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Systemic Therapy for Hereditary Breast Cancers

  • Elizabeth J. Harvey-Jones
    Affiliations
    The Breast Cancer Now Research Unit, Guy's Hospital Cancer Centre, SE1 9RT, United Kingdom

    The City of London Cancer Research UK Centre at Kings College London, SE1 9RT, United Kingdom
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  • Christopher J. Lord
    Affiliations
    The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom

    The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
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  • Andrew N.J. Tutt
    Correspondence
    Corresponding author. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, England SW3 6JB.
    Affiliations
    The Breast Cancer Now Research Unit, Guy's Hospital Cancer Centre, SE1 9RT, United Kingdom

    The City of London Cancer Research UK Centre at Kings College London, SE1 9RT, United Kingdom

    The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom
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      Keywords

      Key points

      • 5-10% of all breast cancers are associated with mutations in hereditary breast cancer genes several of which are involved in the DNA damage response.
      • BRCA1 and BRCA2 mutation is not associated with poor prognosis in breast cancers, but infact better prognosis when treated with chemotherapy in comparison to similar non BRCA mutated breast cancers.
      • Treatment with the small molecule PARP inhibitor olaparib after chemotherapy improves overall survival in patients with early breast cancer and germline BRCA1 or BRCA2 mutations.
      • Platinum based chemotherapy is highly active in those with germline BRCA1 or BRCA2 mutations but cross resistance between platinum agents and PARP inhibitors can be mediated by somatic “reversion mutations” in BRCA1 or BRCA2 and is a clinical challenge.
      • Understanding the underlying mechanisms of overlapping or distinctive resistance is vital to therapy development in this evolving area of translational medicine.

      Introduction

      Approximately 5% to 10% of the 2.3 million breast cancer cases diagnosed annually are associated with a mutation in a known hereditary breast cancer predisposition gene such as BRCA1 or BRCA2.
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      Global, regional, national burden of breast cancer in 185 countries: evidence from GLOBOCAN 2018.
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      Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women.
      The integration of genomics into the standard diagnostic pathways for breast cancer patients and the availability of targeted treatment approaches for those with hereditary breast cancer predisposition gene mutations means that the management of these patients is now distinct to that a decade ago. In this review, we discuss the recent advances made in systemic treatments for hereditary breast cancer and highlight future challenges that must be addressed for improvements in clinical outcomes to be achieved in this distinct subgroup.

      Hereditary Breast Cancer Genes

      Many of the germline mutations associated with hereditary breast cancer occur in “caretaker” tumor suppressor genes (genes whose normal function is to maintain the integrity of the genome and whose dysfunction leads to genome instability) and include BRCA1, BRCA2, PALB2, ATM, CHEK2, and p53.
      • Kinzler K.W.
      • Vogelstein B.
      Landscaping the cancer terrain.
      For example, germline deleterious mutations in BRCA1 (gBRCA1m) or BRCA2 (gBRCA2m), which play key roles in DNA repair by homologous recombination (HR), are associated with an increased lifetime risk of developing breast, ovarian, prostate and pancreatic cancer.
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      • Allen J.
      • et al.
      Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women.
      ,
      • Rahman N.
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      The genetics of breast cancer susceptibility.
      ,
      • Hu C.
      • Hart S.N.
      • Gnanaolivu R.
      • et al.
      A Population-Based Study of Genes Previously Implicated in Breast Cancer.
      gBRCA1m carriers have a cumulative lifetime breast cancer risk of 46% to 60% and when diagnosed with breast cancer typically have the basal-like, triple negative (B-L, TNBC), subtype of the disease. gBRCA2m carriers have a cumulative lifetime breast cancer risk of 43% to 55% and tend to develop estrogen receptor-positive (ER+), luminal B subtype, breast cancers (significantly more so than for gBRCA1m carriers).
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      • et al.
      The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2.
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      • Lopez A.
      • et al.
      Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer.
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      • Barrowdale D.
      • Andrulis I.L.
      • et al.
      Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA).
      • Brekelmans C.T.M.
      • Tilanus-Linthorst M.M.A.
      • Seynaeve C.
      • et al.
      Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared with sporadic breast cancer cases.
      gBRCA1/2m breast cancers in those who have a strong family history are usually detected at a younger age than sporadic breast cancers.
      Germline pathogenic variants in PALB2 (Partner and localizer of BRCA2)––also involved in DNA repair by HR––were first associated with increased cancer risk in 2007.
      • Rahman N.
      • Seal S.
      • Thompson D.
      • et al.
      PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.
      In 2014 Antoniou and colleagues reported a cumulative risk of developing breast cancer by 70 years old of 35% in patients with gPALB2m. This particular study included 311 women with gPALB2m of whom 229 had breast cancer, and 51 men of whom seven had breast cancer.
      • Antoniou A.C.
      • Casadei S.
      • Heikkinen T.
      • et al.
      Breast-cancer risk in families with mutations in PALB2.
      BRCA1, BRCA2, and PALB2 are often regarded as high-penetrance breast cancer susceptibility genes, penetrance here being defined as the likelihood of a particular genotype (eg, gBRCA1m) resulting in a related phenotype (breast cancer). The TP53 tumor suppressor (encoding p53) is also a high penetrance hereditary breast cancer susceptibility gene; individuals who carry a germline mutation in TP53 carry an 80% risk of developing breast cancer by 60 years old.
      • Schon K.
      • Tischkowitz M.
      Clinical implications of germline mutations in breast cancer: TP53.
      TP53 has both caretaker (preventing genome instability) and gatekeeper (preventing uncontrolled cell division and the transmission of mutations to daughter cells) functions. Lower penetrance breast cancer susceptibility genes exist, including the caretaker genes ATM (Ataxia telangiectasia mutant) and CHEK2 (Checkpoint kinase 2). The lifetime risk of developing breast cancer if an individual has germline deleterious mutations in either ATM or CHEK2 is 25% to 30%.
      • Lee A.
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      • et al.
      BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors.
      ,
      • Southey M.C.
      • Goldgar D.E.
      • Winqvist R.
      • et al.
      PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

      Homologous Recombination

      BRCA1, BRCA2, and PALB2 encode proteins involved in the DNA damage response (DDR), playing integral roles in the process of HR. HR, when using an available sister chromatid as a DNA repair template, is a highly conserved, error-free DDR pathway that is activated by the detection of double-stranded DNA breaks (DSB) and stalled DNA replication forks. Upon recognition of such DNA damage, the checkpoint kinase ATM is activated, which leads to a cascade of protein phosphorylation events that localize BRCA1 to the site of DNA damage. BRCA1 recruits the MRN complex (MRE11-RAD50-NBN) to the site of damage, which in turn resects DNA on either side of DSB, generating DNA with ‘3 single-stranded overhangs which becomes bound by the RPA protein. In a PALB2- and BRCA1-dependent process, BRCA2 loads the DNA recombinase RAD51 onto these 3′ single-stranded overhangs, displacing RPA. The DNA/RAD51 nucleoprotein filament that forms then uses RAD51’s ATPase activity to invade the double helix of the homologous strand of DNA which is then used as a template for DNA synthesis, resulting in error-free DNA repair (Fig. 1).
      • Moynahan M.E.
      • Jasin M.
      Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis.
      Loss of function mutations in BRCA1, BRCA2, or PALB2 cause a defect in this process, which ultimately leads to the elevated use of nonconservative forms of DNA repair. These nonconservative DNA repair pathways likely foster tumorigenesis by causing mutations in additional cancer driver genes (reviewed in Lieber and colleagues
      • Lieber M.R.
      The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway.
      ).
      Figure thumbnail gr1
      Fig. 1Homologous recombination. On recognition of DNA damage, the checkpoint kinases ATM, and ATR are activated; BRCA1 localizes to the double-strand break and activates resection of the DNA through recruitment of the MRN complex, which generates 3′ overhangs. In a PALB2 and BRCA1-dependent process BRCA2 loads RAD51 onto single-stranded DNA at the double-strand break site. RAD51 then undertakes a homology search, strand invasion, and DNA repair. ATM, ataxia telangietasia mutant; ATR, ataxia telangietasia and RAD3 related.

