Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients With EGFR Mutation

Su, Shan; Dong, Zhong‐Yi; Xie, Zhi; Yan, Li; Li, Yufa; Su, Jian; Liu, Siyang; Yin, Kun; Chen, Ruilian; Huang, Shu‐Mei; Chen, Zhihong; Yang, Jing; Tu, Hai‐Yan; Zhou, Qing; Zhong, Wen‐Zhao; Zhang, Xuchao; Wu, Yi‐Long

doi:10.1016/j.jtho.2018.07.016

Cited by 107 publications

(123 citation statements)

References 45 publications

(52 reference statements)

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…Progression‐free survival was significantly shorter in patients with high PD‐L1 expression than in those with low PD‐L1 expression. High PD‐L1 expression had been reported by several recent studies to correlate with shorter PFS after EGFR‐TKI treatment in EGFR ‐mutated NSCLC . The results of our study were similar to those of the previous reports, in terms of this point.…”

Section: Discussionsupporting

confidence: 92%

“…However, in their study, not all the tumor samples analyzed by IHC staining were obtained in the advanced stage and the cases that used EGFR‐TKIs as second‐line or higher therapy were also included; therefore, their result might not have reflected the actual TME during the initial administration of EGFR‐TKIs. However, Su et al reported a high proportion of PD‐L1 + /CD8 + cases among patients with de novo resistance to first‐line EGFR‐TKIs for advanced NSCLC; their results were similar to ours. These results, including our representative case, suggested that tumors with high expression of both PD‐L1 and CD8 + TIL, despite harboring EGFR mutations, are likely to benefit less from EGFR‐TKI therapies.…”

Section: Discussionsupporting

confidence: 88%

“…As previously mentioned, type 1 TME is a phenotype that had been considered to most likely benefit from anti‐PD‐1/PD‐L1 blockade. Actually, the response to anti‐PD‐1 inhibitors has been reported for several cases of EGFR ‐mutated advanced NSCLC with both high PD‐L1 and CD8 + TILs . Therefore, immunotherapy as a treatment option for such a selected subset, even EGFR ‐mutant NSCLC patients, could leave room for further investigation in the context of personalized medicine.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

et al. 2019

View full text Add to dashboard Cite

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) as first‐line treatment in 70 patients with advanced EGFR‐mutant non‐small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28‐8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death‐1 ligand‐1 (PD‐L1), as high (50% or more) or low (less than 50%), and ligand‐2 (PD‐L2) expression, respectively. The extent of CD8+ tumor‐infiltrating lymphocytes was evaluated on a scale of 0‐3, with 0‐1 as low and 2‐3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD‐L1 tumor proportion and CD8+ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD‐L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression‐free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR‐TKIs differed according to the TME, and the phenotype with high PD‐L1 and CD8+ expression might be the subset that would poorly benefit from such treatment.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

et al. 2019

View full text Add to dashboard Cite

show abstract

“…PD‐L1 is overexpressed in approximately 20–30% of TNBC patients and is associated with poor prognosis . Increased PD‐L1 expression in response to chemotherapy and targeted therapies leads to drug resistance in multiple cancers . Hence, combining immunotherapy targeting the PD‐1/PD‐L1 axis with conventional chemotherapy and targeted therapy represents an effective approach for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Raninga

Lee

Sinha

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

Triple‐negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non‐TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA‐approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA‐MB‐231 xenograft and patient‐derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T‐cell tumor infiltration in vivo and upregulated immune checkpoint PD‐L1 expression in an ERK1/2‐MYC‐dependent manner. Moreover, combination of AF with anti‐PD‐L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti‐PD‐L1 antibody that warrants further clinical investigation for TNBC patients.

show abstract

“…Lin et al found that when treating an EGFR mutant NSCLC patient with EGFR‐TKIs, PD‐L1‐positive patients had longer progression‐free and overall survival than PD‐L1 negative patients . However, several other studies drew the opposite conclusion . The patient in our report experienced a rapid relapse after gefitinib treatment and thus exhibited significantly short progression‐free and overall survival.…”

Section: Discussionmentioning

confidence: 99%

EGFR exon 21 L858R as an acquired resistance mechanism to nivolumab in a lung cancer patient originally driver gene‐negative

2019

View full text Add to dashboard Cite

The use of immune checkpoint inhibitors targeting PD‐1 and PD‐L1 in advanced non‐small cell lung cancer (NSCLC) has been one of the most significant improvements in recent years. However the resistance mechanisms of immune checkpoint inhibitors require further investigation. Herein we attempted to determine the possible resistance mechanism of nivolumab in a male smoker with advanced adenosquamous carcinoma. After experiencing disease progression on systematic chemotherapy, he was administered nivolumab as a result of high PD‐L1 expression. Larger panel gene detection was performed after the failure of nivolumab treatment to investigate the possible resistance mechanism and a new EGFR exon 21 L858R mutation was detected. After a achieving a response with gefitinib, the patient suffered a rapid relapse and died of tumor progression. This case represents the first time EGFR exon 21 L858R has been detected as an acquired resistance mutation to nivolumab. Patients with high PD‐L1 expression may exhibit a poor response to EGFR‐tyrosine kinase inhibitors. Large panel gene detection remains the optimal choice when confronted with drug resistance.

show abstract

Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients With EGFR Mutation

Cited by 107 publications

References 45 publications

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

EGFR exon 21 L858R as an acquired resistance mechanism to nivolumab in a lung cancer patient originally driver gene‐negative

Contact Info

Product

Resources

About