Alterations In DNA Repair Genes Research Articles

Are DNA Repair Gene Alterations Associated With the Response to Platinum-Based Regimen and Immune Checkpoint Inhibitors in Patients With Solid Tumors?

We analyzed the antitumor activity of platinum-based chemotherapies and then immune checkpoint inhibitors (ICI) in all-comers patients with solid tumors having a somatic DNA damage repair gene alteration (DDR-GA) identified through a prospective precision medicine study (NCT02534649). Each DDR-GA was classified as pathogenic (Pa), probably pathogenic (PPa), and unknown pathogenicity (UPa) according to OncoKB and ClinVAR databases. Between January 2018 and May 2020, 662 patients were screened. One hundred ninety-nine tumors with DDR-GA were found in 121 (18.3%) patients. Ninety-six patients received platinum-based chemotherapy in the advanced setting. No difference in objective response rate (ORR) under platinum regimen was observed between the 3 DDR-GA groups. The only predictor of worse progression-free survival (PFS) in Cox regression was the existence of a Pa alteration compared to the UPa group: HR = 2.11 (95% CI = 1.2-3.7), P = .009. Forty-eight patients received ICI alone or in combination. We observed a significant trend in better ORR to ICI according to the DDR-GA status: 1/11 (9%) patients in UPa, 5/17 (29.4%) patients in PPa, and 9/20 (45%) patients in Pa (P = .003, Cochran-Armitage trend test), and an increased 6-month PFS probability of 11%, 44%, and 50% in the UPa, PPa, and Pa groups, respectively (P = .37, log-rank test). Overall, somatic pathogenic DDR-GAs were not associated with ORR or PFS to platinum-based chemotherapy in patients with unselected advanced solid tumors. However, DDR-GA seemed to impact ORR and PFS to ICI, paving the way for a therapeutic combination with ICI and molecules targeting the DDR mechanisms, which are currently evaluated in ongoing clinical trials.

Chronic low-dose chromium VI exposure induces oxidative stress and apoptosis with altered expressions of DNA repair genes and promoter hypermethylation in the liver of Swiss albino mice.

The present investigation dealt with harmful effects of hexavalent chromium (Cr [VI]) on liver of Swiss albino mice. This variant exhibited cytotoxicity, mutagenicity, and carcinogenicity. Our study focused on elucidating the hepatotoxic effects of chronic low-dose exposure to Cr (VI) (2, 5, and 10ppm) administered via drinking water for 4 and 8months. The observed elevation in SGPT, ALP, and SGOT and increased oxidative stress markers unequivocally confirmed the severe disruption of liver homeostasis at these low treatment doses. Noteworthy alterations in histoarchitecture, body weight, and water intake provided further evidences of the harmful effects of Cr (VI). Production of reactive oxygen species (ROS) during metabolism led to DNA damages. Immunohistochemistry and qRT-PCR analyses revealed that chronic low-dose exposure of Cr (VI) induced apoptosis in liver tissue. Our study exhibited alterations in the expression pattern of DNA repair genes (Rad51, Mutyh, Mlh1, and Ogg1), coupled with promoter hypermethylation of Mutyh and Rad51, leading to transcriptional inhibition. Our findings underscored the potential of low-dose Cr (VI) exposure on hepatotoxicity by the intricate interplay between apoptosis induction and epigenetic alterations of DNA repair genes.

Abstract 2954: Androgen deprivation therapy (ADT) and senescence-associated secretory phenotype (SASP) in vitro: Correlation with SASP in tumor specimens as well as in the serum of patients after ADT

