Prognostic impact of an integrative landscape of clinical, immune, and molecular features in Non-Metastatic Rectal Cancer

ISEAS, SOLEDAD; SENDOYA, JUAN M.; ROBBIO, JUAN; CORAGLIO M; KUJARUK, MIRTA; MIKOLAITIS, VANESA; RIZZOLO, MARIANA; CABANNE, ANA; RUIZ, GONZALO; SALANOVA, RUBEN; GUALDRINI, UBALDO; MÉNDEZ G; ANTELO M; CARBALLIDO, MARCELA; ROTONDARO, CECILIA; VIGLINO, JULIETA; ELETA M; DI SIBIO A; PODHJACER, OSVALDO; ROCA, ENRIQUE; LLERA A; GOLUBICKI, MARIANO; ABBA MC

Frontiers in Oncology

Frontiers Media S.A

Lugar: Lausana; Año: 2022

Rectal Cancer (RC)is a complex disease that involves highly variable treatmentresponses. Currently, there is a lack of reliable markers beyond TNMto deliver a personalized treatment in a cancer setting where thegoal is a curative treatment. Here, we performed an integratedcharacterization of the predictive and prognostic role of clinicalfeatures mismatch-repair deficiency markers, HER2, CDX2, PD-L1expression, and CD3 − CD8 + tumor-infiltrating lymphocytes (TILs)coupled with targeted DNA sequencing of 76 non-metastatic RC patientsassigned to total mesorectal excision upfront (TME; n = 15) orneoadjuvant chemo-radiotherapy treatment (nCRT; n = 61) followed byTME. Ninety-six percent of RC casesdisplayed mutations affecting cancer driver genes such as TP53, APC,KRAS, ATM, and PIK3CA. Good response to nCRT treatment was observedin approximately 40% of the RC cases, and poor pathological tumorregression was significantly associated with worse disease-freesurvival (DFS, HR = 3.45; 95%CI = 1.14?10.4; p = 0.028). Highneutrophils-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 poorresponse to nCRT treatment in a multivariate analysis. Furthermore, aCox proportional-hazard model showed that the KRAS mutational statuswas an independent prognostic factor associated with higher risk oflocal recurrence (HR = 9.68; 95%CI = 1.01?93.2; p <0.05) andshorter DFS (HR = 2.55; 95%CI = 1.05?6.21; p <0.05), while highCEA serum levels were associated with poor DFS (HR = 2.63; 95%CI =1.01?6.85; p <0.05). Integrated clinical and molecular-basedunsupervised 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-freesurvival (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 prognosiscluster 2 was enriched by stage III high-risk clinical tumors, poorresponders to nCRT, with low TILs density and high frequency of KRASand TP53 mutated cases compared with the best prognosis cluster 1 (p<0.05). Overall, this study provides a comprehensive andintegrated characterization of non-metastatic RC cases as a newinsight to deliver a personalized therapeutic approach.p { margin-bottom: 0.1in; line-height: 115% }