I-SPY 2: a Neoadjuvant Adaptive Clinical Trial Designed to Improve Outcomes in High-Risk Breast Cancer

  • Haiyun Wang
  • Douglas YeeEmail author
Clinical Trials (JE Lang, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Clinical Trials


Purpose of Review

The I-SPY 2 trial is an adaptive clinical trial platform designed to improve outcomes in high-risk breast cancer patients by testing new drugs in the neoadjuvant setting. The intent of this review is to discuss background, study structure, innovation, and outcomes of the I-SPY 2 trial.

Recent Findings

I-SPY 2 evaluates new agents combined with standard therapy with pathologic complete response (pCR) as the primary endpoint. I-SPY-2 uses clinical biomarkers to classify breast cancer into 10 subtypes, with Bayesian adaptive randomization to allow individualized patient assignment to therapy arms to maximize treatment effects. A total of 7 drugs have graduated from I-SPY 2. Multiple new agents are currently in active enrollment in I-SPY 2.


I-SPY 2 uses an individualized approach in clinical trial design to improve high-risk breast cancer outcomes. The purpose of this review is to encourage further research and innovation in this area and bring more precise treatment options to breast cancer patients.


I-SPY 2 Breast cancer Neoadjuvant chemotherapy Pathological complete response Adaptive randomization 