Abstract Introduction: Androgen Deprivation Therapy (ADT) is a highly effective treatment for prostate cancer. However, resistance to ADT develops in most patients, leading to a lethal state of castration-resistant prostate cancer (CRPC). Senescent prostate cancer (SPC) cells can arise after ADT and contribute to therapy resistance. SPCs can restore replicative function and alter the tumor microenvironment through pro-tumorigenic senescence-associated secretory phenotype (SASP). We aimed to characterize changes in SASP in prostate cancer cell lines and serum samples from patients receiving ADT. Methods: SASP factors (Luminex 100/200 System, xMAP Instruments) were analyzed in patients undergoing ADT. To correlate SASP with the sensitivity to ADT, we sought to evaluate the regulation of SASP in vitro using PCa cell lines. The PC3 (AR resistant) and LNCaP (AR sensitive) cell lines were used in the experiments. We performed an analysis of archival tumor tissue (paired) from 18 patients with or without alterations in DNA repair genes (BRCA1, BRCA2, and CDK12). We performed immunohistochemical (IHC) staining of known SASP markers, such as P16, uPAR, gamma-H2AX, and Lamin B1. Results: In a cohort of patients (n=8) with pre and post-ADT matched status, we demonstrate increased levels of SASP factors such as IL-6 (pre-ADT: 1.54±0.24 pg/ml, post-ADT: 5.23±1.3 pg/ml p=0.001), IL-7 (pre-ADT: 3.11±0.6 pg/ml, post-ADT: 13.5±2.7 pg/ml p=0.01), IL-1 alpha (pre-ADT: 1.06±0.3 pg/ml, post-ADT: 15.3±3.5 pg/ml p=0.001), IL-15 (pre-ADT: 15.6±3.1 pg/ml, post-ADT: 37.1±4.8 pg/ml p=0.002), MIF (pre-ADT: 1036±67.6pg/ml, post-ADT: 2362±55.5 pg/ml p=0.003), and IL-15 (pre-ADT: 5±2.1 pg/ml, post-ADT: 37.5±5.1 pg/ml p=0.002). In vitro, the AR-responsive LNCaP cell line, exposed to AR blockade, showed similar findings in upregulating IL-6, IL-7, and IL-15 but not the PC3 cell line. We also demonstrate measurable differences between the expression of u-PAR, gamma-2AX, p16, and loss of Lamin B1 expression in tumor specimens from patients with advanced castration-resistant prostate cancer (n=18). The expression of p16 was significantly upregulated post-treatment irrespective of DDR status (p=0.0417). Other SASP factors showed a trend in upregulation but were insignificant (u-PAR p=0.056, gamma-H2AX p=0.62, Lamin B1 p=0.72) Conclusion: These results provide evidence of systemic increases in SASP-related cytokines following treatment with ADT. The in vitro results suggest that secretion of SASP is promoted by an AR-mediated mechanism. Preliminary results from tumor specimens suggest increased senescence marker p16 expression induced by therapy. Ongoing experiments are further characterizing the senescence markers in prostate tumor specimens and correlated to treatment effect. Citation Format: Maximilian Schwermann, Matthew Hadfield, Shaolei Lu, Praveen Srinivasan, Vida Tajiknia, William MacDonald, Andrew George, Shengliang Zhang, Leiqing Zhang, Kimberly Meza, Andre De Souza, Dragan Golijanin, Elias Hyams, Galina Lagos, Sheldon Holder, Anthony Mega, John Sedivy, Howard Safran, Wafik El-Deiry, Benedito Carneiro. Androgen deprivation therapy (ADT) and senescence-associated secretory phenotype (SASP) in vitro: Correlation with SASP in tumor specimens as well as in the serum of patients after ADT [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 2954.

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...

Comprehensive analysis of targetable alterations in urachal cancer by NGS.

