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Partners in Crime: Co-Occurring Genetic Alterations in EGFR-Mutant NSCLC

*February 2024*

Co-occurring genetic alterations in solid tumors are a critical and influential prognostic factor that holds substantial importance in understanding the disease progression and guiding treatment strategies. Tumor cells acquire somatic mutations in both oncogenes and tumor suppressor genes (TSGs) leading to tumorigenesis.The event of multiple mutations emerging concurrently is referred to as co-occurring genetic alterations or co-mutations. Although the impact of the oncogene alterations has been mostly studied, cooperative effects induced by multiple co-mutations, especially from TSGs, have been gaining appreciation lately. One well-known and extensively studied gene associated with various solid tumors is TP53, which encodes the tumor protein p53. TP53 is often referred to as the “guardian of the genome” because it plays a fundamental role in maintaining genomic stability and preventing the development of cancer. Mutations in TP53 can lead to the loss of its tumor-suppressive functions, allowing uncontrolled cell growth and contributing to the initiation of progression in numerous cancer types. In the context of NSCLC, TP53 mutations have been identified as a prominent and prognostically significant factor. Notably, TP53 has been associated with negative outcomes in EGFR-mutant NSCLC. In a recent, large, real-world analysis of 356 patients with EGFR-mutant NSCLC, TP53 mutations were observed in 61% of the tumors and associated with inferior outcomes for both progression-free survival (PFS) on EGFR tyrosine kinase inhibitors (TKIs) and overall survival (OS).

Nevertheless, TP53 is not the only co-mutation that affects prognosis in EGFR-mutant NSCLC. Prior studies have indicated that mutations in CDK family and PI3K pathways also negatively affect outcomes, yet most of the studies were limited by sample size and analysis of single-gene alteration.One study revealed that TP53-mutated EGFR-mutant NSCLC tumors had higher mutational burdens and increased mutagenesis with exposure to therapy and tobacco. When TP53 mutations occur in conjunction with cell cycle alterations, worse OS was observed in this patient population.  In this issue of the Journal of Thoracic Oncology, Stockhammer et al.took a comprehensive approach to characterize the impact of co-mutations to the outcome of patients with EGFR-mutant NSCLC treated with EGFR TKIs. They first leveraged the initial cohort of Yale Cancer Center of patients with EGFR-mutant NSCLC who were TKI naive (n = 101). In this cohort, TP53 co-mutations were identified in 65% of the patients, consistent with prior reports.,Interestingly, in this cohort, TP53 was associated with liver metastasis, which was associated with worse clinical outcomes. Then, American Association for Cancer Reasearch-GENIE database was queried, and patients who received erlotinib for their EGFR-mutant NSCLC were identified for analysis (n = 182).

In addition to the evaluation of TP53, the study conducted a comprehensive analysis including other TSGs to gain insights into their potential impact to EGFR-mutant NSCLC outcomes. These TSGs, including ARID1AATMBRCA1CDKN2ANF1PTENRB1SMAD4, and STK11, were investigated in the context of TP53 mutational status in both study cohorts. It was observed that these TSGs exhibited a higher frequency of mutations in TP53-mutated (TP53mut) tumors compared with TP53 wild-type (TP53wt) tumors. This increased mutation rate is likely related to the genomic instability associated with alterations in TP53, as its role is to maintain genomic integrity.

Next, the authors asked how those alterations affect clinical outcomes, especially when those patients were treated with EGFR TKIs. Building on the knowledge that tumors with TP53 mutations often have a less favorable clinical outcome with EGFR TKIs, the authors further categorized the patients into the following three groups: TP53mut/TSG wild-type (TSG wt), double mutation (both TP53mut and TSGmut), and double wild-type (both TP53wt and TSG wt). They observed that the group with double mutations had the worst PFS and OS compared with the TP53 wild-type group.

To provide a more rigorous analysis of these findings, the authors performed multivariate Cox regression analysis to assess the independent impact of TP53mut/TSGmut status on PFS and OS while controlling for other clinicopathologic parameters. The results of this analysis revealed that the TP53mut/TSGmut status was significantly and independently associated with inferior PFS (hazard ratio [HR] = 2.19, confidence interval: 1.24–3.87, p = 0.007) and OS (HR = 2.29, confidence interval: 1.23–4.25, p = 0.009) in patients undergoing EGFR TKI therapy. This suggests that the presence of concurrent mutations in TP53 and TSGs has a substantial and detrimental impact on the clinical outcomes of patients receiving EGFR TKI treatment, even when considering other relevant clinical factors.
The authors displayed a conscientious approach by evaluating the function aspects of TP53 mutation function. It was found that TP53 mutations described in the two cohorts are predominantly located within the DNA-binding domain, as mutations within the DNA-binding domain region of TP53 are well-documented leading to a loss of its tumor-suppressive capabilities as a transcription factor responsible for regulating the expression of various genes, particularly those involved in cell cycle control, DNA repair, and apoptosis.

The authors also appropriately exercised caution in their interpretation of the study’s findings. They emphasized the retrospective nature of the cohort and that a substantial portion of the patients in the study had been treated with first- and second-generation EGFR TKIs; therefore, the results might not be directly translatable to the current standard of third-generation TKIs.

In summary, the study not only highlighted the connection between the increased frequency of mutations in various TSGs in TP53mut tumors but also revealed the adverse impact of TP53mut/TSGmut status on the prognosis of patients treated with EGFR TKIs, reinforcing the importance of understanding these genetic alterations in guiding clinical decisions and improving patient care.
The study is thought provoking, especially in time for us to think about intensification strategies. In 2023, a few trials exploring intensification strategies for first-line treatment of EGFR-mutant NSCLC prompt significant considerations. They not only reveal the potential to extend PFS through combination therapies but also introduce added toxicities. Determining the right patient population for these strategies becomes crucial. In FLAURA2 trial, the addition of platinum-pemetrexed chemotherapy to osimertinib resulted in a prolonged PFS with HR at 0.62; in MARIPOSA trial, the addition of amivantamab to lazertinib leads to a prolonged PFS with HR at 0.70; and in RAMOSE trial, the addition of ramucirumab to osimertinib improved PFS with HR at 0.55.Now that all three trials had positive results in prolonging PFS, the challenge of balancing benefits and risks and selecting the most suitable patients for these intensified approaches requires consideration of various factors. Clinical factors, such as central nervous system or liver metastasis, help identify those who might benefit from intensification. In addition, genomic profiling, especially co-mutations in TSGs, plays a crucial role. This paper emphasized the significance of not only TP53 but other TSGs in understanding the disease aggressiveness and tailoring treatment. In addition, the patient’s preferences, treatment goals, and their capacity to handle medical and logistical side effects are equally vital. Read more.