bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-18-03: Clinicopathological features among patients with HER2-positive breast cancer with prolonged response to trastuzumab based therapy
Authors: Vaz-Luis I , Seah D , Olson E , Metzger O , Wagle N , Sohl J , Litsas G , Burstein H , Krop I , Winer E , Lin NU 
Published: August 2014

Abstract
Background: HER2-positivity is a predictor of benefit from trastuzumab (TRZ), but fails to depict the observed interpatient variability in terms of treatment (tx) duration. In this study we described the relationship between clinicopathological features and TRZ tx duration.
Methods: A retrospective consecutive series of 343 HER2+ breast cancer (BC) patients (pts) treated with TRZ at the Dana-Farber Cancer Institute from 1999–2008 was identified. 139 pts treated with 1st line TRZ-based tx were selected for analysis. Pts who received any non-TRZ prior tx for metastatic disease were excluded. TRZ tx duration was defined as time from start of 1st line therapy to the 1st day of 2nd line therapy or death. Central nervous system (CNS) progression with TRZ maintenance was not considered change of tx. Pts were divided equally into 3 groups based on the duration of 1st line tx distribution. Short-term responders (STR) were on the 1st line tx for &lt;7 months (m), intermediate responders (IR) 7–15m and long responders (LTR) for &gt;15m. An additional group of extremely LTR (ELTR) was defined as being in the 90th percentile of tx duration (&gt;37m). Descriptive analysis was performed; fisher exact test, Kruskal-Wallis and logistic regression methods were used to compare groups.
Results: Median follow-up time since metastatic diagnosis was 4 years (y) (range 0–11). Median age at diagnosis was 47y (22–83), 25% of stage I-III pts at diagnosis received adjuvant/neoadjuvant TRZ. The median disease free interval (DFI) was 20m (0–172), median number of metastatic sites was 2(1–5), 68% of pts had visceral disease. Median duration of 1st line tx was 10m (2–105). TRZ was given with CT in 86%, hormone tx in 6% and as monotherapy in 9%. 25% of pts developed CNS progression and continued tx. There were only small absolute differences for clinicopathological characteristics among STR, IR and LTR.

ELTR had a median 1st line TRZ tx duration of 49m (37–105) and similar clinicopathological features to LTR. A higher proportion of LTR had hormone receptor (HR)-positive disease compared with STR, however no significant association between LTR and STR was found for HR status, DFI and visceral involvement.
Conclusions: TRZ tx duration varies widely in the 1st-line advanced setting. No clinicopathological features were associated with TRZ tx duration. Our results suggest that despite CNS progression some pts continue to have long term benefit to TRZ tx. A major research priority is to identify molecular predictors of benefit and resistance to anti-HER2-based therapies.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-03.
Abstract P5-18-06: Trastuzumab emtansine in HER2-positive metastatic breast cancer: pooled safety analysis from seven studies
Authors: Diéras V , Harbeck N , Budd GT , Greenson JK , Guardino E , Samant M , Chernyukhin N , Smitt M , Krop IE 
Published: August 2014

Abstract
Background: The antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1) combines the antitumor activities of trastuzumab with intracellular delivery of the cytotoxic agent DM1 and represents a new approach to therapy for HER2-positive MBC. Recently, the first phase 3 data have been reported with significant improvements in PFS (9.6 vs 6.4 months; HR=0.650; P&lt;0.0001) and lower incidence of grade ≥3 adverse events (AEs) (57% vs 41%) vs capecitabine + lapatinib (Blackwell 2012). This pooled analysis reports the overall safety profile of T-DM1 3.6 mg/kg q3w in 882 patients treated with T-DM1.
Methods: Data were included from treated patients in 7 studies of single-agent T-DM1 3.6 mg/kg q3w: 1 phase 1 study in previously treated MBC (TDM3569g, Krop 2010, n=15 treated at 3.6 mg/kg q3w); 3 phase 2 single-arm studies in previously treated MBC (TDM4258g, Burris 2011, N=112; TDM4374g, Krop 2012, N=110; TDM4688g, Gupta 2011, n=51); 1 randomized phase 2 study in previously untreated MBC (Hurvitz 2011, TDM4450g/BO21976, n=69); 1 extension study (TDM4529/BO25430, n=43 from parent studies); and 1 phase 3 study in MBC previously treated with trastuzumab and a taxane (EMILIA, Blackwell 2012, n=490). Data were analyzed in 4 groups: (1) all T-DM1-treated pts (7 studies, N=882), (2) pts originally enrolled in single-arm studies (n = 288), (3) T-DM1 pts from TDM4450g (n = 69), and (4) T-DM1 pts from EMILIA (n = 490).
Results: Among all pts (N = 882), median age was 53 years (range 25–85 years); 52.7% had ≥3 metastatic sites; 81.7% had received prior treatment for MBC; and the median number of prior non-endocrine agents for MBC was 3.0 (range 0–19). All-grade AEs occurring in ≥25% of patients were fatigue (45.4%), nausea (42.3%), headache (28.7%), thrombocytopenia (28.7%), and constipation (25.5%). Grade ≥3 AEs occurring in ≥2% were thrombocytopenia, increased AST, increased ALT, fatigue, hypokalemia, and anemia. Table 1 describes the grade ≥3 incidence of these AEs, as well as selected AEs with known association to T-DM1 or potential risk based on the components of T-DM1 or on preclinical data.

