bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-11-05: Safety of fertility preservation indicated by a diagnosis of breast cancer: A Swedish registry-matched cohort study
Authors: Rodriguez-Wallberg KA , Eloranta S , Krawiec K , Lissmats A , Liljegren A 
Published: May 2016

Abstract
Purpose
The number of women that perform fertility preservation (FP) before initiating chemotherapy for treatment of breast cancer is increasing. Our purpose was to investigate the safety of performance of fertility preservation with and without hormonal stimulation in the incidence rate of breast cancer relapse.
Patients and methods
The study was designed as a matched cohort study. Women who had undergone FP at the Reproductive Medicine clinic of Karolinska University Hospital (N=187), irrespective of whether hormonal stimulation was required or not, were considered exposed. For all exposed women, two age-matched women who had not undergone fertility preservation were identified in the Regional Breast Cancer Registry Stockholm-Gotland and the Swedish National Quality Registry for Breast Cancer (N=319). The proportional hazards assumption was evaluated by applying the Grambsch-Therneau test on the Schoenfeld residuals obtained from each model, respectively. When interpreting the test results, a significance level of 5% was used to determine statistical significance.
Results
In the exposed cohort, a higher proportion of women underwent FP with hormonal stimulation aiming at freezing eggs or embryos (81%, N=142), whereas only 19% underwent freezing of ovarian tissue or attempted egg retrieval without hormonal stimulation (N=35). The mean follow up time was 6.3 years (range: 1.5-17.8 years), and median follow-up: 5.7 years.
There was no evidence of non-proportional hazards with respect to the effects of fertility preservation on the risk of relapse in the whole FP cohort, irrespective if the women underwent hormonal stimulation or not for FP, or of receptor status or tumour size at diagnosis. A stratified Cox regression model that allowed separate baseline hazard functions for each level for the investigation of the effect of number of involved lymph nodes was performed. In this model, the effect of fertility preservation on the risk of relapse was virtually unchanged (IRR: 1.02, 95% CI:0.56-1.84).
Conclusion
Fertility preservation either using hormone stimulation or not is unlikely to cause substantially increase recurrence risk of breast cancer, and irrespective of the receptor status, tumorur size of lymph node compromise. The incidence of breast cancer relapse after hormonal or non-hormonal fertility preservation was not different from that of matched controls from the Regional Breast Cancer Registry in this large cohort study.
Citation Format: Rodriguez-Wallberg KA, Eloranta S, Krawiec K, Lissmats A, Liljegren A. Safety of fertility preservation indicated by a diagnosis of breast cancer: A Swedish registry-matched cohort study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-05.
Abstract P4-13-20: Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution
Authors: Argolo D , Friedman M , Smyth L , Iyengar N , Singh J , Patil S , Norton L , Baselga J , Hudis C , Dang C 
Published: May 2016

Abstract
Background: Dual anti-HER2 blockade with trastuzumab and pertuzumab (HP) plus chemotherapy is an effective therapy (Rx) in the 1st-line setting for HER2-positive metastatic breast cancer (MBC). Our single arm phase II study included patients (pts) treated with HP plus paclitaxel in the 2nd-line setting with progression-free survival (PFS) benefit. Recently, we reported results from a retrospective study of pts treated at our institution, suggesting a longer PFS for those who received HP-based Rxs when compared to any other anti-HER2 based Rxs in the 2nd-line setting. To further assess the activity of this combination in later Rx lines, we conducted a retrospective analysis of pts with HER2-positive MBC who had progressive disease after 2nd-line and were treated with HP-based Rxs in the 3rd and later lines at MSKCC. Historically, the median (med) PFS in this setting with trastuzumab-based Rx is about 3-4 months.
Methods: Pts diagnosed with HER2-positive MBC and treated with HP-based Rxs at MSKCC between 1-1-2011 and 03-30-2015 and who progressed on 2nd-line Rx were identified through an institutional database. Primary endpoint was PFS in 3rd and later treatment lines.
