Lung cancer is a heterogeneous group of tumors with more than 50 histomorphological subgroups and one of the most fatal forms of cancer worldwide. Non-small cell lung carcinoma (NSCLC) accounts for about 85% to 90% of malignant lung diseases, with adenocarcinomas (ADC, 40-50%) and squamous cell carcinomas (SCC, 20-30%) being the most frequent histological subgroups. Only few patients are diagnosed at an early stage of disease (stage I or II). In more than 60% of cases, there is a locally advanced or metastasized carcinoma (stage III or IV), in which resection is no longer possible. The 5-year survival rate for all stages is about 17% on average, whereas for stage IV NSCLC it is only 2% or less. The therapeutic strategy evolved to genetically guided therapy. Hence, therapy-relevant variants should be determined in all stage IV patients before the start of a drug-based first-line therapy.
GENOMIC ALTERATIONS
Activating variants in the EGFR gene, found in 10% to 12% of Caucasians with NSCLC and more common in non-smokers, women and patients with East Asian ethnicity, were the first molecular lesions to be targeted for treatment. EGFR variants are found in about 30% of ADC and rarely in SCC. A number of EGFR tyrosine kinase inhibitors (EGFR TKI) are now available, the effectiveness of which depends on the TKI and the type of EGFR variant.
The most frequent EGFR variants are deletions in exon 19 (Del19) and the exon 21 Leu858Arg variant (85-90%). Further variants are found mainly in exons 18 and 20. In the majority of patients, disease progression occurs in the course of targeted treatment due to mechanisms of primary and secondary acquired resistance to targeted drugs. In patients with an activating EGFR variant treated with first and second-generation EGFR TKIs, the most frequent cause of resistance (49‑60%) is the occurrence of the Thr790Met missense variant in exon 20 of EGFR. This has led to the development of successor TKIs, for example, third-generation TKIs, which therapeutically cover both the activating and the resistance variant Thr790Met. In some cases, this resistance variant is detectable in the primary tumor at the time of diagnosis. Where there is disease progression under TKI treatment and suspected resistance, the Thr790Met variant should be sought in a tissue or liquid biopsy. This material also allows the investigation of other resistances that occur in EGFR positive NSCLC (e.g., Cys797Ser).
ALK rearrangements, mainly translocations, occur in about 3% to 13% of ADC, usually in younger patients and those who have never smoked and only in the absence of EGFR and KRAS variants. Furthermore, pleural, pericardial and brain metastases are more likely to be described here. In most cases, there is a fusion with EML4. ALK-TKIs are available for the treatment of patients with ALK rearrangements. However, ALK resistance variants can occur under therapy with ALK-TKI (especially crizotinib), or other signaling pathways can be switched on, e.g., by the occurrence of activating variants in EGFR, which should be checked with a tissue rebiopsy in case of disease progression under ALK-TKI therapy and suspected resistance.
ROS1 rearrangements are found in about 1% to 2% of NSCLC; they exclude ALK, EGFR and KRAS alterations and qualify patients for therapy with crizotinib. Lorlatinib and carbozantinib are second-generation TKIs for ROS1 positive patients who have developed resistance to crizotinib.
Variants in BRAF, predominantly at amino acid position Val600, are found in approximately 6% of ADC and 4% of SCC. These can be treated with a combination therapy composed of dabrafenib and trametinib.
POSSIBLE THERAPIES
There are numerous other changes for which specific therapeutic concepts are being tested, and effective inhibitors are available in clinical trials: HER2 amplifications, KRAS variants, MET alterations, NRG fusions, NTRK fusions and RET translocations.
Various studies have shown that patients with these genetic changes who received a targeted therapy, had a significant improvement in overall survival compared to those patients in whom no suitable biomarkers could be detected and who did not receive targeted treatment.
In patients without genetic alterations for whom targeted therapies are approved, it is recommended that PD-L1 expression is determined for possible immunotherapy with checkpoint inhibitors. Determination of the tumor mutation burden (TMB) in patients with NSCLC can serve as a predictive biomarker to support the selection of patients who may benefit from immune checkpoint inhibitor therapy and has already been recommended in the National Comprehensive Cancer Network (NCCN) guidelines for immunotherapy with checkpoint inhibitors (nivolumab with or without ipilimumab) as first-line therapy in metastatic NSCLC with high TMB.
The diagnosis of lung carcinoma is usually based on morphology from small biopsies. After the pathologist has determined the entity, all investigations to determine the biomarkers relevant for therapy must be carried out on this usually limited material. Therefore, diagnostic approaches that allow the simultaneous characterization of all relevant variants, and determination of TMB and microsatellite instability, are preferred.
TARGETED PANEL
BRAF, EGFR, ERBB2, KRAS, Fusion Genes: ALK, NTRK1/2/3, RET, ROS1, MSI
