bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-21-05: GM-CSF is an autocrine driver of HER2+ breast leptomeningeal carcinomatosis
Authors: Bhan Arunoday Kuldeep , Ansari Khairul I , Chen Clara , Jandial Rahul 
Published: March 2022

Abstract
Leptomeningeal carcinomatosis (LC) occurs when tumor cells spread to the cerebrospinal fluid containing leptomeninges surrounding the brain and spinal cord. LC is an ominous complication of cancer with a dire prognosis. Although any malignancy can spread to the leptomeninges, breast cancer, particularly the HER2+ subtype, is its most common origin. HER2+ breast LC (HER2+ LC) remains incurable, with few treatment options, and the molecular mechanisms underlying proliferation of HER2+ breast cancer cells in the acellular, protein, and cytokine-poor leptomeningeal environment remain elusive. Therefore, we sought to characterize signaling pathways that drive HER2+ LC development as well as those that restrict its growth to leptomeninges. Primary HER2+ LC patient-derived ("Lepto") cell lines in co-culture with various central nervous system (CNS) cell types revealed that oligodendrocyte progenitor cells (OPC), the largest population of dividing cells in the CNS, inhibited HER2+ LC growth in vitro and in vivo, thereby limiting the spread of HER2+ LC beyond the leptomeninges. Cytokine array-based analyses identified Lepto cell-secreted granulocyte-macrophage colony-stimulating factor (GM-CSF) as an oncogenic autocrine driver of HER2+ LC growth. Liquid chromatography-tandem mass spectrometry-based analyses revealed that the OPC-derived protein TPP1 proteolytically degrades GM-CSF, decreasing GM-CSF signaling and leading to suppression of HER2+ LC growth and limiting its spread. Lastly, intrathecal delivery of neutralizing anti-GM-CSF antibodies and a pan-Aurora kinase inhibitor (CCT137690) synergistically inhibited GM-CSF and suppressed activity of GM-CSF effectors, reducing HER2+ LC growth in vivo. Thus, OPC suppress GM-CSF-driven growth of HER2+ LC in the leptomeningeal environment, providing a potential targetable axis.
Citation Format: Arunoday Kuldeep Bhan, Khairul I Ansari, Clara Chen, Rahul Jandial. GM-CSF is an autocrine driver of HER2+ breast leptomeningeal carcinomatosis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-05.
Abstract P1-24-01: Does modified radical mastectomy in de novo stage IV inflammatory breast cancer patients improve disease specific survival?
Authors: Chen JC , Li Yaming , Fisher James L. , Tsung Allan , Obeng-Gyasi Samilia 
Published: March 2022

Abstract
Introduction: Inflammatory breast cancer (IBC) is an aggressive breast cancer subtype with poor prognosis. In the non-metastatic setting, the current literature suggests modified radical mastectomy (MRM) in conjunction with chemotherapy and radiation therapy improve clinical outcomes. However, for de novo metastatic IBC patients, surgical management is mostly palliative, and little is known about its implications for survival. The objective of this study is to evaluate the association between MRM and disease specific survival (DSS) among a contemporary cohort of de novo stage IV IBC patients. Methods: The Surveillance, Epidemiology and End Results (SEER) Program was queried for IBC (T4d) patients diagnosed between 2010-2016. The study cohort was divided into two groups- MRM vs no MRM. Surgical management was limited to patients who underwent MRM. Bivariable analysis was conducted to compare sociodemographic and clinical variables between the groups. The surgery group was nearest matched to the no-surgery group (1:2) on age, year of diagnosis, location of metastasis (e.g., bone only), number of metastatic sites, breast cancer subtype, chemotherapy and radiation therapy. A Kaplan-Meier curve was used to evaluate DSS between the two groups in the matched sample. Results: Of the 1293 patients who met study criteria, 240 underwent MRM and 1053 had no surgery. Patients undergoing MRM were more likely to be younger (MRM 55.7years±13.5, no MRM 59.40years±13.4; p&lt;0.001), have poorly differentiated tumors (grade 3; MRM 63.7%, no MRM 46.7%; p&lt;0.001) and metastasis in only one organ site (MRM 69.8%, no MRM 52.2%; p&lt;0.001). On matched analysis, patients who underwent MRM had longer DSS than those who did not undergo surgery (p=0.001). Moreover, the 5-year survival rate for surgical patients was 31.4% compared to 17.7% for the no surgery group. The median survival time was 38 months for patients who underwent MRM (interquartile range [IQR] 27-45 months] compared to 27 months (22-29 months) among those who did not have surgery. Conclusion: In this SEER cohort of de novo metastatic IBC patients, MRM was associated with an improved disease specific survival compared to no surgery. These results suggest surgical management should be considered in this population. Future prospective studies are needed to better define which subset of de novo metastatic IBC patients derive the most benefit from surgery, and consequently, should routinely undergo surgery.
