Update Mammakarzinom 2018 (Teil 3) – Genomforschung, individualisierte Medizin und Immuntherapien – mitten in einer neuen Ära: Prävention und Therapie des frühen Mammakarzinoms

Achim Wöckel; Michael P. Lux; Wolfgang Janni; Andreas D. Hartkopf; Naiba Nabieva; Florin-Andrei Taran; Friedrich Overkamp; Peyman Hadji; Hans Tesch; Johannes Ettl; Diana Lüftner; Volkmar Müller; Manfred Welslau; Erik Belleville; Sara Y. Brucker; Florian Schütz; Peter A. Fasching; Tanja N. Fehm; Andreas Schneeweiss; Hans-Christian Kolberg

doi:10.1055/a-0869-8666

Senologie - Zeitschrift für Mammadiagnostik und -therapie, Table of Contents

Senologie - Zeitschrift für Mammadiagnostik und -therapie 2019; 16(01): 23-32
DOI: 10.1055/a-0869-8666

Wissenschaftliche Arbeit

Update Mammakarzinom 2018 (Teil 3) – Genomforschung, individualisierte Medizin und Immuntherapien – mitten in einer neuen Ära: Prävention und Therapie des frühen Mammakarzinoms

Update breast cancer 2018 (part 3) – genomics, individualized medicine and immune therapies – in the middle of a new era: prevention and treatment strategies for early breast cancer

Achim Wöckel

¹Department of Gynecology and Obstetrics, University Hospital Würzburg

,

Michael P. Lux

²Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen

,

Wolfgang Janni

³Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm

,

Andreas D. Hartkopf

⁴Department of Obstetrics and Gynecology, University of Tübingen, Tübingen

,

Naiba Nabieva

²Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen

,

Florin-Andrei Taran

⁴Department of Obstetrics and Gynecology, University of Tübingen, Tübingen

,

Friedrich Overkamp

⁵OncoConsult Hamburg GmbH, Hamburg

,

Peyman Hadji

⁶Department of Bone Oncology, Nordwest Hospital, Frankfurt

,

Hans Tesch

⁷Oncology Practice at Bethanien Hospital Frankfurt, Frankfurt

,

Johannes Ettl

⁸Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich

,

Diana Lüftner

⁹Charité University Hospital, Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology and Tumour Immunology, Berlin

,

Volkmar Müller

¹⁰Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg

,

Manfred Welslau

¹¹Onkologie Aschaffenburg, Hämatolo-Onkologische Schwerpunktpraxis am Klinikum Aschaffenburg, Aschaffenburg

,

Erik Belleville

¹²ClinSol GmbH & Co KG, Würzburg

,

Sara Y. Brucker

⁴Department of Obstetrics and Gynecology, University of Tübingen, Tübingen

,

Florian Schütz

¹³Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg

,

Peter A. Fasching

²Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen

,

Tanja N. Fehm

¹⁴Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf

,

Andreas Schneeweiss

¹³Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg

¹⁵National Center for Tumor Diseases, Division Gynecologic Oncology, University Hospital Heidelberg, Heidelberg

,

Hans-Christian Kolberg

¹⁶Department of Gynecology and Obstetrics, Marienhospital Bottrop, Bottrop

› Author Affiliations

Abstract

Zusammenfassung

Beim primären, frühen Mammakarzinom zielt die Behandlungsplanung auf ein immer besseres Verständnis der Erkrankung ab. Die Identifikation von Patientinnen mit einer exzellenten Prognose könnte dieser Gruppe helfen, unnötige Therapien zu vermeiden.Weiterhin wird die Planung der Therapie immer weiter auf die Patientin abgestimmt. Das Wissen über Patientinnen, die besonders von einer Chemotherapie profitieren, wächst genauso wie das Wissen um Patientinnen, die von einer Immuntherapie profitieren könnten. Hinsichtlich der Immuntherapien stehen die durchgeführten Studien kurz vor der Publikation. Einzelne kleinere Studien bieten einen ersten Einblick in die Wirksamkeit der Checkpoint-Inhibitoren (Anti-PD1 / PDL1-Therapien). Nicht zuletzt konnte kürzlich eine der größten Brustkrebsstudien aller Zeiten zu Ende geführt werden. Die Anwendung eines Multigentests konnte zeigen, dass er ausreicht, um Patientinnen mit einer so guten Prognose zu identifizieren, dass keine Chemotherapie nötig ist. Dieser Review-Artikel soll die aktuellen Studien zusammenfassen und einen Ausblick der gegenwärtigen Entwicklungen geben.

