Circulating Tumour DNA for Monitoring Treatment Response to Anti-PD-1 Immunotherapy in Melanoma Patients

Abstract

Anti-programmed cell death-1 (anti-PD-1) antibody shows high therapeutic efficacy in patients with advanced melanoma. However, assessment of its therapeutic activity can be challenging because of tumour enlargement associated with intratumoural inflammation. Because circulating tumour DNA (ctDNA) correlates with tumour burden, we assessed the value of ctDNA levels as an indicator of tumour changes. Quantification of ctDNA (BRAFmutant or NRASmutant) levels by droplet digital PCR in 5 patients with BRAF or NRAS mutant melanoma during the treatment course showed dynamic changes corresponding to radiological and clinical alterations. In 3 cases in which the anti-PD-1 antibody was effective, ctDNA levels decreased within 2-4 weeks after treatment initiation. In 2 cases in which the anti-PD-1 antibody was ineffective, ctDNA levels did not decrease after treatment initiation. ctDNA could be a useful biomarker to predict early response to treatment in patients with advanced melanoma treated with anti-PD-1 immunotherapy.

Serum 5‐S‐cysteinyldopa behavior in the early phase of nivolumab treatment of 12 melanoma patients

“…Another study showed that circulating tumor DNA in the peripheral blood began decreasing between 2 and 4 weeks from the initial administration of Nivo in response cases. 13 In fact, one of the PR patients in this series (case 2) showed a transient increase in serum 5-S-CD from 71.3 nmol/L at baseline to 111.9 nmol/L at 11 days afterwards, which had later decreased to 9.2 nmol/ L at 39 days. Therefore, we presumed that serum 5-S-CD within 3 weeks of Nivo commencement would also be influenced by melanoma onycholysis.…”

“…In that report, circulating tumor DNA became temporarily elevated within 5 days after starting BRAF inhibitor therapy, probably due to onycholysis. Another study showed that circulating tumor DNA in the peripheral blood began decreasing between 2 and 4 weeks from the initial administration of Nivo in response cases . In fact, one of the PR patients in this series (case 2) showed a transient increase in serum 5‐ S ‐CD from 71.3 nmol/L at baseline to 111.9 nmol/L at 11 days afterwards, which had later decreased to 9.2 nmol/L at 39 days.…”

Circulating Tumour DNA Reflects Tumour Burden Independently of Adverse Events Caused by Systemic Therapies for Melanoma

“…Conversely, LDH levels can remain within the normal range despite tumour progression. CtDNA is also a useful marker of tumour load during treatment of patients with melanoma (5,6). Here, we show that measuring ctDNA is a reliable tool for disease monitoring because ctDNA levels reflect tumour burden independently of therapy-related AEs.…”

“…Circulating tumour DNA (ctDNA), which is released from tumour cells into the peripheral blood, is a novel biomarker of tumour status (4) as it harbours the same genetic alterations present in the tumour. Also, the amount of ctDNA correlates strongly with tumour burden in cancer patients, including those with melanoma (5). Here, we show that melanoma therapies induced severe AEs, which increase LDH levels, but do not affect ctDNA levels.…”

“…They provided written informed consent for the use of their peripheral blood and resected tumour tissues. Cell-free DNA was extracted from peripheral blood from patients with melanoma, and ctDNA was measured by droplet digital polymerase chain reaction (QX200 ddPCR system; BIO-RAD, Hercules, CA, USA), as described previously (5). Each AE was evaluated using Common Terminology Criteria for Adverse Events (version 4.0).…”