Liquid Biopsy at Cancer Progression: This Is the Future

Liam Davenport

December 12, 2016

MUNICH — So-called liquid biopsies, which are based on standard blood draws, can identify molecular alterations that drive disease progression and hence drug resistance in almost 80% of patients, say researchers, who predict their findings that will change oncology practice during the next 5 years.

Speaking here at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, the researchers also showed that in comparison with standard tumor biopsy in gastrointestinal cancer patients, analysis of circulating tumor DNA (ctDNA) in plasma samples was able to detect additional mechanisms of resistance in more than 60% of cases.

"Overall, these data show how routine clinical implementation of liquid biopsy at the time of disease progression...can effectively identify important mechanisms of resistance and may offer certain advantages relative to tumor biopsies," commented lead researcher Ryan Corcoran, MD, PhD, translational research director, Center for Gastrointestinal Cancers, Massachusetts General Hospital Cancer Center, Boston.

"Furthermore, liquid biopsies may better capture 'tumor heterogeneity,' or the evolution of distinct resistance mechanisms in different tumor cells in independent metastases in the same patient, which might be missed by a needle biopsy of a single tumor lesion," he added.

Jean-Charles Soria, MD, chair of the scientific committee for the EORTC-NCI-AACR symposium and director of the Site de Recherche Intégrée sur le Cancer (SIRIC) Socrate project at Gustave Roussy Cancer Campus, Paris, France, described liquid biopsy as "a patient-friendly approach to obtaining critical insight into the intrinsic tumor biology.

"In this case, they have allowed rapid and robust identification of the mechanism of acquired resistance that can help clinicians to select further therapies for the patient," he said.

Discussing the findings at a press conference, he said that liquid biopsies are going to "completely change the rules of engagement" for patient management and clinical practice.

Dr Soria continued: "I really think ― and I'm ready to bet ― that this is the most transformational thing that's going to happen in oncology in terms of how it's going to impact cancer clinical trials and cancer daily management for the next 5 years."

Explaining the biological basis of the research, Dr Corcoran said: "Circulating tumor DNA is shed by tumor cells throughout the body into the bloodstream and can be isolated from a routine blood draw.

"Since tumor cells residing in different metastatic tumor lesions in the same patient can often evolve distinct mechanisms of drug resistance, liquid-biopsy analysis of circulating tumor DNA can frequently identify the simultaneous presence of multiple resistance alterations that would be missed by a single-lesion tumor biopsy," he aded.

For the study he reported at the meeting, Dr Corcoran and colleagues studied 31 patients with molecularly defined gastrointestinal cancers, including 22 colorectal, seven biliary, and two gastroesophageal cancers. All of the patients had achieved a response or prolonged stable disease through targeted therapies.

Plasma was collected at disease progression, and ctDNA was sequenced. Any molecular alterations the researchers identified were compared to ctDNA and/or tissue taken before treatment to examine potential mechanisms of acquired resistance. Biopsy specimens taken after progression were also analyzed, if available.

The team was able to identify one or more molecular mechanisms of resistance at disease progression in 24 (77%) patients. Eleven (36%) patients had more than one resistance alteration; the median was three, and the range was 2 to 12.

For 13 patients, the results of tumor biopsy performed at the time of disease progression were available. Of those patients, resistance alterations were identified via tumor biopsy for nine patients (69%); all of those alterations were also detected on ctDNA analysis. Moreover, for eight patients (62%), ctDNA was able to detect resistance mechanisms that were not identified on tumor biopsy.

Multiple progression tumor biopsy results were available for seven patients. The results these tumor biopsies revealed that distinct metastases had different resistance alterations, all of which were, again, detected on ctDNA. In six patients (86%), the liquid biopsy technique also identified additional resistance alterations not found through any of the tumor biopsies.

Crucially, ctDNA analysis was able to identify several critical and/or novel resistance alterations across tumor types treated with diverse therapies. For example, 21 resistance alterations (including 10 distinct ones) affecting five genes were identified in 12 of 15 patients with RAS wild-type colorectal cancer who received epidermal growth factor receptor antibodies.

Moreover, 10 resistance alterations (including nine distinct ones) that affected MAPK genes were identified in 3 of 5 patients with BRAF mutant colorectal cancer who received BRAF inhibitor combination therapy.

The team concluded: "Compared to parallel tumor biopsies, ctDNA more effectively captured the heterogeneity of acquired resistance mechanisms. Further studies to optimize integration of ctDNA in clinical decision-making are warranted."

Will Eventually Be Affordable, May Become Standard

Dr Soria predicted that, despite the initial high costs of liquid biopsy, the technology will eventually prove to be both affordable and cost-effective.

He explained that currently, standard tumor biopsy "is one of the most expensive things to do, especially in the US but even in Europe."

He continued: "You have the cost of the interventional radiologist, then you have the cost of pathology, the technician in pathology to cut the slides, the extraction of the DNA."

Liquid biopsy, on the hand, relies on the drawing of blood, which is "happening every day in the clinic, and therefore the cost of interventional radiology, pathology, and technical pathology are gone."

George D. Demetri, MD, a member of the AACR board of directors and professor of medicine at Harvard Medical School in Boston, Massachusetts, agreed, saying: "Whenever new technology comes out, it looks like it's going to be an add-on, but I think about what it could replace." He added that although the technique is currently expensive, "it's going to become a commodity."

He said: "I was in medical school when some of the first-generation CT scans were introduced, and people were saying: 'How are we ever going to afford this? It's going to be unsustainable.'

"That was in the late 1970s, and it's proven to be quite sustainable because it replaced other things, like ineffective surgeries and guesswork, and I think that's what's going to happen with liquid biopsy."

As we get more precise in our care, this will be part of the landscape of a doctor making an accurate, precise diagnosis Dr George Demetri

Dr Demetri concluded: "What you have to count against it is non-use, the sparing of other, expensive wrong drugs so that, as we get more precise in our care, this will be part of the landscape of a doctor making an accurate, precise diagnosis."

The study was funded by philanthropic giving. The investigators have disclosed no relevant financial relationships.

EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium. Abstract 4LBA, presented December 1, 2016.

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