bluuebunny/crossref_metadata_2025_split huggingface dataset:
Poor survival outcomes in HER2 positive breast cancer patients with low grade, node negative tumours. Implications for trastuzumab therapy?.
Authors: Tovey SM , Marla S , Brown S , Burton P , Canney P , Stallard S , Mallon E , Edwards J , Cooke T 
Published: December 2010

Abstract
Abstract #702
HER2 status is established as a poor prognostic marker for survival in breast cancer and has been validated as a predictive marker for response to trastuzumab following chemotherapy.We determined the number of patients both eligible for and actually receiving trastuzumab therapy for early breast cancer (EBC) in 2006 in a tertiary breast oncology unit. We also performed a retrospective analysis of the impact of HER2 status on survival in a large cohort of low grade, node negative patients who would currently be deemed ineligible for trastuzumab treatment.&#x2028; Methods&#x2028; 1. Data for all patients diagnosed with EBC in 2006 was recorded prospectively in a database. Case notes were consulted where the HER2positive patients had not received trastuzumab, to ascertain the reasons.&#x2028; 2. A retrospective cohort of 367, grade 1 or 2, node negative patients diagnosed between 1980-2002 (median followup 6.2yrs) was analysed to assess the impact of HER2 status (Herceptest 3+/FISHpos) on survival.&#x2028; Results&#x2028; 1. A total of 951 patients were diagnosed with Breast Cancer in 2006. 417(43.9%) of these were screen-detected. 123(12.9%) were HER2positive (117 were EBC) and 59 (50.4%) of the HER2 positive EBCs received trastuzumab therapy. Of the 58 (49.6%) patients who did not receive trastuzumab, 25 (43%) were patients considered low risk due to small, node negative, low grade tumours.&#x2028; 2. Retrospective cohort. The overall hazard ratio for HER2 positivity was 6.78 with 5yr breast cancer specific survival rates of 96% (HER2 neg) and 68% (HER2 pos). The reduction in survival in HER2 positive cases persisted when patients were split into subgroups by ER status, tumour size and age.&#x2028; &#x2028; Conclusions&#x2028; Only 50% of our HER2 positive EBC patients received trastuzumab therapy in 2006. The commonest reason for not receiving trastuzumab was low risk status precluding chemotherapy.&#x2028; However, the substantial reduction in survival shown in our retrospective cohort provides support for the use of trastuzumab in these 'low risk' HER2 positive patients who typically are classified as very good prognosis, are not routinely offered standard chemotherapy, and as such do not fit current prescribing guidelines for trastuzumab. A clinical trial to assess the benefit of adjuvant trastuzumab alone in this group of patients is suggested. Our results are in keeping with the HERA trial where the best prognosis tumours (node negative and size 1-2cm) had benefit similar to the overall cohort.&#x2028; The persistence of poor outcomes in our ER positive subgroup despite endocrine therapy confirms the recent trans-ATAC analysis based on HER2 status and suggests that we cannot not rely solely on adjuvant endocrine therapy in these largely ER positive patients.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 702.
Combination antiHER therapeutics — efficacy of alternative dosing regimens in ER+/HER2+ breast cancer xenografts.
Authors: Wiechmann LS , Soliz R , Hilsenbeck S , Rimawi M , Osborne CK , Schiff R 
Published: December 2010