663 Background: Urachal cancer (UrC) is a rare genitourinary cancer with molecular drivers commonly found in colorectal cancer and harbors fewer actionable alterations. Although prior studies have identified genomic alterations associated with UrC, these lack comprehensive genomic profiling, often using targeted panels, and lack RNA interrogation. This study presents detailed characterization of molecular profiles and the tumor microenvironment of real-world UrC patient samples. Methods: UrC samples (n = 42) were profiled using next-generation sequencing (NGS) of DNA and RNA. Prevalence was calculated for pathogenic SNVs/Indels and copy number amplifications, dMMR/MSI status assessed by IHC and NGS, PD-L1 expression measured by IHC, and TMB-H defined as ≥ 10 mut/Mb. Immune cell fractions of TME were estimated using RNA deconvolution. Mann-Whitney U, chi-square, and Fisher exact tests were applied where appropriate, with p-values adjusted for multiple comparisons. Histological features were reviewed by a genitourinary pathologist. Results: UrC samples were collected from 19 males and 23 females with a median age at sample collection was 58.5 years (range: 24-86 years). Pathology review revealed the majority were adenocarcinomas (n=41/42, 97.6%), including mucinous (n=17/41, 41.5%) and enteric adenocarcinomas (n=10/41, 24.4%). Pathogenic variants were most commonly observed in TP53 (n = 35, 83.3%), KRAS (n=15, 36%), GNAS (n=5, 12%), SMAD4 (n=4, 10%), PIK3CA (n=4, 10%), STK11 (n=3, 7%), BRCA2 (n=3, 7%), ARID1A (n=2, 5%), PTEN (n=2, 5%), ERBB2 (n=2, 5%), BRAF (n=2, 5%), and APC (n=2, 5%). MAPK pathway alterations were present in 52.3% (n=22) overall, with increased MAPK pathway activation in MAPK-altered UrC (median MPAS: 0.77 vs -0.61, p = 0.066). Loss of heterozygosity was prevalent (n = 9, 29%). While no UrC tumors had dMMR/MSI, 5% (n=2) were TMB-H and 9% (n=3) were PD-L1+. The mean fraction of T cells – CD8 (0.4%) and monocytes (0.0%) represented a smaller fraction UrC TME composition compared to macrophages M1 (5.19%) and neutrophil (6.4%). The median NK cell fraction was significantly higher in MAPK-altered UrC patients (3.5 vs 2.7%, p = 0.022), yet a transcriptional signature of response to immunotherapy (IFN-g) was similar between MAPK-altered and MAPK-WT UrC patients (median IFN: -0.366 vs -0.384, p = 0.052). Conclusions: This study provides a comprehensive molecular characterization of UrC and the associated immune landscape. While MAPK and DNA repair gene alterations were common, UrC tumors rarely harbored predictive markers of response to immunotherapy, suggesting limited efficacy in this patient population. However, the recurrence of MAPK alterations and associated pathway activation in UrC warrants further investigation of MAPK-targeted therapies in prospective clinical trials.

PARP Inhibitors for Metastatic Urothelial Carcinoma: A Systematic Review of Efficacy and Safety.

Poly (ADP-ribose) polymerase (PARP) inhibitors have activity in various cancers. Metastatic urothelial carcinoma (MUC) is platinum sensitive and a subset harbour DNA repair gene alterations. To assess evidence for efficacy and safety of PARP inhibition for MUC. This systematic review included randomised clinical trials (RCTs) evaluating PARP inhibitors as monotherapy, or in therapeutic combinations, compared to relevant comparators or best supportive care. The primary endpoint was progression free survival (PFS). We searched MEDLINE (Ovid), EMBASE, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials from March 2013 to March 2023. Each study was appraised using the Cochrane Risk of Bias 2 Tool. Study results were synthesised descriptively. Registration: PROSPERO CRD42023403145. From 247 identified reports, we included three phase 2 RCTs including 252 patients. Two RCTs assessed PARP inhibition in unselected patient groups (one first line platinum ineligible, one post chemotherapy maintenance) and found no evidence of efficacy. All three RCTs assessed subgroups defined by biomarker selection for somatic DNA repair defects. Two of these identified PFS benefit with PARP inhibition compared to a relevant comparator (one first line in combination with immunotherapy, one maintenance monotherapy). Safety outcomes were consistent with prior experience of PARP inhibitors. The risk of bias across the outcomes was generally low. PARP inhibitors lack efficacy for unselected MUC patients. Phase 2 RCTs support further investigation of PARP inhibition within biomarker-selected patient subsets. The optimal biomarker is not yet determined. Limitations in the current evidence relate to small sample sizes and low statistical power.

140P Predictive value of DNA damage response and repair gene alterations and neoscore for neoadjuvant immunotherapies in non-small cell lung cancer

140P Predictive value of DNA damage response and repair gene alterations and neoscore for neoadjuvant immunotherapies in non-small cell lung cancer

Cervical cancer benefits from trabectedin combination with the β-blocker propranolol: in vitro and ex vivo evaluations in patient-derived organoids.

