How do rare driver gene mutations in non-small cell lung cancer relate to age?

*For medical professionals only

The impact of patient age on clinical diagnosis and treatment is worth paying attention to!

Written by | Cow bright red

Source | "Medical Community" public account

In patients with non-small cell lung cancer (NSCLC), patients with two sensitive mutations of EGFR/ALK often have more obvious clinical features, which are helpful for clinicians to carry out targeted detection and treatment. In addition to the two major sensitive mutations, rare mutations with a detection rate of <5% in NSCLC have also heated up rapidly in recent years, and targeted therapy has progressed very rapidly.

RARE driver gene mutations such as MET14 exon jump mutations, RET rearrangements, and BRAF V600E are already available therapeutic sites, so what are the clinical characteristics of patients carrying these driver genes? A recent recent analysis from mainland scholars has evaluated the relationship between different driver gene mutations and the age of patients with NSCLC [1].

The study revealed an age-related correlation between mutations in the 8 major driver genes

In the analysis, published in Journal of Cancer, the research team evaluated a total of 2025 patients with neoplastic tissue samples in 2025 patients with emerging lung adenocarcinoma (LUAD) in second-generation sequencing (NGS). The study defined ≤ 50 years of age were young patients, ≥ 70 years of age were elderly patients, and patients of the remaining age groups were in the intermediate group.

A total of eight "clinically targeted driver gene mutations" were included in the analysis, namely: EGFR, ALK, KRAS, HER2 exon 20 insertion mutation, ROS1 fusion, RET rearrangement, BRAF V600E mutation, and MET amplification/MET14 exon-skipping mutation.

The detection rate of clinically targeted driver gene mutations in each group of patients is shown in Table 1, and the incidence of ALK mutations, HER2 20 exon insertion mutations, and RET rearrangement mutations in young patients is significantly higher (P<0.05), while the incidence of KRAS mutations, MET amplification/MET14 exon jump mutations in elderly patients is significantly higher, and the incidence of EGFR, ROS1 fusion, and BRAF V600E mutations is not significantly different between young patients and elderly patients [1].

Table 1.Differences in detection rates of driver gene mutations in patients of different age groups in the study

Accurate diagnosis and treatment will help NSCLC benefit more

In addition to the two common sensitive mutations of EGFR/ALK, most of the above driver gene mutations are available in mainland China, including MET14 exon jump mutation, RET rearrangement, BRAF V600E mutation and ROS1 fusion.

1. MET14 exon jump mutation

Of particular note is that the incidence of MET amplification and META14 exon jump mutations in elderly patients with NSCLC is significantly higher than in younger patients. Previous studies at home and abroad have generally found that for example, META14 exon jump mutation is more common in elderly patients, the median age of patients is 69-75 years old [2-5], in addition, patients are often female, non-smoking, pathological staging is in the early stage [2-3], but in clinical practice, the elderly and histological types of non-adenocarcinoma patients should also actively carry out MET gene testing.

Considering that elderly patients are often in poor physical condition and have other diseases, the use of targeted therapy may be more valuable for elderly patients with advanced NSCLC mutations with EXON JUMP mutations in META14, such as the use of tyrosine kinase inhibitors (TKI) targeted drug therapy, which is expected to achieve both good efficacy and reduce treatment-related adverse reactions compared with chemotherapy [5].

Taking MET-TKI cevotinib, the first approved marketing in mainland China, as an example, the final survival data of the clinical phase II study recently published at the European Lung Cancer Congress (ELCC) showed that the median survival (OS) of cevotinib treated with exon-jumping mutation MET14 could reach 12.5 months at the median age of 68.7 years[6], and the objective response rate (ORR) and disease control rate (DCR) were high, suggesting significant and long-lasting tumor shrinkage. Disease control and survival benefits.

Based on the clinical characteristics of patients with EXON jump mutations in MET14 and the significant benefits of TKI targeted drug therapy, relevant tests should be actively carried out in clinical work to achieve "precision treatment and detection first". The Clinical Practice Guidelines for Molecular Pathological Detection of Non-Small Cell Lung Cancer (2021 Edition) in Mainland China have proposed that detection methods such as NGS can be used in clinical practice to detect the META14 exon jump mutation and other driver gene variants at the same time, and can also detect patients with negative other driver gene variants alone [8].

2. BRAF V600E mutation

In the above analysis, the incidence of BRAF V600E mutations did not correlate significantly with the age of patients with NSCLC[1]. In 2016, American scholars analyzed 2237 patients with NSCLC and found that in the multivariate analysis model, braf V600E patients were relatively older when they were diagnosed [9], but only 24 patients with mutations were found in the study, and the conclusion may have certain limitations.

