DNA Damage Repair Gene Mutations Research Articles

DNA damage response and repair gene mutations predict clinical outcomes in biliary tract cancer.

This study aims to explore the genetic characteristics of biliary tract cancer (BTC), with a particular focus on the impact of DNA damage response and repair (DDR) genes on clinical outcomes. A total of 180 patients with BTC and next-generation sequencing data were retrospectively analyzed. Clinical outcomes were compared between DDR-positive and DDR-negative groups. DDR mutations were found in 28.3% of patients, with ATM (7.8%), BAP1 (5.6%), and BRCA2 (3.3%) being the most common. DDR-positive patients receiving first-line platinum-based chemotherapy (n=73) had a significantly higher objective response rate (50.0% vs. 14.9 %; p=.001), longer median progression-free survival (mPFS) (7.7 vs. 3.8 months; p=.001) and longer median overall survival (28.6 vs. 11.9 months; p<.001). Multivariate analysis confirmed that deleterious DDR gene mutations were independently associated with prolonged mPFS (hazard ratio [HR], 0.37; 95% CI, 0.20-0.67; p<.001) and median overall survival (mOS) (HR, 0.19; 95% CI, 0.08-0.46; p<.001). In 56 patients receiving immunotherapy combined with chemotherapy, DDR-positive patients had a significantly higher overall response rate (45% vs. 8.3%; p=.001), longer mPFS (7.7 vs. 3.8 months; p=.009), and longer mOS (12.7 vs. 8.8 months; p=.011). Multivariate analysis showed that the presence of deleterious DDR gene mutations was associated with significantly longer mPFS (HR, 0.34; 95% CI, 0.16-0.73); p=.005] and mOS (HR, 0.23; 95% CI, 0.08-0.62; p=.004). Deleterious DDR gene mutations are associated with improved clinical outcomes in patients with BTC treated with platinum-based chemotherapy or immunotherapy combined with chemotherapy.

Clinical relevance of protein-truncating variants of germline DNA repair genes in prostate cancer

BackgroundInterpreting genetic variants remains a challenge in prostate cancer (PCa). Although many annotation tools are available for prioritizing causal variants, the clinical relevance of these variants is rarely studied.MethodsWe collected a cohort study that included 274 PCa patients from June 2017 to December 2020 and sequenced 19 DNA damage repair (DDR) genes in these patients and explored the clinical consequence of these different approaches. We also examined all-cause and PCa-specific survival in DDR gene mutation carriers compared to non-carriers after androgen receptor (AR)-directed therapy.ResultsWe identified 13 variants from 19 DDR genes in a total of 14 (5.1%) patients who had at least one presumed pathogenic mutation using different annotation methods. Four variants were annotated as pathogenic, 11 variants were predicted as protein-truncating variants (PTVs), four variants received proxy-deleterious (Combined Annotation-Dependent Depletion scores of > 30), and only one variant was identified as a pathogenic variant or as having a functional effect by all three methods. PCa patients with PTVs were significantly associated with early onset, high cancer stage, and a worse response to AR-directed treatment. However, patients carrying a proxy-deleterious variant were only associated with a higher T (tumor) stage and N (node) stage than those without such a variant, but not associated with other clinical characteristics. In patients treated with AR-directed therapy, patients with a PTV showed an increased risk of all-cause death (adjusted hazard ratio (aHR) = 3.51, 95% confidence interval (CI): 1.06 ~ 11.56) and PCa-specific death (aHR = 4.49, 95% CI: 1.87 ~ 10.77) compared to non-PTV carriers after adjustment. We were unable to examine gene-specific risks due to the small number of patients.ConclusionsPTVs may assist in guiding treatment and early screening in PCa, while population-specific data for pathogenic variants are still being amassed.

Skin metastasis of BRCA mutated prostate cancer: A case report and a brief review of literature.

Metastatic castration-resistant prostate cancer has a poor prognosis especially when harboring DNA damage repair gene mutations, nevertheless, in the case of pathogenic BRCA gene mutations, PARPi demonstrated a survival benefit and is a validated treatment. Nowadays, there is no data regarding unusual metastases after these drugs. Cutaneous metastases appear rarely in prostate cancer and were associated with a worse prognosis. Moreover, there are no consolidated data concerning skin tropism of prostate cancer cells, neither in the case of BRCA-associated cancers. Here, we report the case of a patient with a long history of BRCA1-mutated metastatic castration-resistant prostate cancer who developed a skin lesion on the scalp while on his fifth line of systemic therapy with olaparib. After a complete radical surgical excision, the pathology report showed prostate cancer localization. A diagnosis of skin metastasis from prostate cancer was reported. The patient then continued olaparib therapy; after 7 months from excision, he experienced further bone and biochemical progression but not cutaneous progression. A literature review of all reported cases of cutaneous metastasis in prostate cancer was conducted to shed light on the incidence, clinical presentation, diagnosis, treatment, and prognosis of this entity. We also reviewed published cases of skin metastasis in BRCA-associated cancers with an effort to correlate skin involvement with PARPi treatment, BRCAness status, and prognosis.

