bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lapatinib is active in patients with HER2-amplified breast tumors expressing p95HER2.
Authors: Guix M , Aura CM , Jimenez J , Scaltriti M , Gomez HL , Doval DC , Ellis C , Gagnon R , Liu Y , Koehler M , Baselga J 
Published: December 2010

Abstract
Abstract #708
Background: A subgroup of HER2 overexpressing tumors also express p95HER2, a truncated fragment of the HER2 receptor that lacks the extracellular domain and retains kinase activity. Tumors expressing p95HER2 have a worse clinical outcome and are resistant to trastuzumab therapy (Scaltriti M. et al, JNCI 2007). The hypothesis that lapatinib, a small molecule inhibitor that targets the intracellular kinase domain of EGFR and HER2, would be active in these tumors was tested by correlating p95HER2 expression with clinical response to lapatinib in EGF20009, a lapatinib monotherapy study&#x2028; Methods: Archival tumor blocks were obtained from patients (pts) participating in study EGF20009. In this study, pts with untreated locally advanced or metastatic HER2 amplified breast tumors either received lapatinib 1500mg daily or 500mg BID (H.L. Gomez et al, J Clin Oncol 2008). Pre-treatment samples were analyzed for p95HER2 expression by immunofluorescence using 2 antibodies against HER2, binding to the intracellular and extracellular domain, respectively, plus a pan-cytokeratin antibody. Tumors were scored as p95HER2 positive (p95HER2+) [if any cytoplasmic staining was detected with the intracellular HER2 antibody and this staining co-localized with the pan-cytokeratin antibody], negative (p95HER2-) [no intracellular HER2 cytoplasmic staining) or non-evaluable (N/E) [no cytokeratin or HER2 staining by immunofluorescence]. The presence of p95HER2 was then correlated with response rate (RR), stable disease for over 100 days (SD) and progression-free survival (PFS) to lapatinib. A Cox-proportional hazards model was used to compare the groups. In order to correlate the presence of p95HER2 with HER2 extracellular domain in the serum, a quantitative determination of the 105 kD ECD level in serum (Oncogene Science HER2/neu Microtiter ELISA) has also been performed.&#x2028; Results: 68/105 tumors were evaluable for p95HER2 expression. Fourteen were p95HER2+ (20.5%) and 54 were p95HER2- (79.5%). The observed percentage of p95HER2+ tumors is concordant with published reports. Among the 14 pts with p95HER2+ tumors, 7 responded (RR: 50%) and 1 had SD for &gt; 100 days for an overall clinical benefit rate of 57% (RR+SD). In the p95HER2- population (N=54), 24 pts responded (RR: 44.4%) and 16 pts had SD &gt;100 days for an overall clinical benefit rate of 56% (RR+SD). PFS was similar in both groups, with a median PFS of 24 wks in pts with p95HER2+ and p95HER2- tumors (p=0.97, HR 1.1). These findings compare with the median PFS of 20.7 wks for the entire population in the trial (N=138pts). Further correlation of p95 status and HER2 ECD status of the tumors will be presented.&#x2028; Conclusion: These data demonstrate that lapatinib has similar activity in pts with p95HER2+ or p95HER2-, HER2 amplified breast tumors.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 708.
MCF-7 cells selected for acquired resistance to an anti IGF-IR antibody remain sensitive to fulvestrant and to an IGFIR tyrosine kinase inhibitor (TKI).
Authors: Zhang X , Seidel B , LaPara KS , Yee D 
Published: December 2010

