Homologous Recombination Deficiency as an Ovarian Cancer Biomarker in a Real-World Cohort

Abstract

The diagnostic evaluation of homologous recombination deficiency (HRD) is central to define targeted therapy strategies for patients with ovarian carcinoma. We evaluated HRD in 514 ovarian carcinoma samples by next-generation sequencing of DNA libraries, including BRCA1/BRCA2 and 26,523 single-nucleotide polymorphisms using the standardized Myriad HRD assay, with the predefined cut point of ≥42 for a positive genomic instability score (GIS). All samples were measured in the central Myriad laboratory and in an academic molecular pathology laboratory. A positive GIS was detected in 196 (38.1%) of tumors, whereas 318 (61.9%) were GIS negative. Combining GIS and BRCA mutations, a total of 200 (38.9%) of the 514 tumors were HRD positive. A positive GIS was significantly associated with high-grade serous histology (P < 0.000001), grade 3 tumors (P = 0.001), and patient age <60 years (P = 0.0003). The concordance between both laboratories for the GIS status was 96.9% (P < 0.000001), with a sensitivity of 94.6% and a specificity of 98.4%. Concordance for HRD status was 97.1% (499 of 514 tumors). The percentage of HRD-positive tumors in our real-life cohort was similar to the proportion observed in the recently published PAOLA-1 trial, with high concordance between central and local laboratories. Our results support introduction of the standardized HRD assay in academic molecular pathology laboratories, thus broadening access to personalized oncology strategies for patients with ovarian cancer worldwide. The diagnostic evaluation of homologous recombination deficiency (HRD) is central to define targeted therapy strategies for patients with ovarian carcinoma. We evaluated HRD in 514 ovarian carcinoma samples by next-generation sequencing of DNA libraries, including BRCA1/BRCA2 and 26,523 single-nucleotide polymorphisms using the standardized Myriad HRD assay, with the predefined cut point of ≥42 for a positive genomic instability score (GIS). All samples were measured in the central Myriad laboratory and in an academic molecular pathology laboratory. A positive GIS was detected in 196 (38.1%) of tumors, whereas 318 (61.9%) were GIS negative. Combining GIS and BRCA mutations, a total of 200 (38.9%) of the 514 tumors were HRD positive. A positive GIS was significantly associated with high-grade serous histology (P < 0.000001), grade 3 tumors (P = 0.001), and patient age <60 years (P = 0.0003). The concordance between both laboratories for the GIS status was 96.9% (P < 0.000001), with a sensitivity of 94.6% and a specificity of 98.4%. Concordance for HRD status was 97.1% (499 of 514 tumors). The percentage of HRD-positive tumors in our real-life cohort was similar to the proportion observed in the recently published PAOLA-1 trial, with high concordance between central and local laboratories. Our results support introduction of the standardized HRD assay in academic molecular pathology laboratories, thus broadening access to personalized oncology strategies for patients with ovarian cancer worldwide. The concept of synthetic lethality1Negrini S. Gorgoulis V.G. Halazonetis T.D. Genomic instability--an evolving hallmark of cancer.Nat Rev Mol Cell Biol. 2010; 11: 220-228Crossref PubMed Scopus (1463) Google Scholar has recently entered clinical practice for patients with ovarian cancer, and poly (ADP-ribose) polymerase inhibitors have been integrated into therapy concepts in several clinical trials.2Coleman R.L. Fleming G.F. Brady M.F. Swisher E.M. Steffensen K.D. Friedlander M. Okamoto A. Moore K.N. Efrat Ben-Baruch N. Werner T.L. Cloven N.G. Oaknin A. DiSilvestro P.A. Morgan M.A. Nam J.H. Leath 3rd, C.A. Nicum S. Hagemann A.R. Littell R.D. Cella D. Baron-Hay S. Garcia-Donas J. Mizuno M. Bell-McGuinn K. Sullivan D.M. Bach B.A. Bhattacharya S. Ratajczak C.K. Ansell P.J. Dinh M.H. Aghajanian C. Bookman M.A. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.N Engl J Med. 2019; 381: 2403-2415Crossref PubMed Scopus (431) Google Scholar, 3Moore K.N. Secord A.A. Geller M.A. Miller D.S. Cloven N. Fleming G.F. Wahner Hendrickson A.E. Azodi M. DiSilvestro P. Oza A.M. Cristea M. Berek J.S. Chan J.K. Rimel B.J. Matei D.E. Li Y. Sun K. Luptakova K. Matulonis U.A. Monk B.J. