bluuebunny/crossref_metadata_2025 huggingface dataset:
Perioperative Management of a Patient with Secreting Paraganglioma Undergoing Cesarean Section
Authors: Bettencourt Ana Rita , Alves Catarina
Published: March 2022

Paraganglioma is a catecholamine-secreting tumor (CST) in extra-adrenal autonomic ganglia and a rare cause of hypertension during pregnancy. If not properly treated, it can lead to disastrous outcomes for both the mother and fetus. This report describes the successful anesthetic management of a paraganglioma diagnosed during pregnancy. A pregnant woman, with 32 weeks of gestational age, presented with severe paroxysmal hypertension, refractory to methyldopa and nifedipine at maximum dosages, headache, sweating, and palpitations. Diagnostic work-up was positive for elevated serum and urinary normetanephrines, and magnetic resonance showed a solid nodule above the hilum of the right kidney, suggestive of paraganglioma. Optimal alpha-blockade was achieved with doxazosin, and given the advanced gestational age, tumor resection was postponed until after delivery. Cesarean delivery was scheduled at 34 weeks, under combined spinal-epidural anesthesia and continuous blood pressure monitoring. Antihypertensive drugs were prepared for immediate administration as needed. Intraoperative and postoperative periods went uneventfully for both the mother and newborn, both under intensive care observation for 24 h.
Kernel Least Logarithmic Absolute Difference Algorithm
Authors: Fu Dongliang , Gao Wei , Shi Wentao , Zhang Qunfei
Published: March 2022

Kernel adaptive filtering (KAF) algorithms derived from the second moment of error criterion perform very well in nonlinear system identification under assumption of the Gaussian observation noise; however, they inevitably suffer from severe performance degradation in the presence of non-Gaussian impulsive noise and interference. To resolve this dilemma, we propose a novel robust kernel least logarithmic absolute difference (KLLAD) algorithm based on logarithmic error cost function in reproducing kernel Hilbert spaces, taking into account of the non-Gaussian impulsive noise. The KLLAD algorithm shows considerable improvement over the existing KAF algorithms without restraining impulsive interference in terms of robustness and convergence speed. Moreover, the convergence condition of KLLAD algorithm with Gaussian kernel and fixed dictionary is presented in the mean sense. The superior performance of KLLAD algorithm is confirmed by the simulation results.
Noncanonical Function of AGO2 Augments T-cell Receptor Signaling in T-cell Prolymphocytic Leukemia
Authors: Braun Till , Stachelscheid Johanna , Bley Nadine , Oberbeck Sebastian , Otte Moritz , Müller Tony Andreas , Wahnschaffe Linus , Glaß Markus , Ommer Katharina , Franitza Marek , Gathof Birgit , Altmüller Janine , Hallek Michael , Auguin Daniel , Hüttelmaier Stefan , Schrader Alexandra , Herling Marco
Published: March 2022

T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-refractory T-cell malignancy with limited therapeutic options and a poor prognosis. Current disease concepts implicate TCL1A oncogene-mediated enhanced T-cell receptor (TCR) signaling and aberrant DNA repair as central perturbed pathways. We discovered that recurrent gains on chromosome 8q more frequently involve the argonaute RISC catalytic component 2 (AGO2) gene than the adjacent MYC locus as the affected minimally amplified genomic region. AGO2 has been understood as a protumorigenic key regulator of miRNA (miR) processing. Here, in primary tumor material and cell line models, AGO2 overrepresentation associated (i) with higher disease burden, (ii) with enhanced in vitro viability and growth of leukemic T cells, and (iii) with miR-omes and transcriptomes that highlight altered survival signaling, abrogated cell-cycle control, and defective DNA damage responses. However, AGO2 elicited also immediate, rather non–RNA-mediated, effects in leukemic T cells. Systems of genetically modulated AGO2 revealed that it enhances TCR signaling, particularly at the level of ZAP70, PLCγ1, and LAT kinase phosphoactivation. In global mass spectrometric analyses, AGO2 interacted with a unique set of partners in a TCR-stimulated context, including the TCR kinases LCK and ZAP70, forming membranous protein complexes. Models of their three-dimensional structure also suggested that AGO2 undergoes posttranscriptional modifications by ZAP70. This novel TCR-associated noncanonical function of AGO2 represents, in addition to TCL1A-mediated TCR signal augmentation, another enhancer mechanism of this important deregulated growth pathway in T-PLL. These findings further emphasize TCR signaling intermediates as candidates for therapeutic targeting.