Abstract
Abstract #706
Background In preclinical studies of HER2 positive breast cancer, combination antiHER therapy with lapatinib (L) and trastuzumab (T), is more promising than monotherapy. To reduce side effects, cost and increase patient compliance, we investigated novel dosing and scheduling of the L and T combination to find alternative treatment approaches.&#x2028; Methods Mice bearing xenograft tumors of BT474 (ER+/HER2-amplified) cells were treated with control estrogen supplementation, with estrogen withdrawal alone, or with estrogen withdrawal in combination with one or two HER inhibitors (T-10mg/Kg biweekly, L-100mg/Kg 5d/wk) continuously. Alternative dosing regimens included limited treatment duration (14, 42 days), intermittent administration (14 days on/ 14 days off L+T treatment), and dose adjustments (1/2L + 1/2T). Tumor volumes and weights were evaluated weekly. Results were analyzed with the Fisher's exact test or survival analysis methods (Kaplan-Meier estimates) and generalized Wilcoxon test. Group sizes were designed to rule out relatively large decrements in efficacy [i.e. 99% complete regression (CR) vs 65% CR]. All statistical tests were two-sided.&#x2028; Results At day 140 of the experiment, BT474 xenografts demonstrate de novo resistance to estrogen deprivation (ED) and respond more rapidly to the drug combination (L+T) compared to L or T alone. CR rates for xenograft tumors treated for 14 or 42 days are similar to full therapy, although relapses occur earlier (47% relapses at day 140 for 14 day treatment, compared to 20% and 0% for 42 day or full treatment, respectively). Intermittent treatment is as effective as full dose (one mouse demonstrating small palpable growth following CR died before confirmation of relapse). Decreasing the dose did not substantially change the percentage of tumors that undergo complete regression (CR) and did not accelerate treatment failure [Progression Free Survival (PFS) at day 140], but was associated with longer time to complete tumor regression (TTR).&#x2028; &#x2028; Conclusion Intermittent treatment with combined T and L is a promising strategy that warrants further investigation. Though 42 days of therapy led to complete tumor regression, our preliminary data suggest that a sustained response is more likely to be achieved by treatment &gt;42 days. Longer follow up is needed to determine the effectiveness of decreased dose regimens.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 706.
Superiority of sequential docetaxel over standard FE100C in patients with intermediate risk breast cancer: survival results of the randomized intergroup phase III trial EC-Doc.
Authors: Nitz U , Huober J , Lisboa B , Harbeck N , Fischer H , Moebus V , Hoffmann G , Augustin D , Weiss E , Gluz O , Kuhn W 
Published: December 2010

Abstract
Abstract #78
Background: Taxane based adjuvant chemotherapy (CHT) is standard of care in node-positive breast cancer. Several pre-planned subgroup analyses detected the maximum benefit from taxanes in patients with 1-3 positive lymph nodes (LN).&#x2028; According to the St. Gallen consensus CHT in endocrine responsive tumors is optional in these patients. Recently the ABCSG reported excellent survival data after endocrine therapy +/- bisphosphonates without CHT in low to intermediate risk breast cancer (Gnant et al., ASCO 2008). The EC-Doc trial compares a modern sequential taxane-based regimen with standard FE100C in patients with 1-3 positive LN.&#x2028; Methods: Patients from 18 to 65 years with primary breast cancer and 1 to 3 positive LN were eligible if they had operable breast cancer with histologically confirmed free margins. M0 status was assessed by conventional staging. 2011 patients were randomized to a phase III trial comparing 4 cycles E90C600 q3w followed by 4 cycles of Docetaxel100 q3w (n=1008) (Arm A) versus 6 cycles of F500E100C500 q3w (n=828) or C600M40F600 d1, 8 q4w (n=175) (Arm B). The primary endpoint is EFS. Secondary endpoints are OS, toxicity and quality of life.&#x2028; Results: Baseline characteristics were well balanced between both study arms. Arm A/B: mean age 51.5/51.5 years, median tumor size 2.0/2.0, HR positive 77.7% / 78.3%, G3 34.1% / 34.4%. Toxicity data from the EC-Doc trial were recently presented (Nitz et al. , ASCO 2008). After a median follow up of 41 months both estimated 5-year EFS (91% vs. 86%, p=0.005) and OS (95% vs. 90%, p=0.004) were significantly better in the EC-Doc arm.&#x2028; For the comparison of EC-Doc vs. FE100C the respective values were: HR 0.58, p=0.004, estimated 5 year EFS 91% / 85% and 5 year estimated OS 95% / 91% (p =0.03). For the hormone receptor positive subpopulation the HR was 0.51 in favour of EC-Doc (p= 0.007).&#x2028; Conclusions: Our study indicates a superiority of sequential taxane-based EC-Doc CHT in terms of EFS and OS over standard FE100C in an intermediate risk group. The addition of modern third generation taxane based CHT to conventional endocrine treatment is associated with excellent EFS and OS in patients with 1-3 positive LN.&#x2028; As shown even for the subgroup of patients with HR positive disease the benefit from third generation taxane based CHT is substantial so that an endocrine only adjuvant strategy may result in undertreatment. With respect to the excellent survival rates prospective randomized trials testing the existing genetic tests are mandatory.&#x2028; Updated survival and efficacy analysis in distinct molecular subtypes (Her-2/neu, triple-negative) will be presented.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 78.
Assessing the spatial extent of breast tumor intrinsic optical contrast using ultrasound and diffuse optical spectroscopic imaging.
Authors: Liu J , Cerussi AE , Li A , Tanamai W , Kwong R , Hsiang D , Tromberg BJ 
Published: December 2010

