D Yee

Abstract S5-02: Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL

Background: I-SPY 2 is a multicenter, phase 2 screening trial using adaptive randomization within biomarker subtypes to evaluate a series of novel agents/combinations when added to standard neoadjuvant therapy (paclitaxel q wk x 12, doxorubicin & cyclophosphamide q 2-3 wk x 4, T/AC) vs. T/AC (control arm) for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. Our goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient biomarker-linked Phase 3 neoadjuvant trial. Experimental regimens can “graduate” in at least 1 of 10 possible signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP), with a maximum number of 120 total patients enrolled. We report final efficacy results of the oral PARP inhibitor veliparib (V, ABT-888) in combination with carboplatin (carbo), 1 of 7 experimental regimens evaluated in the trial to date. Methods: Women with tumors ≥2.5 cm by clinical exam and ≥2 cm by imaging are eligible for screening. Tumors that are MP low/HR+/HER2- are ineligible for randomization. MRI scans (baseline, 3 weeks after start of therapy, at completion of weekly T, and prior to surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. V+carbo was assigned to HER2- tumors only, which limits its possible signatures to: all HER2-, HR+/HER2-, HR-/HER2-. For these 3 signatures we provide estimated pCR rates with associated 95% Bayesian probability intervals for V+carbo and concurrently randomized controls. Analysis is intent to treat with patients who switched to non-protocol therapy regarded as non-pCRs. For each signature we provide probabilities of superiority for V+carbo over control and Bayesian predictive probabilities of success in a neoadjuvant Phase 3 trial equally randomized between V+carbo and control. Results: When V+carbo met the 85% predictive probability criterion in HR-/HER2- and all HER2-, this regimen graduated and accrual to V+carbo was stopped. V+carbo was assigned to 72 patients, and there were 62 concurrently randomized controls (44 HER2- controls). The following table shows final results based on available pCR information. Two patients assigned to V+carbo withdrew consent during treatment and are not included in the table. Conclusion: Adaptive randomization successfully identified a biomarker signature for V+carbo on the basis of a modest number of patients. V+carbo has graduated with a triple-negative (TN) breast cancer signature, and is the subset recommended for this regimen9s subsequent development. There is a suggestion that HR+/HER2- tumors benefit little from this regimen and inclusion of tumors in this subset would therefore dilute its effect in a subsequent trial. Analyses are currently underway to define additional biomarkers that may be predictive of response. The I-SPY 2 standing trial mechanism efficiently evaluates agents/combinations in biomarker-defined patient subsets, with future agents/combinations reported as available. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-02.

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

Veliparib combined with carboplatin (VC) was an experimental regimen evaluated in the biomarker-rich neoadjuvant I-SPY 2 trial for breast cancer. VC showed improved efficacy in the triple negative signature. However, not all triple negative patients achieved pathologic complete response and some HR+HER2− patients responded. Pre-specified analysis of five DNA repair deficiency biomarkers (BRCA1/2 germline mutation; PARPi-7, BRCA1ness, and CIN70 expression signatures; and PARP1 protein) was performed on 116 HER2− patients (VC: 72 and concurrent controls: 44). We also evaluated the 70-gene ultra-high risk signature (MP1/2), one of the biomarkers used to define subtype in the trial. We used logistic modeling to assess biomarker performance. Successful biomarkers were combined using a simple voting scheme to refine the ‘predicted sensitive’ group and Bayesian modeling used to estimate the pathologic complete response rates. BRCA1/2 germline mutation status associated with VC response, but its low prevalence precluded further evaluation. PARPi-7, BRCA1ness, and MP1/2 specifically associated with response in the VC arm but not the control arm. Neither CIN70 nor PARP1 protein specifically predicted VC response. When we combined the PARPi-7 and MP1/2 classifications, the 42% of triple negative patients who were PARPi7-high and MP2 had an estimated pCR rate of 75% in the VC arm. Only 11% of HR+/HER2− patients were PARPi7-high and MP2; but these patients were also more responsive to VC with estimated pathologic complete response rates of 41%. PARPi-7, BRCA1ness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care.Biomarkers: Gene expression tests predict response to PARP inhibitor combined with carboplatinSeveral predictive gene signatures can help identify breast cancer patients likely to respond to veliparib, an investigational PARP inhibitor, combined with the chemotherapy agent carboplatin. A team led by Denise Wolf, Christina Yau, and Laura van ‘t Veer from the University of California, San Francisco, used data from the I-SPY 2 trial to assess the predictive value of six different biomarkers in determining which women with early stage and locally advanced, aggressive breast cancer would have no signs of disease after veliparib—carboplatin treatment. They found three biomarkers with predictive value: a 7-gene expression signature that predicts breast cancer cell line sensitivity to another PARP inhibitor called olaparib; a 77-gene expression signature that detects molecular features shared with BRCA1-mutant tumours; and a 70-gene signature of recurrence risk called MammaPrint.

