Abstract
The absence of established predictive markers with value to anticipate response to neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) represents a current major challenge in locally advanced rectal cancer (LARC). The tumor suppressor microRNA (miR)-199b has been reported to play a key role determining 5-FU sensitivity of colorectal cancer cells through the regulation of several signaling pathways, and has emerged as a novel molecular target to overcome the 5-FU resistant phenotype. Moreover, miR-199b downregulation was described as a common alteration that predicts lack of response to preoperative CRT in LARC but this issue needs to be confirmed in independent larger cohorts. Here, we evaluate the clinical impact of miR-199b in LARC and perform additional analyses to further clarify its potential relevance as novel marker in this disease. Thus, miR-199b expression was quantified by real-time-PCR in a cohort of 185 LARC patients, observing this miR downregulated in 22.2% of cases and significantly associated with higher tumor size (p = 0.026) and positive lymph node after CRT (p = 0.005), and higher pathological stage (p = 0.004). Notably, this alteration showed a strong independent predictive value of poor pathological response to neoadjuvant CRT (p = 0.004). Moreover, the subgroup of cases with low miR-199b levels had a markedly shorter overall (p < 001) and event-free survival (p < 0.001), and multivariate analyses showed that miR-199b deregulation represents an independent prognosticator for patient outcome in LARC. Interestingly, the prognostic impact of this miR was strongly significant in both younger and elderly patients, and was very effective determining patient recurrence (p = 0.004). Finally, we compared miR-199b expression profiles in a set of cases with pre and post-treatment samples available, observing that only a minimal response leads to miR-199b increase levels, further suggesting its potential clinical and therapeutic relevance as a promising marker and novel molecular target for the management of LARC.
Highlights
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide (10%), and the second leading cause of cancer death (9.4%)
We quantified the expression levels of miR-199b in a cohort of 185 locally advanced rectal cancer (LARC) patients in order to analyze the prevalence of miR-199b downregulation, observing this alteration in 22.2% of cases (41 out of 185)
We found no association of miR-199b downregulation with patient age, ECOG status or stage in this patient cohort (Table S1)
Summary
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide (10%), and the second leading cause of cancer death (9.4%). The current standard treatment recommended for LARC patients is referred to a multimodal neoadjuvant treatment consisting of a long-course preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) and short-course preoperative radiotherapy (SCPRT) followed by total mesorectal excision (TME) [7,8]. This therapeutic strategy has improved the management of LARC patients and was established after numerous studies demonstrating that in patients with resectable rectal cancer, SCPRT or CRT before TME significantly leads to a lower local relapse rate and better response than TME followed by adjuvant CRT or TME alone [9,10,11]. With the implementation of total mesorectal excision surgery and neoadjuvant chemoradiotherapy (nCRT), local recurrence rates have markedly declined and complete pathological response (pCR) is observed in more than 20% of cases [11]
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