Citation Format: JC Chen, Yaming Li, James L. Fisher, Allan Tsung, Samilia Obeng-Gyasi. Does modified radical mastectomy in de novo stage IV inflammatory breast cancer patients improve disease specific survival? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-24-01.
Abstract P2-08-22: Correlation of ER (ESR1), PR (PGR), and HER2 (ERBB2) at protein and mRNA levels in operable breast cancer
Authors: Lei Lei , Wang Xiaojia , Cheng Skye Hung-Chun 
Published: March 2022

Abstract
Background:. We aimed to analyze the concordance between ER (ESR1), PR (PGR), and HER2 (ERBB2) levels and breast cancer subtyping results obtained by using the immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction (RT-PCR) methods and to assess recurrence-free survival (RFS) between subtypes as determined by the two methods. Patients and Methods:. We included a total of 441 operable breast cancer patients, consisting of the training (n = 116), testing (n = 56) and validation (n = 269) cohorts in this study. Protein levels of estrogen receptor (ER) and progesterone receptor (PR) were obtained by using the IHC and that of human epidermal growth factor receptor 2 (HER2) by the IHC/FISH methods. Expression (mRNA) levels of the corresponding genes, ESR1, PGR, and ERBB2, respectively, were determined by the RT-PCR method. We then compared the status of ER (ESR1), PR (PGR), and HER2 (ERBB2) in the training, testing and validation cohorts. We categorized all validation cases into luminal (ER/PR-positive and HER2-negative), HER2 (HER2-positive regardless of ER/PR status), and triple negative (TN: ER-, PR-, and HER2-negative) subtypes accordingly. The concordance of the two methods and RFS estimated by the Kaplan-Meier methods of the three different subtypes were revealed to evaluate the clinical performance. Results:. The concordance rates between the two methods in the validation cohort were 95.1% (Kappa = 0.74) for ER (ESR1), 91.1% (Kappa = 0.67) for PR (PGR), and 93.6% (Kappa = 0.59) for HER2 (ERBB2). Kappa statistic was 0.66 for the resulting luminal, HER2 and TN subtypes. The 5-year RFS was 83.3% for luminal vs. 73.9% for HER2 vs. 48.4% for TN subtypes as determined by the IHC (p = 0.019), and 84.3% vs. 66.3% vs. 54.4% by the RT-PCR method (p = 0.016). Conclusions:. Whereas discordance existed for some cases between the IHC and RT-PCR methods for determination of the ER (ESR1), PR (PGR), and HER2 (ERBB2) status and the resulting subtypes; both the methods showed values in RFS prognosis of the population studied. It is arguable that supplementing the conventional IHC with the molecular method for subtyping of breast cancer may have beneficial clinical implications.
Citation Format: Lei Lei, Xiaojia Wang, Skye Hung-Chun Cheng. Correlation of ER (ESR1), PR (PGR), and HER2 (ERBB2) at protein and mRNA levels in operable breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-22.