Abstract S2-06: DNA repair deficiency biomarkers and MammaPrint high1/(ultra)high2 risk as predictors of veliparib/carboplatin response: Results from the neoadjuvant I-SPY 2 trial for high risk breast cancer

Background: The PARP inhibitor veliparib in combination with carboplatin (VC) was one of the experimental regimens evaluated in the phase 2 neoadjuvant I-SPY 2 standing trial for high risk breast cancer patients. VC graduated in the triple negative (TN) signature. However, not all TN patients achieved pathologic complete response (pCR) and some HR+HER2- patients responded. The I-SPY 2 biomarker component provides a platform for rigorous evaluation of mechanism-of-action-based markers in the context of established biomarkers (HR, HER2, MammaPrint) within the trial. Here, we report results from 5 investigator-submitted biomarker proposals and the MammaPrint High1/High 2 (MP1/2) classification as specific predictors of VC response. Methods: Data from 116 HER2- patients (VC: 72 and concurrent controls: 44) were available. BRCA1/2 germline mutation was assessed by Myriad Genetics. 3 expression signatures relating to DNA damage repair deficiency (PARPi-7, BRCAness and CIN70) and MP1/2 classification were evaluated on Agilent 44K arrays. PARP1 levels were measured using reverse phase protein arrays. We used logistic modeling to assess biomarker performance. A biomarker is considered a specific predictor of VC response if it associates with response in the V/C arm but not the control arm, and if the biomarker x treatment interaction is significant (likelihood ratio test, p Results: BRCA1/2 germline mutation status associates with VC response, but its low prevalence in the control arm precludes further evaluation. Of the biomarkers evaluated, three (PARPi-7, BRCAness, and MP1/2) associate with response in the VC arm but not the control arm, and have biomarker x treatment interactions with p Conclusion: If verified in a larger trial, PARPi7, BRCAness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care. Evaluation of the combined signature for patients treated with platinum-based chemotherapy is ongoing. Citation Format: Wolf DM, Yau C, Sanil A, Glas A, Petricoin C, Wulfkuhle J, Brown-Swigart L, Hirst G, I-SPY 2 TRIAL Investigators, Buxton M, DeMichele A, Hylton N, Symmans F, Yee D, Paoloni M, Esserman L, Berry D, Rugo H, Olapade O, van 9t Veer L. DNA repair deficiency biomarkers and MammaPrint high1/(ultra)high2 risk as predictors of veliparib/carboplatin response: Results from the neoadjuvant I-SPY 2 trial for high risk breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-06.

