Narrative Review: Predictive Biomarkers of Tumor Response to Neoadjuvant Radiotherapy or Total Neoadjuvant Therapy of Locally Advanced Rectal Cancer Patients
by
, , , , and
Joao Victor Machado Carvalho
1,2,3
,
Jeremy Meyer
4,
Frederic Ris
4,
André Durham
5,
Aurélie Bornand
6,
Alexis Ricoeur
7,
Claudia Corrò
1,2,3,† and
Thibaud Koessler
1,2,3,*,† 1
Translational Research Center in Onco-Hematology, Department of Medicine, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland
2
Swiss Cancer Center Léman, 1005 Lausanne, Switzerland
3
Department of Oncology, Geneva University Hospital, 1205 Geneva, Switzerland
4
Division of Digestive Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland
5
Department of Radiation Oncology, University Hospitals of Geneva, 1205 Geneva, Switzerland
6
Pathology Department, Geneva University Hospitals, 1205 Geneva, Switzerland
7
Service of Radiology, Geneva University Hospital, 1211 Geneva, Switzerland
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2025, 17(13), 2229; https://doi.org/10.3390/cancers17132229
Submission received: 15 May 2025
/
Revised: 22 June 2025
/
Accepted: 30 June 2025
/
Published: 3 July 2025
(This article belongs to the Special Issue Radiotherapy and New Biological Paradigms in Cancer Treatments (2nd Edition))
Simple Summary
Locally advanced rectal cancer treatment consists of neoadjuvant treatment (NAT) followed by surgery. Neoadjuvant treatments can include chemoradiotherapy (CRT), short-course radiotherapy (SCRT), radiotherapy (RT) or total neoadjuvant treatment (TNT). Each of these treatment modalities impact a patient’s quality of life. Finding predictive markers of tumor response enabling a personalized treatment approach is of high interest. Most of the research on biomarkers has focused on tumor response following CRT. This review aims at gathering current knowledge of biomarkers predicting response to neoadjuvant treatments other than CRT, such as SCRT, RT and TNT regiments.
Abstract
Background/Objectives: Treatment of locally advanced rectal cancer (LARC) very often requires a neoadjuvant multimodal approach. Neoadjuvant treatment (NAT) encompasses treatments like chemoradiotherapy (CRT), short-course radiotherapy (SCRT), radiotherapy (RT) or a combination of either of these two with additional induction or consolidation chemotherapy, namely total neoadjuvant treatment (TNT). In case of complete radiological and clinical response, the non-operative watch-and-wait strategy can be adopted in selected patients. This strategy is impacted by a regrowth rate of approximately 30%. Predicting biomarkers of tumor response to NAT could improve guidance of clinicians during clinical decision making, improving treatment outcomes and decreasing unnecessary treatment exposure. To this day, there is no validated biomarker to predict tumor response to any NAT strategies in clinical use. Most research focused on CRT neglects the study of other regimens. Methods: We conducted a narrative literature review which aimed at summarizing the status of biomarkers predicting tumor response to NAT other than CRT in LARC. Results: Two hundred and fourteen articles were identified. After screening, twenty-one full-text articles were included. Statistically significant markers associated with improved tumor response pre-treatment were as follows: low circulating CEA levels; BCL-2 expression; high cellular expression of Ku70, MIB-1(Ki-67) and EGFR; low cellular expression of VEGF, hPEBP4 and nuclear β-catenin; the absence of TP53, SMAD4, KRAS and LRP1B mutations; the presence of the G-allel of LCS-6; and MRI features such as the conventional biexponential fitting pseudodiffusion (Dp) mean value and standard deviation (SD), the variable projection Dp mean value and lymph node characteristics (short axis, smooth contour, homogeneity and Zhang et al. radiomic score). In the interval post-treatment and before surgery, significant markers were as follows: a reduction in the median value of circulating free DNA, higher presence of monocytic myeloid-derived suppressor cells, lower presence of CTLA4+ or PD1+ regulatory T cells and standardized index of shape changes on MRI. Conclusions: Responders to neoadjuvant SCRT and RT tended to have a tumor microenvironment with an immune–active phenotype, whereas responders to TNT tended to have a less active tumor profile. Although some biomarkers hold great promise, scarce publications, inconsistent results, low statistical power, and low reproducibility prevent them from reliably predicting tumor response following NAT.