Conclusions: The safety profile of T-DM1 3.6 mg/kg q3w was consistent across the studies and the different patient populations with HER2-positive MBC. Additional analyses on hepatic transaminase increases and those exploring potential associations between thrombocytopenia and hemorrhage will be presented.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-06.
Abstract P5-18-08: Identification of ErbB2 function in the heart: implication for anti-ErbB2 therapy in breast cancer
Authors: Perry M-C , Eichner LJ , Dufour CR , Muller WJ , Giguère V 
Published: August 2014

Abstract
The ErbB2 receptor tyrosine kinase is essential for cardiac development during embryogenesis. The importance of its signaling in the adult heart was revealed by an unexpected cardiotoxic side effect of trastuzumab, a monoclonal antibody against ErbB2 used in the treatment of breast cancer. Considering that trastuzumab-associated cardiotoxicity is usually largely reversible, we hypothesized that ErbB2 signaling in the heart is important to maintain cardiac homeostasis.
As genetic experiments showed that ErbB2-deficient embryos die at mid-gestation, whereas conditional inactivation of ErbB2 in the heart leads to early and severe cardiac dysfunction, the role of ErbB2 in the mature heart can not be analyzed in those animal models. Thus, we chose an ErbB2 hypomorph (HP) mouse model in which ErbB2 is expressed at only 10% of its endogenous level to study the role of ErbB2 in the adult heart. Histopathological analyses of the heart in this model revealed that at birth, the ErbB2 HP mice have similar heart mass and cardiomyocite size as the control animals. However, we found that the rapid growth of the heart during early postnatal development is impaired in ErbB2 HP mice, indicating that the heart is unable to increase cell size in order to adapt to the pressure overload that mice face following birth. This incapacity of the ErbB2 HP heart to maintain homeostasis eventually leads to the development of cardiac dysfunction in this model, as characterized by a decrease of the left ventricular function. Microarray and ChIP-seq analyses were applied to identify the ErbB2-responsive pathways which may explain the phenotype observed. Taken together, our results demonstrate that ErbB2 signaling is required for the physiological adaptive response of the mature heart to pressure burden. The results generated by this study reveal the biological function of Erbb2 in the adult heart, but also provide important information for devising strategies to prevent and mitigate the cardiotoxic effects of Trastuzumab treatment, allowing for the potential use of this drug to treat all cancer patients overexpressing ErbB2.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-08.
Abstract P5-18-13: Inhibiting telomerase to reverse trastuzumab (T) resistance in HER2+ breast cancer
Authors: Miller KD , Steding CE , Prasad N , Rojas LA , Herbert B-S 
Published: August 2014

