PURPOSE
Tumors with neomorphic mutations in IDH1/2 have defective homologous recombination repair, resulting in sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. The Olaparib Combination trial is a phase II, open-label study in which patients with solid tumors harboring IDH1/2 mutations were treated with olaparib as monotherapy, with objective response and clinical benefit rates as the primary end points.
METHODS
Ten patients with IDH1/2-mutant tumors by next-generation sequencing were treated with olaparib 300 mg twice daily.
RESULTS
Three of five patients with chondrosarcomas had clinical benefit, including one patient with a partial response and two with stable disease lasting > 7 months. A patient with pulmonary epithelioid hemangioendothelioma had stable disease lasting 11 months. In contrast, clinical benefit was not observed among four patients with cholangiocarcinoma.
CONCLUSION
These results indicate preliminary activity of PARP inhibition in patients with IDH1/2-mutant chondrosarcoma and pulmonary epithelioid hemangioendothelioma. Further studies of PARP inhibitors alone and in combination in this patient population are warranted.
INTRODUCTION
Mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1/2) have been identified in more than 80% of low-grade gliomas,1 approximately 50% of conventional chondrosarcomas2 and up to 30% of intrahepatic cholangiocarcinomas,3-6 and in a small percentage (< 5%) of other solid tumors.7 Normally, these enzymes catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in the citric acid cycle. Most IDH1/2 mutations are heterozygous missense mutations that confer a neomorphic activity on the encoded enzymes, converting α-KG to a novel product, (R)-2-hydroxyglutarate [(R)-2-HG].8 (R)-2-HG induces chromatin hypermethylation by inhibiting α-ketoglutarate (αKG)–dependent dioxygenases and is also thought to cause mitochondrial dysfunction.9
CONTEXT
Key Objective
Based on preclinical data indicating that IDH1/2 mutations result in homologous recombination repair deficiency and sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors in solid tumor models, we sought to determine, for the first time, the clinical efficacy of the PARP inhibitor olaparib for patients with IDH1/IDH2-mutant solid tumors.
Knowledge Generated
Among 10 patients with IDH1/IDH2-mutant solid tumors, clinical benefit was seen in four of six patients with mesenchymal sarcomas with one patient experiencing a partial response and three having prolonged stable disease. No clinical benefit was seen in four patients with IDH1/IDH2-mutant cholangiocarcinoma. No new safety signals were observed.
Relevance
Olaparib appears to be safe with preliminary evidence of efficacy in patients with IDH1/IDH2-mutant mesenchymal sarcomas; further prospective studies of PARP and other DNA damage repair inhibitors in this population are ongoing.
Recent work has shown that IDH1/2-mutant tumors inherently possess defective base excision repair and homologous recombination repair (HRR).10 At baseline, these tumors are deficient in NAD+, a necessary substrate for the activating autoribosylation of poly (ADP-ribose) polymerase (PARP), an enzyme involved in base excision repair and double-strand break repair. Without NAD+, PARP cannot recruit additional proteins critical for the execution of these DNA repair pathways.11 The accumulation of (R)-2-HG also results in defective HRR via the inhibition of two αKG-dependent dioxygenases, KDM4A and KDM4B. These histone lysine demethylases are directly implicated in the DNA damage response. Inhibition of KDM4A may result in recruitment of 53BP1 to sites of DNA damage,12 suppressing HRR; similarly, KDM4B also orchestrates recruitment of repair factors to sites of DNA damage so that its inhibition is also linked to impaired HRR.13 Finally, mutant IDH1 also downregulates expression of ataxia-telangiectasia mutated through altered histone methylation, contributing to altered DNA repair capacity (Fig 1).14
FIG 1.
(A) Patient 6360-020 metastatic chondrosarcoma (mutant IDH1). (B) Patient 6363-020 metastatic chondrosarcoma (mutant IDH1).
