bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-18-06: Targetable ERBB2 mutations independently predict an aggressive phenotype in primary, ERBB2 non-amplified, hormone receptor positive lobular breast cancer
Authors: Kurozumi Sasagu , Green Andrew R , Ellis Ian O , Rakha Emad A , Fujii Takaaki , Shirabe Ken , Heery David , Zwart Wilbert , Oesterreich Steffi , Johnston Simon J 
Published: March 2020

Abstract
Invasive lobular carcinoma accounts for 10-15% of breast cancer cases and typically expresses hormone receptors. Despite this, lobular tumours respond less well to endocrine therapy, and long-term patient outcomes are inferior to those with other breast cancer subtypes. In primary lobular tumours, HER2 is rarely overexpressed due to relative infrequency of ERBB2 amplification. However, somatic mutation of ERBB2 may provide an alternative and tractable mechanism for upregulation of HER2 activity, which can be effectively targeted using a second generation HER2/EGFR tyrosine kinase inhibitor such as neratinib.
In this study we performed comparative in silico analysis of ER/PR(+), HER2(-) cases of invasive lobular (N=352) and ductal carcinoma (N=1,820) from the three largest primary breast cancer clinical datasets with somatic mutations called from next generation sequencing (TCGA, METABRIC and MSK, N=2,172). Using existing functional data from in vitro, cell line and xenograft experiments, ERBB2 mutations were stratified into known ‘oncogenic‘ or ‘uncharacterized‘ and integrated with lymph node status, tumour size and grade. The primary endpoint was overall survival as these data were available across datasets. We find that lobular tumours comprise 11% of all cases but contain 40% of the somatic mutations in ERBB2 in the dataset. The overall rate of mutated ERBB2 in lobular cases is 6% (N=21) versus 1.8% (N=32) in ductal cases (p&lt;0.0001). Using a Cox regression model, we show that oncogenic ERBB2 mutation status independently predicts overall poor survival only in lobular cases (HR 3.6, 95% CI 1.57 - 8.26; p=0.0026). For patients with lobular disease, overall survival was significantly lower if tumours harboured oncogenic ERBB2 mutation (median 64 versus 170 months, p&lt;0.0002). We conclude that ERBB2 mutations are enriched in ERBB2 non-amplified, ER/PR(+) lobular tumours and predict poor outcome despite use of adjuvant endocrine therapy according to standard protocols. Targeted sequencing of ERBB2 should be available for patients with lobular breast cancer and represents an actionable strategy to improve patient outcomes.
Citation Format: Sasagu Kurozumi, Andrew R Green, Ian O Ellis, Emad A Rakha, Takaaki Fujii, Ken Shirabe, David Heery, Wilbert Zwart, Steffi Oesterreich, Simon J Johnston. Targetable ERBB2 mutations independently predict an aggressive phenotype in primary, ERBB2 non-amplified, hormone receptor positive lobular breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-06.
Abstract P1-18-24: Trastuzumab Emtansine (T-DM1): No radiosensitizing effect in vitro on HER2-positive breast cancer cells (study in vitro)
Authors: Mignot Fabien , Kirova Youlia , Verrelle Pierre , Teulade-Fichou Marie-Paule , Megnin-Chanet Frédérique 
Published: March 2020

Abstract
Purpose/Objective(s): To determine the effects of concurrent irradiation and T-DM1 on HER2-positive breast cancer cell lines.
Materials/Methods: Five human breast cancer cell lines (in vitro study) presenting various levels of HER2 expression were used to determine the potential therapeutic effect of T-DM1 combined with radiation. The toxicity of T-DM1 was assessed using CellTiter-Glo® assays and cell cycle analysis was performed by flow cytometry after BrdU incorporation. HER2 cells were irradiated at different dose levels after exposure to T-DM1. Survival fractions were determined by cell survival after 5 population doubling times.
Results: The results revealed that T-DM1 induced significant lethality due to the intracellular action of DM1 on the cell cycle with significant G2/M phase blocking. Even after a short time incubation, the potency of T-DM1 was maintained and even enhanced over time, with a higher rate of cell death. After irradiation alone, the D10 (dose required to achieve 10% cell survival) was significantly higher for high HER2-expressing cell lines than for low HER2-expressing cells, with a linearly increasing relationship. In combination with irradiation, using conditions that allow cell survival, T-DM1 does not induce a radiosensitivity, both effects are strictly additive.