Compliance with Ethical Standards

Conflict of Interest

Douglas Yee reports grants from QuantumLeap, grants from the National Cancer Institute (P30-CA077598), and grants from the National Cancer Institute (P01 CA210961) during the conduct of the study. Dr. Yee also reports personal fees from AstraZeneca and Puma outside the submitted work. Haiyun Wang declares no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Oliver RT. Regarding: Valero V, Buzdar AU, Hortobagyi GN. Locally advanced breast cancer. The Oncologist 1996;1:8-17. Oncologist. 1996;1(4):278–9.PubMedGoogle Scholar
  2. 2.
    Tryfonidis K, Senkus E, Cardoso MJ, Cardoso F. Management of locally advanced breast cancer—perspectives and future directions. Nat Rev Clin Oncol. 2015;12(3):147–62. Scholar
  3. 3.
    Newman LA, Mamounas EP. Review of breast cancer clinical trials conducted by the National Surgical Adjuvant Breast Project. Surg Clin North Am. 2007;87(2):279–305, vii. Scholar
  4. 4.
    DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:20–33. Scholar
  5. 5.
    Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, et al. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet. 2004;364(9437):858–68. Scholar
  6. 6.
    Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111–21. Scholar
  7. 7.
    Cardoso F, van’t Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717–29. Scholar
  8. 8.
    DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003;22(2):151–85. Scholar
  9. 9.
    Fehrenbacher L, Cecchini R, Geyer C, Rastogi P, Costantino J, Atkins J et al., editors. NSABP B-47 (NRG oncology): phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-low IBC). San Antonio Breast Cancer Symposium; 2017; San Antonio, Texas: SABCS.Google Scholar
  10. 10.
    Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744–52. Scholar
  11. 11.
    •• Park JW, Liu MC, Yee D, Yau C, van’t Veer LJ, Symmans WF, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016;375(1):11–22. report from I-SPY 2 showing neratinib plus paclitaxel was superior to trastuzumab plus paclitaxel.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Amiri-Kordestani L, Wedam S, Zhang L, Tang S, Tilley A, Ibrahim A, et al. First FDA approval of neoadjuvant therapy for breast cancer: pertuzumab for the treatment of patients with HER2-positive breast cancer. Clin Cancer Res. 2014;20(21):5359–64. Scholar
  13. 13.
    von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122–31. Scholar
  14. 14.
    Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 2009;86(1):97–100.CrossRefGoogle Scholar
  15. 15.
    Cardoso F, Van’t Veer L, Rutgers E, Loi S, Mook S, Piccart-Gebhart MJ. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008;26(5):729–35. Scholar
  16. 16.
    Berry DA. Bayesian clinical trials. Nat Rev Drug Discov. 2006;5(1):27–36. Scholar
  17. 17.
    DeMichele A, Berry DA, Zujewski J, Hunsberger S, Rubinstein L, Tomaszewski JE, et al. Developing safety criteria for introducing new agents into neoadjuvant trials. Clin Cancer Res. 2013;19(11):2817–23. Scholar
  18. 18.
    Paoloni M, Lyandres J, Buxton M, Berry D, Esserman L, DeMichele A et al., editors. Abstract P2-11-02: a longitudinal look at toxicity management within a platform trial: lessons from the I-SPY 2 TRIAL 2017 February 15 2017; Cancer ResGoogle Scholar
  19. 19.
    • Das S, Lo AW. Re-inventing drug development: a case study of the I-SPY 2 breast cancer clinical trials program. Contemp Clin Trials. 2017;62:168–/. review of the innovations contained within I-SPY 2.CrossRefPubMedGoogle Scholar
  20. 20.
    Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project protocols B-18 and B-27. J Clin Oncol. 2008;26(5):778–85.CrossRefGoogle Scholar
  21. 21.
    Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;30:96–102.CrossRefGoogle Scholar
  22. 22.
    Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164–72. Scholar
  23. 23.
    Administration FDA. Guidance for industry: pathological complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval.:; October 2014.
  24. 24.
    Berry DA, Hudis CA. Neoadjuvant therapy in breast cancer as a basis for drug approval. JAMA Oncol. 2015;1(7):875–6. Scholar
  25. 25.
    Esserman LJ, Berry DA, DeMichele A, Carey L, Davis SE, Buxton M, et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL—CALGB 150007/150012, ACRIN 6657. J Clin Oncol. 2012;30(26):3242–9. Scholar
  26. 26.
    • Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS et al., editors. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL. San Antonio Breast Cancer Symposium; 2017; San Antonio, Texas: SABCS. I-SPY 2 report of the association between pCR and event-free and distant disease-free survival.Google Scholar
  27. 27.
    Freidlin B, Korn EL, Gray R, Martin A. Multi-arm clinical trials of new agents: some design considerations. Clinical Cancer Research: an official journal of the American Association for Cancer Research. 2008;14(14):4368-4371. doi: Scholar
  28. 28.
    Korn EL, Freidlin B. Adaptive clinical trials: advantages and disadvantages of various adaptive design elements. J Natl Cancer Inst. 2017;109(6).
  29. 29.
    • Wolf DM, Yau C, Sanil A, Glas A, Petricoin E, Wulfkuhle J, et al. DNA repair deficiency biomarkers and the 70-gene ultra-high risk signature as predictors of veliparib/carboplatin response in the I-SPY 2 breast cancer trial. NPJ Breast Cancer. 2017;3:31. analysis from I-SPY 2 identifies potential signatures associated with improved response to carboplatin-containing regimens.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Castano Z, Marsh T, Tadipatri R, Kuznetsov HS, Al-Shahrour F, Paktinat M, et al. Stromal EGF and IGF-I together modulate plasticity of disseminated triple-negative breast tumors. Cancer Discov. 2013;3(8):922–35. Scholar
  31. 31.
    Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, et al. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res. 2008;68(3):826–33.CrossRefGoogle Scholar
  32. 32.
    Deeks ED. Neratinib: first global approval. Drugs. 2017;77(15):1695–704. Scholar
  33. 33.
    • Rugo HS, Olopade OI, DeMichele A, Yau C, van’t Veer LJ, Buxton MB, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016;375(1):23–34. I-SPY 2 report of veliparib, carboplatin, and paclitaxel improving pCR rates.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    • Loibl S, O’Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, 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. Lancet Oncol. 2018;19(4):497–509. 3 randomized trial validating findings from I-SPY 2 (ref. 33). Trial showed improved pCR rates were due to carboplatin but not veliparib.CrossRefPubMedGoogle Scholar
  35. 35.
    Severson TM, Wolf DM, Yau C, Peeters J, Wehkam D, Schouten PC, et al. The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting. Breast Cancer Res. 2017;19(1):99–9.
  36. 36.
    Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724–34. Scholar
  37. 37.
    Buxton M, DeMichele AM, Chia S, van’t Veer L, Chien J, Wallace A et al., editors. Abstract CT106: efficacy of pertuzumab/trastuzumab/paclitaxel over standard trastuzumab/paclitaxel therapy for HER2+ breast cancer: results from the neoadjuvant I-SPY 2 TRIAL 2016: AACR.Google Scholar
  38. 38.
    DeMichele AM, Moulder S, Buxton M, Yee D, Wallace A, Chien J et al., editors. Abstract CT042: efficacy of T-DM1+ pertuzumab over standard therapy for HER2+ breast cancer: results from the neoadjuvant I-SPY 2 TRIAL 2016: AACR.Google Scholar
  39. 39.
    Schott AF, Hayes DF. Defining the benefits of neoadjuvant chemotherapy for breast cancer. J Clin Oncol. vol 15. United States 2012. p. 1747-1749.CrossRefGoogle Scholar
  40. 40.
    Alexander BM, Wen PY, Trippa L, Reardon DA, Yung WK, Parmigiani G, et al. Biomarker-based adaptive trials for patients with glioblastoma—lessons from I-SPY 2. Neuro-Oncology. 2013;15(8):972–8. Scholar
  41. 41.
    Messmer MF, Wilhelm EE, Shoulson I. I-SPY 2 breast cancer trial as a model for innovation in Alzheimer disease therapies. JAMA Neurol. 2017;74(9):1027–8. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Masonic Cancer CenterUniversity of MinnesotaMinneapolisUSA

Personalised recommendations