Combined histopathological risk score using TP53 protein expression, CD8⁺ T cell density and intratumoral budding is an independent predictor of neoadjuvant therapy response in rectal adenocarcinoma

Abstract

Combined histopathological risk score using TP53 protein expression, CD8 + T cell density and intratumoral budding is an independent predictor of neoadjuvant therapy response in rectal adenocarcinomaAims: Neoadjuvant therapy is the recommended treatment for locally advanced rectal adenocarcinoma; however, there remains significant variability in response to therapy. Tumour protein 53 (TP53) has been associated with therapy response and prognosis with conflicting data. Recently, we demonstrated that immune cell density and intratumoral budding (ITB) are predictive factors in rectal cancer. We investigated the predictive value of TP53 immunohistochemistry with CD8 + T cell density and ITB on pretreatment biopsies of rectal adenocarcinoma for response to neoadjuvant therapy. Methods and results: Pretreatment biopsies of rectal adenocarcinoma from 117 patients with neoadjuvant therapy were analysed for TP53 expression by immunohistochemistry, ITB, CD8 + T cell density and mismatch repair protein (MMR) status. Most rectal adenocarcinomas displayed aberrant TP53 expression (86 of 117, 74%). Compared to wild-type TP53, aberrant TP53 expression was associated with proficient MMR status (P = 0.003) and low CD8 + T cell density (P = 0.001). Aberrant TP53 was significantly associated with a partial to poor response to neoadjuvant therapy [odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.04-5.62, P = 0.04]. A combined histopathological risk score (HRS) was created using CD8 + T cell density, ITB and TP53 expression. Patients were separated into low (none to one factor) and high (two to three factors) HRS categories. In the multivariable model, patients with a high HRS were 3.25-fold more likely to have a partial or poor response to neoadjuvant therapy (95% CI = 1.48-7.11, P = 0.003). Conclusions: Our study demonstrates that aberrant TP53 expression, high ITB and low CD8 + T cell density in pretreatment biopsies can help predict response to neoadjuvant therapy. These biomarkers may be helpful in identifying patients at risk for therapy resistance.

Intratumoral Budding in Pretreatment Biopsies, among Tumor Microenvironmental Components, Can Predict Prognosis and Neoadjuvant Therapy Response in Colorectal Adenocarcinoma

“…Assessing TB inside the tumor, that is, ITB, yielded results similar to those obtained by evaluating this factor at the invasive front [ 34 ]; thus, ITB could be a prognostic biomarker in PBSs [ 25 ]. Furthermore, ITB in PBSs can play a role in predicting prognosis and the response to neoadjuvant anticancer therapies [ 22 , 23 , 24 , 26 , 27 ]. Moreover, ITB is correlated with poor clinicopathological factors, such as lymph node metastasis, extranodal tumor deposits, local recurrence, distant metastasis, pT stage, and lymphatic and venous invasion [ 35 , 36 , 37 , 38 , 39 ].…”

“…Previously, Rogers et al classified ITB as being present or absent in 185 patients; however, there was no significant association between ITB and the tumor regression grade [ 23 ]. Nevertheless, Chen et al [ 26 ] and Farchoukh et al [ 27 ] counted the number of TBs per 0.785 mm 2 in 117 patients. They revealed that high-grade ITB (≥2 cells in 0.785 mm 2 ) was significantly associated with tumor regression in univariate [ 26 , 27 ] and multivariate [ 27 ] analyses.…”

“…Nevertheless, Chen et al [ 26 ] and Farchoukh et al [ 27 ] counted the number of TBs per 0.785 mm 2 in 117 patients. They revealed that high-grade ITB (≥2 cells in 0.785 mm 2 ) was significantly associated with tumor regression in univariate [ 26 , 27 ] and multivariate [ 27 ] analyses. Given the small number of studies and their relatively small number of included patients, further studies are still warranted to confirm the predictive power of ITB for neoadjuvant therapy.…”

“…In addition, some factors, such as TB [ 5 , 13 ], peritumoral inflammation [ 14 , 15 , 16 , 17 ], and the degree [ 15 , 16 , 18 ] or features [ 19 , 20 , 21 ] of fibrosis, are measurable without additional immunohistochemistry, as semi-quantitative or three-tier scoring systems have been developed. In particular, the detection of TB in pretreatment biopsy samples (PBSs), that is, intratumoral budding (ITB) [ 22 , 23 , 24 , 25 , 26 , 27 ] and CD8-positive T cells [ 26 , 27 ], has been proposed as a predictor of prognosis and/or response to neoadjuvant therapy. However, its prognostic role has not been confirmed and a method of ITB assessment has not been standardized.…”

“…In this study, we investigated whether TME factors detected in PBSs using hematoxylin–eosin (HE) staining exclusively can predict prognosis and the neoadjuvant treatment response. For this purpose, we evaluated ITB using various methods that were reported previously and compared their prediction powers regarding survival and therapy response [ 22 , 23 , 24 , 26 , 27 ]. In addition, we classified the type of desmoplastic reaction (DR) as mature, intermediate, or immature [ 19 , 20 , 21 ].…”