Phase I clinical trial of peposertib plus radiation in adults with newly diagnosed MGMT-unmethylated glioblastoma.

2076 Background: DNA-dependent protein kinase (DNA-PK) is a pivotal component of DNA damage repair (DDR) pathways and is an attractive target in glioblastoma because its expression renders tumors less vulnerable to radiotherapy. Peposertib is a small molecule DNA-PK inhibitor that has been pre-clinically shown to potentiate radiotherapy and regress glioblastoma tumors. We conducted a two-stage phase I trial of peposertib plus radiation in patients with newly-diagnosed MGMT-unmethylated glioblastoma (NCT04555577). Methods: In stage 1, patients received concurrent peposertib plus standard-of-care radiotherapy to determine the maximum-tolerated dose (MTD) based on the Bayesian Optimal Interval design (maximum n=24). Stage 2 is a window-of-opportunity expansion cohort and will include 5 surgical patients to evaluate intratumoral drug concentration. Both groups receive 6 cycles of adjuvant temozolomide. Results: Eighteen patients completed the 10-week dose-limiting toxicity (DLT) period; 3@50mg, 3@100mg, 3@200mg, 9@300mg. One DLT (G3 radiation necrosis [RN] at 300mg) was observed. Enrollment of the last three patients into the 300mg dose level began in December 2023 and will complete stage 1. To date, most notable toxicity was transient G3 dermatitis of the scalp (2@200mg, 1@300mg; not a DLT per protocol). Therefore, radiation dose constraints to the skin were incorporated and subsequent patients did not experience this toxicity. After a median follow up of 14.3 months (9.3-18.4), the median OS was 22.9 months [95% CI (16-NR)] and median PFS was 12.7 months [95% CI (9-NR)]. Next-generation sequencing (NGS) was available for 16 archival tumor tissue specimens from patients treated on this trial. Two patients had pathology-proven RN (one within and one outside of the DLT period). Both tumors had baseline mutations in DDR genes (i.e. ATRX, DICER1). Recurrent tissue was available for 4 patients after treatment with peposertib, 2 of which demonstrated gain of DDR gene mutations (2 ATM mutations in one patient and gain of MAD2L2 mutation in another patient). Conclusions: The initial safety data of peposertib plus radiation in patients with newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors with DDR mutations, the gain of DDR mutations in recurrent tumors, and the cases of scalp dermatitis suggest peposertib activity may correlate with DDR function, and possibly potentiates the effect of radiation. Stage I is an independent stage of the protocol that will enable MTD determination. Complete safety and survival data and correlations with genomics and spatial transcriptomics for Stage I patients will be presented at the meeting. The study was supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755). Clinical trial information: NCT04555577 .

Characterization of DNA damage repair mutations in lung cancer in an underserved urban patient population.

e20058 Background: DNA-damage repair (DDR) mutations in lung cancer have shown potential for use as therapeutic targets and predictive biomarkers. However, the relationship between DDR mutations and socioeconomic factors remains largely unknown. In this study, we characterize the distribution of DDR gene mutations in lung cancer patients at a single academic medical center serving a unique population consisting of primarily underserved, underinsured patients. Methods: All lung cancer patients seen at the University of Illinois Chicago (UIC) between 11/2/2015 and 9/11/2023 with TEMPUS genetic data available were included in the study (N = 235). DDR mutations of interest were ARID1A, ATM, ATR, ATRX, BAP1, BRCA1, BRCA2, BRIP1, CHEK2, ERCC3, FANCA, FANCC, MLH3, MRE11, MSH6, MUTYH, NBN, PALB2, and RAD50. The population was subdivided into a DDR mutation positive group and a DDR mutation negative group. Each group was compared with respect to lung cancer type, tumor mutational burden (TMB), and socioeconomic factors including sex, race, insurance category, and zip code. Results: The overall frequency of DDR mutations in the population was 28.5% (n = 67). The most common DDR mutations were ARID1A (20.7%), CHEK2 (12.8%), ATM (9.9%), BRCA2 (9.9%), ATRX (7.9%), and MUTYH (7.9%). The histological distribution of the DDR mutation positive group was adenocarcinoma (76.1%), squamous cell carcinoma (4.4%), adenosquamous carcinoma (2.9%), neuroendocrine carcinoma (5.9%), and other (10.4%). The histological distribution of the DDR negative group was adenocarcinoma (60.1%), squamous cell carcinoma (22.0%), adenosquamous carcinoma (1.1%), neuroendocrine carcinoma (4.1%), and other (12.5%). There was a significant effect in TMB, t(55) = 2.97, p = 0.004, with a higher mean TMB in the DDR positive group (M = 14.4, SD = 11.1) compared to the DDR negative group (M = 9.4, SD = 5.1). The most common zip codes in the DDR positive groupwere 60608 (9.0%), 60629 (9.0%), and 60616 (7.5%) compared to 60616 (8.3%), 60609 (5.3%), and 60624 (4.7%) in the DDR negative group. Demographic factors of the two groups are compared below. Conclusions: The frequency and distribution of DDR mutations in lung cancer at UIC appears similar to what has been previously reported in the literature. There is a higher tumor mutational burden in lung cancers with DDR mutations, which may suggest greater susceptibility to immunotherapy. There may be a correlation between the presence of DDR mutations and lung cancer type, insurance category, and patient geographic distribution. Future work will include obtaining further geographic data for the study population such as average income, pollution exposure, and smoking rate by neighborhood. [Table: see text]

Genomic Correlates of Prostate-Specific Membrane Antigen Expression and Response to 177Lu-PSMA-617: A Retrospective Multicenter Cohort Study.

