Early Age of Onset Is an Independent Predictor for a Worse Response to Neoadjuvant Therapies in Sporadic Rectal Cancer Patients

SIMPLE SUMMARY: Early-onset rectal cancer (EORC) patients are more likely to undergo neoadjuvant therapies due to the advanced stage of cancer at diagnosis. The response to therapies in this group of patients is still unknown. The aim of this study was to explore the effect of age of onset on the pathological response to neoadjuvant therapies in locally advanced RC patients. A higher rate of incomplete response was reported in EORC patients and early age of onset presented as a risk factor for a worse response in a multivariable analysis. The results of this study call for a different multimodal strategy in EORC patients. ABSTRACT: The incidence of rectal cancer (RC) is increasing in the population aged ≤ 49 (early-onset RC-EORC). EORC patients are more likely to present with locally advanced disease at diagnosis than late-onset RC (LORC; aged ≥ 50) patients. As a consequence, more EORC patients undergo neoadjuvant therapies. The response to treatment in EORC patients is still unknown. This study aims to explore the effect of age of onset on the pathological response to neoadjuvant therapies in sporadic locally advanced RC (LARC) patients. Based on an institutional prospectively maintained database, LARC patients undergoing neoadjuvant therapies and radical surgery between January 2010 and December 2022 were allocated to the EORC and LORC groups. The primary endpoint was the rate of incomplete response (Dworak 0–2). A total of 326 LORC and 79 EORC patients were included. Pre-neoadjuvant tumor features were comparable. A significantly higher rate of incomplete response was observed in EORC patients (49% vs. 35%; p = 0.028). From multivariable analysis, early age of onset, smoking and extramural invasion presented as independent risk factors for a worse response. This study demonstrates that an early age of onset is related to a worse response and calls for different multimodal strategies in this group of patients.