Abstract P3-08-03: Mobile phone multimedia messaging intervention for breast cancer screening

Background. Korean American women have one of the highest breast cancer mortality rates and lowest breast cancer screening rates among American women. In response to the need to enhance breast cancer screening, this study aims to develop and test a 7-day mobile phone application (app)-based Mammogram (mMammogram) intervention designed to promote breast cancer screening among Korean American women. To date, mobile app technology has not been used for mammogram promotion. Methods. Using FBM Model, we developed a mammogram intervention designed to increase knowledge of breast cancer screening, intent to receive mammogram, and the receipt of a mammogram. A series of focus groups were conducted to inform the development of the intervention. A randomized controlled trial was conducted with baseline, one week post-intervention, and 6-month follow-up testing among 120 Korean American women who were aged 40 and older and had not had mammograms within the last 2 years. The intervention group (60) received an individually and culturally tailored text messages via mobile app with health navigation services. The control group (60) received a brochure including information on breast cancer, screening guidelines, and a list of clinics that offer low-cost or free mammography without health navigation services. Results. At one week post-test, statistically significant between-group differences were found; intervention subjects reported higher scores of knowledge in breast cancer and screening guideline than subjects in control group (mean differences: 1.70, p Conclusions. This study provides evidence of the effectiveness and feasibility of the mammogram intervention with health navigation services in promoting breast cancer screening. Mobile application-based intervention is a promising tool to increase both knowledge and receipt of mammograms. Given the widespread usage of mobile phone among minority populations, a mobile phone-based health intervention could be an effective method of reaching hard-to-recruit populations with high breast cancer burden, using individually tailored messages that cover broad content areas and overcome restrictions to place and time of delivery. Citation Format: Lee HY, Le C, Ghebre R, Yee D. Mobile phone multimedia messaging intervention for breast cancer screening. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-08-03.

A Type I Insulin-Like Growth Factor Receptor Kinase Inhibitor (PQIP) Enhances the Cytotoxicity of Doxorubicin in Human Cancer Cell Lines.

The type-I insulin like growth factor (IGF-IR) is either activated and/or overexpressed in a wide range of tumor types and contributes to tumorigenicity, proliferation, survival, metastasis and drug resistance. Disruption of IGF-IR signaling alone or in combination with other cytotoxic agents has emerged as an important strategy in cancer therapy. Our laboratory has shown that sequentially combining doxorubicin with anti-IGF-IR antibodies significantly enhances the response of chemotherapy, while the opposite sequence causes cells resistant to chemotherapy. Here, we show that a novel small-molecule IGF-IR kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) inhibited IGF-IR and insulin receptor (IR) kinase activity and proliferation in MCF-7 and MDA435/LCC6 cell lines. Moreover, PQIP treatment blocked both IGF-I and insulin stimulated activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase in both cell lines. At doses that inhibited monolayer cell growth, the compound also inhibited cell motility, blocked IGF-I stimulated S-phase progression and induced autophage; at higher doses, it also caused PARP cleavage. Combining PQIP with doxorubicin significantly enhanced cytotoxicity but did not further enhance doxorubicin-induced PARP cleavage in monolayer cell growth. Furthermore, our sequencing studies showed that combining PQIP with doxorubicin simultaneously or doxorubicin followed by PQIP significantly inhibited the anchorage-independent growth in both MCF-7 and MDA435/LCC6 cells. In contrast, pre-treatment with PQIP followed by doxorubicin did not enhance the cytotoxicity of doxorubicin in anchorage-independent growth, which is similar as anti-IGF-IR antibodies in combination with doxorubicin. In summary, these results suggest that the IGF-IR tyrosine kinase inhibitor PQIP can be used alone or in combination with chemotherapy to enhance cytotoxicity of human tumor cell lines, and the timing of IGF-IR inhibition may affect responses to doxorubicin. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6110.

MCF-7 cells selected for acquired resistance to an anti IGF-IR antibody remain sensitive to fulvestrant and to an IGFIR tyrosine kinase inhibitor (TKI).

