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Table of Contents

1.I-SPY 1 TRIAL Publications

2.I-SPY 2 Publications

   o I-SPY 2 Background

   o I-SPY 2 Results

           - Manuscripts

           - Agent Abstracts

           - Other Abstracts

I-SPY TRIAL Publications

Pathologic Complete Response Predicts Recurrence-Free Survival More Effectivelyby Cancer Subset: Results From the I-SPY 1 TRIAL—CALGB 150007/150012, ACRIN 6657. JCO, 2012

Purpose: Neoadjuvant chemotherapy for breast cancer provides critical information about tumor response; how best to leverage this for predicting recurrence-free survival (RFS) is not established. The I-SPY 1 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) was a multicenter breast cancer study integrating clinical, imaging, and genomic data to evaluate pathologic response, RFS, and their relationship and predictability based on tumor biomarkers.

 

Locally Advanced Breast Cancer: MR imaging for Prediction of Response to Neoadjuvant Chemotherapy – Results from ACRIN 6657 / I-SPY TRIAL. Radiology 2012

Purpose: To compare magnetic resonance (MR) imaging findings and clinical assessment for prediction of pathologic response to neoadjuvant chemotherapy (NACT) in patients with stage II or III breast cancer.

 

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). Breast Cancer Res Treat, 2012.

Abstract: Interval cancers (ICs), defined as cancers detected between regular screening mammograms, have been shown to be of higher grade, larger size, and associated with lower survival, compared with screen-detected cancers (SDCs) and comprise 17% of cancers from population-based screening programs. We sought to determine the frequency of ICs in a study of locally advanced breast cancers, the I-SPY 1 TRIAL. Screening was defined as having a mammogram with 2 years, and the proportion of ICs at 1 and 2 years was calculated for screened patients. Differences in clinical characteristics for ICs versus SDCs and screened versus non-screened cancers were assessed. For the 219 evaluable women, mean tumor size was 6.8 cm. Overall, 80% of women were over 40 and eligible for screening; however, only 31% were getting screened. Among women screened, 85% were ICs, with 68% diagnosed within 1 year of a previously normal mammogram. ICs were of higher grade (49% vs. 10%) than SDCs. Among non-screened women, 28% (43/152) were younger than the recommended screening age of 40. Of the entire cohort, 12% of cancers were mammographically occult (MO); the frequency of MO cancers did not differ between screened (11%) and non-screened (15%). ICs were common in the I-SPY 1 TRIAL suggesting the potential need for new approaches beyond traditional screening to reduce mortality in women who present with larger palpable cancers.

 

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) Breast Cancer Res Treat, 2012.

Abstract: Neoadjuvant chemotherapy for breast cancer allows individual tumor response to be assessed depending on molecular subtype, and to judge the impact of response to therapy on recurrence-free survival (RFS). The multicenter I-SPY 1 TRIAL evaluated patients with C3 cm tumors by using early imaging and molecular signatures, with outcomes of pathologic complete response (pCR) and RFS. The current analysis was performed using data from patients who had molecular profiles and did not receive trastuzumab. The various molecular classifiers tested were highly correlated. Categorization of breast cancer by molecular signatures enhanced the ability of pCR to predict improvement in RFS compared to the population as a whole. In multivariate analysis, the molecular signatures that added to the ability of HR and HER2 receptors, clinical stage, and pCR in predicting RFS included 70-gene signature, wound healing signature, p53 mutation signature, and PAM50 risk of recurrence. The low risk signatures were associated with significantly better prognosis, and also identified additional patients with a good prognosis within the no pCR group, primarily in the hormone receptor positive, HER-2 negative subgroup. The I-SPY 1 population is enriched for tumors with a poor prognosis but is still heterogeneous in terms of rates of pCR and RFS. The ability of pCR to predict RFS is better by subset than it is for the whole group. Molecular markers improve prediction of RFS by identifying additional patients with excellent prognosis within the no pCR group.

 

ISPY 2 TRIAL Publications

I-SPY 2 Background

I-SPY 2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy. Nature Publishing Group, 2009.