The incidence of BRAF V600E mutations in NSCLC is approximately 2% to 4% [10], and targeted therapy mainly uses a combination of BRAF inhibitors and MEK inhibitors to effectively inhibit the RAS-RAF-MEK-ERK signaling pathway. The recent combination of braf inhibitor darafenib + MEK inhibitor trametinib is an indication for the treatment of BRAF V600E mutation NSCLC in mainland China, and it is also the first BRAF V600E mutation targeted therapy in mainland China.

Data on the 5-year survival of the clinical phase II study of darafenib +trimetinib combined therapy showed that the ORRs of the combination targeted therapy were 68.4% and 63.9%, the median progression-free survival (PFS) was 10.2 months and 10.8 months, the median OS was 18.2 months and 17.3 months, and the 5-year survival rate was 19% and 22%, respectively, when treated or initially treated braf V600E, suggesting that targeted therapy was versus BRAF Significant and long-lasting benefits for patients with V600E mutation NSCLC [11].

3. RET rearrangement

The correlation between RET rearrangement and patient age has not been unanimously determined, and the analysis of 6125 patients with NSCLC by previous mainland scholars showed that the median age of 84 patients with RET rearrangement was 58 years old when they were diagnosed, which was not significantly different from the overall population of patients analyzed [12]. The TKI-targeted new drug praratinib (Pralsetinib), which has been approved in mainland China for the treatment of RET reflow NSCLC patients treated with platinum-containing chemotherapy, has 79% and 62% orr of pratinib treatment when used in patients treated with platinum chemotherapy and initial treatment[12], respectively, and can induce lasting remission and long-term disease control.

Summary:

From the existing research and analysis data, the relationship between rare mutations in NSCLC and the age of patients is not the same, among which the META14 exon jump mutation is more common in elderly patients, but the relationship between RET rearrangement, BRAF V600E mutation and patient age is still controversial, and cannot be simply generalized. In the case that the above-mentioned driving gene mutations are available with therapeutic drugs, clinical practice should consider improving the detection of each site as much as possible for patients, and try to avoid errors in judgment and missed tests caused by the age of patients, so as to provide NSCLC patients with accurate targeted treatment options as much as possible.

Bibliography:

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[3] Song Y,Li G,Ju K,et al. Mesenchymal-Epithelial Transition Exon 14 Skipping Mutation and Amplification in 5,008 Patients With Lung Cancer[J]. Frontiers in Oncology,2021:3929.

[4] Champagnac A,Bringuier P P,Barritault M,et al. Frequency of MET exon 14 skipping mutations in non-small cell lung cancer according to technical approach in routine diagnosis:results from a real-life cohort of 2,369 patients[J]. Journal of Thoracic Disease,2020,12(5):2172-2178.

[5] Schrock A B,Frampton G M,Suh J,et al. Characterization of 298 patients with lung cancer harboring MET exon 14 skipping alterations[J]. Journal of Thoracic Oncology,2016,11(9):1493-1502.

[6] Lu S,Fang J,Li X,et al. Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations:a multicentre,single-arm,open-label,phase 2 study[J]. The Lancet Respiratory Medicine,2021,9(10):1154-1164.

[7] Lu S,Fang J,Li X,et al.2MO Final OS results and subgroup analysis of savolitinib in patients with MET exon 14 skipping mutations(METex14+)NSCLC[J]. Annals of Oncology,2022,33(S2):S27.

[8] Chinese Medical Association Pathology Branch, National Center for Pathology Quality Control, Lung Cancer Group of Chinese Medical Association Oncology Branch, etc. Clinical Practice Guidelines for Molecular Pathology Detection of Non-Small Cell Lung Cancer (2021 Edition)[J].Chinese Journal of Pathology,2021,50(4):323-332.

[9] Sacher A G,Dahlberg S E,Heng J,et al. Association between younger age and targetable genomic alterations and prognosis in non–small-cell lung cancer[J]. JAMA Oncology,2016,2(3):313-320.

[10] Lin Q,Zhang H,Ding H,et al. The association between BRAF mutation class and clinical features in BRAF-mutant Chinese non-small cell lung cancer patients[J]. Journal of Translational Medicine,2019,17(1):298.

[11] Planchard D,Besse B,Groen H J M,et al. Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic NSCLC:updated 5-year survival rates and genomic analysis[J]. Journal of Thoracic Oncology,2022,17(1):103-115.

[12] Curigliano G,Gainor J F,Griesinger F,et al. Safety and efficacy of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer:Update from the ARROW trial[J]. Journal of Clinical Oncology,2021,39(15_suppl):9089.

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