Abstract #72 Monoclonal antibodies and tyrosine kinase inhibitors (TKI) targeting the type-1 Insulin-like growth factor receptor (IGFIR) are currently in clinical trials. Resistance to several targeted therapies has been observed and is not well understood. Estrogen receptor (ER) has been shown to interact with IGFIR signaling to promote cell growth. To examine acquired resistance to IGF1R monoclonal antibodies, we selected ER positive MCF7L cells in increasing concentrations of an IGFIR inhibitory antibody (scFvFc, treated over 2 years). These cells (MCF7L-scFvFc) had downregulated IGFIR levels, increased basal phosphorylation of IRS-1 with constitutive activation of Akt. MCF7L-scFvFc cells had enhanced basal growth and were no longer responsive to IGF-I and estradiol (E2). To examine the relationship between IGF1R and ER function, we used the pure steroidal anti-estrogen fulvestrant to examine effects on growth of the parent and antibody-resistance cells. In parent MCF7L cells, fulvestrant inhibited growth responses to IGF-I and E2 treatment when each ligand was given individually, but when both ligands were given together, the growth inhibition was reversed. In MCF7L-scFvFc, fulvestrant inhibited growth response to IGF-I, but cells still responded to E2 even in the presence of fulvestrant. Fulvestrant inhibition of MCF7L-scFvFc basal growth was associated with downregulation of ER and IGFIR system components. Fulvestrant treatment induced PARP cleavage in MCF7L, but not in MCF7L-scFvFc cells. IGF-I partially protected cells against fulvestrant induced PARP cleavage, and E2 treatment has full protective effects on these cells. These data suggest that MCF7L-scFvFc cells were more resistant to cell apoptosis induced by fulvestrant. Other monoclonal antibodies directed against IGF1R were ineffective in reversing the resistance in MCF7L-scFvFc cells. To determine if activated IGF1R was responsible for the behavior of MCF7L-scFvFc cells, we used the IGF1R TKI AEW541. AEW541 inhibited growth of these antibody resistant cells and a combination of fulvestrant and AEW541 completely inhibited cell growth and IGF signaling in both MCF7L and MCF7L-scFvFc cells. Thus, activated IGFIR signaling was still required for the growth of MCF7L-scFvFc cells. In conclusion, MCF7L-scFvFc had low levels of IGF1R but retained activated IGF1R signaling that was inhibited by TKI (AEW541). In addition, the ER antagonist fulvestrant also inhibited growth of these cells. In these ER-positive cells, combined blockade of ER and IGF1R could provide a more prolonged inhibition of cell growth. Moreover, cells selected for resistance to an IGF1R antibody remain sensitive to IGF1R TKIs. Thus, concurrent or sequential targeting of IGF1R and ER function should be examined in breast cancer clinical trials of ER positive breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 72.

Abstract P6-11-02: Efficacy of Hsp90 inhibitor ganetespib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial

Background: Pathologic complete response(pCR) after neoadjuvant therapy is an established prognostic biomarker for high-risk breast cancer(BC). Improving pCR rates may identify new therapies that improve survival. I-SPY 2 uses response-adaptive randomization within biomarker subtypes to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer; the goal is to identify regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR), HER2 status and MammaPrint (MP). We report the results for Ganetespib, a selective inhibitor of Hsp90 that induces the degradation/deactivation of key drivers of tumor initiation, progression, angiogenesis, and metastasis.Ganetespib + taxanes previously have resulted in a superior therapeutic response compared to monotherapy in multiple solid tumor models including BC. Methods: Women with tumors ≥2.5cm were eligible for screening and participation. MP low/HR+ tumors were ineligible for randomization. QTcF >470msec and HbA1C >8.0% were ineligible. MRI scans (baseline, +3 cycles, following weekly paclitaxel, T, and pre-surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. Ganetespib was given with weekly T at 150 mg/m 2 IV weekly (3 weeks on, 1 off). Patients were premedicated (dexamethasone 10mg and diphenhydramine HCl 25-50 mg, or therapeutic equivalents). Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. The Ganetespib regimen was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2- and HR-/HER2-. Results: Ganetespib did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual stopped. Ganetespib was assigned to 93 patients; there were 140 controls. We report probabilities of superiority for Ganetespib over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganetespib and control, for the 3 biomarker signatures, using the final pCR data from all patients. Safety data will be presented. Conclusion: The I-SPY 2 adaptive randomization model efficiently evaluates investigational agents in the setting of neoadjuvant BC. The value of I-SPY 2 is that it provides insight as to the regimen9s likelihood of success in a phase 3 neoadjuvant study. Although no signature reached the efficacy threshold of 85% likelihood of success in phase 3, we observed the most impact in HR-/HER2- patients, with a 16% improvement in pCR rate. While our data do not support the continued development of Ganetespib alone for neoadjuvant BC, combinations with Ganetespib, which could potentiate its effect, may be worth pursuing in I-SPY 2 or similar trials. Citation Format: Forero A, Yee D, Buxton MB, Symmans WF, Chien AJ, Boughey JC, Elias AD, DeMichele A, Moulder S, Minton S, Kaplan HG, Albain KS, Wallace AM, Haley BB, Isaacs C, Korde LA, Nanda R, Lang JE, Kemmer KA, Hylton NM, Paoloni M, van9t Veer L, Lyandres J, Perlmutter J, Hogarth M, Yau C, Sanil A, Berry DA, Esserman LJ. Efficacy of Hsp90 inhibitor ganetespib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-02.

