Journal Article
. 2016 Feb;5().
doi: 10.1186/s40064-016-1736-1.

Patterns in target-directed breast cancer research

Sofia Torres 1 Christine Simmons 2 Jean-François Boileau 3 Deanna McLeod 4 Ilidio Martins 4 Maureen Trudeau 1 
Affiliations
  • PMID: 26877907
  •     73 References

Abstract

We undertake an analysis of ongoing BC targeted therapy trials registered to CT.gov to describe patterns of ongoing clinical research, highlight gaps in current research programs and identify ways of optimizing ongoing initiatives. A search of clinicaltrials.gov was conducted on September 4, 2013 to identify ongoing randomized phase II and III trials of targeted therapies in BC. A total of 280 trials were analyzed, the majority conducted in either human epidermal growth factor receptor 2 (HER2)-positive (n = 79, 28.2 %) or hormone receptor (HR)-positive (n = 104, 37.1 %) populations. Less than half of all trials were conducted in populations selected to match the agent under investigation (n = 126, 45 %). HER2-directed therapy is the single most investigated class of targeted agents (n = 73, 26.1 %), but trials investigating anti-angiogenic agents are also common (n = 49, 17.5 %). The most common new classes of agents under investigation in HR-positive and triple negative (TN)/BRCA-positive disease, are non-receptor protein kinase-inhibitors (n = 12; 11.5 %) and poly (ADP-ribose) polymerase inhibitors (n = 6; 30 %), respectively. The majority of regimens combine new targeted agents with either chemotherapy (n = 164, 58.6 %) or endocrine therapy (n = 113, 40.4 %); a total of 8 trials (2.8 %) investigated peptide-drug conjugates. The most frequently utilized end-points were pathological complete response in the neo-adjuvant setting (n = 36, 52.9 %) and time-to-event end-points in the adjuvant and advanced settings (77.3 and 72.6 %, respectively). Our findings suggest a need for more target-matched agent development, maintenance of a value-based focus in research and a need for the clinical development of agents to treat TN/BRCA-positive and HR-positive BC.

Keywords: Biomarkers; Breast cancer; Clinical trials; Patient profiling; Randomized trials; Target-directed research.

Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.
Kathy D Miller, Linnea I Chap, +9 authors, Hope S Rugo.
J Clin Oncol, 2005 Feb 01; 23(4). PMID: 15681523
Highly Cited.
Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer.
John R Mackey, Manuel Ramos-Vazquez, +17 authors, Miguel Martin.
J Clin Oncol, 2014 Sep 04; 33(2). PMID: 25185099
Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer.
David W Miles, Arlene Chan, +13 authors, Gilles Romieu.
J Clin Oncol, 2010 May 26; 28(20). PMID: 20498403
Highly Cited.
Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.
José Baselga, Mario Campone, +18 authors, Gabriel N Hortobagyi.
N Engl J Med, 2011 Dec 14; 366(6). PMID: 22149876    Free PMC article.
Highly Cited.
Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer.
Zhongzhen Guan, Binghe Xu, +14 authors, Henry Gomez.
J Clin Oncol, 2013 Mar 20; 31(16). PMID: 23509322
Trastuzumab emtansine for HER2-positive advanced breast cancer.
Sunil Verma, David Miles, +12 authors, EMILIA Study Group.
N Engl J Med, 2012 Oct 02; 367(19). PMID: 23020162    Free PMC article.
Highly Cited.
Triple-negative breast cancer.
William D Foulkes, Ian E Smith, Jorge S Reis-Filho.
N Engl J Med, 2010 Nov 12; 363(20). PMID: 21067385
Highly Cited. Review.
Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.
Charles L Vogel, Melody A Cobleigh, +10 authors, Michael Press.
J Clin Oncol, 2002 Feb 01; 20(3). PMID: 11821453
Highly Cited.
Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer.
José Baselga, José Getúlio Martins Segalla, +21 authors, Frederico Costa.
J Clin Oncol, 2012 Mar 14; 30(13). PMID: 22412143
Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer.
Carlos H Barrios, Mei-Ching Liu, +12 authors, Miguel Martin.
Breast Cancer Res Treat, 2010 Mar 27; 121(1). PMID: 20339913    Free PMC article.
Supervised risk predictor of breast cancer based on intrinsic subtypes.
Joel S Parker, Michael Mullins, +17 authors, Philip S Bernard.