Background: Cervical cancer (CC) is characterized by genomic alterations in DNA repair genes, which could favor treatment with agents causing DNA double-strand breaks (DSBs), such as trabectedin. Hence, we evaluated the capability of trabectedin to inhibit CC viability and used ovarian cancer (OC) models as a reference. Since chronic stress may promote gynecological cancer and may hinder the efficacy of therapy, we investigated the potential of targeting β-adrenergic receptors with propranolol to enhance trabectedin efficacy and change tumor immunogenicity. Methods: OC cell lines, Caov-3 and SK-OV-3, CC cell lines, HeLa and OV2008, and patient-derived organoids were used as study models. MTT and 3D cell viability assays were used for drug(s) IC50 determination. The analysis of apoptosis, JC-1 mitochondrial membrane depolarization, cell cycle, and protein expression was performed by flow cytometry. Cell target modulation analyses were carried out by gene expression, Western blotting, immunofluorescence, and immunocytochemistry. Results: Trabectedin reduced the proliferation of both CC and OC cell lines and notably of CC patient-derived organoids. Mechanistically, trabectedin caused DNA DSBs and S-phase cell cycle arrest. Despite DNA DSBs, cells failed the formation of nuclear RAD51 foci and underwent apoptosis. Under norepinephrine stimulation, propranolol enhanced trabectedin efficacy, further inducing apoptosis through the involvement of mitochondria, Erk1/2 activation, and the increase of inducible COX-2. Notably, trabectedin and propranolol affected the expression of PD1 in both CC and OC cell lines. Conclusion: Overall, our results show that CC is responsive to trabectedin and provide translational evidence that could benefit CC treatment options. Our study pointed out that combined treatment offset trabectedin resistance caused by β-adrenergic receptor activation in both ovarian and cervical cancer models.

Neo-adjuvant PARP inhibition prior to prostatectomy: A phase II biomarker-driven trial for men with high-risk, localized prostate cancer and alterations in DNA repair genes.

TPS401 Background: Many men with localized prostate cancer will experience recurrence and progression after radical prostatectomy. While radiation therapy for high-risk prostate cancer is routinely given with systemic androgen therapy, peri-operative systemic therapy is not part of the standard of care with prostatectomy. Defective DNA repair pathways represent a non-hormonal target for PARP inhibitors which have proven efficacy in the metastatic, castrate resistant setting. We designed a novel biomarker driven neoadjuvant trial with niraparib prior to prostatectomy for men with clinically localized high risk prostate cancer and alterations in DNA repair genes (NCT04030559). Methods: We instituted a phase II trial for men with NCCN high and very high-risk prostate cancer. All men who met inclusion by clinical variables underwent targeted genomic sequencing for somatic and/or germline alterations in genes involved in DNA repair pathways. Enrolled patients are treated with oral Niraparib 300mg/day for 90 days before surgery. The primary endpoint is pathologic response at prostatectomy defined as complete response or minimal residual disease (<0.5 cc3) of histological viable cancer. The secondary endpoint is biochemical free survival as well as molecular endpoints including disease responses stratified by mutational status. We have screened 37 men and 10 have met genomic criteria. We have enrolled 8 out of planned 30 men to date, 7 have undergone prostatectomy. Enrolled men have alterations in BRCA2 (germline), MSH6, ZMYM3, MUTYH, ATM, CDK12, ERCC3 and KMT2c. Clinical trial information: NCT04030559 .

Development of PARP Inhibitors in Targeting Castration-Resistant Prostate Cancer.

Prostate cancer is a genetically heterogenous disease and a subset of prostate tumors harbor alterations in DNA damage and repair (DDR) genes. Prostate tumor DDR gene alterations can arise via germline or somatic events and are enriched in high-grade and advanced disease. Alterations in genes in the homologous recombination (HR) repair pathway are associated with sensitivity to PARP inhibition in breast and ovarian cancer, and data from recently completed randomized trials also demonstrate benefit of PARP inhibitor therapy in patients with advanced metastatic castration-resistant prostate cancer (mCRPC) and tumor HR gene alterations. PARP inhibitors have been investigated in first-line mCRPC in biomarker-selected and unselected populations, and are currently under study in earlier disease states in patients with DDR gene alterations. This chapter focuses on the current state of PARP inhibitor development in prostate cancer with particular emphasis on biomarkers and combination therapy approaches.

Characteristics of BRCA2 Mutated Prostate Cancer at Presentation.

Genetic alterations of DNA repair genes, particularly BRCA2 in patients with prostate cancer, are associated with aggressive behavior of the disease. It has reached consensus that somatic and germline tests are necessary when treating advanced prostate cancer patients. Yet, it is unclear whether the mutations are associated with any presenting clinical features. We assessed the incidences and characteristics of BRCA2 mutated cancers by targeted sequencing in 126 sets of advanced prostate cancer tissue sequencing data. At the time of diagnosis, cT3/4, N1 and M1 stages were 107 (85%), 54 (43%) and 35 (28%) samples, respectively. BRCA2 alterations of clinical significance by AMP/ASCO/CAP criteria were found in 19 of 126 samples (15.1%). The BRCA2 mutated cancer did not differ in the distributions of TNM stage, Gleason grade group or histological subtype compared to BRCA2 wild-type cancers. Yet, they had higher tumor mutation burden, and higher frequency of ATM and BRCA1 mutations (44% vs. 10%, p = 0.002 and 21% vs. 4%, p = 0.018, respectively). Of the metastatic subgroup (M1, n = 34), mean PSA was significantly lower in BRCA2 mutated cancers than wild-type (p = 0.018). In the non-metastatic subgroup (M0, n = 64), PSA was not significantly different (p = 0.425). A similar trend was noted in multiple metastatic prostate cancer public datasets. We conclude that BRCA2 mutated metastatic prostate cancers may present in an advanced stage with relatively low PSA.

