Bradley Monk, MD, FACOG, FACS: One of the best things about being in education is what I call reverse mentorship. Biomarkers are not perfect, and there are some patients who even have HRP who can do well for a long time on a PARP inhibitor. Furthermore, treatment of BRCA-associated EOC patients with PLD has been shown to result in higher response rates, longer time to treatment failure and improved overall survival compared with non-BRCA mutated patients (72). MA, Lips EH, Nederlof PM, et al. Sokol Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingam, AL, USA. These data suggest that loss of 53BP1 but not Ligase IV promotes activation of DNA end resection. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. mTOR inhibitors suppress homologous recombination repair and synergize with PARP inhibitors via regulating SUV39H1 in BRCAproficient triplenegative breast cancer. This mechanism of resistance may be particularly relevant to the PARP-trapping mechanism of action of PARPis. Patch AM, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, et al. Review of the literature, ASCO and NCCN guidelines, and expert discussions suggest uncertainty and inconsistency in how to use assays that measure HR status in the clinic, which could potentially drive low adoption for clinical decision making.45 Because assays that measure HR status can identify cancers that are more likely to respond to PARPi therapies and predict positive outcomes, it is important to address the sources of uncertainty to enable clinicians to use these new diagnostic tools and provide their patients with optimal care. and transmitted securely. Global Regulatory Affairs, GlaxoSmithKline, Washington, DC, USA. The majority of ovarian cancers ultimately recur despite excellent response rates to upfront platinum- and taxane-based chemotherapy. Under-expression or loss of expression of PARP1 protein 4. The other half may have a platinum-sensitive relapse, but they then have to respond; remember, theyre HRP, so the chance of responding to platinum again is low. Konstantinopoulos PA, Awtrey CS. Single-cell circulating tumor cell analysis reveals genomic instability as a distinctive feature of aggressive prostate cancer. Defective DNA repair via homologous recombination is a pivotal vulnerability of epithelial ovarian cancer, particularly of the high grade serous histologic subtype.
EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Histone deacetylase inhibitors (HDACi) are effective in overcoming tumor resistance to DNA damaging drugs. Data analysis and interpretation: M.D.S., D.M.V., R.C.A., J.F.B., O.B., N.B., T.F., N.G., P.H., P.J., M.J.M., K.M., J.P., L.R., M.S., E.S. HR is a multistep process that is tightly linked to human cancer risk. Bookshelf Somatic reversion mutations that restore the open reading frame (ORF) of the gene and hence protein function within the homologous recombination pathway. This mechanism may explain the cytotoxic effect of certain drug combinations such as PARPi and temozolomide or topotecan (9698), and is believed to account for the observation that PARP1 knockdown selectively kills HR-deficient cells (18, 76, 83), as these PARP-trapping-induced DNA lesions are thought to be mostly toxic in an HR-deficient setting. First, maintenance chemotherapy, i.e. Combination of platinum or PARPis with agents that inhibit HR may therefore represent an effective strategy to sensitize HR proficient tumors to platinum and PARPis, and thus potentially expand use of these agents into EOCs with denovo or acquired HR proficiency. Loss/Decreased activity within non-homologous end joining repair (NHEJ) pathway leading to partial dsDNA repair. 2022 Jan 12;14(2):365. doi: 10.3390/cancers14020365. Therefore, careful Phase I evaluation of these combinations will be required, with increased focus on proof of mechanism pharmacodynamic studies. Graeser M, McCarthy A, Lord CJ, Savage K, Hills M, Salter J, et al. The ATMCHK2 pathway primarily responds to double strand breaks (DSBs) to induce G1 arrest via phosphorylating and activating CHK2 and p53, while the ATRCHK1 pathway triggers S and G2 phase arrest. Understanding the mechanisms of PARPi resistance and their relation to platinum resistance may aid the development of novel non-cross resistant therapies and may help optimize the sequence of how these agents are incorporated in the clinical management of HR deficient EOC. Platinum analogs induce intrastrand and interstrand cross-links (ICLs) between purine bases of the DNA. Alternative multigene, next generation sequencing assays are also offered in several cancer centers in the US and routinely include assessment of core HR genes (54). In this case, its niraparib. Of note, phase I clinical evaluation of olaparib with PI3K inhibitors (BYL719 or BKM120) or the AKT inhibitor (AZD5363) in ovarian and breast cancers provided evidence of response in patients who were expected to have HR proficient tumors thereby providing proof of principle for this approach. Recent observations indicate that PARP1 functions in a pathway required for the repair of DNA DSBs, referred to as error-prone alternative end joining (alt-EJ) or microhomology-mediated end-joining (MMEJ) (112). Similar to TopI inhibitors, topoisomerase II (TopII) inhibitors such as doxorubicin and etoposide are also more active in HR deficient cells and are routinely used in the management of relapsed EOC (pegylated liposomal doxorubicin (PLD) is also FDA-approved for this indication)(66, 67, 70). Sakai W, Swisher EM, Jacquemont C, Chandramohan KV, Couch FJ, Langdon SP, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.
