College of American Pathologists
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  Non-small cell lung cancer in the targeted
  therapy era





November 2007
PAP/NGC Programs Review

Maureen F. Zakowski, MD

Epidermal growth factor receptor (EGFR) is a protein on the cell surface to which epidermal growth factor (EGF) binds. When EGF attaches to EGFR, it activates the enzyme tyrosine kinase and triggers cell growth. EGFR may be found at abnormally high levels on the surface of many cancer cells. New nonchemotherapy agents such as the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib (Iressa and Tarceva) are now available to treat non-small cell lung cancer alone or in the adjuvant setting. The TKIs "target" the EGFR to turn off cell activity and help control the growth of non-small cell lung cancer, or NSCLC.

Attempts were made to predict pretreatment which patients would respond to these agents, and it became obvious that the category of NSCLC was no longer sufficient. Before the era of targeted therapy, the important pathologic distinction in lung cancer was between small cell and non-small cell. Small cell got chemotherapy, and non-small cell got surgery, if possible, and chemotherapy in the adjuvant, neoadjuvant, or palliative setting. There was no real difference in the treatment of NSCLC, whether adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or any other combination.

Adenocarcinoma has begun to emerge as a different kind of NSCLC. It has now surpassed squamous cell as the most common primary lung cancer. The incidence in women is rising, and it is the subtype found in never smokers, particularly in the West and in Japan. And, most important, it is the type of NSCLC most likely to respond to tyrosine kinase inhibitors.

The mutations that underlie the sensitivity of adenocarcinoma to tyrosine kinase inhibitors were discovered in 2004. These activating mutations, mostly in exons 19 and 21 on chromosome 7, are found in tumors from patients responsive to TKIs. These tumors have all been adenocarcinomas. Patients with squamous cell carcinoma or small cell carcinoma do not carry these mutations and do not respond to TKI therapy. A great deal of attention has been paid to determining just what types of the usually heterogeneous adenocarcinomas respond. Many studies suggest that adenocarcinomas with a bronchoalveolar component, or BAC, are most likely to harbor the EGFR mutations. There is some disagreement about the importance of BAC, with some investigators suggesting that papillary subtype is more often associated with mutations. This may be due to intra- and interobserver variability in diagnosis or in the difficulty of separating papillary subtype from BAC in a heterogeneous tumor. Interestingly, EGFR mutations are never found in mucinous BAC. These tumors are strongly associated with KRAS mutations. EGFR and KRAS mutations are mutually exclusive.

Another small-molecule, nonchemotherapy drug called bevacizumab or Avastin is a monoclonal antibody against endothelial growth factor and is now being used in the treatment of NSCLC. While no factors similar to TKIs seem to underlie tumor responsiveness to Avastin, histopathology plays a major role in the selection of patients for treatment. Patients with squamous cell carcinoma of the lung are at high risk for the development of fatal pulmonary hemorrhage when exposed to Avastin. Whether this is due to histology alone or anatomic location of the tumor or cavity formation by the squamous cell carcinoma is unclear. Based on a number of deaths in a phase one trial of Avastin where the common feature among the patients with lethal complications was squamous histology, patients with tumors of squamous type in the lung were ineligible for a phase two trial.

So the distinction between small cell and non-small cell lung cancer is no longer good enough in the practice of cytopathology or surgical pathology. Every attempt must be made to categorize lung cancer accurately to allow optimal treatment outcomes.

Immunohistochemistry plays a strong role in separating adenocarcinoma from squamous cell carcinoma. Markers such as TTF-1 and PE 10, when positive, will statistically support adenocarcinoma, and positivity in 4A4, P63, and 34bE12 will suggest squamous differentiation. Mucin, while somewhat "old fashioned," remains very useful in this setting. Tumors found to be adenocarcinoma should be sent for molecular testing for EGFR mutations.

The pathologist is in an ideal position to influence appropriate testing and treatment in the era of targeted therapy.

Dr. Zakowski, a member of the CAP Cytopathology Committee, is attending pathologist, Memorial Sloan-Kettering Cancer Center, New York, NY, and professor of pathology, Weill Cornell Medical College.