bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-11-05: ANG4043, a brain-penetrant anti-HER2 mAb increases survival in mice bearing intracranial BT-474 breast tumor cells
Authors: Lachowicz JE , Demeule M , Regina A , Houle E , Tripathy S , Castaigne J-P 
Published: August 2014

Abstract
Background: Treatment options for metastatic brain tumors originating from HER2-positive breast disease are limited due to the inability of most anti-tumor agents to enter the brain. While the selectively permeable blood-brain barrier (BBB) restricts access of therapeutics such as mAbs to the brain, transcytosis of hormones, nutrients, and other homeostatic modulators is mediated by transporters and endogenous receptors such as the low density lipoprotein receptor-related protein 1 (LRP1). We have created a family of peptides (Angiopeps) that are recognized by LRP1 and enter the brain via receptor-mediated transcytosis. Using these proprietary Angiopeps, we have created novel, brain-penetrant Peptide-Drug Conjugates. An iterative process of linker selection and reaction condition optimization led to the discovery of ANG4043, a conjugate of the peptide Angiopep-2 (An2) and an anti-HER2 mAb similar to trastuzimab. This brain-penetrant An2-mAb conjugate, which displays HER2 binding affinity and in vitro anti-proliferative properties similar to that of the native mAb, was tested in a murine model of breast tumor brain metastases. Methods: Athymic nude mice were stereotactically implanted 1.5 mm anterior and 2.5 mm lateral to bregma with 1×106 BT-474 cells twelve days prior to initiation of drug treatment. Body weight and morbidity/mortality were monitored daily. Separate groups of mice received mAbs that were labeled with the fluorescent probe Cyto-750 to allow for near infrared in vivo imaging. Results: Median survival in the control group was 45 days, compared with 68 days and 80 days for the 5 mg/kg (p = 0.0005) and 15 mg/kg (p = 0.0003) groups, respectively, demonstrating a 51% and 78% improvement over the control group. In addition, a greater degree of fluorescence was observed in intracranial BT-474 brain tumors in the ANG4043 group compared to the native anti-HER2 mAb group. Conclusions: These data demonstrate that ANG4043 reaches its target in brain tumors and increases survival in a mouse HER2-positive intracranial tumor model. These results extend the validation of An2 conjugation beyond small molecules and peptides to include larger molecules such as therapeutic mAbs for development of new brain-penetrant anti-tumor therapeutics. We intend to progress this program to clinical stages both as monotherapy and in combination with ANG1005, the An2-paclitaxel conjugate that has shown encouraging results in clinical studies with primary brain tumors and breast cancer brain metastases.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-05.
Abstract P6-11-08: Risk of CNS relapse following adjuvant trastuzumab therapy – Updated literature-based meta-analysis
Authors: Mathew A , Brufsky AM 
Published: August 2014

Abstract
Background: Randomized trials of adjuvant trastuzumab in HER2-positive early breast cancer observed an increased risk for central nervous system (CNS) as site of first relapse. A meta-analysis of three trials with a total of 6752 patients followed up for a median of 2 years found an 82% increased risk for CNS relapse as first disease free survival (DFS) event with adjuvant trastuzumab use. It is thought that the greater risk for CNS as first relapse site is due to the lack of penetration of trastuzumab through the blood-brain barrier combined with better disease control in other visceral sites rather than the drug itself predisposing patients to CNS disease. Therefore, we hypothesize that the effect size of this association will decrease with increasing duration of follow-up.
Methods: A comprehensive literature search was performed. Updated results from the three randomized trials of adjuvant trastuzumab were identified. The NSABP B-31 and the NCCTG N9831 trials compared four cycles of doxorubicin and cyclophosphamide (AC) followed by four cycles of Paclitaxel (T) with the same regimen combined with trastuzumab for a year. The HERA trial compared one or two years of adjuvant trastuzumab with observation. We abstracted the number of CNS relapse events in these trials and performed a meta-analysis with fixed-effect model using Mantel-Haenzel method.
Results: Out of a total of 7456 patients included in the analysis, CNS DFS events occurred in 98 patients receiving trastuzumab compared to 68 patients in the control group over a median follow-up period of 4 years. We found a 43% increased risk for CNS relapse as first DFS event in patients who received adjuvant trastuzumab compared to the group that did not receive the drug (RR 1.43; 95% confidence interval 1.06, 1.95). We found no inconsistency in risk ratio estimates between the three trials (I2 = 0%).
