Biomarkers Consortium - I-SPY TRIAL-2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and MoLecular Analysis): An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy

The I-SPY 2 trial was setup to accelerate the pace of qualifying effective novel agents for breast cancer by testing new agents in high-risk women with locally advanced (Stage 2 and 3) newly diagnosed breast cancer in the neoadjuvant setting. The trial used extensive biomarker testing and an adaptive design, with intermediate markers (complete pathologic response (pCR), MR imaging, and biomarkers) as a way to measure drug efficacy and move successful regimens and biomarkers to focused phase III trials. This project involves collaboration from all sectors including Food and Drug Administration scientists, National Cancer Institute scientists, clinical trialists, industry, and patient advocate groups.


  • Phase II trial of novel investigative breast cancer agents in the neoadjuvant setting that uses biomarkers and adaptive design to accelerate the clinical trial process.
  • Using biomarkers from individual patients’ tumors to screen promising new treatments, identifying which treatments are most effective in specific types of patients.  
  • Utilizing an adaptive trial design enables researchers to use early data from one set of patients to guide decisions about which treatments might be more useful for patients later in the trial, while minimizing the exposure of patients to treatments that do not benefit them. 

Results & Accomplishments

Completed Phase II testing on eleven drugs (neratinib, veliparib, AMG386, ganitumab, MK2206, pertuzumab, TDM1+pertuzumab, ganetespib, PLX3397, patritumab, and pembrolizumab) to date. Three of these trials were completed and did not proceed to a Phase III in this clinical setting (AMG386, ganitumab, and ganetespib). Two of these drugs were halted during the Phase II study (PLX3397 and patritumab), and the remaining six drugs graduated to Phase III (neratinib, veliparib, MK2206, pertuzumab, TDM1+pertuzumab, and pembrolizumab). An addition four drugs have been added to the trial and are currently in Phase II testing (talazoparib, SGN-LIV1A, and durvalumab+olaparib).

Scientific Publications

Effect of MR Imaging Contrast Thresholds on Prediction of Neoadjuvant Chemotherapy Response in Breast Cancer Subtypes: A Subgroup Analysis of the ACRIN 6657/I-SPY 1 TRIAL. Li W, Arasu V, Newitt DC, Jones EF, Wilmes L, Gibbs J, Kornak J, Joe BN, Esserman LJ, Hylton NM; ACRIN 6657 Trial Team and I-SPY Investigators Network. Tomography. 2016 Dec;2(4):378-387. doi: 10.18383/j.tom.2016.00247. PMID: 28066808

I-SPY 2: optimising cancer drug development in the 21st century. Bartsch R, de Azambuja E. ESMO Open. 2016 Nov 15;1(5):e000113. eCollection 2016. PMID: 27900209

I-SPY 2--Toward More Rapid Progress in Breast Cancer Treatment. Carey LA, Winer EP. N Engl J Med. 2016 Jul 7;375(1):83-4.

Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer. Rugo HS, Olopade OI, DeMichele A, Yau C, van 't Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, Symmans WF, Yee D, Chien AJ, Wallace AM, Kaplan HG, Boughey JC, Haddad TC, Albain KS, Liu MC, Isaacs C, Khan QJ, Lang JE, Viscusi RK, Pusztai L, Moulder SL, Chui SY, Kemmer KA, Elias AD, Edmiston KK, Euhus DM, Haley BB, Nanda R, Northfelt DW, Tripathy D, Wood WC, Ewing C, Schwab R, Lyandres J, Davis SE, Hirst GL, Sanil A, Berry DA, Esserman LJ; I-SPY 2 Investigators. N Engl J Med. 2016 Jul 7;375(1):23-34.

Adaptive Randomization of Neratinib in Early Breast Cancer. Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. N Engl J Med. 2016 Jul 7;375(1):11-22.

I-SPY 2--A Glimpse of the Future of Phase 2 Drug Development? Harrington D, Parmigiani G. N Engl J Med. 2016 Jul 7;375(1):7-9. T-DM1 Combo Graduates from I-SPY 2. [No authors listed] Cancer Discov. 2016 Jun;6(6):OF5.

