DNA Test May Distinguish Primary From Metastatic Lung Cancer

Marie-Christine Aubry, M.D. Professor of Laboratory Medicine and Pathology Consultant, Department of Laboratory Medicine and Pathology, Mayo Clinic in Rochester, Minn.MedicalResearch.com Interview with:
Marie-Christine Aubry, M.D.

Professor of Laboratory Medicine and Pathology
Consultant, Department of Laboratory Medicine and Pathology,
Mayo Clinic in Rochester, Minn.


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

Dr. Aubry: Up to 20% of patients will present with multifocal lung cancer or will develop a second lung cancer.  The main clinical issue is distinguishing between independent primaries from true intrapulmonary metastases since this distinction will drive the therapy of the patient.  Currently no ancillary studies allows for this distinction and the distinction is provider specific based on a combination of clinical, radiologic and pathologic assumptions. Based on our prior research using a method called mate pair sequencing , we observed that the probability of detecting identical chromosomal breakpoints in two unrelated tumors, from 2 different patients was basically zero. Similarly, when assessing different components within a single tumor, we always found identical chromosomal breakpoints between these components.  We thus hypothesized that if two tumors within a patient were related, i.e. true metastasis, we should always find a number of identical chromosomal breakpoints between the tumors. And in contrast, if 2 tumors were truly independent primaries, we should not observe any chromosomal breakpoints in common.

We first studied a control group of patients that had
1- a primary lung cancer with a known distant metastasis (usually brain metastasis),
2- two lung cancers of different histologic subtype, adenocarcinoma and squamous cell carcinoma which are accepted as true independent primaries and
3- 1 tumor with different portions of the tumor being analyzed individually and compared as true relatedness.

There were thus a total of 11 pairs of tumors with predetermined status of independent primaries versus relatedness (ie metastasis or same tumor).  The mate pair generated data showed a perfect concordance with this status.  We then studied 11 pairs of lung tumors of similar histology (2 adenocarcinomas or 2 squamous cell carcinomas).  The current gold standard for the distinction between independent primaries and intrapulmonary metastasis relies on a pathologist’s comparative morphologic assessment. In order to strengthen this gold standard, 2 pulmonary pathologists independently made this assessment. Interestingly, the pathologists agreed on the status of independent primaries and intrapulmonary metastasis in 9 (of 11) cases demonstrating the shortcomings of this gold standard.  Furthermore, there were discordance between the pathologists’ prediction and the clinicians’ assessment in 3 of the 11 patients and the clinician could not come to a final assessment in 1 patient.  The MP data was concordant with the pathology assessment in 8 of these 9 cases, and supported the pathologists’ prediction in 2 (of the 3) discordance with the clinical assumptions.

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

Dr. Aubry: The results of our research demonstrate great promise for an ancillary test that would distinguish independent primaries from metastatic disease in lung cancer.

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

Dr. Aubry: This work needs to be performed on more cases to confirm our preliminary data.  Furthermore, all our research was performed on frozen tissue of resected tumors and we need to pursue our work on paraffin embedded tissue and look at small biopsy specimens. Also we believe this method is applicable to other cancer types and not limited to lung cancer.


Identification of Independent Primary Tumors and Intrapulmonary Metastases Using DNA Rearrangements in Non-Small-Cell Lung Cancer

Stephen J. Murphy, Marie-Christine Aubry, Faye R. Harris, Geoffrey C. Halling, Sarah H. Johnson, Simone Terra, Travis M. Drucker, Michael K. Asiedu, Benjamin R. Kipp, Eunhee S. Yi, Tobias Peikert, Ping Yang, George Vasmatzis, and Dennis A. Wigle

JCO JCO.2014.56.7644; published online on November 10, 2014;