Tumor response heterogeneity, a powerful independent predictor of treatment outcome in advanced lung adenocarcinoma.
Authors: Zheng Xinlong , Lu Tao , Wu Shiwen , Zheng Xiaobin , Jiang Kan , Long Feng , Miao Qian , Xu Yiquan , Wang Haibo , Bai Jing , Peng Wenying , Mok Tony S. K. , Lin Gen 
Published: June 2022

e21146 Background: Tumor response heterogeneity (TRH) to treatment is common across different foci within the same cancer patient. However, the effect of heterogeneity on clinical outcome remains unclear. Here, we developed a quantitative assessment of TRH and explored the correlation of TRH with the clinical outcome. Methods: In this retrospective study, the main eligibility criteria were: patients with advanced lung adenocarcinoma, 3-10 measured foci, ECOG 0-1 and received first-line chemotherapy or targeted therapy. Percent change of the longest diameter in each measurable lesion were quantified with RECIST1.1. TRH score was the absolute value of the dispersion coefficient of the percentage value of each target lesion. Patients were randomly divided into a learning and a validation set. The optimal cutoff value of TRH score was identified according to progression free survival information in the discovery cohort. Then, we confirmed and analyzed the correlation of TRH scores with clinicopathological features in the validation cohort. The Next-generation sequencing was performed for mechanism exploration. Results: Between January 2016 and December 2020, 174 patients were enrolled, 101 (58.0%) treated with platinum-based doublet chemotherapy and 73 (42.0%) with targeted therapy. Median follow-up was 19.8 months (95% CI, 14.5 to 25.0). In the discovery cohort (n = 85), 0.46 was defined as the optimal cut-off point of TRH score. Patients with high TRH score had poor PFS (median PFS 4.5 months vs. 15.8 months, HR 4.43; 95% CI 2.14 to 9.16; P < 0.001) compared to those with low TRH score. In validation cohort (n = 89), high TRH score was confirmed to be associated with significantly shorter PFS (median PFS 5.1 months vs. 12.9 months, HR 2.69; 95% CI 1.59 to 4.55; P < 0.001). The median value of TRH score followed the order of PD, SD and PR ( P < 0.001). Patients with high TRH score had poor ORR (30.0% vs. 68.0%; Fisher's exact test, P < 0.001) compared with those with low TRH score. In all population, high TRH score was further confirmed as an independent biomarker for PFS by univariate and multivariate analysis. Moreover, TRH score were able to further distinguish the outcomes in PR and SD subgroup. In PR, high TRH score was associated with significantly shorter PFS in PR subgroup (HR 2.79; 95% CI 1.24 to 6.29; P < 0.001) and SD subgroup (HR 2.55; 95% CI 1.44 to 4.49; P = 0.002), respectively. Compared with low TRH score, high TRH score was associated with higher tumor mutation burden and high frequency variation of cell cycle signal pathway. Conclusions: TRH score, a novel parameter for evaluating tumor response heterogeneity, was a powerful independent predictor of outcome in advanced lung adenocarcinoma. The TRHscore further stratifies patients with the same RECIST assessment results and is a useful addition to the RECIST assessment system. Further prospective studies are warranted.