Discussion: Adjuvant trastuzumab is associated with a higher risk for CNS as first relapse site despite an increase in duration of follow-up. The reduction in effect size from the previously reported 82% increased risk observed with a 2 year follow-up period, to 43% with 4 years of follow-up adds to the body of evidence that the drug itself does not predispose a patient to CNS recurrence. On the contrary, the reduction in effect size could also be attributed to the crossover study design in HERA trial, where nearly 50% of patients in the control group eventually received trastuzumab. In summary, we propose that the adjuvant trials of the newer HER2 targeted therapy should be designed to look into CNS disease as not only first site of recurrence but also gather additional data on all CNS recurrences to further elucidate the mechanism of CNS disease with HER2 directed therapy.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-08.
Abstract P6-11-10: Central nervous system metastases in breast cancer: Impact of tumour sub-type and outcome from current treatments
Authors: Chan A , O'Carrigan B , McGregor S , Beith J 
Published: August 2014

Abstract
Background: The use of more effective systemic therapies in the management of metastatic breast cancer has led to increased response rates, progression-free survival and overall survival. The incidence of central nervous system (CNS) metastases has become an increasingly important area of unmet need. It is important to identify tumour-related factors which may predict for CNS occurrence and assess the efficacy of treatments in current use.
Methods: Consecutive patients (pts) with breast cancer (BC) seen at 2 institutions following establishment of breast cancer databases were included: January 2000 (institution A) and January 2003 (institution B) to December 2012. Patient demographic data, tumour pathology and systemic treatment given were reviewed in those patients who developed CNS metastases. Multivariate analysis of factors impacting on overall survival in this patient population will be performed.
Results: Over the study period, 4751 pts with a median age of 52.7 yrs were seen, where 86.4% and 13.6% of pts presented with early and metastatic disease, respectively. In the entire population, 77% of tumours were hormone receptor positive, 21% HER2 positive, and 15% triple negative. Overall, 228 (4.8%) pts had CNS metastases with a median age of 48.9 yrs. CNS involvement was present at the time of first metastatic recurrence in 27% of pts who had CNS metastases. The proportion of pts developing CNS metastases according to tumour subtypes were: 48% hormone receptor positive, 36% Her2 positive, and 20% triple negative. Median time from diagnosis to development of CNS metastases (excluding pts with CNS involvement at the time of first metastatic disease) was 48.9 (4.7-248 months, m). The median time to development of CNS recurrence was 61m, 43m, 23m respectively, according to tumour subtype. CNS disease was parenchymal only, leptomeningeal only or both in 78%, 9%, 13% respectively. Pts who died from BC, had a median overall survival from initial BC diagnosis of 53.6m, whereas median overall survival from CNS metastases was 4.8 m. The impact of whole brain radiation with or without stereotactic therapy, surgical resection of brain metastases and type of systemic therapy administered following development of CNS disease on overall survival will be presented.
Discussion: CNS metastases occurred in up to 5% of breast cancer pts seen at two large cancer centres. Despite improvements in overall survival of metastatic BC pts with the use of more effective systemic treatments, the prognosis following CNS involvement remains extremely poor. Until specific interventions are available to manage CNS metastases in pts with breast cancer, it remains important to assess outcomes from current standard treatment in these pts.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-10.
