Pathological complete response in a POLE-mutated non-small cell lung cancer patient treated with perioperative chemo-immunotherapy: A case report and review of the literature

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all lung cancer cases. Despite significant advances in early detection and targeted therapy, the prognosis for patients with locally advanced stage III NSCLC remains poor, with five-year survival rates ranging from 20% to 40% depending on the specific stage and treatment approach. The treatment landscape for stage III NSCLC has undergone a dramatic transformation in recent years with the introduction of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly agents targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis.

Landmark clinical trials have demonstrated that neoadjuvant chemo-immunotherapy significantly improves event-free survival and increases the rate of pathological complete response (pCR) compared with chemotherapy alone in resectable stage III NSCLC, establishing this approach as a new standard of care. Similarly, adjuvant immunotherapy following chemoradiation has demonstrated significant overall survival benefit in unresectable stage III disease. Despite these advances, a substantial proportion of patients do not derive significant benefit from immunotherapy, and identifying predictive biomarkers of response remains a critical unmet clinical need. Currently, PD-L1 expression by immunohistochemistry is the most widely used predictive biomarker, but it has significant limitations, including imperfect correlation with treatment response and substantial inter-observer and inter-laboratory variability.

Tumor mutational burden (TMB) has emerged as another potential predictive biomarker, but its clinical utility remains controversial and it is not routinely used in clinical practice. DNA polymerase epsilon (POLE) is a critical enzyme involved in DNA replication and repair, playing a central role in maintaining genomic stability through its proofreading exonuclease activity. POLE is responsible for leading-strand DNA synthesis during replication, and its 3'-5' exonuclease domain provides proofreading activity that corrects mispaired nucleotides, ensuring high-fidelity DNA replication. Germline mutations affecting the proofreading domain of POLE (and the related POLD1 gene) were first identified in 2013 as a cause of hereditary colorectal cancer predisposition, and subsequent studies have demonstrated that somatic POLE mutations occur in a variety of human cancers, including endometrial cancer, colorectal cancer, and, less frequently, NSCLC. POLE mutations, particularly those affecting the exonuclease proofreading domain, lead to a hypermutator phenotype characterized by markedly increased tumor mutational burden and a specific mutational signature (Signature 10), resulting from the accumulation of replication errors that would normally be corrected by the proofreading activity.

The high TMB associated with POLE mutations leads to increased neoantigen generation and enhanced presentation of tumor-specific antigens on major histocompatibility complex molecules, which in turn promotes increased tumor immunogenicity and enhanced recognition by the immune system. Mechanistically, this increased immunogenicity is thought to underlie the observed association between POLE mutations and increased sensitivity to immune checkpoint inhibitor therapy, which has been demonstrated in endometrial cancer, colorectal cancer, and other tumor types. In NSCLC, POLE mutations are relatively rare, occurring in approximately 1-2% of cases, and their potential as predictive biomarkers for immunotherapy response remains incompletely explored, with only limited case reports and small series published to date.

This case report describes a 52-year-old woman who presented with stage IIIA (T2N2M0) non-small cell lung cancer, specifically adenocarcinoma histology. The patient underwent comprehensive molecular profiling of her tumor, which revealed a somatic POLE mutation (NM_006231.4: c.1270C>G, p.Leu424Val) in the absence of other targetable driver alterations, including EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, MET exon 14 skipping mutations, RET rearrangements, NTRK fusions, and KRAS G12C mutations. Notably, the tumor demonstrated negative PD-L1 expression (tumor proportion score < 1%), a factor that would typically be associated with a reduced likelihood of response to single-agent immunotherapy. Given the patient's resectable stage III disease and the presence of a POLE mutation, which has been associated with increased immunotherapy sensitivity in other tumor types, a perioperative chemo-immunotherapy approach was selected.

The patient received three cycles of neoadjuvant therapy consisting of carboplatin, pemetrexed, and pembrolizumab (an anti-PD-1 monoclonal antibody), administered every three weeks. Restaging computed tomography after completion of neoadjuvant therapy revealed a significant radiographic response, with substantial reduction in the size of the primary tumor and mediastinal lymph nodes. The patient subsequently underwent curative-intent surgical resection, and histopathological examination of the surgical specimen demonstrated a pathological complete response (pCR), defined as the absence of viable tumor cells in both the primary tumor resection specimen and the resected lymph nodes. This represents a particularly remarkable outcome given the patient's negative PD-L1 expression, which would typically predict a lower likelihood of deep response to immunotherapy-containing regimens.