Lung cancer is increasingly being understood as a disease that is defined by specific genetic subgroups. For example, lung cancers carrying mutations in the EGFR gene can respond dramatically to treatment with targeted EGFR inhibitors and have a better overall prognosis. In contrast, lung cancers carrying mutations in the KRAS gene do not respond to available targeted therapies and have a worse overall prognosis, though new therapies targeting KRAS are under investigation. Testing for mutations in the EGFR and KRAS genes is now a standard part of lung cancer treatment, but can involve an often cumbersome process of DNA extraction from a tumor biopsy followed by testing in a pathology laboratory. In situations where a biopsy is unavailable or too risky, genetic testing of the tumor may not be possible, making it difficult to personalize a patient's treatment. The research in this proposal aims to develop a noninvasive tool for characterizing the genetics of a lung cancer through studying a patient's blood specimen. Using a highly sensitive quantitative assay we have developed, we can now measure the amount of tumor DNA that is floating in a patient's blood that carries a mutation in EGFR or KRAS. In proposed research, we will study strategies of using this blood assay for improved delivery of personalized lung cancer therapy. Our hope is to demonstrate that this new technology can allow for efficient and accurate analysis of lung cancer genetics in order to accelerate improvements in lung cancer research and patient care. In this way, the proposed research aligns with this grant mechanism's emphasis on understanding predictive and prognostic markers to identify responders and non-responders to therapy.

The primary investigator for this project is Dr. Geoffrey Oxnard, a thoracic oncologist and junior investigator at Dana-Farber Cancer Institute. Dr. Oxnard's research focuses on the development of improved biomarkers and therapies for genetically defined subtypes of lung cancer. The proposed research represents a new direction of investigation, now focusing on noninvasive assays for genetic characterization of lung cancers. This grant will allow Dr. Oxnard to have protected research time to focus on this new area of investigation, while also supporting a training plan focusing on strategies for rigorous and efficient biomarker development.

The proposed research has the potential to make an immediate and lasting impact on the personalized delivery of targeted therapies, both for patients with lung cancer and with other cancers. Noninvasive tools for understanding cancer biology have been studied widely over recent years, but existing technologies (such as analysis of circulating tumor cells) have been difficult to implement clinically and have had a limited clinical impact. Analysis of DNA floating in patient blood has a key technical advantage over analysis of circulating tumor cells -- it has the potential to be performed on routine blood specimens and therefore could be easily implemented in the clinical setting. By providing an oncologist with genetic results within a few days, analysis of floating tumor DNA in patient blood could avoid risky and costly biopsy procedures and could accelerate the delivery of personalized cancer therapy. By the completion of the 2-year grant period, we aim to have demonstrated definitively the clinical usefulness of this technology for lung cancer care. We will then study broader application to other cancer types where tumor genetics is having an increasingly important role (melanoma, colon cancer, pancreatic cancer, brain cancer, etc.).