Originally published as JCO Early Release 10.1200/JCO.2003.05.988 on October 27 2003

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Epidermal Growth Factor Receptor Overexpression: The Importance of Context

Vanderbilt-Ingram Cancer Center, Nashville, TN

LUNG CANCER is both common and lethal, which is a deadly combination. Perhaps because less than 15% of patients survive 5 years, it has historically lacked a strong advocacy group and has lagged behind many other less common tumor sites in research funding. A decade or two ago, most patients diagnosed with unresectable non–small-cell lung cancer (NSCLC) were treated only with morphine and hospice care and, perhaps, palliative radiation therapy.

In the 1990s, a handful of new agents showed promising single-agent activity in NSCLC, and it became increasingly clear that at least a subset of patients with NSCLC benefited from combination chemotherapy. Early phase II studies of combination chemotherapy with paclitaxel and carboplatin showed response rates of 50% or greater, including some clinical complete responses,¹ resulting in its widespread adoption in the United States, despite high cost. As is often the case, initial optimism was tempered by the reality that true response rates in subsequent studies were significantly less than 50%,^2,3 though a small—but clear—clinical benefit became more widely recognized. Attention then focused on other novel combinations with promising response rates, and a large randomized clinical trial compared four of these combinations.⁴ To the dismay of the oncology community, there was near complete equivalence of all four regimens. Together with other studies, it is clear that progress is unlikely to be made by further combinations of these agents or their derivatives, and attention has turned to other approaches.

Prominent among these approaches are the new targeted therapies, designed molecular missiles aimed at specific cancer cellular command centers. Various types are being developed: the tyrosine kinase inhibitors (TKIs), designed to block specific cellular receptors or groups of receptors; antibodies against receptors or ligands; and other intracellular signaling targeted therapeutics, such as farnesyl transferase inhibitors and antisense molecules.

One of the important cellular targets identified to date is the epidermal growth factor receptor (EGFr), with EGFr-targeted agents such as gefitinib, OSI-774, and cetuximab in current clinical development. Anecdotal reports, and later large phase II studies, have demonstrated that gefitinib is effective in a small subset of lung cancer patients. Probably one of the most important observations indicating that the mechanism of action of these agents is dissimilar to traditional chemotherapy is that tumor response rates seem to be similar or even perhaps better in patients who have receiver prior chemotherapy. This is in stark contrast to response rates with standard chemotherapy agents that typically decline by half or more with each successive therapy. Absolute response rates with these novel agents, however, are unfortunately low—between 10% and 20% less than those achieved with first-line chemotherapy.

Low response rates may be a logical and direct consequence of tumor biology, however. Lung cancer is biologically and clinically complex and, unlike hematologic malignancies, epithelial cells seem to require multiple redundant system derangements to result in malignant tumors. Thus the 10% of patients who are responders might represent 100% effectiveness in the 10% of tumor cells that depend primarily on that targeted pathway for growth, metastasis, angiogenesis, or resistance to apoptosis. The more precise our weapons, the more likely we are to miss targets of strategic importance, particularly when we don’t know where they are with certainty. Effectiveness requires both precision and intelligent targeting—a huge bomb can destroy a city, whereas precision weapons can take out individual houses, but the problem lies in knowing the important ones. We currently treat all cases of NSCLC as if they were the clinically and biologically the same, and we are only slowly beginning to realize that they are not. Clinical hints have come from the gefitinib studies: response rates are higher in adenocarcinomas than squamous cell tumors, higher in women than men, and higher in nonsmokers than smokers, facts that probably account for response rates that are almost twice as high in Japan than in the United States.

Hirsch et al,⁵ in the October 15, 2003 issue of the Journal of Clinical Oncology, studied the relationship of clinical and pathologic parameters with EGFr gene copy number and protein overexpression in NSCLC. They addressed a number of questions. How often is the protein overexpressed and in what subtypes of tumors? How often is the gene or chromosome present in increased copy number? Is there a direct association of either on prognosis? To answer these questions, they used the high throughput technology of tissue microarrays to examine 183 tumor specimens simultaneously, in triplicate, for EGFr overexpression by immunohistochemistry and gene amplification by fluorescence in situ hybridization. Their data, and those of others, document that the EGFr is frequently overexpressed in lung cancer: 62% of all tumors, 89% of squamous tumors, 41% of adenocarcinomas, and 80% of bronchioloalveolar tumors. These results, however, are not correlated with clinically observed response patterns to EGFr TKIs in lung cancer: high in adenocarcinomas and low in squamous tumors. The most important aspect of this study is the correlation of protein overexpression with evaluation of gene amplification by fluorescence in situ hybridization, which might be predicted to be more clinically informative than immunohistochemistry alone based on an analogous situation in breast cancer. Specifically, and perhaps counterintuitively, the data in breast cancer are that responses to an antibody (trastuzumab) specific for HER2 receptor protein (a relative of the EGFr) are more correlated with gene amplification than protein overexpression.⁶ This article is the first to study the relationship of overexpression and gene amplification in a large number of lung cancer tumors.

