Abstract Background: Pathologic complete response (pCR) is an established prognostic biomarker for aggressive HER2+ breast cancer (BC). Improving pCR rates may identify new therapies that improve survival. T-DM1 and pertuzumab have established benefits in metastatic HER2+ BC. We tested their ability when combined, without paclitaxel, to improve pCR rates (ypT0ypN0) over standard therapy in the randomized, phase 2, I-SPY 2 neoadjuvant trial. Methods: Enrolled patients (pts) had invasive breast cancer ?2.5 cm in HER2-positive subsets. Pts were adaptively randomized to 12 wkly cycles of paclitaxel+trastuzumab (TH, control) or T-DM1+pertuzumab (T-DM1+P) without T, followed by doxorubicin/cyclophosphamide (AC) x 4 and surgery. We utilized all TH control pts accrued over the course of the trial, adjusting for potential differences due to time period treated, which were informed by the several other treatment arms that have been in the trial. Adaptive assignment to the various experimental arms in the trial was based on current Bayesian probabilities of superiority vs. control. “Graduation” by signature and futility stopping were based upon Bayesian predictive probability of success in a future 2-arm, N = 300 neoadjuvant Phase 3 randomized 1:1 trial of T-DM1+P vs. control with pCR endpoint. Results: T-DM1+P met the predictive probability criterion and graduated from I-SPY 2 in 3 signatures: all HER2+, HER2+/HR+, HER2+/HR- (Table 1). Final accrual: 52 T-DM1+P and 31 TH. Safety data will be shown. Conclusions: I-SPY 2's standing platform trial mechanism efficiently evaluates agents in biomarker-defined pt subsets. T-DM1+P (w/o T) -> AC substantially improves pCR rates over standard TH -> AC in all 3 HER2+ signatures, including HR+ and HR- subsets. These findings warrant further investigation of these agents without paclitaxel in a neoadjuvant trial powered for survival endpoints. Table 1Signature*Estimated pCR Rate (95% probability interval)Probability T-DM1+P Is Superior to Control**Predictive Probability of Success in Phase 3T-DM1+PControl (TH)HER2+52% (36%-68%)22% (5%-39%)99.5%94%HER2+/HR+46% (26%-66%)17% (0% - 34%)99.1%93%HER2+/HR-64% (39%-88%)33% (6%-59%)98%90%*HR = Hormone Receptor Citation Format: Angela M. DeMichele, Stacy Moulder, Meredith Buxton, Douglas Yee, Anne Wallace, Jo Chien, Claudine Isaacs, Kathy Albain, Judy Boughey, Kathleen Kemmer, Barbara Haley, Julie Lang, Henry Kaplan, Susan Minton, Andres Forero, Anthony Elias, Rita Nanda, Larissa Korde, Richard Schwab, Michelle Melisko, Ashish Sanil, Michael Hogarth, Nola Hylton, Melissa Paoloni, Fraser Symmans, Jane Perlmutter, Julia Lyandres, Christina Yau, Don Berry, Laura Esserman, I-SPY 2 TRIAL Investigators. Efficacy of T-DM1+pertuzumab over standard therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT042.
It has been previously reported that the indigent patient population is less likely to seek breast reconstruction. It has also been reported that lower income women who do chose to undergo reconstruction are less satisfied with the results. This study assesses the level of breast reconstruction satisfaction in women treated at Los Angeles County Medical Center (LAC). For those women with lower satisfaction, we seek to identify the root source of this dissatisfaction.Patients who underwent breast reconstruction at LAC from 2007 to 2012 were identified by Current Procedural Terminology codes. Eligible participants were administered the BREAST-Q postreconstruction module. Demographic data were obtained from the patient and/or their medical records.A total of 65 patients completed the surveys. The satisfaction scores for the appearance of the breast were 61 (24) and satisfaction with overall outcome was 80 (26). The occurrence of major complications was associated with lower satisfaction scores with respect to the appearance of the breast (P<0.0001) and overall outcome (P=0.02). In addition, patients with delayed reconstruction were also noted to be more satisfied with respect to appearance of the breast (P=0.03).Despite suggestions that the indigent and the underserved patient population are less satisfied with the results of their breast reconstruction procedures, patients at LAC demonstrated comparable satisfaction levels to other published reports. The occurrence of major complications and immediate reconstruction were significantly associated with lower levels of satisfaction.