Significance:

The identification of AGO2-mediated activation of oncogenic T cells through signal amplifying protein–protein interactions advances the understanding of leukemogenic AGO2 functions and underlines the role of aberrant TCR signaling in T-PLL.
Abstract CS1-1: Oligometastatic disease: Definitions and practice patterns
Authors: Lievens Y
Published: March 2022

Available evidence on oligometastatic disease (OMD) and its treatment, more in particular the use of metastasis directed radiotherapy (MDRT), mostly derives from retrospective, single-center series, with significant heterogeneity in patient inclusion criteria, definition of OMD, and outcomes reported. No molecular biomarker being clinically available for the identification of patients with true OMD, its diagnosis is typically based on imaging findings. However, the presentation on imaging may represent a whole range of different clinical scenarios, depending on the moment in the disease history, and the use - or not - of systemic therapy. Based on the available data, consensus was reached amongst radiation oncology experts representing ASTRO and ESTRO, that OMD can to date be defined as 1-5 metastatic lesions, both occurring synchronously or metachronously, in which a controlled primary tumor is considered optional but with as prerequisite that all metastatic sites must be safely treatable. Moreover, in a collaboration between the ESTRO and EORTC, subclassification into oligorecurrence, oligoprogression, and oligopersistence was suggested, depending on whether OMD is diagnosed during a treatment-free interval or during active systemic therapy and whether or not an oligometastatic lesion is progressing on current imaging.While further evidence is being generated in (randomized) clinical trials as well as through collecting real-world data from clinical practice, it is imperative to use consistent definitions and reporting to further refine and validate the OMD classification and nomenclature, and to acquire a better understanding of the true impact of MDRT in different clinical scenarios.

Citation Format: Y Lievens. Oligometastatic disease: Definitions and practice patterns [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 CS1-1.
Abstract ES3-2: Clinical management of moderate penetrance genes
Authors: Kurian AW
Published: March 2022

Genetic epidemiologic studies have found that germline pathogenic mutations in the following 12 genes confer a substantial (two-fold or higher) increase in breast cancer risk: ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D and TP53. Mutations in several of these genes, including the notable examples of ATM, CHEK2 and PALB2, are classified as “moderate penetrance”: conferring a relative risk of breast cancer that is between two-times and five-times higher than that of the average woman. Next-generation sequencing technology and lower costs have enabled the widespread use of multiplex germline testing panels that contain both high and moderate penetrance genes. Recent studies have reported a relatively high prevalence of ATM, CHEK2 and PALB2 mutations among unselected breast cancer patients (approximately 0.5-1% per gene), including among women diagnosed at older ages. ATM and CHEK2 mutations are associated with elevated risks of hormone receptor-positive breast cancer, while PALB2 mutations are more associated with triple-negative disease. Important recent developments in the clinical management of patients with moderate penetrance gene mutations include model-based estimates of optimal breast screening protocols; evidence suggesting the safety of adjuvant radiotherapy; emerging data on susceptibility to targeted therapy with poly(ADP-ribose) polymerase inhibitors; and characterization of the risks of developing other, non-breast cancers. Ongoing studies and future research priorities will be discussed.

Citation Format: AW Kurian. Clinical management of moderate penetrance genes [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 ES3-2.
Abstract ES8-2: Can radiation replace ALND after positive SLNB?
Authors: Jagsi R
Published: March 2022

Growing recognition of the adverse impact of lymphedema on quality of life of survivors of breast cancer has motivated efforts to identify alternatives to axillary lymph node dissection. In some patients who have positive sentinel lymph nodes, radiation therapy may provide a more tolerable alternative to ALND without compromising disease control. This session will focus on the results of the key randomized trials directly evaluating this question: AMAROS and OTOASOR, as well as the implications of other trials that can help to identify patients in whom de-escalation of axillary surgery appears safe.