J Clin Oncol, 2009 Feb 11; 27(8). PMID: 19204204    Free PMC article.
Highly Cited.
Pathological complete response and accelerated drug approval in early breast cancer.
Tatiana M Prowell, Richard Pazdur.
N Engl J Med, 2012 Jun 01; 366(26). PMID: 22646508
Highly Cited.
Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.
Luca Gianni, Tadeusz Pienkowski, +17 authors, Pinuccia Valagussa.
Lancet Oncol, 2011 Dec 14; 13(1). PMID: 22153890
Highly Cited.
A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses.
David Cameron, Michelle Casey, +21 authors, Charles E Geyer.
Breast Cancer Res Treat, 2008 Jan 12; 112(3). PMID: 18188694
Highly Cited.
Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), C Davies, +11 authors, R Peto.
Lancet, 2011 Aug 02; 378(9793). PMID: 21802721    Free PMC article.
Highly Cited.
Molecular portraits of human breast tumours.
C M Perou, T Sørlie, +15 authors, D Botstein.
Nature, 2000 Aug 30; 406(6797). PMID: 10963602
Highly Cited.
Gene expression profiling predicts clinical outcome of breast cancer.
Laura J van 't Veer, Hongyue Dai, +13 authors, Stephen H Friend.
Nature, 2002 Feb 02; 415(6871). PMID: 11823860
Highly Cited.
Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group.
Lancet, 1998 May 30; 351(9114). PMID: 9605801
Highly Cited.
Reading the prognosis of the individual with breast cancer.
R W Blamey, S E Pinder, +4 authors, J L Haybittle.
Eur J Cancer, 2007 Feb 27; 43(10). PMID: 17320376
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.
Jack Cuzick, Mitch Dowsett, +10 authors, John F Forbes.
J Clin Oncol, 2011 Oct 13; 29(32). PMID: 21990413
Highly Cited.
Drug development: Raise standards for preclinical cancer research.
C Glenn Begley, Lee M Ellis.
Nature, 2012 Mar 31; 483(7391). PMID: 22460880
Highly Cited.
Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial.
Mitch Dowsett, Craig Allred, +17 authors, Aman Buzdar.
J Clin Oncol, 2008 Jan 30; 26(7). PMID: 18227529
Highly Cited.
Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group.
A Buzdar, W Jonat, +8 authors, P V Plourde.
J Clin Oncol, 1996 Jul 01; 14(7). PMID: 8683230
Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31.
Edith A Perez, Edward H Romond, +7 authors, Norman Wolmark.
J Clin Oncol, 2011 Jul 20; 29(25). PMID: 21768458    Free PMC article.
Highly Cited.
Equipoise lost: ethics, costs, and the regulation of cancer clinical research.
David J Stewart, Simon N Whitney, Razelle Kurzrock.
J Clin Oncol, 2010 Apr 22; 28(17). PMID: 20406924
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
Patricia Cortazar, Lijun Zhang, +34 authors, Gunter von Minckwitz.
Lancet, 2014 Feb 18; 384(9938). PMID: 24529560
Highly Cited. Review.
Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study.
Sandra M Swain, Sung-Bae Kim, +11 authors, José Baselga.
Lancet Oncol, 2013 Apr 23; 14(6). PMID: 23602601    Free PMC article.
Highly Cited.
Breast cancer statistics, 2013.
Carol DeSantis, Jiemin Ma, Leah Bryan, Ahmedin Jemal.
CA Cancer J Clin, 2013 Oct 12; 64(1). PMID: 24114568
Highly Cited. Review.
The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis.
C A Harris, R L Ward, +2 authors, S Pearson.
Ann Oncol, 2010 Dec 02; 22(6). PMID: 21119031
Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
José Baselga, Javier Cortés, +12 authors, CLEOPATRA Study Group.
N Engl J Med, 2011 Dec 14; 366(2). PMID: 22149875    Free PMC article.
Highly Cited.
Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review.
Shaheenah Dawood, Kristine Broglio, +2 authors, Sharon H Giordano.
J Clin Oncol, 2009 Nov 26; 28(1). PMID: 19933921    Free PMC article.
Highly Cited.
Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group.
Michel Marty, Francesco Cognetti, +14 authors, Jean-Marc Extra.
J Clin Oncol, 2005 May 25; 23(19). PMID: 15911866
Highly Cited.
Immunohistochemistry of estrogen and progesterone receptors reconsidered: experience with 5,993 breast cancers.