Conclusion: Although intrinsic HER2 expression is a factor of radioresistance, the results indicated that T-DM1 is not a radiation-sensitizer under the experimental conditions of this study. However, further investigations are needed, in particular in vivo studies before reaching a final conclusion.
Citation Format: Fabien Mignot, Youlia Kirova, Pierre Verrelle, Marie-Paule Teulade-Fichou, Frédérique Megnin-Chanet. Trastuzumab Emtansine (T-DM1): No radiosensitizing effect in vitro on HER2-positive breast cancer cells (study in vitro) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-24.
Abstract P1-19-28: Genomic screening reveals UBA1 as a potent and druggable target in diverse models of triple negative breast cancer
Authors: Jacob Sheeba , Turner Tia H. , Yu Ann K. , Coon Colin M. , Alzubi Mohammad A. , Jakubik Charles T. , Bouck Ynes , Dozmorov Mikhail G. , Boikos Sosipatros A. , Koblinski Jennifer , Harrell Joshua C. , Benes Cyril H. , Costa Carlotta , Faber Anthony C. 
Published: March 2020

Abstract
Triple negative breast cancer (TNBC) confers the poorest prognosis of the major subtypes of breast cancers, and often inflicts young, African-American and Hispanic women. Steadily improving survival in other subsets of breast cancers are attributed to the implementation of effective targeted therapies, which are non-chemotherapy drugs that target a specific gene in a cancer. For instance, hormone positive BCs are treated effectively with anti-hormone targeted therapy, and HER2 amplified BCs are treated effectively with anti-HER2 targeted therapy. The CRISPR/CRISPR-associated protein-9 nuclease (Cas9) system, which enables specific gene editing to occur throughout the genome, allows for broad and unbiased discovery of new drug targets. We took advantage of this system to ask whether it may identify new druggable targets to treat TNBC and performed whole genome CRISPR/cas9 screening in two TNBC cell lines, BT549 and MDA-MB-468. To account for the heterogeneity found in TNBC, we further expanded the screen into seven other TNBC cell lines, by focusing on a select number of hits from the initial screen. This helped us identify a novel druggable target in TNBC, the ubiquitin activating enzyme 1 (UBA1). We took advantage of a recently reported small molecule inhibitor of UBA1, TAK-243, which is already in clinical trial evaluation in hematological cancers. Characterization of TAK-243 in cell culture models of TNBC and ex-vivo patient-derived xenografts (PDXs) demonstrated nanomolar IC50 toxicity, which was significantly lower than for tissue-derived normal cells. Mechanistically, TAK-243 therapy induced ER stress and the unfolded protein response in TNBC both in vitro and in vivo, leading to upregulation of activation transcription factor 4 (ATF4) and ATF6. Blocking ATF4 led to loss of NOXA and TAK-243 efficacy. TAK-243 induced tumor regressions in two PDX models of TNBC. Overall, these data demonstrate UBA1 is a novel drug target in TNBC.
Citation Format: Sheeba Jacob, Tia H. Turner, Ann K. Yu, Colin M. Coon, Mohammad A. Alzubi, Charles T. Jakubik, Ynes Bouck, Mikhail G. Dozmorov, Sosipatros A. Boikos, Jennifer Koblinski, Joshua C. Harrell, Cyril H. Benes, Carlotta Costa, Anthony C. Faber. Genomic screening reveals UBA1 as a potent and druggable target in diverse models of triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-28.
Abstract P1-19-36: Exploratory analysis of TreatER+ight; a Canadian prospective real-world observational study in HR+ advanced breast cancer
Authors: Doyle Catherine , Califaretti Nadia , Ferrario Cristiano , Iqbal Nayyer , Hilton John , Vandenberg Theodore , Mates Mihaela , Glenns Vivian , Kulkarni Swati , Bains Puneet , Haftchenary Sina , Perri Sabrina , Chia Stephen 
Published: March 2020

Abstract
Background: TreatER+ight is the 1st prospective observational study in Canadian HR+ HER2- advanced breast cancer patients currently receiving endocrine therapy (ET) alone or in combination with targeted therapy (TT) (NCT02753686).
