Micropapillary: A component more likely to harbour heterogeneous EGFR mutations in lung adenocarcinomas

Cai, Yiran; Dong, Yujie; Wu, Hongbo; Liu, Zichen; Zhou, Lijuan; Su, Dan; Chen, Xuejing; Zhang, Li; Zhao, Yongjian

doi:10.1038/srep23755

Cited by 20 publications

(11 citation statements)

References 31 publications

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“…In the present study we found that sub-clonality for KRAS or EGFR mutation was associated with shorter survival times. The presence of sub-clonality for the common drivers in lung adenocarcinoma is in accordance with some previous reports [ 7 , 8 , 10 , 15 , 16 ]. However, different cohorts report lack of sub-clonality [ 17 ] or claim that it is probably a rare condition [ 36 ].…”

Section: Discussionsupporting

confidence: 92%

“…Additionally, even within the same lesion, multi-region sampling provided evidence for sub-clonality for EGFR mutation status [ 13 , 14 ] and for ALK rearrangement [ 15 ]. In one study, EGFR sub-clonality was specifically linked to micropapillary histological variant [ 16 ]. On the other hand, an analysis of 862 cases with EGFR mutations did not find dual mutations and different areas of the tumor as well as paired primary and metastasis were concordant for the mutation [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Clinically significant sub-clonality for common drivers can be detected in 26% of KRAS/EGFR mutated lung adenocarcinomas

et al. 2017

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Genetic sub-clonality has been described in multiple malignancies, however the presence of sub-clonality for major drivers in lung adenocarcinoma and its clinical significance is a subject under debate. Using molecular and morphometric approach, 347 lung adenocarcinoma samples were analyzed for KRAS and EGFR sub-clonality, which was further correlated with clinical and pathological variables.KRAS and EGFR mutations were identified in 100 (29%) and 82 (23%) cases, respectively. One hundred and forty four KRAS or EGFR positive cases were also available for morphometric analysis, among which 37 (26%) were defined as sub-clonal. The presence of sub-clonality was associated with shorter survival time (p=0.02). Interestingly, cases with sub-clonality were also associated with earlier disease stage (89% vs 66% stage I disease in sub-clonal vs clonal cases, respectively, p=0.01) and less lymph node involvement (8% vs 25% in sub-clonal vs clonal cases, respectively, p=0.02). Our findings demonstrate the presence of sub-clonality for mutations in common drivers in lung adenocarcinoma and link it both to earlier disease stage and to poor survival. These findings are in line with the different evolutionary models that can present with genetic sub-clonality.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Clinically significant sub-clonality for common drivers can be detected in 26% of KRAS/EGFR mutated lung adenocarcinomas

et al. 2017

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“…A higher proportion of solid or micropapillary pattern refers to worse prognosis. Local recurrence, nodal involvement and distant metastases are more frequent among these neoplasms [9]. Some authors have found that even 1% [10][11][12][13] or 5% [5,[14][15][16][17][18] of these components may cause an unfavourable outcome.…”

Section: Introductionmentioning

confidence: 99%

The more the micropapillary pattern in stage I lung adenocarcinoma, the worse the prognosis—a retrospective study on digitalized slides

et al. 2018

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Although the majority of lung adenocarcinomas show mixed pattern, only the predominant component is taken into account according to the novel classification. We evaluated the proportion of different patterns and their impact on overall survival (OS) and disease-free survival (DFS). Patterns were recorded according to predominance and their proportions were rated and calculated by objective area measuring on digitalized, annotated slides of resected stage I lung adenocarcinomas. Spearman's rank correlation, Kaplan-Meier models and the log rank test were used for statistical evaluation. Two hundred forty-three stage I adenocarcinoma were included. Lepidic pattern is more frequent in tumours without recurrence (20 vs. 8%), and lepidic predominant tumours have favourable prognosis (OS 90.5%, DFS 89.4%), but proportions above 25% are not associated with improving outcome. Solid and micropapillary patterns are more frequent in patients with recurrence (48 vs. 5% and 13 vs. 4%) and predominance of each one is associated with unfavourable prognosis (OS 64.1%, DFS 56.3% and OS 28.1%, DFS 28.1%, respectively). Above 25%, a growing proportion of solid or micropapillary pattern is not associated with worsening prognosis. In contrast, tumours having micropapillary pattern as secondly predominant form a different intermediate group (OS 51.1%, DFS 57.8%). Our study was based on measured area of each growth pattern on all available slides digitalized. This is the most precise way of determining the size of each component from the material available. We propose using predominant and secondly predominant patterns for prognostic purposes, particularly in tumours having solid or micropapillary patterns.

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“…Physicians and oncologists turn on comprehensive therapies combined to targeted treatment and immune checkpoint inhibitors. Molecular discordances between primary and metastatic tumors differ among histological types [4]. A subset of patients with EGFRmutant LACs fosters MRs to EGFR-TKIs.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous components of lung adenocarcinomas confer distinct EGFR mutation and PD-L1 expression

Cai

Shi

et al. 2020

BMC Cancer

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Background: 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 determine 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. Cutoffs < 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. 58.8, 29.4 and 11.8% in ALK positive LACs (N = 17) were found PD-L1 expression via cutoffs of < 1, 1-49% and > =50%, respectively (P > 0.05). Conclusion: Intratumoral genetic heterogeneity of LACs was demonstrated associated with histological patterns. Heterogeneous PD-L1 expression in higher level usually occurred in solid component both in EGFR mutated and EGFR wild-typed LACs. EGFR mutated LACs heterogeneously had sensitizing and resistant mutation and was accompanied with PD-L1 expression, but discordant among histological constituents. Immune checkpoint inhibitor combined with third generation EGFR tyrosine kinase inhibitor should be more effective to these LACs.

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Micropapillary: A component more likely to harbour heterogeneous EGFR mutations in lung adenocarcinomas

Cited by 20 publications

References 31 publications

Clinically significant sub-clonality for common drivers can be detected in 26% of KRAS/EGFR mutated lung adenocarcinomas

Clinically significant sub-clonality for common drivers can be detected in 26% of KRAS/EGFR mutated lung adenocarcinomas

The more the micropapillary pattern in stage I lung adenocarcinoma, the worse the prognosis—a retrospective study on digitalized slides

Heterogeneous components of lung adenocarcinomas confer distinct EGFR mutation and PD-L1 expression

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