Association between certain non–small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death‐ligand 1 inhibition

Liang, Wenhua; Guo, Meihua; Pan, Zhenkui; Li, Caichen; Zhao, Yi; Liang, Hengrui; Yang, Haiying; Wang, Zhen; Chen, Wenting; Xu, Caijun; Yang, Xinyun; Sun, Jing; He, Ping; Gu, Xia; Yin, Weiqiang; He, Jianxing

doi:10.1111/cas.14032

Cited by 13 publications

(9 citation statements)

References 27 publications

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“…It appeared that the molecular subtypes in our study were not related to certain gene mutations but the pattern of mutations involving multiple genes, which is quite different to the molecular alterations when the driver genes were not excluded. [ 5,20,21 ] Therefore, further investigation in this regard is warranted. Furthermore, since the molecular subtypes described were associated with survival to first‐line chemotherapy, it is possible they may similarly associate with survival to subsequent line chemotherapies (e.g., docetaxel or gemcitabine in NSCLC or topotecan in SCLC).…”

Section: Discussionmentioning

confidence: 99%

Mutational Profile Evaluates Response and Survival to First‐Line Chemotherapy in Lung Cancer

Song

Wang

et al. 2020

Advanced Science

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Evaluating the therapeutic response and survival of lung cancer patients receiving first‐line chemotherapy has always been difficult. Limited biomarkers for evaluation exist and as a result histology represents an empiric tool to guide therapeutic decision making. In this study, molecular signatures associated with response and long‐term survival of lung cancer patients receiving first‐line chemotherapy are discovered. Whole‐exome sequencing is performed on pretherapeutic tissue samples of 186 patients [145 non‐small cell lung cancer (NSCLC) and 41 small cell lung cancer (SCLC)]. On the basis of genomic alteration characteristics, NSCLC patients can be classified into four subtypes (C1–C4). The long‐term survival is similar among different subtypes. SCLC patients are also divided into four subtypes and significant difference in their progression free survival is revealed (P < 0.001). NSCLC patients can be divided into three subtypes (S1–S3) based on TMB. A trend of worse survival associated with higher TMB in subtype S3 than in S1+S2 is found. In contrast, no significant correlations between molecular subtype and therapeutic response are observed. In conclusion, this study identifies several molecular signatures associated with response and survival to first‐line chemotherapy in lung cancer.

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Section: Discussionmentioning

confidence: 99%

Mutational Profile Evaluates Response and Survival to First‐Line Chemotherapy in Lung Cancer

Song

Wang

et al. 2020

Advanced Science

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“…Genetic alternations were assessed by targeted next-generation sequencing (NGS) to cover critical mutations involving nine major drivers ( EGFR, ALK, RAS, ROS1, RET, BRAF, PIK3CA, MET , and HER2 ) in NSCLC. 21 In brief, DNA was extracted and quantified by using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany) and Qubit fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturers’ instructions. The products were then captured and sequenced on the Ion Proton Sequencer (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

PD-L1 expression with respect to driver mutations in non-small cell lung cancer in an Asian population: a large study of 1370 cases in China

Xie

et al. 2020

Ther Adv Med Oncol

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Background: Programmed cell death ligand 1 (PD-L1) expression with respect to genetic alternations has not been well established in non-small cell lung cancer (NSCLC), especially in the Asian population. Methods: We reviewed 1370 NSCLC patients from a prospectively maintained database. Immunohistochemistry was performed on tumor cells and tumor-infiltrating lymphocytes (TILs) using the VENTANA (SP142) anti-PD-L1 antibody. The tumor proportion score (TPS) cutoff values were set at ⩾1% and ⩾50%, and the immune proportion score (IPS) cutoff values were set at ⩾1% and ⩾10%. Results: In tumor cells, PD-L1 positivity was observed in 405 (29.6%), 122 (8.9%), and 27 (2.0%) patients with TPS cutoff values at ⩾1% and ⩾50%. Contrastingly, TILs of 1154 (84.2%) and 346 (25.3%) patients stained positive at IPS cutoff values of ⩾1% and ⩾50%, respectively. PD-L1 expression was more common in patients who were mutation-negative irrespective of the TPS cutoff values and tumor size. PD-L1 expression in tumor cells was less frequent in patients harboring EGFR mutations (18.8% TPS ⩾ 1% and 4.6% TPS ⩾ 50%). Conversely, PD-L1 expression was high in the presence of KRAS mutations (47.3% TPS ⩾ 1% and 22.5% TPS ⩾ 50%). Overall, KRAS, BRAF, PICK3A, MET mutations and ROS1 and RET translocations were more frequent, while EGFR and HER2 mutations and ALK translocations were less frequent compared with the overall PD-L1 expression levels. Although the difference between TILs among the PD-L1-positive cases was comparatively small, PD-L1 positivity was less prevalent in EGFR-mutated tumors and more common in those with KRAS mutations, ROS1 translocations, BRAF mutations, or MET mutations. Conclusion: Our study showed the heterogeneity in PD-L1 expression with respect to nine major oncogenic drivers in China. Future studies are warranted to further clarify the association between PD-L1 expression and driver mutations in NSCLC.