Abstract
Abstract #72
Monoclonal antibodies and tyrosine kinase inhibitors (TKI) targeting the type-1 Insulin-like growth factor receptor (IGFIR) are currently in clinical trials. Resistance to several targeted therapies has been observed and is not well understood. Estrogen receptor (ER) has been shown to interact with IGFIR signaling to promote cell growth. To examine acquired resistance to IGF1R monoclonal antibodies, we selected ER positive MCF7L cells in increasing concentrations of an IGFIR inhibitory antibody (scFvFc, treated over 2 years). These cells (MCF7L-scFvFc) had downregulated IGFIR levels, increased basal phosphorylation of IRS-1 with constitutive activation of Akt. MCF7L-scFvFc cells had enhanced basal growth and were no longer responsive to IGF-I and estradiol (E2). To examine the relationship between IGF1R and ER function, we used the pure steroidal anti-estrogen fulvestrant to examine effects on growth of the parent and antibody-resistance cells. In parent MCF7L cells, fulvestrant inhibited growth responses to IGF-I and E2 treatment when each ligand was given individually, but when both ligands were given together, the growth inhibition was reversed. In MCF7L-scFvFc, fulvestrant inhibited growth response to IGF-I, but cells still responded to E2 even in the presence of fulvestrant. Fulvestrant inhibition of MCF7L-scFvFc basal growth was associated with downregulation of ER and IGFIR system components. Fulvestrant treatment induced PARP cleavage in MCF7L, but not in MCF7L-scFvFc cells. IGF-I partially protected cells against fulvestrant induced PARP cleavage, and E2 treatment has full protective effects on these cells. These data suggest that MCF7L-scFvFc cells were more resistant to cell apoptosis induced by fulvestrant. Other monoclonal antibodies directed against IGF1R were ineffective in reversing the resistance in MCF7L-scFvFc cells. To determine if activated IGF1R was responsible for the behavior of MCF7L-scFvFc cells, we used the IGF1R TKI AEW541. AEW541 inhibited growth of these antibody resistant cells and a combination of fulvestrant and AEW541 completely inhibited cell growth and IGF signaling in both MCF7L and MCF7L-scFvFc cells. Thus, activated IGFIR signaling was still required for the growth of MCF7L-scFvFc cells. In conclusion, MCF7L-scFvFc had low levels of IGF1R but retained activated IGF1R signaling that was inhibited by TKI (AEW541). In addition, the ER antagonist fulvestrant also inhibited growth of these cells. In these ER-positive cells, combined blockade of ER and IGF1R could provide a more prolonged inhibition of cell growth. Moreover, cells selected for resistance to an IGF1R antibody remain sensitive to IGF1R TKIs. Thus, concurrent or sequential targeting of IGF1R and ER function should be examined in breast cancer clinical trials of ER positive breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 72.
NSABP B-30: definitive analysis of quality of life (QOL) and menstrual history (MH) outcomes from a randomized trial evaluating different schedules and combinations of adjuvant therapy containing doxorubicin, docetaxel and cyclophosphamide in women with operable, node-positive breast cancer.
Authors: Ganz PA , Land SR , Geyer CE , Costantino JP , Pajon ER , Fehrenbacher L , Atkins JN , Polikoff JA , Vogel VG , Erban JK , Livingston RB , Perez EA , Mamounas EP , Wolmark N , Swain SM 
Published: December 2010

Abstract
Abstract #76
Background: QOL and MH outcomes were integrated into the NSABP B-30 trial as secondary outcomes to the efficacy analyses which are being presented separately. Explicit secondary aims of the NSABP B-30 study were 1) to compare toxicities among the regimens, 2) to compare QOL, and 3) to examine differences in amenorrhea and its relationship to symptoms, QOL, and efficacy. Here we examine the secondary aims of the study as a companion to the efficacy results that are presented separately.&#x2028; Materials and Methods: 5351 pts with cT1-3, N0-1, M0 were enrolled from 3/1/99 to 3/31/2004. 2170 were enrolled on the QOL study, and 2449 were enrolled on the MH study and were randomized to one of three treatment groups: Group 1 [doxorubicin (A) 60 mg/m2 and C 600 mg/m2 q 3 weeks (wks) x 4 followed by docetaxel (T) 100 mg/m2 q 3 wks x 4; Group 2 [A 50 mg/m2 and T 75 mg/m2 q 3 wks x 4]; Group 3 [A 50 mg/m2 T 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 q 3 wks x 4]. All patients with ER-positive tumors received hormonal therapy after completing chemotherapy. Preliminary results from Group 1 have been reported previously (Swain, et al. Breast Cancer Res Treat, 2008).&#x2028; Results: The protocol specifies that 800 deaths are required for the definitive analysis of treatment, QOL, and MH outcomes, which are expected to occur by fall 2008. For this final report, results from a comparison of the three arms will be analyzed and presented.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 76.
BCIRG 005 main efficacy analysis: a phase III randomized trial comparing docetaxel in combination with doxorubicin and cyclophosphamide (TAC) versus doxorubicin and cyclophosphamide followed by docetaxel (AC→T) in women with Her-2/neu negative axillary lymph node positive early breast cancer.
Authors: Eiermann W , Pienkowski T , Crown J , Chap L , Pawlicki M , Martin M , Saleh M , Sehdev S , Provencher L , Von Minckwitz G , Semiglazov V , Slamon D , Tabah-Fisch I , Buyse M , Riva A , Taupin H , Sauter G , Mackey J ,   on Behalf of the BCIRG005 Investigators
Published: December 2010

