ESTRO 2021 Abstract Book

S488

ESTRO 2021

Conclusion Organ preservation strategy using CXB+ CRT yielded 5-year clinical outcomes (cancer specific survival, local recurrence and distant metastases) similar to matched patients treated with standard CRT+ RP-TME. In selected T2-3 early rectal cancer such organ preservation strategy could be offered as a good option to well informed patients. OC-0623 SMAD3 expression and genetic variation could predict response to chemoradiation in rectal cancer E. Palazzari 1 , E. Cecchin 2 , E. De Mattia 2 , J. Polesel 3 , R. Innocente 1 , F. Navarria 1 , C. Belluco 4 , A. Lauretta 4 , V. Canzonieri 5 , A. Buonadonna 6 , G. Spolverato 7 , S. Pucciarelli 7 , G. Franchin 1 , G. Toffoli 2 , A. De Paoli 1 1 Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Radiation Oncology Dept, Aviano, Italy; 2 Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Experimental and Clinical Pharmacology Unit, Aviano, Italy; 3 Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Unit of Cancer Epidemiology, Aviano, Italy; 4 Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Surgical Oncology Dept, Aviano, Italy; 5 Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Pathology Unit, Aviano, Italy; 6 Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Medical Oncology Dept, Aviano, Italy; 7 University Hospital of Padova, Department of Surgical, Oncological and Gastroenterological Sciences, Ist Clinical Surgery, Padova, Italy Purpose or Objective Patients (pts) with locally advanced rectal cancer (LARC) exhibit heterogeneous responses to Preoperative Chemoradiotherapy (CRT). The identification of clinical and biologic predictive factors of response remains a challenge. SMAD3 is a major transcription factor in the transforming growth factor-β (TGF-β) downstream signaling pathway and is crucial for the immunosuppressive and radioresistant phenotype related to TGF-β. The aim of this work is to evaluate the role of SMAD3 protein expression in pre-CRT tumor tissue, also in its C- terminal phosphorylated SMAD3 (p-SMAD3) form, and of SMAD3 germline genetic profile in predicting the response to CRT of LARC pts Materials and Methods From March 1994 to November 2015 76 LARC pts undergoing CRT and surgery, with available formalin fixed paraffin embedded (FFPE) tumor biopsy taken before CRT and a peripheral blood sample were selected for this study. The tumor expression of SMAD3 and p-SMAD3 was assessed by immunohistochemistry (IHC) and evaluated as predictive marker of response, reported according to Mandard tumor regression grade (TRG) on the pathologic exam of the surgical specimen. Furthermore, SMAD3 gene was sequenced using the germline DNA extracted from peripheral blood, to capture the presence of polymorphisms potentially related to the constitutive SMAD3 expression level. Differences between percentages were evaluated according to Fisher’s exact test. The risk of TRG 2-4 was estimated through logistic regression model, adjusting for potential confounders Results After CRT, 24/76 (31.6%) pts achieved a complete pathological response (TRG1), while 52/76 (68.4%) pts reported a partial or no tumor response (TRG2-4). Overall a high SMAD3 tumor expression (SMAD3 cellularity (cell) above 55% (p=0.0011); moderate/high immunostaining intensity (IS-I) (p=0.0090); H-score (summarizing cell and IS-I) ≥1 vs H-score 0 (P=0.0009)) was related with a non complete response (TRG2-4). The adjusted logistic regression analysis confirmed that pts with a SMAD3 cell above 55% (OR:10.36, p=0.0004), or a moderate/high SMAD3 IS-I (OR:5.20, p=0.0038), or a H-score ≥1 (OR:9.84, p=0.0004) had an increased risk to not achieve a TRG1. When considering the association between p-SMAD3 IHC and tumor response, only the H- score parameter (> 2) remained significantly associated with a non complete response (TRG2-4) (p=0.0253) and this was confirmed by a multivariate model (OR:4.23, p=0.0158). The sequencing of SMAD3 gene (cds, UTRs and intron boundaries) revealed that it is highly conserved. The addition of pts genotype information for SMAD3-rs745103 to the SMAD3 tumor expression level improved the identification of pts with an increased risk to not achieve TRG1 respect the use of only tumor expression features Conclusion A pre-treatment evaluation of SMAD3 status (i.e. IHC tumor expression and genetic polymorphisms) could