Abstract
Abstract #806
Background: Near infrared (NIR) light is sensitive to several important tissue components and has been used to detect, characterize, and monitor breast tumor functions. However, little is known about the relationship between anatomic and functional contrast derived from intrinsic optical signals. Diffuse Optical Spectroscopic Imaging (DOSI) is a non-invasive, bedside functional imaging technique that quantifies the concentrations and molecular states of tissue hemoglobin, water, and lipids. Pilot studies have shown that DOSI may be a useful tool for breast lesion detection/characterization and therapeutic monitoring.&#x2028; Materials and Methods: DOSI data were compared with theoretical computer simulations to estimate the nature and extent of optical contrast with respect to standard ultrasound imaging. DOSI reflectance measurements were obtained from 10 breast tumor patients, with both malignant (N=5) and benign (N=5) lesions. Patient average ages: 35+/-7.8 years vs. 44.3+/-14.7 years, lesion depth 10.9+/-5.5 mm vs. 15.8+/-5.3 mm, and maximum size 13.0+/-6.0 mm vs. 14.8+/-4.9 mm for benign and malignant, respectively. Two trial tumor models were simulated to model actual tumor optical properties (hemoglobin): (a) a discrete target constrained to ultrasound dimensions, and (b) a distributed target that spatially extended beyond ultrasound dimensions.&#x2028; Results: High optical contrast (i.e., the ratio target to background) was observed for both benign (1.53+/-0.17) and malignant (2.06+/-0.4) lesions, even for this younger population. While the discrete target model could not match experiment and simulation, a distributed model provided excellent agreement. The spatial extent of optical properties in breast tumor was significantly greater than anatomical dimensions reported by ultrasound imaging. The extent of the distribution was greater in the malignant lesions than in the benign ones. Further simulations also suggested that invasive breast tumors in this population with anatomical size 10 mm may still be detectable at depth 30 mm using DOSI in reflectance.&#x2028; Discussion: The spatial extension of tumor optical contrast complicates co-registration of optical functional images with anatomic images. The true optical contrast is significantly higher in breast cancer tumors, likely 4-5x than the hemoglobin levels in normal tissues. Breast tumor optical contrast is more realistically modeled as a spatially distributed target, which facilities a fast 3D imaging scheme in reflectance geometry. Results from these topographic reconstructions will be discussed.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 806.
Targeting of chemotherapy to Tie-2-receptor positive angiogenic endothelial cells of tumor vasculature.
Authors: Li P , Liu Y , Maynard J , Tang Y , Deisseroth A 
Published: December 2010

