Valid Biomarker Predicts Local Regrowth and Distant Metastasis in Rectal Cancer

For patients with rectal cancer, no biomarker capable of improving monitoring and selection exists for those managed with a watch-and-wait (W&W) strategy, notes Franck Pagès, MD, PhD. Following neoadjuvant chemoradiotherapy, he explains, W&W acts as a preservative strategy for patients with rectal cancer with clinical complete response (cCR).

An initial study proposed that the Immunoscore biopsy (IS_B), a standardized assay for quantifying immune infiltrate, could be used to help predict clinical outcomes in patients with early- and advanced stage colorectal cancer. To confirm the efficacy of IS_B used on pretreatment biopsies to predict time to recurrence (TTR), Dr. Pagès and colleagues conducted an international, retrospective validation cohort study that included 249 W&W patients. The findings were published in the Journal of Clinical Oncology.

IS_B Is Independent of and Superior to Clinical Parameters in TTR Prediction

As a predictive tool for patients with rectal cancer, the IS_B proves to be a valid biomarker, according to Dr. Pagès. _ISB categories are strongly correlated with a gradual scaling of the risk for both distant metastasis and local regrowth (ISB High vs Intermediate vs Low). “IS_B is independent and superior to clinical parameters in predicting TTR (Figure),” the study authors wrote.

The authors quantified the density of intratumoral CD3+ and CD8+ T cells on pretreatment rectal biopsies via digital pathology and converted the results to IS_B. Stratified Cox regression adjusted for confounders was used to assess links between IS_B and outcomes. Of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery, the immune status of tumor draining lymph nodes (n=161) was investigated by 3’RNA-Seq and immunofluorescence.

IS_B Is Significantly Correlated With Disease-Free Survival

The study team observed that recurrence-free rates at 5 years were 91.3% (95% CI, 82.4%- 100.0%), 62.5% (95% CI, 53.2%-73.3%), and 53.1% (95% CI, 42.4%-66.5%) with ISB High, IS_B Intermediate, and IS_B Low, respectively (HR for IS_B Low vs High, 6.51; 95% CI, 1.99-21.28; log-rank P<0.001). IS_B was also significantly correlated with disease-free survival (log-rank P<0.001) and predicted both local regrowth and distant metastasis.

In multivariate analysis, _ISB was independent of patient age, sex, tumor location, clinical primary tumor (cT) stage, and clinical regional lymph node (cN) stage, and was the strongest predictor for TTR (HR [ISB High vs Low], 6.93; 95% CI, 2.08-23.15; P=0.0017). The addition of ISB to a clinical-based model significantly improved the prediction of recurrence. Furthermore, B-cell proliferation and memory in draining lymph nodes was observed in the draining lymph nodes of patients with cCR.

These findings, the study team noted, bolster previous evidence supporting the use of IS_B as a marker in colorectal cancers. The potential value of IS_B as a valuable prognostic tool, they add, is exemplified in non-operative management of localized rectal cancer.

Could Preserved Lymph Nodes Be a Risk Factor for Local Recurrence?

“The data from this large international cohort of [patients with] rectal cancer with cCR [that was] managed nonoperatively validate the prognostic value of IS_B and could pave the way for prospective therapeutic trials guided by IS_B to adjust monitoring and/or therapy of W&W patients,” the study authors wrote. For future research, Dr. Pagès and colleagues would like to explore the hypothesis that preserved lymph nodes in a W&W strategy may be considered a risk factor for local recurrence. “Our findings not only raise this possibility but raise speculation that the lymph nodes may act as a relevant immune site,” they noted.