Abstract P2-10-04: Breast cancer risk assessment tool (BCRAT) predicted breast cancer incidence and breast cancer mortality in the women's health initiative
Authors: Nelson Rebecca , Pan Kathy , Chlebowski Rowan , Rohan Thomas E , Mortimer Joanne , Wactawski-Wende Jean , Lane Dorothy , Kruper Laura 
Published: March 2022

Abstract
Purpose Commonly used breast cancer risk models estimate breast cancer incidence. However, such model performance, re-purposed to predict breast cancer mortality, are largely unknown. Therefore, we examined whether the BCRAT model predicts long-term breast cancer mortality in postmenopausal women in the WHI. Participants and Methods Of 161,808 WHI participants aged 50-79 years, after exclusions,145,408 were in the analysis. BCRAT risk was calculated, with incident breast cancers verified by central medical record review. Breast cancer mortality was related to BCRAT 5-year risk groups (&lt; 1%, 1-2.99%, ≥ 3%) using unadjusted Cox proportional hazard models and in age-stratified, multi-variable models. An addition analysis compared proportion of participants with BCRAT risk ≥ 1.67% and ≥ 3% (former and current prevention thresholds). Results Of 145,408 participants, the ≥1.67% and the ≥3.0% risk groups included 40% and 9% of participants, respectively. Compared to women with BCRAT&lt;1% risk, women with BCRAT ≥ 3% risk had more common breast cancer family history and lower BMI. After 20 years median follow-up, with 8,849 breast cancers and 1,076 deaths from breast cancer, risk of death from breast cancer in BCRAT risk group ≥ 3% was not higher compared to BCRAT risk group &lt;1%. (Hazard Ratio [HR] 1.06 95% Confidence Interval [CI] 0.80-1.40, P = 0.76). Similarly, risk of death from breast cancer in BCRAT risk group 1-2.99% was not higher compared to BCRAT risk group &lt;1 (HR 1.15 95% CI 0.93-1.43). Conclusions Current guideline recommendation for threshold for endocrine-targeted interventions substantially reduces postmenopausal prevention candidates from 40% to &lt;10%. The BCRAT prediction model, even at the ≥ 3% 5-year risk threshold, does not identify women at significantly increased risk of death from breast cancer.
Citation Format: Rebecca Nelson, Kathy Pan, Rowan Chlebowski, Thomas E Rohan, Joanne Mortimer, Jean Wactawski-Wende, Dorothy Lane, Laura Kruper. Breast cancer risk assessment tool (BCRAT) predicted breast cancer incidence and breast cancer mortality in the women's health initiative [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-04.
Abstract P2-10-09: Oxysterol profiling in breast adipose tissue identifies brassicasterol and 24-hydroxycholesterol as breast cancer risk predictors
Authors: Chen I-Chun , Kuo Wen-Hung , Hu Fu-Chang , Wang Ming-Yang , Lu Yen-Shen , Lütjohann Dieter , Lin Ching-Hung 
Published: March 2022

Abstract
Background: Hyperlipidemia and serum oxysterol levels are known to be associated with breast cancer risk. In murine model, altered oxysterol levels in adipose tissue were identified in obese mice. However, the significance of oxysterol levels in human adipose tissue and their association with breast cancer risk were largely unknown. In this study, we aimed to quantify the levels of different oxysterols in adipose tissue and to establish their association with breast cancer risk. Methods: The breast adipose tissue was collected from patients who underwent surgery at a tertiary medical center for benign breast disease or breast cancer. We have profiled oxysterol levels by liquid chromatography-mass spectrometry. Multivariate analysis was used to analyze the relationship of adipose tissue oxysterol levels and breast cancer risk. Result: Breast adipose tissue from 279 subjects (benign low risk, n=58; benign high risk, n=33, and breast cancer, n=188) collected between March 2009 and November 2014 were included in this analysis. Parity is a protective factor both for breast cancer in premenopausal and postmenopausal groups. Brassicasterol ≤0.28 ng/mg (OR=6.739, 95% C.I.=2.092-21.707, p=0.001) and age &gt;40.06 years old (OR=3.774, 95% C.I.=1.328-10.722, p=0.013) in premenopausal patients; high log (7α-. hydroxycholesterol) levels (OR=6.690, 95% C.I.=1.915-23.369, p=0.003) and 24-hydroxycholesterol &gt;0.92ng/mg (OR=4.539, 95% C.I.=1.153-17.866, p=0.030) in postmenopausal patients were associated with increased BC risk. Sitosterol ≤3.03ng/mg (OR=0.057, 95% C.I.= 0.016-0.205, p &lt;0.0001) and brassicasterol level (OR=0.011, 95% C.I.= 0.001-0.222, p=0.003) were most important protective factors for BC in premenopausal and postmenopausal patients, respectively. Conclusion: Taken together, our study is the first cohort to prospectively profile oxysterol levels in breast adipose tissue. Brassicasterol and 24-hydroxycholesterol levels in adipose tissue predict breast cancer risk both in premenopausal and postmenopausal patients.