Methods: This exploratory analysis displays real-world evidence on baseline demographics, treatment patterns, sequencing, and method of access to therapy. More specifically this abstract focuses on treatment decisions around CDK4/6-based therapy at various lines of treatment. At data cut-off of April 1st 2019, 305 patients were enrolled from 24 sites since Mar'16 with 113 patients receiving CDK4/6is at baseline. 300 patients were evaluable for treatment analysis.
Results:
Baseline CharacteristicsOverall (n=305)CDK4/6 + ET (n=113)Median age, years (range)67 (23 - 92)67 (23-87)ECOG 0,1,2*95, 104, 1941,32, 4Post-menopausal*21468Pre/peri-menopausal*6530Therapy by disease severity at baselineVisceral (n = 196)Bone only (n = 101)CDK4/6 + ET7338ET5941mTOR + ET6421PI3K + ET01Current therapy on the study Overall (N = 300)CDK4/6 + ET113ET100mTOR + ET86 PI3K + ET1Current CDK therapy by line of treatmentAll CDK4/6 (N = 113)First line60Second line38Third line13 Fourth line2Overall treatment patterns by lineFirst-Line (n = 154)Second-Line (n = 111)Third-Line (n = 64)CDK 4/6i + ET855317ET582711mTOR + Exemestane82114Chemo31022Median duration on therapy in months1L2LCDK4/6 + ET8.87 (median follow-up of 9.6 mos)8.77 (median follow-up of 11.6 mos)*Data missing for some patients at the time of this analysis
Conclusions: The majority of patients enrolled (66.6%) are receiving combination therapy with the most common treatment being a CDK4/6-based therapy (56.5%). Of the patients receiving CDK4/6 at baseline a majority are receiving this therapy in the 1L (53.1%) and 2L (33.6%), with the median duration on therapy of respectively 8.87 and 8.77 months. For patients receiving CDK4/6 therapy in 1L, the most common 2L treatment is either endocrine therapy single agent and in certain parts of the country everolimus + exemestane. Further sequencing information will be analyzed and shared for this abstract.
Citation Format: Catherine Doyle, Nadia Califaretti, Cristiano Ferrario, Nayyer Iqbal, John Hilton, Theodore Vandenberg, Mihaela Mates, Vivian Glenns, Swati Kulkarni, Puneet Bains, Sina Haftchenary, Sabrina Perri, Stephen Chia. Exploratory analysis of TreatER+ight; a Canadian prospective real-world observational study in HR+ advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-36.
Abstract P2-02-05: Sensitivity of screening mammography by density and texture: A cohort study from a population based screening programme in Denmark
Authors: von Euler-Chelpin My 
Published: March 2020

Abstract
Background Screening mammography works better in fatty than in dense breast tissue. Computerized assessment of parenchymal texture is a non-subjective method to obtain a refined description of breast tissue, potentially valuable in addition to breast density scoring for identification of women in need of supplementary imaging. We studied sensitivity of screening mammography by a combination of radiologist assessed BI-RADS density score and computer assessed parenchymal texture marker, MTR, in a population-based screening program, Capital Region, Denmark.
Methods Breast density was coded according to the 4th Edition of the BI-RADS density code, and MTR marker was divided into quartiles from 1 to 4. Screening data were followed-up for identification of screen-detected and interval cancers. We calculated sensitivity and specificity with 95% confidence intervals (CI) by BI-RADS density score, MTR marker, and combination hereof.
Results In total, 55 350 women were screened from 1 November 2012 to 31 December 2013. Full data were available for 54 997 women, of whom 28% had BI-RADS density score 1, 40% score 2, 27% score 3, and 5% score 4. Density and texture were strongly correlated, but the combination led to identification of subgroups with different sensitivity. Sensitivity was high, about 80%, in women with BI-RADS density scores 1 and MTR markers 1 or 2.Sensitivity was low, 67%, in women with BI-RADS density score 2 and MTR marker 4. For women with BI-RADS density scores 3 and 4, the already low sensitivity was further decreased for women with MTR marker 4. Specificity was 97-99% in all subgroups.
Conclusion Our study showed that women with low density constituted a heterogenous group. Classifying women for extra imaging based on density only might be a too crude approach. Screening sensitivity was systematically high in women with fatty and homogeneous breast tissue.
