bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract MS2-2: Genomics to personalize therapy of metastatic breast cancers
Authors: André F 
Published: May 2016

Abstract
Genomic studies have shown that breast cancer includes large number of rare genomic segments. This led to the development of precision medicine where sequencing could be used to identify drivers in individuals, that would be treated accordingly. 10 to 20 molecular alterations are being investigated in the context of biomarker-driven therapeutic trials. This includes PIK3CA, AKT1, ERBB2, PTEN, BRCA1/2, ESR1 mutations, FGFR1, CCND1 amplifications, AR expression. Beyond the question of clinical utility of detecting these variants, there are several challenges that precision medicine is facing in breast cancer.
The first challenge will be to better define which genomic alterations are drivers in individuals and how to target them. The recent failures of prospective trials testing precision medicine (SAFIR01, SHIVA) highlights the need to better understand what defines a targetable alteration. These trials also pointed out the need to target the molecular alterations, rather than the pathway. Also, it's important to better understand the role that alterations on multiple drivers could play on resistance. As illustration, several reports suggest that PIK3CA mutations could be associated to a lower sensitivity to dual Her2 inhibition in neoadjuvant setting.
The second challenge will be to generate genomic tests that predict the sensitivity of therapies that target pathways, like mTOR or CDK4 inhibitors. To this regards, gene expression looks particularly attractive since it allows quantifying pathway activation.
The third challenge will be to predict earlier the resistance to targeted therapies. The development of circulating DNA as a diagnostic tool could be useful for early diagnosis of resistance. Clinical trials testing this technology are currently starting.
Finally, one of the major challenge will be to integrate immunotherapeutics in the application field of precision medicine. High mutational loads and neoantigen expression could predict efficacy of immunotherapeutics. Further combination with targeted therapies should be rationalized based on genomics.
Overall, while candidate biomarkers exist and technologies are available, precision medicine failed to deliver until now for patients with metastatic breast cancer. Nevertheless, ongoing randomized trials testing drugs according to genomic alterations should open the door of treatment decisions based on genomics for breast cancer patients.
Citation Format: André F. Genomics to personalize therapy of metastatic breast cancers. [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 MS2-2.
Abstract OT3-01-01: HERMIONE: A phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with chemotherapy of physician's choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine (T-DM1)
Authors: Miller K , Cortes J , Hurvitz SA , Krop IE , Tripathy D , Verma S , Riahi K , Reynolds JG , Wickham T , Molnar I , Yardley DA 
Published: May 2016

Abstract
Background: Although HER2-targeted therapies such as pertuzumab and T-DM1 have improved patient outcomes, treatment resistance typically occurs. MM-302 is a HER2-targeted liposomal doxorubicin in development by Merrimack Pharmaceuticals. In a Phase 1 study, patients with HER2-positive metastatic breast cancer (MBC) were treated with MM-302 alone and in combination with trastuzumab with or without cyclophosphamide. MM-302 had an acceptable safety profile and promising efficacy was observed in patients not previously exposed to an anthracycline.
Trial design: HERMIONE (NCT02213744) is a randomized Phase 2, two-arm, open-label trial designed to evaluate if MM-302 can address an unmet medical need in patients with anthracycline naïve, trastuzumab-, pertuzumab- and T-DM1-pretreated HER2-positive locally advanced breast cancer (LABC)/MBC. Patients are randomized 1:1 to receive MM-302 (30mg/m2, Q3W) plus trastuzumab (6mg/kg, Q3W) or chemotherapy of physician's choice (vinorelbine, capecitabine, or gemcitabine) plus trastuzumab (6mg/kg, Q3W).
Eligibility criteria: Centrally confirmed HER2-positive LABC/MBC, no prior anthracycline exposure, prior trastuzumab in any setting, prior pertuzumab and T-DM1 in the LABC/MBC setting, unlimited prior lines of therapy, ECOG 0-1 and LVEF ≥50%. CNS metastases are permitted if stable and without symptoms or steroids for 4 weeks.