While 177Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes. This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA50 response (ie, ≥50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups. One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received ≥1 prior androgen receptor-signaling inhibitor, and 121 (96%) received ≥1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in TP53, RB1, or PTEN tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of ≥1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; P = .034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; P = .023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; P = .044) on multivariable analysis. Univariate analysis of patients with ATM mutations had significantly higher rates of PSA50 response, PSA PFS, and OS. Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified.

Abstract 5559: The anti-tumor efficacy and immune effects of combining of ceralasertib, an oral ATR kinase inhibitor, with imipridones, in prostate cancer treatment in vitro and in vivo

Abstract Prostate cancer is the most common cancer and the second leading cause of cancer death among men in the United States. There is an estimated 10% to 50% of cases progress to metastatic castration resistant prostate cancer (mCRPC) state within 3 years of diagnosis. mCPRC remains lethal despite therapeutic advances. There is approximately 20% of mCRPC patients present somatic DNA damage repair (DDR) gene mutations. Ceralasertib, formerly known as AZD6738, is a potent and selective orally bioavailable inhibitor of the ataxia tenlangiectasia and Rad3-related (ATR) kinase, which is involved in DNA repair in response to DNA damage and replication stress. Preclinical studies have demonstrated ATRi sensitizing alterations in DNA damage response (DDR) genes. Ceralasertib’s antitumor activity as a monotherapy in treating prostate cancer is moderate. Thus, we combined ceralasertib with imipridones (ONC201 and ONC206), which target mitochondrial caseinolytic protease P (ClpP) and the integrated stress response, resulting in enhanced antitumor efficacy in vitro. Prior data have demonstrated sensitivity of 4 prostate cancer lines to ceralasertib and imipridones monotherapies, synergistic activities with the combination treatments, and immune enhancement effects with the combination treatments when co-cultured with NK92MI cell line. We proceeded to a short term in-vivo study validating the combination treatment efficacy. Preliminary results include cytokine profiling using the Luminex 200 technology to understand treatment induced changes in the tumor microenvironment (TME) from both in vitro and in vivo studies. Our results guide novel clinical trials for effective clinical responses in mCPRC patients. Citation Format: Yutong Linda Xia, Leiqing Zhang, Maryam Ghandali, Maximilian P. Schwermann, Wafik El-Deiry. The anti-tumor efficacy and immune effects of combining of ceralasertib, an oral ATR kinase inhibitor, with imipridones, in prostate cancer treatment in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5559.

CTNI-42. PHASE I CLINICAL TRIAL OF PEPOSERTIB PLUS RADIATION IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract BACKGROUND DNA-dependent protein kinase (DNA-PK) is a pivotal component of DNA damage repair (DDR) pathways and is an attractive target in glioblastoma because its expression renders tumors less vulnerable to radiotherapy. Peposertib is a small molecule DNA-PK inhibitor that has been shown to potentiate radiotherapy and regress glioblastoma tumors pre-clinically. We conducted a two-stage phase I trial of peposertib plus radiation in newly-diagnosed MGMT-unmethylated glioblastoma (NCT04555577). Method: In stage 1, patients received peposertib plus standard-of-care radiotherapy to determine the maximum-tolerated dose (MTD) based on the Bayesian Optimal Interval design (maximum n = 24). Stage 2 is a window-of-opportunity expansion cohort and will include 5 surgical patients to evaluate tumor drug concentration. Both groups receive adjuvant temozolomide for 6-cycles. RESULTS Fifteen completed the 10-week dose-limiting toxicity (DLT) period; 3-50mg, 3-100mg, 3-200mg, 6-300mg. One DLT (G3 radiation necrosis [RN] at 300mg) was observed. Most notable toxicity was 3 patients with transient G3 dermatitis of the scalp (not DLT per protocol) (2-200mg, 1-300mg). Therefore, radiation dose constrains to the skin were incorporated and subsequent patients did not experience this toxicity. Next-generation sequencing (NGS) was available for 13 archival tissue. Two patients had pathology-proven RN (one within and one outside of the DLT period). Both tumors had mutations in DDR genes (i.e. ATRX, DICER1). Recurrent tissue was available for one patient after treatment with peposertib showed gain of two ATM mutations. CONCLUSION The initial safety data of peposertib plus radiation in newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors with DDR mutations, the gain of two ATM mutations in a recurrent tumor and the cases of scalp dermatitis suggest that peposertib is active and possibly potentiates the effect of radiation. Safety and survival data and correlations with genomics will be presented. The study was supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755).

