Clinical outcomes and impact of mismatch repair deficiency (dMMR) in patients with pT4N0 colon cancer (CC): Data from a large, consecutive, multicenter, real-world cohort.
Authors: Puccini Alberto , Rossini Daniele , Daprà Valentina , Schietroma Francesco , Perazzo Serena , Ceccarelli Anna , Zoratto Federica , Costantini Manuel , Formica Vincenzo , Rofei Michela , Mauri Gianluca , Bonazzina Erica , Tamburini Emiliano , Signorelli Carlo , Antonuzzo Lorenzo , Damonte Camilla , Spinelli Antonino , Tortora Giampaolo , Santoro Armando , Salvatore Lisa 
Published: June 2024

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Background: T4 is widely recognized as one of the most important and independent prognostic factors in adjuvant setting for CC patients. However, the optimal management in terms of adjuvant treatment in stage II (pT4N0) as well as the impact of DNA mismatch repair deficiency (dMMR) in this subset of patients remain unclear. Here, we present a large, multicenter, real-world analysis of pT4N0 CC patients. Methods: A real-world database including pts treated at 9 Italian institutions from April 2010 to November 2023 was queried. Clinico-pathological characteristics of pts diagnosed with a stage II pT4N0 CC were analyzed. Pts were stratified according to duration of treatment, DNA mismatch repair (MMR) status, type of adjuvant chemotherapy (ACT). The primary endpoints were median relapse-free survival (RFS) and overall survival (OS). Results: A total of 380 pts was included, and outcomes data were available for 288 pts.Median age was 73 years and 49% of pts were male. 47 pts (16%) had dMMR CC, among which Lynch Syndrome was diagnosed in 19%. 10% of pts had BRAF mutant tumor, and 38% KRAS mutant tumor. After a median follow-up of 40.6 months (37.9-49.3), 3-yr RFS and 5-yr RFS were 70% and 55%, respectively, regardless treatment; 3-yr OS was 88% and 5-yr OS 73%. 154 pts (53%) received ACT: oxaliplatin (oxa)-based CT was given to 103 pts (67%), compared to 51 pts who received monotherapy (33%). Six-month ACT was given to 38 pts (74.5%) and 75 pts (72.8%) in the monotherapy and oxa-based group, respectively. Pts receiving 6-month ACT had a significant longer OS compared to those who did not receive ACT (HR 0.17; 0.08-0.34; p <.001). A trend towards improved OS was observed in pts receiving 6-month ACT versus pts receiving 3-month ACT (HR 0.46; 0.16-1.29; p 0.129). Similar results were observed in terms of RFS: 6-month ACT showed a longer RFS compared to 3-month ACT (HR 0.58; 0.32-1.05; p .068), and a significantly longer RFS compared to no-ACT (HR 0.50; 0.32-0.77; p .001). Oxa-based ACT was associated with a significant improvement in OS compared to monotherapy (HR 0.30; 0.11-0.85; p .016). Overall, pts with dMMR CC did not show a statistically significant difference in terms of OS and RFS (p .66 and .19 respectively) compared to proficient MMR pts. Conclusions: In this large real-world dataset, T4 was confirmed being a key poor prognostic factor, independently to MMR status. We observed that ACT provides large benefit in this population, and oxa-based ACT may be better than monotherapy. In addition, 6-month oxa-based ACT showed a trend towards a better outcome in comparison to 3-month ACT, even if not statistically significant. Given the retrospective nature of the study, these data should be validated in larger and prospective cohorts; however, this work may help oncologists in shared decision making in this specific subgroup of patients.