      Preclinical Evidence of Effects of BRCA1/2 Mutation on Chemotherapy Efficacy

      Tumor cells with defects in HR, including those with BRCA1 or BRCA2 mutations, exhibit in vitro (and in some cases in vivo) sensitivity to drugs that cause forms of DNA damage that ultimately stall and/or collapse replication forks; these include mitomycin C,
      • Garcia-Higuera I.
      • Taniguchi T.
      • Ganesan S.
      • et al.
      Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.
      bifunctional alkylating agents such as melphalan or the cyclophosphamide metabolite, phosphoramide mustard,
      • Fu D.
      • Calvo J.A.
      • Samson L.D.
      Balancing repair and tolerance of DNA damage caused by alkylating agents.
      topoisomerase II inhibitors,
      • Treszezamsky A.D.
      • Kachnic L.A.
      • Feng Z.
      • et al.
      BRCA1- and BRCA2-deficient cells are sensitive to etoposide-induced DNA double-strand breaks via topoisomerase II.
      ,
      • Jeggo P.A.
      • Caldecott K.
      • Pidsley S.
      • et al.
      Sensitivity of Chinese hamster ovary mutants defective in DNA double strand break repair to topoisomerase II inhibitors.
      the DNA minor groove binding compounds lurbinectedin and trabectedin,
      • Soares D.G.
      • Escargueil A.E.
      • Poindessous V.
      • et al.
      Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743.
      topoisomerases I inhibitors
      • Rahden-Staroń I.
      • Szumiło M.
      • Grosicka E.
      • et al.
      Defective Brca2 influences topoisomerase I activity in mammalian cells.
      and platinum-based chemotherapeutic agents.
      • Tutt A.
      • Tovey H.
      • Cheang M.C.U.
      • et al.
      Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT Trial.
      There are five platinum chemotherapy analogs approved for the treatment of cancer: cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin. The cytotoxic action of the two most commonly used in the treatment of breast cancer, cisplatin, and carboplatin, is largely caused by the formation of intrastrand DNA cross-links between purine bases––that is, platinum-containing molecular bonds between bases on the same DNA strand (interstrand cross-links being formed between bases on opposite strands). The distorted double helix formed by these cross-links is repaired by pathways including nucleotide excision repair and HR. Given DNA damage induced by platinum chemotherapy relies heavily on the repair by HR, it is unsurprising that this group of patients typically respond well to platinum agents, and as such are now commonly given this in the neoadjuvant and advanced settings.
      • Tutt A.
      • Tovey H.
      • Cheang M.C.U.
      • et al.
      Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT Trial.

      Poly-(ADP Ribose) Polymerase Enzymes and Synthetic Lethality

      PARP (Poly-(ADP Ribose) Polymerase) enzymes use NAD + to synthesize, poly-(ADP-ribose) (PAR) chains on substrate proteins, a process known as PARylation.
      • Satoh M.S.
      • Lindahl T.
      Role of poly(ADP-ribose) formation in DNA repair.
      Most of the PARylation events that occur in cells are carried out by PARP1, a protein that detects damaged DNA including alkylated bases and single double-strand breaks in the double helix. PARP1 binds to DNA via N-terminal zinc-finger (ZnF) domains,
      • Langelier M.-F.
      • Planck J.L.
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      Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1.
      ,
      • D’Amours D.
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      • et al.
      Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions.
      an event which causes a conformation change in PARP1’s structure and activation of its catalytic activity. In broad terms, PARP1’s PARylation activity instigates DNA repair by two mechanisms; by PARylating histones, PARP1 activity leads to the remodeling of chromatin structure to a degree that DNA repair is enabled, and by PARylating DNA repair proteins (including XRCC1) PARP1 activity concentrates DNA repair effectors at the site of DNA damage.
      • Krastev D.B.
      • Wicks A.J.
      • Lord C.J.
      PARP Inhibitors - Trapped in a Toxic Love Affair.
      Once DNA has been successfully repaired, PARP1 autoPARylates. This autoPARylation imparts a negative charge on PARP1, repelling it from DNA once it has detected and amplified the DDR.
      • Hilz H.
      • Stone P.
      Poly(ADP-ribose) and ADP-ribosylation of proteins.
      ,
      • Purnell M.R.
      • Stone P.R.
      • Whish W.J.
      ADP-ribosylation of nuclear proteins.
      The role of PARP1 (and also its paralog PARP2) in DNA repair provided the rationale for discovering small molecule inhibitors of PARP1 and PARP2 (PARPi), which were initially envisaged to be used as chemo- or radiosensitisers.
      • Zaremba T.
      • Curtin N.J.
      PARP inhibitor development for systemic cancer targeting.
      Clinically approved PARPi such as olaparib, talazoparib, niraparib, and rucaparib trap PARP1 and 2 on DNA as well as inhibiting PARP catalytic activity; this PARP1 trapping capacity appears to make a greater contribution to tumor cell cytotoxicity in BRCA1/2 defective tumor cells than the ability to inhibit the catalytic activity of PARP1. For example, the experimental PARPi veliparib is a potent catalytic inhibitor but has lower PARP1 trapping capacity when compared with other PARPi; its ability to elicit BRCA1/2 synthetic lethality is also much reduced when compared with PARPi with higher trapping properties.
      • Shen Y.
      • Rehman F.L.
      • Feng Y.
      • et al.
      BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency.
      ,
      • Murai J.
      • Huang S.Y.N.
      • Das B.B.
      • et al.
      Trapping of PARP1 and PARP2 by clinical PARP inhibitors.
      In 2005, two independent research groups showed that BRCA1 and BRCA2 defective cells were profoundly sensitive to drug-like PARPi, both in vitro and in vivo.
      • Farmer H.
      • McCabe H.
      • Lord C.J.
      • et al.
      Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
      ,
      • Bryant H.E.
      • Schultz N.
      • Thomas H.D.
      • et al.
      Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
      Subsequent work showed that defects in other HR genes also caused profound PARPi sensitivity.
      • McCabe N.
      • Turner N.C.
      • Lord C.J.
      • et al.
      Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.
      These observations provided the preclinical rationale for instigating clinical trials assessing the potential of PARPi as single agent synthetic lethal treatments for HR defective cancers, using BRCA1m or BRCA2m as a surrogate of this HR defective status and as patient stratification biomarkers.

