Somatic KRAS mutations are the most common oncogenic alterations detected in non-small cell lung cancer (NSCLC), accounting for 25% of the cases (1). Clinical course of KRAS-mutant NSCLC is very heterogenous, suggesting an underlying biological complexity that is not comprehensively understood. For example, the signaling of downstream RAS pathway is specific of transversion/transition subtypes of KRAS mutation (2). Transversion and transition subtypes are associated to different clinico-pathological profiles but the relationship with treatment efficacy is debatable (3). While KRAS mutations remain desperately untargetable, the knowledge of the tumor status for EGFR and BRAF600 activating mutations as well as for ALK and ROS1 rearrangements is a keystone of the treatment decision making in advanced NSCLC. Indeed, effective targeted therapies are labeled in the setting of these oncogenic alterations, leading to substantial improvement of the overall survival compared to what is historically observed with chemotherapy alone (4-7). Next-generation sequencing (NGS) strategy has been implemented in cancer-dedicated institution, allowing the diagnosis of several oncogenic alterations and a broad detection of other genetic alterations in one assay. Genomic alterations in tumor suppressor genes and cancer-related pathways may be detected and “co-occurred” with oncogenic alterations in the same tumor. A growing body of evidence suggest that “co-occurring” genomic alterations may refine our current molecular classification using KRAS/EGFR/BRAF/ALK/ROS1/other oncogenes (8-10). In this setting, STK11/LKB1 alterations have been described as a major driver of primary resistance to PD-1 blockade in KRAS-mutant lung adenocarcinoma using an NGS approach (10).
In the article of Arbour et al. published in Clinical Cancer Research accompanying this editorial, the authors report the results of a single institution, retrospective analysis of co-occurring genomic alterations detected with the MSK-IMPACT NGS assay on the outcomes of 330 KRAS mutant advanced NSCLC (11). In their paper, Arbour et al. identified a subgroup of patients with NSCLC harboring co-occurring genomic alterations in KRAS and KEAP1/NFE2L2 pathway (27% of the cases) leading to a worse prognosis and shorter clinical benefit with platinum-based chemotherapy and anti-PD-1 compounds. Other co-occurring genomic alterations subgroups, i.e., KRAS+/TP53+ (42% of the cases) and KRAS+/STK11+ (29% of the cases) did not have a negative prognostic value and were not associated with worse clinical benefit.
To date, this is the first study that supports the notion that KEAP1/NFE2L2 co-occurring pathway alteration in NSCLC harboring KRAS mutation may be clinically relevant. NFE2L2 gene encodes the NRF2 protein, a transcription factor that is a critical stress response mediator in mammalian cells (12). Under homeostatic conditions, NRF2 is degraded via the proteasome through binding to KEAP1 protein. NSCLC with high NRF2 and low KEAP1 levels of expression are associated with poor prognosis, due not only to their chemo- and radio-resistance but also to their aggressive proliferative nature (13-15). Recent large-scale genomic studies from The Cancer Genome Atlas (TCGA) project have revealed alterations in components of the KEAP1/NFE2L2 pathway in 23% of lung adenocarcinomas (16). In accordance with TCGA data and previous report, KEAP1 genomic alterations are the more common KEAP1/NFE2L2 pathway alteration in Arbour et al. work, whereas NFE2L2 alterations are known to be more frequent in squamous cell carcinoma (11). In the largest cohort of KEAP1/NFE2L2-altered NSCLC published to date, this molecular subgroup was also associated to resistance to chemotherapy, especially in KEAP1-altered NSCLC (17). In this cohort, KEAP1 alterations co-occurred with KRAS mutation in 44.9% of the cases.
Some limitations have to be underlined in this work. First, a selection bias is suspected that is inherent to the retrospective nature of this study. From the 330 patients KRAS-mutant NSCLC, females are over-represented (59%), the patient are younger than expected and in good shape. This likely explains that classical prognostic factors did not have prognostic value in multivariate analysis of overall survival (sex, smoking habit, performance status) or very marginally (age at diagnosis). Second, a major overlapping is observed between STK11- and KEAP1/NFE2L2 co-occurring genomic alterations subgroups, with 74% of KEAP1/NFE2L2-altered tumors that are also STK11-altered and 66% of STK11-altered tumors that are also KEAP1/NFE2L2-altered. It would be very interesting to test de prognostic value of KEAP1/NFE2L2/STK11-altered tumors, that perhaps trigger the negative prognostic value of KEAP1/NFE2L2 co-occurring genomic alteration. Third, duration of treatment is an uncommon and inaccurate surrogate biomarker of clinical benefit of therapy. There are many reasons other than disease progression to stop a therapy such as, adverse events, patients willing, cancer-related complications… Fourth, response to anti-PD-1 and duration of treatment with anti-PD-1 were not different according to the co-occurring genomic alterations (STK11, TP53 or KEAP1/NFE2L2) and only KEAP1/NFE2L2 co-occurring genomic alterations were associated to shorter overall survival on anti-PD-1. It is likely to result from the bad prognosis value of KEAP1/NFE2L2 co-occurring genomic alterations and not to a lack of activity of anti-PD-1. These data are also somewhat conflicting with the report that STK11/LKB1 genomic alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinomas (see above) (10).
Finally, the findings of Arbour et al. show that broad genomic alterations testing with NGS in routine practice is not only a way to test many oncogenic alterations with one assay, but also a way to build new relevant molecular hypotheses explaining the heterogeneous clinical course of advanced NSCLC. According to these data, KEAP1/NFE2L2 co-occurring genomic alterations in KRAS-mutant NSCLC is a new field of investigations and the impact on outcomes with chemotherapy and immunotherapy should be prospectively explored.
George Washington said “It’s far better to be alone that to be in bad company.” In this way, we need more prospective data to define who is(are) such a bad companion(s) in the setting of advanced NSCLC with characterized oncogenic alterations.
Conflicts of Interest: M Duruisseaux has received research funding from Novartis and Pfizer for institutional research program outside of the submitted paper. He has served as a consultant (advisory board) and received fees from Astra Zeneca, Boerhinger Ingelheim, Lilly, Novartis, Pfizer, Roche, Abbvie, MSD, BMS and Takeda. J Cadranel has received research funding for his institution from Astra Zeneca, Boerhinger Ingelheim, Novartis and Pfizer outside of the submitted paper. He has served as a consultant (advisory board) and received fees from Astra Zeneca, BMS, Boerhinger Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche and Takeda.
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