Consequently, IDH1/2-mutant tumors have been found to be sensitive to PARP inhibition, as demonstrated in multiple preclinical models, including patient-derived glioma cells and AML bone marrow cultures in vitro, and in genetically matched tumor xenografts.10,11 The HRR defect induced by IDH1/2 mutation results in sensitivity to PARP inhibition by a variety of mechanisms related to both catalytic inhibition of PARP1 and PARP trapping. Treatment with a small molecule IDH1/2 inhibitor reverses PARP inhibitor sensitivity in IDH1/2-mutant cells, whereas treatment with either 2HG enantiomer confers sensitivity in IDH1/2–wild-type cells. These findings demonstrate the critical role played by 2-HG in mediating PARP inhibitor sensitivity.10
The Olaparib Combination (OLAPCO) trial is a phase II, open-label study that assesses the value of PARP inhibition, alone and in combination with other DNA damage repair (DDR) inhibitors, in patients with tumors harboring deleterious HRR mutations, including mutations in IDH1/2, providing an opportunity to demonstrate whether the link between oncometabolites and altered DNA repair can be exploited therapeutically. We report here on the outcomes of patients treated on the olaparib monotherapy arm whose tumors had mutations in IDH1/2.
METHODS
Patients who were at least 18 years of age were eligible for enrollment if they had metastatic cancer (solid tumors, not including hematologic malignancies); disease that had progressed through standard first-line therapy (or had a tumor type for which no standard therapy existed); an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; at least one measurable lesion according to the RECIST, version 1.1; and tumor harboring a deleterious mutation affecting HRR, identified by testing of the most recent tumor biopsy in a Clinical Laboratory Improvement Amendments–certified laboratory. Next-generation sequencing was performed using the Dana Farber Oncopanel (447 genes), Oncomine (161 genes), SNaPshot (104 genes), Caris (592), and FoundationOne (324 genes) multigene sequencing platforms.
This study (Yale Human Protection Committee 1508016363) and the Informed Consent Form were approved by the Yale HPC, December 1, 2014, and approved at the participating institutions, Dana-Farber/Harvard Cancer Center, Vanderbilt-Ingram Cancer Center, and Cleveland Clinic before participation. The study has the clinicaltrials.gov identifier NCT02576444. The sponsor (AstraZeneca) Award number to Yale Cancer Center is 1508016363. The IRES number is 15-004200.
HRR mutations were determined to be deleterious as defined in reports in curated databases; ClinVar was used for germline mutations and the Catalogue of Somatic Mutations in Cancer was used for somatic mutations, which were allowed with evidence of loss of heterozygosity by variant allele frequency. Patients were excluded if they had a primary CNS malignancy, had active or untreated brain metastases, or had received previous PARP inhibitor therapy (for the olaparib monotherapy arm only). Full eligibility criteria included heart, liver, lung, and kidney function standard for phase II clinical trials. Patients needed a hemoglobin > 10 g/dL, an absolute neutrophil count > 1,500/µL, platelets > 100,000/µL, and no evidence of myelodysplasia on peripheral blood smear. Patients had an ECOG PS of 0-2 and full recovery from any previous therapy.
In the open-label, nonrandomized phase II OLAPCO program, patients were assigned to various treatment arms based on the HRR mutation present in their tumor. Patients with tumors harboring IDH1/2 mutations as their only actionable HRR mutation were treated with olaparib 300 mg PO twice a day.
Treatment was continued until radiographic progression, unacceptable toxicity, investigator decision, or patient withdrawal of consent. The use of granulocyte-macrophage colony-stimulating factor was permitted as needed. Additional details regarding the management of adverse events are available in the protocol.
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Assessment of tumor response was performed at 8-week intervals according to RECIST, version 1.1. Patients were followed for 30 days after end of treatment or until death and were contacted every 12 weeks by phone to assess survival.
The primary end point was overall response rate 16 weeks after starting study treatment, according to RECIST v1.1. Secondary end points included clinical benefit rate (CBR), defined as the proportion of patients with a complete response, partial response (PR), or stable disease (SD); progression-free survival (PFS); duration of response and duration of SD.
The study (ClinicalTrials.gov identifier: NCT02576444) was approved by the Yale HIC/Human Investigations Committee and by the Human Protection committees at the Dana-Farber Cancer Institute and the Vanderbilt-Ingram Cancer Center.
RESULTS
Ten patients whose tumors possessed a mutation in IDH1 or IDH2 were treated. Patient demographics are shown in Table 1. The median age was 59 (range 42-82). Half were female, and all patients were White. The median number of previous therapies was 1.5 (range 0-4). Histologies included cholangiocarcinoma (four patients), chondrosarcoma (five patients), and pulmonary epithelioid hemangioendothelioma (EHE) (one patient).
TABLE 1.