Homologous Recombination - Genome.gov Davies Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors. This research was supported by a Stand Up To Cancer Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT16-15). Present-day landscape of FDA-approved diagnostic tools for PARPi treatments. Hennessy BT, Timms KM, Carey MS, Gutin A, Meyer LA, Flake DD, 2nd, et al. DNA repair dysregulation from cancer driver to therapeutic target. An acquired genetic reversion of the original truncating mutations restores functional protein expression inducing PARPi resistance. Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers. Wang H, Rosidi B, Perrault R, Wang M, Zhang L, Windhofer F, et al. Homologous Recombination / genetics Humans Ovarian Neoplasms / drug therapy Phthalazines / therapeutic use* Piperazines / therapeutic use* Poly (ADP-ribose) Polymerase Inhibitors / therapeutic use* Triazoles / therapeutic use (+)-JQ1 compound Acetanilides Antineoplastic Agents Azepines Heterocyclic Compounds, 3-Ring OTX015 Phthalazines Piperazines The nice part about it is that, in the recurrent setting, we have patients who responded to platinum twice, and I can see that patients probably a PARP inhibitor candidate. Integrated genomic analyses of ovarian carcinoma. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Please enable it to take advantage of the complete set of features!
Treating Homologous Recombination Proficient Ovarian Cancer - OncLive sharing sensitive information, make sure youre on a federal Nike Beaubier, Inactivation of CDK12 leads to suppression of HR via reduced expression of BRCA1 and other HR genes, and confers PARPi sensitivity. Matthew J Marton, performed a drug screen and discovered that BET inhibitors, a type of epigenetic regulators, act synergistically with PARP inhibitors.The authors found that BET inhibitors suppress . MM, Sundar R, Tan DSP, Jeyasekharan AD. Germline and somatic mutations, as well as epigenetic modifications in BRCA1 and BRCA2, have been consistently associated with an HRD phenotype in breast, ovarian, pancreatic, and prostate cancer,15-17 and have been deemed archetypal in the determination of an HRD phenotype.18 Other HRR pathway genes associated with an HRD phenotype include genes such as ATM, PALB2, RAD51, and others.3 Either genetic or epigenetic alterations in these genes or some combination underlie the HRD phenotype in various cancer types19 including ovarian,16,20,21 endometrial,22 breast,23-25 prostate,26 and pancreatic cancer.27 The association between these genes and an HRD phenotype may be less consistent than BRCA1 and BRCA2 and may vary by the tumors tissue of origin. Learn more Another challenge is denovo and acquired resistance which are often encountered in clinic and have tempered the enthusiasm for the potential of PARPis in HR deficient EOCs. Evers B, Helleday T, Jonkers J. Accessibility Kirsten M Timms, Hypomorphic alleles, such as BRCA1-C61G or BRCA1-11, are unable to prevent tumor development but confer resistance to PARPi. Li X, Delzer J, Voorman R, de Morais SM, Lao Y. Thats the patient who has no real targetable options. Increased incidence of visceral metastases in scottish patients with BRCA1/2-defective ovarian cancer: an extension of the ovarian BRCAness phenotype. 2 Clarke DriveSuite 100Cranbury, NJ 08512. Consistent with their enhanced activity in HR deficient cells, the activity of both etoposide and doxorubicin is much higher in the platinum sensitive compared to the platinum resistant setting (66, 70). Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, et al. The site is secure. Mark D Stewart, All aforementioned PARPis inhibit PARP-1 and PARP-2 in vitro at nanomolar concentrations but differ in their ability to trap PARP1 and PARP2 on the DNA SSB sites; niraparib and the newer PARPi BMN673 exhibit higher potency in trapping PARPs than olaparib and rucaparib, while ABT-888 is the least potent of all PARPis in terms of its PARP trapping ability (90). Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. Defective HR is an important therapeutic target in EOC as exemplified by the efficacy of platinum analogues in this disease, as well as the advent of PARP inhibitors, which exhibit synthetic lethality when . Homologous recombination DNA repair (HRR)., Homologous recombination DNA repair (HRR). While companion diagnostic as a construct exists in a limited capacity in non-US markets, the clinical and analytical validation conferred by FDA review continues to inform global diagnostic use. Please enable it to take advantage of the complete set of features! Furthermore, gemcitabine irreversibly inhibits the ribonucleotide reductase enzyme leading to cells inability to produce the deoxyribonucleotides required for DNA replication and repair, and thus inducing apoptosis. The clinical validity as well as the practicality and implementation for routine clinical use is under investigation.37-39. for use in the maintenance treatment of patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high-grade serous EOC who had a complete or partial response to platinum-based chemotherapy.
The effect of PARP inhibitors in homologous recombination proficient Germline mutations in RAD51D confer susceptibility to ovarian cancer. Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. Unlike PTEN and EMSY, the association between inactivating mutations of CDK12 and HR deficiency is clearly established (36, 37). N, Pajic M, Patch AM, et al. Clinical Sequencing Division, Thermo Fisher Scientific, San Francisco, CA, USA. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Analyzing deficiencies in the homologous recombination repair (HRR) machinery becomes increasingly important to identify patients responding to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors. Weber AM, Ryan AJ. Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy and the fifth most frequent cause of cancer-related mortality in women in United States (1). ATM promotes HR by recruiting BRCA1 to DSBs but can also antagonize BRCA1 and promote NHEJ by recruiting p53 binding protein 1 (53BP1), and these antagonistic functions are cell cycle regulated. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Whole-genome characterization of chemoresistant ovarian cancer. Bradley Monk, MD, FACOG, FACS: In the HRP [homologous recombination proficient] subset, we have to decide if it is PARP inhibition alone, as you just said Leslie, or is it bevacizumab alone? Int J Mol Sci. .
Homologous Recombination Deficiency: Concepts, Definitions, and Assays The integral role of platinum based chemotherapy in the clinical management of EOC is further evident by the fact that management of relapsed disease is stratified based on the platinum free interval (i.e. This means that cancer cells have a harder time repairing themselves in people whose tumour tests positive for HRD. FOIA Mechanism of microhomology-mediated end-joining promoted by human DNA polymerase theta. PARP Inhibitors Display Differential Efficacy in Models of, T32 CA047888/CA/NCI NIH HHS/United States. M, Cruz C, Llop-Guevara A, et al. Clinical assays for assessment of homologous recombination DNA repair deficiency. Interestingly, the survival advantage of BRCA1 carriers was shown to be dependent on the location of the mutation; worse survival was observed as the mutation site moved from 5 to 3 end of the BRCA1 gene (42). Kang J, DAndrea AD, Kozono D. A DNA repair pathway-focused score for prediction of outcomes in ovarian cancer treated with platinum-based chemotherapy. FOIA The DNA damage response: making it safe to play with knives. Recently, three quantitative metrics of these structural chromosomal aberrations have been developed using single nucleotide polymorphism (SNP) array data. 3. Precision Medicine & Biosamples, AstraZeneca, Cambridge, UK. Vigil is an anticancer immuno-therapeutic. Liu JF, Konstantinopoulos PA, Matulonis UA. Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingam, AL, USA. Rebecca C. Arend: AstraZeneca, Clovis Oncology, GlaxoSmithKline, KIYATEC, Leap Therapeutics, Merck & Co, Sutro Biopharma, VBL Therapeutics (SAB), Caris Life Sciences (C/A); Jonathan F. Baden: Bristol Myers Squibb (E, OI), Johnson & Johnson (OI); Olena Barbash: GlaxoSmithKline (E); Lakshman Ramamurthy: GlaxoSmithKline (E); Nike Beaubier: Tempus Labs, Inc. (E); Jerod Parsons: Tempus Labs, Inc. (E); Tim French: AstraZeneca (E, OI); Petar Jelinic: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., (E, OI); Matthew J. Marton: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., (E, OI); Kimberly McGregor: Foundation Medicine (E), Roche (OI); Ethan S. Sokol: Foundation Medicine (E), Roche (OI); Mark Sausen: Bristol Myers Squibb (E, OI); Albrecht Stenzinger: Aignostics, AstraZeneca, AGCT, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, Thermo Fisher (SAB), Bayer, BMS, Chugai, Incyte (RF); Kirsten M. Timms: Myriad Genetics Inc. (E, OI); Diana Turco: Myriad Genetics Inc. (E, OI); J. Andrew Williams: AstraZeneca (E); Iris Wang: Novartis Pharmaceuticals Corporation (E, OI); Elaine Wong-Ho: Thermo Fisher Scientific (E). J Biol Chem. Similarly, Brca111/11; p53/ mouse mammary tumors, which only express the BRCA1-11 isoform (generated by the exon 11 splicing) can acquire resistance to cisplatin (149, 150) showing that some hypomorphic BRCA alleles, although unable to prevent tumor development, can affect response to therapy. Transl Oncol. Vigil vs. placebo shows benefit of RFS and OS (HR = 0.386, p = 0.007; HR = 0.342, p = 0.019). Defective DNA repair mechanisms in prostate cancer: impact of olaparib. A., J.F.B., O.B., N.B., T.F., N.G., P.H., P.J., M.J.M., K.M., J.P., L.R., M.S., E.S.S., A.S., H.S., K.M.T., D.T., I.W., J.A.W., E.W.-H., J.A. An official website of the United States government. Molecular Genetic Pathology Regional Laboratory, SCPMG Regional Reference Laboratories, Los Angeles, CA, USA. HOP2 in vitro shows two distinctive activities: when it is incorporated into a HOP2-MND1 complex it stimulates DMC1 and RAD51 recombination activities and the purified HOP2 alone is proficient . Ciccia A, Elledge SJ. V, Timms KM, Hennessy BT, et al. Defining HRD in terms of specific genetic mutations and/or the success of a PARPi may be a too narrow approach. Subtyping analysis of Fanconi anemia by immunoblotting and retroviral gene transfer. Pulsipher M, Kupfer GM, Naf D, Suliman A, Lee JS, Jakobs P, et al. Tim French, Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. L, Martens J, Van Hoeck A, et al. This review seeks to outline current strategies employed by clinicians and scientists to overcome PARPi resistance-either acquired or inherent to the tumor. Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. We learned from the VELIA trial that the assays, wherever we draw these lines, are really tricky. Independent Cancer Research Patient Advocate, Charlotte, NC, USA. These clinical features may be at least partly related to the high degree of genomic instability that is characteristic of BRCA1/2-mutated tumors. Ovarian cancer: is dose intensity dead? 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Zimmermann M, Lottersberger F, Buonomo SB, Sfeir A, de Lange T. 53BP1 regulates DSB repair using Rif1 to control 5 end resection. Poly (adp-ribose) polymerase inhibitors: recent advances and future development. Indeed, 2 out of 15, 4 out of 9 and 2 out of 15 correlated genes were identified as HR genes in 103 lung, 52 colorectal and 221 breast tumour samples, respectively. Functional ex vivo assay reveals homologous recombination deficiency in breast cancer beyond BRCA gene defects. TCGA. Not necessarily applicable for all PARPi and indications. Bethesda, MD 20894, Web Policies Furthermore, in the same study (146), reversal of BRCA1 promoter methylation has also been reported in one patient as a mechanism of platinum resistance. BRCA1/2 mutated tumors are also associated with higher grade (grade 2 or grade 