Abstract

In primary early breast cancer, the aim of treatment planning is to obtain an increasingly better understanding of the disease. The identification of patients with an excellent prognosis could help this group avoid unnecessary treatments. Furthermore, the planning of treatment is becoming increasingly patient-focussed. There is a growing understanding of those patients who benefit particularly from chemotherapy, as well as of those who could benefit from immunotherapy. Studies conducted on immunotherapies will be published shortly. Smaller individual studies offer an initial insight into the efficacy of checkpoint inhibitors (anti-PD1 / PDL1 therapies). Not least, one of the largest breast cancer studies of all times has recently come to an end. The use of a multigene test has shown that it is sufficient to identify patients with such a good prognosis that chemotherapy is unnecessary. This review article is intended to summarise the current studies and give an outlook on current developments.

Schlüsselwörter

Mammakarzinom - Behandlung - Metastasen - CDK4/6 - PD1/PDL1 - Studien - Risiko - Prävention

Key words

breast cancer - treatment - metastases - CDK4/6 - PD1/PDL1 - studies - risk - prevention

Full Text

References

Literatur
1 Taran FA, Schneeweiss A, Lux MP. et al. Update Breast Cancer 2018 (Part 1) – Primary Breast Cancer and Biomarkers. Geburtsh Frauenheilk 2018; 78: 237-245
2 Schneeweiss A, Lux MP, Janni W. et al. Update Breast Cancer 2018 (Part 2) – Advanced Breast Cancer, Quality of Life and Prevention. Geburtsh Frauenheilk 2018; 78: 246-259
3 Untch M, Wurstlein R, Marschner N. et al. 4th International Consensus Conference on Advanced Breast Cancer (ABC4), Lisbon, November 4, 2017: ABC4 Consensus: Assessment by a Panel of German Experts. Geburtsh Frauenheilk 2018; 78: 469-480
4 Ghoussaini M, Fletcher O, Michailidou K. et al. Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet 2012; 44: 312-318
5 Michailidou K, Beesley J, Lindstrom S. et al. Genome-wide association analysis of more than 120000 individuals identifies 15 new susceptibility loci for breast cancer. Nat Genet 2015; 47: 373-380
6 Michailidou K, Hall P, Gonzalez-Neira A. et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 2013; 45: 353-361, 361.e1–361.e2
7 Michailidou K, Lindstrom S, Dennis J. et al. Association analysis identifies 65 new breast cancer risk loci. Nature 2017; 551: 92-94
8 Ahmed S, Thomas G, Ghoussaini M. et al. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 2009; 41: 585-590
9 Antoniou AC, Wang X, Fredericksen ZS. et al. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 2010; 42: 885-892
10 Bojesen SE, Pooley KA, Johnatty SE. et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet 2013; 45: 371-384, 384e1–384e2
11 Cox A, Dunning AM, Garcia-Closas M. et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 2007; 39: 352-358
12 Easton DF, Pooley KA, Dunning AM. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007; 447: 1087-1093
13 Fasching PA, Ekici AB, Adamietz BR. et al. Breast Cancer Risk – Genes, Environment and Clinics. Geburtsh Frauenheilk 2011; 71: 1056-1066
14 Fasching PA, Ekici AB, Wachter DL. et al. Breast Cancer Risk – From Genetics to Molecular Understanding of Pathogenesis. Geburtsh Frauenheilk 2013; 73: 1228-1235
15 Fletcher O, Johnson N, Orr N. et al. Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. J Natl Cancer Inst 2011; 103: 425-435
16 French JD, Ghoussaini M, Edwards SL. et al. Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers. Am J Hum Genet 2013; 92: 489-503
17 Garcia-Closas M, Couch FJ, Lindstrom S. et al. Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat Genet 2013; 45: 392-398, 398e1–398e2
18 Haiman CA, Chen GK, Vachon CM. et al. A common variant at the TERTCLPTM1 L locus is associated with estrogen receptor-negative breast cancer. Nat Genet 2011; 43: 1210-1214
19 Milne RL, Benitez J, Nevanlinna H. et al. Risk of estrogen receptor-positive and ‑negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042. J Natl Cancer Inst 2009; 101: 1012-1018
20 Milne RL, Kuchenbaecker KB, Michailidou K. et al. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet 2017; 49: 1767-1778
21 Siddiq A, Couch FJ, Chen GK. et al. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. Hum Mol Genet 2012; 21: 5373-5384