Abstract PD3-5: Survival benefit conferred by the androgen receptor is lost in aromatase inhibitor treated breast cancer
Authors: Ali A , Bane F , Hao Y , McCartan D , O'Gaora P , Hill ADK , Young LS , McIlroy M 
Published: August 2014

Abstract
Aromatase Inhibitors have proven to be most effective in the treatment of post-menopausal breast cancer. Their mode of action is to inhibit the synthesis of estrogen (estrone) by the aromatase enzyme Cyp 19 thereby blocking ligand-dependent activation of the estrogen receptor. What has not been addressed to date is how cells that are deprived of estrogen, may potentially, adapt to the more androgenic environment resulting from long-term treatment with AI therapy. Research from our lab has identified the homeobox protein, HOXC11, to be an indicator of poor response to endocrine therapy and development of metastasis. To further our understanding of HOXC11 and its role in the development of endocrine-resistance and metastatic spread we undertook an RNA-seq experiment to identify its target genes in resistant breast cancer. This analysis identified PSAP, IFIT1 and HSP90AA1. Both PSAP (an androgen agonist) and HSP90AA1 (AR chaperone) are closely associated with AR which led to further investigation into the role of HOXC11 in the development of steroidal adaptability in Letrozole-resistant breast cancer. We hypothesize that HOXC11 regulated expression of PSAP results in oncogenic activation of AR in an AI resistant setting. Our findings have shown that AI-resistant cell lines in vitro have significantly elevated levels of AR and that loss of HOXC11 results in concommitant decrease in AR mRNA. In AI resistance expression of HOXC11 results in upregulation/stabilization of AR by PSAP thus enabling the tumour to adapt to use androgenic steroids for cell proliferation. The anti-androgen, Bicalutamide, reduces cell proliferation and cell motility in AI resistant cell lines. Survival analysis of AR in a TMA (n = 488) indicates that AR confers a survival benefit in the tamoxifen treated population. This protective effect is diminished in patients receiving AI therapy and is reflected in the altered Hazard Ratio of AR from the total population (HR: 0.485) to the AI treated cohort (HR: 1.197). Secreted PSAP was readily detectable in breast cancer patient serum and associates significantly with expression of HOXC11 in matched patient tissue (∼20). PSAP is associated with poor response to endocrine therapy and metastatic spread of prostate cancer and as it is secreted it could potentially be used to monitor patients on AI who might benefit from dual targeted therapy treatment.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-5.
Abstract PD3-7: Disease-free survival and Ki67 analysis of a randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer (JONIE-1 study)
Authors: Miura D , Hasegawa Y , Horiguchi J , Ishikawa T , Hayashi M , Takao S , Kim SJ , Tanino H , Miyashita M , Konishi M , Shigeoka Y , Yamagami K , Kaise H , Akazawa K , Kohno N 
Published: August 2014

Abstract
Background:
Zoledronic acid (ZOL) has been found to have a synergistic anti-proliferative effect when used in combination with antitumor drugs. We suggested that the addition of ZOL to neoadjuvant chemotherapy (CT) has potential anti-cancer benefit in postmenopausal patients with triple-negative breast cancer in JONIE-1 Trial (50% pCR rate in ZOL+CT: CTZ versus 0% in CT, p = 0.029). We analyzed the disease-free survival (DFS) as a secondary endpoint and baseline Ki67 levels between two groups.
Methods:
Women with Stage IIA-IIIB HER-2-negative breast cancer were randomly assigned 1:1 to CTZ group or CT group, CT was FEC100 q3w × 4 cycles followed by weekly paclitaxel for 12 cycles and ZOL 4mg was administered every 3-4 weeks. Among 188 patients recruited between March 2010 and April 2012 excluding 10 from the primary assessment, 178 patients were assessed. The aims of this study were to compare the relative efficacy or CTZ with the efficacy of CT in prolonging DFS in all patients and also to compare the pCR rates between baseline Ki67 high (20% and &gt;20%) with Ki67 low (&lt;20%) in ER positive cohort.
Results:
During a mean follow-up period of 34.4 months, breast cancer specific events (recurrence and death) occurred 17 participants, 7 in CTZ group and 10 in CT group. The 1-year, 2-year, and 3-year DFS rates were 97.7%, 88.4%, and 88.4% in CTZ versus 100%, 84.8%, and 81.1% in CT, respectively. In the ER positive cohort studied for Ki67 consist of 109 patients, 40 were in Ki67 low group and 69 were in Ki67 high group. Among Ki67 low group, number of pCR was none out of 18 in CTZ and 1 out of 22 in CT (p = .550). Among Ki high group, that was 6 out of 38 in CTZ and 3 out of 31 (p = .352).
Conclusion:
We could not find a modest improvement in disease-free survival compared the addition of ZOL to neoadjuvant CT with CT alone. Ki67 study for central analysis has been under investigation.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-7.
