bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract S5-6: Activating HER2 mutations in HER2 gene amplification negative breast cancers.
Authors: Bose R , Kavuri SM , Searleman AC , Shen W , Shen D , Koboldt DC , Monsey J , Li S , Ding L , Mardis ER , Ellis MJ 
Published: August 2014

Abstract
Background: Breast cancer genome sequencing projects, performed by the genome sequencing centers in the U.S., Canada, and the U.K., are elucidating the somatic mutations and other genomic alterations that occur in human breast cancer. These studies recently identified somatic HER2 mutations in breast cancers lacking HER2 gene amplification.
Results: Compilation of data from seven sequencing studies documented 22 patients with somatic HER2 mutations. These mutations clustered in three regions. The first cluster was at amino acid (aa) 309–310 (exon 8), located in the extracellular domain. These aa residues form part of the HER2 dimerization interface. The second cluster was at aa 755–781, located in the kinase domain (exons 19–20). This was the most common location for HER2 mutations, with 17 out of 22 patients having somatic mutations here. The third region was at aa 835–896, also in the kinase domain (exons 21–22). Using multiple experimental approaches (cell line experiments, in vitro kinase assays, protein structure modeling, and xenograft experiments), we tested seven of these HER2 mutations and showed that 4 of them are activating mutations that are sensitive to lapatinib and trastuzumab. Another 2 mutations were found to be lapatinib resistant and we determined their sensitivity to neratinib, canertinib, and gefitinib.
Conclusions: These findings biologically validate somatic HER2 mutations as good targets for breast cancer treatment, but the appropriate choice of targeted drug is dependent on the precise mutation present. This study is among the first to functionally characterize mutations identified by breast cancer genome sequencing. A prospective, multi-institutional clinical trial has been launched to screen for HER2 mutation positive patients and determine the clinical outcome of treatment with HER2 targeted drugs.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S5-6.
Abstract S6-5: Primary results of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative breast cancer
Authors: Cameron D , Brown J , Dent R , Jackisch C , Mackey J , Pivot X , Steger G , Suter T , Toi M , Parmar M , Bubuteishvili-Pacaud L , Henschel V , Laeufle R , Bell R 
Published: August 2014

Abstract
Background: Bevacizumab (BEV), an anti-VEGF antibody, significantly enhanced progression-free survival in metastatic breast cancer (BC) (E2100, AVADO, RIBBON-1, RIBBON-2) and pathologic complete response rates in the neoadjuvant setting (GeparQuinto, NSABP B-40) when combined with chemotherapy (CT). The dependence of micro-metastases on angiogenesis [Holmgren 1995] suggests that patients might benefit from anti-angiogenic strategies applied in the adjuvant setting. The BEATRICE trial was designed to test this hypothesis in patients with triple-negative BC, who have a poor prognosis and lack targeted options for treatment.
Methods: In this open-label randomized multinational phase III trial, patients with centrally confirmed triple-negative operable primary invasive BC (pT1a-pT3) were randomized 1:1 after definitive surgery to receive ≥4 cycles of either CT alone or the same CT + 1 year of BEV 5 mg/kg/wk equivalent. CT was anthracycline [anth] and/or taxane-based. Patients were stratified by nodal status (0 vs 1–3 vs ≥4 involved nodes), CT backbone (anth vs anth + taxane vs taxane), hormone receptor status (negative vs low), and surgery (breast-conserving vs mastectomy). The primary objective is to compare invasive disease-free survival (IDFS) [Hudis 2007] with adjuvant CT ± 1 year of BEV. Secondary outcome measures are overall survival (OS), breast cancer-free interval, disease-free survival (DFS), distant DFS, and safety (NCI CTCAE v3.0). The sample size was calculated to provide 80% power for a HR=0.75 at α=0.05 assuming 5-year IDFS of 72.0% with CT vs 78.2% with CT + BEV with 388 events. BEATRICE also includes evaluation of potential predictive and prognostic biomarkers.
Results: Between Dec 2007 and Mar 2010, 2591 patients were randomized. At data cut-off (Feb 29, 2012), median follow-up was 32 months.

