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BACKGROUND: RAD001 is an oral mTOR inhibitor that has exhibited activity in breast cancer. Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents that cause interstrand cross-links. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in at least two different breast cancer cell lines (including ER/PR negative cell lines). We propose that combination RAD001 and carboplatin may have activity in triple-negative breast cancer. MATERIALS AND METHODS: The primary objective of the study is to determine clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD more than 6 months)) and the toxicity of this combination in triple negative metastatic breast cancer who have had 0–3 prior chemotherapy regimens for metastatic disease. Twenty-five subjects were to be entered in this Phase II study. This design has greater than 80% power to test the null hypothesis that the clinical benefit rate is less than or equal to 10% versus the alternative hypothesis that clinical benefit rate is greater than or equal to 30%. Prior carboplatin is allowed. Women with treated brain metastasis are eligible. Secondary objectives are to determine progression free survival and relationship between pretreatment sensitivity (biopsy at baseline) and clinical response (biopsy post 2 cycles) using IHC staining for abundance of key proteins in the Akt-mTOR pathway and their activity using surrogate phosphorylation site-specific antibodies. According to the original study plan, carboplatin AUC 6, was to be given intravenously every three weeks. Five mg of RAD001 was to be given daily with a 3 patient run-in and then 10 mg daily if there were no dose-limiting toxicities. Due to a surprising amount of thrombocytopenia with this combination the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (and no plan to escalate to 10 mg). RESULTS: 23 patients of a planned 25 have been recruited thus far. Median age is 59. Of the 20 patients assessable for response at this time, there have been 1 CR, 5 PRs, 8 SDs and 6 PDs. One SD was achieved in a patient progressing on single agent Carboplatin at study entry. Median duration of CR+ SD +PR thus far is 13 weeks (range: 6–74 weeks). 5 of 22 patients assessable for toxicity had grade 3/4 thrombocytopenia and 4 patients had grade 3 neutropenia (no febrile neutropenia). 13 out of eighteen patients have had treatment held and/or dose reductions secondary to hematological toxicity, however, since amendment for starting dose of Carboplatin to AUC 4 the regimen has been very well tolerated with only 1 out of eleven patients with grade 3 neutropenia and grade 3 thrombocytopenia. 1 patient suffered from grade 3 dehydration. The estimated clinical benefit rate is 45% (95% confidence interval: 23%, 67%). Median time to progression or death is 85 days from start of treatment. CONCLUSIONS: Our study has met the primary end point of demonstrating clinical benefit in triple negative metastatic breast cancer. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. We continue to accrue study subjects at the amended dosing. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-05.

Background: RAD001 is an oral mTOR inhibitor that has exhibited activity in breast cancer. Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents that cause interstrand cross-links. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in at least two different breast cancer cell lines (including ER/PR negative cell lines). We propose that combination RAD001 and carboplatin may have activity in triple-negative breast cancer. Methods: The primary objective of the study is to determine clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD)) and the toxicity of this combination in women with triple negative metastatic breast cancer who have had 0–3 prior chemotherapy regimens for metastatic disease. Secondary objectives are to determine progression free survival as well as investigating the relationship between pretreatment sensitivity (biopsy at baseline) and clinical response (biopsy post 2 cycles) using IHC staining for abundance of key proteins in the Akt-mTOR pathway and their activity using surrogate phosphorylation site-specific antibodies (Akt and phospho-serine 473, phospho-threonine and phospho-threonine 308 Akt; mTOR and phospho-serine 2448 mTOR; ribosome protein S6 kinase (S6K) and phospho-threonine 378 S6K; 4E-BP1 and phospho-serine 65 4E-BP1). Prior carboplatin is allowed. Women with treated brain metastasis are eligible. According to the original study plan, carboplatin AUC 6, was to be given intravenously every three weeks. Five mg of RAD001 was to be given daily with a 3 patient run-in and then 10 mg daily if there were no dose-limiting toxicities. Due to a unexpected amount of thrombocytopenia with this combination the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (and no plan to escalate to 10 mg). Results: Fourteen patients of a planned 25 have been recruited thus far. Median age is 58.5. Median number of prior regimens is 2 (0-3). Of the 7 patients assessable for response at this time, there have been 2 PR's and 5 patients with SD. One SD was achieved in a patient progressing on single agent carboplatin at study entry. Median duration of SD + PR is 28.5 weeks (5 patients have ongoing response ranging from 8–46.5 weeks). Five of 8 patients assessable for toxicity had grade 3 or 4 thrombocytopenia and 2 patients had grade 3 neutropenia. No cases of febrile neutropenia were observed. Four patients have required blood transfusion and one patient has required platelet transfusion. All patients have had treatment held and/or dose reductions secondary to hematological toxicity, however, since amended carboplatin dose the regimen has been very well tolerated with only one out of six patients) with grade 3 neutropenia and grade 3 thrombocytopenia. There have been no non-hematological grade 3 or 4 toxicities. Conclusions: Clinical benefit was observed in all 7 assessable patients. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. We continue to accrue study subjects at the amended dosing. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-07.

Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multi-modality therapy results in a 5 year OS of 30%, underscoring the unmet need for targeted therapy. Our preclinical research in cell lines & xenograft tumor models has identified a role for hyper-activated PI3K/mTOR signaling in IBC. IBC cells express IL-6 and IL-8, which recruit tumor activated macrophages (TAMs) that further induce inflammatory cytokines and activate the JAK2/STAT3 pathway. We investigated the independent and combined activity of these pathways in IBC patient tissues. Methods: Archived tissue specimens of 42 IBC patients (dx 1999-2009) and 27 non-IBC patients (dx 2001-2005) with invasive ductal carcinoma (IDC) were obtained. Surrounding non-tumor normal tissue from IBC (companion controls) was also utilized. All specimens were analyzed using immunohistochemistry (IHC) and scored by 3 independent pathologists. Results were defined as 0 = negative; 1+,2+ = positive for activated mTOR (P-S6); activated JAK2/STAT3 (P-JAK2; P-STAT3); cytokine (IL-6); macrophage infiltration (CD68) and TAM (CD163). Proportions of IBC cases with positive expression were compared with non-IBC cases (Fisher's exact test) & companion controls (McNemar's test). Clinical & survival data were obtained. Results: Median age at diagnosis: 46 yrs (31-62) in early stage IBC [EIBC] (n = 37) & 41 yrs (29-57) in pts with de novo metastatic IBC [MIBC] (n = 5). In EIBC, 19/36: HER2+ (1 unk); 8/19: ER+/HER2+; 8/36: ER-/HER2-. In MIBC, all were ER- (1 unk) & 3/4 were HER2+ (1 unk). 88% were rx with neoadjuvant &/or adjuvant anthracycline & taxane w/o adjuvant trastuzumab. There were 24 pt deaths (5/5 MIBC). Median f/u for EIBC: 6.3 yrs and for MIBC: 3.4 yrs. Median OS: 81.4 mo (95% CI lower 48 mo) for EIBC & 41 mo (95% CI 8-81 mo) for MIBC. Median RFS: 18 mo (95% CI 18-79 mo) for 23 pts (13 NED; 1 unk). The non-IBC patients were all stage 2-3 with median age at diagnosis: 58 yrs (39-94). 19/27: ER+; 7/25 HER2+ (2 unk); 15/25 ER+/HER2-; 3/25 ER-/HER2-. 78% were rx with adjuvant anthracycline & taxane, 4% were rx with FEC and 18% did not receive adjuvant chemotherapy. 18% received adjuvant trastuzumab. Median f/u: 8.0 yrs. Median OS: not yet reached and median RFS: 111.3 mo (95% CI lower 34.5 mo). EIBC cases were compared with non-IBC cases & companion controls (Table 1). PS6, pJAK2 and pSTAT3 expression was significantly increased in IBC compared to non-IBC. Of the 29 EIBC patients with complete biomarker data who were PS6+, 28/29 (97%) were JAK2+, 15/29 (52%) were STAT3+, 26/29 (90%) were CD68+, 20/29 (69%) were CD163+ and 28/29 (97%) were IL6+. Conclusion: This is the first study to validate preclinical findings & show a strong co-association between hyper-activation of mTOR & JAK/STAT pathways in most IBC patient tumors when compared to surrounding non-tumor tissue and non-IBC (IDC) tumors and tissues. These findings suggest a key role for dual blockade of mTOR & JAK/STAT pathways for IBC in phase I trials. BiomarkerMcNemars p-value: Early Stage IBC vs companion controls (N = 37)Fishers p-value: Early stage IBC (N = 37)vs non-IBC (N = 27)PS6 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-6.

Background/Aims: Neovascularization involves angiogenesis and vasculogenesis mediated by cytokines and soluble chemokines. The predominant stimulus is ischemia, however, recent data suggest that ionizing radiation (IR) has angiogenic potential. In this study we evaluated whether IR increases vascularity and perfusion in vivo. Methods: In wild-type mice, a full-thickness, pedicled skin flap was created and isolated for localized irradiation at a dose of 5 Gy. Serial Doppler analysis of the flap was performed. The skin flaps were then harvested at various time points for vascularity and histologic analysis. Blood was concurrently harvested for serum and hematopoietic progenitor cell population analysis. Results: IR to an ischemic flap augmented the angiogenic cytokines SDF-1 and VEGF. Serum MMP-9 and s-kit levels, which are critical for progenitor cell mobilization, were also increased. When hematopoietic progenitor cells were evaluated by Sca1+/Flk1+ cells, a correlate 2-fold increase was seen compared to controls. When the flaps were examined, both vascularity and perfusion were increased. Conclusion: In this study we demonstrate that local, low-dose IR upregulates angiogenic chemokines and results in progenitor cell mobilization to the systemic circulation. There is a resultant increase in the vascularity of the irradiated flap, suggesting that the pro-angiogenic effects of IR can be harnessed locally.