Results: 70 pts who received any HP-based Rx in the 3rd or later lines of treatment were eligible. The med number of prior anti-HER2 Rx was 3. The baseline characteristics and Rxs are summarized in Table 1. The med PFS for the entire cohort was 5.7 months (95% CI, 4.8-6.5).
Conclusions: In this retrospective analysis involving heavly pretreated patients, HP-based Rx appears to be an active regimen and compares favorably to historical data. This supports the NCCN endorsement of HP-based Rx in later lines if HP has not been delivered previously.
Baseline Characteristics and treatments (n=70)Characteristic(n)(%)Age Median56 Range27-83 Gender Female70100.0Male00.0Race Black1014.3White5477.1Other68.6Ethnicity Non Hispanic6694.3Hispanic45.7ER/PR status ER and PR negative2738.6ER and/or PR positive4361.4Type of disease Non visceral1622.9Visceral5477.1Visceral CNS2130.0Anti-HER2 in early stage Yes2941.4No4158.6Line of therapy 3rd line1927.14th line1521.45th line912.96th line912.97th line811.48th line and beyond1014.3HP-based regimens Chemotherapy + HP5477.1Endocrine therapy + HP57.1HP alone912.9Other22.9
Citation Format: Argolo D, Friedman M, Smyth L, Iyengar N, Singh J, Patil S, Norton L, Baselga J, Hudis C, Dang C. Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-20.
Abstract P4-14-09: Cardiac safety of trastuzumab without an anthracycline in patients with HER2-positive early stage breast cancer: A single center experience
Authors: Mukku RB , Verma S , Liu J , Steingart R , Hudis C , Yu AF , Dang C 
Published: May 2016

Abstract
Background: Trastuzumab (H) improves disease-free survival and overall survival in HER2+ early breast cancer (EBC) but is associated with risk of treatment-induced cardiotoxicity especially when administered after an anthracycline. We performed a single center retrospective study to assess the cardiac safety of adjuvant trastuzumab therapy without anthracyclines in a real-world clinical setting.
Methods: Patients (pts) with HER2+ early breast cancer (EBC) who received H without anthracycline-based chemotherapy between January 2010 and June 2014 were studied. Patients enrolled in a clinical trial were excluded. Tumor characteristics, chemotherapy regimen, cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. A cardiac event (C.E.) was defined as New York Heart Association class III or IV heart failure with LVEF decline of &gt; 10% to &lt; 55% or possible/probable cardiac death, as previously defined by the NSABP B-31 trial.
Results: In total, 174 pts with HER2+ EBC treated with H-based therapy without anthracyclines were identified. Median age was 59 years (range, 32 to 85 years), 72 (41%) had hypertension, 55 (32%) had hyperlipidemia, 29 (16%) had diabetes, and 5 (3%) had coronary artery disease. At baseline, all pts had a LVEF &gt; 50% (median, 66%; range, 50% to 81%). Two (1.1%) pts developed a C.E. Both pts had risks factors for C.E. (1 - age &gt; 60 years, hypertension, and prior history of anthracycline exposure; 1- age &gt; 60 years, hypertension, hyperlipidemia, and baseline LVEF of 50-55%). After discontinuation of H, both patients had recovery of LVEF to &gt; 50% and resolution of heart failure symptoms. Twelve (6.9%) pts developed asymptomatic LVEF decline of &gt; 10% points to &lt; 55% during H therapy. Of the 14 patients who developed cardiotoxicity, H was prematurely interrupted or discontinued in 8 patients.
Conclusion: In our single center experience of patients being treated off study, the incidence of C.E.s and asymptomatic LVEF decline during H therapy without an anthracycline was 1.1% and 6.9%, respectively. These appeared higher than events reported in clinical trials possibly due to the inclusion of an older group of women with a higher prevalence of cardiovascular risk factors. Overall, the incidence of symptomatic heart failure is low for H without an anthracycline even in this older group.