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“…Immune checkpoint inhibitors (ICIs) such as programmed cell death‐1 (PD‐1)/programmed cell death ligand‐1 (PD‐L1) antibodies have led to unprecedented durable clinical benefit for NSCLC, but response rates are low for patients with targetable driver mutations 15 . Biomarker studies have revealed a significant correlation between PD‐L1 expression and the likelihood of a response to PD‐1 inhibitors, whereas EGFR mutation appears to be a negative predictive factor 16,17 . Given that most sensitizing EGFR mutations are not responsive to PD‐1 blockade either exon 19 deletions or L858R in exon 21; however, it is unclear whether such treatment is also without benefit in patients with uncommon EGFR mutations 18 .…”

Section: Introductionmentioning

confidence: 99%

Immune microenvironment features and efficacy of PD‐1/PD‐L1 blockade in non‐small cell lung cancer patients with EGFR or HER2 exon 20 insertions

et al. 2020

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Background: Insertions in exon 20 (Ex20ins) of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are relatively insensitive to firstand second-generation EGFR-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). This study aimed to investigate the immune microenvironment features and efficacy of PD-1/PD-L1 blockade of NSCLC with EGFR and HER2 Ex20ins. Methods: Clinical characteristics, coexisting mutations, and outcomes to EGFR-TKIs and immune checkpoint blockade were reviewed for NSCLC patients with exon 20 mutations of EGFR or HER2. Data obtained included the molecular spectrum (extended genotyping for mutations in 324 cancer-related genes), as well as tumor mutational burden (TMB), PD-L1 protein expression, and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs). Results: A total of 1270 NSCLC patients were identified. Of these, 504 (39.7%) cases had EGFR mutations and 6.9% (35/504) of them had EGFR Ex20ins. Meanwhile, 21 (1.7%) cases with HER2 Ex20ins were detected. Comprehensive genomic profiling identified A767_V769dup variant (25.0%) was the most common type in tumors with EGFR Ex20ins. Co-occurring mutations were not uncommon including TP53 (45%), PIK3CA (20%), CDKN2A (10%), and EGFR amplification (20%). The average TMB was 3.3 mutations/megabase. PD-L1 expression in patients with EGFR Ex20ins was significantly higher than for those with HER2 mutations (48.6% vs. 19.0%, P = 0.027). High TMB and PD-L1 expression was independently associated with significantly poor prognosis (P = 0.025, P = 0.045, respectively) while there was no association between CD4+/CD8+ TILs and prognosis in EGFR or HER2 mutant NSCLC. Finally, patients harboring EGFR Ex20ins seemed to be sensitive to PD-1/PD-L1 blockage whereas it showed limited efficacy in patients with HER2 Ex20ins. Conclusions: NSCLC patients with EGFR/HER2 Ex20ins had similar genomic characteristics and distinct immune features. Patients with EGFR Ex20ins had significantly higher PD-L1 expression than those with HER2 mutations, which may be the potential reason for the different responses to PD-1/PD-L1 blockage.

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Association between certain non–small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death‐ligand 1 inhibition

Cited by 13 publications

References 27 publications

Mutational Profile Evaluates Response and Survival to First‐Line Chemotherapy in Lung Cancer

Mutational Profile Evaluates Response and Survival to First‐Line Chemotherapy in Lung Cancer

PD-L1 expression with respect to driver mutations in non-small cell lung cancer in an Asian population: a large study of 1370 cases in China

Immune microenvironment features and efficacy of PD‐1/PD‐L1 blockade in non‐small cell lung cancer patients with EGFR or HER2 exon 20 insertions

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