Patient Characteristics (Totally 10 Patients)
Two patients had tumors with IDH2 mutations; all other had IDH1-mutant tumors. Eight patients had tumors with IDH1/2 mutations known to be neomorphic, whereas two patients had tumors with an IDH1 and IDH2 mutation of undetermined significance, respectively (Table 2).
TABLE 2.
Patient Characteristics
One of ten patients (10%) had a PR lasting 14 months (Table 2). The CBR was 40% with a median duration of response of 10.5 months. The median PFS was 2 months. Three of eight patients with IDH1-mutated tumors had clinical benefit, whereas one of two patients with IDH2-mutated tumors had clinical benefit; of note, this patient’s tumor had a variant of unknown significance in IDH2.
Three of five patients with chondrosarcomas and the patient with EHE derived clinical benefit from olaparib (Table 2). A PR (59% tumor reduction for 14 months) was achieved in a 55-year-old patient with Maffucci Syndrome and IDH1-mutant chondrosarcoma. This patient had previously had surgery to resect or debulk six previous chondrosarcomas and developed metastatic disease in 2014, at which time her tumor was found to have an IDH1 R132C mutation. She was treated on two clinical trials of oral IDH inhibitors. She experienced SD for 4 months on a clinical trial of vorasidenib /AG-881. She also received AG-270, a methionine adenosyltransferase II alpha (MAT2A) inhibitor, with SD as the best response. She was then treated with nivolumab, which was complicated by transaminitis, necessitating discontinuation. Best response to olaparib was achieved at 10 cycles and maintained for 14 cycles. She developed new lung nodules at the time of her next restaging scan (after 16 cycles) and was taken off study therapy. Given her excellent response, we performed whole-exome sequencing (WES) on archival tumor to identify any additional factors that might have influenced the clinical outcome. Special attention, with read depth to 50,000, was given to mutations in BRCA1, BRCA2, and other HRR genes that might have contributed to the response, but none was found (Table 2).
Two additional patients with chondrosarcoma had SD as best response on olaparib. A 73-year-old man with chondrosarcoma metastatic to the lung harboring an IDH1 R132S mutation and PI3KR1 mutations had been previously treated with AG-270 for 24 months, with best response of SD before progression. He experienced a 16% regression by RECIST 1.1 after six cycles of treatment on olaparib. After eight cycles, olaparib was dose reduced for anemia and his disease progressed in a nonindex lung lesion after 10 cycles. A 47-year-old man who had previously undergone resection of a primary rib chondrosarcoma and metastectomy of a lung metastasis was found to have an IDH1 R132C mutation in his tumor without other mutations. He had SD on study for seven cycles and was taken off study when he was found to have 16% growth of target lesions in the midst of cycle 8. WES of archived tumor did not show any additional mutations.
A 64-year-old man with pulmonary EHE metastatic to the liver was treated with olaparib and had SD for 10 cycles before developing progressive hepatic disease. His tumor was diagnosed by IHC (CD31, factor VIII and diffuse, strong ERG nuclear staining).15 Notably, his tumor had an IDH2 V305M mutation not previously described as causing HRR deficiency. He had previously been treated only with pazopanib for 1 month, which had induced transaminitis. No significant additional DNA mutations were found.
Two patients with chondrosarcoma did not achieve clinical benefit at 16 weeks. One was a 57-year-old woman with IDH1 R132C–mutant chondrosarcoma who had undergone multiple resections and had most recently received cyclophosphamide and sirolimus with disease progression after 6 months. Her first scan showed SD (+8%) after two cycles after which she withdrew consent. Finally, a 42-year-old man with Ollier Disease and metastatic IDH1 R132C–mutant chondrosarcoma whose disease had not responded to cisplatin and adriamycin developed disease progression (+21%) after two cycles and discontinued treatment. Profiling of his tumor using the Oncomine platform did not reveal any additional mutations.
None of the four patients with IDH1/2-mutant cholangiocarcinoma derived clinical benefit from olaparib. However, one harbored an IDH1 R13F mutation not known to induce HDR deficiency. In all four cases, tumor molecular profiling demonstrated multiple other mutations, including those in chromatin modulators or putative signal transduction drivers (Table 2).
Safety
No unexpected or unacceptable toxicities were observed. Two patients required dose reductions for a second episode of grade 2 anemia; no other treatment-related adverse events occurred.
