Circulating Osteopontin Predicts Clinical and Radiological Response in First-Line Treatment of Advanced Non-Small Cell Lung Cancer

Abstract

Purpose: Pembrolizumab-based regimens are conditioned by the expression of PD-L1, but durable response rate is limited by innate and acquired resistance mechanisms. Here, we focus on osteopontin (OPN), an upfront biomarker of senescence, which closely associated with natural history of non-small cell lung cancer (NSCLC).

Methods: Seventy-nine patients eligible to pembrolizumab regimens-alone or in combination with chemotherapy-as first-line treatment of advanced NSCLC were enrolled. Predictive value of OPN toward iRECIST progression disease (PD) was set as first outcome. Secondary ones included performance status (ECOG) at baseline, early (first and best) responses, and overall survival (OS).

Results: High Serum OPN characterized patients with worse ECOG-PS (p = 0.015) at baseline and subjects experienced PD/death at first (OR 1.17 [1.02 to 1.35]; p = 0.030) and best responses (0.04 [0.00 to 0.81]; p = 0.035). OPN was associated with time-to-progression (B -2.74 [-4.46 to -1.01]) and time-to death (-0.13 [-0.20 to -0.05]). Cox regression models unveil a predictive value for iRECIST-PD (HR 1.01 [1.00 to 1.02]; p = -0.005), RECIST-PD (HR 1.01 [1.00 to 1.02]; p = 0.017), and OS (HR 1.02 [1.01 to 1.03]; p = 0.001). These models were internally validated through bootstrap resampling and characterized by relevant discrimination ability at ROC curve analyses.

Conclusion: Baseline levels of serum OPN is closely associated with performance status and short/long term outcomes in patients with advanced NSCLC, which are candidate to pembrolizumab-based regimens. As upfront biomarker of senescence, OPN may pave the way for future studies focusing on senescence patterns in NSCLC.

Keywords: Immunotherapy; Lung cancer; Mortality; Osteopontin; Pembrolizumab; Progression-free survival.

Fig. 1

Osteopontin is closely associated with clinical presentation of advanced non-small cell lung cancer. Panels A and B summarized performance status according with performance status (ECOG; Eastern Cooperative Oncology Group) and early response defined by first/best responses at computerized tomography (CT) and categorized as: complete response (CR), partial response (PR), stable disease (SD), progression disease (PD) or death. Outcomes were classified according with immune-related criteria (iRECIST) (C and D). Association studies of osteopontin (OPN) with white blood cell (WBC) and neutrophil (PMN) counts, and ECOG as well are also reported (MMP: matrix metalloproteinase) (E to H)

Fig. 2

Osteopontin predicts early clinical response to therapies in advanced non-small cell lung cancer. White blood cell (WBC) and neutrophil (PMN) counts, matrix metalloproteinase (MMP) and osteopontin (OPN) were tested as predictor of and early response defined by first (A to D) and best (E to H) responses at computerized tomography (CT) and categorized as: complete response (CR), partial response (PR), stable disease (SD), progression disease (PD) or death. Outcomes were classified according with immune-related criteria (iRECIST) (C and D)

Fig. 3

Osteopontin predicts late clinical response to therapies in advanced non-small cell lung cancer. Performance status (ECOG; Eastern Cooperative Oncology Group) White blood cell (WBC) and neutrophil (PMN) counts, matrix metalloproteinase (MMP), myeloperoxidase (MPO), osteopontin (OPN), and tissue inhibitor of matrix metalloproteinase (TIMP) were tested as predictor of and late response defined by progression disease (PD) assessed by both immune-related or not criteria (iRECIST and RECIS, respectively) and presented as hazard ratio (HR) with 95% confidence interval (CI) (A to C). Models then built were then test at receiver operator characteristic (ROC) curve analysis (D)