1. Goodwin, Peter M.

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GENEVA, Switzerland-Three studies have reported the benefit of plasma genotyping to predict treatment outcomes in patients with non-small cell lung cancer (NSCLC) at the European Lung Cancer Conference (ELCC) 2016.

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Such "liquid biopsies"-assaying circulating tumor DNA (ctDNA)-could soon play a key role along with tumor biopsies, said James Yang PhD MD, from National Taiwan University Hospital, Taipei, lead author of two single-arm phase II registration studies: "This blood test is very sensitive, very specific. It potentially can replace re-biopsy of the tissue."


ELCC Scientific Chair Wilfried Eberhardt, MD, a medical oncologist at the West German Cancer Center, University Hospital Essen, University of Duisburg-Essen said: "My impression is liquid biopsy is the method of the future."


He noted that a simple liquid biopsy to detect the EGFR T790M mutation could potentially identify patients who can benefit from the drug osimertinib (a third-generation anti-EGFR inhibitor specifically targeting this mutation) so that they could avoid tissue re-biopsy.


"It is not the standard of care yet," he said, noting that both techniques have advantages and disadvantages. But he said that, although repeat tissue biopsy is the gold standard, it has a limitation. "We cannot do a re-biopsy on some patients. In those cases liquid biopsy is possible, it's much easier, and it's available."


Eberhardt told Oncology Times he expected that plasma genotyping would become more sensitive in the future than the current 70-80 percent. "I would assume that this number would increase dramatically in the next 1 of 2 years. So if we come up to 90 or 95 percent, this would probably also be a very effective [way] of diagnosing the T790M mutation," he said, adding the advantage of liquid biopsy is that you can repeat it several times, it's easy, and it's cheap.


Detection of EGFR Mutations

The large non-interventional ASSESS (NCT01785888) study looking at the accuracy of EGFR mutation-positive detection in plasma compared with tumor demonstrated that ctDNA is suitable and feasible for EGFR mutation analysis in real-world practice and that patient age and disease burden were important factors influencing its sensitivity.


Sensitivity of ctDNA testing was inversely associated with age. It was 63 percent in patients younger than 65, but only 37 percent in over 65. Increasing number of organs with metastases raised sensitivity from 9 percent in primary disease to 69 percent in patients who had more than three organs involved. Higher tumor stage was also associated with higher sensitivity for mutation positivity detection-20 percent for stage 3a tumors compared with 48 percent for stage 4.


"The increased ability to detect EGFR mutations in plasma from patients with a higher number of organs with metastases makes sense biologically as these patients have higher tumor burden and we could expect more ctDNA to be released in the blood," said lead author of ASSESS Nicola Normanno, MD, chief of the Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples, Italy. But he said the link with age was more difficult to understand.


He said the use of plasma might increase knowledge about molecular evolution of lung cancer. And he looked forward cautiously to the possibility of using liquid biopsies more widely. "If plasma testing is more reliable for some patients with certain characteristics, this may have implications in the way that we conduct mutation testing for patients with NSCLC, and ultimately impact upon treatment decisions," he said.


Normanno noted that for the majority of patients with metastatic disease a plasma test may be sufficient to determine EGFR mutation status, although biopsies would still be recommended in plasma-negative cases.


Tumor Tissue vs. Blood

The phase I AURA trial of osimertinib reported that the blood test distinguished patients with T790M positive tumors very effectively. Lead author Geoffrey Oxnard, MD, a thoracic cancer physician at the Dana-Farber Cancer Institute, Boston, said the issue of false negatives needed to be addressed while sensitivities were no higher than 80 percent. "If you have a negative result in the blood test it may be that the mutation was present but not detected," he said.


He added that testing tumor tissue from patients who were T790M negative in the blood could differentiate between those who do better or worse on osimertinib and that a tissue biopsy was an effective "fall-back" to clarify who should or who should not get the drug. "We conclude that a two stage approach is needed, starting with the blood test. Patients who test positive for T790M on the blood test can receive osimertinib. Those who test negative should have a biopsy test to clarify their T790M status," he said.


A surprising result from AURA was that some patients were T790M negative in the tumor tissue but positive in the blood test. "This suggests that the resistant mutation might be present in just a subset of the cells, or only in some sites of the tumor," said Oxnard. And he suggested this could be because biopsy may not capture the cancer's resistance across all sites of disease but that a blood test does. "There may be other resistance mechanisms hidden in the tumor which reduce the effect of the drug," he said.


Commenting on the three studies, Sanjay Popat, MRCP, PhD, consultant thoracic medical oncologist at the Royal Marsden Hospital in London, UK, said, "These studies confirm the potential clinical utility of using ctDNA EGFR genotyping in routine practice and give information on the magnitude of false negatives." But he called for validation in real world settings and he said plasma testing was not ready routinely to replace the gold standard tissue biopsy for mutation testing. "It would be a complementary test, and may be a replacement in some patients-for example those in whom a tissue biopsy is not possible," he said.


Peter M. Goodwin is a contributing writer.