22 Stacey SN, Manolescu A, Sulem P. et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 2007; 39: 865-869
23 Stacey SN, Manolescu A, Sulem P. et al. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 2008; 40: 703-706
24 Stevens KN, Fredericksen Z, Vachon CM. et al. 19p13.1 is a triple-negative- specific breast cancer susceptibility locus. Cancer Res 2012; 72: 1795-1803
25 Thomas G, Jacobs KB, Kraft P. et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 2009; 41: 579-584
26 Turnbull C, Ahmed S, Morrison J. et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 2010; 42: 504-507
27 Wunderle M, Olmes G, Nabieva N. et al. Risk, Prediction and Prevention of Hereditary Breast Cancer – Large-Scale Genomic Studies in Times of Big and Smart Data. Geburtsh Frauenheilk 2018; 78: 481-492
28 Zheng W, Long J, Gao YT. et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 2009; 41: 324-328
29 Purrington KS, Slager S, Eccles D. et al. Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer. Carcinogenesis 2014; 35: 1012-1019
30 Stevens KN, Fredericksen Z, Vachon CM. et al. 19p13.1 is a triple-negative-specific breast cancer susceptibility locus. Cancer Res 2012; 72: 1795-1803
31 Vachon CM, Scott CG, Fasching PA. et al. Common breast cancer susceptibility variants in LSP1 and RAD51L1 are associated with mammographic density measures that predict breast cancer risk. Cancer Epidemiol Biomarkers Prev 2012; 21: 1156-1166
32 Garcia-Closas M, Gunsoy NB, Chatterjee N. Combined associations of genetic and environmental risk factors: implications for prevention of breast cancer. J Natl Cancer Inst 2014; 106: pii: dju305. doi:10.1093/jnci/dju305
33 Mavaddat N, Pharoah PD, Michailidou K. et al. Prediction of breast cancer risk based on profiling with common genetic variants. J Natl Cancer Inst 2015; 107: pii: djv036 . doi:10.1093/jnci/djv036
34 Vachon CM, Pankratz VS, Scott CG. et al. The contributions of breast density and common genetic variation to breast cancer risk. J Natl Cancer Inst 2015; 107: pii: dju397 . doi:10.1093/jnci/dju397
35 Rudolph A, Song M, Brook MN. et al. Joint associations of a polygenic risk score and environmental risk factors for breast cancer in the Breast Cancer Association Consortium. Int J Epidemiol 2018;
36 Haberle L, Hein A, Rubner M. et al. Predicting Triple-Negative Breast Cancer Subtype Using Multiple Single Nucleotide Polymorphisms for Breast Cancer Risk and Several Variable Selection Methods. Geburtsh Frauenheilk 2017; 77: 667-678
37 Simard J, Chiarelli AM. Personalized risk assessment for prevention and early detection of breast cancer: Integration and Implementation. 2018 Online: https://www.genomecanada.ca/sites/default/files/2017lsarp_backgrounder_en.pdf ; last access: 01.04.2018
38 Unicancer. Randomized, Comparison Of Risk-Stratified versus Standard Breast Cancer Screening In European Women Aged 40–74. 2017 Online: https://cordis.europa.eu/project/rcn/212694_en.html ; last access: 01.04.2018
39 Shieh Y, Eklund M, Madlensky L. et al. Breast Cancer Screening in the Precision Medicine Era: Risk-Based Screening in a Population-Based Trial. J Natl Cancer Inst 2017;
40 Evans DG, Astley S, Stavrinos P. et al. Improvement in risk prediction, early detection and prevention of breast cancer in the NHS Breast Screening Programme and family history clinics: a dual cohort study. Southampton (UK): NIHR Journals Library; 2016
41 ASSURE Consortium. Final Report Summary – ASSURE (Adapting Breast Cancer Screening Strategy Using Personalised RiskEstimation). 2016 Online: https://cordis.europa.eu/result/rcn/187468_en.html ; last access: 01.04.2018
42 Couch FJ, Hart SN, Sharma P. et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 2015; 33: 304-311
43 Couch FJ, Shimelis H, Hu C. et al. Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer. JAMA Oncol 2017; 3: 1190-1196
44 Fasching PA, Loibl S, Hu C. et al. BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the Gepar-Quinto Study. J Clin Oncol 2018;
45 Wunderle M, Gass P, Haberle L. et al. BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients. Breast Cancer Res Treat 2018; 171: 85-94