Abstract
Abstract #77
Background: The relative benefits of adjuvant breast cancer chemotherapy with docetaxel in combination with anthracycline, or given sequentially after an anthracycline-based regimen, are unknown.&#x2028; Material and Methods: We randomized women with axillary lymph node positive, central HER-2 nonamplified, breast cancer to either TAC (75/50/500 mg/m2 q3wk x 6 cycles) or AC (60/600 mg/m2 q3wk x 4 cycles) followed by T (100 mg/m2 q3wk x 4 cycles). Patients were prospectively stratified by number of positive nodes (1-3 vs. 4+) and hormone receptor status. Patients with ER and/or PR positive (HR+) tumors received hormonal therapy after chemotherapy. The primary endpoint was disease-free survival (DFS) with 80% power to detect an absolute difference of 5%. Secondary endpoints included overall survival and safety.&#x2028; Results: A total of 3298 patients (1649 per arm) were recruited between August 2000 and February 2003. Baseline characteristics were well balanced: age&lt;50 yrs 47%, 1-3 nodes 61%, HR+ 82%, T &gt; 2 cm 58%. The planned 6 cycles of TAC were given to 93.5% of patients and 8 cycles of AC-T to 90.5%. Febrile neutropenia (17.9% vs. 8.5%) was more frequent with TAC, while grade 3 / 4 neutropenic infections were equivalent (8.7% with TAC vs. 8.0%). One septic death occurred in the TAC arm. Grade 3 / 4 non-hematological toxicity rates were fatigue (5.2% vs. 6.3%), nausea (4.5% vs. 4.1%), vomiting (4.2% vs. 4.1%), diarrhea (2.9% vs. 3.1%), stomatitis (2.6% vs. 3.0%), peripheral edema (1.3% vs. 2.6%), neuropathy-sensory (0.6% vs. 2.0%) and CHF (0.1% vs. 0.4%) in the TAC and AC-T arms, respectively. The other Garde 3 / 4 docetaxel specific toxicities (nail and skin toxicities were observed in less than 0.5% in both arms. The protocol specified main efficacy analysis triggered by 688 DFS events will be presented, with a median follow-up of 60 months.&#x2028; Discussion: The safety profile of the two docetaxel-based adjuvant chemotherapy regimens is comparable with the exception of a higher incidence of febrile neutropenia with TAC. This analysis will define the relative efficacy of combination vs. sequential docetaxel-containing chemotherapy in the adjuvant treatment of women with node positive, HER-2 negative breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 77.
Clinical trial of optical mammography.
Authors: Ogura H , Sakahara H , Nasu H , Teruya C , Yamashita D , Ueda Y , Ohmae E , Suzuki T , Oda M , Yamashita Y 
Published: December 2010

Abstract
Abstract #807
Objectives: Optical mammography (O-MMG), which utilizes near-infrared light for the detection of abnormal breast tissue, can be a potentially useful and non-invasive tool for the screening of breast cancer patients. Here we report on the results of our initial clinical trial using a time-resolved O-MMG system developed by Hamamatsu Photonics (Hamamatsu, Japan).&#x2028; Materials and Methods: In principle, the technique involves sequential irradiation of the breast tissue with a pulsed laser with a wavelength of 800 nm, which is then detected by the system at multiple sites after passing through the breast tissue. The irradiation takes place with the breast incorporated in a breast cup. The space between the cup and the breast tissue is filled with a liquid interface material, which is prepared beforehand on the basis of the optical properties of the breast tissue of each individual patient. The data are analyzed and tomographic images of the absorption coefficient of the breast are then reconstructed based on our tomographic reconstruction algorithm.&#x2028; The clinical trial was started in January 2007. A total of forty-two breast cancer patients participated in the trial and written informed consent was obtained from all of the patients.&#x2028; Results: Only optical properties without tomographic images were obtained for eight of the forty-two patients because of system malfunctions or due to patients' wishes. Higher absorption areas were noted in 22 out of the remaining 34 patients, which were identified as positive for abnormal breast tissue. No such positive tissue signals were identified in 12 patients.&#x2028; Conclusion: In this initial clinical trial, we believe that optical mammography as a non-invasive and painless investigative tool may have some advantages over conventional mammography in the initial screening of breast cancer patients. Currently, we launched multiwavelength measurements to improve the diagnostic performance.&#x2028; This work was partially supported by a Grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, to promote leading projects on "Research and Development of Technology for Measuring Vital Function Merged with Optical Technology."&#x2028; &#x2028; &#x2028; &#x2028;
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 807.
Harnessing apoptosis to kill breast cancer cells.
Authors: Letai A 
Published: December 2010