French AFU Cancer Committee Guidelines - Update 2022-2024: prostate cancer - Management of metastatic disease and castration resistance

The objective of the French Urology Association Cancer Committee is to propose an update of the recommendations for the management of prostate cancer. A systematic review of the literature from 2020 to 2022 was conducted by the CCAFU on the elements of therapeutic management of metastatic and castration-resistant prostate cancer (PC), while evaluating the references and their levels of evidence. Androgen deprivation therapy (ADT) remains the standard treatment for metastatic prostate cancer. ADT intensification is now a standard of care in the management of metastatic prostate cancer. This intensification is discussed in relation to the patient and the characteristics of the disease. For all metastatic hormone-sensitive PC (synchronous and metachronous), the overall survival benefit associated with good tolerability makes the combination of ADT and novel hormonal agents (NHA) a standard. For patients with high-volume/high-risk de novo metastatic disease, treatment with docetaxel in addition to ADT + NHA can be discussed for eligible patients. In patients with castration-resistant prostate cancer (CRPC), the contribution of new therapies that have become available in recent years, as well as the advent of precision medicine, help to improve the control of tumour progression and survival, and highlight the value of testing for alterations in DNA repair genes within the tumour tissue or constitutionally. This update of the French recommendations should help to improve the management of patients with prostate cancer.

Analysis of genetic alterations of DNA repair genes as prognostic marker of survival in cholangiocarcinoma

Analysis of genetic alterations of DNA repair genes as prognostic marker of survival in cholangiocarcinoma

B7-H3 as a Therapeutic Target in Advanced Prostate Cancer

BackgroundB7-H3 is a cell surface immunomodulatory glycoprotein overexpressed in prostate cancers (PCs). Understanding its longitudinal expression at emergence of castration resistance and association with tumour genomics are critical to the development of and patient selection for B7-H3 targeted therapies. ObjectiveTo characterise B7-H3 expression in same-patient hormone-sensitive (HSPC) and castration-resistant (CRPC) PC biopsies, associating this with PC genomics, and to evaluate the antitumour activity of an anti–B7-H3 antibody-drug conjugate (ADC) in human CRPC in vitro and in vivo. Design, setting, and participantsWe performed immunohistochemistry and next-generation sequencing on a cohort of 98 clinically annotated CRPC biopsies, including 72 patients who also had HSPC biopsies for analyses. We analysed two CRPC transcriptome and exome datasets, and PC scRNASeq datasets. PC organoids (patient-derived xenograft [PDX]-derived organoids [PDX-Os]) were derived from PDXs generated from human CRPC biopsies. Outcome measurements and statistical analysisWe evaluated B7-H3 mRNA expression in relation to a panel of 770 immune-related genes, compared B7-H3 protein expression between same-patient HSPC and CRPC biopsies, determined associations with PC genomic alterations, and evaluated the antitumour activity of DS-7300a, a topoisomerase-1 inhibitor payload anti–B7-H3 ADC, in human PC cell lines, organoids (PDX-Os), and xenografts (PDXs) of different histologies, B7-H3 expressions, and genomics. Results and limitationsB7-H3 was among the most highly expressed immunomodulatory genes in CRPCs. Most CRPCs (93%) expressed B7-H3, and in patients who developed CRPC, B7-H3 expression was frequently expressed at the time of HSPC diagnosis (97%). Conversion from B7-H3 positive to negative, or vice versa, during progression from HSPC to CRPC was uncommon. CRPC with neuroendocrine features were more likely to be B7-H3 negative (28%) than adenocarcinomas. B7-H3 is overexpressed in tumours with defective DNA repair gene (ATM and BRCA2) alterations and is associated with ERG expression, androgen receptor (AR) expression, and AR activity signature. DS7300a had antitumour activity against B7-H3 expressing human PC models including cell lines, PDX-Os, and PDXs of adenocarcinoma and neuroendocrine histology. ConclusionsThe frequent overexpression of B7-H3 in CRPC compared with normal tissue and other B7 family members implicates it as a highly relevant therapeutic target in these diseases. Mechanisms driving differences in B7-H3 expression across genomic subsets warrant investigation for understanding the role of B7-H3 in cancer growth and for the clinical development of B7-H3 targeted therapies. Patient summaryB7-H3, a protein expressed on the surface of the most lethal prostate cancers, in particular those with specific mutations, can be targeted using drugs that bind B7-H3. These findings are relevant for the development of such drugs and for deciding which patients to treat with these new drugs.

