**Predicting the Role of DNA Polymerase** β **Alone or with** *KRAS* **Mutations in Advanced NSCLC Patients Receiving Platinum-Based Chemotherapy**

**Maria Francesca Alvisi 1,**†**, Monica Ganzinelli 2,**†**, Helena Linardou 3,**†**, Elisa Caiola 4,**†**, Giuseppe Lo Russo 2, Fabiana Letizia Cecere 5, Anna Cecilia Bettini 6, Amanda Psyrri 7, Michele Milella 8, Eliana Rulli 1, Alessandra Fabbri 9, Marcella De Maglie 10,11, Pierpaolo Romanelli 10,11, Samuel Murray 12, Gloriana Ndembe 4, Massimo Broggini 4,\*, Marina Chiara Garassino 2,**‡ **and Mirko Marabese 4,\*,**‡


Received: 26 June 2020; Accepted: 28 July 2020; Published: 30 July 2020

**Abstract:** Clinical data suggest that only a subgroup of non-small cell lung cancer (NSCLC) patients has long-term benefits after front-line platinum-based therapy. We prospectively investigate whether KRAS status and DNA polymerase β expression could help identify patients responding to platinum compounds. Prospectively enrolled, advanced NSCLC patients treated with a first-line regimen containing platinum were genotyped for KRAS and centrally evaluated for DNA polymerase β expression. Overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR) were recorded. Patients with KRAS mutations had worse OS (hazard ratio (HR): 1.37, 95% confidence interval (95% CI): 0.70–2.27). Negative DNA polymerase β staining identified a subgroup with worse OS than patients expressing the protein (HR: 1.43, 95% CI: 0.57–3.57). The addition of KRAS to the analyses further worsened the prognosis of patients with negative DNA polymerase β staining (HR: 1.67, 95% CI: 0.52–5.56). DNA polymerase β did not influence PFS and ORR. KRAS may have a negative role in platinum-based therapy responses in NSCLC, but its impact is limited. DNA polymerase β, when not expressed, might indicate a group of patients with poor outcomes. KRAS mutations in tumors not expressing DNA polymerase β further worsens survival. Therefore, these two biomarkers together might well identify patients for whom alternatives to platinum-based chemotherapy should be used.

**Keywords:** NSCLC; KRAS; DNA polymerase beta; platinum-based first-line