Abstract
Abstract #902
Background: There are at least three types of cells in tumor tissue which express the Tie2 receptor (Tie2R): dividing vascular endothelial cells (TVECs), Tie2R-expressing monocytes (TEMs) and Tie2R-expressing mesenchymal progenitor cells (TMPCs).&#x2028; &#x2028; We tested if the targeting of chemotherapy to these classes of Tie2R positive cells could suppress tumor cell growth.&#x2028; Material and Methods: We constructed replication incompetent adenoviral vectors carrying the cytosine deaminase (CD) suicide gene driven by the mouse Tie2R transcriptional promoter and enhancer sequences. In these viruses, we inserted an RGD-4C peptide into the HI loop of the fiber knob domain of the vector to increase its transduction efficiency in TVECs. At the same time, we added two mutations (S408E and P409A) in the AB loop of the fiber, which ablated the CAR-binding ability of the vector. The resulting vector was named AdTie2RCD(MRGD).&#x2028; Results: In vitro viral infection assays involving the human umbilical vein endothelial cells (HUVECs) showed that the RGD-modified vectors have a higher transduction efficiency as compared with their adenoviral vector counterparts which have a wild type fiber protein. Mice carrying the rat Her-2-Neu positive N202 mouse breast cancer cells and the mouse B16 melanoma cells were treated with intravenous injections of Hetastarch and the AdTie2RCD(MRGD) vector followed by intraperitoneal injections of 5-Fluorocytosine (5-FC). The Hetastarch was given before the intraveinous infusion of the adenoviral vector in order to reduce the uptake of the adenoviral vector by the reticuloendothelial cell system. The Tie2R targeted chemotherapy sensitization vectors induced greater degrees of suppression of tumor cell growth than did the control group, achieved the similar treatment effect to its CMV promoter counterpart, but with less side effect.&#x2028; &#x2028; Histological analysis showed that these vectors specifically targeted the TVECs, TEMs and TMPCs through which they may have exerted cytotoxic effects in the presence of 5-FC on the tumor cells.&#x2028; Discussion: Our results showed that N202 breast cancer cell line is more responsive to the Tie2R-targeting therapy compared to B16 mouse melanoma cell line and the Tie2R-directed anti-angiogenic therapy deserves further study, in combination with other types of therapy to pave the way for future clinic trails.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 902.
Bevacizumab (BV) maintenance therapy significantly delays disease progression (PD) or death compared with placebo (PL) in the AVADO trial (BV + docetaxel [D] vs D + PL in 1st-line HER2-negative locally recurrent [LR] or metastatic breast cancer [mBC]).
Authors: Fumoleau P , Greil R , Rayson D , Müller V , Barni S , Aleknavicius E , Tellez E , Wilson C , Miles DW 
Published: December 2010

Abstract
Abstract #903
Background: BV (Avastin®) is a monoclonal antibody to VEGF that significantly improved PFS and response rate when combined with 1st-line taxane chemotherapy (CTx) in two randomised phase III studies in patients (pts) with LR or mBC: E2100 (weekly paclitaxel ± BV) and double-blind, PL-controlled study AVADO (D ± two different BV doses). Preclinical data suggest that BV inhibits tumour neovascularisation and can limit tumour vascular regrowth. Both above trial protocols recommended BV use until PD, even after discontinuation of concomitant CTx. In the NO16966 trial in metastatic colorectal cancer, PFS was longer for pts continuing BV following cessation of CTx than for those where BV and CTx were stopped at the same time. We report results of an exploratory analysis of time to PD or death after cessation of D in pts in AVADO.&#x2028; Methods: AVADO compared BV 7.5 or 15mg/kg + D 100mg/m2 with PL + D in 736 pts with inoperable LR or mBC, ECOG PS 0–1 and adequate LVEF. D and BV/PL were administered q3w, with D given for up to 9 cycles and BV/PL continued until PD or unacceptable toxicity.&#x2028; Results: The table presents median time from discontinuation of D until PD or death in different subgroups in the AVADO study. Approximately 70% of pts in each arm discontinuing D went on to receive at least one dose of BV or PL before PD.&#x2028; &#x2028; Conclusions: Continuation of single-agent BV at either dose after discontinuation of D significantly delayed PD or death compared with single-agent PL. These results support the hypothesis that BV may inhibit tumour neovascularisation and progression following CTx and suggests that clinical benefit may be maximised by treatment with BV until progression.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 903.
Cancer clinical trials in the 21st century: the need for a paradigm shift in design, conduct, and support.
Authors: Piccart MJ , Philippe B 
Published: December 2010