      Systemic Treatment in Early Breast Cancer

      Neoadjuvant chemotherapy

      BRCA1/2 mutation-associated breast cancer carries a better prognosis when treated with chemotherapy. For example, in a study conducted by Rennert and colleagues in 2007, the hazard ratio (HR) for death among gBRCA1m breast cancer patients receiving chemotherapy was 0.48 (95%CI 0.19–1.21, P = .12) compared with those who did not receive chemotherapy.
      • Rennert G.
      • Bisland-Naggan S.
      • Barnett-Griness O.
      • et al.
      Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations.
      Multiple studies have reviewed the efficacy of neoadjuvant chemotherapy (NACT) in gBRCAm breast cancer, some of which are summarized in Table 1. The surrogate endpoint for clinical efficacy in such studies is usually pathologic response, a metric measured by analyzing the residual disease volume in a surgical specimen retrieved following NACT. A prospective cohort study carried out by Byrski and colleagues in 2010 looked specifically at pathologic response in patients with gBRCA1m following NACT (n = 103). They reported a higher pathologic complete response (pCR) rate (83.3%) in the group treated with cisplatin in comparison to other standard NACT regimens.
      • Byrski T.
      • Gronwald J.
      • Huzarski T.
      • et al.
      Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy.
      In the same year Silver and colleagues published data on the efficacy of neoadjuvant cisplatin in TNBC in a cohort of 28 patients, five of whom exhibited low tumoral expression of BRCA1 mRNA and two of which had gBRCA1m.
      • Silver D.P.
      • Richardson A.L.
      • Eklund A.C.
      • et al.
      Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer.
      The gBRCA1m carriers achieved pCR after treatment with cisplatin and the five patients with low BRCA1 mRNA expression had a better clinical response to treatment than those with high BRCA1 mRNA expression (although did not achieve pCR), suggesting that TNBC patients whose tumors exhibited “BRCAness” (ie, a phenocopy of gBRCAm cancer, for example, caused by reduced BRCA1 mRNA levels)
      • Lord C.J.
      • Ashworth A.
      BRCAness revisited.
      may be more sensitive to platinum agents than non BRCA associated TNBC.
      Table 1Clinical trials published in early breast cancer
      Trial NamePhaseTreatmentSettingEndpointKey ResultsAuthors
      GeparSixtoIICarboplatin vs SOC chemotherapyNeoadjuvantpCRpCR 65 % vs 66.7% (gBRCAm group)Hahnen et al.
      • Hahnen E.
      • Lederer B.
      • Hauke J.
      • et al.
      Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial.
      INFORMIICisplatin vs ACNeoadjuvantpCRpCR 18% vs 26%Tung et al.
      • Tung N.
      • Arun B.
      • Hacker M.R.
      • et al.
      TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial).
      ISPY-2IIIVeliparib + carboplatin (VC) + paclitaxel + AC vs paclitaxel + ACNeoadjuvantpCRpCR 51% (VC TNBC group) vs 26% (no VC TNBC group)Rugo et al.
      • Rugo H.S.
      • Olopade O.I.
      • DeMichele A.
      • et al.
      Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer.
      BrighTNessIII3 groups: 1. Veliparib, carboplatin + paclitaxel (VCP) + AC 2. carboplatin + paclitaxel (CP) + AC 3. Paclitaxel + AC (P)NeoadjuvantpCRpCR VCP 53% vs P 31% P<.0001. pCR VC 58%, P = .36Loibl et al.
      • Loibl S.
      • O’Shaughnessy J.
      • Untch M.
      • et al.
      Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.
      GeparOLAIIOlaparib + paclitaxel (OP) vs carboplatin + paclitaxel (CP)NeoadjuvantpCRpCR OP 55.1% vs CP 48.6%Fasching et al.
      • Fasching P.A.
      • Jackisch C.
      • Rhiem K.
      • et al.
      GeparOLA: A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (BC) and homologous recombination deficiency (HRD).
      OlympIAIIIOlaparib vs placeboAdjuvantIDFSIDFS 87.5% vs 80.4%Tutt et al.
      • Tutt A.N.J.
      • Garber J.E.
      • Kaufman B.
      • et al.
      Adjuvant Olaparib for Patients with BRCA1 - or BRCA2 -Mutated Breast Cancer.
      CREATE-XIIICapecitabine + standard post-surgical treatment vs no capecitabine (control)AdjuvantDFSDFS 69.8% vs 56.1%Masuda et al.
      • Masuda N.
      • Lee S.-J.
      • Ohtani S.
      • et al.
      Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy.
      Abbreviations: AC, doxorubicin + cyclophosphamide; DFS, disease free survival; IDFS, invasive disease free survival; pCR, pathologic complete response; SOC, standard of care.
      Data on germline BRCA1 and BRCA2 carriers have since become available from larger scale randomized control trials (RCTs) such as GeparSixto, a phase II RCT which reviewed the efficacy of adding carboplatin to standard of care (SOC) NACT. GeparSixto enrolled 588 patients with TNBC or HER2+ breast cancer who were randomized to receive either a backbone of paclitaxel and liposomal doxorubicin, or paclitaxel/liposomal doxorubicin plus carboplatin. An increased response rate was seen in the TNBC group subgroup who received carboplatin.
      • von Minckwitz G.
      • Schneeweiss A.
      • Loibl S.
      • et al.
      Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): A randomised phase 2 trial.
      In a subsequent analysis, the same investigators sought to determine if gBRCA1m or gBRCA2m status affected therapy response in patients with TNBC. The study recruited 291 patients with TNBC, of which 50 had gBRCA1/2m. In the non-carboplatin arm, those with gBRCAm achieved a pCR rate of 66.7% (16/24 patients) in comparison to the non-gBRCAm group pCR rate = 36.4% (44/121 patients). The pCR rate in the carboplatin arm in those with gBRCAm was 65.4% (17/26 patients), but in those without gBRCAm, was 55% (66/120 patients). The investigators concluded that: (i) the addition of carboplatin benefitted the non-gBRCAm group; (ii) those with gBRCAm showed superior response rates to both carboplatin and non-carboplatin containing regimens; (iii) compared with those without mutations, the gBRCAm group did not exhibit any observed extra benefit from the addition of carboplatin.
      • Hahnen E.
      • Lederer B.
      • Hauke J.
      • et al.
      Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial.
      The INFORM study, a phase III RCT carried out by Tung and colleagues, assessed pathologic response in patients with stage 2 to 3 HER2– breast cancer with gBRCAm. Patients were randomized to receive single agent cisplatin (CDDP) or AC (doxorubicin + cyclophosphamide) before definitive surgery. The pCR rate in the CDDP group was 18% versus 26% in the AC group (risk ratio (RR) 0.70; 90% confidence interval (CI) 0.39–1.2). The investigators concluded that pCR was not significantly higher with CDDP versus AC in gBRCAm carriers.
      • Tung N.
      • Arun B.
      • Hacker M.R.
      • et al.
      TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial).
      Data from GeparSixto and INFORM suggest that the addition of platinum treatment to the SOC NACT regimens does not necessarily improve the pCR rate of gBRCAm carriers. Tumors in this group of patients are sensitive to chemotherapeutic agents that intercalate or cross-link DNA such as anthracyclines or alkylating agents; this likely means that, when given in the neoadjuvant setting, the response to SOC chemotherapy is so high that pathologic response rates reach a plateau and any additional effect of platinum agents is thus modest. In contrast, when a DNA cross-linking platinum agent is directly compared with standard-of-care microtubule stabilizing agents in metastatic disease, gBRCAm does predict a greater response to the platinum (discussed later).
      • Tutt A.
      • Tovey H.
      • Cheang M.C.U.
      • et al.
      Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT Trial.
      ,
      • Hu X.C.
      • Zhang J.
      • Xu B.H.
      • et al.
      Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): A randomised, open-label, multicentre, phase 3 trial.

