Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. PATIENTS AND METHODS: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). RESULTS: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. CONCLUSIONS: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

Interpretation of lipoprotein-associated phospholipase A2 levels is influenced by cardiac disease, comorbidities, extension of atherosclerosis and treatments.

PURPOSE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker secreted in the atherosclerotic plaque. Blood levels of Lp-PLA2 predict future cardiovascular events in patients with ischemic disease and heart failure. This association seems to be independent of traditional cardiovascular risk factors. The aims of our study were (1) to assess relationships between Lp-PLA2 levels, cardiac disease and treatments; (2) to evaluate the association of Lp-PLA2 level with the severity of angiographic coronary artery disease (CAD) and the extracoronary atherosclerosis. METHODS: Between December 2009 and June 2010, 494 subjects were recruited from a population scheduled for diagnostic coronary angiography. Routine clinical (age, gender, BMI and treatment), cardiac (echocardiography, coronarography, carotid ultrasonography) and biochemical parameters were recorded for all patients. Lp-PLA2 mass concentration was assessed in serum with a Plac®-test turbidimetric immunoassay. Control Lp-PLA2 values were specifically obtained in 61 healthy subjects aged 44.5 ± 17.6 years (range: 25 to 59 years) without known cardiovascular risk factors (diabetes, smoking, hypertension, dyslipidemia) or cardiac treatment. RESULTS: In healthy controls, mean Lp-PLA2 level was 163 ± 43 µg/L (166 ± 45 µg/L in men and 159 ± 39 µg/L in women, non significant difference). In our cohort of 494 patients (69.8% men) aged 64.2 ± 16.7 years, the main etiologies of cardiomyopathies were ischemic (40%), valvular (22%), cardiac failure with left ventricular (LV) dysfunction (14%), infection (5%) and aortic aneurysm (7%). Mean Lp-PLA2 levels were 216 ± 17 µg/L. Lp-PLA2 correlated with age, BMI, current smoking, history of hypertension but not with diabetes and gender. The bivariate analysis showed a significant correlation between Lp-PLA2, and BMI (p=0.001) but no correlation with serum creatinine or NYHA status. A multivariate correlation showed that Lp-PLA2 was associated with total cholesterol, LDL-cholesterol and apoB (r=0.95, p<0.0001) but not with Lp(a). We observed that Lp-PLA2 was significantly associated with treatments such as statins and ACEi/ARA2 but not with ß-blockers, antiaggregant drugs or diuretics. Lp-PLA2 levels were significantly higher in patients with CAD than in patients without CAD (223 ± 54 vs. 208 ± 52 µg/L, respectively; p<0.007). Moreover, Lp-PLA2 levels were significantly higher in patients with the most extensive angiographic CAD [single (n=24)=215.2 ± 52 µg/L; two (n=55)=222 ± 53 µg/L and three vessels (n=140)=251.9 ± 53.7 µg/L, respectively; p<0.0001]. Patients with heart failure, sepsis or aortic aneurysm had increased Lp-PLA2 levels: 256.2 ± 46.8; 226.7 ± 47.3; 218.1 ± 38.9 µg/L, respectively, as compared to controls (p<0.0001). In patients with carotid artery disease, Lp-PLA2 significantly increased with the severity of atherosclerosis. Mean Lp-PLA2 levels were 218.8 ± 51 µg/L in the group without any stenosis (n=108), 224 ± 51 µg/L in the group with mild stenosis (n=101), and 231 ± 46 µg/L in the group with severe stenosis (n=22); p=0.004. CONCLUSION: This study clearly shows that interpretation of Lp-PLA2 levels needs a good assessment of cardiac parameters and treatments, especially statins and ACEi/ARA2. Lp-PLA2 levels are significantly associated with coronary heart disease and with the extension of extra coronary disease after adjustment for age and gender.