Systemic Therapy of Advanced Bronchioloalveolar Cell Carcinoma: Challenges and Opportunities

Bronchioloalveolar cell carcinoma (BAC) has fascinated physicians with its unique epidemiology, pathology, clinical manifestations, and natural history when compared with other non–small-cell lung cancer (NSCLC) subtypes. However, the relative rarity of pure BAC as defined by the WHO, and the inconsistent definitions used in various series, has limited systematic study of this entity. Retrospective and prospective studies suggest that patients with BAC treated with cytotoxic chemotherapy have a longer median survival than those with other subtypes of NSCLC. However, the widely accepted view that BAC is less chemosensitive than other NSCLCs is not clearly supported by the small body of available literature. Antitumor activity of cytotoxic agents and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors has been documented in phase II trials but no phase III trials have been conducted in this disease. The observation that profound responses to gefitinib and erlotinib often occurred in NSCLC patients with BAC, and that EGFR tyrosine kinase domain mutations were identified in large part by careful study of such patients, serves as a paradigm for translational research in this disease. The recognition that pure BAC and adenocarcinoma with BAC features behave similarly and as such represent a relatively common entity will facilitate accrual to BAC specific studies. Alternatively, stratification of these histologic subtypes in broader clinical trials in NSCLC is warranted. However, for either strategy to succeed in advancing our understanding of the molecular biology of BAC, it must be accompanied by central pathologic review with detailed classification of such, and of adequate tissue for measurement of known or putative targets of action of the agent under study.