Customizing Therapies for Lung Cancer

Photo of male and female smoking

Photo of male and female smoking

Lung cancer is the leading cause of cancer-related death in both men and women. Although there have been modest improvements in short-term survival over the last few decades, five-year survival rates for lung cancer remain low at only 16 percent. Treatment for lung cancer depends on the stage of the disease at diagnosis, but generally consists of some combination of surgery, chemotherapy, and radiation therapy. Increasing attention has been paid in recent years to customizing therapies based on the molecular characteristics of patients’ tumors. Some of these targeted regimens have already been integrated into the treatment arsenal for lung cancer and others are still being studied in clinical trials, including several being conducted by researchers at NCI’s Center for Cancer Research.

A case study of a patient treated in one of these trials—recently published in the Journal of Clinical Oncology by CCR clinical researchers Ronan Kelly, Corey Carter, and Giuseppe Giaccone—illustrates the potential value in individualizing therapy for patients with non-small cell lung cancer. The patient—a 50-year old man who had never smoked—was diagnosed with advanced-stage non-small cell lung cancer. When his cancer progressed after several months of standard chemotherapy (which included bevacizumab, a targeted therapy that blocks growth of new blood vessels), the patient underwent treatment with a series of targeted therapies selected based on the characteristics of his tumor. Early molecular analysis revealed that the tumor overexpressed a signaling protein called epidermal growth factor receptor, or EGFR, so the patient was treated with the targeted therapy erlotinib, which inhibits this protein. Unfortunately, erlotinib could not prevent the cancer from progressing.

At this time, the patient enrolled in a clinical trial at NCI that is testing an experimental drug—called PF-00299804—that inhibits several members of the EGFR family, including EGFR. Laboratory tests revealed that, in addition to EGFR, the patient’s tumor expressed high levels of HER2, an oncogene that is a member of the EGFR family and a target of PF-00299804. A CT scan revealed that the patient’s tumor shrunk substantially after only 4 weeks of treatment with PF-00299804, although it resumed growing a few months later. Most recently, the patient was treated with trastuzumab, an antibody that causes death of cells that express HER2, along with a standard chemotherapeutic agent. Like PF-00299804, this approach caused a reduction in tumor size. Interestingly, levels of HER2 circulating in the patient’s blood mirrored the tumor’s growth, decreasing when the tumor shrank and becoming elevated when the tumor started growing again, indicating that that measuring HER2 levels may allow doctors to monitor patients’ responses to PF-00299804.

Clinical trials of HER2 inhibitors, including trastuzumab, alone and in combination with standard chemotherapies have not yielded promising results in lung cancer. However, this case study provides support for the idea that that blockade of both EGFR and HER2 signaling in lung tumors that overexpress both of these markers may yield superior results compared with inhibitors that target only a single pathway. It also highlights the importance of identifying the molecular profiles of tumors in order to inform treatment for lung cancer patients. The identification of biomarkers—like circulating HER2 levels—may also provide information to guide therapeutic decisions.

Summary Posted: 09/2010

Reference

J Clin Oncol. 2010 Aug 2. [Epub ahead of print] PubMed Link