Non-small cell lung cancer (NSCLC) [C34.-]
Dipl.-Ing. (FH) Tanja Hinrichsen,
Prof. Dr. med. Barbara Dockhorn-Dworniczak
Carcinoma of the lung is the most common fatal cancer worldwide. Approximately 80% of all patients with lung carcinomas suffer from a non-small-cell lung carcinoma (NSCLC), which exhibits two histological subtypes: Adenocarcinoma of the lung (LAC) and squamous cell carcinoma (SCC). NSCLC is often first discovered in a late, inoperable stage. Even newly developed chemotherapeutic regimens hardly influence the survival time. The median survival is 8-10 months. The 5-year survival time is less than 15%. NSCLCs generally show numerous somatic mutations and genomic rearrangements. LAC show mutations in the following genes in particular: 46% TP53, 17% STK11, 17% KEAP1, 33% KRAS, 14% EGFR and 10% BRAF. In SCC, 83% of mutations are found in TP53. Unfortunately targeted therapies are only available for some of the mentioned genes.
Epidermal growth factor receptor (EGFR) is a tyrosine kinase, normally activated by binding with a ligand. Mutations in the EGFR gene lead to a constitutive activation and consequently increased cell proliferation. EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib and afatanib, compete with ATP for binding in the tyrosine kinase pocket of the receptor and inhibit both the tyrosine kinase activity and the EGFR signaling pathway. TKIs are front-line therapy for patients with activating mutations in EGFR, and they can improve progression-free survival as well as response rate. Detection of a mutation in the EGFR gene of the tumor tissue is therefore considered a major positive predictive factor for the response to treatment.
Mutations frequently occur in adenocarcinomas, women and non-smokers. They are found in 9% of all cases in exon 18, in 51% in exon 19, in 18% in exon 20 and in 22% in exon 21 of the EGFR gene. However, approximately 5% of all EGFR mutations result in a secondary resistance to EGFR TKI. The presence of the mutation T790M is the most common mechanism of EGFR TKI therapy resistance. Clinical studies are currently testing EGFR TKIs (AZD9291 and rociletinib) that can be specifically used for this mutation.
Furthermore, in advanced tumor stages, the onset of EGFR TKI resistance can occur with MET amplification and occasionally with MET mutations. In this case, the use of MET inhibitors and antibodies is a therapeutic option.
Mutations in KRAS are found more frequently in NSCLC patients who smoke or have smoked. They usually exclude the simultaneous presence of a mutation in EGFR, BRAF or a ALK or ROS rearrangement. KRAS mutations appear to have a negative prognostic effect and are associated with a negative treatment response to EGFR-TKI. New therapy concepts for patients with a KRAS mutation could involve MEK inhibition with selumetinib or trametinib in combination with conventional therapy.
Half of the mutations in BRAF show the classic V600E mutation. This occurs more frequently in light- or non-smokers, micropapillary growth pattern and female patients. In contrast, non-V600E mutations are found more frequently in smokers and show a progressive course of disease. The BRAF TKIs vemurafenib and dabrafenib offer patients with a BRAF V600 mutation a partial response in 54% of cases. Although patients with non-V600 BRAF mutations appear to be resistant to these TKIs, they exhibit sensitivity to MEK inhibitors. Just as for malignant melanomas, combined BRAF/MEK therapy can be discussed.
In addition to the mutations described above, a portion of NSCLC patients also have gene rearrangements. Approximately 5% of patients show a EML4-ALK1 rearrangement as well as in about 1% of cases other fusions with ALK1. EML4-ALK1 is seen particularly in patients with proven adenocarcinoma with focal differentiation in signet ring cells or a micropapillary growth pattern. A further 1% of NSCLC patients have ROS1 rearrangements. Both patients with ALK1 and ROS1 rearrangements respond well to therapy with an ALK1 Inhibitor such as crizotinib or ceritinib. Despite the good response, the majority of patients show disease progression after about 9-13 months. This is possibly due to the presentation of newly occurring mutations in the ALK1 gene. In a further 1% of patients RET rearrangements can be documented. Preclinical data shows a response by these tumors to RET or multikinase inhibitors like cabozantinib.