Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer: New England Journal of Medicine

A.N.J. Tutt; J.E. Garber; B. Kaufman; G. Viale; D. Fumagalli; P. Rastogi; R.D. Gelber; E. de Azambuja; A. Fielding; J. Balmaña; S.M. Domchek; K.A. Gelmon; S.J. Hollingsworth; L.A. Korde; B. Linderholm; H. Bandos; E. Senkus; J.M. Suga; Z. Shao; A.W. Pippas; Z. Nowecki; T. Huzarski; P.A. Ganz; P.C. Lucas; N. Baker; S. Loibl; R. McConnell; M. Piccart; R. Schmutzler; G.G. Steger; J.P. Costantino; A. Arahmani; N. Wolmark; E. McFadden; V. Karantza; S.R. Lakhani; G. Yothers; C. Campbell; Jr. Geyer C.E.

doi:10.1056/NEJMoa2105215

Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer: New England Journal of Medicine

A.N.J. Tutt, J.E. Garber, B. Kaufman, G. Viale, D. Fumagalli, P. Rastogi, R.D. Gelber, E. de Azambuja, A. Fielding, J. Balmaña, S.M. Domchek, K.A. Gelmon, S.J. Hollingsworth, L.A. Korde, B. Linderholm, H. Bandos, E. Senkus, J.M. Suga, Z. Shao, A.W. PippasZ. Nowecki, T. Huzarski, P.A. Ganz, P.C. Lucas, N. Baker, S. Loibl, R. McConnell, M. Piccart, R. Schmutzler, G.G. Steger, J.P. Costantino, A. Arahmani, N. Wolmark, E. McFadden, V. Karantza, S.R. Lakhani, G. Yothers, C. Campbell, Jr. Geyer C.E.

Istituto Europeo di Oncologia

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND Poly(adenosine diphosphate–ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation–associated early breast cancer. METHODS We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)–negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease–free survival. RESULTS A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease–free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P

Original language	English
Pages (from-to)	2394-2405
Number of pages	12
Journal	New Engl. J. Med.
Volume	384
Issue number	25
DOIs	https://doi.org/10.1056/NEJMoa2105215
Publication status	Published - 2021

Keywords

antineoplastic agent
epidermal growth factor receptor 2
ERBB2 protein, human
nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor
olaparib
phthalazine derivative
piperazine derivative
adjuvant chemotherapy
adult
breast tumor
clinical trial
controlled study
disease free survival
double blind procedure
female
genetics
germline mutation
human
mastectomy
middle aged
mortality
multicenter study
phase 3 clinical trial
randomized controlled trial
tumor suppressor gene
Adult
Antineoplastic Agents
Breast Neoplasms
Chemotherapy, Adjuvant
Disease-Free Survival
Double-Blind Method
Female
Genes, BRCA1
Genes, BRCA2
Germ-Line Mutation
Humans
Mastectomy
Middle Aged
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Receptor, ErbB-2

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10.1056/NEJMoa2105215

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85108610136&doi=10.1056%2fNEJMoa2105215&partnerID=40&md5=294507a1f762059139e9ba9ef651ebd4

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Tutt, A. N. J., Garber, J. E., Kaufman, B., Viale, G., Fumagalli, D., Rastogi, P., Gelber, R. D., de Azambuja, E., Fielding, A., Balmaña, J., Domchek, S. M., Gelmon, K. A., Hollingsworth, S. J., Korde, L. A., Linderholm, B., Bandos, H., Senkus, E., Suga, J. M., Shao, Z., ... Geyer C.E., J. (2021). Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer: New England Journal of Medicine. New Engl. J. Med., 384(25), 2394-2405. https://doi.org/10.1056/NEJMoa2105215

Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer : New England Journal of Medicine. / Tutt, A.N.J.; Garber, J.E.; Kaufman, B.; Viale, G.; Fumagalli, D.; Rastogi, P.; Gelber, R.D.; de Azambuja, E.; Fielding, A.; Balmaña, J.; Domchek, S.M.; Gelmon, K.A.; Hollingsworth, S.J.; Korde, L.A.; Linderholm, B.; Bandos, H.; Senkus, E.; Suga, J.M.; Shao, Z.; Pippas, A.W.; Nowecki, Z.; Huzarski, T.; Ganz, P.A.; Lucas, P.C.; Baker, N.; Loibl, S.; McConnell, R.; Piccart, M.; Schmutzler, R.; Steger, G.G.; Costantino, J.P.; Arahmani, A.; Wolmark, N.; McFadden, E.; Karantza, V.; Lakhani, S.R.; Yothers, G.; Campbell, C.; Geyer C.E., Jr.

In: New Engl. J. Med., Vol. 384, No. 25, 2021, p. 2394-2405.

Research output: Contribution to journal › Article › peer-review

Tutt, ANJ, Garber, JE, Kaufman, B, Viale, G, Fumagalli, D, Rastogi, P, Gelber, RD, de Azambuja, E, Fielding, A, Balmaña, J, Domchek, SM, Gelmon, KA, Hollingsworth, SJ, Korde, LA, Linderholm, B, Bandos, H, Senkus, E, Suga, JM, Shao, Z, Pippas, AW, Nowecki, Z, Huzarski, T, Ganz, PA, Lucas, PC, Baker, N, Loibl, S, McConnell, R, Piccart, M, Schmutzler, R, Steger, GG, Costantino, JP, Arahmani, A, Wolmark, N, McFadden, E, Karantza, V, Lakhani, SR, Yothers, G, Campbell, C & Geyer C.E., J 2021, 'Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer: New England Journal of Medicine', New Engl. J. Med., vol. 384, no. 25, pp. 2394-2405. https://doi.org/10.1056/NEJMoa2105215

Tutt, A.N.J. ; Garber, J.E. ; Kaufman, B. ; Viale, G. ; Fumagalli, D. ; Rastogi, P. ; Gelber, R.D. ; de Azambuja, E. ; Fielding, A. ; Balmaña, J. ; Domchek, S.M. ; Gelmon, K.A. ; Hollingsworth, S.J. ; Korde, L.A. ; Linderholm, B. ; Bandos, H. ; Senkus, E. ; Suga, J.M. ; Shao, Z. ; Pippas, A.W. ; Nowecki, Z. ; Huzarski, T. ; Ganz, P.A. ; Lucas, P.C. ; Baker, N. ; Loibl, S. ; McConnell, R. ; Piccart, M. ; Schmutzler, R. ; Steger, G.G. ; Costantino, J.P. ; Arahmani, A. ; Wolmark, N. ; McFadden, E. ; Karantza, V. ; Lakhani, S.R. ; Yothers, G. ; Campbell, C. ; Geyer C.E., Jr. / Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer : New England Journal of Medicine. In: New Engl. J. Med. 2021 ; Vol. 384, No. 25. pp. 2394-2405.

@article{3516e94cd4084f94be1d56556c9c8252,

title = "Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer: New England Journal of Medicine",

abstract = "BACKGROUND Poly(adenosine diphosphate–ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation–associated early breast cancer. METHODS We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)–negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease–free survival. RESULTS A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease–free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P",

keywords = "antineoplastic agent, epidermal growth factor receptor 2, ERBB2 protein, human, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor, olaparib, phthalazine derivative, piperazine derivative, adjuvant chemotherapy, adult, breast tumor, clinical trial, controlled study, disease free survival, double blind procedure, female, genetics, germline mutation, human, mastectomy, middle aged, mortality, multicenter study, phase 3 clinical trial, randomized controlled trial, tumor suppressor gene, Adult, Antineoplastic Agents, Breast Neoplasms, Chemotherapy, Adjuvant, Disease-Free Survival, Double-Blind Method, Female, Genes, BRCA1, Genes, BRCA2, Germ-Line Mutation, Humans, Mastectomy, Middle Aged, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Receptor, ErbB-2",