Abstract Background: Limonene is a highly lipophilic monoterpene found in citrus peel oil that has demonstrated anticancer properties in preclinical studies. The purpose of this study was to evaluate whether limonene and its primary metabolite perillic acid (PA) would distribute extensively to the breast tissue and reach an effective drug concentration. Secondary endpoints included evaluation of changes in cancer-related biomarkers in plasma and tissue. Methods: Participants (N = 40) with newly diagnosed stage 0 - 2 breast cancer took 2 grams daily of oral limonene for 2 - 6 weeks (21.5 ± 8.8 days) prior to planned surgical tumor resection. Blood was drawn pre/post intervention for measurement of serum concentration of limonene, PA, and protein biomarkers, as well as to assess toxicity profiles. A small piece of breast tissue adjacent to the tumor mass was also collected for analysis of limonene and PA levels. Limonene and PA levels in tissue and serum were analyzed using specific chromatography-based assays. Results: Limonene was found to preferentially concentrate in breast tissue (332.3 + 336.1 uM) versus plasma (0.49 + 0.67 uM) with tissue-to-plasma concentration ratio (TPCR) of 1,667 + 312.5 (P<0.001). PA did not concentrate in breast tissue (5.73 + 10.28 uM) versus plasma (3.89 + 6.81 uM) with TPCR of 1.4 + 0.56. Post-intervention serum levels of leptin, adiponectin, TGF-beta1, IGFBP-3 and IL-6 were unchanged from baseline. There was a small but statistically significant post-intervention increase in IGF-1, however the change was no longer significant after adjustment for number of days on agent. Possibly or probably related adverse events were primarily GI-related and were not dose-limiting. No clinically significant changes in complete blood count, renal, hepatic or other blood chemistry studies were noted. Analysis of the intervention effects on tissue biomarkers of proliferation, apoptosis, and cell cycle regulation is ongoing. Discussion: Oral limonene preferentially concentrates in the breast tissue and has a favorable side effect profile. PA does not readily concentrate in breast tissue when administered as oral limonene. Short-term limonene intervention resulted in minimal changes in systemic biomarkers. Further clinical trials with a longer intervention are necessary to establish limonene's potential role as a chemopreventive agent in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3558. doi:1538-7445.AM2012-3558
Abstract Background: Cutaneous Metastases (CM) are an infrequent presentation of advanced solid tumors and are usually associated with symptoms of pain, pruritus, and secondary infections, all of which negatively affect quality of life and result in additional morbidity. Systemic chemotherapy, advanced wound care, topical agents, cryo-, electro-, photodynamic-, laser and intralesional therapies have been limited by inconsistent efficacy, inconvenience, or toxicity. In this open-label phase 1/2 clinical trial, submicron particle paclitaxel in an anhydrous base (SOR007) was evaluated for topical treatment of CM from breast cancer (n=21), leiomyosarcoma (n=1) and Paget’s disease (n=1). Previously, in vitro, in vivo, and clinical studies demonstrated penetration of paclitaxel into the dermis with the silicone-based anhydrous producing subtoxic plasma levels in GLP toxicology studies and early clinical trials. Trial Design: The phase 1/2 open label trial evaluated 3 doses of SOR007 (0.15%, 1.0%, 2.0%). Approximately 0.5 grams (1 FTU) of SOR007 per 50 cm2 treatment area was applied BID during a 3+3 dose-rising phase for 28 days (n=10) or a dose-expansion phase at 2% strength BID for 28 days (n=2) or 56 days (n=11) unless discontinuation became necessary due to clinical course of the underlying disease. Results: At least one eligible lesion was treated per subject and classified per RECIST 1.1. In the 28-day application group, 10 subjects were treated and in the 56-day application group, 11 subjects were treated. Lesion response is summarized in the table below for data to date. Lesion response was evaluated within 2 weeks of last treatment day in most subjects. Conclusions: SOR007 was safe when applied to CM lesions. SOR007 resulted in decreased lesion progression or reduced lesion area in the majority of CM subjects. These clinical benefits became more consistent and pronounced at 2% strength with longer treatment suggesting a dose/duration response. Lesion pain reduction is also suggested from the study. Additional clinical research with more subjects and longer treatment periods is in the early planning stage. Lesion ResponseLesion response by SUBJECTLesion response by SUBJECTLesion response by INDIVIDUAL LESIONLesion response by INDIVIDUAL LESIONDose-rising 0.15%, 1%, 2% & Dose expansion 2%Dose-expansion 2%Dose-rising 0.15%, 1%, 2% & Dose expansion 2%Dose-expansion 2%BID x 28 daysBID x 56 daysBID x 28 daysBID x 56 daysN (subjects or lesions)8111823Complete Response0% (0/8)9.1% (1/11)5.5% (1/18)26% (6/23)Objective Response Rate13% (1/8)45% (5/11)17% (3/18)43% (10/23)No lesion progression in evaluable subjects 63% (5/8)82% (9/11)61% (11/18)83% (19/23) Citation Format: Mario E Lacouture, Julie E Lang, Sant Chawla, Shari Goldfarb, Alina Markova, Alexander Pan, Rose Marie Cavanna-Mast, Peter Mast, Christopher Savoie, Gere diZerega. Phase 1/2 clinical trial of a topical submicron particle paclitaxel (SOR007) for the treatment of cutaneous metastases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-05.
