Abstract 1369: Analysis of association between homologous recombination deficiency and tumor mutational burden in solid tumors

e21043 Background: Homologous recombination (HR) is an important repair method for DNA double-strand damage. HR is involved with complex signaling pathways and multiple steps, including BRCA1/2. Homologous Recombination Deficiency (HRD) can be caused by the loss of function of BRCA1/2 proteins due to gene mutation. Tumor mutational burden (TMB) was indicated to involved with HRD, which is critical to the guidance of immunotherapy. Methods: Patients available with tumor specimen genomic testing for lung cancer were enrolled in this study. The sequencing library was captured using a 605-gene panel. Homologous recombination (HR)-related gene list included 102 genes. Genomic alterations of HR-related genes were assessed by next-generation sequencing assay, including nonsense, nonstop, frameshift, splice site, damaging missense mutations in somatic variants and pathogenic germline variants. Then, TMB was calculated by dividing the total number of mutations counted by the size of the coding region. Results: A total of 741 patients was enrolled and 182 of them (25.6%) had at least one genomic alteration of the HR genes. The top mutant HR genes included ATM (4.1%), DNMT3A (2.8%), ATR (1.8%), CHEK2 (1.5%), BRCA2 (1.5%), ABL1 (1.4%), FANCA (1.2%), RIF1 (1.1%), FANCI (1.1%), RAD50 (0.9%), BRCA1 (0.9%), and MRE11A (0.9%). The most common mutational type was missense mutation (69.2%), followed by frameshift (15.6%), and nonsense mutation (15.2%). The median age was 62 in the HRD group (age < 45:5.4%, 45-65:59.6%, > 65:34.9%) compared to 60 in the rest of the patients (age < 45:11.3%, 45-65:61.3%, > 65:27.4%). There were overall 57.5% males and 42.5% females in terms of gender. HRD group had a significantly higher rate than Non-HRD group in males (72.1% vs 52.8%, p < 0.01). The occurrence of HRD mutations was significantly correlated with a high level of TMB (p < 0.01). The median TMB of HRD group (7.9 muts/Mb, 95%CI:7.1-9.2 muts/Mb) was significantly higher than that of Non-HRD group (3.8 muts/Mb, 95%CI:3.3-4.2 muts/Mb). In addition, the upper quantile value (7.5 muts/Mb) was used to identify patients with high TMB. HRD group had a significantly higher rate of TMB-high patients than Non-HRD group (51.1% vs 17.0%, p < 0.01). Conclusions: Our study demonstrated genomic alterations of the HR genes in about one fourth’s lung cancer. Besides, there was a significant positive correlation between HRD mutations and TMB level. The significance of HRD genomic mutation on predicting the efficacy of immunotherapy deserves further study.

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Identification of SLX4 as the most frequently mutated gene in homologous recombination deficiency in Asian gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.4570 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 4570-4570

Author(s):

Shi Zhang ◽

Tianhao Mu ◽

Shiying Dang ◽

Tanxiao Huang ◽

Jingxian Duan ◽

...

Keyword(s):

Gastric Cancer ◽

Homologous Recombination ◽

Genetic Recombination ◽

Coding Region ◽

Homologous Recombination Deficiency ◽

Asian Patients ◽

Mutational Burden ◽

Sequencing Library ◽

Tumor Mutational Burden ◽

Common Malignancy

4570 Background: Gastric cancer is the third most common malignancy worldwide. Homologous recombination (HR) is a type of genetic recombination, and homologous recombination deficiency (HRD) is highly involved in multiple types of cancers and can predict response to anticancer therapies. However, homologous recombination deficiency is not well characterized in patients with Asian gastric cancer. Methods: 196 Asian patients with gastric cancer were analyzed in this study. A list of 102 genes related to HRD was compiled based on previous literature. Haplox 605-gene panel was used to capture the sequencing library. Mutations related to HRD were analyzed following next-generation sequencing. In addition, tumor mutational burden (TMB) was calculated by dividing the total number of mutations by the size of the coding region. The correlation analysis between HRD and TMB was also conducted. Results: In total, 43 (21.94%) of 196 Asian patients with gastric cancer harbored at least one HRD gene. The top 10 mutant HRD genes included SLX4 (3.57%), ATR (2.04%), RECQL (1.53%), NBN (1.53%), ERCC4 (1.53%), BAP1 (1.53%), ATM (1.53%), RAD54L (1.02%), BRCA1 (1.02%) and PARP1 (1.02%). In addition, the occurrence of HRD mutations was significantly correlated with a higher TMB. The median TMB of HRD group (8.28 muts/Mb) was significantly higher than that of the Non-HRD group (3.07 muts/Mb) (p < 0.01). The overall upper quantile value (4.80 muts/Mb) was used to screen patients with high TMB (TMB-H). The TMB-H in HRD group was significantly higher than the Non-HRD group (44.19% VS 17.92%, p < 0.01). Conclusions: Our study described that SLX4 was the most frequently mutated HR-related gene in Asian gastric cancer. Moreover, the positive correlation with homologous recombination deficiency (HRD) and tumor mutational burden (TMB) was observed in these patients.