DISCUSSION
The OLAPCO trial was designed to test the hypothesis that PARP inhibition as monotherapy or in combination with targeted agents could be used for therapeutic intervention in patients with cancer with mutations in genes directly involved in HRR or affecting HRR proficiency as a basket design analogous to trials conducted specifically for oncogenic driver mutations. We report here on clinical outcomes of 10 patients with IDH1/2-mutant tumors who were treated with olaparib monotherapy. Preclinical data generated independently by two groups of investigators have demonstrated a BRCA loss phenotype among IDH1/2-mutant tumors that renders them susceptible to PARP inhibition.10,11 In this study, we identified a protocol-defined CBR (PR or SD > 16 weeks) of 33.3% with particular activity in patients with IDH1-mutant sarcomas (CBR 66.7%).
There was marked difference in sensitivity to olaparib treatment between the sarcomas and the GI carcinoma type evaluated here. None of the four patients with cholangiocarcinoma responded, although one patient possessed an IDH1 mutation not known to produce 2-HG, the oncometabolite conferring HRR deficiency. In contrast, four of six patients with sarcomas (including three chondrosarcomas and one pulmonary hemangioendothelioma) achieved either PR or prolonged SD.
The reasons for this discrepancy are unclear. Sarcomas typically have fewer genetic mutations than carcinomas, so it is possible that mutated IDH1/2 functions as a dominant driver in these tumors rather than as one of the several contributing mutations seen in cholangiocarcinomas. WES and Oncomine sequencing of three patients with chondrosarcoma did not reveal any additional mutations beyond those in IDH1. However, limited data suggest that the tumor mutation burden of cholangiocarcinoma is also low,16 especially in patients with actionable mutations such as those in IDH1/2.17 Chondrosarcomas have a varying natural progression, including slower growth in patients with IDH1/2 mutations.18 Although outcomes can vary by histologic subtype, median PFS after anthracycline-based cytotoxic chemotherapy is 4-5 months, so that in addition to the PR observed, the durability of SD achieved here suggests promise.
Tumors with HRR defects demonstrate a high mutation rate and clonal evolution, which might be accelerated by selection pressures induced by anticancer therapies including inhibitors of DDR.19 Therefore, relying on a mutational profile or a composite homologous recombination deficiency score from a patient’s primary tumor may miss the emergence of compensatory genomic or transcriptional alterations that restore HRR and induce resistance to inhibitors of DNA repair such as olaparib.20,21 This may be less of an issue for chondrosarcomas, as these tumors are frequently less heavily pretreated and not challenged with platinum-based chemotherapy. In contrast, cholangiocarcinomas and colorectal cancers are typically treated with such regimens, and this previous exposure might have changed the status of HRR deficiency before olaparib treatment. In this regard, a pretreatment biopsy performed immediately before DDR inhibitor treatment and subjected to WES RNA-seq and a functional assay for HRR may serve to best identify patients with IDH1/2-mutant tumors where HRR deficiency is preserved and likely to respond to PARP inhibitor monotherapy. A promising functional assay is the detection of RAD51 foci, the presence of which indicates restored HR. RAD51 foci may be detected either by immunofluorescence or by immunohistochemistry even in tumor samples not subjected to exogenous DNA damage.22-24
Based on the scientific rationale and these early results, a clinical trial of olaparib monotherapy in IDH1/2-mutant tumors has been initiated (ClinicalTrials.gov identifier: NCT03212274), incorporating pretreatment biopsies for WES, RNA-seq, and assessment of RAD51 foci. This trial will evaluate patients with IDH1/2-mutant cholangiocarcinomas and those with glioblastoma and other tumor types (ie, chondrosarcomas). Additionally, for each tumor type, patients who have received an IDH inhibitor and those who are IDH inhibitor–naïve will be enrolled. Additionally, a study of the combination of olaparib and AZD6738, an ataxia-telangiectasia and Rad3-related (ATR) inhibitor, is underway in IDH1/2mt cholangiocarcinomas and other solid tumors (ClinicalTrials.gov identifier: NCT03878095). Both studies use biopsy specimens to evaluate tumors for functional evidence of HRR as described above. Based on our findings, a study of PARP inhibition limited to patients with chondrosarcomas may also be warranted. Using rigorous correlative science, these studies may further elucidate which patients are most likely to benefit from a DNA repair–based approach for their IDH1/2-mutated cancers.