Abstract
Abstract #ES-2
Most of the therapies that are used to treat breast cancer induce programmed cell death via the intrinsic apoptosis pathway. The key step in commiting to cell death via this pathway is permeabilization of the mitochondrion with subsequent release of proapoptotic factors. Control over permeabilization is mainly exerted by the BCL-2 family of proteins which consists of both pro- and anti- apoptotic proteins. However, it is generally poorly understood how the targeting of intracellular niches by both conventional and targeted therapies ultimately signals to the BCL-2 family. I will discuss how conventional chemotherapy as well as more modern targeted therapies enlist pro-apoptotic BCL-2 family proteins to induce apoptosis. Furthermore, I will discuss the potential role of novel drugs that specifically target the apoptotic pathway in the treatment of breast cancer.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr ES-2.
Communicating with patients and the risks of cancer risk prediction.
Authors: Elmore JG 
Published: December 2010

Abstract
Abstract #MS1-4
BACKGROUND&#x2028; Patients may ask, “What is my risk of getting cancer?” and they may use cancer risk prediction models that are readily available on the web. Unfortunately, our risk models are less able to predict cancer at the level of the individual patient and our ability to communicate numeric information is limited.&#x2028; ASSESSMENT OF RISK MODELS&#x2028; Most cancer risk prediction models perform well at the population level. The calibration of risk prediction models is assessed at the population level by comparing the number of patients who the model estimated would develop cancer with the number of patients who actually were diagnosed with cancer.&#x2028; Unfortunately, risk prediction models often fall short on their ability to discriminate at the level of the individual patient. The models are less able to separate individuals who are, and are not, going to develop diseases like cancer. Many “low risk” individuals develop cancer, while many “high-risk” individuals do not. Discrimination is the degree to which the estimates from the risk model are consistently higher for individuals who develop cancer, compared to those who do not develop cancer.&#x2028; COMMUNICATION&#x2028; Communicating information to individuals about their risk of developing cancer is challenging. There is a great deal of fear about cancer in the community and a heightened sense of risk. Much of the discussion about cancer risk is in terms of relative risks, which sound more threatening than absolute risk differences. Use of both positive and negative framing of the risk estimate numbers is helpful. However, the challenge of understanding numbers is not unique to patients; clinicians are also challenged with both understanding and communicating this information.&#x2028; CONCLUSION&#x2028; Although we have high-tech medical programs and decades of research on cancer, our ability to individually tailor cancer risk prediction tools is sorely lacking. Our current risk prediction models may be appropriate for educating patients about aggregate or population-level cancer risk statistics. However, patients should be counseled that the estimates say little about which specific individuals will develop cancer. We need to develop better risk prediction tools and tools that facilitate basic communication regarding risk and benefit. Both of these challenges may be difficult, but would be extremely worthwhile.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr MS1-4.
Breast ultrasound in the screening and diagnosis of breast cancer.
Authors: Berg WA 
Published: December 2010

Abstract
Abstract #MS3-1
Six single center and two multicenter studies of screening breast ultrasound have shown a consistent detection yield of 3-5 per 1000 for supplemental screening breast ultrasound after mammography. The vast majority of these additional cancers seen only on ultrasound are invasive, with mean tumor size of 9-11 mm across series, and, where reported, approximately 90% are node negative. Supplemental detection is mainly seen when the breast tissue is dense. Screening ultrasound carries a substantial risk of false positives, with 9-11% of biopsies prompted by ultrasound proving malignant. In the first year of the ACRIN 6666 protocol, 1 in 40 women had an unnecessary biopsy due to mammography, compared to 1 in 10 after both mammography and ultrasound. Modeling to predict impact on mortality and cost-effectiveness of screening ultrasound is in progress, and results of incidence screens in ACRIN 6666 will be forthcoming.&#x2028; Ultrasound is widely used to characterize abnormalities seen on mammography and to guide biopsy, including biopsy of MRI-depicted suspicious findings. At the time of biopsy of suspicious masses, ultrasound of the ipsilateral axilla can help identify and guide FNAB of suspicious node(s) if present. In the setting of widespread malignant-appearing calcifications, ultrasound can help identify a mass which may represent an invasive component. Ultrasound has also been shown to be more accurate in identifying the source of abnormal nipple discharge than galactography.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr MS3-1.
Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930
Authors: Yap Timothy A. , Walton Mike I. , Hunter Lisa-Jane K. , Valenti Melanie , de Haven Brandon Alexis , Eve Paul D. , Ruddle Ruth , Heaton Simon P. , Henley Alan , Pickard Lisa , Vijayaraghavan Gowri , Caldwell John J. , Thompson Neil T. , Aherne Wynne , Raynaud Florence I. , Eccles Suzanne A. , Workman Paul , Collins Ian , Garrett Michelle D. 
Published: December 2010

