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Homologous recombination deficiency in breast cancer

Homologous recombination deficiency in breast cancer short review memo (2020) 13:375–379 https://doi.org/10.1007/s12254-020-00624-x Homologous recombination deficiency in breast cancer Thomas Bartl · Alex Farr Received: 2 April 2020 / Accepted: 14 May 2020 / Published online: 9 June 2020 © The Author(s) 2020 Summary BRCA mutation-related DNA repair defi- Keywords BRCA · Breast cancer · Homologous ciencies increase the individual sensitivity to DNA- recombination deficiency · PARP inhibitor targeting agents. Therefore, the patient’s BRCA muta- Abbreviations tional status is evaluated in clinical practice as a pre- DSB Double-strand break dictive marker in response to platinum salts and poly- HR Homologous recombination ADP-ribose polymerase (PARP) inhibitors for breast ORR Overall response rate cancer treatment. A substantial subset of BRCA wild- PARP Poly-ADP-ribose polymerase type breast cancer lesions, however, share both promi- pCR Pathological complete response nent molecular characteristics and clinical behavior SSB Single-strand break patterns with cancer that harbors BRCA mutations, TNBC Triple-negative breast cancer including DNA repair deficiencies. Also referred to as “BRCAness”, this observation is related to aberrations of the homologous recombination (HR) repair path- Introduction way, which deprive cancer cells of the ability to ade- quately mend potentially lethal double-strand breaks Growing evidence supports the increased clinical effi- and result in a BRCA-like genomic instability. Hence, cacy of DNA-targeting therapies in breast cancers har- HR deficiency is a promisingtargetfor related ther- boring BRCA1 and/or BRCA2 mutations as BRCA func- apeutic options and the predictive potential of HR tion is pivotal to DNA-damage response [1]. BRCA testing for treatment response has been increasingly mutations are observed in approximately 5–10% of studied. Several HR deficiency-testing assays have unselected breast cancers and 20–40% of all triple- been proposed and prospectively validated for vari- negative breast cancers (TNBCs). Up to 15% more ous cancer types; however, preliminary results in early have been hypothesized to express non-BRCA-related breast cancer are inconsistent. As scientific evidence alterations in the DNA repair pathway of homologous for a potential therapeutic benefit in breast cancer is recombination (HR) repair [2–4]. TNBCs typically ex- scarce, HR testing remains highly experimental and press few therapeutic targets; defining a predictive should be limited to the boundaries of clinical studies marker to identify patients that will most likely bene- until results of ongoing phase 3 trials are available. fit from DNA targeting agents, such as platinum salts and poly-ADP-ribose polymerase (PARP) inhibitors, may therefore expand the therapeutic armamentar- ium for a clinically highly relevant subset of patients with breast cancer. Dr. T.Bartl,MD BA ·A. Farr,MD PhD () Division of General Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Homologous recombination deficiency as Medical University of Vienna, Waehringer a marker for treatment response Guertel 18–20, 1090 Vienna, Austria alex.farr@meduniwien.ac.at The ability to adequately repair DNA double-strand breaks (DSBs) relies on HR repair, which reconstructs Dr. T.Bartl,MD BA thomas.bartl@meduniwien.ac.at damaged DNA by copying the respective undam- K Homologous recombination deficiency in breast cancer 375 short review aged strand from the homologous sister chromatid. Defining and diagnosing homologous A complex set of proteins is required to interact recombination deficiency within this procedure, including the gene products of BRCA1, BRCA2, PALB2, RAD51, ATM,and CHEK2. Several methodologically different approaches to test Any dysfunctional protein involved may impair the HR deficiency in breast cancer have been proposed. ability to adequately mend DSBs, thereby inducing The so-called “genomic scarring” assays aim to quan- a phenotypical cell behavior termed HR deficiency or tify genomic aberrations by next-generation whole “BRCAness.” As HR repair fails, DSBs are frequently genome sequencing. The “myChoice” HR deficiency referred to non-homologous end joining (NHEJ) re- test (Myriad Genetics Inc., Salt Lake City, Utah, USA) pair, an error-prone process of random end-to-end calculates a score of sections of losses of heterozy- fusion of damaged strands, which inevitably leads to gosity, large-scale transitions, and telomeric allelic information loss, accumulation of genetic damage, imbalance as three combined DNA-based measures and ultimately to cell death. Since the ability of HR- of genomic instability [10]. The “CDx BRCA LOH” deficient cells to cope with DNA damage is there- (Foundation Medicine, Cambridge, Massachusetts, fore limited, phenotypical HR deficiency is associated USA) assesses deleterious BRCA1 and/or BRCA2 mu- with increased sensitivity