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Metastasis is the end product of an evolutionary process in which diverse interactions between cancer cells and their microenvironment yield alterations that allow these cells to transcend their programmed behavior. Tumor cells thus populate and flourish in new tissue habitats and, ultimately, cause organ dysfunction and death. Understanding the many molecular players and processes involved in metastasis could lead to effective, targeted approaches to prevent and treat cancer metastasis.

Background Immunotherapy targeting the PD-1 axis has activity in several tumor types. We aimed to determine the efficacy and safety of pembrolizumab in patients with untreated brain metastases. Here we present results from a Phase II trial of the PD-1 inhibitor pembrolizumab in patients with new or progressive brain metastases from melanoma or non-small cell lung cancer (NSCLC). Methods Thirty-six patients were enrolled, 18 with melanoma and 18 with NSCLC. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in longest diameter without associated neurologic symptoms or the need for corticosteroids. NSCLC patients had tumor tissue demonstrating PD-L1 expression. Patients were treated with pembrolizumab 10 mg/kg every two weeks until progression, and brain metastasis response was assessed every eight weeks by modified RECIST. The primary endpoint was brain metastasis response rate and the analysis was performed on an intent-to-treat basis. The trial is ongoing and here we present an early analysis. The study is registered with clinicaltrials.gov, number NCT02085070. Findings Brain metastasis response rate was 22% and 33% among patients with melanoma and NSCLC, respectively. Responses were durable, with all but one patient who responded demonstrating an ongoing response at the time of data analysis. Treatment-related serious and grade 3–4 adverse events were rare and included transaminitis, colitis, pneumonitis, fatigue, endocrine abnormalities, and acute kidney injury (1 patient each). Serious neurological adverse events included cognitive dysfunction and seizures (1 and 3 patients, respectively), due to pembrolizumab, metastases or both. Interpretation Pembrolizumab demonstrates activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, indicating that there may be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. Funding Merck and the Yale Cancer Center.

Purpose: In patients whose lung adenocarcinomas harbor epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations, acquired resistance to the tyrosine kinase inhibitors (TKI) gefitinib (Iressa) and erlotinib (Tarceva) has been associated with a second-site EGFR mutation, which leads to substitution of methionine for threonine at position 790 (T790M). We aimed to elucidate the frequency and nature of secondary EGFR mutations in patients with acquired resistance toTKI monotherapy. Experimental Design: Tumor cells from patients with acquired resistance were examined for secondary EGFR kinase domain mutations by molecular analyses. Results: Eight of 16 patients (50% observed rate; 95% confidence interval, 25-75%) had tumor cells with second-site EGFR mutations. Seven mutations were T790M and one was a novel D761Y mutation found in a brain metastasis. When combined with a drug-sensitive L858R mutation, the D761Y mutation modestly reduced the sensitivity of mutant EGFR to TKIs in both surrogate kinase and cell viability assays. In an autopsy case, theT790M mutation was found in multiple visceral metastases but not in a brain lesion. Conclusions: TheT790M mutation is common in patients with acquired resistance. The limited spectrum of TKI-resistant mutations in EGFR, which binds to erlotinib in the active conformation, contrasts with a wider range of second-site mutations seen with acquired resistance to imatinib, which binds to ABL and KIT, respectively, in closed conformations. Collectively, our data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target.

Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological approaches, we show that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2, and the matrix metalloproteinases 1 and 2, when expressed in human breast cancer cells, collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis. These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations.

Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell surface HLA class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knock-out of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.

Summary Metastasis from lung adenocarcinoma can occur swiftly to multiple organs within months of diagnosis. The mechanisms that confer this rapid metastatic capacity to lung tumors are unknown. Activation of the canonical WNT/TCF pathway is identified here as a determinant of metastasis to brain and bone during lung adenocarcinoma progression. Gene expression signatures denoting WNT/TCF activation are associated with relapse to multiple organs in primary lung adenocarcinoma. Metastatic subpopulations isolated from independent lymph node-derived lung adenocarcinoma cell lines harbor a hyperactive WNT/TCF pathway. Reduction of TCF activity in these cells attenuates their ability to form brain and bone metastases in mice, independently of effects on tumor growth in the lungs. The WNT/TCF target genes HOXB9 and LEF1 are identified as mediators of chemotactic invasion and colony outgrowth. Thus a distinct WNT/TCF signaling program through LEF1 and HOXB9 enhances the competence of lung adenocarcinoma cells to colonize the bones and the brain.

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