Abstract
IntroductionIn a retrospective analysis of two randomized phase III trials in mCRC patients treated first line with oxaliplatin, fluoropyrimidine with and without Bevacizumab (the AIO KRK 0207 and R091 trials) we evaluated the association of high microsatellite instability (MSI-H), immunoscore (IS) and PD-L1 expression in relation to overall survival (OS).MethodsIn total, 550 samples were analysed. Immunohistochemical analysis of the MMR proteins and additionally fragment length analysis was performed, molecular examinations via allele-discriminating PCR in combination with DNA sequencing. Furthermore PD-L1 and IS were assessed.ResultsMSI-H tumors were more frequent in right sided tumors (13.66% vs. 4.14%) and were correlated with mutant BRAF (p = 0.0032), but not with KRAS nor NRAS mutations (MT). 3.1% samples were found to be PD-L1 positive, there was no correlation of PDL1 expression with MSI-H status, but in a subgroup analysis of MSI-H tumors the percentage of PD-L1 positive tumors was higher than in MSS tumors (9.75% vs. 2.55%). 8.5% of samples showed a positive IS, MSI-H was associated with a high IS. The mean IS of the pooled population was 0.57 (SD 0.97), while the IS of MSI-H tumors was significantly higher (mean of 2.4; SD 1.4; p =< 0.0001).DiscussionRegarding OS in correlation with MSI-H, PD-L1 and IS status we did not find a significant difference. However, PD-L1 positive mCRC tended to exhibit a longer OS compared to PD-L1 negative cancers (28.9 vs. 22.1 months).
Highlights
In a retrospective analysis of two randomized phase III trials in mCRC patients treated first line with oxaliplatin, fluoropyrimidine with and without Bevacizumab we evaluated the association of high microsatellite instability (MSI-H), immunoscore (IS) and PD-L1 expression in relation to overall survival (OS)
Regarding IS-negative vs. -positive pts. (21.1 months vs. 22.1 months; p = 0.25, Fig. 5c). In this pooled analysis of two randomized phase III trials (AIO KRK 0207, R091; Hegewisch-Becker et al 2015, Porschen et al 2007) of newly diagnosed mCRC treated first line with ox, FP with and without bev, we investigated the prognostic value of MSI-H, IS and PD-L1 expression and their correlation
Microsatellite status (MS) in mCRC correlated with a positive IS, but not with PD-L1 expression, none of these immune markers seemed prognostic for OS in mCRCs
Summary
The development of colorectal cancer (CRC) follows distinct pathways involving microsatellite instability (MSI-H) or chromosomal instability (CIN) and is triggered by molecular mutations (BRAF, RAS, PI3K, APC, EGFR, TP53, etc.) which may offer individualized therapy strategies. These affect immune cells mainly T-lymphocytes to invade into the tumor microenvironment to present these neoantigens via MHC to recruit more immune active cells To eliminate this immunological unbalance, MSI-H tumors increase the expression of immunosuppressive checkpoints such as PD-1, PD-L1, and CTLA4 (Llosa et al 2015). Likewise tumor mutational burden (TMB) may function as a predictor for response and prognosis, a retrospective analysis from the CALGB/SWOG80405 trial demonstrated a superior OS among tumors with high TMB (Innocenti et al 2019) This is a retrospective analysis of two randomized phase III trials (AIO KRK 0207, R091; (HegewischBecker et al 2015; Porschen et al 2007)) of the association of mCRC treated first line with oxaliplatin (ox), fluoropyrimidine (FP) with and without bevacizumab (bev) and MSI-H, IS and PD-L1 expression in relation to OS
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