DNA damage response and repair gene mutations are associated with tumor mutational burden and outcomes to platinum-based chemotherapy/immunotherapy in advanced NSCLC patients

BackgroundDNA damage response and repair (DDR) genes are crucial for maintaining the integrity of the genome. This study aims to explore the correlation of DDR gene mutations with TMB, clinical characteristics, and outcomes to platinum-based chemotherapy and platinum-based chemotherapy/immunotherapy in non-small cell lung cancer (NSCLC) without EGFR and ALK alterations.MethodsTumor tissue from 49 patients with stage III or IV NSCLC who were without EGFR and ALK alterations were analyzed using targeted next-generation sequencing (NGS). Among them, 13 patients received first-line platinum-based chemotherapy, 32 patients received first-line platinum-based chemotherapy/immunotherapy.ResultsIn these NSCLC patients without EGFR and ALK alterations, the frequently mutated genes included TP53, KMT2D and KRAS, the most frequently mutated DDR gene was FANCG, DDR gene mutations were detected in 20 patients. The mutation frequency of homologous recombination (HR) pathway was significantly higher in lung squamous cell carcinoma (LUSC) than that in lung adenocarcinoma (LUAD) (30.8% vs. 5.7%). Among DDR positive patients, a lower percentage exhibited metastasis. Patients with DDR gene mutations, cell-cycle checkpoint pathway mutations, and BER pathway mutations had significantly higher TMB compared to those without corresponding mutations. In the patients receiving platinum-based chemotherapy/immunotherapy, the disease control rate was significantly lower in the DDR-positive group compared with that in the DDR-negative group (55.6% vs. 100.0%). Among LUAD patients receiving platinum-based chemotherapy/immunotherapy, we observed a worse overall survival (OS) in DDR-positive group, as well as poorer progression-free survival(PFS)and OS in BER-positive and FANCG mutated group.ConclusionsDDR gene mutations are associated with tumor metastasis, TMB, and outcomes to platinum-based chemotherapy/immunotherapy in advanced NSCLC patients.

The correlation between clinical outcomes and genomic analysis with high risk factors for the progression of osteosarcoma.

Osteosarcoma (OS) is a rare but aggressive malignancy. Despite previous reports, molecular characterization of this disease is not well understood, and little is known regarding OS in Chinese patients. Herein, we analyzed the genomic signatures of 73 Chinese OS cases. TP53, NCOR1, LRP1B, ATRX, RB1, and TFE3 were the most frequently mutated gene in our OS cohort. In addition, the genomic analysis of Western OS patients was performed. Notably, there were remarkable disparities in mutational landscape, base substitution pattern, and tumor mutational burden between the Chinese and Western OS cohorts. Specific molecular mechanisms, including DNA damage repair (DDR) gene mutations, copy number variation (CNV) presence, aneuploidy, and intratumoral heterogeneity, were associated with disease progression. Additionally, 30.1% of OS patients carried clinically actionable alterations, which were mainly enriched in PI3K, MAPK, DDR, and RTK signaling pathways. A specific molecular subtype incorporating DDR alterations and CNVs was significantly correlated with distant metastasis-free survival and event-free survival, and this correlation was observed in all subgroups with different characteristics. These findings comprehensively elucidated the genomic profile and revealed novel prognostic factors in OS, which would contribute to understanding this disease and promoting precision medicine of this population.

Application value of DNA damage repair variants in adjuvant therapy of triple negative breast cancer

Objective: To investigate the correlation between adjuvant chemotherapy with platinum-containing regimens and DNA damage repair (DDR) defects in early-stage triple negative breast cancer (TNBC), and to provide a basis for precise treatment of TNBC. Methods: Next-generation sequencing (NGS) testing was performed on postoperative breast cancer specimens selected from the Cancer Hospital of Chinese Academy of Medical Sciences from June 2009 to October 2015 to analyze the correlation between DDR gene variants and the efficacy of adjuvant chemotherapy with TNBC platinum-containing regimens, and thus to screen the superior population for adjuvant chemotherapy with TNBC platinum-containing regimens. The study used t-test, χ(2) test, Fisher's exact test, rank sum test and multifactorial logistic analysis to assess the associations between mutated genes and clinicopathological characteristics and prognosis, and Log-rank test and Cox proportional risk model were used for survival and correlation analysis. Results: NGS results were successfully obtained in 149 patients (74 in the platinum-containing group and 75 in the platinum-free group), with a 97.3% (145/149) DDR gene mutation rate and a median number of 4 mutations in all patients. 5-year disease-free survival (DFS) was 85.4% and 75.0% for patients with DDR gene mutations and DDR gene wild-type, respectively, without statistical difference (P=0.825). The 5-year DFS rates of patients with homologous recombination repair (HRR) pathway mutation were 84.6% in platinum-containing (TCb) group and 84.9% in platinum-free (EC-T) group (P=0.554), respectively. The 5-year DFS rates of patients with and without mutations in the platinite-containing HRR pathway were 84.9% and 85.0%, respectively (P=0.751). The number of DDR pathways with mutations and the number of DDR gene mutations were not associated with prognosis (both P>0.05). PIK3CA mutation patients in TCb group had a worse prognosis than wild-type patients (5-year DFS were 71.4% and 88.1%, P=0.037), and KMT2D mutation patients in EC-T group had a worse prognosis than wild-type patients (5-year DFS were 76.9% and 86.8%, P=0.039). Conclusions: DDR gene variation is common in TNBC, more clinical studies are needed to prove whether DDR variation can serve as effective biomarkers for treatment with platinum.

