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

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.

DNA damage response gene alterations are associated with high tumor mutational burden and clinical benefit from programmed death 1 axis inhibition in non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9077-9077 ◽  
Author(s):  
Biagio Ricciuti ◽  
Michael L. Cheng ◽  
Gonzalo Recondo ◽  
Mizuki Nishino ◽  
Renato Umeton ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Small Cell Lung Cancer ◽  
Dna Damage Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Damage Response ◽  
Tumor Mutational Burden ◽  
Gene Alterations

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.

scholarly journals First-Line Nivolumab Plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers

2019 ◽  
Vol 37 (12) ◽  
pp. 992-1000 ◽  
Author(s):  
Neal Ready ◽  
Matthew D. Hellmann ◽  
Mark M. Awad ◽  
Gregory A. Otterson ◽  
Martin Gutierrez ◽  
...  
Keyword(s):  
Low Dose ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Free Survival ◽  
Mutational Burden ◽  
Programmed Death ◽  
Tumor Mutational Burden ◽  
First Line Treatment

PURPOSE CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non–small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.

scholarly journals 53 Predictors of response to immune checkpoint inhibitor therapy in metastatic solid tumors: real world evidence

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A57-A58
Author(s):  
Aasems Jacob ◽  
Jianrong Wu ◽  
Jill Kolesar ◽  
Eric Durbin ◽  
Aju Mathew ◽  
...  
Keyword(s):  
Real World ◽  
Immune Checkpoint Inhibitor ◽  
Statistical Significance ◽  
Progression Free Survival ◽  
Real World Data ◽  
Free Survival ◽  
Mutational Burden ◽  
Kaplan Meier ◽  
Tumor Mutational Burden ◽  
Study Population

BackgroundImmune checkpoint inhibitor (ICI) therapy is increasingly being used in oncology and novel predictive biomarker for efficacy and side effects are an unmet need.1 2 The study aims to do a comprehensive analysis of factors affecting outcome from ICI therapy with real-world data and identify potential predictive biomarkers in diverse populations.MethodsWe performed a retrospective analysis of patients with metastatic solid tumors who received ICI and underwent molecular profiling with FoundationOne® CDx panel between 2016 and 2020 at Markey Cancer Center, Lexington KY. Progression-free survival (PFS), radiological response, and autoimmune side effects were analyzed and compared with various molecular biomarkers (figure 1). Logistic regression, Fisher’s exact test, Kaplan-Meier method, log-rank test, and Cox regression were used to analyze clinical features and efficacy outcomes.Abstract 53 Figure 1Mutational analysis of patients receiving immunotherapy grouped based on radiologic response, in the order of mutational load and frequency of mutationsAbstract 53 Figure 2Kaplan-Meier graphs depicting progression free survival in patients based on tumor samples showing (a) High TMB and low/intermediate TMB; (b) PDL1 expression; (c) Presence of IRAEs; (d) Presence of PIK3 mutation; (e) Presence of FGFR mutation; (f) Presence of BRAF mutationAbstract 53 Table 1Baseline characteristics of the study populationAbstract 53 Table 2Treatment and biomarker characteristics of study populationAbstract 53 Table 3ORR based on various factors with odds ratio calculated using logistic regression modelAbstract 53 Table 4Identified PIK3 mutations in tumor samples, with their chromosomal position and protein changesResults69 patients were included in the study (tables 1 and 2). A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks. HR=2.51. 95%CI 1.23, 5.14; table 3 and figure 2). This was independent of tumor mutational burden (TMB) status or PDL1 expression status (HR 3.24, p=0.016). PIK3 mutants had a higher overall response rate (ORR) than the wild type (69.6% vs. 43.5%, OR 0.34; p=0.045; tables 3 and 4). PIK3 mutants had a higher risk of developing immune-related adverse events (IRAEs) (73.9% vs. 37%, p=0.004). PIK3 mutation did not associate with TMB, PDL1 expression or microsatellite stability status. Median PFS was higher in the high TMB cohort compared to the low-intermediate group and reached statistical significance (median not reached vs. 26 weeks; HR=0.37. 95%CI 0.13, 1.05). PDL1 expression had no significant effect on the radiologic response, but PFS improvement in patients with tumors expressing PDL1 trended towards statistical significance (median 18 vs. 40 weeks. HR=1.43. 95%CI 0.93, 4.46). BRAF mutation conferred shorter PFS (median 17 vs. 39 weeks. HR=0.35. 95%CI 0.14, 0.91) (figure 2).ConclusionsHigh tumor mutational burden and PIK3 mutation conferred better progression-free survival with immunotherapy across cancer types. The improvement in PFS in PIK3 mutated patients was independent of PDL1 status or TMB. The results should prompt further evaluation of these potential biomarkers and more widespread real-world data publications to help determine biomarkers that could benefit specific populations.Ethics ApprovalThe study was approved by University of Kentucky Institutional Review Board, approval number 49450ReferencesTopalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–2454.Spencer KR, Wang J, Silk AW, Ganesan S, Kaufman HL, Mehnert JM. Biomarkers for Immunotherapy: Current Developments and Challenges. Am Soc Clin Oncol Educ Book. 2016; 35:e493–503.

