The tumour-stroma ratio as predictive aid towards a biopsy-based treatment strategy in rectal carcinoma

Abstract

Aims: Tumour-stroma ratio (TSR) scores of biopsy material in rectal carcinoma (RC) could aid a biomarker-based, upfront and personalised treatment strategy selection for RC patients. In a large retrospective, multicentre cohort, we aimed to validate the predictive value of biopsy-scored TSR on neoadjuvant therapy response, and secondarily, disease-free and overall survival (DFS, OS).

Methods and results: Scanned haematoxylin and eosin-stained RC biopsy slides were collected from Leiden University Medical Center (N = 116) and from the clinical PROCTOR-SCRIPT (N = 142) and RAPIDO (N = 271) trials. TSR was scored per protocol and categorised as stroma-low (≤ 50%) or stroma-high (> 50%). Major response was defined as tumour regression grade (TRG) 1 + 2 by Mandard, including pathological complete response. Ultimately, a large and varied cohort with 373 RC patients was established. Locally advanced RC was more often stroma-high (P < 0.001). We subsequently observed significantly lower major response rates in the stroma-high RC after a neoadjuvant treatment approach (hazard ratio = 0.63, 95% confidence interval = 0.41-0.99; P = 0.044). Despite correction for well-known risk factors in Cox hazard regression analysis, such as (y)pTNM substages or residual tumour status, the TSR had no singular significant influence on DFS nor OS in multivariate analysis (P = 0.438; P = 0.934, respectively).

Conclusions: Biopsy-scored TSR can predict neoadjuvant therapy efficacy, as RC patients with stroma-high biopsies show less major response. However, patient survival is multifactorial, although response is an important predictor, influenced by TSR. Scoring TSR on RC biopsy material is a reliable histological parameter, implementation of which in treatment guidelines could improve upfront selection for a watch-and-wait strategy.

Keywords: neoadjuvant treatment; prediction; rectal cancer; tumour microenvironment; tumour regression grade; tumour response; tumour–stroma ratio.

Figure 1

The process of scoring the tumour–stroma ratio (TSR) on haematoxylin and eosin‐stained biopsy material using light microscopy. First, using 1.0–2.5× magnification for a general overview of the complete slide, the area with the highest amount of tumour stroma is selected. Subsequently, the TSR is scored on a 10.0× magnifying objective, as per protocol by van Pelt et al. Finally, the biopsy is categorised as stroma‐high (> 50% intratumoural stroma; example shown above) or stroma‐low (≤ 50% intratumoural stroma; example shown below). Created in BioRender.com. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Flowchart showing the patient population with initial inclusion rates per separate cohort [PROCTOR‐SCRIPT, Leiden University Medical Center (LUMC) or RAPIDO] and exclusion numbers and reasons, leading to the ultimately included final patient cohort (N = 373). TSR, tumour–stroma ratio.