Heterogeneity analysis of PD-L1 expression and copy number status in EBUS-TBNA biopsy specimens of non-small cell lung cancer: Comparative assessment of primary and metastatic sites

Yoshimura, Katsuhiro; Suzuki, Yuzo; Karayama, Masato; Tsuchiya, Kazuo; Mori, Kazutaka; Suzuki, Yuzo; Iwashita, Yuji; Kahyo, Tomoaki; Kawase, Akikazu; Tanahashi, Masayuki; Ogawa, Hiroshi; Yokomura, Koushi; Inui, Naoki; Funai, Kazuhito; Shinmura, Kazuya; Niwa, Hiroshi; Suda, Takafumi; Sugimura, Haruhiko

doi:10.1016/j.lungcan.2019.06.002

Cited by 34 publications

(40 citation statements)

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“…Likewise, solid LACs had a similar prognosis between the groups of TPS < 1% and TPS 1-49% even if it was not significant. K. Yoshimura, et al [14] reported that PD-L1 are also heterogeneously expressed in the same primary tumor tissue in a patchy pattern, as shown in our study (Fig. 1c and Fig.…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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

Cai

Shi

et al. 2020

BMC Cancer

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“…Likewise, solid LACs had a similar prognosis between the groups of TPS <1% and TPS 1%-49% even if it was not significant. K. Yoshimura, et al [14] reported that PD-L1 are also heterogeneously expressed in the same primary tumor tissue in a patchy pattern, as shown in our study ( Fig 1C and Fig 5B). Histological subtypes were really associated with heterogeneous PD-L1 expression and patients' prognosis.…”

Section: Discussionsupporting

confidence: 88%

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

Cai

Shi

et al. 2020

Preprint

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KEYWORDS 2 lung adenocarcinoma, EGFR mutation, PD-L1, heterogeneity 3 Abstract 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. 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. 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

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“…Yoshimura et al in the study on 71 patients presented the evaluation of PD-L1 positive cells in EBUS-TBNA derived specimens by IHC and FISH. They found good concordance between PD-L1 detected in LNs and transbronchial biopsy (TBB), resected primary tumors, and resected metastatic tumors (70). Thus, these results confirmed the usefulness of EBUS/TBNA material, a typical method in lung cancer diagnosis, for the studies of local immune alterations.…”

Section: Lung Cancer Immunitymentioning

confidence: 92%

New Frontiers for Molecular Pathology

Domagała‐Kulawik

2019

Front. Med.

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Lung cancer remains a serious oncological problem worldwide. The delayed diagnosis and a prevalence of advanced stages in up to 70% of cases at recognition are still observed. Thanks to targeted therapies and immunotherapy a significant progress in achieving prolonged survival in some lung cancer patients is reported. A precise histopathological diagnosis, especially the recognition of adenocarcinoma, and a progress in the methods of clinical staging underlie the proper qualification of patients for a tailored therapy. The deep molecular characteristics of lung cancer in liquid biopsy, for example blood, bronchoalveolar lavage fluid (BALF), cell suspension from needle aspirates, are currently available. The molecular characteristic has recently been extended with molecular aberrations of BRAF, KRAS, MET, ERBB2, RET, NTRK next to the well-known EGFR mutations and ALK, ROS-1 relocation. The present paper discusses the usefulness of adequate pathological methods and molecular testing for the identification of a broad spectrum of predictive biomarkers for a molecular-directed lung cancer therapy. Immunotherapy with immune checkpoint inhibitors (ICIs) is approved in the first line therapy of advanced non-small-cell lung cancer. To date only PD-L1 expression on tumor cells has been found to be a marker of response to ICIs. The efficacy of ICIs as well as the susceptibility to immune-related adverse events are highly individual, so immune biomarkers are widely investigated. The candidates for predictive factors for ICIs immunotherapy include cancer cell antigenicity, presence of regulatory/suppressory molecules on cancer cells, cancer stem cells or on exosomes, and, on the other hand, an immune status of the patient. Cancers with high immune infiltration in the tumor milieu, referred to as “hot” tumors, seem to ensure a better response to ICIs than the “cold” ones. BALF analysis may replace cancer tissue examination, which is of limited access in advanced stages, for the recognition of the nature of immune response in the tumor environment. Tumor mutational burden (TMB) was shown to correlate with a good response to ICIs, especially when combined with other anticancer therapies. The present paper demonstrates the results of recent studies on lung cancer characteristics which bring us closer to the definition of useful prognostic/predictive factors.

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Heterogeneity analysis of PD-L1 expression and copy number status in EBUS-TBNA biopsy specimens of non-small cell lung cancer: Comparative assessment of primary and metastatic sites

Cited by 34 publications

References 50 publications

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

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

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

New Frontiers for Molecular Pathology

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