Impact of DNA Damage Response and Repair (DDR) Gene Mutations on Efficacy of PD-(L)1 Immune Checkpoint Inhibition in Non–Small Cell Lung Cancer

Ricciuti, Biagio; Recondo, Gonzálo; Spurr, Liam F.; Li, Yvonne Y.; Lamberti, Giuseppe; Venkatraman, Deepti; Umeton, Renato; Cherniack, Andrew D.; Nishino, Mizuki; Sholl, Lynette M.; Shapiro, Geoffrey I.; Awad, Mark M.; Cheng, Michael L.

doi:10.1158/1078-0432.ccr-19-3529

Cited by 108 publications

(129 citation statements)

References 45 publications

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“…harboring mutations in DDR genes had longer progressionfree survival and overall survival under an ICI treatment (Ricciuti et al, 2020).…”

Section: Potential Regulation Of Neoantigen Production In Dna Damage mentioning

confidence: 99%

“…The result of the database analysis is supported by a recent study by Cheng’s group, which reported that the analysis of tumor samples from patients with non-small cell lung cancer treated with anti-PD-1/PD-L1 antibody using next-generation sequencing revealed that patients with DDR mutation (the most commonly mutated DDRs were ATM , ATR , BRCA2 , POLQ , and RAD50 in the analysis) exhibited high TMB. The patients harboring mutations in DDR genes had longer progression-free survival and overall survival under an ICI treatment ( Ricciuti et al, 2020 ).…”

Section: Potential Regulation Of Neoantigen Production In Dna Damage mentioning

confidence: 99%

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DNA Repair and Signaling in Immune-Related Cancer Therapy

Kakoti

Sato

Laskar

et al. 2020

Front. Mol. Biosci.

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Cancer therapy using immune checkpoint inhibitors (ICIs) is a promising clinical strategy for patients with multiple types of cancer. The expression of programmed cell death ligand-1 (PD-L1), an immune-suppressor ligand, in cancer cells is a factor that influences the efficacy of ICI therapy, particularly in the anti-programmed cell death protein-1 (PD-1)/PD-L1 antibody therapy. PD-L1 expression in cancer cells are associated with tumor mutation burden including microsatellite instability because the accumulation of mutations in the cancer genome can produce abnormal proteins via mutant mRNAs, resulting in neoantigen production and HLA-neoantigen complex presentation in cancer cells. HLA-neoantigen presentation promotes immune activity within tumor environment; therefore, known as hot tumor. Thus, as the fidelity of DNA repair affects the generation of genomic mutations, the status of DNA repair and signaling in cancer cells can be considered prior to ICI therapy. The Cancer Genome Atlas (TCGA) and The Cancer Immunome Atlas (TCIA) database analysis showed that tumor samples harboring mutations in any non-homologous end joining, homologous recombination, or DNA damage signaling genes exhibit high neoantigen levels. Alternatively, an urgent task is to understand how the DNA damage-associated cancer treatments change the status of immune activity in patients because multiple clinical trials on combination therapy are ongoing. Recent studies demonstrated that multiple pathways regulate PD-L1 expression in cancer cells. Here, we summarize the regulation of the immune response to ICI therapy, including PD-L1 expression, and also discuss the potential strategies to improve the efficacy of ICI therapy for poor responders from the viewpoint of DNA damage response before or after DNA damage-associated cancer treatment.

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“…harboring mutations in DDR genes had longer progressionfree survival and overall survival under an ICI treatment (Ricciuti et al, 2020).…”

Section: Potential Regulation Of Neoantigen Production In Dna Damage mentioning

confidence: 99%

Section: Potential Regulation Of Neoantigen Production In Dna Damage mentioning

confidence: 99%

DNA Repair and Signaling in Immune-Related Cancer Therapy

Kakoti

Sato

Laskar

et al. 2020

Front. Mol. Biosci.

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“…The FANCA gene is important for the repair of double-stranded DNA breaks and is involved in the cellular process known as the Fanconi anemia pathway. Outcomes have been assessed in patients treated with ICIs, and the results showed significantly higher objective response rate, longer median PFS, and longer median OS with patients on PD-(L)1 therapy [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular and Clinical Features of Hospital Admissions in Patients with Thoracic Malignancies on Immune Checkpoint Inhibitors