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Abstract LB012: Efficacy of atezolizumab in the treatment of solid tumors with high tumor mutational burden (TMB): A MyPathway study cohort

10.1158/1538-7445.am2021-lb012 ◽

2021 ◽

Author(s):

John Hainsworth ◽

Claire F. Friedman ◽

Razelle Kurzrock ◽

David R. Spigel ◽

Howard Burris ◽

...

Keyword(s):

Solid Tumors ◽

Study Cohort ◽

Mutational Burden ◽

Tumor Mutational Burden

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The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors

Biomolecules ◽

10.3390/biom10050666 ◽

2020 ◽

Vol 10 (5) ◽

pp. 666 ◽

Cited By ~ 5

Author(s):

Evangelos Koustas ◽

Panagiotis Sarantis ◽

Athanasios G. Papavassiliou ◽

Michalis V. Karamouzis

Keyword(s):

Solid Tumors ◽

Checkpoint Inhibitors ◽

Resistance Mechanisms ◽

Epigenetic Alterations ◽

Primary Resistance ◽

Cellular Processes ◽

Mutational Burden ◽

Number Of Patients ◽

Tumor Mutational Burden

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors.

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Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors

Cancer Discovery ◽

10.1158/2159-8290.cd-20-0522 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1808-1825

Author(s):

Dan Sha ◽

Zhaohui Jin ◽

Jan Budczies ◽

Klaus Kluck ◽

Albrecht Stenzinger ◽

...

Keyword(s):

Solid Tumors ◽

Predictive Biomarker ◽

Mutational Burden ◽

Tumor Mutational Burden

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Clinical response and biomarker analysis of a phase II basket trial of toripalimab, a PD-1 mAb in combination with standard chemotherapy as a first-line treatment for patients with solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15083 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15083-e15083

Author(s):

Chao Ren ◽

Xiao-Li Wei ◽

Nong Xu ◽

Lin Shen ◽

Guanghai Dai ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Response ◽

Solid Tumors ◽

Squamous Cell ◽

Line Treatment ◽

First Line ◽

Standard Chemotherapy ◽

Mutational Burden ◽

Tumor Mutational Burden

e15083 Background: Platinum based chemotherapy is the standard care for 1st line treatment of metastatic gastric adenocarcinoma (GC), esophageal squamous cell carcinoma (ESSC), nasopharyngeal carcinoma (NPC) and head and neck squamous cell carcinoma (HNSCC). Combinations of PD-1 blockade with chemotherapy have shown promising but mixed results in solid tumors. Predictive biomarkers for chemo-immunotherapy combination as 1st line treatment remain undefined. Methods: Patients (n = 60) included in this analysis were four complete cohorts from a multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in combination with standard chemotherapy for the 1st line treatment of GC, EC, NPC and HNSCC (excluding NPC). Whole exome sequencing (WES), RNA sequencing and immunohistochemistry were performed on tumor biopsy samples. PD-L1 expression and tumor mutational burden (TMB) were evaluated for correlation with clinical efficacy. Results: From Oct 2016 to Feb 2019, 33 GC, 12 ESSC, 12 NPC and 3 HNSCC patients were enrolled and treated with 240mg or 360 mg toripalimab Q3W via IV infusion in combination with Oxaliplatin/Capecitabine (XELOX), Paclitaxel/Cisplatin (PP), Gemcitabine/Cisplatin (GP) and Docetaxel/Cisplatin/5-FU(TPF) respectively. By the data cutoff date of Nov 15, 2019, all patients experienced treatment related adverse event (TRAE). There was one TRAE (heart failure) leading to death. Grade 3-4 TRAEs occurred in 67% patients, mostly attributed to chemotherapy, including 27% neutropenia, 23% thrombocytopenia, 18% leukopenia and 12% anemia. As assessed by investigators according to RECIST v1.1, the ORR/DCR were 54.5%/84.8%, 66.7%/91.7%, 75.0%/83.3% and 33.3%/100% respectively for GC, EC, NPC and HSNCC cohorts. The median duration of response was 8.3, 6.8, 7.7 and 7.1 months respectively. WES showed distinctive patterns of genomic alterations among different cohorts. The clinical response was not correlated with either PD-L1 expression or tumor mutational burden. Conclusions: Toripalimab in combination with chemotherapy as first-line treatments showed promising results for metastatic GC, EC, NPC and HNSCC patients. Two randomized Phase III trials of toripalimab in combination with Paclitaxel/Cisplatin or Gemcitabine/Cisplatin versus chemotherapy alone are ongoing to further evaluate the combination as first-line treatments in metastatic EC and NPC patients. Clinical trial information: NCT02915432 .