author = "A.N.J. Tutt and J.E. Garber and B. Kaufman and G. Viale and D. Fumagalli and P. Rastogi and R.D. Gelber and {de Azambuja}, E. and A. Fielding and J. Balma{\~n}a and S.M. Domchek and K.A. Gelmon and S.J. Hollingsworth and L.A. Korde and B. Linderholm and H. Bandos and E. Senkus and J.M. Suga and Z. Shao and A.W. Pippas and Z. Nowecki and T. Huzarski and P.A. Ganz and P.C. Lucas and N. Baker and S. Loibl and R. McConnell and M. Piccart and R. Schmutzler and G.G. Steger and J.P. Costantino and A. Arahmani and N. Wolmark and E. McFadden and V. Karantza and S.R. Lakhani and G. Yothers and C. Campbell and {Geyer C.E.}, Jr.",

note = "Cited By :10 Export Date: 1 October 2021 CODEN: NEJMA Correspondence Address: Tutt, A.N.J.; Breast Cancer Now Toby Robins Research Centre, 237 Fulham Rd., United Kingdom; email: andrew.tutt@icr.ac.uk Chemicals/CAS: epidermal growth factor receptor 2, 137632-09-8; olaparib, 763113-22-0; Antineoplastic Agents; ERBB2 protein, human; olaparib; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Receptor, ErbB-2 Funding details: National Cancer Institute, NCI Funding details: AstraZeneca Funding text 1: Supported by grants (U10CA180868, UG1CA189867, and U10CA180822) from the National Cancer Institute and funding and provision of olaparib and placebo by AstraZeneca as part of an alliance between AstraZeneca and Merck. References: Dorling, L., Carvalho, S., Allen, J., Breast cancer risk genes — Association analysis in more than 113,000 women (2021) N Engl J Med, 384, pp. 428-439; Hu, C., Hart, S.N., Gnanaolivu, R., A population-based study of genes previously implicated in breast cancer (2021) N Engl J Med, 384, pp. 440-451; Kuchenbaecker, K.B., Hopper, J.L., Barnes, D.R., Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers (2017) JAMA, 317, pp. 2402-2416; Mavaddat, N., Barrowdale, D., Andrulis, I.L., Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the consortium of Investigators of modifiers of BRCA1/2 (CIMBA) (2012) Cancer Epidemiol Biomarkers Prev, 21, pp. 134-147; Atchley, D.P., Albarracin, C.T., Lopez, A., Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer (2008) J Clin Oncol, 26, pp. 4282-4288; Lakhani, S.R., van de Vijver, M.J., Jacquemier, J., 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 (2002) J Clin Oncol, 20, pp. 2310-8.. , https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf, NCCN genetic/familial high-risk assessment: breast and ovarian version 1. 2020. National Comprehensive Cancer Network, April 2021; Tutt, A., Ashworth, A., The relationship between the roles of BRCA genes in DNA repair and cancer predisposition (2002) Trends Mol Med, 8, pp. 571-576; Davies, H., Glodzik, D., Morganella, S., HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures (2017) Nat Med, 23, pp. 517-525; Staaf, J., Glodzik, D., Bosch, A., Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study (2019) Nat Med, 25, pp. 1526-1533; Tutt, A.N., Lord, C.J., McCabe, N., Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer (2005) Cold Spring Harb Symp Quant Biol, 70, pp. 139-148; Farmer, H., McCabe, N., Lord, C.J., Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy (2005) Nature, 434, pp. 917-921; Bryant, H.E., Schultz, N., Thomas, H.D., Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase (2005) Nature, 434, pp. 913-917; Fong, P.C., Boss, D.S., Yap, T.A., Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers (2009) N Engl J Med, 361, pp. 123-134; Tutt, A., Robson, M., Garber, J.E., Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial (2010) Lancet, 376, pp. 235-244; Audeh, M.W., Carmichael, J., Penson, R.T., Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept trial (2010) Lancet, 376, pp. 245-251; Kaufman, B., Shapira-Frommer, R., Schmutzler, R.K., Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation (2015) J Clin Oncol, 33, pp. 244-250; Shah, P.D., Patil, S., Dickler, M.N., Offit, K., Hudis, C.A., Robson, M.E., Twenty-one-gene recurrence score assay in BRCA-associated versus sporadic breast cancers: Differences based on germline mutation status (2016) Cancer, 122, pp. 1178-1184; Tryggvadottir, L., Olafsdottir, E.J., Olafsdottir, G.H., Tumour diploidy and survival in breast cancer patients with BRCA2 mutations (2013) Breast Cancer Res Treat, 140, pp. 375-384; Mittendorf, E.A., Jeruss, J.S., Tucker, S.L., Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy (2011) J Clin Oncol, 29, pp. 1956-1962; Hudis, C.A., Barlow, W.E., Costantino, J.P., Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: The steep system (2007) J Clin Oncol, 25, pp. 2127-2132; Stone, A., The application of bespoke spending functions in group-sequential designs and the effect of delayed treatment switching in survival trials (2010) Pharm Stat, 9, pp. 151-161; Cuzick, J., Forest plots and the interpretation of subgroups (2005) Lancet, 365, p. 1308; Robson, M., Im, S.A., Senkus, E., Olaparib for metastatic breast cancer in patients with a germline BRCA mutation (2017) N Engl J Med, 377, pp. 523-533; Litton, J.K., Rugo, H.S., Ettl, J., Talazoparib in patients with advanced breast cancer and a germline BRCA mutation (2018) N Engl J Med, 379, pp. 753-763; Fasching, P.A., Link, T., Hauke, J., Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study) Ann Oncol, 2021 (32), pp. 49-57; Burstein, H.J., Curigliano, G., Loibl, S., Estimating the benefits of therapy for early-stage breast cancer: The St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019 (2019) Ann Oncol, 30, pp. 1541-1557; NCCN clinical practice guidelines in oncology — Breast cancer version 5.2020 , p. 2021. , https://www2.tri-kobe.org/nccn/guideline/breast/english/breast.pdf, National Comprehensive Cancer Network, July 15; Tutt, A., Tovey, H., Cheang, M.C.U., Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT trial (2018) Nat Med, 24, pp. 628-637; Zhang, J., Lin, Y., Sun, X.J., Biomarker assessment of the CBCSG006 trial: A randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer (2018) Ann Oncol, 29, pp. 1741-1747; Murai, J., Huang, S.Y., Das, B.B., Trapping of PARP1 and PARP2 by clinical PARP inhibitors (2012) Cancer Res, 72, pp. 5588-5599; Morice, P.M., Leary, A., Dolladille, C., Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: A safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database (2021) Lancet Haematol, 8 (2), pp. e122-e134; Pohl-Rescigno, E., Hauke, J., Loibl, S., Association of germline variant status with therapy response in high-risk early-stage breast cancer: A secondary analysis of the GeparOcto randomized clinical trial (2020) JAMA Oncol, (6), pp. 744-748; Masuda, N., Lee, S.J., Ohtani, S., Adjuvant capecitabine for breast cancer after preoperative chemotherapy (2017) N Engl J Med, 376, pp. 2147-2159; Robson, M.E., Tung, N., Conte, P., OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician{\textquoteright}s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer (2019) Ann Oncol, 30, pp. 558-566; Tutt, A., Ashworth, A., Can genetic testing guide treatment in breast cancer? (2008) Eur J Cancer, 44, pp. 2774-2780",

year = "2021",

doi = "10.1056/NEJMoa2105215",

language = "English",

volume = "384",

pages = "2394--2405",

journal = "New Engl. J. Med.",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "25",

}

TY - JOUR

T1 - Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer

T2 - New England Journal of Medicine

AU - Tutt, A.N.J.

AU - Garber, J.E.

AU - Kaufman, B.

AU - Viale, G.

AU - Fumagalli, D.

AU - Rastogi, P.

AU - Gelber, R.D.

AU - de Azambuja, E.

AU - Fielding, A.

AU - Balmaña, J.

AU - Domchek, S.M.

AU - Gelmon, K.A.