to therapeutic agents tar- tations. With the implementation of HR deficiency geting DNA integrity, particularly PARP inhibitors and testing in treatment decision-making for epithelial platinum salts [1]. ovarian cancer, recent comparative trials have fo- PARP inhibitors induce an excess of DNA single- cused on validating genomic scarring assays. Further, strand breaks (SSBs) by inhibiting the activity of base recent clinical studies have used genomic scarring excision repair and foster DSB by trapping PARP at assays to assess HR deficiencies in breast cancer the DNA, thereby blocking the replication fork [5]. [11–14]. A growing body of evidence, however, also indicates Moreover, previously defined complex patterns of direct involvement of other DNA repair systems, as somatic mutations throughout the whole genome, so- PARP can be trapped on DNA at sites of unrepaired called gene signatures, have been validated as predic- SSBs, thereby directly contributing to lethal effects of tors of HR-deficient tumors. The HRDetect test has PARP inhibitors [6]. Moreover, radiosensitization ef- been designed to detect HR deficiency with high sen- fects of PARP inhibition may be explained by inter- sitivity based on such gene signature analyses [15]. fering with HR-independent so-called PARP1-depen- It has been hypothesized that such gene signature- dent end-joining [7]. In contrast, the principal effect based tests compensate a major shortcoming of ge- of platinum salts relies on the induction of interstrand nomic scarring assays, i.e., recognition of BRCA pro- and intrastrand DNA cross-links. The repair of such moter hypermethylation-related HR deficiency. Such cross-links depends on a complex interaction of man- transcriptional deactivation of BRCA function is re- ifold single- and double-strand repair systems includ- versible and not predictive of therapy response, even ing HR. Therefore, deficient cells often fail to restore though it is associated with higher “myChoice” HR proper DNA architecture. Moreover, cross-link-related scores. Large studies assessing different HR deficiency distortions of the DNA double helix promote SSBs and tests are urgently needed to clarify these findings [16, DSBs [8, 9]. 17]. Lastly, protein function of crucial steps in HR such as RAD51 can be assessed using DNA sequencing and immunostaining assays to predict HR deficiency. Table 1 Clinical trials assessing homologous recombination deficiency in breast cancer patients Study Study design Agent No Patients pCR/ORR in HRd patients with or without platinum PrECOG0105/ Phase 2 Carboplatin, gemcitabine, 148 Neoadjuvant pCR: 42% vs. 10% pooled Cisplatin-1 and single-arm iniparib and cisplatin + TNBC OR 6.52; [1.36–31.2]; p < 0.01 2[8] bevacizumab pCR: 27.5% vs. 0% OR 17; [1.91–2249]; p < 0.01 GeparSixto Phase 2 Paclitaxel, doxoru- 595 Neoadjuvant TNBC pCR: 63.5% vs. 33.9% [17] randomized bicin ± carboplatin and Her2 positive OR 3.4 [1.7–6.9]; p < 0.01 open label GeparOLA (Abstract, Phase 2 Olaparib, paclitaxel 102 Neoadjuvant pCR: 20% vs. 56.2% NCT02789332) randomized versus carboplatin, TNBC or Her2 nega- OR not reported; p < 0.01 open label paclitaxel tive TNT [14] Phase 3 Carboplatin versus docetaxel 376 Unselected ad- ORR 38.2% vs. 40.4% randomized vanced OR not reported; p = 1.0 open label TNBC HR homologous recombination repair, OR odds ratio, ORR overall response rate, pCR pathological complete response, TNBC triple negative breast cancer HR deficiency (HRd) was defined by the “myChoice” HR (Myriad Genetics) assay for all studies listed 376 Homologous recombination deficiency in breast cancer K short review Broad availability and independence of commercial The TNT trial, a randomized, open-label phase 3 testing may favor this approach, especially in lower- study comparing carboplatin with docetaxel in 376 pa- income countries. However, its clinical applicability tients with unselected advanced TNBC, reported that is limited as RAD51 assays cannot be performed on patients with BRCA-mutated tumors achieved higher formalin-fixed paraffin-embedded blocks, but they overall response rates (ORRs) after carboplatin treat- require viable tumor tissue [17]. ment than after docetaxel treatment (68.0% versus 33.3%). There was no significant difference in ORR in patients with HR-deficient tumors after carboplatin Studies assessing homologous recombination and docetaxel treatment (38.2% versus 40.4%). This deficiency in breast cancer patients finding could partially be explained by the fact that Despite promising preliminary results, published tri- the HR deficiency test was performed on archival sam- als comprise heterogeneous populations and study ples of the primary tumor, which could result in lower designs, which hinder direct comparisons and limit positive predictive value as tumor evolution processes drawing conclusions for clinical practice. Table 1 pro- and inherent accumulation of genomic scars could vides an overview of recent clinical studies evaluating not be depicted [22]. the predictive value of HR assessment. Results appear most promising for predicting ther- Future perspectives apy response to platinum salts in a neoadjuvant set- ting.Telli et al.