Before the current study, many studies reported the predictive impact of minor-frequency preT790M on the efficacy of initial EGFR-TKI treatment or on the prognosis, mainly in advanced stage settings. However, there were few reports regarding the clinical significance of preT790M in patients with resected NSCLC. In this prospective exploratory analysis, minor-frequency preT790M in the resected EGFR-mutated NSCLC samples was shown to potentially affect RFS and OS.
In previous analyses of prognostic factors for resected EGFR-mutated NSCLC, older age, male sex, advanced stage, and smoker were shown to be independent factors associated with a poor prognosis (RFS or OS) in many studies, although the covariates evaluated differed depending on the studies [21–31]. In the current study, multivariate analysis, which considered these previous reports, demonstrated that male sex and advanced pathological stage were correlated with shorter RFS, and older age tended to be associated with shorter RFS. Pathological stage was also correlated with shorter OS, and in fact, pathological stage was the most important factor affecting RFS and OS. There were many reports showing that EGFR 19del was associated with worse RFS or OS than L858R [23, 25, 30], but some studies reported that 19del had better RFS or OS than L858R [27, 32], and others reported that EGFR mutation subtype has no prognostic impact . Therefore, whether the EGFR mutation subtype has an impact on prognosis remained controversial. On multivariate analysis in the current study, there was no significant difference in RFS by EGFR mutation subtype, but 19del tended to have worse OS, and uncommon mutations had significantly worse OS than L858R.
Let us consider the impact of preT790M as a prognostic factor for survival. In the current study using ultra-sensitive ddPCR, the overall detection rate of preT790M was 79.9%, and the T790M-MAF ranged from 0.009–26.9% (median MAF 0.044%). Several previous studies indicated that higher MAF of preT790M might have a greater impact on the efficacy of EGFR-TKIs than the presence of preT790M [12, 13, 17]. Therefore, when tumor samples were classified into two groups based on the abundance of T790M-MAF, multivariate analysis demonstrated that high-preT790M was the independent factor related to a poor prognosis (RFS), irrespective of patient background, including pathological stage, age, and sex. A previous retrospective study by Tatematsu et al, which analyzed the incidence of minor-frequency preT790M using competitive allele-specific PCR in 153 surgically resected EGFR-mutated lung adenocarcinoma tissues, the incidence of preT790M was 29.4%, and T790M-MAF ranged from 0.13–2.65% (median MAF 0.20%) . However, in their study, no significant impact of preT790M on RFS was shown. A previous analysis demonstrated that the impact of T790M shifts according to the cutoff level of T790M-MAF . Therefore, differences in analytical sensitivity, the detection rate of preT790M, sample size, and population grouping might result in the differences in the impact of preT790M between their study and the present one. Furthermore, disease stage was the most crucial factor affecting prognosis [21–26, 28–31]. Therefore, it might be important to consider pathological stage in the analysis of clinical significance of minor-frequency preT790M, although the association of preT790M status with patient characteristics was not reported in their study. In fact, the present study showed that higher-preT790M affected RFS in stage IB or more advanced disease, but it seemed unlikely in stage IA. On the other hand, Gao et al analyzed clinical outcomes of coexisting T790M in a surgically resected, EGFR-mutated NSCLC cohort using the Amplification Refractory Mutation System, of which the analytical sensitivity was known to be generally 1% . Their study also demonstrated that RFS of patients with coexisting EGFR T790M was significantly shorter than of those without T790M mutations, and according to the stage, this tendency was observed not only in stage IB-IIIA, but also in stage IA. Greater T790M-MAF, which could be detected by routine clinical genotyping tests, might affect RFS even in stage IA, although ultra-low-level preT790M was thought not to have an impact on RFS in stage IA.
The above-mentioned study by Tatematsu et al also did not show a significant effect of preT790M on OS in surgically resected EGFR-mutated NSCLC . However, in the current study, multivariate analysis demonstrated that preT790M was the independent factor related to a poor prognosis in patients with resected EGFR-mutated NSCLC, irrespective of patient background including pathological stage, age, EGFR mutation subtype, and history of adjuvant chemotherapy. According to pathological stage, high-preT790M showed no prognostic impact in stage IA, but OS in high-preT790M tended to be shorter in stage IB or more advanced settings, as well as in the RFS analysis. To the best of our knowledge, the present research is the first to show that preT790M has a significant impact on OS in resected EGFR-mutated NSCLC in a larger cohort.
