Verifying the Role of Surgical Pathologists in the Precision Medicine of Lung Cancer

The First Line Erbitux in Lung Cancer Phase III clinical trial recently reported that a portion of advanced non–small cell lung carcinoma (NSCLC) patients benefit from the addition of the anti–epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux, Bristol-Myers Squibb, New York, New York, and Eli Lilly and Company, Indianapolis, Indiana) to their conventional platinum-based therapy. Patients whose NSCLC expressed high levels of EGFR based on an immunohistochemistry (IHC) scoring system had improved survival when cetuximab was added to their therapy, in contrast to those with tumors with low levels of EGFR expression.1–3 This observation signifies an important new opportunity for pathologists to participate in predictive biomarker testing using the conventional light microscope, the familiar technique of IHC, and their traditional skills as pathologists. In this issue of the Archives, the article by Dr Rüschoff and his multinational group of collaborators systematically addresses the interobserver reproducibility of the EGFR IHC scoring system used in the First Line Erbitux in Lung Cancer clinical trial, further solidifying, in this context, the value of the surgical pathologist in the personalized health care of lung cancer patients.The discovery in 2004 by several different research groups that somatic mutations in the EGFR gene predicted which lung cancers were likely to respond to therapy with EGFR tyrosine kinase inhibitors (TKIs) was a momentous stride in the treatment of lung cancer.4–6 Pathologists had long known that EGFR protein was overexpressed in the majority of NSCLCs.7 The first generation of selective, reversible EGFR TKIs was introduced in the early 21st century and consisted of gefitinib (Iressa; AstraZeneca, London, United Kingdom) and erlotinib (Tarceva; Genentech, South San Francisco, California, and OSI Pharmaceuticals, Long Island, New York). However, in early clinical trials of unselected patients with advanced lung cancer, the results showed limited value of these drugs prior to the discovery of the predictive value of the EGFR mutations.8–15In 2009, the first report of a clinical trial (IRESSA Pan-Asia Study) was published in which a better response rate and progression-free survival with gefitinib therapy was observed, compared to conventional chemotherapy, in patients whose advanced-stage NSCLC had EGFR mutations.16,17 These observations were confirmed for gefitinib versus conventional chemotherapy in 2 other clinical trials (WJTOG3405 and NEJ002) published in 2010,18,19 and similar results were reported for erlotinib versus conventional chemotherapy in the OPTIMAL and EURTAC studies.20,21In these and other clinical trials, EGFR mutation analysis has proven to be the best test to select patients for EGFR TKI therapy. Studies have shown that EGFR mutations occur in adenocarcinomas, adenosquamous carcinomas and subtypes, or poorly differentiated carcinomas that are likely to be adenocarcinomas, and rarely, and possibly not at all, in squamous cell carcinomas.22–34 Because 70% of NSCLCs present in advanced stage, typically the only specimens for EGFR mutation testing are small biopsies and cytology specimens.35–38 Institutional policies and/or requests by the oncologist determine when EGFR mutation testing is done. Currently, EGFR mutation analysis is widely and increasingly reflexively performed on adenocarcinomas.39,40 It may also be performed when the cell type cannot be determined or when an adenocarcinoma component cannot be excluded because of the limitations of the sample.EGFR polysomy and amplification do not predict response to EGFR TKI therapy as consistently in clinical trials and, therefore, EGFR fluorescence in situ hybridization is not as dependable for selecting patients for EGFR TKI therapy.22–32,41–43 Traditional EGFR IHC, which detects total EGFR expression, is not applicable for EGFR TKI therapy because it is not mutation specific.22–32,44 Mutation-specific EGFR antibodies do not yet account for all potentially actionable mutations, although they may have a possible role in initial screening.45–47The EGFR mutation/EGFR TKI story has generated a great deal of excitement and hope among lung cancer patients, their families and friends, oncologists, pathologists, and the lay public. However, EGFR TKI therapy, as exciting as it is and as important as it is to a subset of patients, is far from a cure-all for lung cancer. For one thing, EGFR mutations occur in only a minority of NSCLCs and, therefore, a limited number of lung cancer patients are potential candidates for this therapy. EGFR mutation frequency ranges up to 32% of NSCLC in East Asians and up to 15% of NSCLC in whites and is about 20% of NSCLC in African Americans, accounting for about 30 000 new cases of EGFR mutation–positive NSCLC in the United States every year.30,48–52 In addition, patients who respond to EGFR TKI therapy eventually develop acquired resistance and relapse, creating a need for additional lines of therapy. Therefore, other types of targeted therapy for lung cancer are in varying stages of clinical validation or investigation.22–30To identify candidates for EGFR TKI therapy, the surgical pathologist or cytopathologist makes the diagnosis of a primary pulmonary adenocarcinoma with the caveats mentioned above and then selects tissue and sends it to the molecular diagnostics laboratory for mutation analysis. This role is very important and requires specialized knowledge and skills, but, unless the pathologist is also directly involved in the molecular diagnostics laboratory, the surgical pathologist or cytopathologist does not personally supervise the EGFR mutation testing.The likely addition of cetuximab to the treatment options for advanced NSCLC patients provides an opportunity for direct predictive biomarker testing by the anatomic pathologist. Cetuximab has been approved for therapy of advanced colon adenocarcinoma and advanced head and neck squamous cell carcinoma.53–57 In 2011 and 2012, subgroup analysis of the First Line Erbitux in Lung Cancer Phase III clinical trial concluded that an EGFR IHC score of 200 or more (high expression) using the Dako (Glostrup, Denmark) pharmDx kit was associated with increased overall survival in advanced NSCLC patients receiving first-line platinum-based chemotherapy plus cetuximab versus chemotherapy alone for both squamous cell carcinomas and adenocarcinomas.1–3Cetuximab therapy opens the door for EGFR IHC as a predictive biomarker test for NSCLC. Immunohistochemistry is a technique familiar to the surgical pathologist and is performed routinely in many hospital laboratories. It requires the ordinary light microscope for interpretation and presents some advantages over molecular testing. Direct observation of tissues by the light microscope allows accurate interpretation even when the number of tumor cells is minimal and/or when the tumor cells are dispersed or diluted by nonmalignant or necrotic tissues that might hamper molecular tests. We have previously discussed these same advantages in regards to the new sensitive antibodies for anaplastic lymphoma kinase protein in NSCLC.58 By following up on recent observations of the First Line Erbitux in Lung Cancer clinical trials with their validation of the reproducibility of the EGFR IHC scoring system, Dr Rüschoff and colleagues have further verified the direct role that surgical pathologists can contribute to the personalized health care of lung cancer patients.