Abstract
Background: Patients with rectal cancer can prospectively be favored for neoadjuvant concurrent chemoradiotherapy (CCRT) to downstage before a radical proctectomy, but the risk stratification and clinical outcomes remain disappointing. Methods: From a published rectal cancer transcriptome dataset (GSE35452), we highlighted extracellular matrix (ECM)-linked genes and identified the serine protease inhibitor Kazal-type 4 (SPINK4) gene as the most relevant among the top 10 differentially expressed genes associated with CCRT resistance. We accumulated the cases of 172 rectal cancer patients who received neoadjuvant CCRT followed by surgery and collected tumor specimens for the evaluation of the expression of SPINK4 using immunohistochemistry. Results: The results revealed that high SPINK4 immunoexpression was significantly related to advanced pre-CCRT and post-CCRT tumor status (both p < 0.001), post-CCRT lymph node metastasis (p = 0.001), more vascular and perineurial invasion (p = 0.015 and p = 0.023), and a lower degree of tumor regression (p = 0.001). In univariate analyses, high SPINK4 immunoexpression was remarkably correlated with worse disease-specific survival (DSS) (p < 0.0001), local recurrence-free survival (LRFS) (p = 0.0017), and metastasis-free survival (MeFS) (p < 0.0001). Furthermore, in multivariate analyses, high SPINK4 immunoexpression remained independently prognostic of inferior DSS and MeFS (p = 0.004 and p = 0.002). Conclusion: These results imply that high SPINK4 expression is associated with advanced clinicopathological features and a poor therapeutic response among rectal cancer patients undergoing CCRT, thus validating the prospective prognostic value of SPINK4 for those patients.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the second major cause of cancer-associated deaths globally [1]
concurrent chemoradiotherapy (CCRT), a published rectal cancer transcriptome dataset (GSE35452) was applied for data mining, incorporating 46 patients undergoing neoadjuvant CCRT followed by standardized curative resection
Twenty-four patients (52.2%) showing a response to CCRT were categorized as responders, whereas 22 patients (47.8%) showing resistance to CCRT were classified as nonresponders
Summary
Colorectal cancer (CRC) is the third most common cancer and the second major cause of cancer-associated deaths globally [1]. Long-term evaluation has shown that preoperative adjuvant therapy contributes to reduced local recurrence [3]; the reduction in mortality has slowed due to the high rate of distant metastasis [4] for rectal cancer. This situation draws attention to the necessity for the conception of better therapeutic strategies focused on controlling elusive micrometastases. With the implementation of precision medicine, recent studies have supported the application of genetic biomarkers to enable better risk stratification and predict clinical outcomes This offers clinicians the opportunity to individually tailor early interventions, which would help optimize therapy. The expression of SPINK4 in tumor tissues from patients receiving neoadjuvant CCRT, as well as its practical importance—especially for rectal cancer—are largely unrevealed
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