Preoperative chemoradiotherapy in locally advanced rectal cancer: correlation of a gene expression-based response signature with recurrence

Abstract

Preoperative chemoradiotherapy is recommended for locally advanced rectal cancer (UICC stage II/III). We recently demonstrated that responsive and nonresponsive tumors showed differential expression levels of 54 genes. In this follow-up study, we investigated the relationship between this gene set and disease-free (DFS) and overall survival (OS). Pretherapeutic biopsies from 30 participants in the CAO/ARO/AIO-94 trial of the German Rectal Cancer Study Group were analyzed using gene expression microarrays. Statistical analysis was performed to identify differentially expressed genes between recurrent and nonrecurrent tumors and to correlate these changes with disease recurrence and outcome. After a median follow-up of 59 months, seven of eight patients with recurrent disease was a nonresponder, and one responsive tumor recurred. Response to chemoradiotherapy was significantly correlated with an improved DFS (log rank P=0.028), whereas OS did not differ significantly (P=0.11). Applying a class comparison analysis, we identified 20 genes that were differentially expressed between recurrent and nonrecurrent tumors (P<0.001). Analyzing the first two principal components of the 54 genes previously identified to predict response, we observed that this response signature correlated with an increased risk of cancer recurrence. These data suggest that the genetic basis of local response also affects the genetic basis of tumor recurrence. Genes that are indicative of nonresponse to preoperative chemoradiotherapy might also be linked to an increased risk of tumor recurrence.

Figures

Fig. 1

Presentation of study design, clinical treatment and follow-up. cUICC refers to pre-therapeutic clinical staging of locally advanced rectal cancers, ypUICC to histopathological assessment of the resected specimens after preoperative chemoradiotherapy; CT, postoperative chemotherapy.

Fig. 2

Survival data for all 30 patients treated with preoperative chemoradiotherapy. A: Responders as measured by T-level downsizing showed a significantly better disease-free survival (DFS) compared to non-responders (p=0.028). B: No statistically significant difference in overall survival (OS) was observed between responders and non-responders (p=0.11).

Fig. 3

Principal Component plot of the 54 genes that were previously identified using cDNA microarrays to be differentially expressed between nine responsive and 14 non-responsive tumors. All responders, illustrated in blue (P1-P9), did not develop disease recurrence, while the red dots indicate those six non-responders who showed tumor recurrence (P11, P14, P17, P18, P20, and P22). The yellow dots display the remaining eight non-responders who did not develop metastatic disease (P10, P12, P13, P15, P16, P19, P21 and P23).