Citations

Abstract 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 <-0.154. MP1/MP2 classification was added to HR and Her2 to define the cancer subtypes used in the I-SPY 2 adaptive randomization engine. 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, where MP2 was not an eligible signature for graduation. Here, we assess the performance of MP1/MP2 class as a specific biomarker of response to V/C. Methods:115 HER2- patients (V/C: 71 and concurrent controls: 44) were considered in this analysis. We assess association between MP1/MP2 and response in the V/C and control arms alone using Fisher’s exact test, and relative performance between arms (biomarker x treatment interaction, likelihood ratio p < 0.05) using a logistic model. This analysis is also performed adjusting for HR status as a covariate. To assess MP1/MP2 in the context of the graduating signature, we added the MP2 patients to the graduating TN subset and evaluated the treatment effect in this ‘biomarker-positive’ group. Our study is exploratory with no claims for generalizability of the data. Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content). This analysis does not adjust for multiplicities of other biomarkers in the trial but outside this study. Results: In the V/C arm vs. concurrent controls, there were 66 MP1 (V/C: 32, Control: 34) and 49 MP2 patients (V/C: 39, Control: 10), 78% of which are TN. The distribution of pCR rates among MP1/MP2 dichotomized groups are summarized in Table 1. V/C (n=71)Control (n=44)MP1 (n=32)MP2 (n=39)MP1 (n=34)MP2 (n=10)TN (n=59)3 / 819 / 303 / 132 / 8HR+HER2- (n=56)1 / 244 / 94 / 210 / 2 The OR between MP1/MP2 risk groups for predicting pCR is 9.71 in the V/C arm (p=6.63E-05), in comparison to an OR of 0.97 in the control arm (p=1). There is a significant biomarker x treatment interaction (p=0.023), which remains upon adjusting for HR status (p= 0.028). Based on the I-SPY 2 Bayesian model, a Phase III trial with 300 MP2 patients has a 95% predictive probability of success. When the MP2 patients are added to the graduating TN subset, the OR associated with V/C is 4.36, which is comparable to that of the TN signature (OR: 4.29), while increasing the prevalence of biomarker-positive patients by ∼10%. Conclusion: In our exploratory analysis, MP2 suggests higher sensitivity to V/C combination therapy relative to controls. This observation has prompted an investigation into the biological mechanisms distinguishing the MP1/MP2 subtype that may account for this specificity. Citation Format: Denise M Wolf, Christina Yau, Ashish Sanil, Jo Chien, Anne Wallace, Angela DeMichele, Hank Kaplan, Doug Yee, Claudine Isaacs, Kathy Albain, Rebecca Viscuzi, Judy Boughey, Stacey Moulder, Steven Chui, Qamar Khan, Toncred Styblo, Kirsten Edmiston, Donald Northfelt, Anthony Elias, Barbara Haley, Debu Tripathy, Lamorna Brown-Swigart, Susan Flynn, Gillian Hirst, Meredith Buxton, Nola Hylton, Melissa Paoloni, Fraser Symmans, Laura Esserman, Don Berry, Hope Rugo, Olufunmilayo I. Olopade, Laura van 't Veer. MammaPrint High1/High2 risk class as a biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy for breast cancer in the I-SPY 2 TRIAL [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-25.