      Neoadjuvant poly-(ADP ribose) polymerase inhibitor monotherapy

      The efficacy and safety of olaparib (PARPi) monotherapy preceding surgery was reported following a window of opportunity study carried out in 2013, where patients were randomized to receive an escalating dose of olaparib 4 days before surgery.
      • Bundred N.
      • Gardovskis J.
      • Jaskiewicz J.
      • et al.
      Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a Phase I multicentre trial in patients scheduled for elective breast cancer surgery.
      A dose-dependent increase in exposure to olaparib was seen but at significantly lower plasma exposure levels than observed in advanced disease studies. The mean maximal PARP inhibition was 51% in peripheral blood and 70% in peripheral tumor tissue. This trial did not lead to an expansion study and there is no current neoadjuvant olaparib (monotherapy) trials.
      Unlike olaparib, talazoparib has been tested in neoadjuvant monotherapy trials in breast cancer. A feasibility study was commenced in 2017 to assess the activity of single-agent talazoparib over 24 weeks and recruited 20 patients with operable HER2 negative, gBRCAm, breast cancer (NCT02282345).
      • Litton J.K.
      • Scoggins M.
      • Ramirez D.L.
      • et al.
      A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity.
      The outcome measure used in this study was residual cancer burden (RCB) with 53% achieving pCR. This proved that delivery and assessment of talazoparib monotherapy was feasible in this setting and a follow-on phase II expansion study was initiated (NEOTALA - NCT 03499353) enrolling 61 patients with stage II-III HER2 negative, gBRCAm, breast cancer. The study's primary endpoint was pCR evaluated by an independent central review. This study reported a pCR rate of 49.2% (80% CI 40.97–57.39).
      • Litton J.K.
      • Scoggins M.E.
      • Hess K.R.
      • et al.
      Neoadjuvant Talazoparib for Patients With Operable Breast Cancer With a Germline BRCA Pathogenic Variant.
      Further neoadjuvant PARPi monotherapy trials are ongoing and include a phase II non-randomized open-label trial (NCT03329937) which has recruited 21 patients with stage 2 to 3 HER2 negative, gBRCAm, breast cancer. Patients in this study receive niraparib monotherapy for 2 months before surgery. The primary outcome measure is tumor response seen on MRI before surgery and secondary outcome is pathologic response in the surgical specimen. The results of this study are awaited.

      Neoadjuvant poly-(ADP ribose) polymerase inhibitor and chemotherapy combinations

      PARPi plus cytotoxic chemotherapy combinations can be challenging to deliver due to issues with toxicity, most notably myelosuppression. However, the I-SPY2 group has reported the feasible combination of the clinical PARPi, veliparib, in combination with carboplatin (VC) and paclitaxel followed by AC in a trial with a Bayesian adaptive design and compared pathologic response outcomes between two groups––either receiving VC or not. The study met the prespecified requirements for graduation to a phase III trial. I-SPY2 reported pCR in 51% of patients who received VC versus 26% without VC in the TNBC subgroup.
      • Rugo H.S.
      • Olopade O.I.
      • DeMichele A.
      • et al.
      Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer.
      Of note, although veliparib is an effective inhibitor of PARP1 catalytic activity, its ability to trap PARP1 and elicit a BRCA1/2 synthetic lethal effect in vitro is limited when compared with other clinical PARPi,
      • Shen Y.
      • Rehman F.L.
      • Feng Y.
      • et al.
      BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency.
      ,
      • Murai J.
      • Huang S.Y.N.
      • Das B.B.
      • et al.
      Trapping of PARP1 and PARP2 by clinical PARP inhibitors.
      which could explain why such a PARPi/chemotherapy combination is achievable with veliparib.
      A further phase III trial, BrighTNess, reported the efficacy of adding veliparib-carboplatin combination to paclitaxel (segment 1) followed by the SOC NACT regimen AC (segment 2) in patients with stage 2 to 3 TNBC. This trial allowed the contribution of veliparib to be dissected away from that of carboplatin by comparing three treatment groups: (i) VC + paclitaxel (VCP); (ii) carboplatin + paclitaxel (CP); and (iii) paclitaxel (P) alone.
      • Loibl S.
      • O’Shaughnessy J.
      • Untch M.
      • et al.
      Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.
      Randomization to segment 1 was stratified by gBRCA1/2m status, nodal stage, and planned schedule for AC administration. A higher pCR rate was seen in the VCP group than in the P group (53% vs. 31%, P<.0001). However, the CP group achieved a pCR rate of 58%, indicating that the increase in pCR achieved by VCP was most likely due to C. A subsequent secondary analysis report at a more mature follow-up focused on an event-free survival (EFS) endpoint and confirmed that the addition of veliparib to carboplatin and paclitaxel did not enhance efficacy over carboplatin and paclitaxel alone.
      • Geyer C.E.
      • Sikov W.M.
      • Huober J.
      • et al.
      Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial.
      There was a strong relationship between pCR and improved EFS that was unaffected by gBRCA1/2m status. As such, it appears the addition of carboplatin improves pCR and EFS in stage II/III TNBC regardless of gBRCA1/2m status and should be offered to high-risk TNBC with gBRCAm. We speculate that the effect of platinum across an unselected group of early TNBCs regardless of gBRCA1/2m status in both BrighTNess and GeparSixto
      • von Minckwitz G.
      • Schneeweiss A.
      • Loibl S.
      • et al.
      Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): A randomised phase 2 trial.
      ,
      • Loibl S.
      • O’Shaughnessy J.
      • Untch M.
      • et al.
      Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.
      may reflect the frequency with which HR is impaired by other genetic and epigenetic mechanisms in early TNBC.
      • Staaf J.
      • Glodzik D.
      • Bosch A.
      • et al.
      Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study.
      Of note the BrighTNess trial has clearly indicated there is no benefit to addition of low trapping potency PARPi such as veliparib, despite the feasibility of combining this PARPi with carboplatin and paclitaxel.
      The PARTNER trial is a phase II/III open-label RCT, testing the potent PARP trapping PARPi olaparib in combination with carboplatin and paclitaxel in the neoadjuvant setting in TNBC including gBRCA1/2m carriers. PARTNER has recently presented the preliminary safety data from the first 2 stages of this trial, describing a manageable toxicity profile for a regimen of low dose of olaparib with brief and intermittent administration of carboplatin.

      Alba K.P., McMurtry E., Vallier A.-L., et al. Abstract P3-10-05: Preliminary safety data from stage 1 and 2 of the phase II/III PARTNER trial: Addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients. In: Poster Session Abstracts. American Association for Cancer Research; 2020. Virtual Meeting - 22-24 June 2020. 10.1158/1538-7445.SABCS19-P3-10-05.

      The most common adverse event with this regimen was hematological; CTCAE grade 3 (G3) neutropenia was noted in 19% of patients, anemia in 15% and thrombocytopenia in 5%. The trial has now completed accrual of its third stage, which evaluates efficacy through measurement of pCR rate but is yet to report its findings.
      GeparOLA, a phase II RCT, reported the safety and efficacy of a reduced but continuous dose olaparib used in combination with 12 weeks of weekly paclitaxel compared with paclitaxel plus carboplatin (AUC2) ahead of four cycles of standard or dose-dense epirubicin-cyclophosphamide (EC) chemotherapy as neo-adjuvant chemotherapy before definitive surgery. This trial included patients with HER2 negative stage 2 to 3 breast cancer with either gBRCAm or a mutational signature of homologous recombination deficiency (HRD). The paclitaxel and olaparib group achieved modestly higher pCR rates when compared with paclitaxel and carboplatin group (55.1% vs. 48.6%), although this did not reach the prespecified pCR rate of greater than 55%.
      • Fasching P.A.
      • Jackisch C.
      • Rhiem K.
      • et al.
      GeparOLA: A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (BC) and homologous recombination deficiency (HRD).
      This high level of pCR was achieved with significantly fewer serious adverse events (SAEs) (13% vs 51%) than with the standard paclitaxel and carboplatin regimen. Of note, the hormone receptor-positive population of patients with HR-deficient breast cancer achieved pCR of 52.6% with olaparib compared with 20% with carboplatin. This provides a strong rationale for continuing to investigate the combination of a potent PARP1 trapping inhibitor in place of carboplatin in larger phase three trials in HR deficient breast cancer.

