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Science Spotlight

A liquid asset: Lung cancer tumor profiling from bronchoalveolar lavage fluid

From Dr. Viswam Nair, Clinical Research Division

Understanding the genetic drivers of cancer can inform treatment decisions and provide additional options for patients if targeted therapies are available. For lung cancer, the most common cause of cancer-related mortality, several therapies have recently received clinical approval to treat advanced or late-stage disease. To assess candidacy for a specific treatment option, a biospecimen from the patient must be analyzed via genomic profiling. “Liquid biopsies from blood or other biofluids are becoming an important part of precision medicine for solid tumor therapy,” commented Dr. Viswam Nair, an Associate Professor in Fred Hutch’s Clinical Research Division. Unfortunately, lung biopsy specimens often do not contain sufficient material for adequate tumor profiling, a problem mirrored in the less invasive liquid biopsy (blood sample) which is often used for other cancers. To combat this obstacle, Dr. Nair led a study with colleagues to investigate an alternate method of sampling tumor DNA for patients with lung cancer. The authors hypothesized that molecular profiling of biofluids, or more specifically, the fluid obtained from routine bronchoalveolar lavage, would contain tumor derived mutant DNA at sufficient levels that would allow for tumor profiling. To test this assertion, the researchers undertook Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) analysis of bronchoalveolar lavage patient samples. Summarizing their study efforts, recently published in Cancer Research, Dr. Nair stated, “this study indicates that bronchoalveolar lavage, or a “lung liquid biopsy” provides additional insight into a tumor’s genomic profile above traditional cytopathology of lavage fluid that is low yield and a blood liquid biopsy.”

Bronchoalveolar lavage fluid can provide information on cancer driver mutations in patients with lung cancer.
Bronchoalveolar lavage fluid can provide information on cancer driver mutations in patients with lung cancer. Image provided by Dr. Nair.

CAPP-Seq is an ultrasensitive detection method, that works based on next-generation sequencing technology to capture and identify mutations present in cell free tumor derived DNA that may be circulating in the body. The authors harnessed this approach to profile tumor DNA from the bronchoalveolar lavage fluid for two patient cohorts – one cohort with confirmed lung cancer undergoing clinical investigation and a second cohort of high-risk patients undergoing screening. In the first cohort of patients, those with clinically diagnosed lung cancer, the authors performed CAPP-seq on patients’ bronchoalveolar lavage fluid, in addition to routine blood draws as a comparator. Promisingly, bronchoalveolar lavage fluid yielded robust levels of cell free DNA. The authors compared levels of tumor DNA in the lung lavage fluid to the blood sample controls and, excitingly, detected almost 2X more cancer driver mutations in the bronchoalveolar lavage fluid than the blood sample. As this finding was aided by sequencing data available from pre-existing tumor specimens that helped to inform their analysis, they repeated this experiment to replicate a standard clinical scenario that would not have the benefit of sequenced tumor data available. Although fewer tumor derived mutations were observed overall by this approach, the authors still detected mutations at a higher rate in the bronchoalveolar lavage fluid samples when compared to the blood samples (74% vs.15%). The authors hope to validate these findings using larger cohorts, to examine the reproducibility of a test of this nature for clinical utility. “If these findings validate in larger cohorts of patients, I believe that routine genomic profiling of lavage fluid could be an important addition during diagnostic evaluation by bronchoscopy to obtain the most comprehensive information on a tumor prior to therapy that will identify the most effective treatments. This is exactly the goal of precision medicine,” emphasized Dr. Nair.

For the second patient cohort, those at high-risk for developing lung cancer, the researchers wanted to determine whether profiling bronchoalveolar lavage fluid could distinguish between patients with or without lung cancer. While cancer driver mutations were detected at a higher level in patients with lung cancer with this approach, the researchers observed another pattern. “Interestingly, we also confirmed that individuals at risk for lung cancer who underwent bronchoscopy to rule it out harbor mutations that look like cancer in their airway. These data corroborate other findings in the lung and other solid organs that a field of cancerization exists,” explained Dr. Nair. Expanding further on this concept and how the authors intend to continue their research efforts going forward, Dr. Nair stated that “field cancerization implies that there is a level of baseline genomic premalignancy that will affect our ability to develop genome diagnostics using lung samples. A lung atlas of alterations in at risk patients will be required to fully understand this baseline. The [National Cancer Institute] NCI has currently funded work to help us build a large biorepository of samples from patients at Fred Hutchinson Cancer Center to study this more comprehensively.” The authors will continue their research to further assess the clinical utility of CAPP-seq and bronchoalveolar lavage fluid in lung cancer, and to better elucidate the pre-malignant genomic landscape. 

This work was supported with grants from the Canary Foundation (V.S. Nair), the Stanford Department of Radiology (V.S. Nair), The Fred Hutchinson Cancer Research Center Support Grant (V.S. Nair), The Tobacco Related Disease Research Program ( V.S. Nair and M. Diehn), the National Cancer Institute (V.S. Nair,M. Diehn and A.A. Alizadeh), the National Institutes of Health Director's New Innovator Award Program (M. Diehn), the Virginia and D.K. Ludwig Fund for Cancer Research (M. Diehn and A.A. Alizadeh), and the CRK Faculty Scholar Fund (M. Diehn).

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Viswam Nair contributed to this work.

Nair VS, Hui AB, Chabon JJ, Esfahani MS, Stehr H, Nabet BY, Zhou L, Chaudhuri AA, Benson J, Ayers K, Bedi H, Ramsey M, Van Wert R, Antic S, Lui N, Backhus L, Berry M, Sung AW, Massion PP, Shrager JB, Alizadeh AA, Diehn M. 2022. Genomic Profiling of Bronchoalveolar Lavage Fluid in Lung Cancer. Cancer Res. 82(16):2838-2847.