1719P Predictive value of DNA repair gene alterations for the response to platinum-based chemotherapy and immunotherapy in advanced solid tumors patients: Results from a single center molecular screening program

Homologous recombination DNA repair deficiency is associated with sensitivity to platinum in certain cancer types, including breast, ovarian, pancreatic, and prostate. We aimed to characterize the antitumor activity of platinum-based therapies in patients (pts) with unselected advanced solid tumors for who a DNA repair gene alteration (DNA-RGA) was identified through a tumor molecular screening program (TMSP). All comers pts from the TMSP of Institut Bergonié, Bordeaux, France, were reviewed. Each DNA-RGA identified was classified as pathogenic (P), probably pathogenic (PP), unknown pathogenecity (UP) according to OncoKB and/or ClinVAR databases and defined 3 pts groups. Between January 2018 and May 2020, 662 pts were screened. 199 tumor DNA-RGA were found in 121 (27.7%) pts. The most frequent mutations were : ATM (N=40), POLE (N=23), BAP1 (N=19), BRCA2 (N=16), PMS2 (N=9), ATR (N=9), MSH2 (N=8) and BRCA1 (N=8). 96 pts received platinum-based chemotherapy in the advanced setting, mostly lung cancer pts (N=28). Platinum was carboplatin in 46 (48%) of the pts. No difference in overall response rate (ORR) under platinum regimen was observed between the 3 (P,PP,UP) pts groups. Median progression free survival (PFS) was 8.4 months (IC95% : 7 – 9.4). The only predictor of worst PFS in Cox regression model was the existence of a P alteration compared to the UP group: HR=2.11 (95%CI = 1.2 – 3.7), P = 0.0094. The UP group had a better 6-months PFS compared to the P/PP group: 81% vs 60%, p=0.0382. 48/96 pts received a immune checkpoint inhibitor (ICI) alone or in combination. Interestingly we observed a trend in an increased ORR to ICI according to the DNA-RGA status : 1/11, 5/16, 9/20 pts (p=0.14; Chi-2 test for trend in proportions: p=0.04) in the UP, PP and P group respectively. The same trend was observed on PFS with a 6-months PFS of 11, 44 and 50% in the UP, PP and P groups respectively (p=0.37). P/PP DNA-RGA impacted the PFS but not the ORR to platinum in advanced solid tumors pts. Though the limited population size, this exploratory study paves the way for further investigations evaluting DNA-RGA as biomarkers of response to ICI.

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.

Future directions for precision oncology in prostate cancer.

Clinical genomic testing is becoming routine in prostate cancer, as biomarker-driven therapies such as poly-ADP ribose polymerase (PARP) inhibitors and anti-PD1 immunotherapy are now approved for select men with castration-resistant prostate cancer harboring alterations in DNA repair genes. Challenges for precision medicine in prostate cancer include an overall low prevalence of actionable genomic alterationsand a still limited understanding of the impact of tumor heterogeneity and co-occurring alterations on treatment response and outcomes across diverse patient populations. Expanded tissue-based technologies such as whole-genome sequencing, transcriptome analysis, epigenetic analysis, and single-cell RNA sequencing have not yet entered the clinical realm and could potentially improve upon our understanding of how molecular features of tumors, intratumoral heterogeneity, and the tumor microenvironment impact therapy response and resistance. Blood-based technologies including cell-free DNA, circulating tumor cells (CTCs), and extracellular vesicles (EVs) are less invasive molecular profiling resources that could also help capture intraindividual tumor heterogeneity and track dynamic changes that occur in the context of specific therapies. Furthermore, molecular imaging is an important biomarker tool within the framework of prostate cancer precision medicine with a capability to detect heterogeneity across metastases and potential therapeutic targets less invasively. Here, we review recent technological advances that may help promote the future implementation and value of precision oncology testing for patients with advanced prostate cancer.