      Adjuvant poly-(ADP ribose) polymerase inhibitor monotherapy

      The OlympiA study (NCT02032823) recruited patients with high-risk HER2 negative breast cancer, with germline pathogenic or likely pathogenic BRCA mutations; these were randomized to receive either 12 months of postoperative olaparib or placebo in a double-blind design. The prespecified interim analysis (at 2.5 years median follow-up) described significant improvements in invasive disease-free survival (IDFS), HR 0.58 (99.5%CI 0.41–0.82; P<.001) and distant disease-free survival (DDFS), HR 0.57 (99.5%CI 0.39–0.83, P<.001).
      • Tutt A.N.J.
      • Garber J.E.
      • Kaufman B.
      • et al.
      Adjuvant Olaparib for Patients with BRCA1 - or BRCA2 -Mutated Breast Cancer.
      Since this, the second prespecified analysis of OS and updated invasive disease-free survival (IDFS) associated with a median follow-up of 3.5 years has been reported. This analysis indicated that olaparib significantly improved overall survival (OS) with an HR for invasive disease or death of 0.68 (95%CI 0.47–0.97; P = .009) and showed that the IDFS and DDFS benefits seen in the first interim analysis were maintained.
      • Tutt A.N.J.
      • Garber J.
      • Gelber R.D.
      • et al.
      VP1-2022: Pre-specified event driven analysis of Overall Survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer.
      This is the first trial reporting the OS benefits of olaparib as monotherapy in the adjuvant setting and has led to an FDA approval as an adjuvant therapy after chemotherapy in patients with high recurrence risk, HER2 negative, gBRCA1/2m early breast cancer and changed treatment guidelines from ASCO,
      • Tung N.M.
      • Zakalik D.
      • Somerfield M.R.
      Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update.
      ESMO,
      • Gennari A.
      • André F.
      • Barrios C.H.
      • et al.
      ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer.
      NCCN
      • Gradishar W.J.
      • Moran M.S.
      • Abraham J.
      • et al.
      NCCN Guidelines® Insights: Breast Cancer, Version 4.2021.
      , and the St Gallen Consensus panel.
      • Burstein H.J.
      • Curigliano G.
      • Thürlimann B.
      • et al.
      Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.

      Adjuvant chemotherapy

      Masuda and colleagues reported the efficacy of adjuvant capecitabine in TNBC patients with HER2 negative breast cancer who have residual disease after NACT (CREATE-X).
      • Masuda N.
      • Lee S.-J.
      • Ohtani S.
      • et al.
      Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy.
      Patients were randomized to receive oral capecitabine in addition to standard post-surgical treatment, or no capecitabine (control). DFS in the TNBC subgroup was longer in the capecitabine group than in the control cohort (69.8% vs. 56.1%, HR 0.58 (95%CI 0.39–0.87)). HR for death at 5 years was 0.52 (95% CI 0.30–0.90). There were no subgroup analyses looking at a BRCA deficient cohort; however, this trial was the first of its kind, reporting the efficacy of a second adjuvant chemotherapy in the high-risk TNBC subpopulation with residual disease after NACT. GEICAM-CIBOMA was a phase III RCT with a different design which looked at the value of adding capecitabine following SOC NACT in patients with TNBC; analysis of this study indicated that additional benefit was limited to the non-B-L subgroup and was not significant overall.
      • Lluch A.
      • Barrios C.H.
      • Torrecillas L.
      • et al.
      Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01).
      The safety of a capecitabine and olaparib combination is untested and so physicians face making a choice as to whether patients with gBRCAm and residual TNBC after NACT will benefit more from capecitabine chemotherapy over olaparib in the early setting. Data from advanced disease trials, discussed below (OlympiAD and EMBRACA), in which the SOC chemotherapy backbone was most commonly capecitabine, suggest that olaparib significantly outperforms capecitabine in the metastatic setting in gBRCAm breast cancer and that the performance of adjuvant capecitabine in B-L breast cancer in the second adjuvant setting appears very poor. As a result, we suggest olaparib would seem the more appropriate choice given the high frequency of B-L breast cancer in gBRCAm carriers.
      • Mayer I.A.
      • Zhao F.
      • Arteaga C.L.
      • et al.
      Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131.

      Systemic Treatment in Advanced Breast Cancer

      Chemotherapy in advanced breast cancer

      When used in the advanced setting, platinums have been shown to elicit profound responses when compared with taxanes. A small phase II study carried out in 2012 reported the efficacy of single-agent cisplatin chemotherapy in gBRCA1m metastatic breast cancer. Patients were treated with 6 cycles of cisplatin; the overall response rate (ORR) was 80% (18 of 20 patients); 45% (9 of 20 patients) achieved a complete clinical response with 35% (7 of 20 patients) experiencing a partial response.
      In 2015 the CBCSG006 phase III RCT was published. This study compared cisplatin + gemcitabine versus paclitaxel + gemcitabine in metastatic TNBC and found that cisplatin + gemcitabine was superior to paclitaxel + gemcitabine (HR for PFS of 0.692, 95% CI 0.523–0.915, p superiority = 0.009). The study group concluded that platinum-based chemotherapy in conjunction with gemcitabine should be considered as first-line treatment of mTNBC.
      • Hu X.C.
      • Zhang J.
      • Xu B.H.
      • et al.
      Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): A randomised, open-label, multicentre, phase 3 trial.
      The phase III RCT, TNT, assessed the role of carboplatin versus SOC docetaxel in advanced TNBC. Patients with gBRCAm in the carboplatin-treated group had a significantly improved progression-free survival (PFS) in comparison to the SOC group (6.8 months vs 4.4 months; P = .002). In addition to convincing data generated in the gBRCAm group, patients were also prespecified to be analyzed as putative ‘BRCAness’ subgroups in which their BRCA1-methylation status and their HRD genomic (HRD) score were taken into account. In contrast to the gBRCAm cohort of patients, these groups seemed to derive no selective benefit from platinum agents over docetaxel; one hypothesis is that in the BRCAness but not gBRCAm patients, the loss of epigenetically driven BRCAness during disease evolution from primary to the metastatic setting might reverse an HR defect and prevent carboplatin sensitivity.
      • Tutt A.
      • Tovey H.
      • Cheang M.C.U.
      • et al.
      Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT Trial.
      Following the publication of the TNT trial, guidelines have included recommending the use of platinum chemotherapy for patients with gBRCAm in early and advanced breast cancer.
      • Gennari A.
      • André F.
      • Barrios C.H.
      • et al.
      ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer.
      ,
      • Giordano S.H.
      • Elias A.D.
      • Gradishar W.J.
      NCCN Guidelines Updates: Breast Cancer.

