Citations

Abstract Background Early tumor shrinkage and depth of response have emerged as potential prognostic indicators in metastatic colorectal cancer (CRC). However, their associations with overall survival, progression-free survival (PFS), and postprogression survival in patients receiving anti–epidermal growth factor receptor (EGFR) antibodies or bevacizumab remain unclear. Methods We analyzed 3219 treatment-naive patients with RAS wild-type metastatic CRC from 8 randomized studies (CRYSTAL, OPUS, PRIME, CAIRO2, CALGB80405, WJOG4407G, ATOM, PARADIGM) in the Aid and Research in Digestive Cancerology database. Early tumor shrinkage was defined as a 20% or more reduction in tumor size at 8 ± 2 weeks, whereas depth of response was assessed by maximum tumor shrinkage at nadir. Cox regression models evaluated the associations of early tumor shrinkage and depth of response with overall survival, PFS, and postprogression survival, adjusting for confounders. A 2-sided test was conducted with a significance level of .05. Results Early tumor shrinkage and depth of response substantially stratified overall survival, PFS, and postprogression survival outcomes across all treatment groups. Early tumor shrinkage positivity was associated with improved overall survival, PFS, and postprogression survival in anti-EGFR and bevacizumab-based therapies, with a trend toward better outcomes in the anti-EGFR group. The depth of response analysis revealed optimal cutoff values of 0.55 for anti-EGFR–based therapy and 0.47 for bevacizumab-based therapy to achieve a median overall survival of approximately 32 months. Conclusions Early tumor shrinkage and depth of response serve as valuable prognostic markers in RAS wild-type metastatic CRC, particularly for patients treated with anti-EGFR antibodies. These findings highlight the potential role of early tumor shrinkage and depth of response in guiding treatment strategies and improving outcomes for patients with CRC.

Background. MicroRNAs are small, single-stranded non-coding RNA molecules that play major role in gene regulation. miRNAs have been reported as both tumor suppressive and oncogenic and are promising candidates for cancer prognosis and treatment. miR-494 is known to promote cell migration and invasion in CRC. Our study aimed to further explore the role of miR-494 modulation (inhibition and overexpression) in CRC. Methods. We evaluated the impact of tumor gene expression of MIR494 on outcomes (overall survival: OS; progression-free survival: PFS) in data for 433 metastatic CRC (mCRC) patients (pts) (bevacizumab [bev] (N = 226) vs cetuximab [cet] (N = 207)) enrolled in randomized phase III CALGB/SWOG 80405 trial obtained from Alliance for Clinical Trials in Oncology. RNA extracted from FFPE tumor samples was sequenced using the HiSeq 2500 (Illumina). Gene expression was divided into high, medium and low. Associations were assessed by log-rank test and multivariable Cox proportional hazards regression model. Treatment-gene interactions were analyzed using the likelihood ratio test. CRC cell lines HCT116 and HT29 were transfected with miR-494 inhibitors and mimics for 48 hours and total RNA was collected, followed by RT-qPCR (miR-494 and target genes BMAL1, PAK1, CDH1, CDH2, SNAI1, TWIST) and clonogenic assays. Results. High miR-494 was significantly associated with worse PFS in overall (median survival: high vs low: 9.3 vs 11.3 months, P<0.025) and cet-treated (median survival high vs low: 9.2 vs 9.6 months, P<0.025) mCRC cohorts, while no significance was observed in bev-treated mCRC. Multivariable Cox model showed significant association between high miR-494 and worse PFS and OS in the cet-treated cohort; however, treatment-gene interaction was not statistically significant. Expression analysis revealed miR-494 was significantly reduced and increased following inhibitor and mimic transfection, respectively. Differential gene expression of the target genes analyzed was observed between the miR-494 inhibitor and mimic-treated HCT116 and HT29 samples. In HCT116 cells, inhibition of miR-494 significantly (P < 0.01) reduced expression of PAK1, while increased the expression of CDH1. The number of colonies formed relatively increased after transfection with miR-494 inhibitor compared to miR-494 mimic. Conclusion. Our findings showed that high miR-494 expression correlated with worse PFS overall and in cet-treated mCRC pts. It would be interesting to check for potential associations with EGFR signaling (direct or indirect). Further studies are warranted for efficient targeting and to gain better understanding of the associated signaling involved in miR-494 modulation in CRC. Support: U10CA180821, U10CA180882; U10CA180888 (SWOG): Genentech. https://acknowledgments.alliancefound.org; P30CA014089, UG1CA180830 [HJL]. Clinicaltrials.gov Identifier: NCT00265850 Citation Format: Pooja Mittal, Joshua Millstein, Shivani Soni, Francesca Battaglin, Karam Ashouri, Sandra Algaze, Priya Jayachandran, Yan Yang, Lesly T. Gonzalez, Unnati H. Shah, Wu Zhang, Fang-Shu Ou, Alan P. Venook, Indrakant K. Singh, Heinz J. Lenz. Effect of miR-494 modulation in colorectal cancer (CRC): Clinical outcome, target expression and cell characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2787.

Objectives Few studies have investigated health outcomes associated with arthritis in low-middle-income countries. Our objective was to examine the association between arthritis and all-cause hospitalization and mortality among middle-aged and older adults in Mexico. Methods Our sample included 12,106 participants aged >50 years from the 2012, 2015, and 2018 waves of the Mexican Health and Aging Study. Logistic regression was used for the associations between arthritis and hospitalization. Kaplan–Meier and Cox proportional hazard models were used for the association between arthritis and mortality. Results Arthritis was associated with higher odds of hospitalization (OR = 1.23; 95% CI = 1.09–1.38), but not mortality. Arthritis with physical limitations had the highest odds of hospitalization (OR = 1.48; 95% CI = 1.27–1.73). Arthritis with joint pain (OR = 1.24; 95% CI = 1.10–1.41) and medication use (OR = 1.28; 95% CI = 1.11–1.48) had higher odds of hospitalization. Conclusion Among middle-aged and older adults in Mexico, arthritis was associated with a high risk of hospitalization.