Interview – Aiming for a new Angle on liquid biopsy

Almost all the companies developing liquid biopsy technologies are doing so by sequencing DNA released by tumours into the bloodstream. Not so Angle: the UK company has developed a device, Parsortix, capable of sieving entire cancer cells from the bloodstream. But DNA is much easier to detect, and other groups have attracted vast investment for this approach. Why is Angle going against the grain?

“The question is probably better posed the other way round: why would everybody else be going for circulating tumour DNA?” asks Andrew Newland, Angle’s chief executive. “And the reason is, because they don’t have a Parsortix instrument.”

Mr Newland clearly has great faith in the system – and, of course, just because most players are pursuing a particular approach it does not necessarily follow that this is the right one.

Angle’s system picks up the cells that split off from tumours and travel throughout the body – essentially the process by which cancer metastasises. These are extremely rare – Mr Newland says there might be a single circulating tumour cell for every billion blood cells.

A patient’s blood sample is pushed through a disposable cassette that slots into the Parsortix system and filters out the cancer cells, which are larger and less deformable than blood cells, behind.

A complete picture

Intact tumour cells can yield a lot more data than can be obtained from circulating tumour DNA (ctDNA), Mr Newland says.

“If you get a living cancer cell which is involved in the process of the cancer spreading, you can look at every aspect of the cell – DNA, RNA and protein expression. You can get a complete picture of what’s happening in the cancer if you’ve got a full, viable, intact cell.”

The alternative approach, looking for fragments of DNA from dead cancer cells, gives a more limited view, according to Mr Newland, as the researchers cannot use RNA or protein levels to assess gene expression.

“It’s a much less effective source of information for medical evaluation. However, it is much easier to get hold of DNA – that’s why people do it – but they’d much rather get the CTCs if they could.”

The Parsortix instrument is CE marked and is sold for research use at a list price of £40,000 ($52,000) – the single-use cassette has a price of £100.

Ultimately the liquid biopsy wars will be won with proof that these systems can be used as diagnostic tools. Angle is trialling its system in breast and ovarian cancers, with its latest clinical data in the latter.

In two trials, one European and one US, Parsortix was used to identify patients with malignancies among 400 women suspected to have ovarian cancer. The blood test used in this setting at the moment detects the tumour marker CA125, but this is not hugely accurate as not all ovarian cancers produce the marker, and other conditions including endometriosis, fibroids and pregnancy can also raise CA125 levels. A positive result on the CA125 blood test must be confirmed with ultrasound.

In its trial, Angle says Parsortix demonstrated sensitivity approaching 95% and specificity of “probably double that of CA125,” Mr Newland says. Pressed, he puts the specificity figure for Parsortix at more than 90% for ovarian cancer. This ought to be enough to rule out ovarian cancer without a confirmatory ultrasound, he says.

It should perhaps be stressed that the starting point of the two studies were women with confirmed ovarian masses, which could have been either malignant or non-cancerous. The specificity and sensitivity of any test used in this setting would need to be high – at least 95% – to be truly clinically useful. This should not be confused with a screening test in healthy women, where lower levels of specificity and sensitivity might be acceptable.

Angle’s idea is that doing this test would allow the health system to triage women, fast-tracking those with positive test results for surgery conducted by specialist gyn-oncology surgeons; the others would undergo watchful waiting. As yet there is no definitive evidence that use of the test would lead to an improvement in care or cancer survival if introduced. There is also no proof that it would save money.

The first ever?

The company intends to begin another round of clinical trials in ovarian cancer in six months or so; these should take around 12-18 months to conclude, and the data could enable regulatory filings.

But the initial indication is breast cancer: a 400-patient study will soon start recruiting patients in the US, with data expected by the end of 2017.

“Ovarian cancer will then be an additional clearance,” Mr Newland says. “No CTC liquid biopsy system is FDA-cleared – we’re hoping to be the first ever.”

The challenges of walking a lone road ought not to be underplayed. Developers of ctDNA-based liquid biopsies, most obviously Guardant Health and the Illumina spinout Grail, have scooped in hundreds of millions of dollars in venture capital (Medtech venture funding total hits all-time high, July 12, 2017). In its last financial report Angle said it had a cash balance at 31 October 2016 of £9.7m ($12.6m).

“They’re definitely going to be able to outspend us, there’s no question about that,” Mr Newland says. “But it’s not a worry, because they’re working on ctDNA, and there are a number of things you just can’t do with ctDNA.”

Ultimately the prize will be won by whichever technique provides the most accurate and useful information for diagnosis and the tracking of treatment at a cost health systems can bear. The years to come will show which company, which device and which approach to liquid biopsy comes out on top.

To contact the writer of this story email Elizabeth Cairns in London at elizabethc@epvantage.com or follow @LizVantage on Twitter

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