Citation Format: I-Chun Chen, Wen-Hung Kuo, Fu-Chang Hu, Ming-Yang Wang, Yen-Shen Lu, Dieter Lütjohann, Ching-Hung Lin. Oxysterol profiling in breast adipose tissue identifies brassicasterol and 24-hydroxycholesterol as breast cancer risk predictors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-10-09.
Abstract P2-12-10: Improving pathological complete response in luminal breast cancer after neoadjuvant chemotherapy
Authors: Cudós Ariadna Gasol , Murillo Serafin Morales , Galindo Alvaro Rodriguez , Subirats Ona Pallisé , Olivé Jordi Melé , Morales Carles Canosa , vilardell villellas Felip , Guzman Douglas René Sanchez , Rodriguez Joel Veas 
Published: March 2022

Abstract
Pathological complete response to neoadjuvant chemotherapy in luminal breast cancer is extremely low so its role is very controversial. We investigated whether the use Oncotype DX recurrence score ® could improve this response.We performed the Oncotype Dx in 103 patients with early breast cancer with high-risk clinical criteria to receive neoadjuvant chemotherapy. We reported the pathologic complete response (pCR) and its association with Oncotype DX.Median age was of 51 (24-87), median tumor size of 26 mm and 51 (57%) patients had initial node involvement. Median estrogen and progesterone receptor by histoscore was 280 and 40 and median Ki67 value was 30. 50 patients were less than 50 years old. Median Oncotype score was 30 (12-76) and 15 (14,6%) in the 11-18 score interval, 21 (20,4%) in the 18-25 and 67 (65%) with a score greater than 25. 24 (23,3%) patients obtained pCR, 22% in initial node involvement and 25% in not nodal involvement.The Oncotype DX its highly correlated with pCR (OD: 1,059, p: 0,004) in the multivariable analysis and in patients with Oncotype DX RS≥25 there was a strong correlation (OD: 18,295, P:0,005). pCR according with age (less or more than 50) and Oncotype Dx interval score is reported in the table.
Conclusion: Oncotype DX recurrence score ® predicts with great accuracy the pathologic complete response. Patients with RS 11-25 had a very low pCR, whereas patients with RS&gt;25 achieve a 34% of pCR. Based on initial considered High risk Score (&gt;31) we achieve a total of 18 to 42 patients of pCR (42%). Oncotype DX recurrence score ® allows a very considerable increase in the complete pathological responses after neoadjuvant chemotherapy, so it should be considered when selecting the patients who should receive neoadjuvant chemotherapy.
LESS THAN 50 YEARSMORE THAN 50 YEARSONCOTYPETOTALpCRTOTALpCRRS 11-18100 (0%)50 (0%)RS 18-25101 (10%)110 (0%)RS &gt; 253011(36%)3712 (32%)
Citation Format: Ariadna Gasol Cudós, Serafin Morales Murillo, Alvaro Rodriguez Galindo, Ona Pallisé Subirats, Jordi Melé Olivé, Carles Canosa Morales, Felip vilardell villellas, Douglas René Sanchez Guzman, Joel Veas Rodriguez. Improving pathological complete response in luminal breast cancer after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-10.
Abstract P2-13-15: VRN101396, a brain-permeable HER2 inhibitor, shows the anti-tumor activity in preclinical HER2-positive cancer models
Authors: Jung Hong-ryul , Kim Sunghwan , Yoo Jihye , Park Chan mi , Lee Somi , Lee Hyoju , Lee Youngyi , Park Jinhee , Seo Kyungah , Seo Dong-Hyuk , Ko Eunhwa , Son Jung Beom , Kim Deakwon , Choi Hwan Geun , Kim Nam Doo 
Published: March 2022

Abstract
Breast cancer (BC) is the second most common cancer associated with brain metastasis (BM) and among patients with breast cancer brain metastasis (BCBM), human epidermal growth factor receptor 2 (HER2)-positive breast cancer is most likely to develop BM. The overall prognosis of HER2-positive BCBM remains dismal with median survival time after BM of less than a year. Drugs like T-DM1, T-DXd and Tucatinib are reported to deliver a progression-free survival benefit in HER2-positive BCBM patients, but there are still unmet needs for a drug that crosses the blood brain barrier more effectively. We develop VRN101396, a brain penetrant, orally available, and irreversible small molecule inhibitor targeting HER2 to offer a new therapeutic option for the treatment of HER2-positive BCBM. VRN101396 potently inhibits catalytic activity of HER2 but spares wild-type EGFR. In HER2-positive breast cancer cell lines BT474 and SK-BR3 and gastric cancer cell line NCI-N87, VRN101396 inhibited the cell proliferation and phosphorylation of HER2 with single- or double-digit nanomolar IC50 values while inhibiting wild type EGFR with an IC50 value of &gt;100 nM. In both subcutaneous and intracranial efficacy mouse models, once-daily oral dose of VRN101396 significantly inhibited tumor growth and achieved tumor regression. In N87 subcutaneous xenograft model, VRN101396 alone showed superior efficacy to the combination of Tucatinib and Trastuzumab. Additionally, in intracranial xenograft model, VRN101396 showed superior efficacy to Tucatinib. Pharmacokinetics of VRN101396 displayed higher brain exposure than tucatinib and lapatinib, indicating better target engagement in the brain. Pharmacodynamic analysis revealed that VRN101396 reduced phosphorylation of HER2, HER3, AKT, and ERK compared to vehicle group after administration up to 24 hours. In conclusion, VRN101396 is a therapeutic candidate for the treatment of HER2-positive BC, BCBM and gastric cancer.
