Low Amounts of ctDNA Can Predict Good Immunotherapy Outcome

Skin cancer, light micrograph
Skin cancer. Light micrograph of a section through a squamous carcinoma of the skin. Whorls of enclosed keratin (orange) are a common feature. Magnification: x120 when printed at 10 centimetres wide.

Cancer patients who have low levels of circulating tumor (ct)DNA before starting treatment with immunotherapy are more likely to have a positive response to the treatment, according to research from the University of Toronto.

The scientists also tested whether changes in ctDNA during treatment could reflect whether patients would have a good treatment response or not. They found that early reductions in ctDNA indicated a good response to treatment, whereas increases in ctDNA levels was a sign of disease progression and a poor outcome.

“It’s like a molecular CT scan that gives us a molecular dimension, an added layer of information to know whether a tumour is growing or not, ” says Lillian Siu, MD, a medical oncologist at the Princess Margaret Cancer Centre and a professor at the University of Toronto, who co-led the research. “That’s why this is so exciting. It helps to predict early on what may happen over time.”

For this phase II study, which was published in the journal Nature Cancer, Siu and colleagues recruited 94 patients with five different types of cancer: squamous cell cancer of head and neck, triple negative breast cancer, high-grade serous ovarian cancer, malignant melanoma and mixed solid tumors.

All the patients had their ctDNA levels tested at the beginning of the study – the researchers designed bespoke assays for each patient based on sequencing analysis of their specific tumor.

“When we looked at all 20,000 genes in each cancer, the range of mutations in different individuals was huge due to the many different cancer types in the study,” commented Trevor Pugh, PhD, a co-senior author on the study, also based at Princess Margaret Cancer Centre and the University of Toronto.

“The novelty is that, rather than taking a one-size-fits-all approach, we designed a personalized blood test for each person based on their own cancer’s mutation list.”

The participants then started treated with the immunotherapy drug pembrolizumab – a checkpoint inhibitor that inhibits the immune system protein PD1.

Patients who had initial levels of ctDNA that were in the lower half of all the levels measured had longer progression-free and overall survival than those with higher levels.

To assess how well ctDNA predicted treatment efficacy the researchers also took follow-up blood tests approximately 6-7 weeks after the patients started their treatment in 74 of the participants.

They found that any rise in ctDNA levels at this time was associated with fast cancer progression and low survival. In contrast, if ctDNA levels decreased after two cycles of pembrolizumab and if ctDNA became undetectable then patient outcomes were significantly better.

While immunotherapy is effective in 20-30% cancer patients, at present it is hard to predict who will respond well to the treatment in advance. Finding a quick and effective way to do this is important to make sure patients get the most effective treatment as quickly as possible.

“Our findings demonstrate that serial ctDNA analysis using a bespoke assay could serve as a generalizable monitoring strategy for patients treated with immune checkpoint blockade,” write the authors.

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