[10] retrospectively assessed the pre- As current evidence is limited, several ongoing clinical dictive value of the “myChoice” HR test in three single- trials assessing treatment response to platinum salts arm trials (PrECOG0105 and pooled cisplatin 1 and and PARP inhibitors, stratified by HR assessment, are cisplatin 2) of neoadjuvant platinum therapy com- expected to further elucidate the role of HR for ther- prising 148 patients with TNBC. Patients with HR- apy decision-making in patients with breast cancer. deficient tumors achieved higher pathological com- A Chinese randomized phase 3 trial (NCT03876886) plete response (pCR) rates with the addition of platin is studying dose-dense epirubicin/cyclophosphamide (PrECOG0105, pCR 42% versus 10%, OR 6.52; 95% CI followed by paclitaxel and carboplatin/paclitaxel as 1.36–31.2, and cisplatin 1 and 2, pCR 27.5% versus 0%, adjuvant therapy of TNBC stratified by HR assess- OR 17; 95% CI 1.91–2249). ment. Moreover, a post-hoc HR deficiency analysis Moreover, a post-hoc analysis of the GeparSixto of the BrighTNess phase 3 trial, comparing veliparib trial, a randomized phase 2 study assessing the addi- plus carboplatin versus carboplatin alone, is currently tional benefit of carboplatin to anthracycline/taxane- underway and may provide insights into the predic- based treatment for neoadjuvant chemotherapy reg- tive value of HR testing in this cohort [23]. imens in 595 patients with primary, nonmetastatic The phase III trials OlympiAD and EMBRACA have TNBC and her2-positive breast cancer, reported proved that PARP inhibitors have the potential to higher pCR rates in patients with HR-deficient tu- increase PFS compared to standard chemotherapy mors with the addition of carboplatin (63.5% vs. in pretreated advanced BRCA mutated breast cancer 33.9%, OR 3.4, 95% CI 1.7–6.9) [18]. The long-term [24, 25]. HR testing could greatly expand the scope survival analysis, however, could not prove a corre- of patients benefiting from these treatment options. lation between HR deficiency and patient prognosis To prove this hypothesis, several clinical phase 2 [19]. trials are currently ongoing, testing the efficacy of The ongoing randomized phase 2 trial TBCRC030 PARP inhibitors depending on the HR status; the (NCT01982448) of neoadjuvant cisplatin versus pa- agents involved in these studies include talazoparib clitaxel in 140 patients with TNBC preliminarily re- in the TBB (talazoparib beyond BRCA) trial, olaparib ported that the pCR rate of patients with HR-defi- in the NOBROLA trial, and rucaparib in the RUBY cient tumors was 21.1% in the carboplatin cohort and trial [26, 27]. In addition, a phase 2 three-armed trial 19.4% in the paclitaxel cohort [20]. The also ongoing (NCT03330847) is testing olaparib in combination GeparOLA (NCT02789332) study, a randomized open- with the DNA damage response inhibitors adavosertib label phase 2 trial of paclitaxel/olaparib 100 mg BID and AZD6737, stratified by HR assessment. versus paclitaxel/carboplatin both followed by epiru- bicin/cyclophosphamide as neoadjuvant treatment in Conclusions 102 patients with her2-negative early breast cancer, preliminarily reported that pCR rate was not statis- Thepredictivevalue of the BRCA mutational sta- tically significant different between the olaparib arm tus has been validated for platinum salt and PARP and the carboplatin arm. In the subgroup of patients inhibitor therapy; however, published trials do not with HR-deficient tumors, pCR rates were 52.6% in provide evidence of whether HR deficiency is an ade- the olaparib arm and 20.0% in the carboplatin arm, quate marker for therapy decision-making in patients whereas in the subgroup of patients with HR-profi- with breast cancer. Further studies and large com- cient tumors, the rates were 56.0 and 59.3%, respec- parative phase 3 trials are warranted to substantiate promising results of the currently published retro- tively [21]. K Homologous recombination deficiency in breast cancer 377 short review 6. Gogola E, Rottenberg S, Jonkers J. Resistance to PARP spective and early clinical studies. Similar to clinical inhibitors: lessonsfrompreclinicalmodelsofBRCA-associ- routines of epithelial ovarian cancer, HR deficiency atedcancer. Annu Rev Cancer Biol. 2019;3(1):235–54. testing may identify subsets of breast cancer patients 7. KotterA,CornilsK,BorgmannK,Dahm-DaphiJ,PetersenC, that are likely to benefit from platinum salt or PARP Dikomey E, et al. Inhibition of PARP1-dependent end-join- inhibition therapy in the future. ing contributes to olaparib-mediated radiosensitization in tumor cells. Mol Oncol. 2014;8(8):1616–25. 8. Hinz JM. Role of homologous recombination in DNA Take-home messages interstrand crosslink repair. Environ Mol Mutagen. 