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.

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Background: I-SPY 2 is a multicenter, phase 2 trial using 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 - investigational agent(I) +paclitaxel(T) qwk, doxorubicin & cyclophosphamide(AC) q2-3 wk x 4 vs. T/AC (control arm). The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify/graduate 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 & MammaPrint (MP). Regimens may also leave the trial for futility (< 10% probability of success) or following accrual of maximum sample size (10%< probability of success <85%). We report the results for experimental arm Ganitumab, a type I insulin-like growth factor receptor (IGF1R) inhibitor. IGF1R inhibitors are known to induce insulin resistance and all patients assigned to Ganitumab received metformin. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ and HER2+ tumors were ineligible for randomization. Hemoglobin A1C≥ 8.0% were ineligible. MRI scans (baseline, 3 cycles 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. Ganitumab was given at 12mg/kg q2 weeks and metformin at 850mg PO BID, while receiving ganitumab. Analysis was intention to treat with patients who switched to non-protocol therapy counted as non-pCRs. Ganitumab/metformin was open only to HER2- patients, and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Results: Ganitumab/metformin did not meet the criteria for graduation in the 3 signatures tested. When the maximum sample size was reached, accrual to this arm stopped. Ganitumab/metformin was assigned to 106 patients; there were 128 controls. We report probabilities of superiority for Ganitumab/metformin over control and Bayesian predictive probabilities of success in a neoadjuvant phase 3 trial equally randomized between Ganitumab/metformin and control, for each of the 3 biomarker signatures, using the final pathological response data from all patients. Safety data will be presented. SignatureEstimated pCR Rate (95% probability interval)Probability Ganitumab/ Metformin Is Superior to ControlPredictive Probability of Success in Phase 3 Ganitumab/ Metformin N = 106Control N = 128  All HER2-22% (13%-31%)16% (10%-23%)89%33%HR+/HER2-14% (4%-24%)12% (4%-19%)66%21%HR-/HER2-32% (17%-46%)21% (11%-32%)91%51% Conclusion: The I-SPY 2 adaptive randomization study estimates the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. The value of I-SPY 2 is to give insight about the performance of an investigational agent's likelihood of achieving pCR. For Ganitumab/metformin, no subtype came close to the efficacy threshold of 85% likelihood of success in phase 3, and this regimen does not appear to impact upfront reduction of tumor burden. Our data do not support its continued development for the neoadjuvant treatment of breast cancer. Citation Format: Yee D, Paoloni M, van't Veer L, Sanil A, Yau C, Forero A, Chien AJ, Wallace AM, Moulder S, Albain KS, Kaplan HG, Elias AD, Haley BB, Boughey JC, Kemmer KA, Korde LA, Isaacs C, Minton S, Nanda R, DeMichele A, Lang JE, Buxton MB, Hylton NM, Symmans WF, Lyandres J, Hogarth M, Perlmutter J, Esserman LJ, Berry DA. The evaluation of ganitumab/metformin 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 P6-11-04.

#6043 Background: ACRIN 6657, the imaging component of the I-SPY trial (CALGB 150007/150012), is a multi-center study testing the ability of MRI to provide in-vivo quantification of breast tumor response to neoadjuvant chemotherapy, for early prediction of response and stratification of risk-of-recurrence following treatment. We report results from preliminary analysis comparing MRI variables for correlation with pathologic response and disease progression. Methods: Women with ≥3 cm invasive breast cancer receiving an anthracycline-cyclophosphamide (AC) neoadjuvant chemotherapy regimen followed by a taxane (T) were enrolled between May 2002 and March 2006. Contrast-enhanced MRI was performed prior to start of treatment (baseline), following 1 cycle of AC chemotherapy (t2), between AC and T regimens (t3), and after all chemotherapy but prior to surgery (t4). MRI assessments included tumor longest diameter (MRLD), tumor volume (MRVol), and signal enhancement ratio (SER), a measure of contrast enhancement kinetics. Clinical size (cSize) and mammographic longest diameter (MGLD) were also recorded. Linear dimension was measured by the radiologist for MGLD and MRLD; MRVol was calculated by computer using SER thresholds. Pathologic residual disease size (pSize) and residual cancer burden (RCB) index were evaluated following surgery. Results: 237 patients were enrolled at 9 institutions. 216 patients with complete imaging formed the preliminary analysis set. At time of analysis 42 patients had progressed or died with mean time-to-progression of 21 months; 174 patients were progression-free with mean follow-up time of 42 months. At t4, MRVol was more strongly correlated with pSize than MRLD, SER or cSize (r=.61 vs .28, .24 and .43), while SER showed a stronger correlation with RCB than MRLD, MRVol or cSize (r = .45 vs .30, .31 and .37). MGLD at t4 did not show a significant correlation with either pSize or RCB. Early measurements of tumor size change from baseline by MRVol at t2, and MRVol, MRLD and SER at t3, all showed significant correlation with RCB. In univariate logistic regressions, all t4 measurements were found to be predictive of disease progression. Conclusion: Among clinical and imaging measurements of residual breast tumor size, MRI appears to most accurately reflect pathologic extent of disease following neoadjuvant treatment. Preliminary findings also suggest that tumor size and contrast kinetics measured by MRI may be useful early predictors of treatment response. ACRIN 6657 is continuing to collect follow-up data toward the primary aim testing MRI for stratification of post-treatment risk groups according to 3-year disease-free survival. This work is funded by NIH/ACRIN Grant U01 CA79778S2, CALGB Grants CA31946 and CA33601, and NCI SPORE Grant CA58207. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6043.