AU - Hollingsworth, S.J.

AU - Korde, L.A.

AU - Linderholm, B.

AU - Bandos, H.

AU - Senkus, E.

AU - Suga, J.M.

AU - Shao, Z.

AU - Pippas, A.W.

AU - Nowecki, Z.

AU - Huzarski, T.

AU - Ganz, P.A.

AU - Lucas, P.C.

AU - Baker, N.

AU - Loibl, S.

AU - McConnell, R.

AU - Piccart, M.

AU - Schmutzler, R.

AU - Steger, G.G.

AU - Costantino, J.P.

AU - Arahmani, A.

AU - Wolmark, N.

AU - McFadden, E.

AU - Karantza, V.

AU - Lakhani, S.R.

AU - Yothers, G.

AU - Campbell, C.

AU - Geyer C.E., Jr.

N1 - Cited By :10 Export Date: 1 October 2021 CODEN: NEJMA Correspondence Address: Tutt, A.N.J.; Breast Cancer Now Toby Robins Research Centre, 237 Fulham Rd., United Kingdom; email: andrew.tutt@icr.ac.uk Chemicals/CAS: epidermal growth factor receptor 2, 137632-09-8; olaparib, 763113-22-0; Antineoplastic Agents; ERBB2 protein, human; olaparib; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Receptor, ErbB-2 Funding details: National Cancer Institute, NCI Funding details: AstraZeneca Funding text 1: Supported by grants (U10CA180868, UG1CA189867, and U10CA180822) from the National Cancer Institute and funding and provision of olaparib and placebo by AstraZeneca as part of an alliance between AstraZeneca and Merck. References: Dorling, L., Carvalho, S., Allen, J., Breast cancer risk genes — Association analysis in more than 113,000 women (2021) N Engl J Med, 384, pp. 428-439; Hu, C., Hart, S.N., Gnanaolivu, R., A population-based study of genes previously implicated in breast cancer (2021) N Engl J Med, 384, pp. 440-451; Kuchenbaecker, K.B., Hopper, J.L., Barnes, D.R., Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers (2017) JAMA, 317, pp. 2402-2416; Mavaddat, N., Barrowdale, D., Andrulis, I.L., Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the consortium of Investigators of modifiers of BRCA1/2 (CIMBA) (2012) Cancer Epidemiol Biomarkers Prev, 21, pp. 134-147; Atchley, D.P., Albarracin, C.T., Lopez, A., Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer (2008) J Clin Oncol, 26, pp. 4282-4288; Lakhani, S.R., van de Vijver, M.J., Jacquemier, J., 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 (2002) J Clin Oncol, 20, pp. 2310-8.. , https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf, NCCN genetic/familial high-risk assessment: breast and ovarian version 1. 2020. National Comprehensive Cancer Network, April 2021; Tutt, A., Ashworth, A., The relationship between the roles of BRCA genes in DNA repair and cancer predisposition (2002) Trends Mol Med, 8, pp. 571-576; Davies, H., Glodzik, D., Morganella, S., HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures (2017) Nat Med, 23, pp. 517-525; Staaf, J., Glodzik, D., Bosch, A., Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study (2019) Nat Med, 25, pp. 1526-1533; Tutt, A.N., Lord, C.J., McCabe, N., Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer (2005) Cold Spring Harb Symp Quant Biol, 70, pp. 139-148; Farmer, H., McCabe, N., Lord, C.J., Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy (2005) Nature, 434, pp. 917-921; Bryant, H.E., Schultz, N., Thomas, H.D., Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase (2005) Nature, 434, pp. 913-917; Fong, P.C., Boss, D.S., Yap, T.A., Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers (2009) N Engl J Med, 361, pp. 123-134; Tutt, A., Robson, M., Garber, J.E., Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial (2010) Lancet, 376, pp. 235-244; Audeh, M.W., Carmichael, J., Penson, R.T., Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept trial (2010) Lancet, 376, pp. 245-251; Kaufman, B., Shapira-Frommer, R., Schmutzler, R.K., Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation (2015) J Clin Oncol, 33, pp. 244-250; Shah, P.D., Patil, S., Dickler, M.N., Offit, K., Hudis, C.A., Robson, M.E., Twenty-one-gene recurrence score assay in BRCA-associated versus sporadic breast cancers: Differences based on germline mutation status (2016) Cancer, 122, pp. 1178-1184; Tryggvadottir, L., Olafsdottir, E.J., Olafsdottir, G.H., Tumour diploidy and survival in breast cancer patients with BRCA2 mutations (2013) Breast Cancer Res Treat, 140, pp. 375-384; Mittendorf, E.A., Jeruss, J.S., Tucker, S.L., Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy (2011) J Clin Oncol, 29, pp. 1956-1962; Hudis, C.A., Barlow, W.E., Costantino, J.P., Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: The steep system (2007) J Clin Oncol, 25, pp. 2127-2132; Stone, A., The application of bespoke spending functions in group-sequential designs and the effect of delayed treatment switching in survival trials (2010) Pharm Stat, 9, pp. 151-161; Cuzick, J., Forest plots and the interpretation of subgroups (2005) Lancet, 365, p. 1308; Robson, M., Im, S.A., Senkus, E., Olaparib for metastatic breast cancer in patients with a germline BRCA mutation (2017) N Engl J Med, 377, pp. 523-533; Litton, J.K., Rugo, H.S., Ettl, J., Talazoparib in patients with advanced breast cancer and a germline BRCA mutation (2018) N Engl J Med, 379, pp. 753-763; Fasching, P.A., Link, T., Hauke, J., Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study) Ann Oncol, 2021 (32), pp. 49-57; Burstein, H.J., Curigliano, G., Loibl, S., Estimating the benefits of therapy for early-stage breast cancer: The St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019 (2019) Ann Oncol, 30, pp. 1541-1557; NCCN clinical practice guidelines in oncology — Breast cancer version 5.2020 , p. 2021. , https://www2.tri-kobe.org/nccn/guideline/breast/english/breast.pdf, National Comprehensive Cancer Network, July 15; Tutt, A., Tovey, H., Cheang, M.C.U., Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: The TNT trial (2018) Nat Med, 24, pp. 628-637; 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PY - 2021

