CT

Melanoma has the highest propensity to metastasize to the brain once the disease has spread, while non-small cell lung cancer (NSCLC) has the highest incidence of brain metastases among all cancers. Approximately 50,000 patients develop brain metastases from these diseases every year. Patients with brain metastases have exceedingly limited therapeutic options since they are typically excluded from clinical trials. Recently a number of new systemic immune therapies, such as nivolumab (BMS-936558) and lambrolizumab (MK-3475), two inhibitors of PD-1 (an immune inhibitory molecule), have led to dramatic responses in metastatic melanoma (MM) and NSCLC. However, these therapies have not been studied in patients with untreated brain metastases.  Little is known about immune cells in the brain, and whether the immune system can be stimulated to reject cancer cells. Moreover, little is known about what tumor characteristics are associated with response to MK-3475 in brain metastases. This research project includes innovative correlative biomarker studies incorporated into a clinical trial uniquely designed to study the activity of MK-3475 in patients with limited, small brain metastases in MM and NSCLC. This drug carries the hope to provide prolonged responses similar to responses seen in other metastatic sites, and might enable patients to avoid radiation therapy, and improve their outcome. As part of this clinical trial, the researchers will collect brain and other metastatic specimens from patients enrolled and study the expression of immune inhibitory molecules utilizing a novel quantitative assay and algorithms that they have developed in preliminary work. These studies will facilitate selection of patients who are more likely to respond to this class of drugs.

It is widely acknowledged that improvements in non-invasive strategies for early detection of lung cancer are likely to translate to substantial reductions in cancer-related deaths. Efforts to develop blood tests for this purpose have largely focused on protein biomarkers, but it has been challenging to identify proteins that are sufficiently cancer-specific. The recent emergence of next-generation, high-throughput DNA sequencing technologies has made it possible to detect and quantify very small quantities of tumor-derived DNA in a patient’s bloodstream. Because such circulating tumor DNA can be identified based on the presence of mutations that are exquisitely tumor-specific and should rarely be found in healthy individuals, it holds promise as a biomarker for cancer screening. This laboratory has developed an ultrasensitive method to measure mutated tumor-derived DNA fragments in blood. By applying novel error-suppression techniques to high-throughput sequence data, they are able to identify and quantify low-abundance mutations within a broad panel of genes that are commonly mutated in lung cancer. To evaluate the potential clinical utility of this approach for lung cancer screening, blood samples obtained from patients with small, early-stage lung tumors will be tested. Samples obtained from individuals with a heavy smoking history and individuals with benign pulmonary nodules will then be compared. If the test performs well at identifying patients with lung cancer with few false-positive results, larger-scale clinical studies for screening of high-risk patients will then be justified.