Background We performed an international meta-analysis of individual patient data to assess the clinical validity of circulating tumor cell (CTC) count in non-metastatic breast cancer (BC) patients (pts) treated by neoadjuvant chemotherapy (NCT). Methods A protocol pre-specified the study objectives. We performed a literature & abstracts search up to Dec 2014, then contacted all centers deemed to have eligible data (published or not): early BC pts treated with NCT with CTC count by CellSearch®. The primary endpoint was overall survival (OS); secondary endpoints included distant disease-free survival (DDFS), locoregional relapse-free interval (LRFI) and pathological complete response (pCR). Non-overlapping CTC time points were: baseline (5-0 weeks before NCT), 1-8 weeks after NCT start, 5-0 weeks before surgery and 1-52 weeks after surgery. We used Cox regression models, stratified by study, and the landmark method to establish the prognostic value of CTC count/changes during treatment and survival. Results We collected 2,156 individual pt data from 21 studies and 16 centers worldwide. With ≥1/≥2/≥5 CTC/7.5ml as thresholds, CTC positivity rate was 25/13/6% at baseline, 17/6/3% after NCT start, 15/5/1% before surgery and 11/4/1% after surgery (decrease, p<0.0001). Before NCT, ≥1 CTC was found in 19%, 22%, 24%, 29% and 41% of cT1, T2, T3, T4a-c and T4d BC, respectively (p<0.0001) and was also marginally associated with hormone-receptors negativity (p=0.04). Later CTC detection rates were not associated with any of the baseline characteristics. pCR (assessed in 2,072 pts; ypT0/isN0 used as pCR definition in 92% of pts) was observed in 24% of pts but was not associated with CTC count, at any time point. 301, 418 and 157 events were reported for OS, DDFS and LRFI, respectively. In univariate analyses, ≥1 CTC at baseline was a prognostic factor for OS (HR=2.6 [1.9-3.4], p<0.0001), DDFS (HR=2.4 [1.9-3.1], p<0.0001) and -importantly- for LRFI (HR=1.8 [1.2-2.7], p=0.001). Similar results were obtained using other thresholds (≥2 & ≥5 CTC) and/or later time points (after NCT start, before surgery). There was no interaction between the prognostic impact of CTC count and tumor subtypes. Although rare, pts with persistently elevated CTC count (≥1CTC) before NCT and before surgery (5% of pts) had a worse OS than patients with persistently null CTC count (HR=6.2 [3.4-11], p<0.0001). Finally, in multivariate analyses, baseline CTC detection (whatever the CTC threshold used : ≥1/≥2/≥5 CTC) was an independent prognostic factor for OS, DDFS and LRFI, together with pCR, cT, cN and tumor subtype, (e.g. for OS: CTC≥2 HR=4.2 [3.0-5.9] p<0.0001, No pCR HR=6.2 [3.7-11] p<0.0001, cT4d HR=2.6 [1.1-6.6] p=0.02, cN+ HR=1.7 [1.2-2.4] p=0.003, triple negative BC HR=3.2 [2.1-5.1]). Similar results were obtained with later time points (after NCT start, before surgery). Conclusions Our study demonstrates with the highest level of evidence that CTCs are a prognostic biomarker in early BC treated by NCT. This impact was independent to that of pCR and was observed on OS, DDFS and also -for the first time- on LRFI. CTC count can usefully complement standard prognostic factors and pCR to improve the prognostication of early BC pts. Citation Format: Bidard F-C, Michiels S, Mueller V, Riethdorf S, Esserman LJ, Lucci A, Naume B, Horiguchi J, Gisbert-Criado R, Sleijfer S, Toi M, Garcia-Saenz JA, Hartkopf A, Generali D, Rothe F, Smerage J, Muinelo L, Stebbing J, Viens P, Magbanua M, Hall CS, Engebråtenm O, Takata D, Vidal-Martínez J, Onstenk W, Fujisawa N, Diaz-Rubio E, Taran F-A, Cappelletti MR, Ignatiadis M, Name N, Proudhon C, Wolf D, Bowman Bauldry J, Borgen E, Nagaoka R, Carañana V, Kraan J, Maestro M, Brucker SY, Weber K, Reyal F, Amara D, Gopalkrishna Karhade M, Ruud Mathiesen R, Tokiniwa H, Llombart-Cussac A, D'Hollander K, Cottu P, Park JW, Loibl S, Pierga J-Y, Pantel K. IMENEO: International MEta-analysis of circulating tumor cell detection in early breast cancer patients treated by NEOadjuvant chemotherapy [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 S3-01.