      Poly-(ADP ribose) polymerase inhibitor monotherapy in advanced breast cancer

      In 2009 Fong and colleagues reported the safety and efficacy of olaparib monotherapy in the phase I study of olaparib in advanced previous treatment-refractory solid tumors. The study enrolled 60 patients overall, including 23 with gBRCAm, three of whom had breast cancer. No objective responses were seen in the non-BRCAm group, whereas 63% of gBRCAm patients derived clinical benefit from olaparib.
      • Fong P.C.
      • Boss D.S.
      • Yap T.A.
      • et al.
      Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers.
      Following publication of this data, two phase II trials were carried out showing proof of concept and tolerability for the efficacy of single agent olaparib in advanced stage breast and ovarian cancer.
      • William Audeh M.
      • Carmichael J.
      • Penson R.T.
      • et al.
      Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
      ,
      • Tutt A.
      • Robson M.
      • Garber J.E.
      • et al.
      Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial.
      FDA approval was awarded for olaparib monotherapy in the advanced breast cancer setting following the publication of the OlympiAD trial in 2017. This phase III open-label RCT compared olaparib monotherapy using 300 mg in a tablet formulation twice daily with SOC chemotherapy in patients with HER2 negative stage 4 breast cancer with gBRCAm. The group reported a significantly prolonged PFS in the olaparib group versus SOC chemotherapy (7.0 vs 4.2 months), HR for disease progression or death was 0.58 (95%CI 0.43–0.80; P<.0001).
      • Robson M.
      • Im S.-A.
      • Senkus E.
      • et al.
      Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.
      In 2019 updated OS data were published, which revealed a median OS of 19.3 months in the olaparib arm versus 17.1 months in the SOC chemotherapy arm, the difference in OS was not statistically significant overall but with suggestion of an OS benefit in a pre-the specified subgroup who had received no prior chemotherapy for advanced disease.
      • Robson M.E.
      • Tung N.
      • Conte P.
      • et al.
      OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.
      As olaparib has proven effective in gBRCAm breast cancer, work has been carried out to determine its use in patients with somatic tumor mutations in BRCA1 or BRCA2 (sBRCA1/2m) or in those with germline mutations in other HR genes (eg, gPALB2m). The TBCRC-048 study reported the use of olaparib in 54 patients with either sBRCA1/2m, or germline pathogenic mutations in other HR-associated genes. An ORR of 50% was seen in those with sBRCA1/2m (n = 16), and ORR of 82% in the gPALB2m group. Interestingly, no responses to olaparib were seen in those with ATM (n = 8), CHEK2 (n = 8) mutations or in those with both ATM and CHEK2 (n = 2) mutations.
      • Tung N.M.
      • Robson M.E.
      • Ventz Steffen
      • et al.
      TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.
      Talazoparib has also been compared with SOC chemotherapy in a phase III RCT (EMBRACA). This study included patients with stage 4 HER2 negative breast cancer with gBRCAm. Patients must have received no more than 3 lines of prior chemotherapy (which must have included an anthracycline or taxane). The group reported a median PFS of 8.6 months versus 5.6 months in the talazoparib group versus SOC chemotherapy. HR for death or disease progression was 0.54 (95%CI 0.41–0.71; P<.001).
      • Litton J.K.
      • Rugo H.S.
      • Ettl J.
      • et al.
      Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.
      Talazoparib has since been approved by regulatory authorities for use in advanced breast cancer patients with gBRCAm. Studies into the efficacy of niraparib in the advanced setting have been less successful. BRAVO, a phase 3 RCT, reported the efficacy of niraparib (a PARPi with similar trapping potency to olaparib) monotherapy in gBRCAm HER2 negative stage 4 breast cancer. Unfortunately, there was a discrepancy between the central and local reviewers in determining the progression of the disease, and as such the primary endpoint of PFS was noncomparable between study arms and the investigators terminated recruitment early.
      • Turner N.C.
      • Balmaña J.
      • Poncet C.
      • et al.
      Niraparib for advanced breast cancer with germline BRCA1 and BRCA2 mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO study.

      Poly-(ADP ribose) polymerase inhibitor and chemotherapy combinations in advanced breast cancer

      Delivering PARPi in combination with chemotherapy, especially those that induce DNA damage, has proven challenging because of the additive or synergistic effects of treatment on rapidly proliferating bone marrow cells. When olaparib was combined with paclitaxel in a phase I dose escalation trial, the investigators reported dose-limiting hematological toxicity when olaparib was delivered at 200 mg twice daily for a 28-day continuous treatment in combination with paclitaxel delivered once weekly (G3 neutropenia was reported in 44%). However, when G1 or above neutropenia was recorded after the first cycle of treatment, patients were supplemented with granulocyte colony-stimulating factor (GCSF) and G3 neutropenia reduced to 20%.
      • Dent R.A.
      • Lindeman G.J.
      • Clemons M.
      • et al.
      Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer.
      The phase II RCT, BROCADE, assessed the use of veliparib in addition to carboplatin and paclitaxel (VCP), or temozolomide (VT) and compared this to placebo + carboplatin + paclitaxel (PCP) in patients with stage 4 breast cancer of all subtypes, with gBRCAm. In the VCP versus PCP analysis, the median PFS was 14.1 months versus 12.3 months, HR 0.78 (95%CI 0.536–1.1.62), P = .227. ORR in the VCP group was higher than PCP; 77.8% versus 61.3%, P = .027. In comparison, the median PFS was 7.4 months in the VT group (HR 1.85, 95%CI 1.278–2.702, P = .001) and ORR of 28.6% (P<.001).
      • Han H.S.
      • Diéras V.
      • Robson M.
      • et al.
      Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study.
      The clear inferiority of treatment with temozolomide and a taxane led to its omission from the phase III RCT, BROCADE3, which recruited patients with stage 4 gBRCAm, HER2 negative, breast cancer to receive VCP or PCP. The investigators reported a small improvement in PFS in the VCP group in comparison to PCP (14.5 months vs. 12.6 months, P = .0016, OS is awaited).
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial.
      Closer examination of the survival curves indicates that separation only occurs after platinum therapy was stopped and veliparib was continued, suggesting that it is the ability to continue PARPi as opposed to platinum chemotherapy that leads to delay of progression. It is likely that this combination is tolerated better than other PARPi because of the weak PARP1 trapping effects of veliparib. A selection of published phase III RCTs summarizing systemic treatment of advanced breast cancer are found in Table 2.
      Table 2Clinical trials published in advanced breast cancer
      Trial NamePhaseTreatmentSettingEndpointKey ResultsAuthors (Year)
      TNTIIICarboplatin vs docetaxelAdvancedORR and PFSgBRCAm ORR 68% vs 33%; PFS 6.4 vs 4.4 moTutt et al.
      • Tutt A.
      • Tovey H.
      • Cheang M.C.U.
      • et al.
      Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT Trial.
      OlympiADIIIOlaparib vs SOCAdvancedPFS and OSPFS 7.0 vs 4.2 mo; OS 19.3 vs 17.1 moRobson et al.
      • Robson M.E.
      • Tung N.
      • Conte P.
      • et al.
      OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.
      EMBRACAIIITalazoparib vs SOCAdvancedPFSPFS 8.6 vs 5.6 moLitton et al.
      • Litton J.K.
      • Rugo H.S.
      • Ettl J.
      • et al.
      Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.
      BROCADE 3IIIVeliparib + carboplatin + paclitaxel vs Placebo + carboplatin + paclitaxelAdvancedPFSPFS 14.5 vs 12.6 moDieras et al.
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial.
      Abbreviations: ORR, overall response rate; OS, overall survival; PFS, progression free survival; SOC, standard of care.