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial.Lancet Oncol. 2019; 20: 636-648Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 4González-Martín A. Pothuri B. Vergote I. DePont Christensen R. Graybill W. Mirza M.R. McCormick C. Lorusso D. Hoskins P. Freyer G. Baumann K. Jardon K. Redondo A. Moore R.G. Vulsteke C. O'Cearbhaill R.E. Lund B. Backes F. Barretina- Ginesta P. Haggerty A.F. Rubio-Pérez M.J. Shahin M.S. Mangili G. Bradley W.H. Bruchim I. Sun K. Malinowska I.A. Li Y. Gupta D. Monk B.J. PRIMA/ENGOT- OV26/GOG-3012 InvestigatorsNiraparib in patients with newly diagnosed advanced ovarian cancer.N Engl J Med. 2019; 381: 2391-2402Crossref PubMed Scopus (787) Google Scholar In the PAOLA-1 trial, the combination of bevacizumab and olaparib was established and registered as maintenance therapy in platinum-responsive high-grade ovarian cancer with BRCA1/2 mutations and/or a homologous recombination deficiency (HRD).5Ray-Coquard I. Pautier P. Pignata S. Pérol D. González-Martín A. Berger R. Fujiwara K. Vergote I. Colombo N. Mäenpää J. Selle F. Sehouli J. Lorusso D. Guerra Alía E.M. Reinthaller A. Nagao S. Lefeuvre-Plesse C. Canzler U. Scambia G. Lortholary A. Marmé F. Combe P. de Gregorio N. Rodrigues M. Buderath P. Dubot C. Burges A. You B. Pujade-Lauraine E. Harter P. PAOLA-1 InvestigatorsOlaparib plus bevacizumab as first-line maintenance in ovarian cancer.N Engl J Med. 2019; 381: 2416-2428Crossref PubMed Scopus (682) Google Scholar The diagnostic evaluation of the genomic instability score (GIS) by molecular assays, defined by a combination of large-scale state transitions (LSTs),6Popova T. Manié E. Rieunier G. Caux-Moncoutier V. Tirapo C. Dubois T. Delattre O. Sigal-Zafrani B. Bollet M. Longy M. Houdayer C. Sastre-Garau X. Vincent-Salomon A. Stoppa-Lyonnet D. Stern M.H. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation.Cancer Res. 2012; 72: 5454-5462Crossref PubMed Scopus (372) Google Scholar telomeric allelic imbalance (TAI),7Birkbak N.J. Wang Z.C. Kim J.Y. Eklund A.C. Li Q. Tian R. Bowman-Colin C. Li Y. Greene-Colozzi A. Iglehart J.D. Tung N. Ryan P.D. Garber J.E. Silver D.P. Szallasi Z. Richardson A.L. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents.Cancer Discov. 2012; 2: 366-375Crossref PubMed Scopus (328) Google Scholar and loss of heterozygosity (LOH),8Abkevich V. Timms K.M. Hennessy B.T. Potter J. Carey M.S. Meyer L.A. Smith-McCune K. Broaddus R. Lu K.H. Chen J. Tran T.V. Williams D. Iliev D. Jammulapati S. FitzGerald L.M. Krivak T. DeLoia J.A. Gutin A. Mills G.B. Lanchbury J.S. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.Br J Cancer. 2012; 107: 1776-1782Crossref PubMed Scopus (426) Google Scholar has been approved as a companion diagnostic approach in the United States and Europe. Currently, the Myriad myChoice assay is the only clinically validated and US Food and Drug Administration–approved molecular HRD test in ovarian cancer. In Europe, the European Medicines Agency has decided against approval of a specific test, but stated that HRD should be determined by an experienced laboratory using a validated test, including LSTs, TAI, and LOH. From the perspective of academic research centers and molecular pathologists, it is important that the complete range of molecular assays is available in a decentralized academic setting. Clinical decisions require the integration of clinical, histopathologic, and molecular information, and many molecular pathologists and clinical oncologists are reluctant to build clinical decisions on molecular assays without the ability to control the assay parameters in their own laboratory environment. Last but not the least, in many European countries including Germany, the structure of the health system does not allow integration of diagnostic procedures performed in central laboratories in other countries. The recent approval of olaparib in combination with bevacizumab for patients newly diagnosed with HRD-positive high-grade ovarian