Prognostic impact of residual HPV ctDNA detection after chemoradiotherapy for anal squamous cell carcinoma.

Purpose: Chemoradiotherapy (CRT) is the current standard of care for patients diagnosed with locally advanced anal squamous cell carcinoma (ASCC), but some patients develop local and/or distant relapse during follow-up. The present study was designed to monitor HPV circulating tumor DNA (ctDNA) levels during CRT in patients with ASCC. Experimental Design: We analyzed samples from patients with HPV16- or HPV18-positive locally advanced ASCC. Blood samples were collected before and after CRT. HPV16 or HPV18 ctDNA detection was performed by droplet digital-PCR. Results: HPV ctDNA was detected before CRT in 29 of 33 patients with stage II-III ASCC (sensitivity: 88%, 95%CI=[72-95]); ctDNA positivity rate was associated with tumor stage (64% and 100% in stage II and III, respectively; p=0.008). Among ctDNA-positive patients at baseline, ctDNA levels were higher in N+ than in N- tumors (median 85 copies/ml, range (8-9333) vs 32 copies/ml, range (3-1350); p=0.03). ctDNA detection at baseline had no significant prognostic impact. After CRT, 3 of 18 (17%) patients displayed residual detectable HPV ctDNA; ctDNA detection after CRT was strongly associated with shorter disease-free survival (p<0.0001). Conclusions: This is the first proof of concept study assessing the prognostic value of ctDNA after CRT in locally advanced ASCC. In most patients, HPV ctDNA can be detected before CRT and becomes undetectable during CRT. In the present study, we show that residual ctDNA levels after CRT are associated with very poor outcome.

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