Blood vessel growth is regulated by angiogenic and angiostatic CXC chemokines, and radiation is a vasculogenic stimulus. We investigated the effect of radiation on endothelial cell chemokine signaling, receptor expression, and migration and apoptosis. Human umbilical vein endothelial cells were exposed to a single fraction of 0, 5, or 20 Gy of ionizing radiation (IR). All vasculogenic chemokines (CXCL1–3/5–8) increased 3–13-fold after 5 or 20 Gy IR. 20 Gy induced a marked increase (1.6–4-fold) in angiostatic CXC chemokines. CXCR4 expression increased 3.5 and 7-fold at 48 h after 5 and 20 Gy, respectively. Bone marrow progenitor cell chemotaxis was augmented by conditioned media from cells treated with 5 Gy IR. Whereas 5 Gy markedly decreased intrinsic cell apoptosis (0 Gy = 16% ± 3.6 vs. 5 Gy = 4.5% ± 0.3), 20 Gy increased it (21.4% ± 1.2); a reflection of pro-survival angiogenic chemokine expression. Radiation induces a dose-dependent increase in pro-angiogenic CXC chemokines and CXCR4. In contrast, angiostatic chemokines and apoptosis were induced at higher (20 Gy) radiation doses. Cell migration improved significantly following 5 Gy, but not 20 Gy IR. Collectively, these data suggest that lower doses of IR induce an angiogenic cascade while higher doses produce an angiostatic profile.

of stage and tumor site between the two groups. The Mann-Whitney U test was used to compare the remaining parameters between the two groups. Analysis was performed using SPSS v.19. Results: There was no significant difference in the distribution of stage (pZ0.19), tumor site (pZ0.63), age (pZ0.99), clinical target volume (CTV) V50 (pZ0.07) and volume of CTV (pZ0.23), heart (pZ0.30), and liver (pZ0.37) between the non-ABC and ABC groups. For all 166 patients, there was a significantly lower ipsilateral lung V5 (pZ0.001), ipsilateral lung V10 (p

Purpose/Objective(s): Currently, no biological molecular targets exist for women diagnosed with triple negative breast cancer (TNBC). In an in vitro murine breast cancer model, we have shown that radiation therapy (RT) combined with carboplatin potentiates immunogenic tumor cell death, thereby contributing to a pro-immunogenic milieu (Golden et al., Oncoimmunology 2014). Thus, we hypothesized that this regimen may not only radio-sensitize, but also trigger an adaptive anti-tumor immune response. We are conducting a phase I-II IRB-approved trial [clinicaltrials. gov NCT01289353] to test the feasibility and clinical efficacy of this combination in terms of rates of local control, distant recurrence, and overall survival. Materials/Methods: Women with Stage I e II (pT1-T2, pN0) TNBC are eligible after segmental mastectomy and axillary lymph node assessment. Weekly carboplatin (AUCZ2.0) is delivered x6 weeks with RT to the whole breast being delivered during weeks 2-4, via a 3D-CRT or IMRT technique in the prone position. The whole breast receives 40.5 Gy in 15 fractions (Monday-Friday). The tumor bed receives an additional 3 Gy boost, delivered on 2 consecutive Sundays (beginning of the 2 and 3weeks of RT). Consequently, a total of 46.5 Gy is delivered to the tumor bed in 17 fractions over 19 days. Adverse effects of treatment are assessed weekly during treatment, and once at 45-60 days, thereafter, using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Results: A total of 33 patients have accrued so far. Acute toxicities are displayed below and never exceeded grade 3. Twenty patients received adjuvant chemotherapy. With a median follow-up of 25.9 months, 97% (32/33) of all women remain alive and without recurrent disease. One patient died with possible distant recurrence occurring at 5.6 months from beginning treatment. Conclusion: Adjuvant concurrent carboplatin and prone accelerated radiation therapy appears to be a safe and effective treatment for women diagnosed with early stage TNBC. Since approximately 50% of TNBC carriers recur within 2 years from treatment, it is encouraging that 97% of the patients in the trial have not experienced a recurrence.

