Beyond Tissue Biopsies: Blood Assays May Provide "Liquid" Molecular Analyses for "Solid" Tumors

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

While a number of biological and clinical factors differentiate so-called “solid” from “liquid” cancers, there is perhaps no single difference that is more relevant than the ability in liquid cancers to easily obtain malignant cells from the blood for subsequent analysis in the laboratory. As a result, it is possible in most cancers categorized as “liquid” to regularly and with ever greater sensitivity evaluate the status of the malignant process. The information generated from such analyses can reveal and quantify initial biological and clinical activity of an antineoplastic treatment, document the extent of response, discover early evidence of progression, and predict the future course of the cancer in the absence of any clinical signs or symptoms of the disease.

In the new world of genomic analysis, it is becoming increasingly possible to define the presence of specific molecular abnormalities in cancers, which may result in the selection of a unique therapeutic strategy or the decision to avoid another approach based on a particular observed mutation or translocation. By defining the molecular events present when a patient’s cancer exhibits evidence of progression, oncologists can be far more precise in the selection of subsequent treatment for an individual rather than simply selecting an FDA approved second-line drug.

While these strategies can be employed for “liquid” cancers, they unfortunately do not currently characterize management of the large majority of cancers that are considered to be within the “solid” tumor category. While the initial diagnostic tissue (eg, tissue obtained during primary surgical intervention) will be critical in a baseline molecular evaluation, access to such material at the time of disease progression or at a defined point in time to assess the status of a cancer when in a “stable” clinical state will likely be quite problematic in most settings. This conclusion results from several considerations, including the safety of tissue acquisition (eg, lung/liver biopsy), uncertainty of the similarity of molecular abnormalities discovered in different metastatic sites (eg, lung vs liver), and even the routine ability to find lesions of sufficient size to permit surgical or imaging-guided biopsies.

Finally, there is always the question of the cost and the so-called medical necessity of such procedures, particularly if undertaken solely for secondary diagnostic rather than therapeutic purposes. And, concern about these issues will be magnified if consideration is given to a third, fourth, or fifth biopsy, etc, obtained for diagnostic purposes only.

However, just as there are data to show that specific genetic abnormalities present within primary solid tumors of individuals are also found in metastatic sites,¹ there is increasing highly provocative evidence provided in several reports in different clinical settings to suggest that unique molecular findings (including relevant “driver mutations”) documented in solid tumor tissue can be found in the blood.^2,3

For example, in a small group of patients with metastatic breast cancer, investigators were able to successfully follow the course of their illness based on the presence and concentration of tumor-specific DNA present within the circulation that had been shown to also characterize the individual’s solid tumor.²

In a second report from this investigative team, plasma DNA from six cancer patients was extensively characterized and found to not only correspond to abnormalities present within the solid tumor over time, but also to reveal unique molecular changes that provided insight into the presence of specific “driver mutations” that may have been responsible for the observed drug resistance and progression of the malignant process.³

It is certainly not difficult to imagine the future impact of such liquid molecular testing, whether undertaken at the time of documented disease progression or during routine monitoring of the course of the illness. The finding of unique abnormalities in the blood could result in changes in the therapeutic program specifically based on the genetic observations in the individual cancer. The potential favorable impact of such an approach to cancer management—including improved outcomes through the selection of the most effective treatment, reduced toxicity through the avoidance of the adverse events of a predicted ineffective therapeutic and the risk associated with a tissue biopsy, and cost reduction—cannot be overstated.

Maurie Markman, MD, editor-in-chief, is senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America. maurie.markman@ctca-hope.com

References

1. Vignot S, Frampton GM, Soria J-C, et al. Next generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer [published online ahead of print April 29, 2013]. J Clin Oncol. 2013; 31(17):2167-2172.
2. Dawson S-J, Tsui DWY, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer [published online ahead of print March 13, 2013]. N Engl J Med. 2013; 368(13):1199-1209.
3. Murtaza M, Dawson S-J, Tsui DWY, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA [published online ahead of print April 7, 2013]. Nature. 2013;497(7447):108-112.