Abstract
AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 is a novel ATP-competitive AKT inhibitor discovered using fragment- and structure-based approaches. It is a potent, advanced lead pyrrolopyrimidine compound exhibiting selectivity for AKT over PKA, achieved by targeting a single amino acid difference. CCT128930 exhibited marked antiproliferative activity and inhibited the phosphorylation of a range of AKT substrates in multiple tumor cell lines in vitro, consistent with AKT inhibition. CCT128930 caused a G1 arrest in PTEN-null U87MG human glioblastoma cells, consistent with AKT pathway blockade. Pharmacokinetic studies established that potentially active concentrations of CCT128930 could be achieved in human tumor xenografts. Furthermore, CCT128930 also blocked the phosphorylation of several downstream AKT biomarkers in U87MG tumor xenografts, indicating AKT inhibition in vivo. Antitumor activity was observed with CCT128930 in U87MG and HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, consistent with its pharmacokinetic and pharmacodynamic properties. A quantitative immunofluorescence assay to measure the phosphorylation and total protein expression of the AKT substrate PRAS40 in hair follicles is presented. Significant decreases in pThr246 PRAS40 occurred in CCT128930-treated mouse whisker follicles in vivo and human hair follicles treated ex vivo, with minimal changes in total PRAS40. In conclusion, CCT128930 is a novel, selective, and potent AKT inhibitor that blocks AKT activity in vitro and in vivo and induces marked antitumor responses. We have also developed a novel biomarker assay for the inhibition of AKT in human hair follicles, which is currently being used in clinical trials. Mol Cancer Ther; 10(2); 360–71. ©2010 AACR.
Pressure-Volume Relationships in Patients With Transthyretin (ATTR) Cardiac Amyloidosis Secondary to V122I Mutations and Wild-Type Transthyretin
Authors: Bhuiyan Taslima , Helmke Stephen , Patel Ayan R. , Ruberg Frederick L. , Packman Jeff , Cheung Kin , Grogan Donna , Maurer Mathew S. 
Published: December 2010

Background—
ATTR cardiac amyloidosis can result from a mutated variant of transthyretin (eg, V122I) or wild-type variant (ATTRwt). We evaluated pressure-volume (PV) indices at baseline and over time to further characterize abnormal pump function in these subjects.

Methods and Results—

Twenty-nine subjects (18 with ATTRwt and 11 with ATTRm (V122I) had 2-dimensional echocardiograms with complete Doppler measures at baseline and every 6 months for up to 2 years. PV indices were derived from echocardiographic measures of ventricular volume coupled with sphygmomanometer-measured pressure and Doppler estimates of filling pressure. The end-systolic and end-diastolic PV relations and the area between them as a function of end-diastolic pressure, the isovolumic PV area (PVA
iso
), were calculated. Clinical, demographic, and PV indices were compared between V122I and ATTRwt subjects and between survivors and nonsurvivors at baseline and over time. Cox proportional hazards model identified correlates for mortality. Stroke volume decline was associated with alterations in ventricular-vascular coupling and a decrease in ventricular capacitance with significant decrement in ejection fraction (56±12% to 48±14%,
P
=0.0001) over 18 months. PVA
iso
was lower in V122I subjects compared with wild-type at baseline and declined over time. Twelve (41%) subjects died or underwent a cardiac transplant after a mean follow-up of 478 days (range, 31 to 807). Multivariable survival analysis demonstrated that initial ejection fraction (a measure of ventricular-vascular coupling) <50% was associated with increased mortality (hazard ratio, 6.6; 95% confidence interval, 1.1 to 40.3).

Conclusions—
In ATTR cardiac amyloidosis secondary to a V122I mutation and wild-type transthyretin, PV analysis reveals alterations that are associated with reductions in the ability of the ventricle to perform work and, ultimately, with reduced survival in these subjects.