Specific aims: The primary endpoint is independently assessed progression free survival (PFS). Secondary endpoints include investigator assessed PFS, overall survival, response rate, safety and patient related outcomes.
Statistics: 250 patients will be enrolled to observe 191 PFS events for 90% power to detect a Hazard Ratio of 0.625. The MM-302 arm will be compared to the control arm on the primary endpoint of PFS using a stratified log-rank test at one-sided 0.025 level.
Accrual status: First patient in was December 2014 and enrollment is expected to be complete in late 2016. Sites are open in the US, Canada and Western Europe and are currently enrolling patients.
Citation Format: Miller K, Cortes J, Hurvitz SA, Krop IE, Tripathy D, Verma S, Riahi K, Reynolds JG, Wickham T, Molnar I, Yardley DA. HERMIONE: A phase 2, randomized, open label trial comparing MM-302 plus trastuzumab with chemotherapy of physician's choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine (T-DM1). [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 OT3-01-01.
Abstract OT3-02-08: Scalp cooling alopecia prevention trial (SCALP) for patients with early stage breast cancer
Authors: Nangia JR , Wang T , Rude M , Osborne C , Papish S , Abraham J , Holmes F , Savin M , Paxman R , Hilsenbeck SG , Osborne CK , Rimawi M 
Published: May 2016

Abstract
Background
Adjuvant chemotherapy treats micro-metastatic disease and decreases the risk of breast cancer recurrence. However, it may be associated with distressing side effects, including alopecia. Women with breast cancer rate chemotherapy-induced alopecia as one of the most severe, troublesome, and distressing side effects of chemotherapy. In many countries, scalp cooling has been introduced to prevent or reduce chemotherapy-induced alopecia. The theory is that scalp cooling causes cutaneous vasoconstriction, which reduces blood flow to the hair follicles during peak plasma concentrations of the chemotherapeutic agents and therefore reduces cellular uptake of these agents. It also results in reduced biochemical activity, which makes hair follicles less susceptible to the damage of the chemotherapy agents. Historically success rates are have been variable, but based on non-randomized studies, scalp cooling appears to be effective in preventing chemotherapy-induced alopecia especially in more recent studies.
Methods
We are conducting a prospective multi-center randomized controlled non-blinded trial to evaluate the safety and efficacy of the Orbis Paxman Hair Loss Prevention System in reducing the incidence of chemotherapy-induced alopecia. Women with stage I-II breast cancer who will receive neoadjuvant or adjuvant anthracycline- or taxane-based chemotherapy, for at least four cycles are eligible. Participants are randomized in a 2:1 ratio to scalp-cooling or no cooling. Scalp-cooling is done using the Orbis Paxman Hair Loss Prevention System prior to, during and after each chemotherapy administration. The primary efficacy endpoints are hair preservation, defined as CTCAE v4 alopecia &lt;2, and device safety. Two hundred and thirty five (235) patients are planned to be enrolled which will provide 85% power to detect a 20% difference in hair preservation, 15% in control group and 35% in scalp-cooling group . Secondary endpoints include: wig/scarf use and quality of life assessed by the EORTC QLQ-30, HADS and BIS. Study participants will be followed for 5 years post-study for time to first recurrence, overall survival, site of first recurrence, and incidence of isolated scalp metastasis.
Citation Format: Nangia JR, Wang T, Rude M, Osborne C, Papish S, Abraham J, Holmes F, Savin M, Paxman R, Hilsenbeck SG, Osborne CK, Rimawi M. Scalp cooling alopecia prevention trial (SCALP) for patients with early stage 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 OT3-02-08.
