P1.04-04 DNA Damage Response Gene Alterations Are Associated with High Tumor Mutational Burden and Clinical Benefit from PD-1 Axis Inhibition in NSCLC

9077 Background: DNA damage response (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with benefit from immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. Methods: Clinicopathologic and genomic data were collected from patients (pts) with advanced NSCLC at the Dana-Farber Cancer Institute treated with PD-(L)1 inhibitors. Targeted next-generation sequencing (NGS) by OncoPanel was used to determine DDR gene mutation status and TMB. DDR positive (DDRpos) cases were defined as those with pathogenic DDR alterations (per COSMIC and ClinVar databases). DDR negative (DDRneg) cases were defined as either DDR wild-type or those with non-pathogenic DDR alterations. Results: Of 468 pts with successful NGS who received ICIs, 242 (51.7%) were identified as having any DDR alteration. Of them, 74 (15.8% in the entire cohort) were defined as DDRpos with pathogenic alterations in the following genes: ATM (41.9%), MLH1/MSH2/MSH6 (18.9%), BRCA1/2 (16.2%), CHEK1/2 (9.4%), FANC genes (9.4%), BAP1 (5.4%), RAD genes (5.4%), ERCC4/6 (4.0%), POLE (2.7%), ATR (2.7%). DDRpos and DDRneg groups were balanced in terms of age, performance status, gender, histology, oncogenic driver mutation, smoking status, ICI line, baseline brain metastases. The median TMB was significantly higher in the DDRpos group compared to the DDRneg group (12.1 vs 9.8 mutations/megabase, P = 0.007). No difference in median PD-L1 tumor proportion score was observed between groups (30% vs 25%, P = 0.33). Compared to DDRneg pts (N = 394), DDRpos pts had a significantly higher objective response rate (31.1% vs 19.1%, P = 0.03), and longer median progression-free survival (4.3 vs 2.6 months, HR: 0.71 [95%CI: 0.53-0.95], P = 0.02) and overall survival (16.3 vs 9.8 months, HR: 0.63 [95%CI: 0.45-0.89], P = 0.009) with PD-(L)1 therapy. Conclusions: Pathogenic DDR alterations are frequent in NSCLC and are associated with higher TMB and improved clinical outcomes in NSCLC pts treated with PD-1 axis inhibition.

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Abstract 1640: Correlations of DNA damage response gene alterations with response to immune checkpoint inhibitors are different in solid tumors

10.1158/1538-7445.am2021-1640 ◽

2021 ◽

Author(s):

Tao Li ◽

Yanling Niu ◽

Tonghui Ma ◽

Danhua Wang ◽

Dong-Dong Jia

Keyword(s):

Dna Damage ◽

Solid Tumors ◽

Dna Damage Response ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Response Gene ◽

Damage Response ◽

Gene Alterations

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DNA Damage Response Gene Alterations in Urothelial Cancer: Ready for Practice?

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-18-2512 ◽

2018 ◽

Vol 25 (3) ◽

pp. 907-909 ◽

Cited By ~ 5

Author(s):

Petros Grivas

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Urothelial Cancer ◽

Response Gene ◽

Damage Response ◽

Gene Alterations

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MA13.03 DNA Damage Response Gene Alterations and their Association with Tumor Mutation Burden and Response to Immunotherapy in NSCLC and SCLC

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.265 ◽

2021 ◽

Vol 16 (3) ◽

pp. S182

Author(s):

Z. Li ◽

Y. Niu ◽

T. Ma ◽

H. Yuan

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Response Gene ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Damage Response ◽

Gene Alterations

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Clinical Activity of Olaparib in Urothelial Bladder Cancer With DNA Damage Response Gene Mutations

JCO Precision Oncology ◽

10.1200/po.18.00264 ◽

2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Randy F. Sweis ◽

Brian Heiss ◽

Jeremy Segal ◽

Lauren Ritterhouse ◽

Sabah Kadri ◽

...

