Abstract 1014: High tumor mutational burden in patients with mismatch repair proficient metastatic colorectal cancer: Single institution cohort

Abstract

Abstract Background: High Tumor Mutational Burden (TMB) in metastatic colorectal cancer (mCRC) is mostly associated to microsatellite instability (MSS/MMRp) or alterations in POLE/POLD1 genes [1]. Tumors harboring these molecular profiles are also associated with specific clinical-pathological features well described in literature [2; 3] and treatment with immune checkpoint inhibitors (ICI) represent the therapy with the highest expected benefit [4; 5; 6; 7; 8]. This subgroup of population represents almost 5% of the entire population of mCRC patients (pts) [9; 10]. About the remaining 95% of the population, for which immunotherapy doesn’t seem to improve outcome [4; 10; 11; 12], we know that a subgroup of pts reported high TMB, not related to MSS/MMRp or mutation in Polymerase genes [1]. For this subgroup data are scarce in the literature. Methods: We selected a case series of MSS/MMRp, non-POLE/POLD1 mCRC cases with documented TMB >= 10mut/Mb at comprehensive genomic profiling tested with Foundation Medicine panel between January 2019 and June 2022. Clinical-pathological features were collected from clinical reports and evaluated with descriptive statistics. Two pathologists reviewed the slides to assess histopathological features. Results: 24 out of 693 (3.5%) pts had MSS/MMRp, non-POLE/POLD1 mCRC with TMB >= 10 Mut/Mb. Average TMB was 19.04 mut/Mb (10 - 104.65 mut/Mb). 56% were male; median age at mCRC diagnosis was 58 years old (IQR 48-64 yo). 16 pts had left-side primary tumor, 6 of which had rectal cancer. 14 had synchronous metastases and the most frequent stage parameters were T3/4 and N+. The following histotypes were documented: 18/24 were adenocarcinoma NOS, 3/24 mucinous, 1/24 of cribriform comedonecrosis type, 1/24 a mixed neuroendocrine-non-neuroendocrine neoplasm (MiNen) and 1/24 not assessable. With regard to grading, 12/24 high-grade cases and 11/24 low-grade cases, 1 case not assessable. 7/18 assessable cases had high tumor infiltrating lymphocytes (TILs) (>=2.0 TILs/HPF) and 18/18 assessable cases showed signs of lympho-vascular invasion. According to comprehensive molecular profiling, the 5 most frequent genes altered were APC (80.0%), TP53 (72.0%), KRAS (24.0%), SMAD2/4 (24.0%), PIK3CA (24.0%). 3 pts had BRAF V600E mutations. In our case study, 23 out of 24 pts started 1st line treatment for metastatic disease, of which 21 with poli-chemo schedules. Data about best response were available for 21 cases and ORR was 61.9%, DCR 90.4%. Median PFS was 13.6 months (IQR 5.6 - 25.9). Median OS was 47.2 months (IQR 25.7 - 63.3). Conclusion: MSS/MMRp, non-POLE/POLD1, TMB >= 10 mut/Mb is a small but defined subgroup of mCRCs. To better understand the molecular behavior of this rare subgroup of cancers, further study should investigate the underlying mechanism, the TMB cut-off relevance in mCRC and the potential predictive impact on immunotherapy efficacy. Citation Format: Giulia Maddalena, Valentina Angerilli, Gianmarco Ricagno, Aldo Montagna, Riccardo Cerantola, Giada Munari, Sara Lonardi, Francesca Bergamo, Matteo Fassan. High tumor mutational burden in patients with mismatch repair proficient metastatic colorectal cancer: Single institution cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1014.