2010;51(6):582–603. Homologous recombination (HR) dec fi iency may rep- 9. Legerski RJ. Repair of DNA interstrand cross-links during S resent a valuable biomarker for therapy response to phase of the mammalian cell cycle. Environ Mol Mutagen. PARP inhibitors and platinum salts. 2010;51(6):540–51. The clinical use of HR deficiency could be of partic- 10. TelliML,TimmsKM,ReidJ,HennessyB,MillsGB,JensenKC, ular importance in women with TNBC. et al. Homologous Recombination Deficiency (HRD) score predicts response to platinum-containing neoadju- Ongoing trials are assessing the predictive value of vant chemotherapy in patients with triple-negative breast commercially available “genomic scarring” assays cancer. Clin Cancer Res. 2016;22(15):3764–73. that aim to quantify HR-related DNA-based mea- 11. Gonzalez-Martin A, Pothuri B, Vergote I, DePont Chris- sures of genomic instability. tensen R, Graybill W, Mirza MR, et al. Niraparib in patients As there is no concrete evidence for the predictive with newly diagnosed advanced ovarian cancer. N Engl J value of HR deficiency, HR testing should currently Med. 2019;381(25):2391–402. be limited to clinical trials. 12. Coleman RL, Fleming GF, Brady MF, Swisher EM, Stef- fensen KD, Friedlander M, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian can- Funding Open access funding provided by Medical University cer. N Engl J Med. 2019;381(25):2403–15. of Vienna. 13. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Re- Conflict of interest T. Bartl and A. Farr declare that they have dondo A, et al. Niraparib maintenance therapy in plat- no competing interests. inum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154–64. Open Access This article is licensed under a Creative Com- 14. Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, mons Attribution 4.0 International License, which permits et al. TBCRC009: a multicenter phase II clinical trial use, sharing, adaptation, distribution and reproduction in of platinum monotherapy with biomarker assessment in any medium or format, as long as you give appropriate credit metastatic triple-negative breast cancer. J Clin Oncol. to the original author(s) and the source, provide a link to 2015;33(17):1902–9. the Creative Commons licence, and indicate if changes were 15. Davies H, Glodzik D, Morganella S, Yates LR, Staaf J, Zou X, made. The images or other third party material in this article et al. HRDetect is a predictor of BRCA1 and BRCA2 are included in the article’s Creative Commons licence, unless deficiency based on mutational signatures. Nat Med. indicated otherwise in a credit line to the material. If material 2017;23(4):517–25. is not included in the article’s Creative Commons licence and 16. Sharma P, Barlow WE, Godwin AK, Pathak H, Isakova K, your intended use is not permitted by statutory regulation or Williams D, et al. Impact of homologous recombina- exceeds the permitted use, you will need to obtain permis- tion deficiency biomarkers on outcomes in patients with sion directly from the copyright holder. To view a copy of this triple-negativebreast cancer treated with adjuvant doxoru- licence, visit http://creativecommons.org/licenses/by/4.0/. bicin and cyclophosphamide (SWOG S9313). Ann Oncol. 2018;29(3):654–60. References 17. Pellegrino B, Mateo J, Serra V, Balmaña J. Controversies in oncology: Are genomic tests quantifying homologous recombinationrepairdeficiency(HRD)usefulfortreatment 1. Garutti M, Pelizzari G, Bartoletti M, Malfatti MC, Ger- decision making? ESMO Open. 2019;4(2):e480. ratana L, Tell G, et al. Platinum salts in patients with 18. Von Minckwitz G, Timms K, Untch M, Elkin EP, Fasching PA, breast cancer: a focus on predictive factors. Int J Mol Sci. Schneeweiss A, et al. Prediction of pathological com- 2019;20(14):3390. plete response (pCR) by homologous recombination de- 2. Tian T, Shan L, Yang W, Zhou X, Shui R. Evaluation of ficiency (HRD) after carboplatin-containing neoadjuvant the BRCAness phenotype and its correlations with clini- chemotherapy in patients with TNBC: results from Gepar- copathological features in triple-negative breast cancers. Sixto. J Clin Oncol. 2015;33(15_suppl):1004. HumPathol. 2019;84:231–8. 19. Loibl S, Weber KE, Timms KM, Elkin EP, Hahnen E, 3. Akashi-Tanaka S, Watanabe C, Takamaru T, Kuwayama T, Fasching PA, et al. Survival analysis of carboplatin added to Ikeda M, Ohyama H, et al. BRCAness predicts resistance an anthracycline/taxane-based neoadjuvant chemother- to taxane-containing regimens in triple negative breast apy and HRD score as predictor of response-final results cancer during neoadjuvant chemotherapy. Clin Breast fromGeparSixto. Ann Oncol. 2018;29(12):2341–7. Cancer. 2015;15(1):80–5. 20. Mayer EL, Abramson VG, Jankowitz RC, Falkson CI, Mar- 4. Peshkin BN, Alabek ML, Isaacs C. BRCA1/2 muta- com PK, Traina TA, et al. TBCRC 030: A random- tions and triple negative breast cancers. Breast Dis. ized phase II study of preoperative cisplatin versus pa- 2010;32(1–2):25–33. clitaxel in TNBC—Evaluating the homologous recom- 5. Yates MS, Timms K, Daniels MS, Oakley HD, Munsell MF, bination deficiency (HRD) biomarker. J Clin Oncol. LanchburyJS,etal. EvaluationofBRCA1/2andhomologous 2019;37(15_suppl):507. recombination defects in ovarian cancer and impact on clinical outcomes. J Clin Oncol. 