Abstract P1-01-04: Early stage breast cancer prognostication using whole tumor or Ki67 heterogeneity-based digital imaging
Authors: Barnes M , Srinivas C , Xu C , Dean S , Singh S , Henricksen LA , Wik N , Morris D , Magliocco A , LaFleur B 
Published: May 2016

Abstract
Introduction:
Accurate prognosis of hormone-positive early stage breast cancer patients offers the opportunity to make more informed follow-up choices, for example the addition of adjuvant chemotherapy. More recently patient prognostication based on immunohistochemistry-scored protein expression (ER, PR, Her2 and Ki67) in the ATAC trial has been described as IHC4 (C-index of 0.78). However, IHC4 clinical translation has not occurred and may be hindered by the need for a clinically-validated standardized assay as well as pathologist scoring reproducibility. To address this idea, we employed a standardized assay system and automated scoring using digital image analysis to assess either whole tumor (WT) IHC expression values or Ki67 heterogeneity (Ki67H) quantification. The goals were to 1) establish a prognostic model based on and potentially improving the IHC4 concept and 2) improve pathologist scoring reproducibility.
Material and Methods:
A paraffin-embedded whole tissue cohort consisting of 120 cases of hormone-positive, HER2-negative, stage I and II, breast cancer patient samples were re-stained with standardized ER, PR, HER2, and Ki67 IHC assays. Three pathologists independently scored conventional glass slides microscopically (CM) and annotated WT on H&E and Ki67 heterogeneous regions on whole slide scanned images (WSI) for each case separately. The annotations were separately registered across serial stained slides and also scored via the digital pathology algorithm.
Results:
The mean patient age at the time of diagnosis is 63 years with a maximum follow-up of 18 years. Patients with regional and/or distal recurrence compose 26% of the cohort with a median recurrence free survival of 8.5 years. years. Clinical variables (CV) plus WT (C-index 0.74, r2 0.38) or Ki67H (C-index 0.77, r2 0.39) models improved on patient prognostication each as compared to the IHC4 plus CV (C-index 0.70, r2 0.19) in this cohort. High inter-pathologist reproducibility for the IHC score, as measured by concordance correlation coefficient was noted for Ki67H (0.90).
Conclusions:
Novel algorithmic scoring methodologies such as WT and Ki67H may improve on the IHC4 concept with high inter-pathology reproducibility. We are currently validating in a larger 600 patient cohort.
Citation Format: Barnes M, Srinivas C, Xu C, Dean S, Singh S, Henricksen LA, Wik N, Morris D, Magliocco A, LaFleur B. Early stage breast cancer prognostication using whole tumor or Ki67 heterogeneity-based digital imaging. [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 P1-01-04.
Abstract P1-03-02: Estrogens contribute to cytokine upregulation and cancer stem cell recruitment upon breast cancer contact with mature human mammary adipocytes: Effects of estrogen type and adipocyte donor weight
Authors: Slingerland J , Picon-Ruiz M , Jang K , Morata-Tarifa C , Pan C , Besser A , Kim M , Ince TA , Howard GA , El-Ashry D 
Published: May 2016

Abstract
Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. While obesity confers increased cancer risk and worse outcome, mechanisms thereof are not fully known. We show prolonged co-culture of fat cells (human adipocyte stem cells, differentiated adipocytes or mature adipocytes) from breast tissue together with breast cancer lines or cultured primary dissociated human breast tumor cells increases secretion of six different pro-inflammatory cytokines, each of which contributes to tumor progression through cancer stem cell recruitment. Prolonged exposure to fat cells or to each cytokine increases the proportion of cells that form mammosphere and express ALDH1 activity in vitro and that can initiate primary orthotopic tumors and metastasis in vivo. Adipocyte and cytokine exposures activate Src, and Src family kinase activity leads to induction of embryonic transcription factors that upregulate miR302b. miR302b induction is Sox2-dependent, promotes cytokine-driven sphere formation, and in turn, stimulates cMYC and SOX2 expression. Src is not only activated by adipocyte or cytokine exposures, it is also required to sustain cytokine induction, since Src inhibitors decrease cytokine production after co-culture. Cytokine upregulation was much greater after co-culture of ER+ breast cancer cells with mature, aromatase positive, adipocytes than with adipocyte stem cells. Cytokine induction was estrogen regulated. The mechanisms of cytokine induction, ER-coactivation and effects of different estrogenic ligands will be presented.