Abstract P5-11-18: Trajectory of patient (Pt) reported physical function (PF) during and after neoadjuvant chemotherapy in the I-SPY 2 trial

Background Patients (pts) receiving chemotherapy for breast cancer experience toxicities impacting short and long-term quality of life (QOL). Within I-SPY 2, a trial adaptively randomizing stage II/III breast cancer pts to neoadjuvant chemotherapy +/- an investigational agent, we are collecting pt reported outcome (PRO) data to understand the impact of investigational agents on QOL. This PRO sub-study provides a unique opportunity to study QOL longitudinally and explore how pt and tumor characteristics, exposure to investigational therapies, and surgical outcome impact QOL. Methods Pts enrolled in this trial receive paclitaxel (T) +/- an investigational agent for 12 weeks followed by 4 cycles of doxorubicin and cyclophosphamide (AC). Surveys include the EORTC QLQ-C30 and BR-23, and PROMIS measures for QOL metrics including but not limited to physical function (PF), anxiety, and depression. Surveys are administered pre-chemotherapy to 2 years post-surgery. PF data from the EORTC and PROMIS instruments was analyzed for 238 pts at 5 sites (UCSF, UCSD, U of Pennsylvania, U of Minnesota, and Swedish Cancer Center). 48 pts completed baseline, inter-regimen (between T and AC), pre-operative and post-surgery surveys. Of the 48 pts 32 completed a 6-month follow up (FUP) and 31 completed a 1-year FUP survey. A linear mixed effect model, adjusting for HER2 status and treatment type was used to evaluate changes in PF over time. Sample size is small and statistics are descriptive rather than inferential. Results Median age of pts in this analysis was 50 (range 27-72). At baseline, mean PROMIS PF scores were higher than the US average (mean = 50) but declined as expected throughout treatment. HER2+ patients experienced a similar degree of recovery as HER2- pts post-surgery despite adjuvant treatment with Herceptin. Analysis of post-operative PROMIS PF indicated an average score within the U.S. general population (mean =50) but did not return to higher functioning seen at baseline levels (mean 52.5, p-value Conclusions: Among a subset of pts who completed all surveys in the I-SPY 2 QOL substudy, PF did not return to baseline at 6-12 months post-operatively. Through transition to an electronic platform of data collection we hope to improve compliance with survey completion. We continue to analyze other QOL measures and plan to correlate QOL data with treatment arm, adverse events, comorbidities, and response to neoadjuvant treatment. Citation Format: Shah M, Jensen R, Yau C, Straehley I, Berry DA, DeMichele A, Buxton MB, Hylton NM, Perlmutter J, Symmans WF, Tripathy D, Yee D, Wallace A, Kaplan HG, Clark A, Chien AJ, I-SPY 2 Investigators, Esserman LJ, Melisko ME. Trajectory of patient (Pt) reported physical function (PF) during and after neoadjuvant chemotherapy in the I-SPY 2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-18.

