February 2016 Edition Vol.11, Issue 2

Hope and Hype: Questions Surround Liquid Biopsies

Honing in on ctDNA

These small studies suggest the power of liquid biopsies, but the data to fully support their use across a range of cancers still needs to be generated.

“The proportion of time that you actually find evidence of colon, breast, or brain cancer in ctDNA is largely unknown,” said Dr. Miller. “It’s almost certainly stage-dependent, with earlier stage cancer shedding less DNA than later stage cancer, and it remains to be elucidated in a tumor-specific manner.”

Dr. Miller stated that a fundamental difference between tissue and liquid biopsies is that much more substantial sequencing is required for liquid biopsies to know if an alteration is real or not, so that problems such as false positives are avoided.

Dr. Miller further explained that Foundation Medicine has undertaken a large study of their ctDNA assay paired with FoundationOne® testing (NCT02620527 on ClinicalTrials.gov). The study, with estimated enrollment of 2000 patients, will include patients with very tight temporal linkage between tissue and blood and also patients with a variable but bigger difference between tissue and blood. For the latter group, the question will be how much the genome is diverging, while samples collected from blood and biopsy at the same timepoint are expected to be quite similar.

The Foundation Medicine study also seeks to answer key questions, such as what proportion of the time does stage IV head and neck cancer shed ctDNA vs thyroid cancer vs colon cancer vs lung cancer? If ctDNA is found, what is the concordance between what shows up on the ctDNA assay and on the tissue assay? What is missed by using the ctDNA assay? For example, Dr. Miller explained that it is harder to detect amplifications, such as MET and HER2, with a ctDNA assay than with a tissue-based assay. If the ctDNA test does not find anything, is that result final, should it be believed, or should the tissue test remain the gold standard and the first-choice option?

“We take a lot of time to do it right, with real rigorous analytical and clinical validation studies, both for FoundationOne and now for Foundation Act,” said Dr. Miller. “The onus is on us to provide the data so discerning clinicians can decide when it’s really prime time."

“If we get the data across ten tissue types that confirm liquid biopsy and can’t really supplant tissue-based testing, then it’s less of a universal, binary switch from tissue to blood across the board—I think it’s naive to assume that’s the way things are going to move.”

Another path to a wealth of liquid biopsy data 

Currently, robust concordance and validation studies comparing ctDNA with tumor tissue have not yet been done. At Caris Life Sciences, David Spetzler, Chief Scientific Officer said, “Theoretically, liquid biopsies could help address tumor heterogeneity, but that has yet to be proven. The false positive rate is a challenge.” Dr. Spetzler explained that Caris found a false positive rate of 40% a few years ago with ctDNA, and so they are focusing on protein content from exosomes.

“Exosomes are secreted by all cells as part of normal function, so they represent a significant source of biological information that includes early perturbations in pathways leading to cancer,” said Dr. Spetzler. “They serve as a biological substrate that allows a systems biology approach to understanding the changes in the system associated with the emergence of cancer. These signals are found earlier than ctDNA and impart more information.”

A validation study of the exosome approach for breast cancer screening for dense breasts was recently presented at the San Antonio Breast Cancer Symposium.4 The ADAPT Biotargeting System™ measures millions of protein complexes simultaneously in a nondestructive manner, and Dr. Spetzler said it can address the complexity of interacting proteins, and thus it enables a systems biology approach to characterizing disease.

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