Stratification to Neoadjuvant Radiotherapy in Rectal Cancer by Regimen and Transcriptional Signatures.

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Neoadjuvant radiotherapy (RT) response in rectal cancer is linked to immune and stromal transcriptional signatures.
• The impact of different chemoradiotherapy regimens and molecular subtypes on these associations and patient survival remains unclear.

Purpose of the Study:

• To investigate how transcriptional signatures associate with pathologic complete response (pCR) across various chemoradiotherapy regimens and consensus molecular subtypes (CMS).
• To determine the predictive value of these signatures for overall survival and recurrence-free survival.

Main Methods:

• Combined gene expression and clinical data from nine cohorts of primary rectal tumors (N = 826).
• Analyzed transcriptomic signatures for pCR, considering treatment regimen (RT, capecitabine/5-fluorouracil [Cap/5FU], with or without oxaliplatin [Ox]) and CMS subtypes.
• Tested significant findings for association with overall and recurrence-free survival.

Main Results:

• Immune and stromal signatures correlated with pCR and non-pCR, respectively, in RT/Cap/5FU-treated patients (N = 387), with the radiosensitivity signature (RSS) being most prominent.
• Addition of oxaliplatin (Ox; N = 123) altered stromal signature direction, increasing pCR likelihood (p for interaction 0.02).
• Cytotoxic lymphocyte association with pCR varied by CMS subtype (CMS1/CMS4 vs. others; p for interaction 0.04) in Cap/5FU patients. pCR and RSS were the only survival predictors.

Conclusions:

• Rectal cancer response to neoadjuvant RT varies with tumor biology, even with similar pCR rates across regimens.
• Oxaliplatin may enhance RT response in stroma-rich rectal tumors.
• Preoperative RSS predicts response to neoadjuvant RT with 5FU.