DOI: 10.1200/JCO.2011.39.4486 Kevin and I first met in the summer of 2007. We were both turning 30 years old that year, neither of us had ever smoked cigarettes, and we each enjoyed listening to the rock band U2. Despite these similarities, we were also different in one major way: Kevin had advanced non–small-cell lung cancer (NSCLC), and I was his healthy medical oncologist. Long before our initial encounter in the oncology clinic, one of Kevin’s normal lung epithelial cells had transformed into a malignant cell. Two genes, each innocuous by itself and unimportant for normal lung function, capriciously rearranged themselves in such a way that the promoter of the echinoderm microtubule-associated protein-like 4 (EML4) gene was abnormally driving expression of the kinase domain of the anaplastic lymphoma kinase (ALK) gene. This rearrangement increased ALK enzyme activity, which prompted that first transformed cell and all of its descendents to copy themselves relentlessly, creating a large tumor that eventually invaded the lymphatics and pleura of Kevin’s left lung. The malignancy also precipitated a pulmonary embolism. Because of the advanced stage of his tumor by the time he first sought medical attention, Kevin’s cancer was considered incurable. Before 2007, many oncologists lumped together all NSCLCs as a single disease and treated them all with similar chemotherapy regimens. But molecular discoveries in the last several years have made it abundantly clear that just like leukemias or lymphomas, NSCLCs that look similar under the light microscope are also molecularly diverse, and the differences from one tumor type to another are as vast as the variation among patients who suffer from NSCLCs. When Kevin was diagnosed with lung cancer, the term personalized medicine was just starting to become part of thoracic oncologists’ vocabulary. In 2004, epidermal growth factor receptor (EGFR) mutations were identified in tumors from approximately 15% of patients with NSCLC, and this finding proved not merely scientifically interesting; it also changed clinical practice. Patients whose tumors harbored EGFR mutations experienced remarkable improvement when they received oral drugs such as gefitinib or erlotinib that block the kinase domain of the EGFR protein. After EGFR mutations were found to be a biomarker predicting response to EGFR-inhibiting drugs, the spark of excitement that rocked the cancer community in the prior decade with the fantastic results from kinase inhibitors in patients with chronic myelogenous leukemia had finally arrived for patients with lung cancer and their physicians, too. Other discoveries soon followed. Japanese investigators reported EML4-ALK fusions in NSCLC in 2007, the first fusion oncogene to be found in a common type of solid tumor. ALK translocations are present in 3% to 7% of NSCLCs overall. Most patients with lung tumors harboring EGFR or ALK genetic changes have either never smoked or smoked only lightly, and their tumors exhibit adenocarcinoma histology rather than squamous cell carcinoma. Although tobacco products and smoking drove lung cancer from obscurity in the early 1900s to the number-one cancer killer globally by the 1980s, people often forget that 10% to 20% of all NSCLCs occur in patients without significant exposure to smoking-related carcinogens. It is still unclear why many never/light smokers develop NSCLC, but it is now widely accepted that in more than half of these cases, a potentially drug-targetable oncogene is present in the tumor cells, with EGFR and ALK being the most clinically relevant of these oncogenes because of the availability of inhibitory drugs in clinical practice. Kevin was the first patient whom I cared for whose tumor was found to have an ALK translocation. In addition to me, his medical team included two talented medical oncology fellows at my hospital, Jess and Susan; two colleagues from other medical centers, Dave and Greg; and another medical oncologist, Bruce. After his diagnosis, Kevin endured six cycles of palliative chemotherapy with a standard platinum doublet, and then, after that failed, he received two additional systemic therapies. Although the initial therapy briefly stabilized his tumor growth, the other treatments were ineffective, and by May 2008, he became symptomatic from his cancer with chest and back pain, shortness of breath with exertion, and fatigue. JOURNAL OF CLINICAL ONCOLOGY A R T O F O N C O L O G Y VOLUME 30 NUMBER 1 JANUARY 1 2012
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May 17, 2018
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