3), poorly differentiated or undifferentiated tumors, higher stage (stage III or IV) at presentation, and serous histology (as opposed to endometrioid, clear cell or mucinous histologies)(23, 24, 42, 47). Z, Diossy M, Krzystanek M, et al. These genetic events were originally observed in BRCA2- and BRCA1-mutated cancer cells under selective pressure due to exposure to cisplatin or PARPis, and were associated with secondary genetic changes on the mutated allele that restored a functional protein and conferred platinum and PARPi resistance (Figure 4) (140143). The new PMC design is here! Recent demonstration of the efficacy of maintenance PARP inhibition in germline BRCA mutated pancreatic cancer has raised hopes that increased understanding of the DNA damage response pathway will lead to new therapies in both homologous recombination (HR) repair-deficient and proficient pancreatic cancer. Purpose: The vast majority of research studies that have described the links between DNA damage repair or homologous recombination deficiency (HRD) score, and tumor biology, have concerned either triple negative breast cancers or cancers with mutation of BRCA 1/2. Deubiquitination of FBP1 by USP7 blocks FBP1-DNMT1 interaction and decreases the sensitivity of pancreatic cancer cells to PARP inhibitors. PA, Spentzos D, Karlan BY, et al. King MC, Marks JH, Mandell JB. Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel. Fattah F, Lee EH, Weisensel N, Wang Y, Lichter N, Hendrickson EA. Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, et al. These scores have been implemented either alone or in combination with targeted sequencing approaches such as the BROCA assay to achieve better sensitivity in capturing HR deficiency (58). Ubiquitinated FANCD2 acts as a landing pad for recruiting several nucleases to coordinate nucleolytic incisions. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Ray-Coquard Unable to load your collection due to an error, Unable to load your delegates due to an error. Bradley Monk, MD, FACOG, FACS: I want our audience to notice, theyre like athletes; they have game faces. HHS Vulnerability Disclosure, Help
Studies have demonstrated the predictive value of assays to determine the HRD phenotype by evaluating response to platinum-based therapies and PARPi in the context of breast and ovarian cancer.4,14 Various multi-omic studies have investigated how a combination of the above patterns and additional genomic and transcriptomic signatures are associated with an HRD phenotype.5,34-36 A number of studies continue to evaluate genomic instability in breast and ovarian cancer as well as additional cancer types, which could lead to refinements in its use.28 Additional approaches, such as the detection of RAD51 foci, may enable a functional assessment of HR status after a cells exposure to a DNA damaging agent. Approximately 50% of EOCs exhibit defective DNA repair via HR and represent a distinct EOC subtype with unique clinical characteristics that have important implications for management. Konstantinopoulos PA, Spentzos D, Karlan BY, Taniguchi T, Fountzilas E, Francoeur N, et al. 2022 MJH Life Sciences and OncLive - Clinical Oncology News, Cancer Expert Insights. -, Li X, Heyer WD. Boboila C, Alt FW, Schwer B. We're going to spend a lot more effort thinking about what to do with these proficient patients, or the patients who had an HRD [homologous recombination deficient] scar who is no longer. Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Friends of Cancer Research, Washington, DC, USA. Genetic Pathology Regional Laboratory, SCPMG Regional Reference Laboratories, Los Angeles, CA, USA impact of.! Christie EL, Etemadmoghadam D, Khan S, et al these clinical features may be a too approach! Of ataxia telangiectasia mutated Carey MS, Gutin a, et al Regional Laboratories. Washington, DC, USA inhibitors: recent advances and future development human cancer risk F! 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