 I-SPY 2 RATIONALE AND BACKGROUND: The daunting statistics that currently define cancer incidence and mortality require innovative strategies that will address the prohibitive expenditures of time and cost associated with the development of new oncology drugs. Although there are many promising new oncology drugs in the pipeline, the current process for development and regulatory review is inefficient and expensive, requiring a decade or more to complete. While biomarkers show promise for informing all aspects of oncology drug development, diagnosis, and treatment, clinical validation (qualification) has proved extremely difficult. The Cancer Steering Committee of the Foundation for the National Institutes of Health Biomarkers Consortium is taking several innovative approaches to remove this "biomarker barrier" in order to qualify both biomarkers and drugs for evidence-based development in clinical trials.

 

Accelerating Identification and Regulatory Approval of Investigational Cancer Drugs. JAMA, 2011.

The development of new drugs is becoming increasingly expensive—and oncology drugs, in particular, have a high clinical failure rate.1,2 The current return on capital investment in drug development byUSpublic companies was recently reported as less than 0.3%.3 The low probability of success, coupled with rapidly accelerating expenses, means that drug development is increasingly the purview of only 2 organization types: a few large companies and myriad small, venture capital–funded start-up firms. At an estimated cost of $1.0 billion to $1.8 billion for developing a successful new drug,4 funding for such risky ventures, particularly for oncology drugs, may diminish.

 

A Model for Accelerating Identification and Regulatory Approval of Effective Investigational Agents. Cureus, 2012.

Introduction And Background: In 2010, U.S. healthcare costs were $2.6 trillion. The Center for Medicare and Medicaid Services projects that by 2020, this economic burden will rise to $4.6 trillion (19.8% of the U.S. GDP [1]). An increasing share of this economic burden reflects the rising cost of drugs, with cancer drugs being a major contributor [2]. There is justifiable concern that, in the near future, new drugs may not be broadly affordable.

 

SPY 2 Results

Abstracts – Agents

Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL. SABCS, 2014.

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.

 

Abstract CT227: Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL. AACR Annual Meeting, 2014.

Background: I-SPY 2 is a multicenter, phase II neoadjuvant trial in women with high-risk stage II/III breast cancer using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard chemotherapy. Primary endpoint is pathologic complete response (pCR). Goal is to identify regimens that meet a high Bayesian predictive probability of statistical significance in a neoadjuvant 300-patient phase III trial defined by hormone-receptor (HR), HER2 status, and MammaPrint (MP). Experimental regimens may "graduate" in 1 of 10 signatures, with a maximum of 120 patients. We report efficacy results for neratinib (N).

 

Adaptively randomized trial of neoadjuvant chemotherapy with or without the Akt inhibitor MK-2206: Graduation results from the I-SPY 2 Trial. ASCO, 2015.

Background: A key node of growth and survival signaling pathways is the Akt serine/threonine kinase that activates mTOR and downstream effectors. I-SPY 2 is a randomized neoadjuvant trial to test agents and combinations added to standard chemotherapy. Pathological complete response (pCR) defined as absence of invasive cancer in breast and nodes is the primary endpoint. We report efficacy results for allosteric Akt inhibitor MK-2206.

 

The evaluation of trebananib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY 2 TRIAL. SABCS 2015.

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 (< 10%="" probability="" of="" success)="" or="" following="" accrual="" of="" maximum="" sample="" size="">< probability="" of="" success=""><85%). we="" report="" the="" results="" for="" trebananib,="" an="" angiopoietin-1/2-neutralizing="" peptibody="" that="" inhibits="" interaction="" with="" the="" tie2="">

 

Manuscripts (In-Press)

  1. I-SPY 2 TRIAL Adaptive Randomization of Neratinib in Breast Cancer. NEJM 2016.

  2. I-SPY 2 TRIAL Adaptive Randomization of Veliparib/Carboplatin in Breast Cancer. NEJM 2016. 

 

Other I-SPY 2 Abstracts

Evaluation of a BRCAness signature as a predictive biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy in high-risk breast cancer: results from the I-SPY 2 TRIAL. EORTC / AACR / NCI Meeting 2014.

