Lung adenocarcinoma (LAC) is composed of lepidic, papillary, mucinous, micropapillary and solid components in its parenchyma. Complex responses to therapeutics result from intratumoral heterogeneity. However, it remains confused that what components in a mixed LAC tumor are responsible to the heterogeneous EGFR mutation and PD-L1 expression. Methods We investigated EGFR status via laser microdissection to capture spatially separated cancer cell subpopulations and digital droplet PCR to

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... the abundance of EGFR sensitizing mutation and naïve T790M. Whilst, PD-L1 expression level via tumor proportion score (TPS) was evaluated by Ventana immunohistochemistry using SP263 antibody. PD-L1 expression levels were tiered in <1%, 1%-49% and >=50% groups. Results EGFR mutation harbored in 154 (59%) of 261 LAC patients and more frequently occurred in papillary, lepidic and micropapillary constituents. Higher levels of PD-L1 were found in LACs at stage III and IV (68.3%) versus those at stage I and II (31.7%) ( P =0.04). Solid predominant LACs (41.3%) expressed PD-L1 with TPS >=50%, versus mucinous and lepidic LACs ( P <0.01). LACs with solid constituents also had more positive proportion of PD-L1 protein. Cut-offs <1%, 1%-49% or >=50% were associated with patients' progression-free survival and longer in the <1% group (22.9 month, 95% CI 17.6-28.2) (P<0.05). LACs consisting of two constituents with PD-L1 TPS <1% had a better prognosis than the groups with single component and more than two components ( P <0.05). Eighteen LACs (6.9%) had concomitantly deletion in exon 19 or L858R and naïve T790M mutation. The abundance of T790M varied diversely with sensitizing mutation. PD-L1 expression was not concordant in same components and usually negative in the EGFR -mutated constituents. Heterogeneous PD-L1 expression occurred in the vicinity of stromal tissues. Conclusion Intratumoral genetic heterogeneity of LACs was demonstrated associated with histological patterns.