Present data illuminate the increased risk of breast cancer after menopause, particularly in obese women and the increased breast cancer mortality with obesity: cancer cell invasion into local fat, in the presence of high local aromatase and intracellular estrogen would establish feed-forward loops to activate Src, maintain pro-inflammatory cytokine production and increase tumor initiating cell abundance, tumor growth and metastasis. These data link obesity related pro-inflammatory cytokines to Src activation and cancer initiating cell abundance, and provide a novel rationale for Src inhibitors together with endocrine therapy for breast cancer.
Citation Format: Slingerland J, Picon-Ruiz M, Jang K, Morata-Tarifa C, Pan C, Besser A, Kim M, Ince TA, Howard GA, El-Ashry D. Estrogens contribute to cytokine upregulation and cancer stem cell recruitment upon breast cancer contact with mature human mammary adipocytes: Effects of estrogen type and adipocyte donor weight. [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 P1-03-02.
Abstract P1-03-04: Response to cyclooxygenase-2 inhibition is regulated by collagen dense stroma
Authors: Esbona K , Inman DR , Saha S , Wilke LG , Keely PJ 
Published: May 2016

Abstract
Women with dense breast have over four-fold risk for breast cancer and high breast density is correlated to increased collagen. In our previously characterized mouse model of MMTV-PyVT x Col1a1tm1jae, increased collagen levels in mammary tumors lead to enhanced tumor formation and progression. Additionally, high collagen density in vitro elevated expression of PTGS2, the gene for cyclooxygenase-2 (COX-2), by over four-fold. Because COX-2 over-expression is observed in 40% of invasive breast carcinoma cases and correlates with poor prognosis, we hypothesized that inhibition of COX-2 may be an effective target in the context of mammary tumors arising in dense tissue. Col1a1tm1jae (HD) or wild-type (wt) tumor mice were randomly assigned at 11 weeks of age to daily treatment with vehicle or celecoxib for 21 days. Tumors in HD mice were larger (p &lt; 0.05) and expressed higher levels of COX-2 (p &lt; 0.05) and PGE2 (p &lt; 0.01). COX-2 and PGE2 expression levels were both decreased with COX-2 inhibition (wt and HD = p &lt; 0.0001, for both markers). Cell proliferation decreased in both wt and HD tumors when COX-2 was inhibited (Epithelium wt and HD p &lt; 0.0001; stroma wt = p &lt; 0.05 and HD = p &lt; 0.01). Notably, several cytokines, immune and stromal cell counts were elevated in HD tumors alone, and COX-2 inhibition reversed this effect. These findings indicate that COX-2 has a direct role in modulating tumor progression in dense matrices and it may be an effective therapeutic target for women with dense breast tissue.
Citation Format: Esbona K, Inman DR, Saha S, Wilke LG, Keely PJ. Response to cyclooxygenase-2 inhibition is regulated by collagen dense stroma. [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 P1-03-04.
Abstract P1-03-05: SPARC expression in primary metastatic breast cancer
Authors: Barinoff J , Brandi C , Thill M , Heinrichs C , Mensah J , Weikel W , Fisseler-Eckhoff A , Sinn P , Meyer A-S , Traut A , Schneeweiss A 
Published: May 2016

Abstract
Aim: To evaluate the prognostic value of the expression of secreted protein acidic and rich in cysteine (SPARC) in primary metastatic breast cancer (PMBC).
Patients and Methods: Fifty-two patients with PMBC diagnosed between 2005 and 2012 at x German centers were retrospectively analyzed for expression of SPARC in tumor cells using an immunoreactive score (IRS) integrating staining intensity and percentage of positive cells (IRS 0-12), and in stroma based on immunohistochemical (IHC) staining intensity only (IHC 0-3+). Association between SPARC expression, tumor characteristics and progression-free survival (PFS) and overall survival (OS) was analyzed.