A Review of the Molecular Landscape of Adenoid Cystic Carcinoma of the Lacrimal Gland.

Adenoid cystic carcinoma (ACC) has a worldwide incidence of three to four cases per million population. Although more cases occur in the minor and major salivary glands, it is the most common lacrimal gland malignancy. ACC has a low-grade, indolent histological appearance, but is relentlessly progressive over time and has a strong proclivity to recur and/or metastasise. Current treatment options are limited to complete surgical excision and adjuvant radiotherapy. Intra-arterial systemic therapy is a recent innovation. Recurrent/metastatic disease is common due to perineural invasion, and it is largely untreatable as it is refractory to conventional chemotherapeutic agents. Given the rarity of this tumour, the molecular mechanisms that govern disease pathogenesis are poorly understood. There is an unmet, critical need to develop effective, personalised targeted therapies for the treatment of ACC in order to reduce morbidity and mortality associated with the disease. This review details the evidence relating to the molecular underpinnings of ACC of the lacrimal gland, including the MYB-NFIB chromosomal translocations, Notch-signalling pathway aberrations, DNA damage repair gene mutations and epigenetic modifications.

Abstract B054: Inherited mutations of DNA damage repair genes in a racially diverse cohort of men with prostate cancer

Abstract Introduction: DNA damage repair genes (DDRGs) play an important role in genomic stability and mutations in DDRGs contribute to clinically significant prostate cancer (PCa). However, the association of germline mutations in DDRGs with PCa progression and therapeutic stratification remain to be defined in African American (AA) men. Our objective was to genomically profile all known DDRGs and provide ancestry specific findings, focusing on PCa patients with African ancestry. Methods: Germline mutations in all DDRGs (N=276) was evaluated by whole genome sequence (WGS) analysis of archived blood DNA samples from 600 PCa patients (300 AA and 300 CA) who underwent primary treatment at Walter Reed National Military Medical Center. The WGS mean coverage exceeded 37x. Principal Component Analysis using the Peddy program was conducted, and ancestry prediction was based on a machine learning approach using 1000G as reference. Variant frequencies in CPDR PCa patients were compared to variant frequencies available from the Exome Aggregation Consortium (ExAC) controls with no PCa. Data analysis approaches included single variant association, gene-based total frequency test and clinico-pathological associations for germline mutations. All statistical tests were two-sided, and FDR adjusted. FDR &amp;lt; 0.05 was set as significance threshold. Results: Comprehensive analysis of 276 DDRGs revealed that germline mutation (Pathogenic/Likely Pathogenic; P/LP) carrier rate was 23.5%, which is three times higher than reported before in both AA and CA men, due to our unbiased WGS approach. We found that only 13 of the 46 DDRGs identified with P/LP mutations were common to AA and CA men, demonstrating clear disparity along ancestry lines. Importantly, RAD family genes (RAD54L, RAD54B, RAD51), which are potentially targetable, as well as PMS2 and BRCA1, were among the most frequently mutated DDRGs in AA, but not in CA men. Germline mutations in RAD51 and PMS2 were enriched in AA cohort as compared to CA men (P 0.01 and 0.03 respectively), while germline mutations in FANCA were significantly enriched in CA cohort (P &amp;lt; 0.01). Pathway analysis showed that the HR pathway (with 15 mutations) was associated with faster disease progression to biochemical recurrence (BCR) (P &amp;lt;0.05), while the NHEJ pathway (with three mutations) was found to be marginally associated with metastasis (p &amp;lt;0.05). Additionally, we found that germline mutations in DDRGs was associated with shorter time to BCR (P &amp;lt;0.05) in AA patients, but not in CA men. Conclusion: Our findings highlight distinct DDRG germline mutation profile across AA and CA prostate cancer men. This may help refine patient stratification for specific targeted therapeutic options especially for under-studied AA men. Future replication studies in an independent patient cohort are warranted to validate our findings. Citation Format: Indu Kohaar, Xijun Zhang, Gregory Chesnut, Clifton Dalgard, Matthew D. Wilkerson, Gyorgy Petrovics. Inherited mutations of DNA damage repair genes in a racially diverse cohort of men with prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B054.

Retrospective evaluation of the value of DNA damage repair gene signature in response to platinum-based chemotherapy in advanced pancreatic ductal adenocarcinoma.