Background: We developed a 77-gene BRCAness gene expression signature that predicts 'BRCA1- like' (vs. 'Sporadic-like') breast cancers with a validated high sensitivity and specificity rate. The BRCAness signature was developed as part of the RATHER project (EU#258967). We hypothesized that BRCA1-like tumors would have a higher sensitivity to PARP inhibitors, including veliparib. In the ISPY II TRIAL, HER2- patients were randomized to receive standard chemotherapy or the oral PARP inhibitor veliparib in combination with carboplatin and chemotherapy (V/C). V/C graduated in the triplenegative (TN) signature. Here we assess the BRCAness signature as a specific biomarker of V/C response.

 

I-SPY 2 Qualifying Biomarker Evaluation (QBE): The Challenge and Opportunity for Interrogating Predicted Pathways in an Adaptive Design Biomarker Rich Trial. SABCS 2014.

Body: I-SPY 2, a multicenter phase 2 neoadjuvant trial in high-risk breast cancer, uses adaptive randomization within biomarker subtypes to evaluate novel agents added to standard chemotherapy. In addition to efficiently evaluating agent/signature pairs, I-SPY 2 is a biomarker rich trial, where samples are profiled for gene expression, protein levels, and mutation status. Biomarkers are classified as established, qualifying, or exploratory. Established biomarkers are those used clinically (HR/HER2 status) or FDA cleared (MammaPrint), and used for adaptive randomization to generate the 10 signatures from which a drug can graduate. Qualifying biomarkers (QB) represent evidence-based, biologic pathway markers (e.g.cell line predictors, known drug targets). QB analyses must be pre-specified and performed under CLIA. Exploratory markers are for discovery and may allow integration of data from different technologies.

 

Evaluation of HER family protein signaling network as a predictive biomarker for pCR for breast cancer patients treated with neratinib in the I-SPY 2 TRIAL. SABCS 2014.

Background: We hypothesize that response to the pan-ERBB inhibitor, neratinib (N), may be predicted by pre-treatment HER2-EGFR signaling. In the I-SPY 2 TRIAL, N graduated in the HR-/HER2+ signature. All patients received at least standard chemotherapy. For HER2+ patients, N was administered in place of trastuzumab. We evaluated 18 HER family signaling proteins as biomarkers of N response using reverse phase protein microarray (RPMA) data from pre-treatment LCM purified tumor epithelium.

 

MammaPrint High1/High2 risk class as a biomarker of response to neratinib plus standard neoadjuvant therapy for breast cancer in the I-SPY 2 TRIAL. SABCS 2014.

Background: Further stratification of the 70-gene MammaPrintTM signature into ‘high’ and ‘ultra-high’ risk groups may help predict chemo-sensitivity. In I-SPY 2, patients were classified as MammaPrint High1 (MP1) or MammaPrint (ultra) High2 (MP2), with MP2 defined as MP_score AC). HER2- patients were randomized to receive N+T- >AC vs. T->AC. For HER2+ patients, neratinib was administered in place of trastuzumab (N+T->AC vs. H+T->AC). Here, we assess the performance of MP1/MP2 class as a specific biomarker of neratinib response.

 

MammaPrint High1/High2 risk class as a biomarker of response to veliparib plus standard neoadjuvant therapy for breast cancer in the I-SPY 2 TRIAL. SABCS 2014.

Body: Background: Further stratification of the 70-gene MammaPrintTM signature into ‘high’ and ‘ultrahigh’ risk groups may help predict chemo-sensitivity. In I-SPY 2, patients were classified as MammaPrint High1 (MP1) or MammaPrint (ultra) High2 (MP2), with MP2 defined as MP_score

 

Evaluation of an in vitro derived signature of olaparib response (PARPi-7) as a predictive biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy in highrisk breast cancer: results from the I-SPY 2 TRIAL. SABCS 2014.

Body: Background: We developed a 7-gene DNA-repair deficiency signature (PARPi-7) that predicts breast cancer cell line sensitivity to the PARP inhibitor olaparib [PMID: 22875744]. We hypothesized that this signature would also predict response to other PARP inhibitors including veliparib. In the I-SPY 2 TRIAL, HER2- patients were randomized to receive standard chemotherapy or the oral PARP inhibitor veliparib in combination with carboplatin (V/C) and chemotherapy. V/C graduated in the triple-negative (TN) signature. Here we assess the PARPi-7 as a specific biomarker of V/C response.