Keyword(s):

Dna Damage ◽

Bladder Cancer ◽

Dna Damage Response ◽

Gene Mutations ◽

Clinical Activity ◽

Urothelial Bladder Cancer ◽

Response Gene ◽

Damage Response ◽

Urothelial Bladder

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Association of Homologous Recombination-DNA Damage Response Gene Mutations with Immune Biomarkers in Gastroesophageal Cancers

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-20-0879 ◽

2021 ◽

pp. molcanther.0879.2020

Author(s):

Michael Cerniglia ◽

Joanne Xiu ◽

Axel Grothey ◽

Michael J Pishvaian ◽

Yasmine Baca ◽

...

Keyword(s):

Dna Damage ◽

Homologous Recombination ◽

Dna Damage Response ◽

Gene Mutations ◽

Response Gene ◽

Immune Biomarkers ◽

Damage Response

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DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.708294 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jiawei Dai ◽

Minlin Jiang ◽

Kan He ◽

Hao Wang ◽

Peixin Chen ◽

...

Keyword(s):

Lung Cancer ◽

Therapeutic Response ◽

Excision Repair ◽

Squamous Carcinoma ◽

Progression Free Survival ◽

Free Survival ◽

Mutational Burden ◽

Damage Response ◽

Tumor Mutational Burden ◽

Gene Alterations

DNA damage response and repair (DDR) gene alterations increase tumor-infiltrating lymphocytes, genomic instability, and tumor mutational burden (TMB). Whether DDR-related alterations relate to therapeutic response and prognosis in lung cancer lacking oncogenic drivers remains unknown. Pretherapeutic cancer samples of 122 patients [86 non-small cell lung cancer and 36 small cell lung cancer (SCLC)] harboring no EGFR/ALK alterations were collected. Through whole-exome sequencing, we outlined DDR mutational landscape and determined relationships between DDR gene alterations and TMB or intratumoral heterogeneity. Then, we evaluated the impacts of DDR gene alterations on therapeutic response and prognosis and established a DDR-based model for prognosis prediction. In addition, we investigated somatic interactions of DDR genes and immunomodulatory genes, immune expression patterns, immune microenvironment, and immune infiltration characteristics between DDR-deficient and DDR-proficient samples. Samples from cBioportal datasets were utilized for verification. We found that deleterious DDR gene alterations were closely associated with higher TMB than proficient-types (p < 0.001). DDR mechanisms attach great importance to the determination of patients’ prognosis after chemotherapy, and alterations of base excision repair pathway in adenocarcinoma, nucleotide excision repair in squamous carcinoma, and homologous recombination pathway in SCLC tend to associate with worse progression-free survival to first-line chemotherapy (all p < 0.05). A predictive nomogram model was constructed incorporating DDR-related alterations, clinical stage, and smoking status, with the area under curve values of 0.692–0.789 for 1- and 2-year receiver operating characteristic curves in training and testing cohorts. Furthermore, DDR-altered tumors contained enhanced frequencies of alterations in various genes of human leukocyte antigen (HLA) class I pathway including TAP1 and TAP2 than DDR-proficient samples. DDR-deficient types had lower expressions of STING1 (p = 0.01), CD28 (p = 0.020), HLA-DRB6 (p = 0.014) in adenocarcinoma, lower TNFRSF4 (p = 0.017), and TGFB1 expressions (p = 0.033) in squamous carcinoma, and higher CD40 (p = 0.012) and TNFRSF14 expressions (p = 0.022) in SCLC. DDR alteration enhanced activated mast cells in adenocarcinoma (p = 0.044) and M2 macrophage in squamous carcinoma (p = 0.004) than DDR-proficient types. Collectively, DDR gene alterations in lung cancer without oncogenic drivers are positively associated with high TMB. Specific DDR gene alterations tend to associate with worse progression-free survival to initial chemotherapy.

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