Abstract PD5-7: Phase Ib study of LCL161, an oral antagonist of inhibitor of apoptosis proteins, in combination with weekly paclitaxel in patients with advanced solid tumors: Safety and efficacy results, including breast cancer cohort
Authors: Dienstmann R , Adamo B , Vidal L , Dees EC , Chia S , Mayer EL , Baney TS , Dhuria S , Sen SK , Papoutsakis D , Cameron S , Infante JR 
Published: August 2014

Abstract
Background: LCL161 is a small molecule that triggers tumor cell apoptosis by selectively antagonizing inhibitor of apoptosis proteins (IAPs). Preclinical studies demonstrated antitumor efficacy of LCL161 alone or in combination with chemotherapeutic agents, acting synergistically with paclitaxel in breast cancer models. A Phase I study confirmed potent pharmacodynamic (PD) effects at well-tolerated doses of 1800 mg once weekly. The purpose of this Phase Ib study was to determine the maximum tolerated dose (MTD)/recommended phase II dose (RP2D), safety, pharmacokinetics (PK), PD, and preliminary antitumor activity of LCL161 in combination with weekly paclitaxel.
Methods: Patients with advanced/metastatic solid tumors were treated with paclitaxel 80 mg/m2 each week, immediately followed by escalating doses of LCL161 administered once weekly. PK and biomarker sampling was performed. Patients with breast or ovarian cancer were treated at the MTD/R2PD in the dose-expansion phase of the study.
Results: As of 4 June 2013, 61 patients have received LCL161 doses of 600 mg (n = 3), 1200 mg (n = 5), 1500 mg (n = 5), and 1800 mg (n = 48), including 26 patients with breast cancer and 19 patients with ovarian cancer. Median duration of exposure was 10 weeks. The most common LCL161-related adverse events (AEs) were diarrhea (53%), anemia (36%), and neutropenia (34%). Eleven patients experienced AEs indicated by the principal investigator as a toxicity requiring dose reduction or a change to a 3 week on/1 week off schedule (ten at 1800 mg and one at 1200 mg), seven of which were neutropenia or febrile neutropenia. The MTD was not reached, and 1800 mg was selected as the RP2D. In the safety expansion group of patients with breast cancer treated at 1800 mg, 17 (out of 20) patients were evaluable for response by investigator assessment using RECIST criteria; of these, 47% achieved a partial response, 35% had stable disease, and 18% developed progressive disease. Interestingly, responses were seen in patients with documented progression to prior taxane-based regimens. Of note, in the ovarian cancer cohort, one patient achieved a complete response. In the study overall, 26% achieved a partial response, and 30% experienced stable disease. No PK interaction between LCL161 and paclitaxel was observed.
Discussion: Combination therapy with LCL161 and paclitaxel is well tolerated, with manageable toxicities and encouraging clinical efficacy in breast cancer. Enrollment of additional patients with breast cancer resistant to paclitaxel is ongoing.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-7.
Abstract PD6-6: A pooled analysis of the prognostic relevance of circulating tumor cells in early breast cancer
Authors: Janni WJ , Rack BK , Terstappen LMWW , Pierga J-Y , Fehm T , Hall C , Groot M , Bidard F-C , Meier-Stiegen F , Friedl TWP , Fasching P , Lucci A 
Published: August 2014

Abstract
Background: While there is unequivocal evidence regarding the prognostic relevance of circulating tumor cells (CTCs) in peripheral blood of patients (pts.) with metastatic breast cancer (BC), less data is available for the prognostic relevance at time of primary diagnosis.
Methods: We conducted a pooled analysis with individual data of 3172 pts with non-metastatic (Stage I-III) BC from five academic institutions. Prevalence and number of CTCs in the peripheral blood were assessed at time of primary diagnosis using the FDA-approved CellSearch System (Veridex, USA). Patient outcomes were analyzed using univariate log-rank tests and multivariate Cox regressions. The median follow-up time was 61 months.
Results: At least one CTC was detected in 20.2% of the pts. The presence of CTCs was associated with larger tumors, more axillary lymph node metastases, and higher histological tumor grade (all p &lt; 0.005). The presence of CTCs was significantly related to poor progression-free (PFS, log-rank test, p &lt; 0.001, hazard ratio [HR] 2.0) and overall survival (OS, p &lt; 0.001, HR 2.6). Multivariate Cox regressions, including tumor size, nodal status, histological tumor grade, hormone receptor status and HER2 status, and CTC prevalence confirmed that the presence of CTCs was an independent prognostic factor for both poor PFS (HR 1.8) and OS (HR 2.1, both p &lt; 0.001). In the univariate subgroup analysis concerning OS, the HR for pts. with positive HRS was 3.1 (p&lt; 0.0001), and 2.0 (p = 0.001) for pts. with a negative HRS. The prognostic relevance of CTC status was similar for patients with HER2 negative and HER2 positive tumors (HR 2.6 and 2.5, respectively). The HR in CTC-positive pts. with HRS positive/HER2 positive tumors was 3.4 (p = 0.003). For patients with more than 3 CTCs, the hazard ratio for death was increased to 5.2 (1.5 - 2.8) in univariate and to 4.0 (2.6 - 6.2) in multivariate analysis.
