Therapeutic insights into epidermal growth factor receptor/reactive oxygen species proto-oncogene 1-receptor co-mutated non-small cell lung cancer: Crizotinib as a promising option

Abstract

This letter provides a review of the report by Peng et al on a unique case of non-small cell lung cancer (NSCLC), specifically lung adenocarcinoma, featuring reactive oxygen species proto-oncogene 1-receptor (ROS1) co-mutation. The case involves a 64-year-old patient who exhibited both epidermal growth factor receptor (EGFR) L858R mutation and ROS1 rearrangement, achieving significant disease stabilization following treatment with crizotinib. This rare EGFR/ROS1 co-mutation poses distinct challenges for clinical management and highlights the necessity of personalized treatment strategies. While third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, are commonly regarded as first-line therapies, recent studies indicate that crizotinib may offer superior disease control in certain EGFR-mutant patients, particularly those who exhibit poor responses to EGFR TKIs. The case also examines the influence of tumor cell genetic heterogeneity on treatment response, underscoring the importance of evaluating tumor characteristics. In patients with EGFR/ROS1 co-mutation, gefitinib is generally effective as a first-line treatment; however, its efficacy can be limited, whereas crizotinib has demonstrated improved disease control. Future research should focus on identifying optimal treatment strategies for patients with EGFR/ROS1 co-mutation to enhance patient outcomes. In conclusion, this case report not only illustrates the effectiveness of crizotinib in managing patients with EGFR/ROS1 co-mutation but also underscores the importance of personalized treatment approaches, offering valuable insights for improving clinical outcomes in NSCLC patients with complex genetic profiles.

Key Words: Adenocarcinoma; Crizotinib; Genetic heterogeneity; Lung cancer; Mutation; Personalized medicine

Core Tip: Epidermal growth factor receptor (EGFR)/ reactive oxygen species proto-oncogene 1-receptor (ROS1) co-mutations in non-small cell lung cancer (NSCLC) are rare and present distinct therapeutic challenges. This case report demonstrates that ROS1 inhibition with crizotinib achieved superior disease control compared to EGFR-targeted therapy, underscoring the need for individualized treatment strategies that may benefit from biomarker guidance to identify the primary oncogenic driver. Tumor genetic heterogeneity could further affect therapeutic responses, highlighting the importance of advanced sequencing techniques in optimizing treatment plans. Larger studies are crucial to establish effective treatment protocols for NSCLC patients with EGFR/ROS1 co-mutations, with the potential to significantly improve survival outcomes in this complex patient population.

TO THE EDITOR

I read with great interest the case report by Peng et al[1], titled “Concomitant Epidermal Growth Factor Receptor Mutation/C-ROS Oncogene 1 Rearrangement in Non-Small Cell Lung Cancer”, published in the World Journal of Clinical Oncology[1]. This report presents a compelling case of the exceedingly rare epidermal growth factor receptor (EGFR)/reactive oxygen species proto-oncogene 1-receptor (ROS1) co-mutation in non-small cell lung cancer (NSCLC), specifically in a patient with lung adenocarcinoma. The authors describe a 64-year-old woman with an EGFR L858R mutation and ROS1 rearrangement, who achieved notable disease stability with prolonged crizotinib treatment. This case, with its distinct clinical features and challenges inherent to EGFR/ROS1 co-mutations, provides valuable insights for the oncology community and underscores the potential efficacy of ROS1-targeted therapies in treating co-mutated NSCLC.

EGFR/ROS1

In patients with EGFR/ROS1 co-mutated NSCLC, although gefitinib, a first-line EGFR tyrosine kinase inhibitor (TKI), is generally effective, its efficacy may be limited. Studies suggest that low-frequency EGFR mutations can lead to suboptimal responses to gefitinib, whereas ROS1 inhibitors, such as crizotinib, may provide superior disease control in certain cases. The rarity of EGFR/ROS1 co-mutations in NSCLC is well-documented, as these mutations are typically mutually exclusive. Consequently, there is limited data to guide optimal treatment strategies for these patients[2].

Emerging evidence indicates that EGFR/ROS1 co-mutations may occur more frequently in specific tumor subtypes[3,4]. For instance, a multi-omics study identified certain subtypes with high mutational burdens and complex genomic features as being more prone to these co-mutations, possibly due to distinct pathogenic mechanisms within tumor cells[5,6]. Case reports further suggest that, while gefitinib is effective in EGFR-mutated tumors, it may fail to achieve adequate disease control in co-mutated cases[2,7]. Notably, one study reported a progression-free survival of up to 53 months with crizotinib in a patient with EGFR/ROS1 co-mutations, underscoring the potential superiority of ROS1 inhibition over EGFR inhibition in specific clinical scenarios[8].

