General introduction and thesis outline 11 1 General introduction and thesis outline Epidemiology of lung cancer Lung cancer constitutes a significant global health challenge, with an estimated 2.2 million new cancer cases and 1.8 million deaths reported worldwide in 2020. It stands as the second most frequently diagnosed cancer and is the leading cause of cancer-related mortality1. In the Netherlands, approximately 14.000 new cases of lung cancer were diagnosed in the year 2019, and the mortality rate exceeded 10.000 deaths attributed to lung cancer during the same period2. Tobacco smoking has been associated to the development of lung cancer in 80% of cases3. Over the decades, trends in smoking have influenced the incidence rates on different continents. For example, in the United States, the incidence rate declined from its peak of 67 per 100.000 individuals in 1992 to 43.2 per 100.000 in 20184, primarily due to increased smoking cessation efforts. Approximately 85% of lung cancer patients form a group of histological subtypes collectively known as non-small cell lung cancer (NSCLC)2. The two most common subtypes are adenocarcinoma (AD) and squamous cell carcinoma (SCC)5. In cases where the morphology of the tumor does not show evidence for either AD or SCC, a positive P40 (>50% of tumor cells) and negative TTF1 immunohistochemical (IHC) staining can confirm squamous cell differentiation. Otherwise, the tumor is classified as NSCLC, not otherwise specified (NOS)5. Almost 50% of patients are diagnosed with advanced stage disease2 that is not curable by surgery alone, leaving systemic therapies as treatment of choice. Treatment of advanced NSCLC Historically, the treatment of advanced stage NSCLC has been chemotherapy consisting of a platinum doublet with either carboplatin or cisplatin with gemcitabine, pemetrexed, vinorelbine, or taxanes (paclitaxel or docetaxel). No clinically meaningful differences in outcome have been found among these cytotoxic regimens6, with the exception of the combination pemetrexed-cisplatin which showed shorter overall survival (OS) compared to the gemcitabine-cisplatin combination in SCC7. The treatment landscape of NSCLC dramatically changed after the development of specific targeted therapies for the treatment of e.g., EGFR-mutant, ALK-rearranged, ROS1-rearranged or BRAFV600E‑mutant advanced-stage NSCLC. Several tyrosine kinase inhibitors (TKIs) targeting these molecular alterations have led to remarkable responses in selected patients8. More recently, immunotherapy, particularly immune checkpoint blockade (ICB), has introduced a new era in lung cancer care. In the tumor microenvironment (TME), activated T cells express a protein called programmed cell death 1 (PD-1). When a T
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