Abstract 3407: Development of a chemokine signature identifying dMMR patients (pts) with poor prognosis
Authors: Wang Ying , Kim Rim S. , Lipchik Corey , Srinivasan Ashok , Feng Huichen , Song Nan , Allegra Carmen J. , Gavin Patrick G. , Jacobs Samuel A. , Wolmark Norman , Lucas Peter C. , Pogue-Geile Katherine L. 
Published: August 2019

BACKGROUND: Colorectal cancer (CRC) pts with deficient mismatch repair (dMMR) tumors have greater immune cell infiltration than pts with proficient (pMMR) tumors and is thought to be partly responsible for the robust response of dMMR pts to PD-1/PD-L1 blockade. Not all pts with dMMR tumors respond to PD-1 blockade. Therefore, we conducted exploratory analyses to understand the complexity of the tumor immune microenvironment. We developed a gene expression signature predictive for MMR status and tested it for associations with prognosis.

METHODS: The one-sided Wilcoxon signed-rank test was used to select genes that were significantly over expressed in dMMR v pMMR tumors in a randomly selected discovery cohort in NSABP C-08 (N=500). Six chemokine genes were selected to build a predictive signature for MMR status because they were among the top 20 most significantly differentially expressed genes and were part of an immune chemo-attractant pathway. Addition of other genes did not improve prediction accuracy. The signature was tested in an independent cohort of C-08 (N=454) and in three other data sets: NSABP C-07 (N=1603), TCGA colon (N=619), and the NSABP Molecular Profiling Registry (MPR-1) (N=263). MPR-1 tissue samples were from primary tumors in pts who had recurred. Survival analyses were performed in C-07, C-08, and TCGA data, using Cox proportional hazards models. MMR status was determined for MPR-1 tissues with IHC using antibodies for MSH2, MLH1, PMS2, and MSH6.

RESULTS: Higher chemokine scores (CKS) were significantly associated with dMMR tumors in all three independent data sets composed of treatment-naïve early-stage CRC pts (P&lt;0.01). However, in primary tumors of dMMR pts who developed recurrent disease, CKS was non-significantly lower than pts with pMMR tumors (P=0.072). As expected, high CKS was associated with a better prognosis in all three data sets, composed of early-stage CRC and was a more robust prognostic indicator in all 3 datasets than was MMR status. When CKS was combined with MMR status in early-stage pts, pts with high CKS had a better prognosis than pts with low CKS regardless of MMR status.

CONCLUSIONS: The CKS score has a strong association with MMR status in three different data sets and is associated with a better prognosis in early-stage CRC. In these pts, dMMR tumors had significantly higher CKS than pMMR tumors, but primary tumors from MPR1 pts who had all become metastatic showed a trend for association in the reverse direction. We conclude that dMMR primary tumors, which are likely to become metastatic, have a very different immune microenvironment than those that do not because the CKS is composed of chemo attractants for a variety of immune cells including NK, T, and B cells. Such a signature could be useful for prospectively identifying dMMR pts with early-stage CRC who are at high risk for relapse. SUPPORT: Genentech; sanofi; U10CA180868, UG1CA189867, U24CA196067, PA DoH; NSABP Foundation.

Citation Format: Ying Wang, Rim S. Kim, Corey Lipchik, Ashok Srinivasan, Huichen Feng, Nan Song, Carmen J. Allegra, Patrick G. Gavin, Samuel A. Jacobs, Norman Wolmark, Peter C. Lucas, Katherine L. Pogue-Geile. Development of a chemokine signature identifying dMMR patients (pts) with poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3407.