Outcomes of IBD-associated colorectal cancer and implications in early-onset colorectal cancer.
Authors: Villarreal Oscar , Zeineddine Fadl A. , Chacko Ray , Parseghian Christine Megerdichian , Johnson Benny , Willis Jason , Lee Michael Sangmin , Morris Van K. , Dasari Arvind , Raghav Kanwal Pratap Singh , Overman Michael J. , You Y. Nancy , Wang Yinghong , Maru Dipen M. , Shen John Paul Y.C. , Kopetz Scott 
Published: January 2022

22 Background: Inflammatory bowel disease (IBD) increases the risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) mortality is on the rise. It has been postulated that CA-CRC may be contributing to the increasing prevalence of early-onset CRC (EOCRC) but supportive studies are currently lacking. Molecular and clinical differences between CA-CRC and sporadic-CRC (S-CRC) have been reported, however outcomes for CA-CRC remains unclear. Signet ring cell carcinoma (SRC) is a rare subtype of CRC which is seen at higher frequencies, along with mucinous histology, in both CA-CRC and EOCRC. In this study, we validate the association of SRC and mucinous (SRC/M) histology with CA-CRC and EOCRC, and utilize it to estimate the amount of EOCRC attributable to undiagnosed or subclinical IBD. Methods: A retrospective study was conducted using three independent mCRC patient datasets from MDACC. The mATTACC discovery cohort consisted of 32 IBD- and 425 S-mCRC patients enrolled in a prospective biomarker trial. Validation of tumor histology was completed with a tumor registry (n=1696), excluding the MSI-High samples, and a real-world evidence (RWE) cohort from MDACC containing 269 CA-mCRC and 29,596 S-mCRC patients, was used as our validation cohort. Results: In the mATTACC cohort SRC/M histology was found in 37.5% of CA-mCRC and 11.7% of S-mCRC, showing a strong association between SRC/M and CA-mCRC (OR = 4.54, 95% CI: 2.19-9.43). The RWE cohort confirmed the correlation of SRC/M with CA-mCRC (28.6%) relative to S-mCRC (11.4%) patients (OR = 3.13, 95%CI: 2.39-4.09). An association was found between SRC/M and EOCRC (OR = 1.35; 95% CI: 1.24-1.47). By comparing the prevalence of SRC/M in EOCRC and late-onset CRC and correcting by the proportion of CA-CRC cases with SRC/M histology, we estimate that between 8.28% to 10.15% of EOCRC may attributable to undiagnosed/subclinical IBD. Using the RWE cohort, median overall survival was determined to be lower for CA-mCRC (31m) relative to S-mCRC (39m; p=0.007), yielding a HR of 1.26 (95% CI: 1.06-1.48). CA-mCRC patients with EOCRC (25m) were also found to have significantly worse outcomes than S-mCRC patients (40m) with EOCRC (p=0.0005; HR = 1.61, 95%CI: 1.23-2.11). Within CA-mCRC, patients with SRC or SRC/M histology (21m) had decreased OS compared to mucinous histology (51m), indicating the poor prognosis of SRC in CA-mCRC (p=0.028; HR=0.53, 95% CI: 0.3-0.94). Conclusions: Tumor biology consistent with CA-CRC, including SRC/M histology, may be present in 8.3% – 10.2% of patients with EOCRC without a clinical diagnosis of IBD, and harbors worse outcomes. Although other confounding biology may be underlying this association, recognition of undiagnosed IBD in CRC patients, especially those with metastatic disease, is important as it may impact prognosis and treatment strategies for this high-risk patient population.