Cox Regression Analysis for Overall SurvivalVariableHazard ratio95% CIP-valueCTCs pos vs. neg2.1081.594 - 2.788&lt;0.001Tumor grade 0.001G2 vs. G11.0730.489 - 2.3540.861G3 vs. G12.2391.028 - 4.8740.042Histological type 0.389lobular vs. ductal1.3200.865 - 2.0150.198other vs. ductal0.8980.498 - 1.6200.722Tumor stage &lt;0.001T2 vs. T11.8531.301 - 2.6380.001T3 vs. T13.7062.310 - 5.947&lt;0.001T4 vs. T13.5382.014 - 6.218&lt;0.001Nodal stage &lt;0.001N1 vs. N01.5471.081 - 2.2130.017N2 vs. N02.5381.660 - 3.879&lt;0.001N3 vs. N03.8242.471 - 5.918&lt;0.001Hormone receptor status pos vs. neg0.4020.294 - 0.550&lt;0.001Her2 status pos vs. neg0.5790.407 - 0.8230.002Menopausal status post vs. pre1.3701.023 - 1.8340.035
Conclusions: In patients with early breast cancer, the presence of CTCs in peripheral blood is an independent predictor of poor progression-free and overall survival.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-6.
Abstract PL02: Adjuvant bisphosphonate therapy in breast cancer
Authors: Gnant M 
Published: August 2014

Abstract
Breast cancer patients face challenges to skeletal integrity, both by caused by the disease but also as a side effect of standard endocrine therapy. Bisphosphonates inhibit osteoclast-mediated bone resorption, are approved as standard therapy for treating malignant bone disease from advanced cancers, and have shown efficacy for preventing cancer treatment-induced bone loss.
Bisphosphonates also have demonstrated anti-cancer activity preclinically and in clinical trials during adjuvant breast cancer therapy. The metastasis-preventing effect of bisphosphonates has been explained by their putative effects on the bone marrow microenvironment, which provides a site for cancer cells to evade immune surveillance and adjuvant systemic anti-cancer therapy. Dormant tumor micrometastases are believed to be the ultimate source of disease persistence and relapse, and it has been suggested that adjuvant bisphosphonate treatment renders the bone marrow microenvironment less conducive to cancer (stem) cell survival. This plenary lecture will provide a brief overview of the numerous preclinical and early clinical studies of bisphosphonates demonstrating a variety of direct and indirect anticancer activities, including the „seed-and-soil” hypothesis, and the proven effects of bisphosphonates on disseminated tumor cells.
However, key questions remain surrounding the role of adjuvant bisphosphonates in breast cancer, including selecting patient populations actually deriving benefit and optimal timing/scheduling of therapy. Despite thousands of patients have been included in randomized clinical trials of adjuvant bisphosphonates, significant controversy persists about the usefulness of this therapeutic approach: current clinical data show clear-cut improvements in disease outcomes with bisphosphonates in many studies, although not in all patient subsets: Strongest support for the potential adjuvant anticancer benefits from bisphosphonates has been demonstrated in women with established menopause (i.e., very low circulating estrogen levels). Also, initiating bisphosphonates early and concomitantly with adjuvant therapy generally provided the greatest benefits.
In addition to earlier trials using oral bisphosphonates such as clodronate, recent clinical data from large phase 3 trials (e.g. ABCSG-12, ZO-FAST, and AZURE) demonstrate significantly improved disease-free survival with zoledronic acid in some patient populations with early breast cancer. Other bone-targeted treatment approaches such as denosumab are currently evaluated for adjuvant therapy in large clinical trials.
This plenary lecture will review the available data and concepts with the ultimate aim of aiding physicians in providing bone-targeted therapy as part of their optimal breast cancer patient counseling and management.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PL02.