Citations

74 Background: Colorectal cancer (CRC) incidence has steadily increased in adults younger than 50 years (EO-CRC) since the 1990s, with a reported higher prevalence in the left colon and rectum. Established precursor lesions of CRCs are adenomas, including advanced adenomas, and sessile serrated polyps. We hypothesized that patients at diagnosis of early-onset colon cancer (EO-CC) would have fewer adenomas compared to patients with later-onset colon cancer (LO-CC). Methods: We performed a retrospective review of electronic health records and identified 58 patients diagnosed with EO-CC who had colonoscopy at Mayo Clinic or Mayo Health System who were then matched with 58 LO-CC patients based on gender and procedure indication (diagnostic in 76%, surveillance 16%, screening 8%)[2012 to 2021]. At colonoscopy where colon cancer was diagnosed, we recorded findings of adenomas, advanced adenomas (≥ 1 cm, villous histology, and/or high-grade dysplasia) and sessile serrated polyps. On CCs, limited molecular data were available [mismatch repair (MMR); BRAFV600E, KRAS]. Results: Among 116 patients included in the EO-CC and LO-CC study arms, the median age at cancer diagnosis were 42 and 74 years, respectively. No significant differences were found between study arms and risk factors for CRC including tobacco, alcohol, BMI, genetic syndromes, family history of CRC, and MMR, BRAFV600E or KRAS status (all p> 0.05). While no difference was found for polyp number by arm, patients with EO-CC had larger polyps (median of 10 mm vs 6 mm, p=0.001) compared with LO-CC. At least 1 adenoma was found in 50% and 52% of patients with EO-CC and LO-CC, respectively. Importantly, advanced adenomas were significantly more common in the EO-CC group compared with the LO-CC group (41% and 21%, p=0.027). Sidedness of all adenomas did not differ significantly for EO-CC vs LO-CCs. Conclusions: Patients found to have a primary EO-CC had a significantly higher likelihood of a synchronous advanced adenoma in the colon compared to those with a primary LO-CRC. Together, these data suggest accelerated carcinogenesis throughout the colorectum with increased risk of synchronous and metachronous patients with EO-CC. [Table: see text]

57 Background: Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) show frequent and durable responses to programmed cell death -1 (PD-1) blockade. While the majority of these tumors are sporadics and observed in elderly patients, first-line data are limited to the KEYNOTE-177 study. Here, we report a consecutive series of elderly patients with dMMR mCRC treated with pembrolizumab in routine clinical practice that includes analysis of clinical outcome based on metastatic site. Methods: Patients with dMMR mCRC received first-line pembrolizumab (200 mg every 3 weeks) (N = 41) at Mayo Clinic and Mayo Clinic Health System (2015-2022). Clinicopathological features including metastatic site and molecular data ( BRAFV600E, KRAS) were analyzed in relationship to tumor response rate (RECIST version 1.1). Furthermore, these variables were also analyzed in relationship to patient progression-free survival (PFS) using Kaplan-Meier methodology and multivariable stepwise Cox regression. Results: Among patients with dMMR mCRC, 29/41 (70.7%) were female, 30 (78.9%) harbored BRAFV600E, and 32 (80%) were sporadic. Median age at start of treatment was 80.6 years (IQR of 75.9, 85.9) and median number of treatment cycles was 9 (IQR: 4, 20). At a median follow-up of 23 months (range, 3.0 to 88.5), patient median PFS was 21.3 months (95% CI: 6.4, 38.5). An overall response was observed in 48.8% (20 of 41) of patients including 13 (31.7%) complete (CR) and 7 (17.1%) partial responses (PR). The median duration of response was 42.2 months (95%CI: 8.6, NR). Patients with metastases that included liver had significantly poorer PFS compared to those with non-liver metastases (HRadj 3.40 (95%CI: 1.27-9.13); Padj= 0. 01). In this regard, responses (CR, PR) to pembrolizumab were observed in 3 (21.4%) patients with liver metastasis compared to 17 (62.9%) of those with non-liver metastases. Treatment-related grade 3 or 4 adverse events were observed in 9 (22.0%) patients of whom two discontinued therapy, and there was one treatment-related death. Conclusions: First-line therapy with pembrolizumab for dMMR mCRC significantly prolonged survival in an elderly patient population with manageable toxicity in routine clinical practice. Moreover, the survival benefit of pembrolizumab was significantly attenuated in patients with liver vs non-liver metastases.

3525 Background: Tumor-infiltrating lymphocytes (TILs) are significantly associated with clinical outcomes in patients with colon cancer. However, the potential for a differential effect of TILs on prognosis based on primary tumor sidedness has not been studied. We determined the interaction between TILs and tumor sidedness in relationship to disease-free survival (DFS). Methods: We analyzed data on TIL densities by primary tumor sidedness in 1532 stage III colon carcinomas from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy (NCCTG N0147). TIL densities were dichotomized as low or high (≤3 /HPF) based on an optimized cutoff previously identified for DFS in this cohort. Right-sided tumors were defined as proximal to the splenic flexure. Analysis of TILs and sidedness with DFS were examined using Kaplan-Meier methodology and multivariable Cox regression. Results: Overall, tumors with high vs low TILs had the best DFS [HRadj: 0.58 (95%CI: 0.45-0.74); Padj <0.0001]. The association of TIL densities with 5-yr DFS differed significantly by primary tumor sidedness ( Pinteraction (adj) = 0.045). Among right-sided tumors, high vs low TILs were significantly associated with improved DFS ( Padj <0.0001)[Table]. Among left-sided tumors, however, DFS did not differ significantly for high vs low TILs ( Padj =0.173)[Table]. Similar results for TILs and DFS by sidedness were found for pMMR cancers. We then analyzed our data in low risk (T1-3, N1) and high risk (T4 and/or N2) tumors. Among low risk tumors, high vs low TILs was significantly associated with improved 5-yr DFS only in right-sided tumors ( Padj =0.006) [Table]. Among high risk tumors, high vs low TILs were significantly associated with better DFS in both right-sided ( Padj<0.001) and left-sided ( Padj =0.024) tumors. Conclusions: Overall, tumors with high TIL densities had significantly better DFS in right-sided but not left-sided cancers. Among low risk patients, the association of high TILs with better DFS was limited to right-sided tumors. These findings suggest that TILs should be interpreted by sidedness for prognostication. ClinicalTrials.gov Identifier: NCT00079274 . [Table: see text]