scholarly journals Atezolizumab with bevacizumab, paclitaxel and carboplatin was effective for patients with SMARCA4-deficient thoracic sarcoma

Immunotherapy ◽  
2021 ◽  
Author(s):  
Hayato Kawachi ◽  
Kei Kunimasa ◽  
Yoji Kukita ◽  
Harumi Nakamura ◽  
Keiichiro Honma ◽  
...  
Keyword(s):  
Partial Response ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Continuous Response ◽  
First Line Therapy ◽  
Thoracic Malignancy ◽  
Mutational Burden ◽  
Line Therapy ◽  
Tumor Mutational Burden

SMARCA4-deficient thoracic sarcoma (DTS) is a recently noted progressive thoracic malignancy. We recently experienced three cases of SMARCA4-DTS who were treated with atezolizumab in combination with bevacizumab, paclitaxel and carboplatin (ABCP) as the first-line therapy. Immunohistopathological analysis revealed absent expression of SMARCA4 in all cases. The tumor mutational burden was over 11/Mb and mutations in SMARCA4 and TP53 were detected in all three cases. Partial response to ABCP treatment was observed in all three cases, with a progression-free survival of approximately 6 months or longer and a continuous response of 1 year or longer in one case. The first-line ABCP treatment demonstrated durable efficacy in SMARCA4-DTS regardless of the degree of PD-L1 expression.

scholarly journals Human Mitochondrial Ribosomal RNA Modification-Based Classification Contributes to Discriminate the Prognosis and Immunotherapy Response of Glioma Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Peng Wang ◽  
Jingying Li ◽  
Miaojing Wu ◽  
Minghua Ye ◽  
Kai Huang ◽  
...  
Keyword(s):  
Ribosomal Rna ◽  
Progression Free Survival ◽  
Rna Modification ◽  
Clinicopathologic Characteristics ◽  
Free Survival ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Number Variation ◽  
Cell Death Protein ◽  
Immune Checkpoint Blockers

BackgroundEpigenetic regulations of the tumor microenvironment (TME) and immunotherapy have been investigated in recent years. Nevertheless, the potential value of mitochondrial ribosomal RNA (mt-rRNA) modification in regulation of the TME and immunotherapy remains unknown.MethodsWe comprehensively investigated the mt-rRNA-modification patterns in glioma patients based on nine regulators of mt-rRNA. Subsequently, these modification patterns were correlated systematically with immunologic characteristics and immunotherapy. An “mt-rRNA predictor” was constructed and validated in multiple publicly available cohorts to provide guidance for prognosis prediction and immunotherapy of glioma patients.ResultsTwo distinct patterns of mt-rRNA modification were determined based on the evidence that nine regulators of mt-rRNA correlated significantly with most clinicopathologic characteristics, immunomodulators, TME, immune-checkpoint blockers (ICBs), and prognosis. Patients with mt-rRNA subtype II presented significantly poorer overall survival/progression-free survival (OS/PFS), but higher tumor mutational burden (TMB), more somatic mutations, and copy number variation (CNV). These two mt-rRNA subtypes had distinct TME patterns and responses to ICB therapy. An mt-rRNA predictor was constructed and validated in four glioma cohorts. The subtype with high mt-rRNA score, characterized by increased TMB, infiltration of immune cells, and activation of immunity, suggested an immune-activated phenotype, and was also linked to greater sensitivity to immunotherapy using anti-programmed cell death protein 1 (PD-1) but resistance to temozolomide.ConclusionsRegulators of mt-rRNA modification have indispensable roles in the complexity and diversity of the TME and prognosis. This novel classification based on patterns of mt-rRNA modification could provide an effective prognostic predictor and guide more appropriate immunotherapy/chemotherapy strategies for glioma patients.

Clinical and utilization outcomes associated with tumor mutational burden in a real-world pan-tumor population

2021 ◽  
Author(s):  
Santosh Gautam ◽  
Sumesh Kachroo ◽  
Richard W DeClue ◽  
Maxine D Fisher ◽  
Anirban Basu
Keyword(s):  
Real World ◽  
Median Overall Survival ◽  
Progression Free Survival ◽  
Cost Of Care ◽  
Advanced Solid Tumor ◽  
Limited Sample ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Aim & methods: This real-world study examined the association of tumor mutational burden (TMB) with clinical and healthcare utilization in adults diagnosed with advanced solid tumor 1 January 2015– 31 January 2019. Results: There were 170 patients in low-TMB group (TMB<10 mut/Mb) and 32 in high-TMB group (TMB ≥10 mut/Mb). Median overall survival was 18.8 (95% CI: 17.3–28.8) and 15.9 months (95% CI: 11.3–18.0) whereas median progression-free survival was 9.9 (95% CI: 8.6–11.4) and 7.8 months (95% CI: 3.8–12.5) for the low- and high-TMB groups, respectively. Hospitalization (49.4 vs 37.5%), emergency visit (25.3 vs 21.9%), and median overall cost of care (US$135,403 vs 87,570) were all lower in low-TMB group. Conclusion: Despite the limited sample, these data provide a historical perspective for examining real-world outcomes associated with TMB.