Zhao

Mambetsariev

et al. 2021

Cancers

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Lung cancer patients undergoing systemic treatment with immune checkpoint inhibitors (ICIs) can lead to severe immune-related adverse events (irAEs) that may warrant immediate hospitalization. Patients with thoracic malignancies hospitalized at City of Hope while undergoing treatment with ICIs were identified. Pathology and available next-generation sequencing (NGS) data, including the programmed death-ligand 1 (PD-L1) status and clinical information, including hospitalizations, invasive procedures, and the occurrence of irAEs, were collected. Unpaired T-tests, Chi-square/Fisher’s exact test, and logistic regression were used to analyze our cohort. The overall survival (OS) was calculated and compared using univariate and multivariate COX models. Ninety patients with stage IV lung cancer were admitted after ICI treatment. Of those patients, 28 (31.1%) had documented irAEs. Genomic analyses showed an enrichment of LRP1B mutations (n = 5/6 vs. n = 7/26, 83.3% vs. 26.9%; odds ratio (OR) (95% confidence interval (CI): 13.5 (1.7–166.1); p < 0.05) and MLL3 mutations (n = 4/6, 66.7% vs. n = 5/26, 19.2%; OR (95% CI): 8.4 (1.3–49.3), p < 0.05) in patients with irAE occurrences. Patients with somatic genomic alterations (GAs) in MET (median OS of 2.7 vs. 7.2 months; HR (95% CI): 3.1 (0.57–17.1); p < 0.05) or FANCA (median OS of 3.0 vs. 12.4 months; HR (95% CI): 3.1 (0.70–13.8); p < 0.05) demonstrated a significantly shorter OS. Patients with irAEs showed a trend toward improved OS (median OS 16.4 vs. 6.8 months, p = 0.19) compared to hospitalized patients without documented irAEs. Lung cancer patients who required treatment discontinuance or interruption due to irAEs (n = 19) had significantly longer OS (median OS 18.5 vs. 6.2 months; HR (95% CI): 0.47 (0.28–0.79); p < 0.05). Our results showed a significant survival benefit in lung cancer patients hospitalized due to irAEs that necessitated a treatment interruption. Patients with positive somatic GAs in MET and FANCA were associated with significantly worse OS compared to patients with negative GAs.

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“…Besides, activating of oncogenic signaling pathways like PI3K-AKT-mTOR pathway, Jak-STAT pathway and KRAS-ERK pathway, can also induce PD-L1 expression in NSCLC or other cancer types [17][18][19]. Recently, NSCLC patients with driver gene mutation in DDR pathways presented signi cant higher TMB values and higher objective response rate, longer median PFS, showing improved clinical responses to anti-cancer immunotherapy in NSCLC [32].We also found DDR pathway, TP53 pathway, cell cycles pathway and NOTCH pathway were highly correlated with high PD-L1 expression in Chinese lung adenocarcinoma patients (P < 0.05), which might provide more evidences for illustrating a clearer molecular mechanism for PD-L1 expression in Chinese patients with lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

In-depth genomic characterization of programmed cell death ligand 1 (PD-L1) expression in Chinese lung adenocarcinoma patients.

et al. 2021

JCO

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e20500 Background: Immune checkpoint blockades have revolutionized anticancer treatments for lung cancers, and PD-L1 expression has been served as crucial predictive biomarkers for immunotherapies. However, PD-L1 expression has been found to be influenced by some extrinsic or intrinsic factors in vitro or to be associated with other biomarkers in vivo. Methods: An amount of tumor tissues was taken from a biopsy or surgery for PD-L1 expression assay and genomic profiling in Chinese lung adenocarcinoma patients using extend targeted sequencing panel. In-depth retrospective analyses of clinical features, gene alternations, singling pathways and immune signatures was conducted in negative group (TPS < 1%), intermediate group (1% ≤ TPS < 50%), and high group (TPS ≥ 50%). Clinical responses to selected mutation were also evaluated from public database such as TCGA and MSKCC. Results: A total of 248 Chinese patients with lung adenocarcinoma was retrospectively identified and included in this study, consisting of negative group (n = 124, 50%), intermediate group (n = 93, 38%), and high group (n = 38, 12%). High tumor mutation burden was significantly as associated with high PD-L1 expression. In addition, PD-L1 expression was highly related with gene alternations such as PRKDC, KMT2D, ERBB2 and SETD2. Moreover, signaling pathways of DDR, TP53, cell cycles and NOTCH also obviously related with PD-L1 expression. Besides, most of patients in high PD-L1 group were determined as high-grade immune subtypes (C2-C4), showing significant higher levels of IFN-gamma, CD8+ T-cells, NK cells, NK CD56 dim cells, Th1 cells, Th2 cells (P < 0.0001). Moreover, the prognostic value of SETD2 mutation was slight positive with overall survival from MSKCC cohort (HR 1.92 [95%CI 0.90-4.10], P = 0.085), and the percentage of IFN-gamma was significantly higher in SETD2 mutant group than in wild-type subgroup ( P < 0.01). Conclusions: This study illustrated in-depth genomic profiles and immune signatures of PD-L1 expression in Chinese lung adenocarcinoma patients, which might interpret more potential molecular mechanisms for anti-cancer immunotherapy in NSCLC. In addition, SETD2 may be potential biomarkers for predicting patients’ prognosis.

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Impact of DNA Damage Response and Repair (DDR) Gene Mutations on Efficacy of PD-(L)1 Immune Checkpoint Inhibition in Non–Small Cell Lung Cancer

Abstract: Impact of DNA damage response and repair (DDR) gene mutations on efficacy of PD-(L)1 immune checkpoint inhibition in non-small cell lung cancerRunning Title: DDR gene mutations and immunotherapy efficacy in NSCLC.

Cited by 108 publications

References 45 publications

DNA Repair and Signaling in Immune-Related Cancer Therapy

DNA Repair and Signaling in Immune-Related Cancer Therapy

Molecular and Clinical Features of Hospital Admissions in Patients with Thoracic Malignancies on Immune Checkpoint Inhibitors

In-depth genomic characterization of programmed cell death ligand 1 (PD-L1) expression in Chinese lung adenocarcinoma patients.

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