Mehrdad Nadji, Carmen Gomez-Fernandez, Parvin Ganjei-Azar, Azorides R Morales.
Am J Clin Pathol, 2005 Mar 15; 123(1). PMID: 15762276
The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine.
Jeffrey S Ross, Elzbieta A Slodkowska, +3 authors, Gabriel N Hortobagyi.
Oncologist, 2009 Apr 07; 14(4). PMID: 19346299
Highly Cited. Review.
Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.
Kathy Miller, Molin Wang, +6 authors, Nancy E Davidson.
N Engl J Med, 2007 Dec 28; 357(26). PMID: 18160686
Highly Cited.
2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial.
Aron Goldhirsch, Richard D Gelber, +23 authors, Herceptin Adjuvant (HERA) Trial Study Team.
Lancet, 2013 Jul 23; 382(9897). PMID: 23871490
Highly Cited.
Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial.
Aman U Buzdar, Vera J Suman, +9 authors, American College of Surgeons Oncology Group investigators.
Lancet Oncol, 2013 Nov 19; 14(13). PMID: 24239210    Free PMC article.
Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer. Analysis at six years by Nolvadex Adjuvant Trial Organisation.
Lancet, 1985 Apr 13; 1(8433). PMID: 2858709
TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer.
Lisa A Carey, Hope S Rugo, +17 authors, Eric P Winer.
J Clin Oncol, 2012 Jun 06; 30(21). PMID: 22665533    Free PMC article.
Highly Cited.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Iniparib plus chemotherapy in metastatic triple-negative breast cancer.
Joyce O'Shaughnessy, Cynthia Osborne, +6 authors, Charles Bradley.
N Engl J Med, 2011 Jan 07; 364(3). PMID: 21208101
Highly Cited.
Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials.
Wenjin Yin, Yiwei Jiang, +2 authors, Jinsong Lu.
PLoS One, 2011 Jun 23; 6(6). PMID: 21695277    Free PMC article.
Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17.
Paul E Goss, James N Ingle, +15 authors, Joseph L Pater.
J Natl Cancer Inst, 2005 Sep 08; 97(17). PMID: 16145047
Highly Cited.
A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
Soonmyung Paik, Steven Shak, +12 authors, Norman Wolmark.
N Engl J Med, 2004 Dec 14; 351(27). PMID: 15591335
Highly Cited.
Incidence of breast cancer in the United States: current and future trends.
William F Anderson, Hormuzd A Katki, Philip S Rosenberg.
J Natl Cancer Inst, 2011 Jul 15; 103(18). PMID: 21753181    Free PMC article.
Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.
Christina Davies, Hongchao Pan, +36 authors, Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group.
Lancet, 2012 Dec 12; 381(9869). PMID: 23219286    Free PMC article.
Highly Cited.
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.
José Baselga, Ian Bradbury, +25 authors, NeoALTTO Study Team.
Lancet, 2012 Jan 20; 379(9816). PMID: 22257673    Free PMC article.
Highly Cited.
High drug attrition rates--where are we going wrong?
Lisa Hutchinson, Rebecca Kirk.
Nat Rev Clin Oncol, 2011 Mar 31; 8(4). PMID: 21448176
Highly Cited.
A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors.
B Fisher, J Costantino, +7 authors, E R Fisher.
N Engl J Med, 1989 Feb 23; 320(8). PMID: 2644532
Highly Cited.
Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer.
Nicholas C Turner, Jungsil Ro, +12 authors, PALOMA3 Study Group.
N Engl J Med, 2015 Jun 02; 373(3). PMID: 26030518
Highly Cited.
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
D J Slamon, B Leyland-Jones, +9 authors, L Norton.
N Engl J Med, 2001 Mar 15; 344(11). PMID: 11248153
Highly Cited.
The EORTC 10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase.
Emiel Rutgers, Martine J Piccart-Gebhart, +12 authors, Fatima Cardoso.
Eur J Cancer, 2011 Nov 05; 47(18). PMID: 22051734
High concordance of protein (by IHC), gene (by FISH; HER2 only), and microarray readout (by TargetPrint) of ER, PgR, and HER2: results from the EORTC 10041/BIG 03-04 MINDACT trial.
G Viale, L Slaets, +11 authors, TRANSBIG Consortium & the MINDACT Investigators.
Ann Oncol, 2014 Mar 29; 25(4). PMID: 24667714    Free PMC article.
Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer.