SUPPORT
Supported by AstraZeneca grant to Yale Cancer Center. Also supported by Cancer Center Support Grants P30 CA016359 and P30 CA006516 to Yale Cancer Center and Dana-Farber/Harvard Cancer Center, respectively.
AUTHOR CONTRIBUTIONS
Conception and design: Joseph P. Eder, Jeffrey S. Sklar, Peter Glazer, Ranjit Bindra, Geoffrey I. Shapiro
Provision of study materials or patients: Geoffrey I. Shapiro
Collection and assembly of data: Joseph P. Eder, Deborah B. Doroshow, Khanh T. Do, Vicki L. Keedy, Jeffrey S. Sklar, Geoffrey I. Shapiro
Data analysis and interpretation: Joseph P. Eder, Deborah B. Doroshow, Khanh T. Do, Jeffrey S. Sklar, Ranjit Bindra, Geoffrey I. Shapiro
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Joseph P. Eder
Consulting or Advisory Role: Roche/Genentech
Deborah B. Doroshow
Consulting or Advisory Role: Ipsen, Atheneum, Boston Healthcare Associates, Dedham Group, Guidepoint Global
Research Funding: Janssen Oncology, Dendreon, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca, Genentech/Roche
Travel, Accommodations, Expenses: Ipsen
Khanh T. Do
Consulting or Advisory Role: Seattle Genetics, Jackson Laboratory for Genomic Medicine, QED Therapeutics
Research Funding: Lilly
Vicki L. Keedy
Consulting or Advisory Role: Karyopharm Therapeutics
Research Funding: MedPacto, Plexxikon, Daiichi Sankyo, Lilly, Immune Design, GlaxoSmithKline, TRACON Pharma, Advenchen Laboratories, Adaptimmune, Deciphera, SpringWorks Therapeutics
Jeffrey S. Sklar
Stock and Other Ownership Interests: Precipio
Research Funding: Jilin Zixin
Peter Glazer
Employment: Cybrexa Therapeutics, Phlip
Stock and Other Ownership Interests: Cybrexa Therapeutics
Consulting or Advisory Role: Cybrexa Therapeutics, Trucode, Phlip
Patents, Royalties, Other Intellectual Property: Patents related to gene editing and gene therapy via peptide nucleic acids. Patents related to oncometabolites and DNA repair for cancer therapy. Patents related to antibody-mediated cancer therapy
Ranjit Bindra
Leadership: Cybrexa Therapeutics, Athena Therapeutics
Stock and Other Ownership Interests: Cybrexa Therapeutics, Athena Therapeutics
Consulting or Advisory Role: Cybrexa Therapeutics, Novocure, Syros Pharmaceuticals, Third Bridge Group
Research Funding: Cybrexa Therapeutics
Patents, Royalties, Other Intellectual Property: Patent filed on PPM1D as a biomarker NAMPTi sensitivity. Patent filed on use of IDH1/2 as a biomarker for PARPi sensitivity
Geoffrey I. Shapiro
Consulting or Advisory Role: G1 Therapeutics, Lilly, Pfizer, Roche, Merck Serono, Sierra Oncology, Cybrexa Therapeutics, Ipsen, Bayer, Fusion Pharmaceuticals, Bicycle Therapeutics, Almac Diagnostics, Astex Pharmaceuticals, Daiichi Sankyo, Angiex, Seattle Genetics, Artios, Boehringer Ingelheim, Concarlo, Atrin Pharmaceuticals, Syros Pharmaceuticals, Zentalis
Research Funding: Pfizer, Genentech, Bayer, Immune Design, Vertex, Millennium, Puma Biotechnology, Tensha Therapeutics, Covidien, Novartis, Cellceutix, Sanofi, Cyclacel, Mirati Therapeutics, AstraZeneca, GlaxoSmithKline, Lilly, Aileron Therapeutics, PharmaMar, PTC Therapeutics, Roche, CanBas, Tesaro, Merck Serono, Sierra Oncology, Syros Pharmaceuticals, Curis, Merck, Array BioPharma, Seattle Genetics, Clovis Oncology, Exelixis, Boehringer Ingelheim, Esperas Pharma, Amgen, Bristol-Myers Squibb
Patents, Royalties, Other Intellectual Property: Patent #: 9872874, Title: Dosage regimen for sapacitabine and seliciclib, Issue Date: January 23, 2018, Provisional. Patent #: 62/538,319, Title: Compositions and methods for predicting response and resistance to CDK4/6 inhibition, Filed: July 28, 2017
Travel, Accommodations, Expenses: Lilly, Pfizer, Bicycle Therapeutics, G1 Therapeutics, Sierra Oncology, Bayer
No other potential conflicts of interest were reported.