 

Detrimental effects of sequential compared to concurrent treatment of Pertuzumab plus T-DM1 in HER2+ breast cancer cell lines. SABCS 2014.

Body: Background. Pertuzumab and T-DM1 are two recently approved monoclonal antibody based therapies targeting HER2+ breast cancer. Pertuzumab interferes with dimerization of HER family members, while T-DM1 binds to HER2 and interferes with its oncogenic function while also specifically delivering a cytotoxic agent (emtansine). One arm of the I-SPY 2 clinical trial is to investigate the efficacy of a combination Pertuzumab plus T-DM1 in HER2+ breast cancer patients. Methods. We performed preclinical screening of response to each agent alone and in combination in a set of 21 HER2+ breast cancer cell lines, with an end goal of identifying markers of response to the therapies.

 

DNA repair deficiency biomarkers identify ER+ breast cancer patients who may benefit from veliparib/carboplatin: results from the I-SPY 2 TRIALASCO. 2015.

Background: In the I-SPY 2 TRIAL, HER2- patients were adaptively randomized to receive standard chemotherapy or the PARP inhibitor veliparib with carboplatin (V/C) and chemotherapy. V/C graduated in the triple-negative (TN) subtype, and we’ve previously shown that DNA repair deficiency signatures [BRCAness and PARPi-7] may predict V/C response. Here we combine these signatures into a composite measure of DNA repair deficiency.

 

Protein activation mapping uncovers exploratory predictive markers for pCR in triple negative breast cancer patients treated with neratinib in the I-SPY 2 TRIAL. ASCO 2015.

 

Residual cancer burden (RCB) with veliparib/carboplatin in the I-SPY2 Trial. SABCS 2015.

Body: Background: I-SPY2 is a multicenter phase 2 trial in high risk stage II/III breast cancer (BC) using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard neoadjuvant chemotherapy. The first regimen to graduate based on the predicted probability of a higher pCR rate within predefined subsets was veliparib/carboplatin + paclitaxel (VC+T→AC vs T→AC) in triple negative BC (TNBC). In TNBC the residual cancer burden (RCB) is prognostic, whether as a continuous index or grouped into classes, with pCR (RCB-0) and RCB-I classes having identical survival. Therefore, we evaluated the use of RCB to further discriminate between investigational and control arms.

 

Prediction of Complete Pathologic Response to Veliparib/Carboplatin plus Standard Neoadjuvant Therapy in HER2 negative breast cancer: Exploratory protein pathway marker results from the I-SPY 2 TRIAL. SABCS 2015.

Body: Background: In the I-SPY 2 TRIAL, HER2- patients were randomized to receive standard chemotherapy or chemotherapy plus the oral PARP inhibitor veliparib in combination with carboplatin (V+C), which graduated in the HR-/HER2- arm. Exploratorym analysis of protein signaling was performed to identify biomarker candidates that correlated with pCR in the HER2- population. We evaluated 110 key signaling proteins using reverse phase protein microarray (RPPA) data from pre-treatment LCM purified tumor epithelium.

 

TN breast cancer patients with multiple sensitivity markers appear more likely to benefit from veliparib/carboplatin: results from the I-SPY 2 TRIAL. AACR 2016.

Background: In the I-SPY 2 TRIAL, HER2- patients were adaptively randomized to receive standard chemotherapy or the PARP inhibitor veliparib with carboplatin (V/C) and chemotherapy. V/C graduated in the triple-negative (TN) subtype, and we’ve previously shown that MammaPrint High1/High2 (MP1/2) risk class and the PARPi-7 signature may specifically predict V/C response. Here we evaluate whether combining these signatures can help identify a subset of TN patients especially likely to respond to V/C.

 

Gene and pathway differences between MammaPrint High1/High2 risk classes: results from the I-SPY 2 TRIAL in breast cancer. AACR 2016.

Background: Further stratification of the 70-gene MammaPrintTM prognostic signature into ‘high’ and ‘ultra-high’ risk groups may help predict chemo-sensitivity. In I-SPY 2, patients were classified as MammaPrint High1 (MP1) or MammaPrint (ultra) High2 (MP2), with MP2 defined as MP_score