In the study by Hirsch et al,⁵ the authors draw distinctions between increased copy number of the entire chromosome or localized increases in the number of copies of EGFr as assessed by coamplification of the centromere of chromosome 7 with the gene. The total copy number of the EGFr gene was greater than two in 60% of patients, 51% had equal increases in both centromeric and locus-specific probes, and 9% showed amplification of the EGFr gene independent of the centromere. High gene copy numbers were more frequent in squamous tumors, whereas low gene copy numbers were more common in nonsquamous tumors, again in contrast to the clinically observed greater likelihood of response to gefitinib in adenocarcinomas. Hirsch et al refer to "balanced polysomy," or coamplification of centromere and gene by more than three copies per cell or selective EGFr amplification. This was found to be associated with high-level protein expression, but they also observed that high-level expression was frequently seen in the absence of increased gene copy number.

These data lead to two main conclusions: that there are multiple mechanisms involved in EGFr protein overexpression and that neither gene amplification nor overexpression will be good predictors of clinical response. This is particularly evident for squamous tumors, which are found to have frequent overexpression but low objective response rates to targeted intervention with gefitinib. Receptor expression may thus be necessary for responses to the EGFr TKIs, but insufficient, and knowledge of the molecular context of other proteins and pathways active in a particular cancer cell expressing the EGF receptor will be crucial to understanding why some patients respond to manipulation of this pathway and others do not.

Unlike cytotoxics, like fluorouracil, which specifically inhibit essential pathways such as nucleotide metabolism essential for every living cell, ideal targeted agents are fundamentally different because they attack pathways essential to a given tumor and dispensable to key normal cells in the host. Patients tolerate chronic doses of EGFr TKIs associated with high degrees of receptor kinase inhibition, but they would not tolerate sustained complete blockade of nucleotide biosynthesis. Hitting a specific target is not therapeutically meaningful unless the tumor depends on that target and, equally important, the host does not. EGFr approaches this ideal in a small subset of lung cancer patients; I have patients with documented metastatic NSCLC, including some who were chemotherapy-refractory, who have sustained excellent responses on gefitinib alone, some for more than 3 years and with a normal quality of life. This, though rare with gefitinib, is unheard of with cytotoxic chemotherapeutics.

Thus with the development of highly targeted therapies comes a requirement for both diverse types of weapons and highly accurate intelligence information about the enemy. The complexity of lung cancer may mean that a given targeted therapeutic drug may be clinically useful only in a small subset of patients, but in those patients it may be exquisitely effective with low toxicity. The day may come when a tumor can be molecularly profiled, the important targets in individual tumors identified, and customized combinations of targeted agents selected for that person. Genomic, cDNA microarray, and proteomic studies are approaching these issues, and the results of these studies are likely to provide additional insight in the coming years.

Much work needs to be done to identify these key therapeutic targets and to determine which tumors are dependent on them. Understanding the frequency, patterns, and mechanisms of target overexpression, as in this study in the Journal of Clinical Oncology, is an important first step.

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following author or his immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: David P. Carbone, AstraZeneca.

REFERENCES

1. Langer CJ, Leighton J, McAleer C, et al: Paclitaxel and carboplatin in the treatment of advanced non-small cell lung cancer. Semin Oncol 22:64–69, 1995[Medline]

2. Johnson DH, Paul DM, Hande KR, et al: Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: A phase II trial. J Clin Oncol 14:2054–2060, 1996[Abstract/Free Full Text]

3. Johnson DH, Einhorn LH: Paclitaxel plus carboplatin: An effective combination chemotherapy for advanced non-small-cell lung cancer or just another Elvis sighting? J Clin Oncol 13:1840–1842, 1995[Free Full Text]

4. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98, 2002[Abstract/Free Full Text]

5. Hirsch F, Varella-Garcia M, Bunn PA, et al: Epidermal growth factor receptor in non–small-cell lung carcinomas: Correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798–3807, 2003[Abstract/Free Full Text]

6. Pauletti G, Dandekar S, Rong H, et al: Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: A direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol 18:3651–3664, 2000[Abstract/Free Full Text]

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