The mean CT exposure was balanced between treatment arms. Median BEV duration was 11.7 months. BEV was associated with an increased incidence of grade ≥3 congestive heart failure/left ventricular dysfunction (3% vs &lt;1% with CT), grade ≥3 hypertension (12% vs &lt;1%), and treatment discontinuation (BEV and/or CT: 20% vs 2%) but no increase in the risk of fatal adverse events (0.3% vs 0.2%). No new safety signals were observed.
Conclusion: There was no statistically significant improvement in IDFS with the addition of 1 year's BEV to adjuvant CT for triple-negative BC. Further follow-up is required to assess the impact of BEV on OS. The safety profile was consistent with previous reports in metastatic BC with a low incidence of fatal adverse events. Protocol-specified biomarker analyses are ongoing. Updated OS results are expected in 2013.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-5.
Abstract BS01-2: Moving breast cancer stem cell therapies to the clinic
Authors: Wicha MS 
Published: August 2014

Abstract
The realization that many cancers, including breast cancer, are driven by cells which display stem cell properties has significant clinical implications. Furthermore, the demonstrated role of these cells in mediating tumor metastasis and treatment resistance suggests the need to develop strategies to specifically target CSC populations. Cancer stem cell self-renewal and survival pathways represent potential therapeutic targets. These self-renewal pathways are regulated by an interacting network of cell intrinsic pathways, as well as extrinsic factors from the tumor microenvironment. These mircroenvironmental factors include cytokines such as IL-6, IL-8 and TGFb. CSCs maintain the plasticity to transition between epithelial-like MET and mesenchymal-like EMT states, a process regulated by the tumor microenvironment through microRNA circuits. We have demonstrated that previously identified cancer stem cell markers are cancer stem cell state specific. CD44+/CD24- CSCs represent mesenchymal-like stem cells capable of tissue invasion which are largely quiescent. In contrast, Aldehyde dehydrogenase expression identifies a more epithelial-like cancer stem cell state associated with self-renewal. Reversible EMT/MET transitions play a crucial role in mediating tumor metastasis.
Preclinical breast cancer models predict that the greatest efficacy of CSC targeting therapeutics will occur when they are used in the adjuvant setting, a concept supported by preclinical models and clinical trials. Tumor regression may reflect effects on bulk cell populations explaining the lack of correlation between tumor shrinkage and patient survival. In contrast, recurrence following adjuvant therapy may be mediated by CSCs, which possesses sufficient self-renewal to form clinically significant metastasies. The important role of HER2 signaling in regulating breast cancer stem cell self-renewal may account for the remarkable clinical efficacy of targeting HER2 in the adjuvant setting. Furthermore, the clinical benefit of such therapies in classically defined HER2-negative breast cancers may be due to selective expression of HER2 in CSCs in the absence of HER2 gene amplification. The clinical benefit of adjuvant trastuzumab in women whose breast cancers are currently classified as HER2-negative is currently being assessed in the randomized national clinical trial B47. These studies may demonstrate the need for reevaluating currently used clinical endpoints and clinical trial designs. Promising new technologies including the isolation and molecular characterization of circulating cancer stem cells may provide the opportunity for real time assessment of the efficacy of CSC targeting agents. A number of agents regulating BCSCs have entered early phase clinical trials which will determine whether effective targeting of CSCs improves patient outcome.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS01-2.
Abstract BS03-1: Tumor-derived exosomes promote pre-metastatic niche formation and organotropism
Authors: Lyden DC , Peinado-Selgas H , Nitadori A , Shen T-L , Aleckovic M , Kang Y , Bromberg J 
Published: August 2014

Abstract
Metastasis is the most deadly aspect of cancer due to a lack of appropriate therapies. Tumor-secreted factors have been recently recognized to be one of the main culprits for metastatic progression. Tumor-secreted factors such as VEGF-A, PlGF, TGFb, TNF-a, and LOX have been shown to play active roles in the recruitment of bone marrow (BM)-derived cells to the primary tumor microenvironment and pre-metastatic niches. We have found that tumor-derived exosomes are abundantly secreted into the circulation in highly metastatic murine models and in patients with stage IV metastatic disease. Tumor-derived exosomes induce vascular leakiness, and hypoxic and pro-inflammatory changes at pre-metastatic sites. Moreover, tumor-derived exosomes preferentially fuse and “educate” BM-derived progenitor cells to a pro-vasculogenic phenotype characterized by upregulation of Tie-2, VEGF-A, VEGFR2, TSP1 and ADAM10. We found that B16-F10 melanoma-derived exosomes help establish pre-metastatic niches, including the recruitment of “educated” BM cells, in specific organs destined to be involved in future metastasis whereas LLC lung cancer-derived exosomes predominant in the lung as the main organ of metastasis. These results suggest that tumor-derived exosomes may have a role in metastatic organotropism, whereby cancer metastasizes to specific organs, as proposed by Stephen Paget's ‘seed and soil’ hypothesis more than a 100 years ago. We believe that the identification of exosomes proteins, with their prognostic and therapeutic potential, may also partially explain the specific receptor-ligand binding of exosomes to a pre-metastatic niche defining an organotropic site for future metastasis.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS03-1.
Abstract ES05-2: Divergent trends in breast cancer subtypes, a manifestation of cancer heterogeneity
Authors: Anderson WF 
Published: August 2014

