Controversies in oncology: are genomic tests quantifying homologous recombination repair deficiency (HRD) useful for treatment decision making? (2019)

Mechanisms that protect DNA are crucial to preserve the genome integrity from injuries produced by environmental agents or those spontaneously generated during DNA metabolism.1.Roy R. Chun J. Powell S.N. BRCA1 and BRCA2: important differences with common interests.Nat Rev Cancer. 2012; 12: 372doi:10.1038/nrc3181-c3Crossref Scopus (10) Google Scholar DNA single-strand breaks (SSBs) are repaired by mismatch repair (MMR), base excision repair (BER) and nucleotide excision repair (NER).1.Roy R. Chun J. Powell S.N. BRCA1 and BRCA2: important differences with common interests.Nat Rev Cancer. 2012; 12: 372doi:10.1038/nrc3181-c3Crossref Scopus (10) Google Scholar Non-homologous end joining (NHEJ) or homologous recombination repair (HRR) processes double-strand breaks (DSBs).1.Roy R. Chun J. Powell S.N. BRCA1 and BRCA2: important differences with common interests.Nat Rev Cancer. 2012; 12: 372doi:10.1038/nrc3181-c3Crossref Scopus (10) Google Scholar While NHEJ solves DSBs in a potentially inaccurate way, HRR is an error-free pathway that restores the genomic sequence of the broken DNA ends by using the sister chromatid as template for repair.1.Roy R. Chun J. Powell S.N. BRCA1 and BRCA2: important differences with common interests.Nat Rev Cancer. 2012; 12: 372doi:10.1038/nrc3181-c3Crossref Scopus (10) Google Scholar Several proteins are involved in the HRR pathway: some of them act as sensors of DSBs such as γH2AX, ATM and ATR, leading to the activation of signal mediator proteins (ie, BRCA1, BRCA2 and PALB2). The final event of the HRR pathway is the loading of a small nuclear protein called RAD51 onto single-stranded DNA, where it promotes strand invasion and replication fork stabilisation (figure 1).2.Murai J. Huang S-yin N. Das B.B. et al.Trapping of PARP1 and PARP2 by clinical PARP inhibitors.Cancer Res. 2012; 72: 5588-5599doi:10.1158/0008-5472.CAN-12-2753Crossref PubMed Scopus (1337) Google Scholar Tumours with HRR deficiency (HRD) were described for the first time in cancers that harbour germline mutations of the tumour suppressors BRCA1 and BRCA2 (BRCA1/2).3.Hoppe M.M. Sundar R. Tan D.S.P. et al.Biomarkers for homologous recombination deficiency in cancer.J Natl Cancer Inst. 2018; 110: 704-713doi:10.1093/jnci/djy085Crossref PubMed Scopus (164) Google Scholar Nonetheless, genetic and epigenetic events can also result in inactivation of other HRR components, leading to HRD in sporadic cancers.3.Hoppe M.M. Sundar R. Tan D.S.P. et al.Biomarkers for homologous recombination deficiency in cancer.J Natl Cancer Inst. 2018; 110: 704-713doi:10.1093/jnci/djy085Crossref PubMed Scopus (164) Google Scholar HRD is harboured by approximately 13% and 15% of ovarian and triple negative breast cancers (TNBC), respectively, and it is attributable to germline BRCA1/2 (gBRCA1/2) mutations.4.Bell D. Berchuck A. Birrer M. et al.Integrated genomic analyses of ovarian carcinoma.Nature. 2011; 474: 609-615doi:10.1038/nature10166Crossref PubMed Scopus (5385) Google Scholar, 5.Akashi-Tanaka S. Watanabe C. Takamaru T. et al.BRCAness predicts resistance to taxane-containing regimens in triple negative breast cancer during neoadjuvant chemotherapy.Clin Breast Cancer. 2015; 15: 80-85doi:10.1016/j.clbc.2014.08.003Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Furthermore, 50% and 40% of ovarian and TNBC, respectively, are characterised by harbouring HRD in the absence of gBRCA1/2 mutations.4.Bell D. Berchuck A. Birrer M. et al.Integrated genomic analyses of ovarian carcinoma.Nature. 2011; 474: 609-615doi:10.1038/nature10166Crossref PubMed Scopus (5385) Google Scholar, 6.Loibl S. Weber K.E. Timms K.M. et al.Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto.Ann Oncol. 