Abstract 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). Methods: Tumors ≥2.5cm by clinical exam & ≥2cm by imaging are eligible for screening. MP low risk/HR+/HER2- tumors are ineligible for randomization. Patients receive chemotherapy (paclitaxel qwk x 12, doxorubicin and cyclophosphamide q2-3 wk x 4, T->AC). HER2- pts were randomized to N+T->AC vs. T->AC and HER2+ pts to N+T->AC vs. trastuzumab+T->AC. Analysis is intent-to-treat with pts who switch to non-protocol therapy regarded as non-pCRs. We provide estimated pCR rates (95% Bayesian probability intervals), probabilities of superiority of neratinib over control, and Bayesian predictive probabilities of success in an equally randomized phase III trial. Results: Neratinib met the predictive probability criterion in HR-/HER2+, “graduated”, and accrual ceased [115 N patients (65 HER2+), 78 concurrently randomized controls (22 HER2+)]. The table shows results for all 10 signatures. Two patients (1 N and 1 control) withdrew consent and are not included. Conclusion: I-SPY 2's standing trial mechanism efficiently evaluates agents in biomarker-defined patient subsets. In a modest number of patients, adaptive randomization successfully identified a biomarker signature (HR-/HER2+) for neratinib's further development. All HER2+ and MP+ tumors may also benefit from this regimen, consistent with preclinical data. Evaluation in I-SPY 3, a phase III registration trial, is planned. SignatureEstimated pCR Rate (95% probability interval)Probability NeratinibIs Superior to ControlPredictive Probability of Success in Phase IIINeratinibControlALL32% (28-36%)23% (19%-28%)92%44%HR+23% (18%-28%)17% (11%-22%)81%40%HR-43% (37%-49%)31% (24%-38%)89%53%HER2+39% (33%-45%)23% (15%-30%)95%73%HER2-26% (21%-32%)24% (18%-29%)63%20%MP+*45% (38%-53%)29% (20%-39%)91%66%HR-/HER2-36% (29%-43%)30% (23%-38%)72%34%HR-/HER2+55% (46%-64%)32% (22%-43%)94%78%HR+/HER2+31% (24%-37%)17% (10%-24%)91%65%HR+/HER2-14% (8%-19%)16% (10%-21%)39%12%* MammaPrint 44K Array Low/High score was adjusted to MammaPrint High1 (MP-) or High2 (MP+), using a pre-defined median cut-point of I-SPY 1 participants, who fit the eligibility criteria of I-SPY 2. Citation Format: John W. Park, Minetta C. Liu, Douglas Yee, Angela DeMichele, Laura van 't Veer, Nola Hylton, Fraser Symmans, Meredith B. Buxton, A. Jo Chien, Amy Wallace, Michelle Melisko, Richard Schwab, Judy Boughey, Debashish Tripathy, Hank Kaplan, Rita Nanda, Stephen Chui, Kathy S. Albain, Stacy Moulder, Anthony Elias, Julie E. Lang, Kirsten Edminston, Donald Northfelt, David Euhus, Qamar Khan, Julia Lyandres, Sarah E. Davis, Christina Yau, Ashish Sanil, Laura J. Esserman, Donald A. Berry. Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT227. doi:10.1158/1538-7445.AM2014-CT227

AbstractThe many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.

Purpose To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer. Patients and Methods A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome. Results Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor–negative/human epidermal growth factor receptor 2 (HER2) –negative tumors (P = .067), with no differences seen with hormone receptor–positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40). Conclusion Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor–negative/HER2-negative tumors.

Abstract Background: In 2000, cyclophosphamide(C), epirubicin(E) and fluorouracil (F) (CEF) and doxorubicin (A) and C followed by paclitaxel (T) (AC/T) given every three weeks were commonly used regimens in Canada and the USA to treat women with node positive or high risk node negative operable breast cancer. In a previous trial in women with locally advanced breast cancer, 3 months of dose-dense EC was equivalent to six months of CEF. We hypothesized that the addition of 3 months of a taxane following dose-dense EC would be superior to CEF alone or AC/T. In a randomized trial in women with early breast cancer we compared CEF, dose dense EC/T and AC/T. An interim analysis (JCO, 2010) conducted when 50% of the events for the relapse-free-survival (RFS) analysis were observed, demonstrated that AC/T administered every 3 weeks was significantly inferior to CEF or EC/T. The results of the final RFS including CEF versus EC/T will be presented. Methods: Women, 60 years or younger, with operable axillary node positive or high risk node negative breast cancer were randomized to adjuvant CEF, EC/T or AC/T. CEF was given for 6 cycles and consisted of: C 75 mg/m2 orally on Days 1–14, and E 60 mg/m2 and F 500 mg/m2, IV on Days 1 and 8. CEF patients received concurrent antibiotic prophylaxis. EC/T consisted of 6 cycles of EC every 14 days; E 120 mg/m2 and C 830 mg/m2, both IV on Day 1 with filgrastim 5 [ug]/kg/day subcutaneous from Days 2–13 and epoetin alpha 40,000 units subcutaneous once weekly. After completion of EC, 4 cycles of T 175 mg/m2 every 21 days with filgrastim and epoetin alpha were given. The AC/T regimen consisted of A 60 mg/m2 and C 600 mg/m2 IV every 21 days for 4 cycles. This was followed by T 175 mg/m2 every 21 days for 4 cycles. The final analysis for RFS was planned when 453 events were observed permitting the detection of a hazard ratio (HR) of 1.43 between CEF and AC/T and a HR of 1.43 between EC/T and the best of the other two arms. Quality of Life data using the EORTC C-30 and the Breast Cancer Chemotherapy questionnaires were collected throughout the study. The results will be available at the time of the presentation. Results: A total of 2104 women were enrolled between December 2000 and April 2005. The required 453 events for the RFS analysis were observed by the clinical cut-off date of March 30, 2012. At this point 369 deaths had been observed. The median follow-up is 87.5 months. Outstanding data and queries are currently being collected and reviewed with an expected database lock and final analysis mid August, 2012. Febrile neutropenia remains higher on the CEF and EC/T arms while more neuropathy was seen in the taxane containing regimens. Conclusions: Although the two regimens considered a standard of care at the time the study was initiated are no longer widely used, the trial results will enhance our understanding of the magnitude of benefit of taxane following an anthracycline, the significance of cumulative anthracycline dose, and the role of dose density/ intensity as backbone of conventional chemo regimens. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-01.

