Clinical Impact of Presurgery Circulating Tumor DNA after Total Neoadjuvant Treatment in Locally Advanced Rectal Cancer: A Biomarker Study from the GEMCAD 1402 Trial

• Published in: Clinical cancer research 2021-05, Vol.27 (10), p.2890-2898
• Main Authors: Vidal, Joana, Casadevall, David, Bellosillo, Beatriz, Pericay, Carles, Garcia-Carbonero, Rocio, Losa, Ferran, Layos, Laia, Alonso, Vicente, Capdevila, Jaume, Gallego, Javier, Vera, Ruth, Salud, Antonieta, Martin-Richard, Marta, Nogué, Miguel, Cillán, Elena, Maurel, Joan, Faull, Iris, Raymond, Victoria, Fernández-Martos, Carlos, Montagut, Clara
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor; Circulating Tumor DNA; Combined Modality Therapy; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Preoperative Period; Prognosis; Rectal Neoplasms - blood; Rectal Neoplasms - diagnosis; Rectal Neoplasms - mortality; Rectal Neoplasms - therapy; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-4769

Total neoadjuvant treatment (TNT) is a valid strategy for patients with high-risk locally advanced rectal cancer (LARC). Biomarkers of response to TNT are an unmet clinical need. We aimed to determine the value of circulating tumor DNA (ctDNA) to predict tumor response, recurrence, and survival in patients with LARC treated with TNT. The GEMCAD 1402 was a phase II randomized, multicentric clinical trial that randomized 180 patients with LARC to modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) +/- aflibercept, followed by chemoradiation and surgery. Plasma samples were collected at baseline and after TNT within 48 hours before surgery (presurgery). An ultrasensitive assay that integrates genomic and epigenomic cancer signatures was used to assess ctDNA status. ctDNA results were correlated with variables of local tumor response in the surgery sample, local/systemic recurrence, and survival. A total of 144 paired plasma samples from 72 patients were included. ctDNA was detectable in 83% of patients at baseline and in 15% following TNT (presurgery). No association was found between ctDNA status and pathologic response. Detectable presurgery ctDNA was significantly associated with systemic recurrence, shorter disease-free survival (HR, 4; = 0.033), and shorter overall survival (HR, 23; < 0.0001). In patients with LARC treated with TNT, presurgery ctDNA detected minimal metastatic disease identifying patients at high risk of distant recurrence and death. This study sets the basis for prospective clinical trials that use liquid biopsy to personalize the therapeutic approach following TNT.