2018; 29: 2341-2347doi:10.1093/annonc/mdy460Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar Also, 10%–12% of advanced prostate cancer harbour germline or somatic BRCA2 inactivation and up to 25% contain a DNA repair defect.7.Robinson D. Van Allen E.M. Wu Y.-M. et al.Integrative clinical genomics of advanced prostate cancer.Cell. 2015; 161: 1215-1228doi:10.1016/j.cell.2015.05.001Abstract Full Text Full Text PDF PubMed Scopus (1993) Google Scholar As HRR is required for the repair of DSBs generated during DNA interstrand cross-link (ICL) resolution, HRR-deficient tumours are sensitive to ICL-generating platinum chemotherapy.3.Hoppe M.M. Sundar R. Tan D.S.P. et al.Biomarkers for homologous recombination deficiency in cancer.J Natl Cancer Inst. 2018; 110: 704-713doi:10.1093/jnci/djy085Crossref PubMed Scopus (164) Google Scholar, 8.Heeke A.L. Baker T. Lynce F. et al.Prevalence of homologous recombination deficiency among all tumor types.JCO. 2017; 35: 1502doi:10.1200/JCO.2017.35.15_suppl.1502Crossref Google Scholar Moreover, BRCA1/2-mutant cells are sensitive to PARP inhibitors (PARPi), a new class of drugs that block SSB repair, favouring accumulation of DSB that HRR-deficient cells cannot repair.9.O'Connor M.J. Targeting the DNA damage response in cancer.Mol Cell. 2015; 60: 547-560doi:10.1016/j.molcel.2015.10.040Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar PARPi also trap PARP onto DNA causing replication stress that is toxic in these cells.9.O'Connor M.J. Targeting the DNA damage response in cancer.Mol Cell. 2015; 60: 547-560doi:10.1016/j.molcel.2015.10.040Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar Several PARPi have been approved for the treatment of ovarian and breast cancers.10.Ledermann J.A. Harter P. Gourley C. et al.Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial.Lancet Oncol. 2016; 17: 1579-1589doi:10.1016/S1470-2045(16)30376-XAbstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 11.Mirza M.R. Monk B.J. Herrstedt J. et al.Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.N Engl J Med. 2016; 375: 2154-2164doi:10.1056/NEJMoa1611310Crossref PubMed Scopus (1472) Google Scholar, 12.Swisher E.M. Lin K.K. Oza A.M. et al.Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial.Lancet Oncol. 2017; 18: 75-87doi:10.1016/S1470-2045(16)30559-9Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar, 13.Robson M. Im S.-A. Senkus E. et al.Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.N Engl J Med. 2017; 377: 523-533doi:10.1056/NEJMoa1706450Crossref PubMed Scopus (1635) Google Scholar, 14.Litton J.K. Rugo H.S. Ettl J. et al.Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.N Engl J Med. 2018; 379: 753-763doi:10.1056/NEJMoa1802905Crossref PubMed Scopus (996) Google Scholar EMA approved olaparib and rucaparib as maintenance treatments for platinum-sensitive ovarian cancer with germline/somatic BRCA1/2-mutation; and niraparib was labelled as maintenance treatment for patients who are in response to platinum-based chemotherapy.10.Ledermann J.A. Harter P. Gourley C. et al.Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial.Lancet Oncol. 2016; 17: 1579-1589doi:10.1016/S1470-2045(16)30376-XAbstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 12.Swisher E.M. Lin K.K. Oza A.M. et al.Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial.Lancet Oncol. 2017; 18: 75-87doi:10.1016/S1470-2045(16)30559-9Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar, 15.European Medicines Agency. Available: https://www.ema.europa.eu/medicines/human/Google Scholar Olaparib and talazoparib have been approved for patients with advanced breast cancer and a gBRCA1/2 mutations who have previously been treated with chemotherapy.13.Robson M. Im S.-A. Senkus E. et al.Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.N Engl J Med. 2017; 377: 523-533doi:10.1056/NEJMoa1706450Crossref PubMed Scopus (1635) Google Scholar, 14.Litton J.K. Rugo H.S. Ettl J. et al.Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.N Engl J Med. 2018; 379: 753-763doi:10.1056/NEJMoa1802905Crossref PubMed Scopus (996) Google Scholar, 15.European Medicines Agency. Available: https://www.ema.europa.eu/medicines/human/Google Scholar The current clinical challenge is the identification of BRCA1/2 wild type (WT) patients who harbour alterations in the HRR pathway and share molecular features of BRCA1/2-mutated tumours (the so-called 'BRCAness' phenotype) and who may also benefit from similar therapeutic approaches.16.Lord C.J. Ashworth A. BRCAness revisited.Nat Rev Cancer. 2016; 16: 110-120doi:10.1038/nrc.2015.21Crossref PubMed Scopus (765) Google Scholar Different approaches are currently being investigated to identify BRCA1/2 WT tumours that can benefit from DNA-damaging agents and PARPi based on the presence of HRD, that is, (1) scores capturing large genomic aberrations, so-called 'genomic scars', (2) analysis of mutational signatures or (3) point mutations identified in HRR genes using DNA sequencing panels.9.O'Connor M.J. Targeting the DNA damage response in cancer.Mol Cell. 2015; 60: 547-560doi:10.1016/j.molcel.2015.10.040Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar, 17.Watkins J.A. Irshad S. Grigoriadis A. et al.Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers.Breast Cancer Res. 2014; 16doi:10.1186/bcr3670Crossref Scopus (207) Google Scholar, 18.Hodgson D.R. Dougherty B. Lai Z. et al.435 candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes.European Journal of Cancer. 2015; 51doi:10.1016/S0959-8049(16)30269-6Abstract Full Text PDF Google Scholar, 19.Abkevich V. Timms K.M. Hennessy B.T. et al.Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.Br J Cancer. 2012; 107: 1776-1782doi:10.1038/bjc.2012.451Crossref PubMed Scopus (434) Google Scholar In BRCA1/2-mutant cells, chromosomal spreads reveal increased gross chromosomal rearrangements. This led to the development of assays to evaluate the 'genomic scars' caused by the loss of HRR function using SNP array data.3.Hoppe M.M. Sundar R. Tan D.S.P. et al.Biomarkers for homologous recombination deficiency in cancer.J Natl Cancer Inst. 2018; 110: 704-713doi:10.1093/jnci/djy085Crossref PubMed Scopus (164) Google Scholar Two commercial genomic scar assays have been tested to identify tumours with HRD in clinical trials. The 'myChoice HRD' assay by Myriad tests for the presence of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) across the genome.17.Watkins J.A. Irshad S. Grigoriadis A. et al.Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers.Breast Cancer Res. 2014; 16doi:10.1186/bcr3670Crossref Scopus (207) Google Scholar The readout of this assay is presented as an 'HRD score': a tumour with an HRD score ≥42 is labelled as HRD-positive. The 'FoundationFocus CDx BRCALOH' is designed to detect the presence of mutations in the BRCA1/2 genes and the percentage of the genome affected by LOH in DNA from tumour tissue samples of patients with ovarian cancer.20.Coleman R.L. Oza A.M. Lorusso D. et al.Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.The Lancet. 2017; 390: 1949-1961doi:10.1016/S0140-6736(17)32440-6Abstract Full Text Full Text PDF PubMed Scopus (955) Google Scholar According to the FoundationFocus test, tumours are categorised as LOH-high if score is ≥16. On the other hand, mutational signatures are characteristic patterns left on the cancer genome by each mutational process: for example, HRD has been associated with the 'signature 3' described by Alexandrov et al.21.Helleday T. Eshtad S. Nik-Zainal S. Mechanisms underlying mutational signatures in human cancers.Nat Rev Genet. 2014; 15: 585-598doi:10.1038/nrg3729Crossref PubMed Scopus (522) Google Scholar, 22.Alexandrov L.B. Nik-Zainal S. Wedge D.C. et al.Signatures of mutational processes in human cancer.Nature. 2013; 500: 415-421doi:10.1038/nature12477Crossref PubMed Scopus (6216) Google Scholar, 23.Peng G. Chun-Jen Lin C. Mo W. et al.Genome-wide transcriptome profiling of homologous recombination DNA repair.Nat Commun. 