From Biomarker Testing to NSCLC Treatment Selection

Targeted Therapy Makes Sense!

The ability to target therapy to driver oncogenic mutations has completely changed the way patients with lung adenocarcinoma are treated. According to a 2014 American study that examined the occurrence of 10 driver mutations and their impact on survival in patients with metastatic lung adenocarcinoma, a targetable driver mutation was found in 64% of lung adenocarcinomas. Patients with a driver mutation who received the corresponding targeted therapy had a median overall survival (OS) of 3.5 years compared to 2.4 years for those who were not treated with targeted therapy.

Detection of Driver Mutations Using Next-Generation Sequencing

The European Society for Medical Oncology (ESMO) Precision Medicine Working Group recommends the routine use of next-generation sequencing (NGS) technologies for detecting so-called level I alterations in advanced non-squamous lung adenocarcinomas (see table). For clinical practice, it is recommended to perform multi-gene NGS from tumor tissue or blood plasma, testing both RNA and DNA to identify the widest range of mutations. Research centers are encouraged to conduct broader multi-gene sequencing as part of molecular screening programs.

Table: Level I alterations in the genome according to ESCAT scoring (ESMO scale for clinical actionability of molecular targets). Level I alterations are those for which a drug capable of targeting them has been validated based on clinical studies. Finding such an alteration in a patient's genome should determine the therapeutic approach in routine clinical practice.

Optimization of Testing Using NGS

To achieve optimal results from NGS testing, attention must be paid to the choice of sample that provides high-quality material (DNA, RNA) with sufficient yield. Technical solutions are also set up to enable maximum clinical and analytical sensitivity, such as optimal concentration and fragmentation of input nucleic acid, analyzer capacity, sample processing speed, or sequencing error rate.

Finally, the most appropriate panel of sequenced genes in the given clinical context must be selected. Specific panels of 10–15 genes can be used, while broader panels may contain up to 50 tested genes. In research, panels encompassing a spectrum of tumor-relevant genes (up to 150 genes) or panels for studying oncogenic mechanisms (up to 400 genes) are used. The larger the panel, the greater the complexity and difficulty of the analysis.

Advantages of NGS

NGS technology allows for a comprehensive analysis of various alterations (mutations, amplifications, fusions) from just two reaction mixtures (derived from DNA and RNA). The analysis can capture rarely occurring mutations and multiple simultaneous alterations (e.g., in the case of mutation leading to drug resistance). NGS allows for the processing of a large number of samples and can be used for small, clinically relevant panels as well as broad panels for translational research.

Disadvantages of NGS

However, the use of NGS places higher demands on the expertise of the testing personnel, especially due to the necessity of bioinformatics analysis of the data obtained. Smaller samples are also sufficient for reverse transcription with polymerase chain reaction (RT-PCR) compared to NGS. When analyzing large panels of genes, there is a problem with insufficient material. Pre-analytical phase issues (especially with RNA samples) can also be problematic, requiring strict procedures to ensure quality, including the need for standardized sample fixation procedures.

Conclusion

The identification of targetable oncogenic alterations has completely changed the treatment protocols for NSCLC. Adequate and timely molecular testing, preferentially using NGS techniques, should be performed for every patient with advanced non-squamous NSCLC. In cases of insufficient tumor tissue, plasma testing (so-called liquid biopsy) can be used.

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Sources:
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3. Mosele F., Remon J., Mateo J. et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol 2020; 31 (11): 1491−1505, doi: 10.1016/j.annonc.2020.07.014.
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