2017;35(15_suppl):5511. 378 Homologous recombination deficiency in breast cancer K short review 21. Fasching PA, Jackisch C, Rhiem K, Schneeweiss A, Klare P, 26. AguirreE,AmillanoK,CortésA,JuanMJ,MárquezA,RuizM, Hanusch C,et al. GeparOLA:Arandomized phase II trial et al. Abstract CT165: A two-stage Simon Design phase II to assess the efficacy of paclitaxel and olaparib in com- study for Non-BRCA metastatic breast cancer (MBC) pa- parison to paclitaxel/carboplatin followed by epirubicin/ tients with homologous recombination deficiency treated cyclophosphamide as neoadjuvant chemotherapy in pa- with OLAparib single agent.(NOBROLA study). Cancer Res. tients(pts)withHER2-negativeearlybreastcancer(BC)and 2018;78(13 Supplement):CT165. homologousrecombinationdeficiency(HRD).JClinOncol. 27. Patsouris A,Tredan O,Nenciu D, Tran-Dien A, Cam- 2019;37(15_suppl):506. pion L, Goncalves A,et al. RUBY:A phaseIIstudy 22. Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, testing rucaparib in germline (g) BRCA wild-type pa- Gazinska P, et al. Carboplatin in BRCA1/2-mutated and tients presenting metastatic breast cancer (mBC) with ho- triple-negative breast cancer BRCAness subgroups: the mologous recombination deficiency (HRD). J Clin Oncol. TNT Trial. NatMed. 2018;24(5):628–37. 2019;37(15_suppl):1092. 23. Loibl S, O’Shaughnessy J, Untch M, Sikov WM, Rugo HS, Publisher’s Note Springer Nature remains neutral with regard McKee MD, et al. Addition of the PARP inhibitor veli- to jurisdictional claims in published maps and institutional parib plus carboplatin or carboplatin alone to standard affiliations. neoadjuvant chemotherapy in triple-negative breast can- cer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018;19(4):497–509. 24. Robson M, Im SA, Senkus E,Xu B,Domchek SM,Ma- suda N, et al. Olaparib for metastatic breast cancer in For latest news from interna- patients with a germline BRCA mutation. N Engl J Med. tional oncology congresses see: 2017;377(6):523–33. http://www.springermedizin.at/ 25. Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, et al. Talazoparib in patients with advanced breast can- memo-inoncology cer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753–63. K Homologous recombination deficiency in breast cancer 379 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png memo - Magazine of European Medical Oncology Springer Journals

Homologous recombination deficiency in breast cancer

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short review memo (2020) 13:375–379 https://doi.org/10.1007/s12254-020-00624-x Homologous recombination deficiency in breast cancer Thomas Bartl · Alex Farr Received: 2 April 2020 / Accepted: 14 May 2020 / Published online: 9 June 2020 © The Author(s) 2020 Summary BRCA mutation-related DNA repair defi- Keywords BRCA · Breast cancer · Homologous ciencies increase the individual sensitivity to DNA- recombination deficiency · PARP inhibitor targeting agents. Therefore, the patient’s BRCA muta- Abbreviations tional status is evaluated in clinical practice as a pre- DSB Double-strand break dictive marker in response to platinum salts and poly- HR Homologous recombination ADP-ribose polymerase (PARP) inhibitors for breast ORR Overall response rate cancer treatment. A substantial subset of BRCA wild- PARP Poly-ADP-ribose polymerase type breast cancer lesions, however, share both promi- pCR Pathological complete response nent molecular characteristics and clinical behavior SSB Single-strand break patterns with cancer that harbors BRCA mutations, TNBC Triple-negative breast cancer including DNA repair deficiencies. Also referred to as “BRCAness”, this observation is related to aberrations of the homologous recombination (HR) repair path- Introduction way, which deprive cancer cells of the ability to ade- quately mend potentially lethal double-strand breaks Growing evidence supports the increased clinical effi- and result in a BRCA-like genomic instability. Hence, cacy of DNA-targeting therapies in breast cancers har- HR deficiency is a promisingtargetfor related ther- boring BRCA1 and/or BRCA2 mutations as BRCA func- apeutic options and the predictive potential of HR tion is pivotal to DNA-damage response [1]. BRCA testing for treatment response has been increasingly mutations are observed in approximately 5–10% of studied. Several HR deficiency-testing assays have unselected breast cancers and 20–40% of all triple- been proposed and prospectively validated for vari- negative breast cancers (TNBCs). Up to 15% more ous cancer types; however, preliminary results in early have been hypothesized to express non-BRCA-related breast cancer are inconsistent. As scientific evidence alterations in the DNA repair pathway of homologous for a potential therapeutic benefit in breast cancer is recombination (HR) repair [2–4]. TNBCs typically ex- scarce, HR testing remains highly experimental and press few therapeutic targets; defining a predictive should be limited to the boundaries of clinical studies marker to identify patients that will most likely bene- until results of ongoing phase 3 trials are available. fit from DNA targeting agents, such as platinum salts and poly-ADP-ribose polymerase (PARP) inhibitors, may therefore expand the therapeutic armamentar- ium for a clinically highly relevant subset of patients with breast cancer. Dr. T.Bartl,MD BA ·A. Farr,MD PhD () Division of General Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Homologous recombination deficiency as Medical University of Vienna, Waehringer a marker for treatment response Guertel 18–20, 1090 Vienna, Austria alex.farr@meduniwien.ac.at The ability to adequately repair DNA double-strand breaks (DSBs) relies on HR repair, which reconstructs Dr. T.Bartl,MD BA thomas.bartl@meduniwien.ac.at damaged DNA by copying the respective undam- K Homologous recombination deficiency in breast cancer 375 short review aged strand from the homologous sister chromatid. Defining and diagnosing homologous A complex set of proteins is required to interact recombination deficiency within this procedure, including the gene products of BRCA1, BRCA2, PALB2, RAD51, ATM,and CHEK2. Several methodologically different approaches to test Any dysfunctional protein involved may impair the HR deficiency in breast cancer have been proposed. ability to adequately mend DSBs, thereby inducing The so-called “genomic scarring” assays aim to quan- a phenotypical cell behavior termed HR deficiency or tify genomic aberrations by next-generation whole “BRCAness.” As HR repair fails, DSBs are frequently genome sequencing. The “myChoice” HR deficiency referred to non-homologous end joining (NHEJ) re- test (Myriad Genetics Inc., Salt Lake City, Utah, USA) pair, an error-prone process of random end-to-end calculates a score of sections of losses of heterozy- fusion of damaged strands, which inevitably leads to gosity, large-scale transitions, and telomeric allelic information loss, accumulation of genetic damage, imbalance as three combined DNA-based measures and ultimately to cell death. Since the ability of HR- of genomic instability [10]. The “CDx BRCA LOH” deficient cells to cope with DNA damage is there- (Foundation Medicine, Cambridge, Massachusetts, fore limited, phenotypical HR deficiency is associated USA) assesses deleterious BRCA1 and/or BRCA2 mu- with increased sensitivity to therapeutic agents tar- tations. With the implementation of HR deficiency geting DNA integrity, particularly PARP inhibitors and testing in treatment decision-making for epithelial platinum salts [1]. ovarian cancer, recent comparative trials have fo- PARP inhibitors induce an excess of DNA single- cused on validating genomic scarring assays. Further, strand breaks (SSBs) by inhibiting the activity of base recent clinical studies have used genomic scarring excision repair and foster DSB by trapping PARP at assays to assess HR deficiencies in breast cancer the DNA, thereby blocking the replication fork [5]. [11–14]. A growing body of evidence, however, also indicates Moreover, previously defined complex patterns of direct involvement of other DNA repair systems, as somatic mutations throughout the whole genome, so- PARP can be trapped on DNA at sites of unrepaired called gene signatures, have been validated as predic- SSBs, thereby directly contributing to lethal effects of tors of HR-deficient tumors. The HRDetect test has PARP inhibitors [6]. Moreover, radiosensitization ef- been designed to detect HR deficiency with high sen- fects of PARP inhibition may be explained by inter- sitivity based on such gene signature analyses [15]. fering with HR-independent so-called PARP1-depen- It has been hypothesized that such gene signature- dent end-joining [7]. In contrast, the principal effect based tests compensate a major shortcoming of ge- of platinum salts relies on the induction of interstrand nomic scarring assays, i.e., recognition of BRCA pro- and intrastrand DNA cross-links. The repair of such moter hypermethylation-related HR deficiency. Such cross-links depends on a complex interaction of man- transcriptional deactivation of BRCA function is re- ifold single- and double-strand repair systems includ- versible and not predictive of therapy response, even ing HR. Therefore, deficient cells often fail to restore though it is associated with higher “myChoice” HR proper DNA architecture. Moreover, cross-link-related scores. Large studies assessing different HR deficiency distortions of the DNA double helix promote SSBs and tests are urgently needed to clarify these findings [16, DSBs [8, 9]. 