2014; 5doi:10.1038/ncomms4361Crossref Scopus (149) Google Scholar 'Signature 3' is also able to accurately classify missense BRCA1/2 mutations with known functional implications and it is associated with silencing of RAD51C and BRCA1 by promoter methylation.24.Polak P. Kim J. Braunstein L.Z. et al.A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer.Nat Genet. 2017; 49: 1476-1486doi:10.1038/ng.3934Crossref PubMed Scopus (294) Google Scholar So, what is the current clinical evidence around the use of genomics scars to quantify HRD and its impact on treatment decision-making? The main open question is whether genomic scars are predictive biomarkers of response to platinum salts or PARPi, beyond BRCA1/2 mutation. In advanced ovarian cancer, the ARIEL2 study demonstrated the efficacy of the PARPi rucaparib as monotherapy in gBRCA1/2 mutated and/or LOH-high relapsed, platinum-sensitive ovarian cancer, and the ARIEL3 trial demonstrated the benefit of rucaparib as maintenance therapy in platinum-sensitive recurrent patients who responded to platinum, regardless of the LOH status (table 1).12.Swisher E.M. Lin K.K. Oza A.M. et al.Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial.Lancet Oncol. 2017; 18: 75-87doi:10.1016/S1470-2045(16)30559-9Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar, 20.Coleman R.L. Oza A.M. Lorusso D. et al.Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.The Lancet. 2017; 390: 1949-1961doi:10.1016/S0140-6736(17)32440-6Abstract Full Text Full Text PDF PubMed Scopus (955) Google Scholar The NOVA trial investigated the role of the PARPi niraparib as maintenance therapy in platinum-sensitive ovarian cancer and showed that patients with BRCA1/2 mutations or HRD-positive according to myChoice assay benefited from PARPi.11.Mirza M.R. Monk B.J. Herrstedt J. et al.Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.N Engl J Med. 2016; 375: 2154-2164doi:10.1056/NEJMoa1611310Crossref PubMed Scopus (1472) Google Scholar Nevertheless, niraparib also improved PFS in BRCA1/2 WT patients with an HRD-negative test, although the magnitude of the benefit was smaller compared to BRCA1/2-mutated or HRD-positive patients (table 1).11.Mirza M.R. Monk B.J. Herrstedt J. et al.Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.N Engl J Med. 2016; 375: 2154-2164doi:10.1056/NEJMoa1611310Crossref PubMed Scopus (1472) Google Scholar From these trials, one may conclude that in the platinum-sensitive population the HRD-genomic scars provide information regarding the magnitude of the clinical benefit, given the high probability of response after platinum sensitivity. Indeed, the magnitude of the benefit is higher among those who are HRD-positive or BRCA1/2-mutated. Most importantly, in the ovarian population, further investigations are needed to verify if an HRD test may be useful to select platinum-resistant tumours that may benefit from PARPi or to identify long responders to PARPi and/or platinum salts.Table 1Efficacy of PARPi according to HRD status in ovarian cancerClinical trialDrugStudy populationHRD roleARIEL-212.Swisher E.M. Lin K.K. Oza A.M. et al.Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial.Lancet Oncol. 2017; 18: 75-87doi:10.1016/S1470-2045(16)30559-9Abstract Full Text Full Text PDF PubMed Scopus (779) Google ScholarRucaparib, monotherapyRelapsed, platinum-sensitive ovarian cancerHigher efficacy in gBRCA1/2-mutated and/or LOH-high compared with LOH-low tumours. Not powered to show a difference between LOH-high and LOH-low tumoursARIEL-320.Coleman R.L. Oza A.M. Lorusso D. et al.Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.The Lancet. 2017; 390: 1949-1961doi:10.1016/S0140-6736(17)32440-6Abstract Full Text Full Text PDF PubMed Scopus (955) Google ScholarRucaparib, maintenance therapyRelapsed, platinum-sensitive ovarian cancerEfficacy regardless of LOH-status. Magnitude of the benefit dependent on LOHNOVA-trial11.Mirza M.R. Monk B.J. Herrstedt J. et al.Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.N Engl J Med. 2016; 375: 2154-2164doi:10.1056/NEJMoa1611310Crossref PubMed Scopus (1472) Google ScholarNiraparib, maintenance therapyRelapsed, platinum-sensitive ovarian cancerEfficacy regardless of HRD-status. Magnitude of the benefit dependent on HRDHRD, homologous recombination repair deficiency; LOH, loss of heterozygosity; PARPi, PARP inhibitors . Open table in a new tab HRD, homologous recombination repair deficiency; LOH, loss of heterozygosity; PARPi, PARP inhibitors . In TNBC, several trials have investigated if HRD-genomic scars predict response to DNA-damaging agents or to the addition of carboplatin to standard chemotherapy beyond BRCA1/2 mutation (table 2). In the neoadjuvant setting, Telli et al retrospectively assessed the predictive value of the 'myChoice HRD' assay in three single-arm trials testing platinum-based therapy.25.Telli M.L. Timms K.M. 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. 2016; 22: 3764-3773doi:10.1158/1078-0432.CCR-15-2477Crossref PubMed Scopus (496) Google Scholar Patients who were HRD-positive had a higher probability to achieve a complete pathological response or minimal residual disease (RCB 0-I) after platinum chemotherapy, even among BRCA1/2 WT tumours.25.Telli M.L. Timms K.M. 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. 2016; 22: 3764-3773doi:10.1158/1078-0432.CCR-15-2477Crossref PubMed Scopus (496) Google Scholar The GeparSixto trial evaluated the benefit of the addition of carboplatin to anthracycline/taxane-based neoadjuvant chemotherapy in TNBC and analysed the predictive and prognostic value of testing for HRD by the composite biomarker including germline/somatic BRCA1/2 mutations and the 'myChoice' assay.6.Loibl S. Weber K.E. Timms K.M. et al.Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto.Ann Oncol. 2018; 29: 2341-2347doi:10.1093/annonc/mdy460Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar Among all patients with TNBC, addition of carboplatin resulted in a marked increment in pCR rates in HRD-positive tumours (from 33.9 to 63.5%, P=0.001), and in HRD-negative tumours (from 20 to 29.6%, P=0.399). However, according to the test of interaction, HRD did not predict for carboplatin benefit in this study. Of note, the control arm in this trial lacked cyclophosphamide, which might have overestimated the carboplatin benefit. Other observations regarding the prognostic value of HRD genomic scars will require a powered study to demonstrate the improvement in disease-free survival (DFS) or overall survival (OS). Litton et al have recently showed the efficacy of PARPi talazoparib in the neoadjuvant setting in patients with BRCA1/2 mutations. In this setting, an HRD test could be useful to identify patients with BRCA1/2 WT who can also benefit from PARPi.26.Litton J.K. Scoggins M. Hess K.R. et al.Neoadjuvant talazoparib (TALA) for operable breast cancer patients with a BRCA mutation (BRCA+).JCO. 2018; 36: 508doi:10.1200/JCO.2018.36.15_suppl.508Crossref Google Scholar Finally, in the adjuvant setting, Sharma et al evaluated the predictive role of the 'myChoice HRD' in TNBC to predict outcome of adjuvant anthracycline and cyclophosphamide regimen.27.Sharma P. Barlow W.E. Godwin A.K. et al.Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with adjuvant doxorubicin and cyclophosphamide (SWOG S9313).Ann Oncol. 2018; 29: 654-660doi:10.1093/annonc/mdx821Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar The study showed a better DFS in patients with high HRD, even beyond gBRCA1/2 status.Table 2Efficacy of platinums or DNA-damaging chemotherapy according to HRD status in breast cancerClinical trialDrugStudy populationHRD rolePrECOG 0105Cisplatin-1 trialCisplatin-2 trial51.Telli M.L. Jensen K.C. Vinayak S. et al.Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1 / 2 Mutation–Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105.JCO. 2015; 33: 1895-1901doi:10.1200/JCO.2014.57.0085Crossref PubMed Scopus (182) Google ScholarPlatinum saltsNeoadjuvant TNBCPatients who were HRD-positive had higher complete pathological responseGepar-Sixto trial6.Loibl S. Weber K.E. Timms K.M. et al.Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto.Ann Oncol. 2018; 29: 2341-2347doi:10.1093/annonc/mdy460Abstract Full Text Full Text PDF PubMed Scopus (145) Google ScholarCarboplatinNeoadjuvant TNBCPatients who were HRD-positive had a better prognosis compared with regarding the predictive role of HRD for addition of P. Barlow W.E. Godwin A.K. et al.Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with adjuvant doxorubicin and cyclophosphamide (SWOG S9313).Ann Oncol. 2018; 29: 654-660doi:10.1093/annonc/mdx821Abstract Full Text Full Text PDF PubMed Scopus (53) Google and TNBCPatients who were HRD-positive had a better even beyond gBRCA1/2 et a phase II clinical trial of platinum monotherapy with biomarker in triple-negative breast 2015; 33: PubMed Scopus Google ScholarPlatinum first or HRD scores were in of BRCA1/2 mutational A. et in BRCA1/2-mutated and triple-negative breast cancer BRCAness the Med. 2018; PubMed Scopus Google first did not with of the homologous recombination repair deficiency; overall response TNBC, triple negative breast Open table in a new tab HRD, homologous recombination repair deficiency; overall response TNBC, triple negative breast In TNBC, et al a phase II trial to the predictive role of genomic scars to platinum HRD scores were in of BRCA1/2 mutational et a phase II clinical trial of platinum monotherapy with biomarker in triple-negative breast 2015; 33: PubMed Scopus Google Scholar However, the predictive role of this HRD test was not in the a phase trial the efficacy of carboplatin in patients with advanced A. et in BRCA1/2-mutated and triple-negative breast cancer BRCAness the Med. 2018; PubMed Scopus Google Scholar According to the biomarker carboplatin resulted in higher overall response rates among patients harbouring a gBRCA1/2 not in with other associated with HRR such as high BRCA1 or BRCA1 evaluated in the A. et in BRCA1/2-mutated and triple-negative breast cancer BRCAness the Med. 2018; PubMed Scopus Google Scholar results could be by the that genomic scars tested in the tumour may have for response in the advanced setting tumours may have the HRR function and to As in the GeparSixto HRD-positive tumours were to to chemotherapy regimens compared with the HRD-negative Several open may from the that are the HRD status in and advanced breast cancer, and that further are required to the role of the HRR function in resistance to PARPi and platinum C. M. S. et as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline breast Oncol. 2018; 29: Full Text Full Text PDF PubMed Scopus Google Scholar Furthermore, the and trials demonstrated the efficacy of PARPi in BRCA1/2-mutated breast M. Im S.-A. Senkus E. et al.Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.N Engl J Med. 2017; 377: 523-533doi:10.1056/NEJMoa1706450Crossref PubMed Scopus (1635) Google Scholar, 14.Litton J.K. Rugo H.S. Ettl J. et al.Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.N Engl J Med. 2018; 379: 753-763doi:10.1056/NEJMoa1802905Crossref PubMed Scopus (996) Google Scholar a of patients did not is needed to if an HRD test to the to benefit. In prostate cancer, the in DNA and therapeutic from the for DNA damage response mutations among with advanced The trial evaluated the of olaparib in advanced prostate cancer, a between the presence of DNA repair defects and response to J. S. S. et defects and olaparib in prostate cancer.N Engl J 2015; PubMed Scopus Google Scholar from the the high response to PARPi of prostate W. et results from a phase II study of rucaparib in patients with prostate cancer associated with homologous recombination repair (HRR) Oncol. 