scholarly journals Apatinib monotherapy for advanced non-small cell lung cancer after the failure of chemotherapy or other targeted therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20626-e20626 ◽  
Author(s):  
Si-Yu Wang ◽  
Zui Liu ◽  
Wei Ou ◽  
Ning Li ◽  
Hui-qi Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Squamous Carcinoma ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Anaplastic Lymphoma

e20626 Background: Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), has been proved to be effective and safe in treating patients with advanced gastric cancer who failed to second-line chemotherapy. As the VEGFR-2 targeted therapy has made encouraging progress in the treatment of a broad range of malignancies, we aimed to explore the efficacy and safety of apatinib in treatment of advanced non-small cell lung cancer after the failure of chemotherapy or other targeted therapy. Methods: In this open-label single-arm, phase II study, patients were treated with apatinib alone in daily dose of 250 mg, po, in the second- or third-line setting. The primary endpoint was progression-free-survival (PFS) and the tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Results: From January 28, 2016 to December 31, 2016, 33 patients were enrolled, including 9 patients with squamous carcinoma and 24 patients with adenocarcinoma. Fourteen patients were detected as EGFR mutations and all the cases have no anaplastic lymphoma kinase (ALK) fusion gene. The median progression free survival (mPFS) of the whole group was 4.0 (95% confidence interval [CI], 0-8.2) months, while the mPFS of adenocarcinoma was 4.0 (95% CI, 2.1-5.9) months and the mPFS of squamous carcinoma was 5.5 (95% CI, 0-13.9) months (P = 0.245). Among the 33 patients, partial response was noted in 3 patients (9.09 %) and stable disease in 14 (42.42%). The disease control rate (DCR) was 51.52%. The common side effects of apatinib were hypertension, hand-foot syndrome and proteinuria, which accounted for 33.33%, 24.24%, and 15.15%, and no grade 3/4 adverse reactions occurred. The toxicity of apatinib was controllable and tolerable. Conclusions: Apatinib appears to be effective and safe for advanced non-small cell lung cancer after the failure of chemotherapy or other targeted therapy. Prospective studies are needed for further investigation.

scholarly journals Treatment Outcome of Different Chemotherapy in Patients With Relapsed or Metastatic Malignant Urachal Tumor

2021 ◽  
Vol 11 ◽  
Author(s):  
Meiting Chen ◽  
Cong Xue ◽  
Ri-qing Huang ◽  
Meng-qian Ni ◽  
Lu Li ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
Progression Free Survival ◽  
Cancer Center ◽  
First Line ◽  
Urachal Carcinoma ◽  
Free Survival ◽  
Mutational Burden ◽  
Platinum Based Chemotherapy ◽  
Significant Difference ◽  
Tumor Mutational Burden

BackgroundMalignant urachal tumor is a rare subtype of genitourinary cancer. Our aim was to explore the optimal chemotherapy regimens for relapsed or metastatic urachal carcinoma.Materials and MethodsWe retrospectively enrolled 24 adult patients with relapsed or metastatic urachal carcinoma from January 2014 to September 2020 at Sun Yat-sen University Cancer Center. We summarized the chemotherapy regimens and classified them as fluorouracil based, platinum based, and paclitaxel based. Nine patients received XELOX (capecitabine and oxaliplatin) regimens, seven patients received TX (paclitaxel and capecitabine) regimens, and eight of them received chemotherapy including GP (gemcitabine and cisplatin), TP (paclitaxel and cisplatin), TN (paclitaxel and nedaplatin), and tislelizumab.ResultsThe disease control rate was 75%. Among all patients, one patient treated with XELOX achieved partial remission (PR), while 17 patients showed stable disease. The median progression-free survival (PFS) and overall survival (OS) in all treated patients was 7.43 and 29.7 months, respectively. The patients receiving first-line platinum-based chemotherapy presented better PFS than those without platinum (median PFS 8.23 vs. 3.80 months, p = 0.032), but not significant for OS between two groups. There is no significant difference in PFS and OS for fluorouracil-based and paclitaxel-based groups as first-line regimen. Next-generation gene sequencing revealed TP53 mutation and low tumor mutational burden in five out of seven cases.ConclusionThe platinum-based chemotherapy regimen is effective for relapsed or metastatic urachal carcinoma.

Sign in / Sign up

Export Citation Format

Share Document