46 Fasching PA, Hu C, Hart SN. et al. Cancer predisposition genes in metastatic breast cancer – Association with metastatic pattern, prognosis, patient and tumor characteristics [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5–9 San Antonio, TX. Philadelphia (PA): AACR. Cancer Res 2018; 78: Abstr. PD1-02
47 Nolan E, Vaillant F, Branstetter D. et al. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 2016; 22: 933-939
48 Sigl V, Jones LP, Penninger JM. RANKL/RANK: from bone loss to the prevention of breast cancer. Open Biol 2016; 6: pii: 160230
49 Sigl V, Owusu-Boaitey K, Joshi PA. et al. RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res 2016; 26: 761-774
50 Bayer CM, Beckmann MW, Fasching PA. Updates on the role of receptor activator of nuclear factor kappaB/receptor activator of nuclear factor kappaB ligand/osteoprotegerin pathway in breast cancer risk and treatment. Curr Opin Obstet Gynecol 2017; 29: 4-11
51 Francis P, Singer C, Saunders C. et al. BRCA‑P: An international randomised phase III study evaluating the RANK ligand inhibitor denosumab for the prevention of breast cancer in BRCA1 mutation carriers [2018–2022]. Online: http://purlorg/au-research/grants/nhmrc/1140715 and https://researchdataandsorgau/brca-p-an-mutation-carriers/1319302 2018 ; last access: 02.04.2018
52 Kuchenbaecker KB, Hopper JL, Barnes DR. et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 2017; 317: 2402-2416
53 Copson ER, Maishman TC, Tapper WJ. et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol 2018;
54 Fasching PA. Breast cancer in young women: do BRCA1 or BRCA2 mutations matter?. Lancet Oncol 2018;
55 Evron E, Ben David MA, Goldberg H. et al. Phase II national clinical trial of prophylactic irradiation to the contralateral breast for BRCA mutation carriers treated for early breast cancer (EBC). J Clin Oncol 2018 36. (Suppl.): Abstr. 514
56 Poortmans PM, Collette S, Kirkove C. et al. Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. N Engl J Med 2015; 373: 317-327
57 Poortmans P, Collette S, Struikmans H. et al. Fifteen-year results of the randomised EORTC trial 22922/10925 investigating internal mammary and medial supraclavicular (IM‑MS) lymph node irradiation in stage I – III breast cancer. J Clin Oncol 2018 36. (Suppl.): Abstr. 504
58 Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin 2017; 67: 65-85
59 McArthur HL, Barker CA, Gucalp A. et al. A phase II, single arm study assessing the efficacy of pembrolizumab (Pembro) plus radiotherapy (RT) in metastatic triple negative breast cancer (mTNBC). J Clin Oncol 2018 36. (Suppl.): Abstr. 1017
60 Formenti SC, Golden EB, Goldberg JD. et al. Results of a phase I – II study of adjuvant concurrent carboplatin and accelerated radiotherapy for triple negative breast cancer. Oncoimmunology 2017; 6: e1274479
61 Ngwa W, Irabor OC, Schoenfeld JD. et al. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer 2018; 18: 313-322
62 Davies C, Godwin J, Gray R. Early Breast Cancer Trialistsʼ Collaborative Group. et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011; 378: 771-784
63 Early Breast Cancer Trialistsʼ Collaborative Group. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 2015; 386: 1341-1352
64 Pagani O, Regan MM, Walley BA. et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014; 371: 107-118
65 Francis PA, Regan MM, Fleming GF. et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 2015; 372: 436-446
66 Francis PA, Pagani O, Fleming GF. et al. Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. N Engl J Med 2018; 379: 122-137
67 Regan MM, Francis PA, Pagani O. et al. Absolute improvements in freedom from distant recurrence with adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) HER2-negative breast cancer (BC): Results from TEXT and SOFT. J Clin Oncol 2018 36. (Suppl.): Abstr. 503
68 Noh WC, Lee JW, Nam SJ. et al. Role of adding ovarian function suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or resume menstruation after chemotherapy: The ASTRRA study. J Clin Oncol 2018 36. (Suppl.): Abstr. 502
69 Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft und Deutsche Krebshilfe und AWMF). S3-Leitlinie Früherkennung, Diagnose, Therapie und Nachsorge des Mammakarzinoms, Version 4.0, 2017 AWMF Registernummer: 032-045OL. 2017 Online: http://www.leitlinienprogrammonkologie.de/leitlinien/mammakarzinom/ ; last access: 23.07.2018