Abstract
Recent studies in the United States show an unexpected divergence of ER positive and ER negative breast cancer incidence rates (JNCI 103: 1397-1402, 2011). ER positive cancers have risen while ER negative cancers have declined over the long-term. Divergent ER-specific trends might reflect statistical anomalies, lower assay thresholds for classifying breast cancers as ER positive, and/or the implementation of widespread screening mammography with increased sensitivity for ER positive cancers. However, the analysis of secular trends in Denmark, where there was better control of these potentially confounding factors, showed similar trends as in the United States (IJC 133: 2201-2206, 2013). ER positive cancers had increased among middle-aged and older Danish women in earlier birth-cohorts (or generations), implying a confluence of risk factor exposures during the peri- and the post-menopausal time periods of a woman's lifetime. In contrast, ER negative cancers had decreased among younger women in more recent birth-cohorts during the premenopausal time periods.
Divergent ER-specific trends among different birth-cohorts in younger and older generations is consistent with breast cancer heterogeneity due to distinct etiologic pathways for ER positive and ER negative breast cancers, which could be due to trends in environmental and lifestyle risk factors with dual effects by ER expression. Two such possible risk factors are pregnancy (or parity) and obesity, which are decreasing and increasing, respectively, in both the United States and Denmark. For example, parity tends to reduce breast cancer risk for ER positive cancer and to increase risk for ER negative cancers. In fact, new breast cancer cases appear to be rising worldwide due to the consequences of changing reproductive, hormonal, and dietary risk factors. For this reason, it is plausible that the same risk factors or at the least risk factors acting through common mechanisms in the United States and Denmark may foreshadow a common pattern worldwide. This is good news since ER negative breast cancers are the most difficult to treat subtypes of breast cancer, especially the so-called triple negative cancers.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES05-2.
Abstract ES08-3: MR imaging for predicting response to neoadjuvant treatment
Authors: Hylton NM 
Published: August 2014

Abstract
Magnetic Resonance Imaging (MRI) of the breast is a sensitive and non-invasive method for assessing both tumor morphology and physiology. In comparison to mammography and ultrasound, MRI has particular advantages for demonstrating the anatomic extent of disease and it is effective for assessing the response of primary breast tumors to pre-operative (neoadjuvant) treatment. Dynamic contrast-enhanced (DCE)-MRI and diffusion-weighted MRI (DWI) are two approaches that provide quantitative in vivo information about the state of disease and have been used to measure breast tumor changes associated with treatment. These techniques add functional information about breast cancer by sensitizing the MRI signal to tumor vascularity, known to be associated with tumor grade and aggressiveness, and water diffusion, a property affected by cell density that can reflect tumor growth as well as cell death from cytotoxic treatment, respectively. MR spectroscopic imaging (MRSI) has also been applied in the breast to study tumor metabolism, although the low spatial resolution currently limits the utility of this technique. This talk will discuss the emerging applications of functional MRI techniques for assessing breast tumor response to treatment in the neoadjuvant setting. The various roles for use of quantitative imaging in assessing neoadjuvant treatment will be considered. Imaging criteria can be the basis for patient inclusion or continuation on therapy, and can also be used as a biomarker to quantify response. Depending on how well the efficacy of an imaging biomarker has been established, it can also serve as the endpoint for evaluating the benefit of treatment, or as a surrogate endpoint for other clinically meaningful outcomes. A promising but more speculative role for imaging biomarkers is for prediction of therapeutic response. Current findings will be presented from the I-SPY (ACRIN 6657/CALGB 150007) trial, a multi-center study integrating biomarkers and imaging to maximize effectiveness of neoadjuvant treatment for patients with locally-advanced breast cancer. The experience implementing standardized MRI protocols in the multi-center setting will be discussed. This talk is intended for imaging scientists and clinical researchers involved in the diagnosis and treatment of breast cancer. It is expected that the audience will gain knowledge leading to the appropriate application of breast MRI techniques in the neoadjuvant treatment setting.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES08-3.
Abstract OT1-2-04: PAM50 HER2-enriched (HER2E) phenotype as a predictor of early-response to neoadjuvant lapatinib plus trastuzumab in stage I to IIIA HER2-positive breast cancer
Authors: Vidal M , de la Peña L , Oliveira M , Cortés J , Llombart A , Prat A 
Published: August 2014