4137 Background: Mutations affecting DNA Damage Repair (DDR) genes have been associated with clinical benefits from platinum-based chemotherapy (PBC) in ovarian and breast cancer. Mutations of DDR genes, including BRCA1/2, PALB2, ATM, ATR, CHK1, or RAD51, are found in around 15% of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, whether advanced PDAC patients harboring DDR gene mutations could benefit more from PBC has not been well established. In this study, we aimed to compare the prevalence of DDR gene mutations between advanced PDAC patients who benefited from PBC and those who did not. Methods: We retrospectively analyzed samples from patients with advanced PDAC who received PBC at our institution from 2008 to 2022. Patients with partial response or progression-free survival (PFS) &gt; 6 months were considered responders, and those with progression disease as the best response were considered non-responders. Tumor molecular profiling was performed on tumor samples by Next Generation Sequencing (NGS) of DNA. Fisher’s exact test was used to compare DDR genomic alterations in responders vs. non-responders. Overall survival (OS) was defined as the time from the start of PBC to the date of death. PFS was defined as the time between the start of PBC and the first date of documented progression or death, whichever occurs first. Survival outcomes were estimated using Kaplan-Meier curves, and differences were tested using the long-rank test. Results: A total of 132 patients with advanced PDAC treated with PBC were included in this study. The median age at diagnosis was 55 years (range 27-79 years), and 71 (53.79%) patients were male. In this cohort, 88 (66.67%) patients were identified as responders. Tumor molecular profiling showed that among responders, 42 patients (47.7%) had genomic alterations in BRCA1/2 or PALB2, and 10 patients (11.3%) had alterations in other DDR genes. In contrast, only 17 patients (38.64%) showed DDR gene alternations among non-responders. Importantly, mutations in DDR genes are significantly associated with the responder group (OR=2.28; 95% CI 1.03-5.17, p=0.04). In line with these findings, patients with DDR gene mutations showed significantly longer PFS (median PFS 9.95 months) compared with patients without DDR gene mutations (median PFS 6.51 months) (HR= 0.57; 95%CI 0.39-0.85; p=0.005). Moreover, significantly longer OS was found in patients with DDR gene mutations (median OS 20.5 months) compared with those without DDR gene mutations (median OS 16.8 months) (HR=0.67; 95%CI 0.45-1; p=0.05). Conclusions: Genomic alterations in DDR genes are significantly associated with the benefit of PBC treatment in advanced PDAC patients. Our results argue in favor of using DDR genes as a decision-making tool for advanced PDAC patient stratification even before the stand-of-care chemotherapies.

PSMA expression and response to 177Lu-PSMA-617 (LuPSMA) in men with vs. without DNA damage repair (DDR) mutations.

5055 Background: LuPSMA, a radioligand targeting the cell surface protein PSMA, is approved for men with PSMA-positive metastatic castration resistant prostate cancer (mCRPC) following an androgen receptor (AR)-signaling inhibitor (ARSI) and docetaxel. DNA damage repair gene (DDR) mutations are common in mCRPC, and given that ionizing radiation induces DNA damage, we hypothesized that the presence of these alterations could associate with improved clinical outcomes to LuPSMA. Data also suggests that the presence of DDR mutations may correlate with PSMA expression, providing further motivation to evaluate if DDR alterations are associated with the clinical activity of LuPSMA. Methods: We abstracted retrospective data from all patients at our center who received at least one cycle of LuPSMA per the FDA label and who had panel-based sequencing performed (e.g. UW-Oncoplex, Foundation One). Patients with somatic or germline alterations in a DDR gene were assigned to the DDR deficient cohort, while patients with somatic testing negative for a DDR gene mutation were assigned to the DDR intact cohort. Mutations in any DDR gene were considered for the purpose of stratifying between genomic subgroups. Differences in baseline PSMA SUVmean and PSA50 responses (i.e. ≥50% decline in PSA) were compared between cohorts. Results: Of 91 patients who received ≥1 cycle of LuPSMA, 54 had genetic testing. 35 (64%) received ≥2 lines of prior ARSI therapy, 30 (56%) received ≥2 lines of prior chemotherapy and 15 (28%) received prior PARP inhibitor. 21 patients had alterations in a DDR gene and the remaining 33 patients had somatic testing without an identifiable DDR mutation. PSMA SUVmean was similar between groups: 8.04 (95% CI: 6.95 - 9.12) (DDR intact) vs. 7.32 (95% CI: 6.23 – 8.41) (DDR deficient), p = 0.37. 7/33 (21%) patients in the DDR intact group achieved PSA50 response compared to 11/21 (52%) in the DDR group (p= 0.018). Survival data is immature but will be presented at the meeting. Rapid autopsy (RA) was performed in one subject with a BRCA2 mutation (baseline PSMA SUVmean 5.6) and immunohistochemistry analysis revealed profound loss of PSMA following progression on LuPSMA. Conclusions: Mutations in DDR genes were associated with a higher PSA50 response rate following LuPSMA compared to patients without a DDR mutation. There was no difference in baseline PSMA expression based on DDR mutational status, suggesting that higher response rates in the DDR cohort may have been mediated primarily by increased sensitivity to ionizing radiation. Evaluation for associations between DDR mutational status and survival endpoints is needed and will require a larger sample size and longer follow up. RA post-LuPSMA revealed loss of PSMA expression, suggesting that antigen loss may be a relevant resistance mechanism. [Table: see text]

