BRAF inhibitors promising in lung adenocarcinoma

The BRAF inhibitors vemurafenib and dabrafenib, currently approved for use in advanced melanoma, are also effective in a subset of lung adenocarcinoma patients with BRAF mutations, according to a retrospective European trial presented at the European Lung Cancer Conference (ELCC) held in Geneva, Switzerland.

In the EURAF cohort study, researchers reviewed data of 35 patients with BRAF mutations who were treated with BRAF inhibitors (29 had BRAF V600E mutation; 6 had other BRAF mutations). Thirty-one patients received one BRAF inhibitor and four patients received two BRAF inhibitors. Altogether, 28 patients received vemurafenib, 10 received dabrafenib, and one received sorafenib. [ELCC 2015, abstract 980_PR]

“Best response by RECIST [Response Evaluation Criteria In Solid Tumours] was available for 36 of the 39 BRAF inhibitor therapies. Overall response rate was 53 percent, including 6 percent complete response, 47 percent partial response, 36 percent stable disease, and 11 percent disease progression. No unexpected toxicities were reported,” said Dr. Oliver Gautschi from Lucern Cantonal Hospital, Switzerland, who presented the results. “These data support BRAF testing in advanced lung adenocarcinoma, and BRAF inhibitor therapy in patients with V600E mutation.”

Commenting on the findings, Dr. David Planchard of the Institut Gustave Roussy in Villejuif, France, noted that only about 2 percent of lung adenocarcinomas harbour BRAF mutations. “Because of the low frequency of BRAF mutations in lung cancer, it is unlikely we will have randomized phase III trials in this population. The results of this study add to growing support for the approval of BRAF inhibitors for use in lung cancer.”

Ongoing studies are evaluating BRAF inhibitors in combination with other therapies and potential drug resistance mechanisms in this population.

Adenocarcinoma of Lung May Spread Through Airways Interview with:
Joao R. Inacio, MD

Cardiothoracic Radiologist Director Visiting Professor Program
Assistant Professor of Radiology, University of Ottawa
Medical Imaging, The Ottawa Hospital Ottawa, ON

Medical Research: What is the background for this study? What are the main findings?

Dr. Inacio: Lung cancer is the most common and most lethal cancer worldwide. Its prognosis remains poor with a 5-year survival rate of 6–18%. Adenocarcinoma has surpassed squamous cell carcinoma as the leading histologic type. The presence of metastases carries the worst prognosis in lung cancer and is the most important in determining staging and management. Hematogenous spread (i.e., carried by blood) is the most common mechanism of intrapulmonary metastasis. Cumulative evidence suggests that intrapulmonary aerogenous spread may exist and is under recognized.

Deriving from our clinical experience, we performed a literature review that supports the hypothesis that lung cancer, particularly adenocarcinoma, may spread through the airways. With aerogenous metastases, it has been postulated that cancer cells growing along the alveolar septa at the primary site detach from the basal membrane, spread through the airways and re-attach and grow along alveolar septa away from the primary focus.

Radiology-pathology correlation studies, using Chest Computed Tomography (CT), have documented the radiological evolution from focal adenocarcinoma to multifocal airspace disease and demonstrated cytologic and histologic findings supportive of aerogenous spread.

Medical Research: What should clinicians and patients take away from your report?

Dr. Inacio: The putative occurrence of intrapulmonary aerogenous metastasis of lung cancer has staging, management, and prognostic implications.

This phenomenon has been described in primary lung adenocarcinoma, particularly those with invasive mucinous, papillary and micro-papillary subtypes.

There are CT features that are suggestive of aerogenous spread, specifically persistent centrilobular nodules and branching opacities (tree-in-bud nodules). Nodules tend to be clustered and invariably grow on serial imaging, in some cases progressing to confluent airspace disease. When these features are found remote from a dominant lung lesion proven to be an adenocarcinoma, and/or in patients with a prior history of treated lung adenocarcinoma, intrapulmonary aerogenous spread should be suspected.

Importantly, aerogenous metastases must be distinguished from multiple synchronous lesions in the spectrum of lung adenocarcinoma. A multidisciplinary approach, including clinicians, radiologists, thoracic surgeons, pathologists and geneticists is required to guide diagnosis and treatment in these cases. Genomic profiling may be beneficial in the future to prove monoclonality when aerogenous metastases are suspected.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Inacio: There is a need for prospective studies combining imaging, pathology and molecular studies to confirm the presence of this phenomenon and elucidate its impact on the prognosis of lung cancer patients.

Future therapies might attempt to address some of the unique aspects of aerogenous dissemination. For instance, drugs targeting mechanisms involved in cancer cell shedding, anchorage-independent survival, and re-attachment in distant alveoli may hold promise. One could hypothesize inhalational therapy as a potential treatment to target the intra-alveolar nature of aerogenous metastases. K-Ras mutations and infiltration of tumor tissue by macrophages and neutrophils have been implicated in the pathogenesis of mucinous adenocarcinoma and aerogenous metastases. Pharmacologic agents modulating K-Ras activation and tumor-associated leukocyte interaction could prove beneficial in the prevention of aerogenous spread.