Abstract
Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m/bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20 cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response.
Highlights
Over the last few decades, progress in the multimodal treatment of locally advanced rectal cancer (LARC) has evolved, substantially improving local disease control [1]
By using seven in silico cell population estimators we consistently found a significant enrichment of B cells in good responders, irrespective of the method used
Integrating multiple analytical approaches based on gene expression data, we identified a collection of curated signaling pathways and clinical features that are significantly associated with sensitivity or resistance to neoadjuvant chemoradiotherapy (nCRT)
Summary
Over the last few decades, progress in the multimodal treatment of locally advanced rectal cancer (LARC) has evolved, substantially improving local disease control [1]. Preoperative chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) and postoperative adjuvant treatment has been associated with considerable advantages over postoperative approaches, mainly offering improvement on the local recurrence rate [2]. Distant metastases remain the most frequent disease recurrence [3]. The current therapeutic standard for LARC treatment is total neoadjuvant therapy (TNT) which comprises induction fluorouracil- and oxaliplatin-based chemotherapy followed by CRT. TNT has been associated with more efficient delivery of systemic therapy and higher response rates [4,5,6]. 20–30% of patients achieve a complete pathological response (pCR) after nCRT, while 50% of patients have a partial response and the remaining subgroup (20–30%) has minimal or no tumor regression [7,8]. The peak of tumor regression has been estimated to occur at least 8–12 weeks after treatment completion [9]
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