Results: Only Her2 expression was associated with expression of SPARC in stroma (p 0.028, OR 13.9 95% 1.3-145.5) but not in tumor cells. SPARC expression in stroma was associated with shorter PFS (hazard ratio (HR) 2.6; 95% confidence interval (CI) 1.2-5.4; p 0.014), but not in tumor cells and shorter OS (HR 4.1; 95% CI 1.04-16; p 0.041) for SPARC expression in stroma of breast tumor. No clear association between expression of SPARC in tumor cells and outcome could be detected.
Conclusion: Only SPARC expression in stroma might be associated with shorter PFS and OS in patients with PMBC. This finding is in line with the known key role of expression of SPARC in the metastastatic process. Confirmation in prospective clinical trials is warranted.
Citation Format: Barinoff J, Brandi C, Thill M, Heinrichs C, Mensah J, Weikel W, Fisseler-Eckhoff A, Sinn P, Meyer A-S, Traut A, Schneeweiss A. SPARC expression in primary metastatic 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 P1-03-05.
Abstract P1-05-04: A novel mechanism of epithelial-mesenchymal transition in breast cancer metastasis: Involvement of prostanoid receptor
Authors: Kwong A , Siu MT , Cheuk I , Ho JC , Chen J , Shin VY 
Published: May 2016

Abstract
Background: Triple-negative breast cancer is associated with higher metastatic rate and poor prognosis than other subtypes of breast cancer due to lack of targeted therapy. Epithelial-mesenchymal transition (EMT) is linked with metastasis with phenotypic conversion of epithelial cells. However, the regulation of EMT in breast cancer metastasis remains largely unstudied. Recent attention has focused on targeting the downstream of COX-2 pathway, understanding the role of prostanoid receptors in breast cancer metastasis may help the development of effective therapeutic interventions for patients with metastasis.
Methods: A stable EP2-expression cell line (MB-231-EP2) was used to study tumorigenesis and distant metastasis in human breast cancer metastatic model. Localization of EP2 and EMT markers were examined by immunostaining and immunofluorescence. Profiles of drug transporters genes were compared between siEP2 and siControl cells. Functional role of EP2 on cell proliferation, invasion and apoptosis were assessed. Alteration of EMT markers were examined by real-time PCR and Western blot analysis.
Results: Expression of EP2 receptor were higher in human primary tumors than non-tumor tissues. EP2 receptor was predominantly expressed in metastatic tumors than primary tumors in human breast cancer metastatic mice model. The metastatic tumors showed a higher Ki67 (cell proliferation) and CD31 (angiogenesis) than primary tumors in the xenograft tissues. Larger tumors and poor survival were seen in MD-231-EP2 bearing mice when compared with control. Silencing of EP2 by siRNA markedly reduced cell proliferation and invasion, but increased apoptosis and expression of solute carrier family 19 member A3 (SLC19A3) gene. Interestingly, SLC19A3 had a lower expression in primary tumors and was inversely correlated with EP2 expression. Ectopic expression of SLC19A3 suppressed cell proliferation and invasion through the restoration of E-cadherin and other EMT markers (Twist, Zeb1 and Snai2). Immunofluorescence staining showed that the localization of Twist and E-cadherin were altered in siEP2 cells.
Conclusion: Our results showed that EP2 promoted EMT and breast cancer metastasis through the downregulation of SLC19A3 expression. Taken together, targeting EP2/SLC19A3 signaling pathway maybe a potential treatment for metastasis and adjuvant chemotherapy to reduce the metastatic risk.
Citation Format: Kwong A, Siu MT, Cheuk I, Ho JC, Chen J, Shin VY. A novel mechanism of epithelial-mesenchymal transition in breast cancer metastasis: Involvement of prostanoid receptor. [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 P1-05-04.