Sensitivity and specificity by combination of density score (BI-RADS) and texture marker (MTR), Denmark 2012-13
MeasureSensitivity % (95% CI)Specificity % (95% CI)BI-RADS 178 (69-85)99 (98-99)MTR 181 (70-90)99 (98-99)MTR 271 (54-85)99 (99-99)MTR 382 (48-98)98 (98-99)MTR 4BI-RADS 275 (70-81)97 (97-97)MTR 173 (57-85)98 (97-98)MTR 277 (66-85)97 (97-97)MTR 380 (64-88)97 (97-98)MTR 467 (51-81)97 (97-98)BI-RADS 369 (62-76)97 (97-97)MTR 171 (52-86)97 (96-98)MTR 2MTR 377 (66-87)97 (97-98)MTR 461 (46-72)97 (97-98)BI-RADS 447 (30-65)98 (97-98)MTR 157 (29-82)98 (97-99)MTR 2MTR 3MTR 441 (21-64)97 (97-98)
Citation Format: My von Euler-Chelpin. Sensitivity of screening mammography by density and texture: A cohort study from a population based screening programme in Denmark [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-02-05.
Abstract P2-05-08: Integrin alpha6beta4 signaling switches double strand break repair from homologous recombination to non-homologous end joining to alter TNBC cells response to cisplatin
Authors: Chen Min , Marrs Brock , Qi Lei , Knifley Teresa , Jarrett Stuart G , Weiss Heidi L , Stewart Rachel L , D'Orazio John A , O'Connor Kathleen L 
Published: March 2020

Abstract
Integrin α6β4 is highly expressed in triple negative breast cancer (TNBC) and drives aggressiveness by stimulating proliferation, angiogenesis, cell migration, invasion and metastasis. Signaling from this integrin stimulates DNA repair and apoptosis resistance, suggesting that it could contribute to therapeutic resistance. Upon testing this hypothesis, we found that integrin α6β4 signaling promoted a three-fold greater sensitivity to cisplatin but exhibited no difference in the response to other chemotherapies tested. Mechanistic investigations revealed that integrin α6β4 stimulated quicker and higher amplitude activations of ATM, Chk2, p53, and 53BP1, which required the β4 signaling domain. Genetic manipulation of gene expression demonstrated that mutant p53 cooperated with integrin α6β4 for cisplatin sensitivity and was necessary for downstream phosphorylation of 53BP1 and enhanced ATM activation. Additionally, we discovered that integrin α6β4 preferentially activated DNA-PKc in response to cisplatin, which led to formation of DNA-PKc-p53 complexes and 53BP1 activation. As a result, integrin α6β4 shifted double strand break repair from homologous recombination (HR) to non-homologous end joining (NHEJ), as demonstrated by HR and NHEJ reporter assays, in normal culture which was amplified by cisplatin treatment. Furthermore, DNA-PKc inhibition blocked integrin α6β4 enhanced cisplatin sensitivity. This signaling, against the backdrop of prominent losses and gains of select DNA repair molecules in breast cancer as a whole, may lead to a novel HR-deficiency that characterizes TNBC and their response to select chemotherapies. In summary, we discovered a novel function of integrin α6β4 in switching DSB repair from HR to NHEJ that results in cisplatin sensitivity in TNBC.
Citation Format: Min Chen, Brock Marrs, Lei Qi, Teresa Knifley, Stuart G Jarrett, Heidi L Weiss, Rachel L Stewart, John A D'Orazio, Kathleen L O'Connor. Integrin alpha6beta4 signaling switches double strand break repair from homologous recombination to non-homologous end joining to alter TNBC cells response to cisplatin [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-05-08.
