ctDNA informs management of metastatic breast cancer

By Mardi Chapman

12 Oct 2020

Circulating tumour DNA (ctDNA) testing should be incorporated into the management of patients with metastatic breast cancer (mBC), according to Australian researchers.

A prospective ctDNA testing program at the Peter MacCallum Cancer Centre, Melbourne, has shown the approach is feasible and valuable as a complement to standard tumour testing in newly diagnosed and established metastatic breast cancer.

The Metastatic Breast Cancer Biomarker (MBCB) study comprised 234 patients with any mBC histological subtype. All participants had a blood sample taken at enrolment and a subset of patients underwent serial ctDNA testing for disease monitoring.

Testing included a multiplexed droplet digital PCR (ddPCR) approach to identify hotspot mutations in PIK3CA, ESR1, ERBB2, and AKT1 and next-generation sequencing – either targeted sequencing or low-coverage whole-genome sequencing.

The study found actionable alterations in 44% of patients overall. Most (41%) were found at baseline and additional alterations emerged between six months and two years after initially negative results at baseline.

Clinical management was directly altered by ctDNA testing in 39% of the cases. For example, patients identified with a PIK3CA mutation were subsequently enrolled on a clinical trial of a PI3K inhibitor and ESR1 mutations typically informed choice of endocrine treatment in other patients.

“The three most common reasons why clinical management was unaffected were no availability of the relevant targeted therapy or appropriate clinical trial at the time of ctDNA testing (32.8%), loss to follow-up (31.3%), or patients not meeting clinical trial eligibility criteria (25.0%),” the study authors said.

Consistent with several other studies, the researchers also showed that high ctDNA levels were associated with inferior survival.

“Overall, our study shows that comprehensive genomic profiling using breast cancer–specific ctDNA testing is a feasible approach that can reveal specific genomic changes underlying metastatic disease,” they concluded.

“Our experience supports routine implementation of ctDNA testing to complement tumour testing in mBC, by enabling actionable targets to be captured in real time to direct clinical management.”

Senior investigator on the study Professor Sarah-Jane Dawson told the limbic she was confident ctDNA testing would be incorporated into routine clinical practice in the near future.

“We have shown that with this kind of testing, you can obtain new information and insights into the molecular make-up of the cancer which can help guide therapy and then you can follow those changes over time which may influence future management.”

“While ctDNA techniques certainly don’t replace tissue biopsies, they can complement them and they have some key advantages.  For example, they can be repeated regularly during someone’s management to understand how the molecular features of the cancer may be changing over time.”

“What we haven’t done as yet is the RCT to show that ctDNA testing actually leads to improved survival outcomes for patients.”

Professor Dawson, head of the Molecular Biomarkers Program at Peter MacCallum Cancer Centre, said ctDNA was still relatively bespoke, only offered in selected research centres, and not yet reimbursed.

“Ideally we would need to demonstrate that these tests lead to improved survival outcomes. I do believe that those RCTs are necessary if we are going to see widespread adoption of these kinds of techniques.”

She said one of the advantages of the test was it required only a simple blood test which opened up opportunities for all patients even in remote and regional areas.

“Almost anyone anywhere can obtain a blood test and there is nothing stopping that blood sample being sent to a specialised centre for this kind of testing.”

“The field has certainly moved rapidly over the last ten years. We are starting to see incorporation of these tests into clinical practice so I absolutely do believe we will see more routine implementation of these tests over time.”

The study was published in PLOS ONE Medicine.

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