REFERENCES
- 1.Suzuki H, Aoki K, Chiba K, et al. : Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 47:458-468, 2015 [DOI] [PubMed] [Google Scholar]
- 2.Meijer D, de Jong D, Pansuriya TC, et al. : Genetic characterization of mesenchymal, clear cell, and dedifferentiated chondrosarcoma. Genes Chromosomes Cancer 51:899-909, 2012 [DOI] [PubMed] [Google Scholar]
- 3.Wang P, Dong Q, Zhang C, et al. : Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 32:3091-3100, 2013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Borger DR, Tanabe KK, Fan KC, et al. : Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 17:72-79, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Goyal L, Govindan A, Sheth RA, et al. : Prognosis and clinicopathologic features of patients with advanced stage isocitrate dehydrogenase (IDH) mutant and IDH wild-type intrahepatic cholangiocarcinoma. Oncologist 20:1019-1027, 2015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Lowery MA, Ptashkin R, Jordan E, et al. : Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: Potential targets for intervention. Clin Cancer Res 24:4154-4161, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Clark O, Yen K, Mellinghoff IK: Molecular pathways: Isocitrate dehydrogenase mutations in cancer. Clin Cancer Res 22:1837-1842, 2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Dang L, White DW, Gross S, et al. : Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739-744, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Losman JA, Kaelin WG Jr: What a difference a hydroxyl makes: Mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 27:836-852, 2013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sulkowski PL, Corso CD, Robinson ND, et al. : 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med 9:eaal2463, 2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Lu Y, Kwintkiewicz J, Liu Y, et al. : Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP1-mediated DNA repair. Cancer Res 77:1709-1718, 2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Mallette FA, Mattiroli F, Cui G, et al. : RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. EMBO J 31:1865-1878, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Young LC, McDonald DW, Hendzel MJ: Kdm4b histone demethylase is a DNA damage response protein and confers a survival advantage following gamma-irradiation. J Biol Chem 288:21376-21388, 2013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Inoue S, Li WY, Tseng A, et al. : Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell 30:337-348, 2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Miettinen M, Wang ZF, Paetau A, et al. : ERG transcription factor as an immunohistochemical marker for vascular endothelial tumors and prostatic carcinoma. Am J Surg Pathol 35:432-441, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Thota R, Christensen B, Fulde G, et al. : Characterization of the tumor mutation burden in hepatobiliary tumors. J Clin Oncol 37, 2019. (suppl; abstr 295) [Google Scholar]
- 17.Silverman IM, Murugesan K, Lihou CF, et al. : Comprehensive genomic profiling in FIGHT-202 reveals the landscape of actionable alterations in advanced cholangiocarcinoma. J Clin Oncol 37, 2019. (suppl; abstr 4080) [Google Scholar]
- 18.Zhu GG, Nafa K, Agaram N, et al. : Genomic profiling identifies association of IDH1/IDH2 mutation with longer relapse-free and metastasis-free survival in high-grade chondrosarcoma. Clin Cancer Res 26:419-427, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.D'Andrea AD: Mechanisms of PARP inhibitor sensitivity and resistance. DNA Repair (Amst) 71:172-176, 2018 [DOI] [PubMed] [Google Scholar]
- 20.Helleday T, Eshtad S, Nik-Zainal S: Mechanisms underlying mutational signatures in human cancers. Nat Rev Genet 15:585-598, 2014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Telli ML, Timms KM, Reid J, et al. : Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 22:3764-3773, 2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. : Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly (ADP-ribose) polymerase inhibitors. Clin Cancer Res 16:2344-2351, 2010 [DOI] [PubMed] [Google Scholar]
- 23.Castroviejo-Bermejo M, Cruz C, Llop-Guevara A, et al. : A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation. EMBO Mol Med 10:e9172, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Waks AG, Cohen O, Kochupurakkal B, et al. : Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer. Ann Oncol 31:590-598, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]