Abstract P2-08-16: The burden and trends of breast cancer from 1990 to 2017 at the global, regional, and national level: Results from the global burden of disease study 2017
Authors: Gong Yue , Ji Peng , Hu Xin , Shao Zhi-Ming 
Published: March 2020

Abstract
Background: Breast cancer is a common diagnosed malignancy and the leading cause of cancer-related death worldwide. Data on burden and changing trends of breast cancer are of value for policymaking. We therefore aimed to determine the pattern of breast cancer incidence, mortality, and disability-adjusted life-years (DALYs), as well as temporal trends, from 1990 to 2017. Methods: We collected detailed information on breast cancer between 1990 and 2017 using the results of the Global Burden of Disease study in 2017. The number of incident cases, deaths and DALYs attributable to breast cancer are reported as well as age standardized rates. Estimated annual percentage changes (EAPCs) in breast cancer age standardized rate were calculated to quantify the temporal trends. Moreover, attributable burden to breast cancer risk factors were also estimated using the comparative risk assessment framework of the GBD study. Results: There were 878,686 incident cases and 349,581 deaths of breast cancer globally in 2017, contributing to 17,708,600 DALYs. The age standardized incidence rate increased between 1990 and 2017, while the age standardized mortality rate and DALY rate decreased. The corresponding EAPCs were 0.41 (95% CI: 0.35 to 0.47), -0.62 (95% CI: -0.68 to -0.55), -0.56 (95% CI: -0.63 to -0.48), respectively. These trends were heterogeneous across regions and countries. The increase in the age standardized incidence rate was more prominent in countries with a low socio-demographic index and the decrease in the age standardized mortality rate and DALY rate was more prominent in countries with a high socio-demographic index. Percentage of breast cancer deaths due to alcohol use (12.94% to 9.64%) and tobacco (7.15% to 5.14%) was decreasing while deaths due to high body-mass index (4.03% to 6.54%) and high fasting plasma glucose (5.94% to 7.26%) was increasing. Conclusion: Breast cancer remains a major public health concern globally. The trends of incidence, mortality, and DALYs were heterogeneous across regions and countries, suggesting that the allocation of appropriate health care resources for breast cancer prevention, screening and treatment should be considered.
Citation Format: Yue Gong, Peng Ji, Xin Hu, Zhi-Ming Shao. The burden and trends of breast cancer from 1990 to 2017 at the global, regional, and national level: Results from the global burden of disease study 2017 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-16.
Abstract P2-13-21: Predicting symptoms and diseases after breast cancer treatment: Development of a nomogram
Authors: Heins Marianne J. , De Ligt Kelly M. , Verloop Janneke , Siesling Sabine , Korevaar Joke C. 
Published: March 2020

Abstract
Background: Women with breast cancer can experience a variety of late adverse effects, depending on age, treatment and time since diagnosis. We developed a nomogram that predicts which symptoms and diseases are likely to occur in breast cancer survivors up to 15 years after diagnosis. Methods: Data from the Netherlands Cancer Registry and NIVEL Primary Care Database were combined in the Primary-Secondary Cancer Care Registry, containing data about the cancer diagnosis/treatment and data from the primary care electronic health records of 12.850 Dutch women diagnosed with breast cancer between 2000-2016. From Nivel Primary Care Database 25.700 control women without breast cancer were obtained. First, Cox regression models were built, stratified by 4 age groups and 2 time windows (1-5 and 5-15 years after diagnosis), in order to determine which symptoms and diseases were more frequently experienced in cases compared to controls (p-value&lt;.05). Second, for each significant symptom and disease, relevant treatment variables (chemo therapy (yes/no), radio therapy (yes/no, and lateralisation), hormone therapy (yes/no), axillary dissection (yes/no)) were added stepwise to the models. Variables with a p-value &lt;.10 were included in a multivariate model and all variables with a p-value &lt;.05 were retained in the final model. Findings: In total, 635 models were constructed, forming the basis for the nomogram. Late effects occurring more frequently in cases compared to controls independent of age and time since diagnosis were chest symptoms, lymphedema/arm symptoms, redness/infections of the skin, nausea, cystitis, insomnia and discussing euthanasia. Others were predominantly relevant 1-5 years after diagnosis, including vomiting and side-effects of medication. Interpretation: This nomogram can provide clinicians and women with breast cancer insight in which symptoms and diseases she has an increased risk to experience in the upcoming years, which is both applicable when making treatment decisions and at follow-up initiation. Besides, it may be a starting point to develop effective preventive measures to limit late side-effects of breast cancer and improve after care for women with breast cancer.
Citation Format: Marianne J. Heins, Kelly M. De Ligt, Janneke Verloop, Sabine Siesling, Joke C. Korevaar. Predicting symptoms and diseases after breast cancer treatment: Development of a nomogram [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-21.