Aleix Prat, Joel S Parker, +5 authors, Charles M Perou.
Breast Cancer Res, 2010 Sep 04; 12(5). PMID: 20813035    Free PMC article.
Highly Cited.
Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: the JO17360 Trial Group.
Kenichi Inoue, Kazuhiko Nakagami, +14 authors, Shinzaburo Noguchi.
Breast Cancer Res Treat, 2009 Aug 20; 119(1). PMID: 19690954
The natural history of hormone receptor-positive breast cancer.
Elgene Lim, Otto Metzger-Filho, Eric P Winer.
Oncology (Williston Park), 2012 Sep 11; 26(8). PMID: 22957400
Review.
Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study.
Gunter von Minckwitz, Andreas du Bois, +15 authors, Sibylle Loibl.
J Clin Oncol, 2009 Mar 18; 27(12). PMID: 19289619
Highly Cited.
A gene-expression signature as a predictor of survival in breast cancer.
Marc J van de Vijver, Yudong D He, +18 authors, René Bernards.
N Engl J Med, 2002 Dec 20; 347(25). PMID: 12490681
Highly Cited.
Assessment of the contribution of the IHC4+C score to decision making in clinical practice in early breast cancer.
S Barton, L Zabaglo, +6 authors, M Dowsett.
Br J Cancer, 2012 Apr 26; 106(11). PMID: 22531639    Free PMC article.
A 50-gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen.
Stephen K Chia, Vivien H Bramwell, +12 authors, Torsten O Nielsen.
Clin Cancer Res, 2012 Jun 20; 18(16). PMID: 22711706    Free PMC article.
Highly Cited.
Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.
Kathy S Albain, William E Barlow, +20 authors, Breast Cancer Intergroup of North America.
Lancet Oncol, 2009 Dec 17; 11(1). PMID: 20005174    Free PMC article.
Highly Cited.
Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG).
Lancet, 2005 May 17; 365(9472). PMID: 15894097
Highly Cited.
Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer.
P M Ravdin, L A Siminoff, +4 authors, H L Parker.
J Clin Oncol, 2001 Feb 22; 19(4). PMID: 11181660
Highly Cited.
Clinical application of the 70-gene profile: the MINDACT trial.
Fatima Cardoso, Laura Van't Veer, +3 authors, Martine J Piccart-Gebhart.
J Clin Oncol, 2008 Feb 09; 26(5). PMID: 18258980
Highly Cited.
RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer.
Adam M Brufsky, Sara Hurvitz, +4 authors, Hope S Rugo.
J Clin Oncol, 2011 Oct 13; 29(32). PMID: 21990397
Highly Cited.
A population-based validation of the prognostic model PREDICT for early breast cancer.
G C Wishart, C D Bajdik, +5 authors, P D P Pharoah.
Eur J Surg Oncol, 2011 Mar 05; 37(5). PMID: 21371853
Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial.
Jan Bogaerts, Fatima Cardoso, +12 authors, TRANSBIG consortium.
Nat Clin Pract Oncol, 2006 Oct 05; 3(10). PMID: 17019432
Review.
Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
T Sørlie, C M Perou, +14 authors, A L Børresen-Dale.
Proc Natl Acad Sci U S A, 2001 Sep 13; 98(19). PMID: 11553815    Free PMC article.
Highly Cited.
Characteristics of oncology clinical trials: insights from a systematic analysis of ClinicalTrials.gov.
Bradford R Hirsch, Robert M Califf, +6 authors, Amy P Abernethy.
JAMA Intern Med, 2013 May 24; 173(11). PMID: 23699837
Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group.
A U Buzdar, W Jonat, +8 authors, D Lee.
Cancer, 1998 Sep 18; 83(6). PMID: 9740079
Treatment of HER2-positive breast cancer: current status and future perspectives.
Carlos L Arteaga, Mark X Sliwkowski, +3 authors, Luca Gianni.
Nat Rev Clin Oncol, 2011 Nov 30; 9(1). PMID: 22124364
Highly Cited. Review.
Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study.
Lisa A Carey, Charles M Perou, +14 authors, Robert C Millikan.
JAMA, 2006 Jun 08; 295(21). PMID: 16757721
Highly Cited.
RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer.
Nicholas J Robert, Véronique Diéras, +9 authors, Joyce O'Shaughnessy.
J Clin Oncol, 2011 Mar 09; 29(10). PMID: 21383283
Highly Cited.