpression of this target in EAC.[24] Another study, employing cell lines, further supported the role of the c-Met receptor as a potential target.[25] This led to the institution of an early-phase clinical trial to evaluate the therapeutic benefit of c-Met inhibition in adenomas of the GEJ and distal esophagus and in gastric carcinoma (NCT00725712).

Other Targets In Early Phases of Clinical Investigation

Targets for which clinical investigations are in early phases include histone deacetylase (HDAC) (NCT00537121), Hedgehog (Smoothened [Smo]), auora kinase, and insulin-like growth factor 1 receptor (IGF1-R).”

Sonic Hedgehog (Smo)
The Sonic Hedgehog (Shh) pathway plays a critical role in the development of endoderm-derived foregut epithelial tissues, including tissues in the esophagus. Accumulating evidence implicates Shh pathway activation in the progression from Barrett esophagus (BE) to EAC.[26-28] Studies have also explored possible mechanisms of action, including epithelial stromal interaction.[29]

IGFR
The IGFR is functionally implicated in the initiation, propagation and maintenance of many solid tumors, including EAC and its precursor lesion, BE. IGFR over-expression, along with over-expression of c-Src and Bcl-XL, is reported in the progression from BE to invasive adenocarcinoma.[30] On the assumption of an autocrine role for IGF-1 in EAC, Liu and colleagues studied two human esophageal cell lines and demonstrated the coexpression of IGF-1 and IGF1-R,[31] with proliferative responses to the addition of IGF-1. Furthermore, the addition of an IGF-1 peptide antagonist decreased the number of CE81T/VGH colonies and the size and incidence of tumor xenografts in severe combined immunodeficiency (SCID) mice. Thus, the available evidence supports IGFR as a potential therapeutic target.

Conclusion

With the exception of trastuzumab in HER2-positive EAC, the absolute proven benefit of targeted agents in EAC remains low. This has been attributed to a lack of appropriate patient selection in the absence of compelling predictive markers. This further underscores the need for future preclinical studies as well as clinical trials evaluating various markers predictive of response to therapy in order to facilitate rational use of targeted agents in selected groups of patients.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Landis SH, Murray T, Bolden S, et al. Cancer statistics, 1998. CA Cancer J Clin. 1998;48:6-29.

2. Landis SH, Murray T, Bolden S, et al. Cancer statistics, 1999. CA Cancer J Clin. 1999;49:8-31.

3. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225-49.

4. Salazar JD, Doty JR, Lin JW, et al. Does cell type influence post-esophagectomy survival in patients with esophageal cancer? Dis Esophagus.1998;11:168-71.

5. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000;19:6550-65.

6. Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37(Suppl 4):S3-8.

7. Rygiel AM, Milano F, Ten Kate FJ, et al. Gains and amplifications of c-myc, EGFR, and 20.Q13 loci in the no dysplasia- dysplasia-adenocarcinoma sequence of Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev. 2008;17:1380-5.

8. Itakura Y, Sasano H, Shiga C et al. Epidermal growth factor receptor overexpression in esophageal carcinoma. An immunohistochemical study correlated with clinicopathologic findings and DNA amplification. Cancer (Phila). 1994;74:795-804.

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. 2007;109:658-67.

10. Gibson MK, Abraham SC, Wu TT, et al. Epidermal growth factor receptor, p53 mutation, and pathological response predict survival in patients with locally advanced esophageal cancer treated with preoperative chemoradiotherapy. Clin Cancer Res. 2003;9:6461-8.

11. Gold PJ, Goldman B, Iqal S et al. Cetuximab as second-line therapy in patients with metastatic esophageal cancer: a phase II Southwest Oncology Group study. Abstract in 2008 ASCO Annual Meeting Proceedings. J Clin Oncol. 2008;26(15S):222s, #4536.

12. Tew WP, Kelsen DP, Ilson DH. Targeted Therapies for Esophageal Cancer. Oncologist. 2005;10:590-601.

13. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523-9.

14. Reichelt U, Duesedau P, Tsourlakis M, et al. Frequent homogeneous HER-2 amplification in primary and metastatic adenocarcinoma of the esophagus. Mod Pathol. 2007;20:120-9.

15. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523-9.

16. Safran H, Dipetrillo T, Akerman P, et al. Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2007;67:405-9.

17. Bang Y-J, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-97.

18. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-42.

19. Burnat G, Rau T, Elshimi E, Hahn EG, Konturek PC. Bile acids induce overexpression of homeobox gene CDX-2 and vascular endothelial growth factor (VEGF) in human Barrett’s esophageal mucosa and adenocarcinoma cell line. Scand J Gastroenterol. 2007;42:1460-5.

20. Vallbohmer D, Peters JH, Kuramochi H, et al. Molecular determinants in targeted therapy for esophageal adenocarcinoma. Arch Surg. 2006;141:476-81. Discussion 481-2.

21. Shah MA, Ramanathan RK, Ilson D, et al. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2006;24:5201-6.

22. Kang Y, Ohtsu A, Van Cutsem E, et al. AVAGAST: A randomized, double-blind, placebo-controlled, phase III study of first-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer (AGC) Abstract in 2010 ASCO Annual Meeting Proceedings. J Clin Oncol. 2010;28(Suppl)18s (abstr LBA4007).

23. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1-26.

24. Herrera LJ, El-Hefnawy T, Queiroz de Oliveira PE, et al. The HGF receptor c-Met is overexpressed in esophageal adenocarcinoma. Neoplasia. 2005;7:75-84.

25. Watson GA, Zhang X, Stang MT, et al. Inhibition of c-Met as a therapeutic strategy for esophageal adenocarcinoma. Neoplasia. 2006;8:949-55.

26. Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425:846.

27. Sui G, Bonde P, Dhara S, et al. Epidermal growth factor receptor and Hedgehog signaling pathways are active in esophageal cancer cells from rat reflux model. J Surg Res. 2006;134:1-9.

28. Ma X, Sheng T, Zhang Y, et al. Hedgehog signaling is activated in subsets of esophageal cancers. Int J Cancer. 2006;118:139-48.

29. Wang DH, Clemons NJ, Miyashita T, et al. Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett’s metaplasia. Gastroenterology. 2010;138:1810-22. Epub 2010 Feb 4.

30. Iravani S, Zhang HQ, Yuan ZQ, et al. Modification of insulin-like growth factor 1 receptor, c-Src, and Bcl-XL protein expression during the progression of Barrett’s neoplasia. Hum Pathol. 2003;34:975-82.

31. Liu YC, Leu CM, Wong FH et al. Autocrine stimulation by insulin-like growth factor I is involved in the growth, tumorigenicity and chemoresistance of human esophageal carcinoma cells. J Biomed Sci. 2002;9(6 Pt 2):665-74.