      Poly-(ADP Ribose) Polymerase Inhibitor and DNA Damage Response Inhibitors

      Preclinical studies suggest that kinase inhibitors that cause replication stress and impair cell cycle checkpoints for example, ATR and WEE1 inhibitors, enhance antitumor cell efficacy in models with HR deficiency.
      • Aarts M.
      • Sharpe R.
      • Garcia-Murillas I.
      • et al.
      Forced mitotic entry of S-phase cells as a therapeutic strategy induced by inhibition of WEE1.
      • Kim H.
      • George E.
      • Ragland R.L.
      • et al.
      Targeting the ATR/CHK1 axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian cancer models.
      • Lloyd R.L.
      • Urban V.
      • Muñoz-Martínez F.
      • et al.
      Loss of Cyclin C or CDK8 provides ATR inhibitor resistance by suppressing transcription-associated replication stress.
      • Wilson Z.
      • Odedra R.
      • Wallez Y.
      • et al.
      ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib.
      On the basis of this work, the VIOLETTE study (NCT03330847), a multicenter open-label phase II RCT was initiated. The study assessed the safety and efficacy of ceralasertib (ATRi) plus olaparib, or adavosertib (WEE1i) plus olaparib versus olaparib monotherapy in mTNBC in three distinct cohorts defined by validated or proposed biomarkers of HR deficiency in tumor sequencing. The trial recently reported no statistically significant difference observed in PFS for ceralasertib plus olaparib versus olaparib monotherapy as 2nd/3rd line therapy for mTNBC in any cohort. There was also no statistically significant difference observed in ORR for ceralasertib + olaparib versus olaparib monotherapy in the BRCAm group or the non-BRCAm (but other HR gene-deficient) group. A signal of improved response was seen in the non-HR deficient TNBC group and is currently being explored in deeper translational analysis.
      • Tutt A.
      • Nowecki Z.
      • Szoszkiewicz R.
      VIOLETTE: Randomised phase II study of olaparib (ola) + ceralasertib (cer) or adavosertib (ada) vs ola alone in patients (pts) with metastatic triple-negative breast cancer (mTNBC).
      Phosphoinositide 3-kinase inhibitors (PIK3i) are currently being assessed as anti-cancer treatments in a variety of cancers. Recent data has shown that mutations in RAS and PIK3CA oncogenes could induce an HR defect and suggested that the inhibition of such proteins may induce a drug-induced form of BRCAness.
      • Guney Eskiler G.
      The Interaction of PI3K Inhibition with Homologous Recombination Repair in Triple Negative Breast Cancer Cells.
      Several trials are ongoing investigating the combination of PI3K/AKTi in combination with PARPi (NCT04729387, nCT02208375, NCT04586335, NCT03586661) in solid tumors with BRCAm and could inform future treatment in gBRCAm breast cancer.

      Poly-(ADP Ribose) Polymerase Inhibitor and Immune Checkpoint Inhibitors

      Recent work has highlighted the contribution of the immune system to the efficacy of PARPi.
      • Parkes E.E.
      • Walker S.M.
      • Taggart L.E.
      • et al.
      Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer.
      • Ding L.
      • Kim H.J.
      • Wang Q.
      • et al.
      PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer.
      • Chabanon R.M.
      • Rouanne M.
      • Lord C.J.
      • et al.
      Targeting the DNA damage response in immuno-oncology: developments and opportunities.
      There are several trials underway examining the safety and efficacy of PARPi in conjunction with immune checkpoint inhibitors. The MEDIOLA trial reported on the 12-week disease control rate (DCR) observed by adding durvalumab to olaparib in patients with advanced solid tumors. MEDIOLA reported a 12-week DCR of 80% in those receiving the combination, which surpassed the prespecified target of 75%.
      • Domchek S.M.
      • Postel-Vinay S.
      • Im S.-A.
      • et al.
      Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study.
      TOPACIO/KEYNOTE-162, a phase I/II trial, reported the use of pembrolizumab in addition to niraparib in patients with advanced TNBC or ovarian cancer. This trial reported an ORR of 18%, with a 12-week DCR of 65%.
      • Konstantinopoulos P.A.
      • Waggoner S.
      • Vidal G.A.
      • et al.
      Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma.
      There are many further ongoing trials reporting the efficacy of adding immune checkpoint inhibitors to PARPi.

      Poly-(ADP Ribose) Polymerase Inhibitor and Platinum Resistance

      Despite PARPi and platinum agents both inducing objective response rates of more than 60% in HR deficient breast cancers, the lack of meaningful response in approximately one-third of patients and median duration of response in those who do respond being approximately 6 months indicates that de novo and acquired resistance is a significant problem.
      • Robson M.E.
      • Tung N.
      • Conte P.
      • et al.
      OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.
      ,
      • Litton J.K.
      • Rugo H.S.
      • Ettl J.
      • et al.
      Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.
      Understanding the biology of the underlying resistance mechanisms is vital and will help aid treatment decisions. Considerable pre-clinical work has identified mechanisms of resistance to PARPi and/or platinum salts, including mutations in PARP1 that prevent PARP1 trapping,
      • Pettitt S.J.
      • Krastev D.B.
      • Brandsma I.
      • et al.
      Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance.
      loss of TP53BP1 or the shieldin complex which normally prevents DSB resection,
      • Jaspers J.E.
      • Kersbergen A.
      • Boon U.
      • et al.
      Loss of 53BP1 causes PARP inhibitor resistance in BRCA1-mutated mouse mammary tumors.
      • Xu G.
      • Ross Chapman J.
      • Brandsma I.
      • et al.
      REV7 counteracts DNA double-strand break resection and affects PARP inhibition.
      • Dev H.
      • Chiang T.W.W.
      • Lescale C.
      • et al.
      Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells.
      • Noordermeer S.M.
      • Adam S.
      • Setiaputra D.
      • et al.
      The shieldin complex mediates 53BP1-dependent DNA repair.
      upregulation of drug efflux transporter genes Abcb1a and Abcb1b which encode for efflux pumps MDR1/P-gp and Abcg2,
      • Rottenberg S.
      • Jaspers J.E.
      • Kersbergen A.
      • et al.
      High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.
      loss of the PAR glycolase PARG
      • Gogola E.
      • Duarte A.A.
      • de Ruiter J.R.
      • et al.
      Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality.
      loss of DNA end protection and restoration of replication fork stability through loss of MRE11 and MUS81
      • Schlacher K.
      • Christ N.
      • Siaud N.
      • et al.
      Double-Strand Break Repair-Independent Role for BRCA2 in Blocking Stalled Replication Fork Degradation by MRE11.
      ,
      • Chaudhuri A.R.
      • Callen E.
      • Ding X.
      • et al.
      Replication fork stability confers chemoresistance in BRCA-deficient cells.
      or secondary, reversion, mutations in HR genes that restores their function.
      • Sakai W.
      • Swisher E.M.
      • Karlan B.Y.
      • et al.
      Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers.
      ,
      • Edwards S.L.
      • Brough R.
      • Lord C.J.
      • et al.
      Resistance to therapy caused by intragenic deletion in BRCA2.
      Of these, reversion mutations are perhaps the most clinically validated mechanism of PARPi resistance; these reversions also cause cross-resistance to platinum-salts as they restore HR. For example, under the selective treatment pressure of PARPi and platinums, reversion mutations in BRCA1, BRCA2, PALB2 or the RAD51 paralogs RAD51 C and RAD51D have been identified.
      • Goodall J.
      • Mateo J.
      • Yuan W.
      • et al.
      Circulating cell-free DNA to guide prostate cancer treatment with PARP inhibition.
      • Tobalina L.
      • Armenia J.
      • Irving E.
      • et al.
      A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance.
      • Pettitt S.J.
      • Frankum J.R.
      • Punta M.
      • et al.
      Clinical brca1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance.
      • Kondrashova O.
      • Nguyen M.
      • Shield-Artin K.
      • et al.
      Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma.
      These reversion mutations are secondary mutations (ie, mutations in addition to the pathogenic mutation) which restore the open reading frame of the gene, thereby restoring HR, rendering PARPi or platinum salts ineffective. More recently, detection of reversion mutations in plasma-derived cell-free tumor DNA (ctDNA) from patients with clinical PARPi resistance has been shown
      • Lin K.K.
      • Harrell M.I.
      • Oza A.M.
      • et al.
      BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma.
      • Christie E.L.
      • Fereday S.
      • Doig K.
      • et al.
      Reversion of BRCA1/2 germline mutations detected in circulating tumor DNA from patients with high-grade serous ovarian cancer.
      • Quigley D.
      • Alumkal J.J.
      • Wyatt A.W.
      • et al.
      Analysis of circulating cell-free DnA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors.
      providing a useful non-invasive method of tracking resistance to treatment in the clinic.