anterior, posterior, superior, and inferior directions. To assess cavity movement from preto post-delivery of each fraction, a total of 100 preand post-fraction MR scans were manually registered based on the cavity, and resultant cavity translations in the longitudinal, vertical, and lateral planes were determined. Results: Onboard sagittal cine MR was visually monitored at the treatment machine and qualitative evaluation demonstrated no significant intrafraction motion of the lumpectomy cavity. In quantitative analysis of intrafraction motion, the mean movement of 4 tracking points placed at the superior, inferior, anterior, and posterior cavity edges was 0.34 0.07, 0.45 0.12, 0.42 0.09, and 0.28 0.07 mm in the ant-post direction; and 0.44 0.09, 0.62 0.10, 0.46 0.08, and 0.61 0.10 mm in the supinf direction, respectively. Overall, the median motion of any tracking point in any direction was < 0.5 mm. Mean translation of the lumpectomy cavity from preto post-fraction scans in the longitudinal, vertical, and lateral planes was 0.44 0.32, 0.40 0.30 and 0.41 0.32 mm, respectively. Conclusion: Analysis of intra-fraction motion of the lumpectomy cavity utilizing continuous on-board cine MR images and preand post-fraction MR imaging confirm minimal cavity motion, on the order of < 0.5 mm, in patients undergoing APBI with MR-IGRT. Given the minimal cavity motion and excellent visualization with onboard MRI, we used a 0 mm margin for setup uncertainty and intra-fraction motion, which maintained the ability to target the cavity and adjacent breast tissue at risk, while treating a smaller resultant PTV. Resultant reductions in dose to the ipsilateral normal breast tissue and adjacent normal structures such as the heart and lungs may impact late effects and cosmesis. This work, to our knowledge, is the first to describe real-time movement of lumpectomy cavities on MRI during radiation therapy. Author Disclosure: B.W. Fischer-Valuck: None. T.R. Mazur: None. S. Acharya: None. H. Wan: None. R. Kashani: None. H. Li: None. I. Zoberi: None. M.A. Thomas: Employee; Washington University.

Purpose: Challenges for radiation therapy in developing countries include unreliable infrastructure and high patient load. We propose a system to treat whole breast in the prone position without computed tomography and/or planning software. Methods: Six parameters are measured using calipers and levels with the patient prone in the treatment position. (1) The largest separation; (2) the angle that separation makes with the horizontal; (3) the separation 2 cm posterior to the nipple; (4) the vertical distance between these two separations; (5) the sup/inf length and (6) angle of the desired posterior field edge. The data in (5) (6) and (2) provide field length, collimator and gantry angles. Isocenter is set to the midpoint of (1), anterior jaw setting is 20cm (half-beam setup), and the dose is prescribed to a point 1.5 cm anterior to isocenter. MUs and wedge angles are calculated using an MU calculator and by requiring 100% dose at that point and 100-105% at the midpoint of (3). Measurements on 30 CT scans were taken to obtain the data 1-6. To test the resulting MU/wedge combinations, they were entered into Eclipse (Varian) and dose distributions were calculated. The MU/wedge combinations were recorded and tabulated. Results: Performing a dose volume histogram analysis, the contoured breast V95 was 90.5%, and the average V90 was 94.1%. The maximum dose never exceeded 114.5%, (average 108%). The lung V20 was

Purpose: To report on the clinical validation of the Varian Pivotal™ Treatment Solution for Prone Breast Care: a platform for prone breast radiation therapy. Methods: Patients treated using Breast Conserving Radiation Therapy may benefit from treatment in the prone position with the breast tissue falling freely away from the body. This geometry allows the breast tissue to be treated while avoiding the lung and heart tissue. Eighteen patients simulated and treated using the Varian Medical Systems Pivotal™ Treatment Solution for Prone Breast Care were monitored over the course of treatment for positioning integrity and reproducibility. As this carbon-fiber platform actually replaces a portion of the couch top, indexing is inherent to its design. Patients were positioned on the couch and aligned using fiducial markers and lateral SSD to the breast fiducial point. The daily couch coordinates then serves as indicators for positioning variability with this system. Results: The variations in couch vertical, longitudinal and lateral positions were centered on a mean value of zero with standard deviations of 0.44cm, 0.75cm and 0.79cm respectively. Other factors explored were variations in distance of mid-sternum to table edge and patient rotation into the opening. The median rotation of the chest wall was foundmore » to be 11.5 degrees at CT-Simulation with a median distance of 2.5cm from midsternum to support opening. Patient rotation was not associated with either breast size or distance from edge of platform. Conclusion: The Pivotal™ Treatment solution consists of a couch top that replaces the standard top and as such is open from beneath without obstruction. This is a distinction from all other solutions which rely on a platform positioned above and indexed to the treatment couch. We found the reproducibility to be consistent with our historical measures while offering benefits of an integrated solution as stated above. supported by Professional Services Agreeement with Varian Medical Systems.« less

TPS1147 Background: Triple-negative breast cancer (TNBC), which comprises ~15% of all diagnosed breast cancers, behaves aggressively and continues to represent a therapeutic challenge. As such, TNB...