Citation Format: Mukku RB, Verma S, Liu J, Steingart R, Hudis C, Yu AF, Dang C. Cardiac safety of trastuzumab without an anthracycline in patients with HER2-positive early stage breast cancer: A single center experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-09.
Abstract P4-14-13: Pertuzumab (P) use in first-line HER2-positive metastatic breast cancer (mBC) in US community oncology practices: Treatment patterns and outcomes
Authors: Robert N , Goertz H-P , Asmar L , Tseng W-Y , Jiao X , Portera C , Yoo B , Patt D , Antao V 
Published: May 2016

Abstract
Background: Pertuzumab was FDA-approved in 6/2012 for use in first-line in combination with trastuzumab (H) and docetaxel for patients (pts) with HER2-positive mBC. This retrospective study investigated the clinical characteristics, treatment patterns, safety, and outcomes for pts with HER2-positive mBC who received a P-containing regimen in first-line in US community oncology practices.
Methods: This study utilized iKnowMed electronic health records, Claims Data Warehouse, and Social Security Death Index. Pts with HER2-positive mBC, who received a P-containing regimen between 6/2012 and 6/2014 and were followed through 12/2014, had ≥2 visits within the McKesson Specialty Health/US Oncology Network, and were not on clinical trials during the study period, were eligible.
Results: Of the 322 pts who received a P-containing regimen in the first-line setting, 25% were ≥65 years of age, 63% were post-menopausal, 61% had hormone receptor-positive mBC, 84% had a performance status of 0 or 1, and 76% had a Charlson Comorbidities Index of 0. Twenty-one percent of pts had 1 site of metastasis noted, 32% had 2 sites, and 47% had 3 or more sites. Pts with de novo mBC made up 40% of this cohort. Of the pts with recurrent mBC, over 60% received H in the early-stage BC setting. In the first-line mBC setting, 93% of the 322 pts received H+P+taxane, and 7% received H+P with other chemotherapy agent(s). Common adverse events reported included: fatigue (49%), diarrhea (44%), nausea (33%), peripheral neuropathy (33%), neutropenia (24%), and rash (22%). Further analyses including outcomes of these 322 pts will be presented.
Conclusions: First-line P was given in combination with H and chemotherapy agent(s) (93% taxane). No new safety signals were observed. More details on the clinical characteristics, specific treatment patterns, and safety will be presented, along with the progression-free survival of these pts receiving first-line P-containing therapy in a real-world setting.
Citation Format: Robert N, Goertz H-P, Asmar L, Tseng W-Y, Jiao X, Portera C, Yoo B, Patt D, Antao V. Pertuzumab (P) use in first-line HER2-positive metastatic breast cancer (mBC) in US community oncology practices: Treatment patterns and outcomes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-13.
Abstract P4-14-26: Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including HER2-positive breast cancer patients with brain metastases
Authors: Baird RD , Arkenau H-T , Deva S , Cresti N , Garcia-Corbacho J , Hogarth L , Frenkel E , Kawaguchi K , Arimura A , Donaldson K , Posner J , Sarker D , Jodrell D , Plummer R , Spicer J , Italiano A 
Published: May 2016

Abstract
BACKGROUND
S-222611 is an oral, reversible ErbB tyrosine kinase inhibitor of EGFR and HER2 with potent pre-clinical activity. MTD was not reached during the dose-escalation phase, (maximum dose 1600 mg QD). PK and efficacy data supported a daily dose of 800 mg. An expansion cohort of patients has been treated to further explore safety and efficacy.
METHODS
Subjects with advanced solid tumors expressing EGFR and/or overexpressing HER2 were enrolled. S-222611 800 mg daily was administered until disease progression or unacceptable toxicity.
RESULTS
76 patients were included in this phase 1 expansion cohort with a variety of tumor types. Dose reduction was required because of adverse events in 15 patients; the most frequent of which being diarrhea and elevated bilirubin. Two patients discontinued treatment due to drug- related adverse events. Of the 25 patients with HER2-positive metastatic breast cancer (MBC), 4 partial responses were observed, and prolonged stable disease (≥ 6 months) was observed in 3 additional patients. These 25 patients had received prior HER2-directed therapy as shown in Table 1.