17]. Lastly, protein function of crucial steps in HR such as RAD51 can be assessed using DNA sequencing and immunostaining assays to predict HR deficiency. Table 1 Clinical trials assessing homologous recombination deficiency in breast cancer patients Study Study design Agent No Patients pCR/ORR in HRd patients with or without platinum PrECOG0105/ Phase 2 Carboplatin, gemcitabine, 148 Neoadjuvant pCR: 42% vs. 10% pooled Cisplatin-1 and single-arm iniparib and cisplatin + TNBC OR 6.52; [1.36–31.2]; p < 0.01 2[8] bevacizumab pCR: 27.5% vs. 0% OR 17; [1.91–2249]; p < 0.01 GeparSixto Phase 2 Paclitaxel, doxoru- 595 Neoadjuvant TNBC pCR: 63.5% vs. 33.9% [17] randomized bicin ± carboplatin and Her2 positive OR 3.4 [1.7–6.9]; p < 0.01 open label GeparOLA (Abstract, Phase 2 Olaparib, paclitaxel 102 Neoadjuvant pCR: 20% vs. 56.2% NCT02789332) randomized versus carboplatin, TNBC or Her2 nega- OR not reported; p < 0.01 open label paclitaxel tive TNT [14] Phase 3 Carboplatin versus docetaxel 376 Unselected ad- ORR 38.2% vs. 40.4% randomized vanced OR not reported; p = 1.0 open label TNBC HR homologous recombination repair, OR odds ratio, ORR overall response rate, pCR pathological complete response, TNBC triple negative breast cancer HR deficiency (HRd) was defined by the “myChoice” HR (Myriad Genetics) assay for all studies listed 376 Homologous recombination deficiency in breast cancer K short review Broad availability and independence of commercial The TNT trial, a randomized, open-label phase 3 testing may favor this approach, especially in lower- study comparing carboplatin with docetaxel in 376 pa- income countries. However, its clinical applicability tients with unselected advanced TNBC, reported that is limited as RAD51 assays cannot be performed on patients with BRCA-mutated tumors achieved higher formalin-fixed paraffin-embedded blocks, but they overall response rates (ORRs) after carboplatin treat- require viable tumor tissue [17]. ment than after docetaxel treatment (68.0% versus 33.3%). There was no significant difference in ORR in patients with HR-deficient tumors after carboplatin Studies assessing homologous recombination and docetaxel treatment (38.2% versus 40.4%). This deficiency in breast cancer patients finding could partially be explained by the fact that Despite promising preliminary results, published tri- the HR deficiency test was performed on archival sam- als comprise heterogeneous populations and study ples of the primary tumor, which could result in lower designs, which hinder direct comparisons and limit positive predictive value as tumor evolution processes drawing conclusions for clinical practice. Table 1 pro- and inherent accumulation of genomic scars could vides an overview of recent clinical studies evaluating not be depicted [22]. the predictive value of HR assessment. Results appear most promising for predicting ther- Future perspectives apy response to platinum salts in a neoadjuvant set- ting.Telli et al.[10] retrospectively assessed the pre- As current evidence is limited, several ongoing clinical dictive value of the “myChoice” HR test in three single- trials assessing treatment response to platinum salts arm trials (PrECOG0105 and pooled cisplatin 1 and and PARP inhibitors, stratified by HR assessment, are cisplatin 2) of neoadjuvant platinum therapy com- expected to further elucidate the role of HR for ther- prising 148 patients with TNBC. Patients with HR- apy decision-making in patients with breast cancer. deficient tumors achieved higher pathological com- A Chinese randomized phase 3 trial (NCT03876886) plete response (pCR) rates with the addition of platin is studying dose-dense epirubicin/cyclophosphamide (PrECOG0105, pCR 42% versus 10%, OR 6.52; 95% CI followed by paclitaxel and carboplatin/paclitaxel as 1.36–31.2, and cisplatin 1 and 2, pCR 27.5% versus 0%, adjuvant therapy of TNBC stratified by HR assess- OR 17; 95% CI 1.91–2249). ment. Moreover, a post-hoc HR deficiency analysis Moreover, a post-hoc analysis of the GeparSixto of the BrighTNess phase 3 trial, comparing veliparib trial, a randomized phase 2 study assessing the addi- plus carboplatin versus carboplatin alone, is currently tional benefit of carboplatin to anthracycline/taxane- underway and may provide insights into the predic- based treatment for neoadjuvant chemotherapy reg- tive value of HR testing in this cohort [23]. imens in 595 patients with primary, nonmetastatic The phase III trials OlympiAD and EMBRACA have TNBC and her2-positive breast cancer, reported proved that PARP inhibitors have the potential to higher pCR rates in patients with HR-deficient tu- increase PFS compared to standard chemotherapy mors with the addition of carboplatin (63.5% vs. in pretreated advanced BRCA mutated breast cancer 33.9%, OR 3.4, 95% CI 1.7–6.9) [18]. The long-term [24, 25]. HR testing could greatly expand the scope survival analysis, however, could not prove a corre- of patients benefiting from these treatment options. lation between HR deficiency and patient prognosis To prove this hypothesis, several clinical phase 2 [19]. trials are currently ongoing, testing the efficacy of The ongoing randomized phase 2 trial TBCRC030 PARP inhibitors depending on the HR status; the (NCT01982448) of neoadjuvant cisplatin