Equivalence of MammaPrint array types in clinical trials and diagnostics. Beumer I, Witteveen A, Delahaye L, Wehkamp D, Snel M, Dreezen C, Zheng J, Floore A, Brink G, Chan B, Linn S, Bernards R, van 't Veer L, Glas A. Breast Cancer Res Treat. 2016 Apr;156(2):279-87.

Neoadjuvant Chemotherapy for Breast Cancer: Functional Tumor Volume by MR Imaging Predicts Recurrence-free Survival-Results from the ACRIN 6657/CALGB 150007 I-SPY 1 TRIAL. Hylton NM, Gatsonis CA, Rosen MA, Lehman CD, Newitt DC, Partridge SC, Bernreuter WK, Pisano ED, Morris EA, Weatherall PT, Polin SM, Newstead GM, Marques HS, Esserman LJ, Schnall MD; ACRIN 6657 Trial Team and I-SPY 1 TRIAL Investigators. Radiology. 2016 Apr;279(1):44-55.

The Neoadjuvant Model Is Still the Future for Drug Development in Breast Cancer. DeMichele A, Yee D, Berry DA, Albain KS, Benz CC, Boughey J, Buxton M, Chia SK, Chien AJ, Chui SY, Clark A, Edmiston K, Elias AD, Forero-Torres A, Haddad TC, Haley B, Haluska P, Hylton NM, Isaacs C, Kaplan H, Korde L, Leyland-Jones B, Liu MC, Melisko M, Minton SE, Moulder SL, Nanda R, Olopade OI, Paoloni M, Park JW, Parker BA, Perlmutter J, Petricoin EF, Rugo H, Symmans F, Tripathy D, van't Veer LJ, Viscusi RK, Wallace A, Wolf D, Yau C, Esserman LJ. Clin Cancer Res. 2015 Jul 1;21(13):2911-5.

Neratinib Graduates to I-SPY 3. [No authors listed] Cancer Discov. 2014 Jun;4(6):624.

Local recurrence rates are low in high-risk neoadjuvant breast cancer in the I-SPY 1 Trial (CALGB 150007/150012; ACRIN 6657). Cureton EL, Yau C, Alvarado MD, Krontiras H, Ollila DW, Ewing CA, Monnier S, Esserman LJ. Ann Surg Oncol. 2014 Sep;21(9):2889-96.

Pretreatment vitamin D level and response to neoadjuvant chemotherapy in women with breast cancer on the I-SPY trial (CALGB 150007/150015/ACRIN6657). Clark AS, Chen J, Kapoor S, Friedman C, Mies C, Esserman L, DeMichele A; I-SPY1 Investigators. Cancer Med. 2014 Jun;3(3):693-701.

Positive results for drug combo in I-SPY 2 trial. [No authors listed] Cancer Discov. 2014 Feb;4(2):OF2.

Biomarker-based adaptive trials for patients with glioblastoma--lessons from I-SPY 2. Alexander BM, Wen PY, Trippa L, Reardon DA, Yung WK, Parmigiani G, Berry DA. Neuro Oncol. 2013 Aug;15(8):972-8.

Clinically meaningful tumor reduction rates vary by prechemotherapy MRI phenotype and tumor subtype in the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Mukhtar RA, Yau C, Rosen M, Tandon VJ; I-SPY 1 TRIAL and ACRIN 6657 Investigators., Hylton N, Esserman LJ. Ann Surg Oncol. 2013 Nov;20(12):3823-30.

Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Alvarez JV, Pan TC, Ruth J, Feng Y, Zhou A, Pant D, Grimley JS, Wandless TJ, Demichele A; I-SPY 1 TRIAL Investigators., Chodosh LA. Cancer Cell. 2013 Jul 8;24(1):30-44.

Molecular subtyping of early-stage breast cancer identifies a group of patients who do not benefit from neoadjuvant chemotherapy. Glück S, de Snoo F, Peeters J, Stork-Sloots L, Somlo G. Breast Cancer Res Treat. 2013 Jun;139(3):759-67.

I-SPY 2 may change how clinical trials are conducted: researchers aim to accelerate approvals of cancer drugs. Printz C. Cancer. 2013 Jun 1;119(11):1925-7.

