Acta Dermato-Venereologica 99-12CompleteContent

1184 SHORT COMMUNICATION Circulating Tumour DNA Reflects Tumour Burden Independently of Adverse Events Caused by Systemic Therapies for Melanoma Atsuko ASHIDA, Kaori SAKAIZAWA, Asuka MIKOSHIBA, Yukiko KINIWA and Ryuhei OKUYAMA* Department of Dermatology, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, 390-8621 Japan. *E-mail: rokuyama@ shinshu-u.ac.jp Accepted Aug 8, 2019; E-published Aug 9, 2019 Significant advances in the field of melanoma therapy have been made in recent years. For example, immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 anti- bodies) and small molecule-targeted therapies (BRAF and MEK inhibitors) offer remarkable long-term benefits. However, these agents often cause severe adverse events (AEs). Thus, a reliable biomarker that reflects tumour status is required in order to provide appropriate treat- ment. Although computed tomography (CT) is useful for evaluating tumour status, frequent imaging is not feasible. Serum lactate dehydrogenase (LDH) is often used as a surrogate marker of tumour status; indeed, changes in LDH levels are associated with tumour bur- den (1). However, LDH levels can increase in response to liver dysfunction and interstitial pneumonia (2, 3). Furthermore, LDH levels are frequently affected by therapy-induced 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 tu- mour. 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. This study examined the utility of BRAF V600E ctDNA as a tool for monitoring melanoma. CASE REPORT Two patients with BRAF V600E -mutated melanoma who had me- tastatic disease were examined. 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). The study was approved by the ethics com- mittee of Shinshu University School of Medicine and conducted according to Institutional Review Board guidelines. Patient 1, a 28-year-old woman diagnosed with BRAF V600E -mutated melanoma on the lateral chest, presented with multiple metastases and was treated with ipilimumab (3 mg/kg every 3 weeks) (i-Day 0; Fig. 1A). Although BRAF V600E ctDNA was detected in plasma DNA on i-Day -5 (540 copies/ml), ipilimumab administration decreased the levels of BRAF V600E ctDNA to undetectable levels by i-Day 98. On i-Day 77, the tumour response was classified as stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) assessment. However, grade 3 liver dysfunction occurred after the third administration of ipilimumab (i-Day 49); therefore, the fourth administration was stopped. BRAF V600E ctDNA levels increased on i-Day 161 (72 copies/ml) and again on i-Day 189 (285 copies/ml). A CT scan on i-Day 245 revealed progressive disease (PD). LDH levels (normal range, <230 IU/l) increased with the onset of ipilimumab-related liver dysfunction (i-Day 98; LDH, 350 IU/l); however, levels normalized as liver function improved (i-Day 217; LDH, 259 IU/ml), a finding that was inconsistent with clinical and imaging evaluation of the melanoma. Treatment was switched to dabrafe- nib (300 mg/day) plus trametinib (2 mg/day) on dt-Day 0 (i-Day 252). A computed tomography (CT) scan revealed that the tumour had not grown; the tumour response was classified as SD on dt- Day 62. The level of BRAF V600E ctDNA fell substantially after 2 weeks of combination therapy (dt-Day 14, 0 copies/ml). However, AEs (grade 2 high fever, grade 3 liver dysfunction, and grade 2 erythema nodosum) meant that dabrafenib and trametinib had to be tapered before withdrawal on dt-Day 49. A CT scan on dt-Day 91 revealed enlargement of the tumour, along with a rebound in BRAF V600E ctDNA levels (dt-Day 105, 540 copies/ml). However, LDH levels appeared to be associated with liver dysfunction rather than with melanoma. Thereafter (p-Day 0 [dt-Day 140]), treatment was switched to pembrolizumab (2 mg/kg every 3 weeks). The patient then achieved SD (p-Days 105 and 189). RECIST status correlated with both ctDNA and LDH levels. Thus, BRAF V600E Fig. 1. Monitoring of circulating tumour DNA (ctDNA) and lactate dehydrogenase (LDH) levels, with clinical follow- up, in (A) patient 1 and (B) patient 2. Graphs show changes in BRAF V600E mutant copy number and LDH levels. The upper limit of normal for LDH is 230 IU/l (dotted line). d: dabrafenib; t: trametinib; PR: partial response; SD: stable disease; PD: progressive disease. doi: 10.2340/00015555-3279 Acta Derm Venereol 2019; 99: 1184–1185 This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.

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