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Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1091 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1091-1091

Author(s):

Sarah Sammons ◽

Andrew Elliott ◽

Jeremy Meyer Force ◽

Nicholas C. DeVito ◽

Paul Kelly Marcom ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Solid Tumors ◽

Immune Checkpoint ◽

Metastatic Breast ◽

Breast Cancers ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Mutational Burden ◽

Tumor Mutational Burden

1091 Background: Tumor mutational burden (TMB) has emerged as an imperfect biomarker of immune checkpoint inhibition (ICI) outcomes in solid tumors. Despite the approval for pembrolizumab in all TMB-high (TMB-H) solid tumors, the optimal clinical approach to TMB-H or hypermutated advanced/metastatic breast cancer (MBC) is unknown with sparse prospective data. We hypothesize that TMB-H MBC will have unique genomic alterations compared to TMB-low (TMB-L) breast cancer that could inform novel therapeutic approaches. Methods: Tumor samples (N = 5621) obtained from patients with MBC were analyzed by next-generation sequencing (NGS) of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). TMB was calculated based on recommendations from the Friends of Cancer Research TMB Harmonization Project (Merino et al., 2020), with the TMB-H threshold set to ≥ 10 muts/Mb. IHC was performed for PD-L1 (Ventana SP142 ≥1% immune cells). Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) was tested by IHC and NGS, respectively. Results: TMB-H was identified in 8.2% (n = 461) of MBC samples, with similar frequencies observed across molecular subtypes (7.8-8.6%, p = 0.85): HR+/HER2- (n = 3087) 7.8%, HR+/HER2+ (n = 266) 8.3%, HR-/HER2+ (n = 179) 7.8%, TNBC (n = 1476) 8.6%. The frequency of TMB-H was significantly increased in lobular (16%) versus ductal (5%) MBC (p < 0.01). TMB-H samples were enriched in genitourinary (42%), soft tissue (20%), and gastrointestinal non-liver (16%) biopsy specimens. Compared to TMB-L tumors, TMB-H tumors exhibited significantly higher mutation rates for TP53 (60 v 52%), PIK3CA (55 vs 31%), ARID1A (34 vs 11%), CDH1 (27 vs 11%), NF1 (22 vs 9%), RB1 (14 vs 5%), KMT2C (12 vs 7%), PTEN (12 vs 7%), ERBB2 (7 vs 2.9%), and PALB2 (3.3 vs 1%) genes (p < 0.05 each). Copy number alteration and fusion rates did not differ between TMB-H and TMB-L breast cancers. PI3K/AKT/MTOR, TP53, Histone/Chromatin remodeling, DNA damage repair (DDR), RAS, and cell cycle pathway alterations were detected in > 25% TMB-H MBCs (p < 0.05 each). dMMR/MSI-High (7.2 vs 0.3%, p < 0.01) and PD-L1 positivity (36 vs 28%, p < 0.05) frequencies were significantly increased in TMB-H tumors. DNA signature analyses including APOBEC and homologous recombination repair deficiency, as well as gene expression profiling to assess immune-related signatures and tumor microenvironment are underway. Conclusions: TMB-H breast cancers contain a unique genomic profile enriched with targetable mutations such as PIK3CA, ARID1A, NF1, PTEN, ERBB2, and PALB2. Concurrent predictive biomarkers of response to immune checkpoint inhibition such as MSI-H and PDL-1 positivity are also more prevalent in TMB-H MBC. These findings suggest novel combination strategies within TMB-H MBC could be explored.

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