Comprehensive whole-exome and transcriptome profiling to identify actionable alterations associated with response to PARP inhibitors in breast cancer.

1096 Background: The use of targeted therapies identified using genetic and genomic approaches is now routine in breast cancer (BC). In this clinical lab experience study the frequency of actionable somatic alterations in DNA repair pathway genes associated with the use of PARP inhibitors (PARPi) is described. Methods: BC samples were sequenced with the Oncomap ExTra assay, which uses whole-exome DNA sequencing with germline subtraction to detect somatic single base substitutions, indels, and copy number alterations, and RNA sequencing to detect gene fusions. Clinically actionable alterations were defined as associated with FDA approved drugs or clinical trial enrollment. Here, the focus is on 49 repair genes associated with PARPi response: ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CDK12, CHEK1/2, EPCAM, ERCC1/2/3/4/5, FANCA/C/D2/E/F/G/I/L/M, MLH1, MRE11A, MSH2/6, MUTYH, NBN, PALB2, PMS2, PPP2R2A, PTEN, RAD21/50/51/51B/51C/51D/52/54L, XRCC1/2/3. Results: Of 1103 BCs, 246 (22.3%) had mutations in repair genes; 69 (6.3%) were in BRCA1/2. Repair gene mutations were less common in HER2+ cancers (n=27, 14.3%) compared to HR+ HER2- (n=156, 23.9%) or TN cancers (n=49, 26.1%) (p<0.01). Across subtypes, the top four most commonly mutated of the repair genes were PTEN (27.2%), ARID1A (22.8%), BRCA2 (14.2%), and BRCA1 (14.2%); 33 cancers (13.4%) had mutations in multiple (≥2) repair genes. For the 69 cancers with BRCA1/2 mutations, 11 (15.9%) carried other repair gene mutations (9 of 35 BRCA1; 3 of 35 BRCA2). RNA sequencing found 19 fusions in repair genes in 17 patients (1.5%); CDK12 was involved in 13 (68.4%), and RAD51C in 3 (15.8%). Fusion incidence was more frequent in HER2+ cancers (p<0.01) (Table). Conclusions: PARPi therapy is FDA approved for HER2- germline BRCA1/2 mutated BC patients. Recent evidence suggests somatic BRCA1/2 mutations predict PARPi benefit (Tung, NM. J Clin Oncol 2020). In addition to BRCA1/2 alterations, our study also highlights the importance of alterations in other DNA repair genes associated with response to PARPi. Trials are ongoing to determine if these genes predict for PARPi benefit.[Table: see text]

Olaparib tolerability and common adverse-event management in patients with metastatic castration-resistant prostate cancer: Further analyses from the PROfound study

BackgroundBased on PROfound, olaparib is approved for patients with metastatic castration-resistant prostate cancer following disease progression on at least enzalutamide or abiraterone and who carry relevant alterations in DNA repair genes. To facilitate continued olaparib treatment as long as the patient derives benefit, we describe further safety assessments from PROfound focusing on the four most common adverse events (AEs) and events of special interest. MethodsPatients were randomized (2:1) to olaparib tablets (300 mg bid) or control (enzalutamide or abiraterone) until disease progression or unacceptable toxicity. Safety was assessed through AE reporting and laboratory assessments. Safety data were also collected from all patients in the control group who experienced radiographic disease progression and subsequently crossed over to olaparib treatment. Results256 patients received olaparib and 130 control. Incidence rates for the four most commonly occurring AEs in the olaparib group (all-causality) were anaemia 50%, nausea 43%, fatigue/asthenia 42% and decreased appetite 31%. All were mostly Grade 1 and 2 and all peaked within the first 2 months of treatment as the events were managed where appropriate, primarily with dose interruptions or dose reductions. The extent of bone metastases at baseline or prior taxane use was not associated with the rate of anaemia. Pneumonitis was reported in 2% and 1.5% of patients in the olaparib and control groups, respectively, and one patient (0.4%) in the olaparib group experienced an event of MDS/AML after a 30-day follow-up period. Venous thromboembolic events occurred in 8% of olaparib and 3% of control patients. ConclusionsThe four most common AEs observed in PROfound were generally manageable without the need for treatment discontinuation, allowing patients to remain on treatment for as long as they were deriving clinical benefit. ClinicalTrialsgov registration number: NCT02987543.