In locally advanced rectal cancer, the standard-of-care strategy combines neoadjuvant chemoradiotherapy with radical surgery. The quality of the response to this preoperative treatment strongly determines the risk of recurrence and survival. In certain patients presenting a complete clinical response, it becomes feasible to avoid rectal amputation by opting for an organ-preservation strategy, known as active surveillance ("Watch-and-Wait"). However, approximately 25% of these patients develop early tumor regrowth, and until now no molecular marker has been able to predict treatment response or to better select candidates for this conservative approach.
To address this gap, the authors evaluated an Immunoscore adapted to the diagnostic biopsy (ISB). In two independent cohorts of patients treated with neoadjuvant therapy followed by surgery (n₁ = 131, n₂ = 118), the initial biopsies were immunostained for CD3+ and CD8+ T lymphocytes and then quantified by digital pathology. Immune gene expression after treatment was analyzed in 64 patients, and the prognostic value of the ISB was tested in a multicenter cohort of 73 patients managed by active surveillance. The choice of the initial biopsy is justified: it constitutes the only material available before any treatment, and the histological remodeling resulting from chemoradiotherapy renders an immune assessment on the surgical specimen impracticable.
The ISB was positively correlated with the degree of histological response (P < 0.001) and with gene expression levels reflecting a Th1 orientation and a cytotoxic immune response after treatment (P = 0.006). A high ISB identified patients at reduced risk of relapse or death compared with a low ISB (HR: 0.21; 95% CI: 0.06-0.78; P = 0.009), a prognostic performance confirmed in the validation cohort. The ISB proved to be an independent parameter, more informative than imaging performed before (P < 0.001) or after (P < 0.05) treatment in predicting disease-free survival. Combined with post-treatment imaging, it made it possible to distinguish the very good responders likely to benefit from organ preservation. In the active surveillance cohort, no relapse was observed among high-ISB patients (23.3% of cases). The authors acknowledge certain limitations: the analysis covers only a fraction of the tumor, without the invasive margin, and mismatch repair, KRAS, and BRAF statuses were not available for the multivariate analysis. Despite the heterogeneity of management and the multinational origin of the patients, the consistent prognostic value of the ISB underscores its robustness. In conclusion, the ISB predicts the response to neoadjuvant treatment and survival, and its usefulness in selecting patients eligible for an active surveillance strategy is strongly suggested. Its validation in larger cohorts is planned within the framework of international collaborative studies.