versus pa- agents involved in these studies include talazoparib clitaxel in 140 patients with TNBC preliminarily re- in the TBB (talazoparib beyond BRCA) trial, olaparib ported that the pCR rate of patients with HR-defi- in the NOBROLA trial, and rucaparib in the RUBY cient tumors was 21.1% in the carboplatin cohort and trial [26, 27]. In addition, a phase 2 three-armed trial 19.4% in the paclitaxel cohort [20]. The also ongoing (NCT03330847) is testing olaparib in combination GeparOLA (NCT02789332) study, a randomized open- with the DNA damage response inhibitors adavosertib label phase 2 trial of paclitaxel/olaparib 100 mg BID and AZD6737, stratified by HR assessment. versus paclitaxel/carboplatin both followed by epiru- bicin/cyclophosphamide as neoadjuvant treatment in Conclusions 102 patients with her2-negative early breast cancer, preliminarily reported that pCR rate was not statis- Thepredictivevalue of the BRCA mutational sta- tically significant different between the olaparib arm tus has been validated for platinum salt and PARP and the carboplatin arm. In the subgroup of patients inhibitor therapy; however, published trials do not with HR-deficient tumors, pCR rates were 52.6% in provide evidence of whether HR deficiency is an ade- the olaparib arm and 20.0% in the carboplatin arm, quate marker for therapy decision-making in patients whereas in the subgroup of patients with HR-profi- with breast cancer. Further studies and large com- cient tumors, the rates were 56.0 and 59.3%, respec- parative phase 3 trials are warranted to substantiate promising results of the currently published retro- tively [21]. K Homologous recombination deficiency in breast cancer 377 short review 6. Gogola E, Rottenberg S, Jonkers J. Resistance to PARP spective and early clinical studies. Similar to clinical inhibitors: lessonsfrompreclinicalmodelsofBRCA-associ- routines of epithelial ovarian cancer, HR deficiency atedcancer. Annu Rev Cancer Biol. 2019;3(1):235–54. testing may identify subsets of breast cancer patients 7. KotterA,CornilsK,BorgmannK,Dahm-DaphiJ,PetersenC, that are likely to benefit from platinum salt or PARP Dikomey E, et al. Inhibition of PARP1-dependent end-join- inhibition therapy in the future. ing contributes to olaparib-mediated radiosensitization in tumor cells. Mol Oncol. 2014;8(8):1616–25. 8. Hinz JM. Role of homologous recombination in DNA Take-home messages interstrand crosslink repair. Environ Mol Mutagen. 2010;51(6):582–603. Homologous recombination (HR) dec fi iency may rep- 9. Legerski RJ. Repair of DNA interstrand cross-links during S resent a valuable biomarker for therapy response to phase of the mammalian cell cycle. Environ Mol Mutagen. PARP inhibitors and platinum salts. 2010;51(6):540–51. The clinical use of HR deficiency could be of partic- 10. TelliML,TimmsKM,ReidJ,HennessyB,MillsGB,JensenKC, ular importance in women with TNBC. et al. Homologous Recombination Deficiency (HRD) score predicts response to platinum-containing neoadju- Ongoing trials are assessing the predictive value of vant chemotherapy in patients with triple-negative breast commercially available “genomic scarring” assays cancer. Clin Cancer Res. 2016;22(15):3764–73. that aim to quantify HR-related DNA-based mea- 11. Gonzalez-Martin A, Pothuri B, Vergote I, DePont Chris- sures of genomic instability. tensen R, Graybill W, Mirza MR, et al. Niraparib in patients As there is no concrete evidence for the predictive with newly diagnosed advanced ovarian cancer. N Engl J value of HR deficiency, HR testing should currently Med. 2019;381(25):2391–402. be limited to clinical trials. 12. Coleman RL, Fleming GF, Brady MF, Swisher EM, Stef- fensen KD, Friedlander M, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian can- Funding Open access funding provided by Medical University cer. N Engl J Med. 2019;381(25):2403–15. of Vienna. 13. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Re- Conflict of interest T. Bartl and A. Farr declare that they have dondo A, et al. Niraparib maintenance therapy in plat- no competing interests. inum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154–64. Open Access This article is licensed under a Creative Com- 14. Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, mons Attribution 4.0 International License, which permits et al. TBCRC009: a multicenter phase II clinical trial use, sharing, adaptation, distribution and reproduction in of platinum monotherapy with biomarker assessment in any medium or format, as long as you give appropriate credit metastatic triple-negative breast cancer. J Clin Oncol. to the original author(s) and the source, provide a link to 2015;33(17):1902–9. the Creative Commons licence, and indicate if changes were 15. Davies H, Glodzik D, Morganella S, Yates LR, Staaf J, Zou X, made. 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Journal

memo - Magazine of European Medical OncologySpringer Journals

Published: Dec 1, 2020

Keywords: oncology; medicine/public health, general

References