Table 1. Prior therapies received by patients with HER2-positive MBCPrior therapyn (%)Trastuzumab22 (88)T-DM13 (12)Lapatinib16 (64)Chemotherapy23 (92)
Six of these patients had brain metastases, in whom 1 intracranial response and 2 prolonged stable disease (≥ 6 months) were observed (Table 2).
Table 2. HER2-positive MBC patients with brain metastases - best overall response to S-222611Pts #HER2 IHCBrain metastasesBest overall response (RECIST 1.1)Patient 13+Target lesionPRPatient 23+Target lesionSD (≥12 M)Patient 33+Target lesionSD (6.0 M)Patient 43+Non-target lesionSD (4.7 M)Patient 53+Non-target lesionSD (3.3 M)Patient 63+Non-target lesionNE
The patient showing intracranial response was previously treated with lapatinib and capecitabine after diagnosis of BM.
CONCLUSIONS
S-222611 was well tolerated at a dose of 800 mg once daily. Anti-tumour activity, including shrinkage of brain metastases, was evident in a heavily pre-treated population of patients with HER2-positive breast cancer.
Citation Format: Baird RD, Arkenau H-T, Deva S, Cresti N, Garcia-Corbacho J, Hogarth L, Frenkel E, Kawaguchi K, Arimura A, Donaldson K, Posner J, Sarker D, Jodrell D, Plummer R, Spicer J, Italiano A. Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including HER2-positive breast cancer patients with brain metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-26.
Abstract P5-03-01: Therapeutic targeting of Rac GTPases in ER+ and HER2+ breast cancer
Authors: Hampsch RA , Shee K , Miller TW 
Published: May 2016

Abstract
As crucial regulators of cell motility, survival, and proliferation, Rac GTPases (Rac1/2/3) have been implicated in cancer. We previously found that P-REX1, a guanine nucleotide exchange factor that activates Rac GTPases, forms a PI3K-driven positive feedback loop to promote activation of Rac enzymes, receptor tyrosine kinases, PI3K/AKT/mTOR, and MEK/ERK in ER+ breast cancer cells. Importantly, inhibition of Rac GTPases with a small molecule (EHT1864) simultaneously suppressed activation of both the PI3K/AKT/mTOR and MEK/ERK pathways. While co-targeting of the PI3K/AKT/mTOR and MEK/ERK pathways with drug combinations has anti-tumor activity in preclinical models and is being tested in ongoing clinical trials, targeting Rac as a common upstream signaling node may be a more efficient means of simultaneously targeting these two oncogenic pathways.
In breast cancer cell lines, treatment with EHT1864 decreased activation of AKT, mTOR, p70S6K, and S6 in a dose-dependent manner. Pulldown of activated Rac from cell lysates revealed that GTP-bound Rac1 and/or Rac3 bind MEK1/2, ERK1/2, p70S6K, S6, Raptor, Rictor, and mTOR. Temporal analysis indicated that EHT1864 inhibits phosphorylation of p70S6K (an mTORC1 substrate) before AKT is inhibited, suggesting that Rac may directly activate p70S6K and/or mTORC1. Mining of sensitivity data from ∼700 cell lines to a panel of 138 drugs (COSMIC/GDSC database) revealed that the growth-suppressive effects of EHT1864 correlate most strongly with growth-suppressive patterns induced by a p70S6K inhibitor, supporting the notion that Rac directly activates p70S6K. Additionally, EHT1864 treatment dose-dependently decreased phosphorylation of ERK1/2 and MEK1/2, and induced apoptosis in breast cancer cell lines. In a panel of 16 breast cancer lines, cells with activating mutations in PIK3CA (encodes the p110-alpha subunit of PI3K) exhibit increased EHT1864 sensitivity. Pharmacokinetic analysis of EHT1864 (100 mg/kg, i.p.) in plasma in NSG mice revealed that drug was present at &gt;50 uM for 1 h after administration. In mice bearing s.c. ER+/HER2+ BT-474 breast cancer xenografts, EHT1864 (100 mg/kg BID) significantly slowed tumor growth compared to vehicle control. Thus, therapeutically targeting Rac could be an effective means of reducing cancer cell proliferation and survival by simultaneously suppressing both the PI3K/AKT/mTOR and MEK/ERK signaling pathways in ER+ and HER2+ breast cancers.
