Prognostic Impact of An Integrative Landscape of Clinical, Immune, and Molecular Features in Non-Metastatic Rectal Cancer.

Soledad Iseas,Enrique Roca,Osvaldo L Podhajcer,Marcela Carballido,Mariano Golubicki,Vanesa Mikolaitis,Alejandro Di Sibio,Marina Antelo,Ubaldo Gualdrini,Mariana Rizzolo,Cecilia Rotondaro,Ana Cabanne,Juan M Sendoya,Juan Robbio,Andrea S Llera,Mariana Coraglio,Mirta Kujaruk,Julieta Viglino,Gonzalo Ruiz,Guillermo Méndez ,Rubén Salanova ,Martín Eleta ,Martı́n C Abba

doi:10.3389/fonc.2021.801880

Abstract

Rectal Cancer (RC) is a complex disease that involves highly variable treatment responses. Currently, there is a lack of reliable markers beyond TNM to deliver a personalized treatment in a cancer setting where the goal is a curative treatment. Here, we performed an integrated characterization of the predictive and prognostic role of clinical features, mismatch-repair deficiency markers, HER2, CDX2, PD-L1 expression, and CD3−CD8+ tumor-infiltrating lymphocytes (TILs) coupled with targeted DNA sequencing of 76 non-metastatic RC patients assigned to total mesorectal excision upfront (TME; n = 15) or neoadjuvant chemo-radiotherapy treatment (nCRT; n = 61) followed by TME. Eighty-two percent of RC cases displayed mutations affecting cancer driver genes such as TP53, APC, KRAS, ATM, and PIK3CA. Good response to nCRT treatment was observed in approximately 40% of the RC cases, and poor pathological tumor regression was significantly associated with worse disease-free survival (DFS, HR = 3.45; 95%CI = 1.14–10.4; p = 0.028). High neutrophils-platelets score (NPS) (OR = 10.52; 95%CI=1.34–82.6; p = 0.025) and KRAS mutated cases (OR = 5.49; 95%CI = 1.06–28.4; p = 0.042) were identified as independent predictive factors of poor response to nCRT treatment in a multivariate analysis. Furthermore, a Cox proportional-hazard model showed that the KRAS mutational status was an independent prognostic factor associated with higher risk of local recurrence (HR = 9.68; 95%CI = 1.01–93.2; p <0.05) and shorter DFS (HR = 2.55; 95%CI = 1.05–6.21; p <0.05), while high CEA serum levels were associated with poor DFS (HR = 2.63; 95%CI = 1.01–6.85; p <0.05). Integrated clinical and molecular-based unsupervised analysis allowed us to identify two RC prognostic groups (cluster 1 and cluster 2) associated with disease-specific OS (HR = 20.64; 95%CI = 2.63–162.2; p <0.0001), metastasis-free survival (HR = 3.67; 95%CI = 1.22–11; p = 0.012), local recurrence-free survival (HR = 3.34; 95%CI = 0.96–11.6; p = 0.043) and worse DFS (HR = 2.68; 95%CI = 1.18–6.06; p = 0.012). The worst prognosis cluster 2 was enriched by stage III high-risk clinical tumors, poor responders to nCRT, with low TILs density and high frequency of KRAS and TP53 mutated cases compared with the best prognosis cluster 1 (p <0.05). Overall, this study provides a comprehensive and integrated characterization of non-metastatic RC cases as a new insight to deliver a personalized therapeutic approach.

Highlights

Colorectal cancer is the third most common cancer worldwide, accounting for approximately 10% of solid tumors [1]
Since the preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) was established as the standard strategy for locally advanced rectal cancer (LARC), the local recurrence rate was reduced approximately 5% [5, 6]
Clinical data collected from patient medical records included age at diagnosis, gender, distance to anal verge, risks factors according to ESMO rectal cancer guidelines [4], CEA and CA19.9 values, histological features, mismatch repair (MMR) protein status by immunohistochemistry, and neutrophil-platelet score (NPS)

Summary

Introduction

Colorectal cancer is the third most common cancer worldwide, accounting for approximately 10% of solid tumors [1]. Rectal cancer (RC) comprises 40% of all colorectal cancers, with about 70–75% staged as a non-metastatic disease at the initial diagnosis. The clinical management of RC is mainly dependent on tumor staging at diagnosis [4], and total mesorectal excision (TME) is considered the cornerstone of curative treatment for early-stage tumors. Since the preoperative chemoradiotherapy (CRT) followed by TME was established as the standard strategy for locally advanced rectal cancer (LARC), the local recurrence rate was reduced approximately 5% [5, 6]. The development of the total neoadjuvant therapy (TNT) whereby consolidation chemotherapy is given after chemoradiotherapy for LARC treatment [7,8,9] has resulted in an increased probability of complete pathological response (pCR), improved tumor resectability, and sphincter preservation without compromising local tumor control [10, 11]. The current 5-year survival rate remains approximately 65% [12]

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Methods

Results