International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy
Carine El Sissy, Amos Kirilovsky, C. Pagès, Florence Marliot, Petra A. Custers, Edina Dizdarevic, Marine Sroussi, Mireia Castillo-Martín, Nacilla Haicheur, Mohamed Dermani, Nicolas Loche, Bénédicte Buttard, Ana-Maria Mușină, Maria-Gabriela Aniței, José G. van den Berg, Annegien Broeks, Soledad Iseas, Mariana Coraglio, Fernando Sánchez Loria, Alfredo Romero, Pierre Laurent‐Puig, Aurélien de Reyniès, Laura M. Fernández, Mehdi Karoui, David Tougeron, Carlos Vaccaro, Juan Pablo Santino, Laurids Østergaard Poulsen, Jan Lindebjerg, Juan Manuel O’Connor, Viorel Scripcariu, Mihail‐Gabriel Dimofte, Jean‐Pierre Gérard, Myriam Chalabi, Nuno Figueiredo, Rodrigo Oliva Perez, Angelita Habr‐Gama, Jérôme Galon, Torben Frøstrup Hansen, Lars Henrik Jensen, Geerard L. Beets, Guy Zeitoun, Franck Pagès
Abstract
PURPOSE No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (IS B ) was recently suggested in a preliminary study. METHODS This international validation study included 249 patients with clinical complete response (cCR) managed by W&W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to IS B . The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between IS B and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence. RESULTS Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with IS B High, IS B Intermediate, and IS B Low, respectively (hazard ratio [HR; Low v High], 6.51; 95% CI, 1.99 to 21.28; log-rank P = .0004). IS B was also significantly associated with disease-free survival (log-rank P = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, IS B was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [IS B High v Low], 6.93; 95% CI, 2.08 to 23.15; P = .0017). The addition of IS B to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR. CONCLUSION The IS B is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome.