DNA Damage Response And Repair Research Articles

Predictive and Prognostic Biomarkers and Tumor Antigens for Targeted Therapy in Urothelial Carcinoma.

Urothelial carcinoma (UC) is the fourth most prevalent cancer amongst males worldwide. While patients with non-muscle-invasive disease have a favorable prognosis, 25% of UC patients present with locally advanced disease which is associated with a 10-15% 5-year survival rate and poor overall prognosis. Muscle-invasive bladder cancer (MIBC) is associated with about 50% 5 year survival when treated by radical cystectomy or trimodality therapy; stage IV disease is associated with 10-15% 5 year survival. Current therapeutic modalities for MIBC include neoadjuvant chemotherapy, surgery and/or chemoradiation, although patients with relapsed or refractory disease have a poor prognosis. However, the rapid success of immuno-oncology in various hematologic and solid malignancies offers new targets with tremendous therapeutic potential in UC. Historically, there were no predictive biomarkers to guide the clinical management and treatment of UC, and biomarker development was an unmet need. However, recent and ongoing clinical trials have identified several promising tumor biomarkers that have the potential to serve as predictive or prognostic tools in UC. This review provides a comprehensive summary of emerging biomarkers and molecular tumor targets including programmed death ligand 1 (PD-L1), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor (FGFR), DNA damage response and repair (DDR) mutations, poly (ADP-ribose) polymerase (PARP) expression and circulating tumor DNA (ctDNA), as well as their clinical utility in UC. We also evaluate recent advancements in precision oncology in UC, while illustrating limiting factors and challenges related to the clinical application of these biomarkers in clinical practice.

Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06)

BackgroundImmune-modulating antibodies targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have demonstrated promising antitumor efficacy in various types of cancers, especially highly mutated ones. Genetic alterations in DNA damage...

Genomic alterations and self-reported Agent Orange exposure in United States veterans with metastatic prostate cancer.

5068 Background: Agent Orange has been posited as an environmental risk factor for prostate cancer among United States Veterans. Prior studies have shown that Veterans with Agent Orange exposure are diagnosed at a younger age and at more advanced clinical stages. It is unknown if there are differences in somatic alterations among Veterans exposed to Agent Orange. Methods: Genomic alterations were identified from clinical tumor testing conducted from 2019 – 2022 in a large cohort of Veterans with metastatic prostate cancer diagnosed from 2001 – 2022. Primary prostate and metastatic carcinoma tissue specimens were submitted for Foundation Medicine tumor-only sequencing. Baseline demographics, clinical, and genomic alterations data were stratified by Veteran self-reported exposure to Agent Orange in accordance with an institutional review board approved protocol. Results: Of the 2673 Veterans with metastatic prostate cancer who underwent tumor-only genomic testing, 629 reported exposure to Agent Orange and 2044 were not exposed. After verification of military service records of Veterans with self-reported Agent Orange exposure to include only Veterans who served in the Vietnam War between 1962 – 1975 and Korean War between 1967 – 1971, 603 patients with self-reported Agent Orange exposure (22.8%) and 2044 without exposure (77.2%) were included in the analysis. On univariate analysis, TMPRSS2-ERG fusions were significantly more frequent in men who reported exposure to Agent Orange (35.3% vs 28.8%, p<0.01) after multiple hypothesis testing with Benjamini-Hochberg. Agent Orange exposure also correlated to higher rates of androgen receptor ( AR) alterations (12.4% vs 9.5%, p=0.04) and FGFR1/2/3/4 alterations (3.2% vs 1.7%, p=0.02). There were no significant differences in alterations by Agent Orange exposure in TP53, CDK12, ERBB2, EGFR, BRCA, and genes implicated in the DNA damage response and repair (DDR), mismatch repair (MMR), and PTEN/PI3K/AKT pathways. On multivariable analysis controlling for race, age at diagnosis, smoking, secondary malignancies, and environment, only alterations in AR (OR 1.43, p=0.02) remained more frequent in Veterans exposed to Agent Orange. As expected, age at diagnosis (OR 0.98, p <0.001) and Black/African-American race (OR 0.33, p<0.001) were associated with decreased odds of TMPRSS2-ERG alterations. Conclusions: Agent Orange exposure may contribute to tumor somatic alterations in Veterans with prostate cancer. These findings hold potential prognostic and therapeutic implications for U.S. Veterans with metastatic prostate cancer. [Table: see text]

PD21-09 GENOMIC ALTERATIONS IN UNITED STATES VETERANS WITH METASTATIC PROSTATE CANCER AND SELF-REPORTED AGENT ORANGE EXPOSURE

You have accessJournal of UrologyCME1 Apr 2023PD21-09 GENOMIC ALTERATIONS IN UNITED STATES VETERANS WITH METASTATIC PROSTATE CANCER AND SELF-REPORTED AGENT ORANGE EXPOSURE JJ Zhang, Adam Weiner, Lorna Kwan, Sara Ahmed, Michael Kelley, Karim Chamie, Kara Maxwell, and Isla Garraway JJ ZhangJJ Zhang More articles by this author , Adam WeinerAdam Weiner More articles by this author , Lorna KwanLorna Kwan More articles by this author , Sara AhmedSara Ahmed More articles by this author , Michael KelleyMichael Kelley More articles by this author , Karim ChamieKarim Chamie More articles by this author , Kara MaxwellKara Maxwell More articles by this author , and Isla GarrawayIsla Garraway More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003287.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Agent Orange has been posited as an environmental risk factor for prostate cancer among United States Veterans. Prior studies have shown that Veterans with Agent Orange exposure are diagnosed at a younger age and at more advanced clinical stages. It is unknown if there are differences in somatic alterations among Veterans exposed to Agent Orange. METHODS: Genomic alterations were identified from clinical tumor testing conducted from 2019–2022 in a large cohort of Veterans with metastatic prostate cancer diagnosed from 2001–2022. Primary prostate and metastatic carcinoma tissue specimens were submitted for Foundation Medicine tumor-only sequencing. Baseline demographics, clinical, and genomic alterations data were stratified by Veteran self-reported exposure to Agent Orange in accordance with an Institutional Review Board approved protocol. RESULTS: Of the 2673 Veterans with metastatic prostate cancer who underwent tumor-only genomic testing, 629 reported exposure to Agent Orange (23.5%) and 2044 were not exposed. TMPRSS2-ERG fusions were more frequent in men who reported exposure to Agent Orange (35.1% vs 28.8%, p<0.01). Agent Orange exposure also correlated to higher rates of androgen receptor (AR) alterations (12.4% vs 9.5%, p=0.04) and FGFR1/2/3/4 alterations (3.3% vs 1.7%, p=0.01). On multivariable analysis, alterations in AR (OR 1.43, p=0.02), and FGFR1/2/3/4 (OR 1.84, p=0.03) remained more frequent in Veterans exposed to Agent Orange. As expected, age at prostate cancer diagnosis (OR 0.98, p<0.001) and Black/African-American race (OR 0.33, p<0.001) were associated with decreased odds of TMPRSS2-ERG alterations. In addition, current smoking status (OR 1.43, p=0.01) and rural environment (OR 1.33, p<0.01) were also associated with increased odds of a TMPRSS2-ERG fusion. There were no significant differences in alterations by Agent Orange exposure in TP53, CDK12, ERBB2, EGFR, BRCA, and genes implicated in the DNA damage response and repair (DDR), mismatch repair (MMR), and PTEN/PI3K/AKT pathways. CONCLUSIONS: Agent Orange exposure may contribute to tumor genomic alterations in AR and FGFR in prostate cancer. These findings hold potential prognostic and therapeutic implications for U.S. Veterans with metastatic prostate cancer. Source of Funding: NIH (K08CA215312, KNM; 5P50CA092131, R01 PAR-20-077, IPG); US DOD (W81XWH211075, IPG) Prostate Cancer Foundation (PCF17CHAL04, IPG; 20YOUNG02, KNM), Burroughs Wellcome Foundation (1017184, KNM); Basser Center for BRCA at UPENN (KNM); Jean Perkins Foundation (IPG), STOP Cancer Foundation (IPG) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e593 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information JJ Zhang More articles by this author Adam Weiner More articles by this author Lorna Kwan More articles by this author Sara Ahmed More articles by this author Michael Kelley More articles by this author Karim Chamie More articles by this author Kara Maxwell More articles by this author Isla Garraway More articles by this author Expand All Advertisement PDF downloadLoading ...

Strategies for the Management of Patients with Pancreatic Cancer with PARP Inhibitors.

A subset of patients with pancreatic adenocarcinomas (PDAC) harbor mutations that are exploitable in the context of DNA-damage response and repair (DDR) inhibitory strategies. Between 8-18% of PDACs harbor specific mutations in the DDR pathway such as BRCA1/2 mutations, and a higher prevalence exists in high-risk populations (e.g., Ashkenazi Jews). Herein, we will review the current trials and data on the treatment of PDAC patients who harbor such mutations and who appear sensitive to platinum and/or poly ADP ribose polymerase inhibitor (PARPi) based therapies due to a concept known as synthetic lethality. Although this current best-in-class precision treatment shows clinical promise, the specter of resistance limits the extent of therapeutic responses. We therefore also evaluate promising pre-clinical and clinical approaches in the pipeline that may either work with existing therapies to break resistance or work separately with combination therapies against this subset of PDACs.

Investigation of prognostic biomarkers in patients with urothelial carcinoma treated with platinum-based regimens.

Bladder cancer (BC) is a heterogeneous malignancy with dismal outcome. Mutations in genes, altered or linked to platinum sensitivity in BC, were examined in 66 patients' tumors along with tumor infiltrating lymphocytes (TILs) density and MMR, PD-L1 and CD8 protein expression, as well as basal and luminal subtypes, defined by protein expression of markers, including CK5/6 and GATA3 or CK20, respectively. 41 tumors harbored mutations, mainly in TP53 (38%), ARID1A (17%) and the DNA damage response and repair (DDR) genes ERCC2 (17%) and BRCA2 (15%). Mutations in other DDR relevant genes were also present. Age showed unfavorable prognosis for overall survival (HR=1.07, P = 0.026); no benefit was seen for patients with TP53, ARID1A, ERCC2 or BRCA2 mutations or mutations in 1 or more DDR genes. PD-L1 status positively correlated with stromal (rho=0.46, P < 0.001) and intratumoral (rho=0.53, P < 0.001) CD8 expression or TILs (rho=0.29, P = 0.018); none associated with overall survival (OS). A statistically significant difference was observed between PD-L1 status and immunohistochemistry (IHC)‑based subtypes, with tumors classified as luminal (GATA3+ and/or CK20+ and CK5/6-) showing lower PD-L1 expression relative to basal (CK5/6+ and GATA3- and/or CK20-) (median value 0 vs. 2.5, P = 0.029). Concerning OS, no statistically significant difference was seen among patients with basal or luminal tumors. No association was seen herein between DDR mutations, TILs, PD-L1, CD8 expression or IHC-based subtypes and patient survival; these observations warrant validation within a larger cohort.

Geriatric Frailty Is Associated With Oxidative Stress, Accumulation, and Defective Repair of DNA Double-Strand Breaks Independently of Age and Comorbidities.

Defects in the DNA damage response and repair (DDR/R) network accumulate during the aging process. Physical frailty, a state of reduced physiological function and decreased resilience to biological stressors, is also exacerbated by aging, but its link with DDR/R aberrations beyond the effect of age and comorbidities is unclear. Fifty-three community-dwelling older adults, aged 65-102 years, who underwent frailty classification according to the Rockwood Clinical Frailty Scale (CFS), and 51 healthy adults younger than 45 years were examined in parallel. The following DDR/R parameters were determined in their peripheral blood mononuclear cells (PBMCs): (a) oxidative stress and abasic (apurinic/apyrimidinic; AP) sites, (b) endogenous DNA damage (alkaline comet assay olive tail moment [OTM] indicative of DNA single-strand breaks [SSBs] and double-strand breaks [DSBs] and γH2AX levels by immunofluorescence [DSBs only]), (c) capacity of the 2 main DNA repair mechanisms (DSB repair and nucleotide excision repair). Older individual-derived PBMCs displayed reduced-to-oxidized glutathione ratios indicative of increased levels of oxidative stress and increased AP sites, as well as increased accumulation of endogenous DNA damage (OTM and γH2AX) and defective DSB-repair capacity, compared with younger controls. These DDR/R aberrations were more pronounced in frail versus nonfrail older adults. Notably, oxidative stress, AP sites, DSBs, and DSB-repair capacity were associated with individual CFS levels after adjusting for chronological age, sex, Charlson Comorbidity Index, and polypharmacy. Geriatric frailty is independently associated with increased DNA damage formation and reduced DSB-R capacity, supporting further research into these measures as potential frailty biomarkers.

Enrichment of “Cribriform” morphologies (intraductal and cribriform adenocarcinoma) and genomic alterations in radiorecurrent prostate cancer

AbstractLocally relapsed prostate cancer (PCa) after radiation therapy (RT) is associated with substantial morbidity and mortality. Morphological and molecular consequences that may contribute to RT resistance and local recurrence remain poorly understood. Locally recurrent PCa tissue from 53 patients with clinically localized PCa who failed with primary RT and subsequently underwent salvage radical prostatectomy (RP) was analyzed for tumor focality, clinicopathological, molecular, and genomic characteristics. Targeted next-generation sequencing with full exon coverage of 1,425 cancer-related genes was performed on 10 representative radiorecurrent PCas exhibiting no RT effect with matched adjacent benign prostate tissue. At RP, 37 (70%) of PCas had no RT effect with the following characteristics: grade group (GG) ≥ 3 (70%), unifocal tumor (75%), extraprostatic disease (78%), lymph node metastasis (8%), and “cribriform” morphologies (84%) [cribriform PCa (78%) or intraductal carcinoma (IDC-P) (61%)] at a median percentage of approximately 80% of tumor volume. In the setting of multifocal tumors (25%) at RP, the cribriform morphologies were restricted to index tumors. Of 32 patients with available pre-RT biopsy information, 16 had GG1 PCa, none had cribriform morphologies at baseline but 81% demonstrated cribriform morphologies at RP. Notable alterations detected in the sequenced tumors included: defects in DNA damage response and repair (DDR) genes (70%) (TP53, BRCA2, PALB2, ATR, POLQ), PTEN loss (50%), loss of 8p (80%), and gain of MYC (70%). The median tumor mutational burden was 4.18 mutations/Mb with a range of 2.16 to 31.86. Our findings suggest that most radiorecurrent PCas are enriched in cribriform morphologies with potentially targetable genomic alterations. Understanding this phenotypic and genotypic diversity of radiorecurrent PCa is critically important to facilitate optimal patient management.

1081P DNA damage response and repair (DDR) gene mutations as an alternative mechanism to generate high TMB in never smoker NSCLC patients

Immune checkpoint inhibitors (IO) single agent or in combination with platinum-based chemotherapy (CT-IO) are standard of care for Stage IV and not oncogene addicted non-small cell lung cancer (aNSCLC) according to PD-L1 expression. The presence of a high tumor mutation burden (H-TMB) is one of the most debated biomarkers for IO response. Smoking-induced harm is a mechanism that generates an H-TMB in aNSCLC smoking patients (S-pts), whereas never-smoking patients (NS-pts) usually have a low TMB and are unresponsive to IO. However, the subgroup of NS-pts with an H-TMB has not yet been well characterized molecularly. We retrospectively collected clinical data from a single-center cohort of 142 aNSCLC pts with PD-L1 ≥ 50% treated with first-line pembrolizumab between January 2017 to March 2021. Next-generation sequencing (NGS) analysis using the FoundationOne®CDx assay (Foundation Medicine, Cambridge, MA, USA) was performed to correlate genetic alterations with clinical characteristics and response outcomes. We classified all detected mutations into eleven main pathways: cell cycle pathway, Hippo pathway, Myc pathway, Notch pathway, Oxidative stress/Nrf2 pathway, PI3K pathway, RTK/RAS/MAP pathway, TGF beta pathway, p53 pathway, beta-catenin/Wnt pathway and DDR pathway. Lastly, we identified the pathways with at least one mutation for each patient and performed enrichment analysis to characterize patients’ subgroups in terms of mutated pathways. With a median follow-up of 22 months (m), mPFS was 9.9 m, and mOS was 10.6 m. There were 111 S-pts and 31 NS-pts. The cohort of S-pts had higher TMB than the NS-pts cohort (TMB average 10.05 vs. 8.86 Mut/Mb). However, a subgroup of 11 NS-pts with high TMB (39-11 Mut/Mb) was identified. This subgroup was particularly enriched in DDR pathway mutations (p-value=0.0016) compared to the rest of the series and the H-TMB/S-pts subgroup. All H-TMB/NS-pts responded to IO treatment with an mPFS of 10.9 m and mOS of 12.7 m. Our data suggest a potential role of DDR signatures as an alternative mechanism to generate H-TMB in NS-pts. This preliminary observation could identify a subgroup of NS-pts responsive to IO and with a better prognosis.

Somatic mutations in DCC are associated with genomic instability and favourable outcomes in melanoma patients treated with immune checkpoint inhibitors.

Deleted in colorectal cancer (DCC) encodes a transmembrane dependence receptor and is frequently mutated in melanoma. The associations of DCC mutation with chromosomal instability and immunotherapeutic efficacy in melanoma are largely uncharacterised. We performed an integrated study based on biological experiments and multi-dimensional data types, including genomic, transcriptomic and clinical immune checkpoint blockade (ICB)-treated melanoma cohorts from public databases. DCC mutation was significantly correlated with the tumour mutational burden (TMB) in The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and ICB-treated melanoma cohorts. DCC expression levels were correlated with DNA damage response and repair (DDR) pathways responsive to irradiation (IR) in the Malme-3M and SK-MEL-2 cell lines. In the TCGA cohort, DCC-mutated samples presented more neoantigens, higher proportions of infiltrating antitumour immunocytes and lower proportions of infiltrating pro-tumour immunocytes than DCC wild-type samples. DCC-mutated samples were significantly enriched in activated immune response and DDR pathways. Furthermore, patients harbouring mutated DCC treated with ICB showed remarkable clinical benefits in terms of the response rate and overall survival. Somatic mutations in DCC are associated with improved clinical outcomes in ICB-treated melanoma patients. Once further validated, the DCC mutational status can improve patient selection for clinical practice and future study enrolment.

Alterations in DNA damage response and repair genes as potential biomarkers for immune checkpoint blockade in gastrointestinal cancer.

Objective:Immune checkpoint inhibitors (ICIs) have achieved remarkable results in cancer treatments. However, there is no effective predictive biomarker for gastrointestinal (GI) cancer.Methods:We conducted integrative analyses of the genomic and survival data of ICI-treated GI cancer patients from the Memorial Sloan Kettering Cancer Center cohort (MSK-GI, n = 227), the Janjigian cohort (n = 40), and the Peking University Cancer Hospital & Institute cohort (PUCH, n = 80) to determine the possible associations between DNA damage response and repair (DDR) gene mutations and clinical outcomes. Data from The Cancer Genome Atlas database were analyzed to determine the possible correlations between DDR gene mutations and the tumor microenvironment.Results:In the MSK cohort, the presence of ≥ 2 DDR gene mutations was correlated with prolonged overall survival (OS). The Janjigian and PUCH cohorts further confirmed that subgroups with ≥ 2 DDR gene mutations displayed a prolonged OS and a higher durable clinical benefit. Furthermore, the DDR gene mutation load could be considered as an independent prognostic factor, and exhibited a potential predictive value for survival in GI cancer patients treated with ICIs. Mechanistically, we showed that the presence of ≥ 2 DDR gene mutations was correlated with higher levels of tumor mutation burden, neoantigen, and T cell infiltration.Conclusions:The DDR gene mutation status was correlated with favorable clinical outcomes in GI cancer patients receiving ICIs, which could serve as a potential biomarker to guide patient selection for immunotherapy.

Deleterious alterations of DNA damage response and repair genes and clinical benefit to anti-PD-1 therapy in esophageal squamous cell carcinoma.

Although DNA damage response and repair (DDR) gene alteration has been demonstrated as a biomarker for anti-PD-1 therapy in several cancer types, its role in esophageal squamous cell carcinoma (ESCC) is unknown. Patients with advanced ESCC treated with anti-PD-1-based immunotherapy were enrolled. Tumor response was evaluated according to RECIST 1.1. Archival ESCC tissues were analyzed using FoundationOne CDx. Deleterious alterations, defined by loss of function, of DDR genes were correlated with patient survival by Cox proportional hazards model. The prognostic significance of deleterious alterations of DDR genes in The Cancer Genome Atlas (TCGA)-ESCC cohort was explored. Forty-three patients were enrolled. The objective response rate (ORR) was 19%. The median tumor mutational burden was 4 mutations/Mb (0-20); none of the tumors were microsatellite instable. Compared with patients with wild-type or other alterations of DDR genes (N = 35, 81%), those with deleterious alterations of DDR genes (N = 8, 19%) had a higher ORR (38 vs. 14%), longer median progression-free survival (4.1 vs. 2.0months), and significantly longer median overall survival (OS; 27.7 vs. 6.1months, P = 0.011). In multivariate analysis, harboring deleterious alterations of DDR genes was a favorable prognostic factor for OS (HR = 0.31 [95% CI: 0.11-0.91], P = 0.033). In the TCGA-ESCC cohort, the presence of deleterious alterations of DDR genes was not a favorable prognostic factor. Deleterious alterations of DDR genes may be associated with improved prognosis and efficacy of anti-PD-1 therapy in patients with advanced ESCC.

Comprehensive genomic analysis of early and late-onset hepatocellular carcinoma.

e16186 Background: Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer and is a leading cause of cancer-related death worldwide. HCC is highly therapy-resistant, and biomarker-driven therapies are emerging as important treatment options. Risk factors have been implied to distinguish early and late-onset patients. A high prevalence of non-cirrhotic HCC attributed to hepatitis B virus infection was found in young Asian patients. In late-onset patients, genetic aberrations accumulated with age in liver cirrhosis and other chronic liver diseases could provide the basis of tumorigenesis. Thus, diverse genomic alteration modes may underlie HCC of different onset ages, but the analysis is lacking. This study aims to explore genomic distinctions underlying early and late-onset HCC, thus facilitating personalized biomarker-driven treatments. Methods: The plasma and tumor samples from 222 Chinese HCCs underwent genomic profiling with hybridization capture-based targeted next-generation sequencing. The patients were categorized into early (male &lt; 40 years or female &lt; 50 years) or late (male ≥ 40 years or female ≥ 50 years) onset in accordance with the American Association for the Study of Liver Diseases guideline. We compared the clinical and molecular characteristics and explored differences between the early and late-onset cohorts. Results: The late-onset cohort accounts for 83.3% (185/222) of all HCC cases, and its male incidence rate is significantly higher than that of early-onset (88.6% vs 56.8%, p&lt; 0.0001). More younger cases have a family history of HCC (21.6% vs 14.6%). The mean somatic alteration numbers per patient are comparable between early and late-onset (8.30 vs 9.92). While TP53, TERT, and MCL1 are the most frequently mutated genes in both cohorts, we identified eight genes with significantly higher mutation frequencies in early-onset. OncoKB Levels 1 to 4 actionable alterations are present in 48.7% and 44.3% of younger and older patients, respectively, whereas the early-onset cohort has a significant enrichment of actionable MDM2 alterations (10.8% vs 1.1%, p= 0.0078). The prevalence of DNA Damage Response and Repair (DDR) gene mutations (35.1% vs 48.6%) and tumor mutation burden (TMB, mean: 4.17 muts/Mb vs 8.11 muts/Mb) are elevated in older patients. Notably, individuals harboring DDR mutations are associated with higher TMB in late-onset (mean TMB in DDR-mutated: 10.44 vs DDR- wildtype: 5.90, p= 0.0016) but not early-onset (mean TMB in DDR-mutated: 3.47 vs DDR- wildtype: 4.54, p= 0.280). Conclusions: Tumors from early and late-onset HCC demonstrated differences in genes and other biomarkers relevant to cancer biology and response to therapy. Specifically, DDR-mutated patients in the late-onset cohort are associated with higher TMB and may benefit from combining targeted and immunotherapy. Future studies are warranted to examine the response to biomarker-driven treatment strategies.

Identification of a DNA Damage Response and Repair-Related Gene-Pair Signature for Prognosis Stratification Analysis in Hepatocellular Carcinoma.

Background: Nowadays, although the cause of hepatocellular carcinoma (HCC) mortality and recurrence remains at a high level, the 5-year survival rate is still very low. The DNA damage response and repair (DDR) pathway may affect HCC patients’ survival by influencing tumor development and therapeutic response. It is necessary to identify a prognostic DDR-related gene signature to predict the outcome of patients. Methods: Level 3 mRNA expression and clinical information were extracted from the TCGA website. The GSE14520 datasets, ICGC-LIRI datasets, and a Chinese HCC cohort were served as validation sets. Univariate Cox regression analysis and LASSO-penalized Cox regression analysis were performed to construct the DDR-related gene pair (DRGP) signature. Kaplan–Meier survival curves and time-dependent receiver operating characteristic (ROC) analysis curves were calculated to determine the predictive ability of this prognostic model. Then, a prognostic nomogram was established to help clinical management. We investigated the difference in biological processes between HRisk and LRisk by conducting several enrichment analyses. The TIDE algorithm and R package “pRRophetic” were applied to estimate the immunotherapeutic and chemotherapeutic response. Results: We constructed the prognostic signature based on 23 DDR-related gene pairs. The patients in the training datasets were divided into HRisk and LRisk groups at median cut-off. The HRisk group had significantly poorer OS than the LRisk group, and the signature was an independent prognostic indicator in HCC. Furthermore, a nomogram of the riskscore combined with TNM stage was constructed and detected by the calibration curve and decision curve. The LRisk group was associated with higher expression of HBV oncoproteins and metabolism pathways, while DDR-relevant pathways and cell cycle process were enriched in the HRisk group. Moreover, patients in the LRisk group may be more beneficial from immunotherapy. We also found that TP53 gene was more frequently mutated in the HRisk group. As for chemotherapeutic drugs commonly used in HCC, the HRisk group was highly sensitive to 5-fluorouracil, while the LRisk group presented with a significantly higher response to gefitinib and gemcitabine. Conclusion: Overall, we developed a novel DDR-related gene pair signature and nomogram to assist in predicting survival outcomes and clinical treatment of HCC patients. It also helps understand the underlying mechanisms of different DDR patterns in HCC.

Effects of Tumor Mutational Burden and Gene Alterations Associated with Radiation Response on Outcomes of Postoperative Radiation Therapy in Non-Small Cell Lung Cancer

Postoperative radiation therapy (PORT) in resected non-small cell lung cancer (NSCLC) improves locoregional outcomes, but recent randomized data do not support its unselected use. We assessed if tumor mutational burden (TMB) and mutations in genes associated with radiation sensitivity can select patients for PORT. Patients with resected NSCLC treated with and without PORT who underwent tumor genomic profiling were examined. The incidence of locoregional failures (LRFs) in patients with deleterious mutations in DNA damage response and repair (DDR) genes and genes associated with radiation resistance (KEAP1/NFE2L2/STK11/PIK3CA) were investigated. Cox modeling and receiver operating characteristic curve (ROC) analysis assessed the relationship between TMB and locoregional control (LRC). Eighty-nine patients with NSCLC treated with PORT were analyzed, with a 2-year LRF rate of 19% (95% confidence interval, 10%-27%). Among patients treated with PORT, those with mutations in radiation resistance genes (n=16 [18%]) had significantly more LRFs than patients without mutations (2-year LRF rate: 60% vs 11%; P < .001). On multivariate analysis, radiation-resistance mutations were associated with LRF after PORT (hazard ratio, 7.42; P < .001). Patients with mutations identified in DDR genes (n=15 [17%]) had significantly improved LRC (P=.048) and no LRF events after PORT. On multivariate analysis, a higher TMB was associated with improved LRC after PORT (hazard ratio, 0.86; P=.01), and TMB was associated with PORT outcomes (area under ROC curve, 0.67-0.77). These genomic markers were not similarly associated with LRF in patients not treated with PORT. The data suggest that patients with radiation-resistance gene alterations may derive minimal benefit from PORT, whereas patients with high TMB and/or alterations in DDR genes may benefit from PORT and be suited for future precision-RT strategies. Prospective studies are necessary to validate these findings.

Co-Inhibition of Androgen Receptor and PARP as a Novel Treatment Paradigm in Prostate Cancer-Where Are We Now?

Simple SummaryThe past decade has seen the development and regulatory approval of a large number of new treatment options for advanced prostate cancer. Despite this, the two most used treatments—abiraterone and enzalutamide—have not been surpassed in efficacy, and eventually, all patients develop resistance to these treatments. Co-inhibition of androgen receptor (AR) and PARP proteins results in cancer cells’ inability to repair DNA. This combination approach has shown impressive early efficacy signals in preclinical and clinical settings and appears to be poised for a breakthrough. We review the science, data from clinical trials, and the future directions for this approach in this article.Metastatic prostate cancer remains lethal with a 5-year survival rate of about 30%, indicating the need for better treatment options. Novel antiandrogens (NAA)—enzalutamide and abiraterone—have been the mainstay of treatment for advanced disease since 2011. In patients who progress on the first NAA, responses to the second NAA are infrequent (25–30%) and short-lasting (median PFS ~3 months). With the growing adoption of NAA therapy in pre-metastatic castration-resistant settings, finding better treatment options for first-line mCRPC has become an urgent clinical need. The regulatory approval of two PARP inhibitors in 2020—rucaparib and olaparib—has provided the first targeted therapy option for patients harboring defects in selected DNA damage response and repair (DDR) pathway genes. However, a growing body of preclinical and clinical data shows that co-inhibition of AR and PARP induces synthetic lethality and could be a promising therapy for patients without any DDR alterations. In this review article, we will investigate the limitations of NAA monotherapy, the mechanistic rationale for synthetic lethality induced by co-inhibition of AR and PARP, the clinical data that have led to the global development of a number of these AR and PARP combination therapies, and how this may impact patient care in the next 2–10 years.