Abstract
Background: Preclinical studies have shown the combination of imetelstat (GRN163L), an inhibitor of telomerase, and T results in synergistic growth inhibition and restoration of T sensitivity in T-resistant cells (Clin Can Res 12(10):3184–92, 2006). Here we translate those findings to the clinic with the first-in-man phase I trial of imetelstat+ T in patients (pts) with T-refractory HER2+ metastatic disease.
Methods: T (6 mg/kg q3 wk) was administered with increasing doses of imetelstat (240/300/375 mg/m2 q3 wk) using a standard 3+3 dose escalation design. Maximum Tolerated Dose (MTD) was based on toxicity observed during cycle 1. Responding or stable pts continued treatment until progression. Tumor biopsy and bone marrow aspirate for biologic correlates were obtained at baseline and prior to cycle 2. Limited pharmacokinetics (PK) for T and imetelstat were included.
Results: Ten pts were enrolled; median age was 54 (28–64). Patients were extensively pre-treated with the number of prior regimens ranging from 3 to &gt;12. Prior cytotoxic therapies included anthracyclines (n = 9), taxanes (n = 9), vinorelbine (n = 8), capecitabine (n = 8), gemcitabine (n = 6), ixabepilone (n = 4), and eribulin (n = 4). Prior anti-HER2 targeted therapies included trastuzumab (n = 10), capecitabine (n = 8), T-DM1 (n = 6), and pertuzumab (n = 1). Therapy was well tolerated; no treatment related grade 4 toxicities were observed. Myelosuppression was limited to one pt with Grade 2 anemia and one each with Grade 2/3 thrombocytopenia. MTD was not reached. There were no objective responses; 2 pts. in cohort 3 had SD. Serial tumor biopsies and bone marrow aspirates have been analyzed for 7 pts (cohort 1: 001–004; cohort 2: 005–007; cohort 3: analysis ongoing). Tumor hTERT (p = ns) and phosphorylated HER2 (p = 0.03) decreased after treatment in nearly all pts. Bone marrow S-phase did not change consistently with treatment.

Conclusion: The combination of trastuzumab + imetelstat is well tolerated and results in decreases in HER2 phosphorylation similar to that seen in preclinical models. Additional biologic correlates and PK analyses are ongoing. Further study of this combination in less heavily pre-treated patients is planned.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-13.
Abstract P5-18-22: Long-term survival of patients with HER2 metastatic breast cancer treated by targeted therapies.
Authors: Fiteni F , Villanueva C , Bazan F , Chaigneau L , Cals L , Dobi E , Montcuquet P , Nerich V , Limat S , Pivot X 
Published: August 2014

Abstract
Purpose: HER2 targeted therapies have substantially improved outcomes of patients with HER2 positive metastatic breast cancer (MBC). Medical records of patients with HER2 positive MBC achieving long survival were reviewed to describe their clinical characteristics and to assess whether curability is possible.
Patients and methods: One thousand and seven hundred patients with MBC were treated between 01/01/2003 and 31/05/2012 in the 5 hospitals from the Franche-Comte region. All 217 patients with HER2 positive MBC region were retrospectively studied.
Results: Among this population of HER2 positive MBC, 56 patients (26%) survived longer than 5 years. The characteristics of these long survivors were the following: median age at diagnosis was 55 years old (range, 33–87); 20 patients (35,7%) were metastatic at presentation; 20 patients (35,7%) had received adjuvant chemotherapy; the median disease-free interval was 17 months; brain, liver, lung, bone metastases were observed in 4 (7%), 19 (34%), 13 (23%), 23 (41%) in cases at occurrence of metastatic disease, respectively; tumours were hormonal receptors positive in 39 cases (70%) of these patients.
A total of 16 (29%), 7 (12,5%), 7 (12,5%) and 26 (46%) cases had received 1, 2, 3 or more lines of chemotherapy at metastatic setting. The proportion of HER2 targeted treatment was 79%, 61%, 50% in first, second and third line, respectively. All patients received trastuzumab or lapatinib for their disease and 18 patients (32%) were given an anthracycline containing regimen.
There were 7 complete response (CR), there were all observed after one line of chemotherapy based on trastuzumab combined with a taxane in all cases. Among these 7 patients, all continued trastuzumab after CR and all RH+ patients received hormonotherapy after CR. Among these 56 patients, 35 (62,5%) were still alive at the date cutoff in 31/05/2012.
Conclusion: A significant proportion of patients with HER2 positive MBC were long survivors. Prospective clinical trials in this subset of patients should take into account this high number of patients with favorable outcome to achieve conclusion in term of survival. Can one consider the curabiblity of some MBC patients with HER2 overexpression?
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-22.
Abstract P5-20-01: A randomized double-blind phase II study of the combination of oral WX-671 plus capecitabine vs. capecitabine monotherapy in first-line HER2− negative metastatic breast cancer (MBC).
Authors: Goldstein LJ , Oliveria CT , Heinrich B , Stemmer SM , Mala C , Selder S , Bevan P , Harbeck N 
Published: August 2014