Abstract New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety. Clin Cancer Res; 19(11); 2817–23. ©2013 AACR.

Abstract Because numerous chemotherapeutic agents exert their cytotoxic effects through generation of reactive oxygen species, the use of antioxidant supplements during treatment is controversial. There are published recommendations to suspend antioxidant supplement use during treatment, despite lack of empirical data from clinical studies; however, it is unclear if patients follow these recommendations. We examined use of multivitamins and vitamin supplements (MV/SP) during treatment for breast cancer, particularly in relation to physician recommendations. High-risk breast cancer patients (n=855) were queried regarding physician recommendations and use of MV/SP via self-administered questionnaires in an ancillary study embedded in a phase III trial of dose-dense compared to metronomic administration of doxorubicin/cyclophosphamide + paclitaxel (SWOG S0221). Of the 658 patients who reported discussing use of supplements during treatment with their physicians, 390 (59%) received no counseling regarding MV/SP use, 85 (13%) received recommendations not to take MV/SP, and 183 (28%) received recommendations to use MV/SP. MV/SP use during treatment was compared to use prior to diagnosis in relation to physician recommendations, with the reference group comprised of those receiving no recommendations. Of those using MV ≥ once/week before diagnosis, recommendations not to take MV/SP were associated with a tenfold reduction in MV use to < once/week during treatment. (OR=10.0, 95% CI=3.7-27.0). MV use was less likely to decrease among patients receiving recommendations to use MV/SP (OR=0.23, 95% CI=0.12-0.44). Similar findings were observed among patients who reported use of vitamin C and vitamin E supplements ≥ once/week before diagnosis, with patients who were advised to take no supplements other than a MV more than 5 times as likely to decrease use of antioxidant supplements. MV use during treatment among previous non-users increased almost sixfold among those whose physicians recommended MV/SP use during treatment (OR=5.92, 95% CI=3.29-10.6). For those reporting vitamin C or vitamin E use < once/week before diagnosis, patients whose physicians recommended MV/SP during treatment were more likely to increase their use of vitamin C (OR=2.05, 95% CI=1.00-4.19) and vitamin E (OR=5.28, 95% CI=2.24-12.4). In this study, physician recommendations were strongly associated with patient use of MV/SP during chemotherapy, regardless of the patient's frequency of use prior to diagnosis. These findings highlight the critical need to better understand the mechanisms by which antioxidants may influence chemotherapeutic outcomes, and to determine if supplement use affects toxicity and/or recurrence. Yearly follow-up in this ongoing study will allow us to assess the impact of MV/SP use treatment outcomes, providing a basis for physician recommendations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4681. doi:10.1158/1538-7445.AM2011-4681