70 Early Breast Cancer Trialistsʼ Collaborative Group. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. 2015; 386: 1353-1361
71 Gnant M, Pfeiler G, Dubsky PC. et al. The impact of adjuvant denosumab on disease-free survival: Results from 3425 postmenopausal patients of the ABCSG‑18 trial. Cancer Res 2016 (Suppl. 4): Abstract S2-02 76.
72 Coleman RE, Finkelstein D, Barrios CH. et al. Adjuvant denosumab in early breast cancer: First results from the international multicenter randomized phase III placebo controlled D-CARE study. J Clin Oncol 2018 36. (Suppl.): Abstr. 501
73 Gnant M, Pfeiler G, Steger GG. et al. Adjuvant denosumab in early breast cancer: Disease-free survival analysis of 3425 postmenopausal patients in the ABCSG‑18 trial. J Clin Oncol 2018 36. (Suppl.): Abstr. 500
74 Early Breast Cancer Trialistsʼ Collaborative Group. Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol 2018; 19: 27-39
75 Cortazar P, Zhang L, Untch M. et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 384: 164-172
76 Fasching PA, Heusinger K, Haeberle L. et al. Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer 2011; 11: 486
77 von Minckwitz G, Untch M, Blohmer JU. et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012; 30: 1796-1804
78 Gianni L, Pienkowski T, Im YH. et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016; 17: 791-800
79 Guarneri V, Dieci MV, Bisagni G. et al. De-escalated treatment with trastuzumab- pertuzumab-letrozole in patients with HR+/HER2+ operable breast cancer with Ki67 response after 2 weeks letrozole: Final results of the PerELISA neoadjuvant study. J Clin Oncol 2018 36. (Suppl.): Abstr. 507
80 Prat A, De Angelis C, Pascual T. et al. HER2-enriched subtype and ERBB2mRNA as predictors of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer: A combined analysis of TBCRC006/023 and PAMELA trials. J Clin Oncol 2018 36. (Suppl.): Abstr. 509
81 von Minckwitz G, Procter M, de Azambuja E. et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med 2017; 377: 122-131
82 Tolaney SM, Barry WT, Dang CT. et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015; 372: 134-141
83 Tolaney SM, Barry WT, Guo H. et al. Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2- positive breast cancer (BC). J Clin Oncol 2017; 35: 511
84 Sawaki M, Saito T, Baba S. et al. Evaluation of trastuzumab without chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly breast cancer patients: Randomized controlled trial (RESPECT). J Clin Oncol 2018 36. (Suppl.): Abstr. 510
85 Cameron D, Piccart-Gebhart MJ, Gelber RD. et al. 11 yearsʼ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 2017; 389: 1195-1205
86 Pivot X, Romieu G, Debled M. et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 2013; 14: 741-748
87 Joensuu H, Fraser J, Wildiers H. et al. Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs. 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: The SOLD Randomized Clinical Trial. JAMA Oncol 2018;
88 Earl HM, Hiller L, Vallier AL. et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol 2018 36. (Suppl.): Abstr. 506
89 Ravdin PM, Siminoff LA, Davis GJ. et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 2001; 19: 980-991
90 Wishart GC, Bajdik CD, Dicks E. et al. PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2. Br J Cancer 2012; 107: 800-807
91 Cardoso F, vanʼt Veer LJ, Bogaerts J. et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med 2016; 375: 717-729
92 Paik S, Shak S, Tang G. et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351: 2817-2826
93 Sparano JA, Gray RJ, Makower DF. et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2018; 379: 111-121
94 Sparano JA, Gray RJ, Makower DF. et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2015; 373: 2005-2014
95 Cuzick J, Dowsett M, Pineda S. et al. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol 2011; 29: 4273-4278
96 Dowsett M, Sestak I, Lopez-Knowles E. et al. Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol 2013; 31: 2783-2790
97 Filipits M, Rudas M, Jakesz R. et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res 2011; 17: 6012-6020
98 Schmidt M, Fasching PA, Beckmann MW. et al. Biomarkers in Breast Cancer – An Update. Geburtsh Frauenheilk 2012; 72: 819-832