Abstract
Background: The efficacy of trastuzumab in different regimens and settings has been well established, including its benefit as neoadjuvant therapy for early HER2-positive disease. Combinations of two different anti-HER2 therapies without chemotherapy have generated great expectations. However, it is unclear which group of patients benefits the most from this strategy. Within HER2-positive breast cancer, the PAM50 assay identifies a HER2-Enriched (HER2-E) intrinsic subtype characterized by high activation of the EGFR/HER2 pathway and low expression of luminal-related genes, and therefore should obtain the greatest benefit from anti-HER2 therapy.
Trial Design: This non-randomized, open-label, multicentric phase II translational research study will evaluate the ability of the PAM50 HER2-E subtype to predict pathological complete response (pCR) to dual HER2 blockade with lapatinib and trastuzumab for a total of 18 weeks. Patients with hormone receptor (HR)-positive disease will also receive endocrine therapy (letrozol or tamoxifen).
Eligibility Criteria: Untreated, histologically confirmed invasive breast carcinoma eligible for definitive surgery (stage I-IIIA), HER2-positive invasive breast cancer by central assessment, premenopausal or postmenopausal, ECOG performance status of 0 or 1, adequate organ function and baseline LVEF &gt;50% measured by echocardiography or MUGA scan.
Specific Aims: The primary objective is to evaluate the ability of the PAM50 assay to predict pCR in the breast at the time of surgery. Secondary objectives are to (1) assess the correlation of HER2-E with pCR in the breast and axilla, (2) assess the correlation of HER2-E with Residual Cancer Burden (RCB) (3) evaluate the gene expression changes from Day 0 to Day 14 and the correlations with Ki67-IHC at Day 14, (4), identify additional gene expression signatures predictive of pCR, and (5) evaluate safety and tolerability.
Statistical Methods: The statistical plan is based on the assumption that breast pCR rate will be 35.0% for HER2-E tumors and 8.0% for non-HER2E. The study will have a 95% power with a significance level of 5% (two-sided) and an assumed drop-out rate of 15%. Biomarker Analyses: Baseline, 14-day treated and post-treatment (surgical) formalin–fixed, paraffin–embedded tissues will be obtained. The expression of 547 genes will be explored with the nCounter platform. Subtype will be identified using the PAM50 predictor (Parker et al. J Clin Oncol 2009). Ki-67-IHC will also be evaluated on pre-treatment and Day-14 samples.
Target Accrual: 150 patients with a maximum of 75 HR-positive patients across Spain and Portugal. Patient enrollment will begin in July 2013.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-2-04.
Abstract OT2-4-02: Young and strong: A randomized trial to evaluate a program for young women with breast cancer
Authors: Partridge AH , Ruddy KJ , Barry WT , Greaney M , Sprunck-Harrild K , Meyer ME , Baker EL , Ligibel J , Emmons KM 
Published: August 2014

Abstract
Young women with newly diagnosed breast cancer face substantial challenges including higher risk of disease recurrence and likelihood of harboring a genetic mutation compared with older women. Many young women are also very concerned about their future fertility and this population often feels isolated from other breast cancer survivors due to their age and life stage. Some worry that their doctors are unsure of how to treat them. To address these issues, we developed a comprehensive program at our institution to coordinate and enhance the care, support, and education for young women with breast cancer. The Young and Strong study is a randomized clinical trial (RCT) to evaluate a virtual, exportable, scalable version of this program designed to improve the quality of care and the psychosocial well-being of this vulnerable population.
The specific aims of this program are:
1) To develop, pilot, and refine an exportable and sustainable educational and support intervention for young women with breast cancer and their oncology providers (Young Women's Intervention; YWI).
2) To determine the effect of the YWI compared to a contact-time control intervention focused on promoting physical activity (Physical Activity Intervention; PAI) on attention to fertility issues in a RCT: “Young and Strong”.
We initially conducted 4 focus groups (n = 36) and 20 key informant interviews, and developed, piloted, and refined the YWI as well as the PAI. Based on this successful work, we launched the Young and Strong study in June 2012 as a cluster-randomized trial at a total of 54 sites (40 community and 14 academic sites across the United States). Randomization is 1:1 between sites, and stratified by practice type (community vs. academic). Each community site will enroll 5-10 participants, each academic site 15 participants. Total recruitment will be 410-610 pts. The primary objective is to evaluate whether YWI, as compared to PAI, is associated with greater attention to fertility issues, assessed via medical record review. In addition, participants will complete assessments at baseline, 3, 6, and 12 months that assess satisfaction with care, psychosocial well-being, physical activity and anthropomorphic changes.
Young and Strong activated in June 2012 and all sites have been identified. As of 6/11/2013 the study has been initiated at 53 out of 54 sites, and total of 282 women have enrolled on the study.
Eligibility Criteria:
1. Women age 18-45 years at diagnosis
2. Stage I-III invasive breast cancer without known recurrence or metastatic disease
3. Newly-diagnosed (within 3 months of initial diagnosis)
4. Have 1st appt. with a medical oncologist at participating site after the site opens to enrollment
5. Able to read and write in English
For further information, contact Ann Partridge, MD, MPH at 888-814-3324.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-4-02.