Nonsentinel lymph nodes (SLNs) are commonly removed at the time of selective sentinel lymphadenectomy (SSL). Their predictive value for the rest of the nodal basin is unknown. A retrospective review of 436 breast cancer patients who underwent SSL between 12/97 and 04/03 at a single institution. One-hundred nineteen patients had non-SLNs removed at SSL; eight were positive (6.7%). Positive non-SLNs predicted that SLNs would also be positive (p = 0.008). There was no difference in rates of additional positive nodes found on completion axillary node dissection between the non-SLN and SLN positive patients (p = 0.62). After adjustment for covariates, the presence of positive non-SLNs was not associated with poorer disease free survival (p = 0.24), time to systemic recurrence (p = 0.57), or overall survival (p = 0.70). Positive non-SLNs removed during SSL are not a significant risk factor for additional positive nodes on completion axillary nodal dissection (CALND) or for worse survival than positive SLNs.
Abstract Background: I-SPY2 is a multicenter, response-adaptive randomization phase 2 trial to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - weekly paclitaxel + investigational treatment x 12 wks followed by doxorubicin & cyclophosphamide(AC) q3 wks x 4 vs. weekly paclitaxel/AC (control). The primary endpoint is pathologic complete response (pCR). The goal for all investigational arms is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with a pCR endpoint within signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Findings from the graduated, previously reported Pembro4 arm (Nanda et al, ASCO 2017) supported investigation of de-escalating therapy, and determining if pembrolizumab (an anti-PD-1 antibody) alone q3 wks x 4 after weekly paclitaxel x 12 wks + pembrolizumab q3 wks x 4 was sufficient to sustain response without AC. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ were ineligible. MRI scans (at baseline, 3 wks, 12 wks, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients (pts). Pts who receive non-protocol therapy (e.g., carboplatin or AC for the Pembro8-noAC arm) count as non-pCR. Pembro8-noAC was open to HER2- pts for evaluation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2-, and HR-/HER2-. Regimens exit the trial for futility (<10% probability of success), maximum sample size accrual (10% <probability of success <85%), or safety as recommended by the independent DSMB. Results: Pembro8-noAC was randomized to 73 pts, 3 of whom progressed while receiving pembrolizumab alone on study. Randomization to this arm continued after the first report because the rate of progression during AC over the course of the trial was estimated to be 6.5% based on serial MRI studies. However, notification of the third case prompted the study team to ask the DSMB for the summary response for this arm. Although it did not meet formal stopping rules for either graduation or futility, Pembro8-noAC was not near the target threshold pCR rates of 60% for HR-/HER2- and 30% for HR+/HER2+. As a result of this information, combined with the on-treatment progressions, assignment to Pembro8-noAC was discontinued. Treatment with pembrolizumab alone was no longer allowed due to the potential concern for progression, and investigators were given the option to administer AC with pembrolizumab or proceed with definitive surgery following the 12 weeks of paclitaxel + pembrolizumab. 34 pts had surgery results at the time the study was closed. Of the remaining 39 pts, 34 pts have on-therapy MRI assessments. Estimated pCR rates were based on all pts with information at the time (see table). Immune-related adverse events included grade 3 colitis (n=2), grade 3 pneumonitis (n=1), grade 3 transaminitis (n=1), grade 3 hypothyroidism (n=1), and grade 1-2 adrenal insufficiency (n=5). Conclusion: Although Pembro8-noAC is performing at least as well as standard paclitaxel/AC, the likelihood is very low that the regimen would be successful in a phase 3 trial. Pembrolizumab alone following 12 weeks of paclitaxel + pembrolizumab was not sufficient to sustain a response. This was quickly assessed with a small number of patients. Estimated pCR rateSignature(95% prob interval)Pembro8-noACControlHER2-0.210.2(0.09-0.32)(0.15-0.25)HR-/HER2-0.270.27(0.09-0.45)(0.19-0.35)HR+/HER2-0.150.15(0.01-0.29)(0.09-0.20) Citation Format: Minetta C. Liu, Patricia A Robinson, Christina Yau, Anne M Wallace, A. Jo Chien, Erica Stringer-Reasor, Rita Nanda, Douglas Yee, Kathy S Albain, Judy C Boughey, Heather S Han, Anthony D Elias, Kevin Kalinsky, Amy S Clark, Kathleen Kemmer, Claudine Isaacs, Julie E Lang, Janice Lu, Tara Sanft, Angela DeMichele, Nola M Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Patricia K Haugen, Amy Wilson, Ruby Singhrao, Smita Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of a novel agent plus standard neoadjuvant therapy in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-02.
Abstract Purpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. Patients and Methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy “graduates” if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. Results: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%–99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. Conclusions: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.
