Lung cancer

Precision medicine bugged by imprecise biopsy samples


The idealistic vision of precision oncology targeting tumours based on oncogene signatures has to overcome the current reality of unsatisfactory paraffin-fixed biopsy samples that can’t provide enough DNA for genome analysis, a conference has been told.

Speaking at the Australasian Lung Cancer trials Group (ALTG) Annual Scientific Meeting in Sydney, Dr Katia Nones (PhD) a genetics researcher at QIMR Berghofer in Brisbane said that genome sequencing is revealing an ever-expanding range of oncogene mutations that may be targeted for individualised therapy.

But while there was potential to move from testing for single treatable gene mutations such as EGFR to panel testing and even whole genome sequencing, there were still many practical barriers.

Dr Nones said in an ideal world every lung cancer patient would undergo whole genome sequencing but there were major issues such as costs, turnaround times and the poor quality of DNA retrieved with current biopsy sampling techniques.

She noted that most lung cancer patients presented with advanced disease and only about 15% were able to undergo surgery that would provide tumour tissue samples.

For most patients, the only samples available for molecular testing were small, formalin-fixed and paraffin-embedded (FFPE) ‘cell block’ biopsies, which are designed to provide histology for disease staging.

“The limitation is that FFPE is designed to allow the pathologist to understand the structure of the tissue but [the process] has an adverse impact on the quality of the DNA, it gets fragmented and broken, and there isn’t a sufficient quantity for analysis,” said Dr Nones.

One possible way forward would be to have a pathologist present during the biopsy procedure to ensure that sufficient tumour tissue is collected, using cytology slides for DNA analysis and the paraffin block for backup.

In addition to EGFR mutations and ALK gene rearrangements, there were many other targetable genes known to be mutated but were not always tested for, including KIT, MET, FLT3, PIK3CA, AKT, BRAF, ERBB2 and ROS1/RET fusion, she noted.

The conference heard that whole-genome sequencing had become less expensive but was still likely to be in the order of $4500 and had a turnaround time of 4-6weeks.

In a separate presentation at the conference, Professor Alex Dobrovic, the head of Australia’s first accredited  ‘liquid biopsy’ service at Austin Health, said circulating tumour DNA (ctDNA) testing could offer an easier and quicker method for tumour diagnostic testing and also monitoring of treatment response.

It was technically feasible, but there were still many implementation barriers to overcome before liquid biopsy would come into routine clinical application, he said. These included issues such as having the right hardware and staff expertise, accreditation of labs and validation of ctDNA tests, and having sufficient patient numbers to justify tests for uncommon mutations

“And we’re going to have a lot of problems with affordability and reimbursement especially if we use [ctDNA] for monitoring as well as diagnosis,” said Professor Dobrovic.

“We get some funding from the hospital but whenever we ask patients to pay $300 for a liquid biopsy they baulk at it,” he said.

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