Abstract ES9-1: Role for IGF/Insulin signaling in breast cancer

Because insulin regulates glucose homeostasis, there has been extensive study into the molecular mechanisms of action of the insulin signaling system. Besides insulin, additional ligands, insulin-like growth factor (IGF) – I and –II and specific receptors for these ligands regulate cellular biology. The receptors share a similar structure and function. Once ligand binds the extracellular domain, a conformational change occurs allowing autophosphorylation of the intracellular tyrosine kinase domains and subsequent activation of multiple signaling pathways that ultimately result in cellular glucose uptake. Type 2 diabetes mellitus (T2D) results from deficient insulin receptor (InsR) signaling and subsequent elevation of serum glucose with compensatory attempt at regulating this pathophysiology by increased insulin production by the pancreas. While the etiology of T2D is complex and multi-factorial, obesity and insulin resistance are epidemiologically and mechanistically linked. Insulin was one of the first peptide growth factors known to stimulate breast cancer proliferation. Epidemiological data link obesity, metabolic syndrome (hyperinsulinemia), and elevated levels of IGFs to breast cancer risk and poor outcome for women diagnosed with breast cancer. These data, in part, led to the development of multiple targeted therapies for breast cancer. Receptor targeting of IGF-receptor signaling was not successful in hormone receptor (HR) positive breast cancers possibly because drugs designed to target this receptor disrupted the negative feedback of this endocrine system and resulted in the elevation of serum insulin levels. Since InsR was not affected by anti-IGF receptor drugs, the potential that InsR was stimulated by these drug treatments could explain their failure. In contrast to receptor targeting strategies, the inhibition of downstream signaling pathways, such as mTORC1, have been successful in HR-positive breast cancer. Preclinical and clinical data have revealed complex intracellular and endocrine feedback pathways that affect the ability of any single targeted drug to effectively disrupt signals from this ligand-receptor family. This session will discuss combination strategies based on clinical and preclinical studies that could translate into effective drug therapies to disrupt this signaling system. Citation Format: Yee D. Role for IGF/Insulin signaling in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES9-1.

Abstract P1-14-03: The evaluation of trebananib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 TRIAL

Background: I-SPY 2 is a multicenter phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate a series of novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR). The goal is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR), HER2 status & MammaPrint (MP). Regimens may also leave the trial for futility ( Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+/HER2- tumors were ineligible for randomization. Serial MRI scans (baseline, 2 during treatment and pre-surgery) were used in a longitudinal model to improve the efficiency of adaptive randomization. Participants are categorized into 8 subtypes based on: HR status, HER2 status and MP High 1 (MP1) or High 2 (MP2). MP1 and MP2 are determined by a predefined median cut-point of I-SPY 1 participants who fit the eligibility criteria for I-SPY 2. Trebananib was initially assigned to HER2- patients only; once safety data with trastuzumab (H) were obtained, it was also assigned to HER2+ patients. Analysis was intent to treat -- patients who switched to non-protocol therapy were designated non-pCRs. Results: Trebananib +/-H did not meet the criteria for graduation in any of the 10 signatures tested. When the maximum sample size was reached, accrual ceased. We report probabilities of trebananib +/-H being superior to control and Bayesian predictive probabilities of success in a 1:1 randomized neoadjuvant phase 3 trial for the 10 biomarker signatures, using the final pCR data from all patients. Citation Format: Albain KS, Leyland-Jones B, Symmans F, Paoloni M, van 9t Veer L, DeMichele A, Buxton M, Hylton N, Yee D, Lyandres Clennell J, Yau C, Sanil A, I-SPY 2 Trial Investigators, Berry D, Esserman L. The evaluation of trebananib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 TRIAL. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-03.