YKL-40/c-Met expression in rectal cancer biopsies predicts tumor regression following neoadjuvant chemoradiotherapy: a multi-institutional study

Abstract

Background: Neoadjuvant chemo-radiotherapy (CRT) followed by surgical resection is the standard treatment for locally advanced rectal cancer, although complete tumor pathological regression is achieved in only up to 30% of cases. A clinicopathological and molecular predictive stratification of patients with advanced rectal cancer is still lacking. Here, c-Met and YKL-40 have been studied as putative predictors of CRT response in rectal cancer, due to their reported involvement in chemoradioresistance in various solid tumors.

Material and methods: A multicentric study was designed to assess the role of c-Met and YKL-40 expression in predicting chemoradioresistance and to correlate clinical and pathological features with CRT response. Immunohistochemistry and fluorescent in situ hybridization for c-Met were performed on 81 rectal cancer biopsies from patients with locally advanced rectal adenocarcinoma. All patients underwent standard (50.4 gy in 28 fractions + concurrent capecitabine 825 mg/m2) neoadjuvant CRT or the XELOXART protocol. CRT response was documented on surgical resection specimens and recorded as tumor regression grade (TRG) according to the Mandard criteria.

Results: A significant correlation between c-Met and YKL-40 expression was observed (R = 0.43). The expressions of c-Met and YKL-40 were both significantly associated with a lack of complete response (86% and 87% of c-Met and YKL-40 positive cases, p< 0.01 and p = 0.006, respectively). Thirty of the 32 biopsies co-expressing both markers had partial or absent tumor response (TRG 2-5), strengthening their positive predictive value (94%). The exclusive predictive role of YKL-40 and c-Met was confirmed using a multivariate analysis (p = 0.004 and p = 0.007 for YKL-40 and c-Met, respectively). TRG was the sole morphological parameter associated with poor outcome.

Conclusion: c-Met and YKL-40 expression is a reliable predictor of partial/absent response to neoadjuvant CRT in rectal cancer. Targeted therapy protocols could take advantage of prior evaluations of c-MET and YKL-40 expression levels to increase therapeutic efficacy.

Fig 1. Distribution of patients according to TRG classes.

Fig 2. Representative examples of rectal carcinoma (A, Hematoxylin & Eosin, original magnification 200X) with mild to strong cytoplasmic immunoreactivity for YKL-40 (B, original magnification 400X) and c-Met (C, original magnification 400X) and high c-Met gene polisomy by FISH analysis.

Fig 3. Distribution of cases into to TRG classes according to YKL-40 immunoreactivity (A) and overexpression of YKL-40 in the non-responder group (TRG2-5) when considered both as continuous (B) and categorical variable (C).

Fig 4. Distribution of cases into to TRG classes according to c-Met immunoreactivity (A) and overexpression of c-Met in the non-responder group (TRG2-5) when considered both as continuous (B) and categorical variable (C).

Fig 5. Stratification of cases into three subgroups, according to the expression of YKL-40 and c-Met on tumor biopsy:-/-: YKL-40-negative/c-Met-negative;-/+: YKL-40-positive/c-Met-negative or YKL-40-negative/c-Met-positive and +/+: YKL-40-positive/c-Met-positive.