| Backgrounds and aims:With great survival benefits,targeted therapies have forged a new pattern of comprehensive treatment.Refined management of molecular features as the milestone of targeted therapies,depends on rapidly-developed gene detection techniques.Beyond them,more and more novel biomarkers show vast potentials for clinical utility,especially for radiological parameters represented by PET/CT.This study would compare differences of PET/CT parameters among different driver genes,EGFR mutation types and EGFR coexisting mutation statuses,aiming at exploring utility value of PET/CT in refined management of molecular features for advanced NSCLC.On the other hand,early response assessment of anticancer drugs plays an important role in guiding standardized treatment.As PET/CT sensitively captures tumor activity by dynamically monitoring metabolic changes,PET/CT has emerging as a key player in this field.This study is also designed to explore whether PET/CT can act as a novel biomarker for early response evaluation,through monitoring metabolic alterations before and after drug treatment with a series of PET/CT.Methods:The study included 117 pathologically-confirmed advanced NSCLC patients who were admitted to the first affiliated Hospital of Xiamen University during 2015 Oct and 2021 Jan.There were three cohorts involved,that is,102 cases in cohort 1 for molecular feature prediction,44 cases in cohort 2 for early response assessment of targeted therapies and 13 cases in cohort 3 for early response evaluation of chemotherapies.Cohort 1 included EGFR mutation or ALK fusion patients who received PET/CT before treatment while cohort 2 and cohort 3 involved patients who received PET/CT dynamic monitoring before and after targeted therapies and chemotherapies,respectively.All three cohorts received PET/CT for three times,named PET0,PET1 and PET2.They were carried out at baseline,the fourteenth day and the forty-twice day of targeted therapies,respectively.For chemotherapies,they were at baseline,the twenty-first day and the sixty-third day,respectively.Changes in SUVmax and TLG of PET1 compared to PET0 were labelled as △ SUV 1%and △TLG1%,respectively.Similarly,those of PET2 compared to PET0 were labelled as △SUV2%and △ TLG2%,respectively.Clinicopathological features,molecular features,PET/CT metabolic parameters and survival data for patients included were collected.Predictive values of PET/CT metabolic parameters(SUVmax and SUVmean)in molecular types for advanced NSCLC were assessed using t-test,non-parameter test,Logistic regression and ROC curve.According to mPERCIST criteria,PET/CT metabolic response assessment was performed based on SUVmax and TLG of targeted lesions,CMR+PMR group and SMD+PMD group were regarded as effective group and invalid group,respectively.Kaplan-Meier and COX regression survival analyses were then harnessed to test whether PET/CT early response assessment correlated with PFS or OS of patients receiving targeted therapies or chemotherapies.Meanwhile,roles of EGFR mutation types and EGFR co-mutation statuses in PET/CT early response assessment were investigated with subgroup analysis.Results:In cohort 1 for PET/CT molecular feature prediction,78 cases with EGFR mutation and 24 ones with ALK fusion were included,among which,there were 34,36,4 and 4 cases of 19del,21L858R,18G719X and exon 20 mutation,respectively,as well as 28 and 33 EGFR-mutant cases with or without co-mutation,respectively.Compared to no co-mutation group,SUVmax of EGFR co-mutation group significantly elevated(P=0.041)while SUVmean of that insignificantly increased(P=0.064),Instead,there were no statistically-significant differences of SUVmax or SUVmean between EGFR mutation group and ALK fusion group,together with 19del group and 21L858R group(P>0.05).Univariate and multivariate Logistic regression analysis revealed that SUVmax was a potential independent predictor of EGFR co-mutation in advanced NSCLC(P=0.04 7 and P=0.059,respectively).As revealed by ROC curve,SUVmax could,in certain extent,predict EGFR-mutant advanced NSCLC patients who carried co-mutation,especially when factors integrated including smoking status,age,gender and stage(AUCSUVmax＝0.640,AUCcombination2=0.742).Besides,in cohort 2 for PET/CT assessment of early responses to EGFR-TKIs,37,5,1 and 1 cases with EGFR mutation,ALK fusion,MET amplification and ROS1 fusion were included,respectively.Based on early response assessment of △SUV 1%,32 and 5 cases out of 37 EGFR-mutant patients were PMR and SMD,respectively,and effective group significantly prolonged PFS(529 days vs.78 days,P<0.001).For △TLG1%,30 and 7 cases were PMR and SMD,respectively,and effective group insignificantly prolonged PFS(524 days vs.109 days,P=0.169).Regarding △SUV2%,30 and 4 cases out of 34 EGFR-mutant patients were PMR and SMD,respectively,and effective group insignificantly prolonged PFS(529 days vs.56 days,P=0.06).As for △TLG2%,31 and 3 cases were PMR and SMD,respectively,and effective group significantly prolonged PFS(529 days vs.45 days,P<0.001).Nevertheless,based on all these four metabolic parameters,differences between effective group and invalid group in OS were not significant(P>0.05).COX regression analysis demonstrated that △SUV 1%(P=0.027)and liver metastasis(P=0.035)were independent predictive biomarkers for EGFR-TKI efficacy in advanced NSCLC.Subgroup analysis unveiled that PET/CT evaluation of early responses to EGFR-TKIs was more fit for 21L858R patients than 19del group,as well as patients with EGFR co-mutation than those without co-mutation.This study also included 5 ALK-positive cases,in whom effective group prolonged PFS compared to ineffective group.Moreover,early metabolic responses were observed in one case harboring MET amplification and another ROS1-positive case who had a response to targeted therapies.Furthermore,in cohort 3 for PET/CT assessment of early responses to chemotherapies,all patients included were adenocarcinoma except for 2 cases of squamous carcinoma.Based on early response assessment of △SUV1%,5 and 8 cases out of 13 patients were PMR and SMD,respectively.For △TLG1%,4 and 9 cases were PMR and SMD,respectively.Regarding △SUV2%,5,2 and 2 cases out of 9 patients were PMR,SMD and PMD,respectively.As for △TLG2%,6,1 and 2 cases were PMR,SMD and PMD,respectively.There were almost no impacts of all four parameters on PFS and OS,except that using △TLG2%-based response assessment,effective group significantly prolonged PFS(236 days vs.89 days,P=0.02).Conclusions:SUVmax can serve as a promising independent predictor of advanced NSCLC patients who carry concurrent genetic alterations with EGFR mutation.Prediction efficacy of SUVmax is improved when clinical features such as smoking,age,gender and stage were integrated.However,SUVmax fails to distinguish patients with EGFR mutation from ALK arrangement,as well as patients harboring EGFR 19del from 21L858R mutation.Dynamic monitoring SUVmax and TLG can be utilized in early responses to EGFR-TKIs for patients with advanced NSCLC.Change in SUVmax and TLG are suitable for the early period and later period,respectively.Change in SUVmax at the fourteenth day and liver metastasis are independent predictive biomarkers of EGFR-TKI efficacy in advanced NSCLC.Moreover,early metabolic response evaluation using PET/CT is expected to expand to targeted therapies against other driver gene positive NSCLC,including ALK fusion,MET amplification and ROS1 fusion.Besides,clinical utility value of PET/CT in predicting early responses to chemotherapies for advanced NSCLC is limited,with only change in TLG at sixty-third day which can predict chemotherapy efficacy. |
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