The impact of DNA damage repair gene mutations on therapeutic response among Chinese patients diagnosed with advanced biliary tract cancer.

e16190 Background: Biliary tract cancer (BTC) is a fatal disease characterized by molecular heterogeneity, which results in variations in biological behavior. Despite this, the knowledge of pathogenic alterations in the Chinese BTC population using next-generation sequencing (NGS) profiles remains limited. Therefore, we performed a retrospective investigation to assess the predictive significance of DNA damage repair (DDR) mutations in facilitating precision medicine for this disease. Methods: NGS profiling was carried out on resected tissues obtained from Chinese patients diagnosed with advanced BTC. In addition, baseline clinical and genetic characteristics were collected, along with data on their survival outcomes. Results: A total of 68 Chinese patients with BTC who received first-line platinum-containing chemotherapies were enrolled in this study [intrahepatic cholangiocarcinoma (ICC), 33; extrahepatic cholangiocarcinoma (ECC), 13; gallbladder carcinoma (GBC), 22]. Genetic alterations were observed in 67 patients (98.5%), with TP53 (50.0%), KRAS (26.8%), ARID1A (16.2%), and CDKN2A (16.2%) being the most commonly mutated genes. Patients with TP53 mutations demonstrated a trend towards reduced median OS (16.6 vs. 20.1 months, P=0.145). Mutations in DDR genes were identified in 29 (42.6%) of overall patients, primarily involving ATM (11.8%) and BAP1 genes (8.8%), and were significantly associated with longer mPFS (6.4 vs. 4.8 months, P=0.022) and mOS (21.2 vs. 14.3 months, P=0.011) in patients who received first-line platinum-containing chemotherapies. DDR-mutated patients treated with PD-1 blockades showed a tendency towards improved overall survival compared to the DDR-naive group (20.8 vs. 14.3 months, P=0.297). Furthermore, tumor mutational burden (TMB) could be estimated in 63 cases and was significantly higher in those with DDR mutations (P=0.029). Conclusions: Genetic information can aid in identifying a subgroup of BTC patients who may benefit from targeted therapy, this retrospective study demonstrated the predictive significance of DDR mutations for platinum-based chemotherapy efficacy in Chinese patients. Nonetheless, additional research is necessary to explore the potential of DDR mutations in predicting sensitivity to PD-1 blockade.

Randomized phase 2 study of maintenance olaparib vs olaparib plus durvalumab for DNA damage repair (DDR) gene mutated unresectable or metastatic biliary tract cancer (BTC) with durable response to first-line platinum-based chemotherapy: OPTIMUM trial.

TPS4180 Background: BTC is rare and aggressive disease with heterogeneous genetic profiles. Gemcitabine plus cisplatin (GemCis) with or without durvalumab is the standard first-line therapy but further improvement in survival outcomes is needed. In a prior study (Chae HJ et al, Eur J Cancer 2019), germline or somatic mutations in DDR genes including BRCA are detected more than half of BTC patients and associated with better survival outcomes with platinum-based chemotherapy. As the potential efficacy of Olaparib in DDR-mutated cancers and synergism between PARP inhibitors and immune checkpoint inhibitors, we designed randomized phase 2 trial investigating the efficacy and safety of olaparib monotherapy vs olaparib plus durvalumab in BTC patients as maintenance therapy for BTC patients who showed durable response to first-line platinum-based chemotherapy. Methods: This is a randomized, open-label phase 2 study conducted in a single center (Asan Medical Center, Seoul, Korea). Key eligibility criteria include histologically documented locally advanced unresectable or metastatic BTC, no progression at least 16 weeks with first-line platinum-based chemotherapy, DDR mutations on targeted sequencing of tumor tissues and ctDNA, ECOG performance status 0–1, and adequate organ function. Eligible patients will be randomized 1:1 into olaparib monotherapy arm (300 mg twice daily, every 4 weeks) or olaparib plus durvalumab (1,500 mg intravenous, every 4 weeks) arm. Study treatment is continued until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response evaluation is performed every 8 weeks (fixed). Stratification factors are tumor location (intrahepatic vs extrahepatic/gallbladder) and best response to platinum-based chemotherapy (CR/PR vs SD). The six-month progression-free survival rates are the primary endpoint and overall survival, progression-free survival, response rates, and safety profiles are secondary endpoints. A total of 62 patients (31 for each arm) are planned, and 23 (37%) patients (ATM [n=6], BRCA2 [n=7], CHEK2 [n=2], BRCA1 [n=1], RAD51C [n=1], and PBRM1 [n=1]) are enrolled as of Jan 2023. Clinical trial information: NCT05222971 .