cancer provides a major challenge for personalized medicine. On the one hand, there is an urgent need for access to validated HRD testing for all patients with ovarian cancer; and on the other hand, there is limited access to only one clinically validated assay, which is not broadly available. As a way to resolve evaluated the of the Myriad myChoice assay to an academic molecular pathology laboratory. We the results of the decentralized testing in with the central Myriad laboratory for a cohort of 514 samples of patients with advanced ovarian on the of genomic instability in a cohort of patients with ovarian carcinoma. the assay of Myriad myChoice in the molecular pathology laboratory of the with the central diagnostic laboratory of Myriad in were concordance of HRD status and of between the laboratories. were an available ovarian patient and available molecular results both laboratories and for BRCA1/2 and On the of a cohort of 514 samples that were to the molecular pathology laboratory between and were Clinical parameters were the pathology and the local diagnostic was approved by the of the of samples were between the and laboratories for DNA and for laboratory was and by pathologists in and for for of a of a in the range of and 200 of genomic DNA as the for are for for were and between both laboratories, All were to the laboratory In of the was the to allow of of were the and DNA was using the DNA were in a in a with and the The genomic DNA was in Myriad myChoice HRD assays were performed in of patient samples and one control Genomic and control DNA were using a to 200 genomic DNA and in an DNA was whereas DNA was into a performed repair and by a A with predefined in the of that were and by DNA were a the was was and for a using the A total of of genomic DNA was the genomic DNA was using a The DNA was to a DNA with for single-nucleotide polymorphisms the was in combination by Myriad and DNA and for of mutations and with a complete of both I. Timms K.M. C. P. J. Lanchbury J.S. S. Sehouli J. of homologous recombination deficiency in and high-grade serous ovarian cancer.Br J Cancer. PubMed Scopus Google K.M. V. E. C. J. B. S. Potter J. Tran T.V. Chen J. Iliev D. Z. E. M. A. Gutin A. Lanchbury J.S. of BRCA1/2 defects with genomic of DNA repair deficiency breast cancer Res. PubMed Scopus Google Scholar for all homologous recombination repair is by the of for with a all and the were with the as as of K.M. V. E. C. J. B. S. Potter J. Tran T.V. Chen J. Iliev D. Z. E. M. A. Gutin A. Lanchbury J.S. of BRCA1/2 defects with genomic of DNA repair deficiency breast cancer Res. PubMed Scopus Google Scholar The DNA was on an to the the with of for the allow for sequencing to a score of were and by sequencing and the all were and to a of targeted of a specific of by a M. A Scholar a of all in the to the the for K.M. V. E. C. J. B. S. Potter J. Tran T.V. Chen J. Iliev D. Z. E. M. A. Gutin A. Lanchbury J.S. of BRCA1/2 defects with genomic of DNA repair deficiency breast cancer Res. PubMed Scopus Google Scholar was with the of the the using a performed by an that a O. for Mol Biol. PubMed Scopus Google Scholar and all are and by using the All clinically were as a that the of and of and the are the of and was was performed for and and GIS was using the on the of TAI, and of the GIS have been defined by that were all published in T. Manié E. Rieunier G. Caux-Moncoutier V. Tirapo C. Dubois T. Delattre O. Sigal-Zafrani B. Bollet M. Longy M. Houdayer C. Sastre-Garau X. Vincent-Salomon A. Stoppa-Lyonnet D. Stern M.H. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation.Cancer Res. 2012; 72: 5454-5462Crossref PubMed Scopus (372) Google Scholar, N.J. Wang Z.C. Kim J.Y. Eklund A.C. Li Q. Tian R. Bowman-Colin C. Li Y. Greene-Colozzi A. Iglehart J.D. Tung N. Ryan P.D. Garber J.E. Silver D.P. Szallasi Z. Richardson A.L. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents.Cancer Discov. 2012; 2: 366-375Crossref PubMed Scopus (328) Google Scholar, V. Timms K.M. Hennessy B.T. Potter J. Carey M.S. Meyer L.A. Smith-McCune K. Broaddus R. Lu K.H. Chen J. Tran T.V. Williams D. Iliev D. Jammulapati S. FitzGerald L.M. Krivak T. DeLoia J.A. Gutin A. Mills G.B. Lanchbury J.S. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.Br J Cancer. 2012; 107: 1776-1782Crossref PubMed Scopus (426) Google Scholar have been as of one for one of but a The of the which was to be with samples that high were of homologous recombination and/or a deficiency in V. Timms K.M. Hennessy B.T. Potter J. Carey M.S. Meyer L.A. Smith-McCune K. Broaddus R. Lu K.H. Chen J. Tran T.V. Williams D. Iliev D. Jammulapati S. FitzGerald L.M. Krivak T. DeLoia J.A. Gutin A. Mills G.B. Lanchbury J.S. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.Br J Cancer. 2012; 107: 1776-1782Crossref PubMed Scopus (426) Google Scholar The TAI, of of and DNA with without in DNA imbalance is by a deficiency in DNA repair to genomic repair as tumors a high of were to be to treatment with a that DNA and with which a defective DNA repair The score was thus defined as the of one the of the and to the been N.J. Wang Z.C. Kim J.Y. Eklund A.C. Li Q. Tian R. Bowman-Colin C. Li Y. Greene-Colozzi A. Iglehart J.D. Tung N. Ryan P.D. Garber J.E. Silver D.P. Szallasi Z. Richardson A.L. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents.Cancer Discov. 2012; 2: 366-375Crossref PubMed Scopus (328) Google Scholar The of the was defined as the of of of of all of for of has been to be associated with and have been to HRD be for samples a high of in their T. Manié E. Rieunier G. Caux-Moncoutier V. Tirapo C. Dubois T. Delattre O. Sigal-Zafrani B. Bollet M. Longy M. Houdayer C. Sastre-Garau X. Vincent-Salomon A. Stoppa-Lyonnet D. Stern M.H. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation.Cancer Res. 2012; 72: 5454-5462Crossref PubMed Scopus (372) Google Scholar The of TAI, and the The predefined cut for the GIS as as the of HRD-positive and tumors, on a combination of GIS and BRCA1/2 are in cut point been by a TAI, and into a that of tumors are B.T. Timms K.M. Carey M.S. Gutin A. Meyer L.A. V. Potter J. D. P. Li Y. Li J. A.M. M. Broaddus Lanchbury J.S. Lu K.H. Mills G.B. mutations in and the of patients that poly polymerase inhibitors in ovarian Oncol. 2010; PubMed Scopus Google Scholar of the combination of the the tumors without BRCA mutations, HRD is by other molecular for US Food and Drug approval of the Myriad myChoice assay as a companion diagnostic in the predefined for positive GIS was as validated in the and the PAOLA-1 clinical A. Pothuri B. Vergote I. DePont Christensen R. Graybill W. Mirza M.R. McCormick C. Lorusso D. Hoskins P. Freyer G. Baumann K. Jardon K. Redondo A. Moore R.G. Vulsteke C. O'Cearbhaill R.E. Lund B. Backes F. Barretina- Ginesta P. Haggerty A.F. Rubio-Pérez M.J. Shahin M.S. Mangili G. Bradley W.H. Bruchim I. Sun K. Malinowska I.A. Li Y. Gupta D. Monk B.J. PRIMA/ENGOT- OV26/GOG-3012 InvestigatorsNiraparib in patients with newly diagnosed advanced ovarian cancer.N Engl J Med. 2019; 381: 2391-2402Crossref PubMed Scopus (787) Google I. Pautier P. Pignata S. Pérol D. González-Martín A. Berger R. Fujiwara K. Vergote I. Colombo N. Mäenpää J. Selle F. Sehouli J. Lorusso D. Guerra Alía E.M. Reinthaller A. Nagao S. Lefeuvre-Plesse C. Canzler U. Scambia G. Lortholary A. Marmé F. Combe P. de Gregorio N. Rodrigues M. Buderath P. Dubot C. Burges A. You B. Pujade-Lauraine E. Harter P. PAOLA-1 InvestigatorsOlaparib plus bevacizumab as first-line maintenance in ovarian cancer.N Engl J Med. 2019; 381: 2416-2428Crossref PubMed Scopus (682) Google Scholar HRD both of the were a test results a GIS of ≥42 and/or a clinically BRCA1/2 the HRD was as positive. the of both laboratories, the results for and were the of GIS and BRCA1/2 mutations, as as the with only the laboratory are The was on a predefined and performed using as as The total indicates the of of the measured the was as total = with the of with the of the = with and the GIS of and for = and the of the The were with C. with and and Google Scholar and were by with a of A total of 514 samples patients with ovarian carcinomas were The age of patients was years to patients high-grade serous on of and was available for and of patients of and to tumors of with and with GIS in