In metastatic stage settings, the appearance of T790M mutation after resistance to initial EGFR-TKI treatment (acquired T790M) has been reported to be associated with a good prognosis in the patients with EGFR-mutated NSCLC [35, 36]. On the other hand, positivity or high-abundance of preT790M has been demonstrated to be associated with poor efficacy of initial EGFR-TKI treatment or a poor prognosis [8–10, 12, 13, 16–19]. In the same way, the present study demonstrated that high-abundance of preT790M was correlated with poor RFS and OS in patients with early-stage NSCLC who had undergone surgical resection. These results suggest that clinical features are likely to be different between preT790M and acquired T790M . A basic research study found that the acquisition of T790M was associated with a slowdown in tumor growth, which might underlie the good prognosis of EGFR-mutated NSCLC with acquired T790M . However, the reason why patients with EGFR-mutated NSCLC harboring preT790M appear to have a poor prognosis has not yet been elucidated, even though the tumor harbors a low-level amount of T790M clones and has undergone surgical resection. This is a subject for future investigation.
Postoperative adjuvant chemotherapy is recommended for patients with completely resected stage II-IIIA and a subset of stage I NSCLC according to the results from large, randomized trials and meta-analyses that have demonstrated a significant OS benefit [38, 39]. However, whether driver mutation-positive patients with resected stage NSCLC also benefit from adjuvant chemotherapy had not been accurately clarified. In particular, for patients with resected NSCLC harboring EGFR mutations, given the role of EGFR-TKIs in advanced EGFR-mutant NSCLC, many clinical trials have been conducted to investigate the efficacy of EGFR-TKIs in the adjuvant setting [40–45]. Most trials demonstrated that adjuvant treatment using first-generation EGFR-TKIs can decrease the risk of recurrence and prolong DFS compared to placebo or chemotherapy, but these DFS advantages did not always translate to OS [46, 47]. A meta-analysis that evaluated the role of EGFR-TKIs as an adjuvant therapy for patients with completely resected EGFR-mutated NSCLC demonstrated that, compared to mono chemotherapy, early-generation EGFR-TKI monotherapy had a superior DFS benefit, but did not show a significant OS benefit, whereas treatment with EGFR-TKIs plus chemotherapy was associated with significantly longer DFS and OS compared to mono chemotherapy . Therefore, these data suggested that it was necessary for the prolongation of DFS and OS in patients with resected EGFR-mutated NSCLC not only to add EGFR-TKIs as adjuvant treatment, but also to perform standard adjuvant chemotherapy as much as possible. On multivariate analysis in the current study, it was observed that OS in the patients who received adjuvant chemotherapy tended to be better than in those who did not receive adjuvant chemotherapy.
The ADAURA trial demonstrated significant improvement of DFS in the adjuvant osimertinib arm (HR for disease recurrence or death, 0.17 [99% CI, 0.11–0.26] in patients with stage II to IIIA disease, and 0.20 [99% CI, 0.14–0.30] in patients with stage IB to IIIA disease) . In that trial, administration of standard postoperative adjuvant chemotherapy was allowed, but not mandatory, although the DFS benefit from osimertinib was documented regardless of whether patients undergone adjuvant chemotherapy. Based on the present study findings, high-preT790M was an independent factor related to a poor prognosis for both RFS and OS in stage IB or more advanced stages. Though the basic correlation between poor prognosis and minor-frequency preT790M in resected EGFR-mutated NSCLC has not yet been elucidated, because osimertinib is expected to be effective for T790M, the efficacy of osimertinib for the population harboring potential preT790M might have resulted in the marked improvement of DFS in the ADAURA trial. Therefore, the addition of adjuvant osimertinib to standard adjuvant chemotherapy might also be expected to have a greater impact on improving OS. The NeoADAURA (NCT04351555) trial, investigating the efficacy and safety of neoadjuvant osimertinib in patients with EGFR-mutated resectable NSCLC, is ongoing. If translational research assessing minor-frequency T790M before osimertinib and after surgery could be conducted, the clinical significance of treatment of preT790M might be elucidated.
The limitations of the current study include the relatively short observation period and the low number of recurrence and death events, which results in a lack of statistical power, although the current study was the largest prospective trial, and the prognostic information was collected exactly. The number of patients in Stage I, especially stage IA, who have good prognosis because of the progress of diagnostic techniques and developments in improved surgical techniques was considerably large, which resulted in decreased incidences of recurrence and death. Therefore, further validation in a larger cohort might be needed for analysis of the prognosis for stage IB or more advanced settings.