B7-H3 is eligible for predicting clinical outcomes in lung adenocarcinoma patients treated with EGFR tyrosine kinase inhibitors

Abstract

Background Not all lung adenocarcinoma (LUAD) patients with activating epidermal growth factor receptor (EGFR) mutations respond to tyrosine kinase inhibitors (TKIs) as intended. Thus, biomarkers are needed to identify patients who benefit most from EGFR-targeted therapy. Our previous in vitro data has shown that the co-signal molecule B7-H3 determines EGFR-TKI gefitinib susceptibility of EGFR-mutated LUAD cell lines, based on the potential crosslinking between B7-H3-induced signaling and EGFR signaling. Methods We detected tumoral B7-H3 expression in the original biopsy from 56 treatment-naïve LUAD patients and analyzed the association between high/low B7-H3 expression with the clinical outcomes of first-line anti-EGFR therapy. The main criteria for the analysis of response were overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS), and the secondary criterion was overall survival (OS). Results In the subgroups of B7-H3 high and low expression, the ORR were 16.0% (4/25) and 74.2% (23/31) (p<0.001), and the DCR were 36.0% (9/25) and 87.1% (27/31) (p<0.001), respectively. The PFS of B7-H3 high [median 8.7, 95% confidence interval (CI) 4.0–13.4] was significantly worse than that of B7-H3 low (median not reached) [HR 6.54 (95% CI 2.18–19.60), p=0.001]. The median OS was 15.9 (95% CI 10.0–21.8) months in the B7-H3 high cohort and 25.7 (95% CI 9.0–42.4) months in the B7-H3 low subjects [HR 2.08 (95% CI 1.07–4.02), p=0.03], respectively. Both the univariate and multivariate analyses identified B7-H3 as an independent factor associated with poor PFS (p=0.001, p=0.000) and OS (p=0.03, p=0.015). Conclusion B7-H3 may serve as a potential biomarker to predict clinical outcomes in EGFR-mutated LUAD patients treated with first-line EGFR-TKIs.

Network Pharmacology-Integrated Molecular Docking Reveals the Expected Anticancer Mechanism of Picrorhizae Rhizoma Extract

“…Loss of function of EGFR and other protein tyrosine kinases or abnormal activity or cell localization of key factors in their related signaling pathways can cause tumors, diabetes, immune deficiency, and cardiovascular diseases. EGFR is a target involved in non-smallcell, lung cancer, lung adenocarcinoma, and cholangiocarcinoma [26][27][28]. ESR1, an estrogen receptor, affects cell proliferation and differentiation in target tissues, participating in the pathological process including breast cancer, endometrial cancer, and osteoporosis [29,30].…”

B7-H3/CD276 Inhibitors: Is There Room for the Treatment of Metastatic Non-Small Cell Lung Cancer?

“…The B7-H3 high group was associated with poor progression-free survival (PFS) and overall survival (OS), suggesting a predictive role of B7-H3 in patients with activating EGFR mutations. However, the distribution of high and low B7-H3 expression was not related to age, sex, tumor size, staging, or EGFR mutation patterns [7].…”

“…B7-H3 is a novel immune checkpoint from the B7 family that is highly expressed in NSCLC. Interestingly, B7-H3 expression in NSCLC seems to be correlated with low PD-L1 expression and with a poor prognosis in EGFR mutant patients, leading to speculation about an alternative biological pathway and suggesting a role for B7-H3 as an ICI in NSCLC patients [7,9,10]. Compared to other ICIs, B7-H3 appears to be a unique and powerful target, having a role in immune-mediated and non-immune-mediated pathways.…”

“…A similar scoring system with a different H7-B3 clone (SP206) was applied by Yang et al [7] in 56 advanced pulmonary adenocarcinoma patients harboring activating EGFR mutations. Briefly, the intensity of membranous and cytoplasmatic B7-H3 reactivity in neoplastic cells was defined as 0 (no staining), 1 (weak), 2 (intermediate), and 3 (strong).…”

“…An overall immunoreactive score was assigned by multiplying the staining intensity and the percentage of positive tumor cells, which yielded a range from 0 to 12. All cases were divided into B7-H3 low (<6) and B7-H3 high groups (6)(7)(8)(9)(10)(11)(12). The B7-H3 high group was associated with poor progression-free survival (PFS) and overall survival (OS), suggesting a predictive role of B7-H3 in patients with activating EGFR mutations.…”