Relations between mutant KRAS and TP53 subtypes and other co-mutations in pancreatic cancer.

e16294 Background: The most common mutations in pancreatic cancer are found in the KRAS, TP53, CDKN2A, or SMAD4 genes. Mutations in genes involved in the DNA damage repair (DDR) pathway are also frequently seen. Despite extensive research on the patho-genomic features of pancreatic cancer, the clinical significance of these recurring mutations remains poorly understood. Methods: We identified patients with pancreatic cancer treated at Yale Cancer Center between 2016 and 2021 who underwent Oncomine tumor profiling. The incidence and subtypes of KRAS and TP53, and their association with other genomic alterations and clinicopathological variables were measured. We compared the overall survival (OS) after the diagnosis of recurrent or metastatic disease using the Kaplan-Meier method and long-rank tests. Results: One hundred fifty-nine patients were identified and KRAS mutations were seen in 144 (90.6%) patients, including 64 G12D (44.4%), 48 G12V (33.3%), 19 G12R (13.2%), 6 Q61H (4.2%), and 7 others (4.9%). TP53 mutations were identified in 117 (73.6%) patients, including 80 loss-of-function (LOF) (68.4%), 24 gain-of-function (GOF) (20.5%), and 13 variants of unclear significance (VUS) (11.1%). TP53 LOF mutations were more common in tumors with KRAS WT (40.0%), G12D (56.3%), and G12V (56.3%), than in G12R (31.6%) and others KRAS mutation (30.1%). Conversely, TP53 GOF mutations were more common in tumors with G12R (26.3%) and other KRAS mutations (23.1%), than in KRAS WT (6.7%), G12D (14.1%), and G12V (12.5%). There was no difference in OS between KRAS subtypes (p=0.48) or TP53 subtypes (p=0.52). Patients with TP53 WT had a numerically longer but not statistically significant survival (median 1.65 years versus 1.16 years in patients with TP53 mutations, p=0.20). When each KRAS subtype was examined, patients with tumors with G12V but no TP53 mutation had longer OS (median 2.42 years) than those with WT KRAS or non-G12V mutation (median 1.38 years, p=0.02). Mutations in DDR genes were more frequently seen in the KRAS WT (33.3%) and G12D groups (15.6%), compared to that in the G12V (10.4%), G12R (10.5%) groups. Unique co-mutations were observed in certain KRAS subtypes but not others. Conclusions: In this retrospective study of comprehensive genomic and clinical data of pancreatic cancers, we found that KRAS or TP53 mutation subtypes had no significant impact on OS. Different KRAS subtypes have unique co-occurring genomic alterations, which may be clinically relevant as novel KRAS inhibitors continue clinical development.[Table: see text]

Roles of the PARP Inhibitor in BRCA1 and BRCA2 Pathogenic Mutated Metastatic Prostate Cancer: Direct Functions and Modification of the Tumor Microenvironment.

Cancer cells frequently exhibit defects in DNA damage repair (DDR), leading to genomic instability. Mutations in DDR genes or epigenetic alterations leading to the downregulation of DDR genes can result in increased dependency on other DDR pathways. Therefore, DDR pathways could be a treatment target for various cancers. In fact, polyadenosine diphosphatase ribose polymerase (PARP) inhibitors, such as olaparib (Lynparza®), have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through synthetic lethality. Recent genomic analytical advancements have revealed that BRCA1/BRCA2 pathogenic variants are the most frequent mutations among DDR genes in prostate cancer. Currently, the PROfound randomized controlled trial is investigating the efficacy of a PARP inhibitor, olaparib (Lynparza®), in patients with metastatic castration-resistant prostate cancer (mCRPC). The efficacy of the drug is promising, especially in patients with BRCA1/BRCA2 pathogenic variants, even if they are in the advanced stage of the disease. However, olaparib (Lynparza®) is not effective in all BRCA1/2 mutant prostate cancer patients and inactivation of DDR genes elicits genomic instability, leading to alterations in multiple genes, which eventually leads to drug resistance. In this review, we summarize PARP inhibitors' basic and clinical mechanisms of action against prostate cancer cells and discuss their effects on the tumor microenvironment.

Analysis of Plasma Circulating Tumor DNA in Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Modified FOLFIRINOX: Clinical Relevance of DNA Damage Repair Gene Alteration Detection.

There are no reliable biomarkers to guide treatment for patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting. We used plasma circulating tumor DNA (ctDNA) sequencing to search biomarkers for patients with BRPC receiving neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (NCT02749136). Among the 44 patients enrolled in the trial, patients with plasma ctDNA sequencing at baseline or post-operation were included in this analysis. Plasma cell-free DNA isolation and sequencing were performed using the Guardant 360 assay. Detection of genomic alterations, including DNA damage repair (DDR) genes, were examined for correlations with survival. Among the 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study. Among the 25 patients with baseline plasma ctDNA data, 10 patients (40%) had alterations of DDR genes detected at baseline, inclu-ding ATM, BRCA1, BRCA2 and MLH1, and showed significantly better progression-free survival than those without such DDR gene alterations detected (median, 26.6 vs. 13.5 months; log-rank p=0.004). Patients with somatic KRAS mutations detected at baseline (n=6) had significantly worse overall survival (median, 8.5 months vs. not applicable; log-rank p=0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, eight patients (61.5%) had detectable somatic alterations. Detection of DDR gene mutations from plasma ctDNA at baseline was associated with better survival outcomes of pati-ents with borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant mFOLFIRINOX and may be a prognostic biomarker.