2018; Scholar Nevertheless, the predictive value of other defects in DNA repair genes such as or to be in of the HRD score tests has been in prostate cancer clinical trials. Of note, in the of LOH-high based on the among prostate cancer was for the BRCA1/2-mutated ovarian cancer S. R. et profiling of tumour DNA and tumour tissue for the of rucaparib in prostate cancer Oncol. 2018; Scholar, N. P. et of BRCA1/2 genomic alterations by genomic profiling of tissue and tumor DNA Oncol. 2018; Scholar current of the genomic scar assays is the to tumour such as a of the HRR function in response to As an it could be useful to functional biomarkers based on assays that the of a repair crucial of HRR is by the RAD51 R. Chun J. Powell S.N. BRCA1 and BRCA2: important differences with common interests.Nat Rev Cancer. 2012; 12: 372doi:10.1038/nrc3181-c3Crossref Scopus (10) Google Scholar In and in the sensitive and predictive of of nuclear RAD51 to PARPi C. M. S. et as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline breast Oncol. 2018; 29: Full Text Full Text PDF PubMed Scopus Google Scholar, M. C. A. et al.A assay in tumor samples PARP inhibitor response beyond BRCA Med. 2018; PubMed Scopus Google Scholar, N. assay to select homologous recombination deficient breast for PARP inhibitor treatment functional assay to select homologous recombination breast for 2014; Scholar, M. A. C.J. of homologous recombination predicts complete response to neoadjuvant chemotherapy in breast 2011; Google Scholar is that the RAD51 assay may to identify tumours that can benefit from J. S. S. et defects and olaparib in prostate cancer.N Engl J 2015; PubMed Scopus Google Scholar, J. J. W. et DNA to prostate cancer treatment with PARP 2017; PubMed Scopus Google Scholar, A. C. S. et of ATM in homologous recombination after end and Res. 2015; PubMed Scopus Google Scholar, N. C.J. et in the repair of DNA damage by homologous recombination and sensitivity to Res. PubMed Scopus Google Scholar are several other tests currently in to identify tumours with a similar as the BRCA1/2-mutated tests not the also or N. et analysis by of breast cancer Cancer Res. 2011; PubMed Scopus Google Scholar, Grigoriadis A. T. et of of samples across and Oncol. 2015; PubMed Scopus Google Scholar, D. et of BRCA that with to chemotherapy and with outcome in patients with epithelial ovarian PubMed Scopus Google Scholar if and that these tests are predictive of high chemotherapy and PARPi the of and regarding large-scale to be for clinical D. et of BRCA that with to chemotherapy and with outcome in patients with epithelial ovarian PubMed Scopus Google Scholar, F. S. et cancers with a DNA after chemotherapy.Clin Cancer Res. 2015; PubMed Scopus Google Scholar, et from breast cancer and benefit of platinum-based chemotherapy in breast cancer Oncol. 2011; 22: Full Text Full Text PDF PubMed Scopus Google Scholar, J.A. et of human triple-negative breast cancer and for of 2011; PubMed Scopus Google Scholar, et response to neoadjuvant chemotherapy among triple-negative breast cancer molecular Cancer Res. 2013; PubMed Scopus Google Scholar, J. et signature in triple negative breast molecular and clinical reveals with therapeutic Oncol. 2015; PubMed Scopus Google Scholar, C. et signature is associated with response to PARP inhibitor treatment control in the 2 neoadjuvant Cancer Res. 2017; PubMed Scopus Google Scholar can that genomic scars associated with HRR defects in ovarian cancer identify patients who benefit from PARPi maintenance after platinum In breast cancer, HRD-genomic scars have a high to DNA-damaging chemotherapy and a to predict the benefit of carboplatin is In prostate cancer, that HRR including are sensitive to Nonetheless, it is of that HRD is in ovarian As is needed to if clinical of HRD tests might be useful to identify patients with platinum-resistant ovarian cancer who may benefit from some BRCA1/2 HRD-positive breast cancers could to Also, the prognostic role of HRD be further investigated with trials in to patients with breast cancer for a between HRD-genomic scars and functional tests such as the RAD51 assay is