In Silico Investigation of the Biological Implications of Complex DNA Damage with Emphasis in Cancer Radiotherapy through a Systems Biology Approach.

Different types of DNA lesions forming in close vicinity, create clusters of damaged sites termed as “clustered/complex DNA damage” and they are considered to be a major challenge for DNA repair mechanisms resulting in significant repair delays and induction of genomic instability. Upon detection of DNA damage, the corresponding DNA damage response and repair (DDR/R) mechanisms are activated. The inability of cells to process clustered DNA lesions efficiently has a great impact on the normal function and survival of cells. If complex lesions are left unrepaired or misrepaired, they can lead to mutations and if persistent, they may lead to apoptotic cell death. In this in silico study, and through rigorous data mining, we have identified human genes that are activated upon complex DNA damage induction like in the case of ionizing radiation (IR) and beyond the standard DNA repair pathways, and are also involved in cancer pathways, by employing stringent bioinformatics and systems biology methodologies. Given that IR can cause repair resistant lesions within a short DNA segment (a few nm), thereby augmenting the hazardous and toxic effects of radiation, we also investigated the possible implication of the most biologically important of those genes in comorbid non-neoplastic diseases through network integration, as well as their potential for predicting survival in cancer patients.

DNA Damage Repair Inhibitors-Combination Therapies.

DNA damage response and repair (DDR) is responsible for ensuring genomic integrity. It is composed of intricate, complex pathways that detect various DNA insults and then activate pathways to restore DNA fidelity. Mutations in this network are implicated in many malignancies but can also be exploited for cancer therapies. The advent of inhibitors of poly(ADP-ribose) polymerase has led to the investigation of other DDR inhibitors and combinations to address high unmet needs in cancer therapeutics. Specifically, regimens, often in combination with chemotherapy, radiation, or other DDR inhibitors, are being investigated. This review will focus on 4 main DDR pathways-ATR/CHK1, ATM/CHK2, DNA-PKcs, and polymerase θ-and the current state of clinical research and use of the inhibitors of these pathways with other DDR inhibitors.

The Role of Circular RNAs in DNA Damage Response and Repair.

Simple SummaryThe role of non-coding RNA, and particularly of circular RNA, in the DNA damage response and repair network is underappreciated. Given the vital role of this network in preserving the genomic integrity and consequently cellular homeostasis, the constantly increasing numbers of discovered circular RNAs and the increasing implication of these molecules in the function of this network unravel a new important field that may open new therapeutic opportunities, but also require detailed investigation.Circular RNAs (circRNA) comprise a distinct class of non-coding RNAs that are abundantly expressed in the cell. CircRNAs have the capacity to regulate gene expression by interacting with regulatory proteins and/or other classes of RNAs. While a vast number of circRNAs have been discovered, the majority still remains poorly characterized. Particularly, there is no detailed information on the identity and functional role of circRNAs that are transcribed from genes encoding components of the DNA damage response and repair (DDRR) network. In this article, we not only review the available published information on DDRR-related circRNAs, but also conduct a bioinformatic analysis on data obtained from public repositories to uncover deposited, yet uncharacterized circRNAs derived from components of the DDRR network. Finally, we interrogate for potential targets that are regulated by this class of molecules and look into potential functional implications.

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy

Modulating the DNA damage response and repair (DDR) pathways is a promising strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related protein, which is crucial for DDR. This phase II trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma who had failed anti-programmed cell death protein 1 therapy. Among the 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Responses were evident across patients with acral, mucosal, and cutaneous melanoma. The median duration of response was 8.8 months (range, 3.8-11.7 months). The median progression-free survival was 7.1 months (95% confidence interval, 3.6-10.6 months), and the median overall survival was 14.2 months (95% confidence interval, 9.3-19.1 months). Common adverse events were largely hematologic and manageable with dose interruptions and reductions. Exploratory biomarker analysis suggested that tumors with an immune-enriched microenvironment or alterations in the DDR pathway were more likely to respond to the study treatment. We conclude that ceralasertib in combination with durvalumab has promising antitumor activity among patients with metastatic melanoma who have failed anti-programmed cell death protein 1 therapy, and constitute a population with unmet needs.