Molecular analysis of HER2 signaling in human breast cancer by functional protein pathway activation mapping. Wulfkuhle JD, Berg D, Wolff C, Langer R, Tran K, Illi J, Espina V, Pierobon M, Deng J, DeMichele A, Walch A, Bronger H, Becker I, Waldhör C, Höfler H, Esserman L; I-SPY 1 TRIAL Investigators., Liotta LA, Becker KF, Petricoin EF 3rd. Clin Cancer Res. 2012 Dec 1;18(23):6426-35.

Lobular histology and response to neoadjuvant chemotherapy in invasive breast cancer. Lips EH, Mukhtar RA, Yau C, de Ronde JJ, Livasy C, Carey LA, Loo CE, Vrancken-Peeters MJ, Sonke GS, Berry DA, Van't Veer LJ, Esserman LJ, Wesseling J, Rodenhuis S, Shelley Hwang E; I-SPY TRIAL Investigators. Breast Cancer Res Treat. 2012 Nov;136(1):35-43.

Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL--CALGB 150007/150012, ACRIN 6657. Esserman LJ, Berry DA, DeMichele A, Carey L, Davis SE, Buxton M, Hudis C, Gray JW, Perou C, Yau C, Livasy C, Krontiras H, Montgomery L, Tripathy D, Lehman C, Liu MC, Olopade OI, Rugo HS, Carpenter JT, Dressler L, Chhieng D, Singh B, Mies C, Rabban J, Chen YY, Giri D, van 't Veer L, Hylton N. J Clin Oncol. 2012 Sep 10;30(26):3242-9.

Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Esserman LJ, Berry DA, Cheang MC, Yau C, Perou CM, Carey L, DeMichele A, Gray JW, Conway-Dorsey K, Lenburg ME, Buxton MB, Davis SE, van't Veer LJ, Hudis C, Chin K, Wolf D, Krontiras H, Montgomery L, Tripathy D, Lehman C, Liu MC, Olopade OI, Rugo HS, Carpenter JT, Livasy C, Dressler L, Chhieng D, Singh B, Mies C, Rabban J, Chen YY, Giri D, Au A, Hylton N; I-SPY 1 TRIAL Investigators. Breast Cancer Res Treat. 2012 Apr;132(3):1049-62.

Neoadjuvant chemotherapy and targeted therapies: a promising strategy. Metzger-Filho O, de Azambuja E. J Natl Cancer Inst Monogr. 2011;2011(43):116-9.

Locally advanced breast cancers are more likely to present as Interval Cancers: results from the I-SPY 1 TRIAL (CALGB 150007/150012, ACRIN 6657, InterSPORE Trial). Lin C, Buxton MB, Moore D, Krontiras H, Carey L, DeMichele A, Montgomery L, Tripathy D, Lehman C, Liu M, Olapade O, Yau C, Berry D, Esserman LJ; I-SPY TRIAL Investigators. Breast Cancer Res Treat. 2012 Apr;132(3):871-9.

I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. Clin Pharmacol Ther. 2009 Jul;86(1):97-100.

Data Access

Trials webpage


Study shows immunotherapy prior to surgery may help destory high-risk breast cancer

Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2.

FNIH Press Release, December 23, 2013: FNIH Announces First Results of I-SPY 2 Breast Cancer Clinical Trial

Side-Out Foundation Awards $160K to the FNIH to Support Breast Cancer Trial

A New Clinical Trial Design Promises to Accelerate Cancer Drug Approvals


Public-Sector Partners:
National Cancer Institute (NCI)
U.S. Food and Drug Administration (FDA)

Private-Sector Partners:
Alexandria Real Estate Equities, Inc.*
Amgen, Inc.*
Avon Foundation for Women*
Buffy M Cafritz*
Edge Hill Inc.*
Eisai Inc.*
Genentech, a member of the Roche Group*
Johnson & Johnson*
Susan B Komen Foundation*
Eli Lilly and Company*
Merck Sharp & Dohme Corp.*
Pfizer Inc.*
QuantumLeap Healthcare Collaborative*
Quintiles Transnational Corporation*
The Safeway Foundation*
The Edmond J. Safra Philanthropic Foundation*
The Side-Out Foundation*

Academic Partners:
MD Anderson Cancer Center
University of California-San Francisco

*Provided financial or in-kind support for this program.

FNIH Contact

Stacey Adam, Ph.D., Director, Cancer, Research Partnerships;