Abstract
Background: uPA and its inhibitor PAI-1 play a key role in tumor invasion, metastasis and tumor growth. High levels of uPA and PAI-1 in breast tumors are statistically significant prognostic factors of disease-free (DFS) and overall survival (OS), which were validated at the highest level of evidence, as well as predictors for benefit of adjuvant chemotherapy. WX-UK1 is an active site competitive inhibitor of uPA with an inhibition constant in the submicromolar range. WX-671 (upamostat) is an oral prodrug of WX-UK1. In preclinical animal tumor models, both WX-UK1 and WX-671 have been shown to reduce the growth rate of implanted tumors, to inhibit invasion, and reduce metastases. This current proof of concept study is designed to substantiate the anti-metastatic properties of upamostat for patients appropriate for first line therapy for MBC.
Methods: Female patients aged &gt;18, with HER2 negative MBC appropriate for first line monotherapy with capecitabine, with adequate performance status, organ function, bone marrow reserve without brain metastases were eligible. Patients were randomized in a double-blind fashion to receive upamostat (200mg orally daily for 21 days) plus capecitabine (1000 mg/m2 orally twice daily for 14 days) vs. capecitabine (1000 mg/m2 orally twice daily for 14 days) in 3 week treatment cycles until progressive disease or unacceptable toxicity. The primary endpoint is to evaluate the efficacy of the combination of upamostat plus capecitabine compared to monotherapy as assessed by comparison of progression free survival. The secondary objectives are OS, objective response rates, safety and tolerability, and to assess the pharmacokinetics (PK) of upamostat and capecitabine when combined.
Results: Between August 2008 and April 2011,132 patients were enrolled. 17 patients are still receiving treatment. 26% of the patients are characterized as triple negative, 13% as only Estrogen Receptor (ER) positive and 4% as only Progesteron Receptor (PR) positive. 57 % of the patients are ER and PR positive.
Conclusions: Progression free survival, response rates and safety will be reported. This abstract is being submitted as a placeholder. A completed abstract will be submitted when the analyses are completed.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-01.
Abstract P5-21-02: Hormone receptor status and endocrine therapy in a prospective observation study on trastuzumab (Herceptin®) in the adjuvant treatment of breast cancer
Authors: Dall P , Friedrichs K , Petersen V , Hinke A , Brucker C , Schmidt P , von der Assen A , Jungberg P , Bohnsteen B 
Published: August 2014

Abstract
Background: Based on the findings from large randomized studies, Trastuzumab (T) was registered in 2006 for the treatment of early stage, HER2+ breast cancer (BC), after surgery, (neo)adjuvant chemotherapy (CT) and/or radiotherapy. However, limited systematic evidence is available on preceding, concomitant or sequential endocrine treatment (ET) based on the hormone receptor (HR) status. This large prospective observation study, reflecting the unrestricted routine practice of HER2 antibody treatment in Germany, allows to examine this topic.
Methods: At present, more than 4000 patients (pts) have been enrolled in this ongoing study; 3446 pts from more than 316 centres were already sufficiently documented to be analysed. Details on concomitant treatment was collected at baseline and for 12 months after start of T.
Results: With respect to an overall HR positivity (HR+), i.e. estrogen and/or progesterone receptor (ER, PR) being positive, of 2181/3446 (63%), these HER2+ pts do not differ from the general BC population. Both hormone receptor types are positive in 47%, while ER+ only or PR+ only was detected in 13% and 3%, respectively. Adjuvant ET of any type, starting before or during T treatment, was given in 87% of HR+ and in 3% of HR- pts. 6% of HR+ pts received T and ET without concomitant CT. Details on the adjuvant treatment options are provided in the table:

After a median follow-up of 26.4 months and the observation of a total of 296 relapse events (9%; HR-: 12%; HR+: 7%) relapse-free survival (RFS) was significantly shorter in the HR- compared to the HR+ group (at 3 years: 86 vs 92%, hazard ratio = 0.56, p &lt; 0.0001).
Conclusion: The vast majority of HER2+ BC pts receives concomitant endocrine therapy in case of a positive HR status. Regardless of the regulatory status in Germany, a small proportion of patients with co-positive early BC received T and ET without concomitant CT. No differences between receptor subgroups could be detected with respect to type of CT and its onset relative to T. HR status remains a paramount prognostic factor in this HER2+ sub-population of BC pts, with risk of early relapse (after a median follow-up of 2 years) almost twice as high in HR- tumors.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-21-02.
Abstract P6-02-07: In vitro 3D Model of Breast Tumor Stroma
Authors: Jaganathan H , Mitra S , Dave B , Godin B 
Published: August 2014

Abstract
One in eight women is diagnosed with breast cancer in the United States every year. Despite advancements for early diagnosis and initial treatment of breast cancer, the complexity and multiplicity of biological factors and barriers in tumor microenvironment prevent potent active agents from reaching their targets in cancer cells. There has been a growing body of evidence about the importance of three-dimensional (3D) culture systems in discovery and modeling of biological processes with in vivo relevance. A few examples that have been reported in 3D monocultures include different growth patterns of normal and malignant breast cancer cells in 3D cultures of laminin-rich gels and effect on cell polarity pathways. These effects are not observed in conventional two-dimensional (2D) cultures, showing that cells organized in a 3D matrix can shed light on novel mechanisms in breast cancer biology. Moreover, neither 2D nor 3D monoculture models available today mimic the complexity of clinically observed tumor microenvironment (tumor stroma), which also contains fibroblasts, macrophages and endothelial cells and represents an important physiological barrier for efficient delivery of therapeutics to breast tumors. In this work we propose and investigate an in vitro system mimicking the tumor microenvironment in which relevant cell populations in tumor microenvironment are co-cultured with breast cancer cells*. The system uses the Nano3D® platform based on magnetic levitation. 3D tumor models for breast cancer were designed and optimized by co-culturing SUM159 and MDA-MB-231, triple negative breast cancer cells, with 293T fibroblasts. The cells were co-cultured at different ratios and for a various time periods. Further, to assess the similarity of the in vitro system to the in vivo disease, we tested an an orthotopic model of breast cancer in SCID beige mice. Histological analysis of frozen tissues from in vitro and in vivo studies confirmed that the in vitro 3D system based on the mixture of fibroblasts and cancer cells has structural similarities to the in vivo observed tumor stroma. Engineering an in vitro 3D tumor model that accurately represents the in vivo tumor will further benefit research efforts in breast cancer diagnosis and therapy.
*Patent pending – inventors: B. Godin, G. Souza, and B. Dave
Acknowledgments: The authors acknowledge a financial support from the Susan G. Komen Postdoctoral Fellowship #PDF12229449.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-02-07.
Abstract P6-04-12: Novel selective estrogen receptors degraders regress tumors in pre-clinical models of endocrine-resistant breast cancer
Authors: Hager JH , Darimont B , Joseph J , Govek S , Grillot K , Aparicio A , Bischoff E , Kahraman M , Kaufman J , Lai A , Lee K-J , Lu N , Nagasawa J , Prudente R , Qian J , Sensintaffar J , Shao G , Heyman R , Rix P , Smith ND 
Published: August 2014

Abstract
80% of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g. Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges. Importantly, the majority of these tumors continue to depend on ERα for growth and survival. The emerging evidence that ERα can signal in both a ligand-dependent and ligand-independent manner supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both modes of signaling.
We have identified novel, non-steroidal ERα antagonists that induce degradation of ERα in breast cancer cell lines at picomolar concentrations resulting in significant reduction in steady state ERα protein levels. Using peptide-based conformational profiling, we show that these Selective Estrogen Receptor Degraders (SERDs) induce estrogen receptor conformations that are distinct from both fulvestrant and tamoxifen indicating a unique mechanism of action. This unique biological profile coupled with good oral pharmacokinetics produces tumor regressions in both tamoxifen-sensitive and -resistant models of breast cancer in vivo. Recent pre-clinical and clinical data indicate that PI3K pathway signaling can contribute to the endocrine resistant state. In a preclinical model of tamoxifen resistant breast cancer in which SERD monotherapy only produces tumor growth inhibition, SERD therapy in combination with torc1/2 inhibition results in frank tumor regressions. These orally bioavailable SERDs hold promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-12.