Investigation of small-cell lung cancer epidemiology in Sweden and analysis of clinical and tumor specific prognostic biomarkers

Small-cell lung cancer (SCLC) accounts for approximately 13% of all newly diagnosed lung cancer (LC) cases. This disease is correlated with heavy smoking. It is characterized by a rapid doubling time combined with a propensity to metastasize quickly and by neuroendocrine differentiation. In patients with locally advanced disease, the standard of care is concurrent radiation and platinum-doublet chemotherapy (PDCT). Patients with stage IV disease have also until recently been treated with PDCT. Even though a majority of SCLC cases initially responds to PDCT, almost all patients inevitably relapse. This thesis aims to deepen the knowledge of SCLC.

Paper I was a population-based study, where we aimed to investigate the possible association between educational levels and overall death of Swedish SCLC patients. The patient population consisted of 4256 subjects. The key findings showed that educational level is an independent prognostic factor in Swedish men diagnosed with SCLC and among patients with Limited disease. In paper II, we performed a validation of the 8th TNM staging system on 706 SCLC cases and compared the system´s prognostic performance to the 6th and 7th TNM editions as well as to the older two-stage system that segmented patients as either having Limited Disease (LD) or Extensive Disease (ED). The study provided additional information supporting the robustness of the 8th TNM edition in prognostically categorizing SCLC and confirms its usefulness in clinical practice. In paper III, we conducted a real-world study on 545 consecutive cases during an eight-year period. The aim was to understand in depth the treatment patterns of SCLC patients from Karolinska University Hospital. Another goal was to examine the outcome of SCLC patients upon re-challenge with PDCT. The survival outcomes for LD and ED SCLC patients were poor, correlating with previous studies. The results also showed that SCLC patients with sensitive relapse after first line PDCT may benefit from re-challenge. In paper IV, the expression of multiple biomarkers, including Notch1, Hes1, Ascl1, and DLL3, were analysed in a selected cohort of 46 SCLC patients. The study, in part, focused on how the expression patterns differed based on patients’ resistance or sensitivity to PDCT. We evaluated the prevalence of expression of these four biomarkers in human samples using biopsies and studied the potential association with survival and benefit from 1st line PDCT. The study showed that Notch1 seems to be an independent prognostic factor in SCLC. Furthermore, a negative association between Notch1 and Ascl1 expression was observed.

In summary, this thesis expands on the understanding of SCLC by analysing epidemiological trends, the impact of socioeconomic status, changes to classifying patients, and possible prognostic biomarkers.

List of scientific papers

I. Tendler S, Holmqvist M, Wagenius G, Lewensohn R, Lambe M, De Petris L. Educational level, management and outcomes in small-cell lung cancer (SCLC): A population-based cohort study. Lung Cancer. 139: 111-117, 2020.
https://doi.org/10.1016/j.lungcan.2019.11.008

II. Tendler S, Grozman V, Lewensohn R, Tsakonas G, Viktorsson K, De Petris L. Validation of the 8th TNM classification for small-cell lung cancer in a retrospective material from Sweden. Lung Cancer. 120:75–81, 2018. Corrigendum: 123;178-179, 2018.
https://doi.org/10.1016/j.lungcan.2018.03.026

III. Tendler S, Zhan Y, Pettersson A, Lewensohn R, Viktorsson K, Fang F, De Petris L. Treatment patterns and survival outcomes for small-cell lung cancer patients- a Swedish single center cohort study. Acta Oncologica. 1-7, 2020.
https://doi.org/10.1080/0284186X.2019.1711165

IV. Tendler S, Kanter L, Lewensohn R, Ortiz-Villalón C, Viktorsson K, De Petris L. The prognostic implications of Notch1, Hes1, Ascl1, and DLL3 protein expression in SCLC patients receiving platinum-based chemotherapy. [Manuscript]