Y1 - 2021

N2 - BACKGROUND Poly(adenosine diphosphate–ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation–associated early breast cancer. METHODS We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)–negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease–free survival. RESULTS A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease–free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P

AB - BACKGROUND Poly(adenosine diphosphate–ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation–associated early breast cancer. METHODS We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)–negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease–free survival. RESULTS A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease–free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P

KW - antineoplastic agent

KW - epidermal growth factor receptor 2

KW - ERBB2 protein, human

KW - nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor

KW - olaparib

KW - phthalazine derivative

KW - piperazine derivative

KW - adjuvant chemotherapy

KW - adult

KW - breast tumor

KW - clinical trial

KW - controlled study

KW - disease free survival

KW - double blind procedure

KW - female

KW - genetics

KW - germline mutation

KW - human

KW - mastectomy

KW - middle aged

KW - mortality

KW - multicenter study

KW - phase 3 clinical trial

KW - randomized controlled trial

KW - tumor suppressor gene

KW - Adult

KW - Antineoplastic Agents

KW - Breast Neoplasms

KW - Chemotherapy, Adjuvant

KW - Disease-Free Survival

KW - Double-Blind Method

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Germ-Line Mutation

KW - Humans

KW - Mastectomy

KW - Middle Aged

KW - Phthalazines

KW - Piperazines

KW - Poly(ADP-ribose) Polymerase Inhibitors

KW - Receptor, ErbB-2

U2 - 10.1056/NEJMoa2105215

DO - 10.1056/NEJMoa2105215

M3 - Article

VL - 384

SP - 2394

EP - 2405

JO - New Engl. J. Med.

JF - New Engl. J. Med.

SN - 0028-4793

IS - 25

ER -

Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer: New England Journal of Medicine

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