Abstract
Abstract #ES-1
Over the last fifteen years, more than 45,000 women with early disease were randomized to taxane versus non-taxane regimens across 26 separate trials. Although collective results from 21 first-generation studies involving more than 36,000 women suggest that the addition of a taxane modestly improves anthracycline therapy, we are still uncertain of which subgroups of patients benefit from taxanes. The shortcomings of this enormous international effort provide many important lessons for the design, conduct, and support of clinical trials in the 21st century. Our growing understanding of the molecular heterogeneity of breast cancer dictates that this “one size fits all” approach to adjuvant therapy is now obsolete. Past efforts to investigate emerging therapies have suffered by the inclusion of women with endocrine responsive, luminal low proliferative disease, who enjoy a favourable long-term outcome in the absence of any adjuvant systemic therapy. Even when a clearly defined population has been defined, such as HER2 positive disease for adjuvant trastuzumab, there has been substantial duplication of efforts by individual co-operative groups. As a result, we remain uncertain of the optimal duration and schedule of adjuvant trastuzumab administration. Post-registration trials testing shorter duration trastuzumab regimens require greater numbers of participants to demonstrate non-inferiority and are now being conducted with considerable opportunity cost. Future registration studies will require careful upfront selection of secondary trials designed to address specific, non-overlapping questions of clinical importance. New-generation trials must mandate prospective collection of biospecimens and integrate cutting-edge technologies as early barometers of efficacy to accelerate the trajectory of novel agents to the clinic with the parallel development of therapeutic biomarkers that can be used to individually tailor treatment. Such a paradigm shift will require a new partnership between investigators, patients, and industry with a unified global commitment to reshape the framework of clinical trials, so that further progress can be made in the fight against breast cancer in the 21st century.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr ES-1.
Management of the contralateral breast in women with breast cancer.
Authors: Tuttle T 
Published: December 2010

Abstract
Abstract #MS1-2
Patients with unilateral breast cancer are at increased risk for developing a second cancer in the contralateral breast. The annual risk of clinically detected metachronous contralateral breast cancer is about 0.7% Some women choose contralateral prophylactic mastectomy (CPM) to prevent cancer in the contralateral breast. A recently published study found that the use of CPM increased by 150% from 1998 to 2003 in the United States. Several studies have demonstrated that CPM significantly decreases the occurrence of contralateral breast cancer; the risk reduction is about 97%. Since the risk of systemic metastases often exceeds the risk of contralateral breast cancer, most patients will not experience any survival benefit from CPM. Moreover, CPM is not risk free, and patients may need to undergo additional surgical procedures, especially if reconstruction is performed. Nevertheless, most patients are satisfied with their decision to undergo CPM. Alternatives to CPM include close surveillance with clinical breast examination, mammography, and possibly breast magnetic resonance imaging. Endocrine therapy with tamoxifen or aromatase inhibitors significantly reduces the risk of contralateral breast cancer and may be more acceptable than CPM for some patients. Ovarian ablation and cytotoxic chemotherapy also reduce the risk of contralateral breast cancer. For women with unilateral breast cancer, management of the normal contralateral breast is complex. Future prospective studies are critically needed to evaluate the decision-making processes leading to CPM.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr MS1-2.
Systems approach to personalized molecular medicine.
Authors: Mills G 
Published: December 2010

Abstract
Abstract #MS2-1
The realization of the promise of personalized molecular medicine will require the efficient development and implementation of novel targeted therapeutics. The overall likelihood of response to particular drugs represents the interaction between predictors of sensitivity with predictors of resistance. The phosphatidylinositol 3'kinase (PI3K) pathway is aberrant at multiple levels across a wide variety of tumors making it the most common activating aberration in cancer. This has led to the development and now early clinical testing of drugs targeting multiple components of the pathway. The efficient utilization of these drugs will require the ability to accurately determine mutation and activation status in tumors as well as determining the interaction between the PI3K pathway and other pathways in driving tumor pathophysiology. The PI3K pathway is critically important to cellular function and is thus under exquisite homeostatic control. The feedforward and feedback loops in the pathway determine the response to perturbation of the pathway by mutation or therapeutic intervention. Strikingly inhibition of the pathway at the level of mTOR or AKT results in the activation of potent feedback loops resulting in activation of multiple cell surface tyrosine kinases, PI3K itself and AKT. This may contribute to the observation that mTOR inhibitors appear to make some patient tumors grow more rapidly an unexpected and disappointing consequence. Our preliminary systems biology-based mathematical and experimental models of the PI3K signaling network accurately predict these consequences as well as the biochemical processes involved. Further, the models suggest combinations of targeted therapeutics likely to reverse the negative effects of the mTOR inhibitors converting the outcome from negative to positive in terms of tumor growth.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr MS2-1.