As such, treatment strategies for EGFR/ROS1 co-mutated patients should prioritize diversity and personalization. While third-generation EGFR-tyrosine kinase inhibitors (TKIs), such as osimertinib or almonertinib, are typically first-line choices, the potential benefits of ROS1 inhibitors should be considered, particularly in cases where EGFR-TKIs show limited efficacy[9]. Additionally, integrating chemotherapy and immunotherapy into comprehensive treatment regimens could further improve patient outcomes[10].

Personalized treatment is vital for patients with EGFR/ROS1 co-mutations in NSCLC[4]. It is essential to thoroughly consider each patient's specific genomic characteristics when selecting the most appropriate treatment regimen. Recent studies suggest that combining immune checkpoint inhibitors with other targeted therapies may lead to improved clinical outcomes for certain patients with distinct genetic mutations. For example, in patients with high programmed death-ligand 1 expression, the combination of immunotherapy and other targeted treatments has shown enhanced efficacy, paving the way for more personalized therapeutic approaches[11,12]. Furthermore, the genetic heterogeneity of tumor cells can significantly impact treatment responses, highlighting the importance of evaluating patients' tumor characteristics and genomic profiles in clinical practice to optimize therapeutic effectiveness[13].

We recommend that clinical decision-making should encompass not only traditional targeted therapies and chemotherapy but also the exploration of immunotherapy's potential. As our understanding of tumor biology continues to evolve, personalized medicine will increasingly depend on advanced genomic analysis techniques to identify key pathogenic drivers, facilitating the development of more precise treatment strategies. This comprehensive approach has the potential to enhance patient survival rates while also improving overall quality of life[13,14].

Although large-scale clinical trial data supporting the use of ROS1 inhibitors as a standalone first-line treatment is currently lacking, existing small-scale case reports suggest that prioritizing crizotinib may yield better clinical outcomes[8,15]. Additionally, combination treatment strategies are gaining traction, with studies indicating that the concurrent use of EGFR TKIs and ROS1 inhibitors may enhance treatment efficacy[6,16]. Future research should further investigate optimal treatment regimens for patients with EGFR/ROS1 co-mutations to refine clinical decision-making and improve patient prognosis[17,18].

Recent studies on transcriptomic subtyping in lung adenocarcinoma have highlighted differences in susceptibility to EGFR mutations and ROS1 rearrangements across various subtypes[1]. For instance, specific subtypes such as "invasive adenocarcinoma" are frequently associated with EGFR mutations, while ROS1 rearrangements predominantly occur in certain lymphocyte-rich or mucinous adenocarcinomas[19]. These subtypes exhibit a favorable response to ROS1 inhibitors. Therefore, it is crucial to consider the molecular characteristics of the tumor when developing treatment strategies to ensure personalized therapy[20,21].

This case highlights critical considerations about the biological mechanisms driving tumorigenesis in NSCLC with co-occurring mutations. The authors propose that tumor cell heterogeneity may play a pivotal role, with distinct driver genes potentially dominating in different cancer cell subpopulations. This hypothesis aligns with the widely accepted notion that genetic heterogeneity significantly contributes to therapeutic resistance and disease recurrence in NSCLC.

Furthermore, the successful treatment of this patient with crizotinib prompts important considerations regarding the prognostic significance of ROS1 rearrangements in EGFR/ROS1 co-mutated NSCLC[1]. Typically, ROS1 fusions are linked to favorable responses to targeted therapies like crizotinib. However, the prognostic value of ROS1 rearrangements within the context of co-mutations remains uncertain[4,16]. To gain a clearer understanding of their clinical implications, larger-scale studies are necessary to compare outcomes between patients with isolated ROS1 rearrangements and those with EGFR co-mutations.

The report also explores the potential benefits of combination TKI therapy. While the concurrent use of EGFR and ROS1 inhibitors may lead to favorable outcomes, the associated toxicity of dual TKI treatment poses a significant challenge[16]. Consequently, for patients who cannot tolerate combination therapies, it is essential to identify biomarkers that can guide treatment selection[4]. This case report highlights the necessity for biomarkers that can predict which driver genes are more active in disease progression, allowing clinicians to adjust treatment strategies accordingly.

CONCLUSION

In conclusion, this case report illustrates the efficacy of crizotinib in a rare patient with EGFR/ROS1 co-mutation. It underscores the challenges associated with treating co-mutated NSCLC and explores potential solutions, highlighting the significance of personalized treatment strategies. This case offers valuable insights for enhancing clinical outcomes in NSCLC patients with complex genetic profiles.