the score positive score patients = years = = = = = = = BRCA1/2 status = parameters are the pathology of and genomic instability high-grade serous not in a Clinical parameters are the pathology of and genomic instability high-grade serous not samples in both laboratories similar both the in the laboratory was in the laboratory as as the a be in the samples that were in the laboratory that were in samples in a range of range of to range of to with the samples range of to range of to and (38.1%) of the 514 patients tumors with a GIS of ≥42 score and were positive for genomic instability on the predefined cut whereas 318 (61.9%) were GIS The GIS was to mutations of were detected by sequencing of the in of the 514 samples A of all and BRCA1/2 detected in be in tumors with BRCA1/2 mutations of a GIS of tumors a clinically BRCA with a GIS of In in were in samples The HRD status tumors that have a positive GIS and/or a BRCA a total of 200 (38.9%) of the 514 tumors were HRD positive. there was a of observed with a of HRD-positive and tumors, and only a with GIS the to the were to between GIS of and the cut point of in a real-life and the concept that the of tumors with high and GIS are in including a serous carcinoma with a GIS of as as high-grade ovarian carcinomas with of and On it is not to tumors with high GIS using the an of all 514 samples that have been in both laboratories, by GIS 514 tumors, an GIS in a concordance of 96.9% between the laboratories. A between the Myriad and laboratories, including a and the is in which high between the laboratories, with a of = (P < and a = of the tumors a BRCA and was HRD positive. the concordance for the HRD status was 97.1% (499 of 514 tumors were The of the of the in GIS between the and all samples was GIS The sensitivity for the GIS status was the specificity was and the total was as score of Genomic between the and positive patients = positive concordance concordance a BRCA and a positive HRD genomic instability homologous recombination a BRCA and a positive HRD in a genomic instability homologous recombination The between the GIS in the laboratories are in A total of of the 514 tumors a of GIS of the 514 tumors a of GIS The tumors with a in GIS status are with a in that only of tumors a and a GIS of score of the tumors GIS to the cut point of a of HRD in the HRD evaluation in of defined by parameters was the in GIS status in of tumors defined by and A positive GIS status was significantly associated with high-grade serous carcinoma of but only of carcinomas were GIS positive (P < a positive GIS status was significantly associated with grade 3 tumors (P = and patient age <60 years (P = 0.0003). In the of tumors with available information, there were in defined by and of and The of is in tumors with patient and The of GIS in tumors with is in GIS were observed in serous carcinoma and In in and the GIS was to the cut point of The combination of olaparib and bevacizumab as a maintenance therapy in high-grade ovarian cancer for patients with ovarian cancer. combination has been to in the PAOLA-1 to in the of patients with a positive HRD I. Pautier P. Pignata S. Pérol D. González-Martín A. Berger R. Fujiwara K. Vergote I. Colombo N. Mäenpää J. Selle F. Sehouli J. Lorusso D. Guerra Alía E.M. Reinthaller A. Nagao S. Lefeuvre-Plesse C. Canzler U. Scambia G. Lortholary A. Marmé F. Combe P. de Gregorio N. Rodrigues M. Buderath P. Dubot C. Burges A. You B. Pujade-Lauraine E. Harter P. PAOLA-1 InvestigatorsOlaparib plus bevacizumab as first-line maintenance in ovarian cancer.N Engl J Med. 2019; 381: 2416-2428Crossref PubMed Scopus (682) Google Scholar positive results and the approval of olaparib plus bevacizumab an challenge for diagnostic pathology to validated HRD testing to all patients be for only be by a of local academic laboratories to a validated the in the decentralized evaluation of the GIS using the molecular assay by Myriad was that it is to sequencing assay in an academic molecular pathology laboratory with high concordance The laboratories similar in sequencing both for and In of 514 tumors, the concordance for the GIS was 96.9% and the