Improving the prognosis for lung cancer patients

Abstract

Lung cancer is one of the leading causes of cancer-related deaths worldwide. At the time of diagnosis, more than half of the patients with non-small cell lung cancer (NSCLC) presents with inoperable, advanced stage III–IV disease [1]. In advanced stage settings, treatment options are based on histology, molecular features and genomic alterations, in addition to the general condition and comorbidities of the patients. Within the last decade, several new treatment modalities have been introduced, e.g., tyrosine kinase inhibitors, immune checkpoint inhibitors, and most recently the combination of chemotherapy and checkpoint inhibitors [2–6]. However, despite advances in treatment, the overall prognosis for NSCLC has not yet improved significantly. The poor prognosis may in part be explained by the large proportion of patients presenting in advanced stage. The effect of lung cancer screening has therefore been investigated in several trials [7–11]. In the National Lung Screening Trial, early diagnosis by low-dose CT (LDCT) screening resulted in a 20% mortality reduction and led to recommendations for LDCT in the US [11]. The Dutch-Belgian NELSON trial was designed to investigate the effect of LDCT screening on lung cancer mortality after 10 years of follow-up. Stage distribution of screening-detected lung cancers seems to be favorable as 64% are diagnosed in stage I and less than 10% in stage IIIb/IV. The true outcome of the trial procedures is yet to be determined [10]. Early mortality is another contributing factor to a poor prognosis. The prevalence of chronic diseases is particularly high in lung cancer patients as smoking is a shared major risk factor, especially chronic obstructive pulmonary disease (COPD), which is observed in 50–70% of patients [12,13]. Selection of patients that will benefit from active systemic treatment, prediction of early mortality and optimized treatment of comorbidity is therefore essential. In Acta Oncologica, Amini et al. present results from a study based on the National Cancer Database in the US investigating early mortality in a large group of patients with NSCLC [14]. Thirteen percent of the patients experienced early mortality, however the majority of these patients did not receive active anticancer treatment. It may indicate that clinicians to some extent actually select patients that may or may not benefit from treatment. Objective predictive factors for selection of patients to treatment are though still warranted in order to optimize cancer care and potentially enhance survival. Several studies have investigated the influence of comorbidities on NSCLC mortality and diverging results have been reported, including the study from Media et al. in Acta Oncologica [15–17]. Data are very heterogeneous, and it remains unclear if the poor treatment outcome is due to comorbidity or perhaps an altered treatment intensity in this group of patients. In the era of personalized medicine and tailored therapies, selection of patients for treatment is essential in order to improve clinical response, but also to avoid unnecessary treatment and toxicity as well as early mortality. The selection may be facilitated by combination of clinical data, imaging features, and various biomarkers. Tissue-based biomarker analysis is still the gold standard. Availability of tumor tissue is therefore crucial for treatment decision. Tumor heterogeneity, clonality, and the perspectives of genomic profiling increase the need for repeated biopsies and molecular characterization of the tumor. In NSCLC, this is challenging due to tumor location, and the fact that tissue is not always available for analysis. Liquid biopsies with analysis of circulating tumor cells and circulating tumor DNA (ctDNA) hold a great potential to overcome these challenges. In Acta Oncologica, Isaksson et al. explore the feasibility of adding ctDNA and a panel of tumor markers to enhance early detection of recurrence in previously operated NSCLC patients with certain driver mutations [18]. However, at present technical challenges, including different test platforms, varying detection rates and difficult-to-interpret data, has to be overcome before liquid biopsy becomes a standard tool. Moreover, the currently most important biomarker for treatment with immunotherapy in NSCLC, i.e., the programed death ligand-1 (PD-L1), is not detectable this way; it still relays on analysis of tumor specimens, which may be challenging. The observational study in Acta Oncologica by Reiniger et al. of PD-L1 and programed death-1 (PD-1) expression and morphological features in lung cancer specimens provides insight to this [19]. In the near future, noninvasive procedures such as positron emission tomography (PET) may also represent a key opportunity for molecular characterization of tumors. Currently, several novel PET tracers targeting various cancer