Citation Format: Hong-ryul Jung, Sunghwan Kim, Jihye Yoo, Chan mi Park, Somi Lee, Hyoju Lee, Youngyi Lee, Jinhee Park, Kyungah Seo, Dong-Hyuk Seo, Eunhwa Ko, Jung Beom Son, Deakwon Kim, Hwan Geun Choi, Nam Doo Kim. VRN101396, a brain-permeable HER2 inhibitor, shows the anti-tumor activity in preclinical HER2-positive cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-15.
Abstract P3-09-06: Targeting tumor subpopulations based on single-cell transcriptomics
Authors: Grible Jacqueline M , Leftwich Tess , Olex Amy L , Duong Alex K , Hairr Nicole , Rashid Narmeen S , Smith Timothy M , Signaevskaia Lia , Boyd David C , Dozmorov Mikhail G , Harrell Joshua C 
Published: March 2022

Abstract
Breast cancers that are hormone receptor negative, such that they do not express the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2), are known as triple-negative breast cancer (TNBC), and are predominantly of the basal-like subtype. These tumors aggressively metastasize, have limited effective therapeutic options, and are prevalent in patients of African descent. In these studies, we utilized a racially diverse set of 21 breast cancer patient-derived xenografts (PDXs) and 6 cell lines to identify new therapeutic combinations that may exhibit increased efficacy for patients based on ancestral heritage. Tumor subpopulation abundance was measured by single-cell RNA-sequencing (scRNAseq) a set of 13 PDXs, including some that had been subjected to long term carboplatin treatment or endocrine therapy in vivo. We identified two to four major cell types per PDX and sought to integrate this information with cytotoxic high throughput screens (HTS) of 516 clinically actionable agents. Among several interesting and overlapping findings from these multiscale models, BIRC5 (Survivin) was identified as a readily actionable target in the proliferative component of all TNBC models assayed. Analysis of public datasets found that BIRC5 expression in TNBC patient tumors was significantly correlated with reduced metastasis-free survival. In vitro and in vivo studies from our group and others found that YM155, which targets Survivin, was highly cytotoxic towards breast cancer cells. YM155 has been previously safely administered in Phase I/II clinical trials. To uncover putative dependency pathways that may be exploited to prevent acquired resistance to BIRC5 (Survivin) inhibition, we performed synergistic HTS assays whereby the efficacy of our 516 therapeutic library was assessed in the presence versus absence of YM155. Those drugs which were found to be more highly effective when given in combination with YM155 were then selected for ongoing in vitro and in vivo applications. Grant ID: 1R01CA246182-01A1 (NIH/NCI), CCR19608826 (Susan G. Komen Foundation), VCU School of Medicine VETAR, the Jeffress Trust, UL1TR002649 (CTSA/NCATS)
Citation Format: Jacqueline M Grible, Tess Leftwich, Amy L Olex, Alex K Duong, Nicole Hairr, Narmeen S Rashid, Timothy M Smith, Lia Signaevskaia, David C Boyd, Mikhail G Dozmorov, Joshua C Harrell. Targeting tumor subpopulations based on single-cell transcriptomics [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-06.