      Future Directions

      Biomarker development in hereditary breast cancer

      Although there is a growing body of preclinical work that identifies possible mechanisms of PARPi resistance, whether all of these operate in the clinical disease, and at what frequency, remains unknown. Given this, molecular profiling (DNA/RNA sequencing, proteomics, and methylation) of biopsies from individuals who develop resistance to drugs used in the treatment of hereditary breast cancer is required to clarify this area. This could lead to the development of clinical biomarkers that help predict response to PARPi. Current biomarkers used to guide the use of PARPi in breast cancer include the identification of pathogenic gBRCA1/2m, whereas in other cancers, the presence of mutations in other HR genes or the presence of a genome-wide mutational scar reflective of a past or extant HR defect are used. Whether such biomarkers could be used to direct the use of PARPi in hereditary breast cancer remains to be seen. Similarly, functional characterization of tumoral HR function through the use of immunohistochemical analysis of RAD51 and the development of biomarkers that predict dose-limiting toxicity (DLT) could lead to improvements in the way PARPi and platinum salts are used.

      Germline PALB2 mutation carriers

      Although there are no specifically approved targeted treatment options for gPALB2m breast cancer, given the integral role of PALB2 in HR, recent studies have suggested treatment with PARPi may be beneficial.
      • Tung N.M.
      • Robson M.E.
      • Ventz Steffen
      • et al.
      TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.
      For example, a phase 3 RCT (PROFOUND) evaluating the efficacy of the PARPi olaparib in men with castration-resistant prostate cancer established that patients with mutations in HR genes other than BRCA1/2, including PALB2, receive some benefit from olaparib treatment.
      • de Bono J.
      • Mateo J.
      • Fizazi K.
      • et al.
      Olaparib for Metastatic Castration-Resistant Prostate Cancer.
      The ACMG has recently recommended consideration of gPALB2m as equivalent to gBRCA1/2m for therapy decisions including systemic therapy decisions.
      • Tischkowitz M.
      • Balmaña J.
      • Foulkes W.D.
      • et al.
      Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).
      Trials in early breast cancers with pathologic response or biomarker efficacy endpoints that can prove equivalence of concept of treatment effects of PARPi between PALB2 and BRCA1/2 mutation carriers, may allow the avoidance of the need to repeat large phase III studies in specifically PALB2 mutation carriers.

      Novel combination therapies

      As we have discussed earlier, DLT is a significant issue limiting the delivery of potent PARPi combination therapies. Recent data from a Phase I study in patients with BRCA1/2, PALB2 or RAD51 C/D mutations presented at AACR in April 2022 (PETRA study, NCT04644068) suggest a new highly selective PARP1 inhibitor, AZD5305, can elicit efficacy with low rates of grade 3 treatment-emergent adverse events, SAEs or discontinuations.

      Yap T, Im S, Schram A. PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations. Presented at American Association for Cancer Research Annual Meeting; April 8-13, 2022; Virtual Accessed April 11, 2022 2022;OF1. 10.1158/2159-8290.CD-NB2022-0039.

      This enhanced tolerability might be because the myelosuppression associated with other PARPi is mediated through effects on PARP2 and other PARP family members, opening up the possibility that this optimized PARPi could provide a clinical agent that is not only an effective PARP1 trapping agent, but which also delivers tolerable regimens when combined with DNA damaging chemotherapy.
      The development of drug combinations to target PARPi resistance including delivery of PARPi with other small molecule inhibitors of oncogenic drivers and survival or DDR pathways
      • Guney Eskiler G.
      The Interaction of PI3K Inhibition with Homologous Recombination Repair in Triple Negative Breast Cancer Cells.
      ,
      • Liu P.
      • Cheng H.
      • Roberts T.M.
      • et al.
      Targeting the phosphoinositide 3-kinase pathway in cancer.
      • Ibrahim Y.H.
      • García-García C.
      • Serra V.
      • et al.
      PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition.
      • Yap T.A.
      • Kristeleit R.
      • Michalarea V.
      • et al.
      Phase i trial of the parp inhibitor olaparib and akt inhibitor capivasertib in patients with brca1/2-and non–brca1/2-mutant cancers.
      • Zatreanu D.
      • Robinson H.M.R.
      • Alkhatib O.
      • et al.
      Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
      and also in combination with immunomodulatory agents and radiotherapy
      • Domchek S.M.
      • Postel-Vinay S.
      • Im S.-A.
      • et al.
      Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study.
      ,
      • Konstantinopoulos P.A.
      • Waggoner S.
      • Vidal G.A.
      • et al.
      Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma.
      ,
      • Li T.
      • Chen Z.J.
      The cGAS-cGAMP-STI NG pathway connects DNA damage to inflammation, senescence, and cancer.
      will remain an very appropriate area for future clinical studies.

      Summary

      Treatment options for patients with hereditary breast cancers have expanded significantly in the past 20 years. These include a new FDA-licensed approach to adjuvant therapy, olaparib, that improves OS in those with gBRCA1/2m. However, resistance to platinum-based chemotherapy and PARPi in this cohort of patients is an issue that requires considerable focus. We have discussed standard approaches to treatment, but have touched on the expanse of pre-clinical and early clinical work being undertaken which will likely shape future treatments in this field of medicine.

      Clinics care points

      • Patients with breast cancer, whether hormone receptor positive or negative should be considered for referral for genetic counselling and testing using agreed international criteria eg. NCCN as it may affect their systemic treatment recommendations.
      • Patients with hereditary breast cancer due to germline BRCA1 and BRCA2 mutations should be reassured that they do not have worse prognosis than those with similar forms of breast cancer without such mutations and have better prognosis when treated with standard adjuvant chemotherapy regimens.
      • In germline BRCA1 or BRCA2 mutation carriers both platinum chemotherapy and the PARP inhibitors olaparib and talazoparib are associated with high response and showed improved progression free survival compared to standard of care advanced disease chemotherapy regimens, but have not been directly compared with one another.
      • PALB2 is a protein with similar functions in homologous recombination DNA repair to BRCA2 and PALB2 mutation carriers with advanced breast cancer have similar response to PARP inhibitors to BRCA1 and BRCA2 mutation carriers4. International guidelines indicate that patients with germline BRCA1 or BRCA2 mutations high risk early breast cancer and should be offered adjuvant olaparib for 12 months following completion (neo)adjuvant chemotherapy and local therapy (including surgery and radiotherapy).

      Disclosure

      E.H.-J. is a clinical PhD fellow funded by Cancer Research UK and AstraZeneca. A.T. is a consultant for AstraZeneca, Merck KGaA, Artios, Pfizer, Vertex, GE Healthcare, Inbiomotion, MD Anderson Cancer Centre; has received grant/research support from AstraZeneca, Myriad, Medivation, and Merck KGaA; and is a stockholder in Inbiomotion. Stands to gain from the use of PARP inhibitors as part of the ICR's “rewards to inventors” scheme. C.J.L. makes the following disclosures: receives and/or has received research funding from: AstraZeneca, Merck KGaA, Artios. Received consultancy, SAB membership or honoraria payments from: Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics. Has stock in: Tango, Ovibio, Enedra Tx., Hysplex, Tesselate. C.J.L. is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their development and use as part of the ICR “Rewards to Inventors” scheme.

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