between the results and was score the tumors with a of GIS status between the laboratories, only a between the of score whereas of score that were tumors with GIS to the cut and the in GIS status are not to the of the The decentralized of the Myriad HRD assay for HRD it academic centers to the validated clinical assay with control of diagnostic procedures and to and that the Myriad HRD assay is a that be in other academic research laboratories as and be by Myriad for laboratories in the assay into their the of molecular pathology and which is important for the of molecular pathology as an academic including clinical and molecular of 514 it was to important results on the and of HRD in ovarian cancer in the a clinical The is of the that established the Myriad score of ≥42 were performed in patient only a of patients in only patients with tumors and a to chemotherapy were A. Pothuri B. Vergote I. DePont Christensen R. Graybill W. Mirza M.R. McCormick C. Lorusso D. Hoskins P. Freyer G. Baumann K. Jardon K. Redondo A. Moore R.G. Vulsteke C. O'Cearbhaill R.E. Lund B. Backes F. Barretina- Ginesta P. Haggerty A.F. Rubio-Pérez M.J. Shahin M.S. Mangili G. Bradley W.H. Bruchim I. Sun K. Malinowska I.A. Li Y. Gupta D. Monk B.J. PRIMA/ENGOT- OV26/GOG-3012 InvestigatorsNiraparib in patients with newly diagnosed advanced ovarian cancer.N Engl J Med. 2019; 381: 2391-2402Crossref PubMed Scopus (787) Google Scholar In it is important to that a positive HRD status is a in ovarian cancer in a cohort with positive A in BRCA1/2 was observed in of samples in which was the of BRCA1/2 mutations in the PAOLA-1 cohort be by the that centers performed BRCA testing as a and only tumors that were BRCA were for HRD The Myriad HRD test the evaluation of the GIS with the of mutations of the diagnostic it is to the complete for clinical decisions in ovarian cancer a In to the assay and are not for decisions in ovarian cancer but that patients and their have a and should be testing and the GIS a which is similar to the one observed in the the GIS cut that there are of ovarian and that the HRD assay is to between both A total of of the tumors with BRCA mutations were to a positive GIS whereas only of the tumors with BRCA mutations a GIS the cut point of results to the the cut G. Timms K.M. J. Gutin A. Krivak T. Hennessy B. J. R. Lanchbury J.S. recombination deficiency (HRD) score with to score TAI, and in serous ovarian cancer. of the of of Scholar which a sensitivity to cut have been that are to have a with patient J.A. A.A. B. M.S. S. C. Y. K. Lanchbury J.S. Timms K. Lu K.H. M.S. of homologous recombination deficiency score and with in epithelial ovarian PubMed Scopus Google Scholar other HRD assays using molecular with a predefined have been published and in the academic HRD and as a companion diagnostic A. A. D. Colombo N. E. M. evaluation of a homologous recombination deficiency (HRD) assay for patients with epithelial ovarian and concordance with a Oncol. Google C.A. J. V. K. and of a genomic assay for PubMed Scopus Google Scholar In all of tumors that were to the laboratory were without the to tumors were but of the tumors a only of the a positive GIS that genomic instability is a of high-grade serous tumors, as in the of the GIS were observed in with GIS in serous carcinoma and In and the GIS was to the cut point of that specific are which clinically cut In the results of have important for standardized diagnostic concepts in ovarian cancer, the concordance results that a standardized central laboratory test be to an academic molecular pathology laboratory with HRD testing should be to all patients with high-grade ovarian cancer. We the molecular pathology and the of in and as as the the Myriad in and Germany, in and for their of genomic instability score (GIS) in 514 ovarian with an of of the genomic instability and including and instability score (GIS) in ovarian tumors with on results the the cut point GIS high-grade serous serous with with with and the and and and patients and samples and all the the of the and The to the for was by all the All the

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