Citation Format: Hampsch RA, Shee K, Miller TW. Therapeutic targeting of Rac GTPases in ER+ and HER2+ breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-03-01.
Abstract P5-03-13: The anticancer effects of Supinoxin® (RX-5902) in triple-negative breast cancer MDA-MB-231 through phosphorylated p68 on Tyr593
Authors: Kim DJ , Yang MY , Lee YB , Remenyi J , Fuller-Pace F 
Published: May 2016

Abstract
Several studies have indicated that the DEAD box RNA helicase DDX5/p68 plays several important roles in cancer (1, 2). In particular, p68 that is phosphorylated on Tyr593 has been shown to be associated with cell transformaton, epithelial mesenchymal transition (EMT) and cell migration (3). Therefore, phosphorylated p68 may be a promising target for novel anti-cancer therapeutics. We previously reported that 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] piperazine (RX-5902, Supinoxin®) inhibits the growth of cancer cells at low nanomolar concentrations by interacting with phosphorylated p68 on Tyr593, interfering with the phosphorylated p68-β-catenin signaling pathway (4). In this study, we sought to determine whether phosphorylated p68 on Tyr593 plays a key role in RX-5902's ability to inhibit cancer cell growth by knocking down p68. p68-siRNA efficiently down-regulated the expression of phosphorylated p68 on Tyr593 as well as p68 in the triple-negative (TN) breast cancer cell line, MDA-MB-231. Exposure of p68-siRNA-transfected cells to the IC50 concentration of RX-5902 protected MDA-MB-231 cells from the cytotoxic effects of RX-5902, indicating the phosphorylated p68 on Tyr593 is a key molecule for RX-5902 cytotoxic effects. We also examined the tumor growth inhibition (TGI) of RX-5902 in the human TN-breast tumor (MDA-MB-231) xenograft mouse model. Not only did RX-5902 demonstrate potent efficacy in this model but also oral administration with RX-5902 resulted in dose-dependent TGI and extended the overall survival of these animals. Oral administration of 160, 320 and 600 mg/kg of RX-5902 showed 54.4%, 84.4% and 100% TGI, respectively whereas 5 mg/kg of Abraxane (iv) showed only 48.2% TGI at day 29. Further studies demonstrated the inhibitory effects of RX-5902 on cellular motility in MDA-MB-231 in wound healing assays, suggesting the potential function of phosphorylated p68 on Tyr593 in cell migration (5). These data support the potential therapeutic activity of RX-5902 in triple negative breast cancers. A Phase 1 study of RX-5902 on relapse/refractory solid tumors is ongoing.
References
1. Fuller-Pace, FV, RNA Biology 10, 121–132 (2013)
2. Dai et al. Journal of Experimental & Clinical Cancer Research, 33, 64-71 (2014
3. Yang et al., Cell, 127, 139–155 (2006)
4. Kost et al., Journal of Cellular Biochemistry ;online: 3 FEB 2015 05:14PM EST | DOI: 10.1002/jcb.25113) (2015).
5. Remenyi et al, presented at 2015 AACR (2015).
Citation Format: Kim DJ, Yang MY, Lee YB, Remenyi J, Fuller-Pace F. The anticancer effects of Supinoxin® (RX-5902) in triple-negative breast cancer MDA-MB-231 through phosphorylated p68 on Tyr593. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-03-13.