Citation Format: R Jagsi. Can radiation replace ALND after positive SLNB? [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 ES8-2.
Abstract P1-06-09: The role of miR-155-5p in MSI2 induced metastasis of prolonged DEHP exposed triple-negative breast cancer cells
Authors: Jadhao Mahendra Gunvantrao , Chiu Chien Chih
Published: March 2022

Phthalate leaching, environmental pollution,and human exposure is major issue. Endocrine disrupting effects of phthalate exposure on human health are well documented affecting hormonal balance, reproductive system, endometriosis, and is a suspected carcinogen. Continuous and prolonged use of plastic products leads to direct human exposure to phthalates, a problem observed in developing countries. In an attempt to mimic continuous human exposure to phthalates, we investigated the effects of long term DEHP exposure at physiological concentration on breast cancer cells. Long-term DEHP exposure enhanced migration and invasion in triple negative breast cancer cells in vitro and in vivo zebrafish xenograft assay indicating ER independent activity of DEHP. NGS identified oncogenic protein, Musashi RNA binding protein2 (MSI2) as metastasis regulator in DEHP exposed breast cancer cells. Elevated MSI2 expression induced metastatic potential through MSI2/Vimentin interaction, EMT and PI3K/Akt/NFκB/MMP9 axis activation. Besides metastatic properties MSI2 overexpression increased stem cell potential in triple negative breast cancer cells. Novel MSI2-Vimentin protein-protein interaction was evidenced in DEHP exposed breast cancer cells highlighting new function of MSI2 apart from RNA-binding and translation regulation. Reduced expression of miR-155-5p was found to negatively regulate MSI2 expression in DEHP exposed breast cancercells. miR-155-5p mimic treatment reduced expression of MSI2 and MSI2 mediated metastasis. MSI2 knockdown reversed EMT and PI3K/Akt/NFκB/MMP9 axis induced metastasis in vitro and in vivo zebrafish xenograft in DEHP exposed breast cancer cells, showing no effect non DEHP exposed breast cancer cells. Organ specific metastasis activity was observed in invivo mouse breast cancer metastasis model showing lung metastasis in DEHP exposed breast cancer cell implanted mice. MSI2 depletion reduced lung metastasis in vivo, however no effectof MSI2 depletion observed on proliferation and tumor size. MSI2 targeting might serve as a promising strategy to overcome highly metastatic breast cancer and to limit stem cell like cancer progression. Keywords: Breast cancer;DEHP; long phthalate exposure; ATP-binding transporter proteins; drug resistance; tariquidar; NGS; MSI2; metastasis; EMT; Vimentin; miR-155-5p;stemness

Citation Format: Mahendra Gunvantrao Jadhao, Chien Chih Chiu. The role of miR-155-5p in MSI2 induced metastasis of prolonged DEHP exposed triple-negative breast cancer cells [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 P1-06-09.
Abstract P1-19-01: Palbociclib plus endocrine therapy significantly enhances overall survival of HR+/HER2- metastatic breast cancer patients compared to endocrine therapy alone - A large institutional study
Authors: Raghavendra Akshara Singareeka , Ha Min Jin , Kettner Nicole M. , Damodaran Senthil , Layman Rachel , Hunt Kelly K , Shen Yu , Tripathy Debu , Keyomarsi Khandan
Published: March 2022

PURPOSE: Cyclin-dependent kinase 4/6 inhibitor (CDKi) therapy combined with endocrinetherapy is considered standard of care for patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer (BC). The Breast Medical Oncology Database at MDAnderson Cancer Center (MDACC) was analyzed to assess effectiveness of CDKi+palbociclib. PATIENTS AND METHODS: From a total of 5402 advanced HR+ HER2- BC patients referred toMDACC between 1997 and 2020, we identified eligible patients who received palbociclib incombination with first- (n=778) and second-line (n=410) endocrine therapy. We furtheridentified “control” patients who received endocrine therapy alone in the first- (n=2452) andsecond-line (n=1183) setting. We conducted a propensity score matching analysis to balancethe baseline demographic and clinical characteristics between the palbociclib treated andcontrol cohorts to assess the effect of palbociclib treatment on progression-free survival (PFS)and overall survival (OS). Stratified log-rank test was used to assess the effect of palbociclib inthe matched cohorts. RESULTS: For the propensity-matched cohort in the first-line setting (n=708), the palbociclibgroup had significantly longer median PFS (17.4 vs. 11.1 months; p<0.0001) compared tocontrols. Median OS (44.3 vs. 40.2 months; p =1) did not show any survival benefit in the firstline setting. However, in the second-line setting, with 380 propensity-matched cohort, thepalbociclib group had significantly longer PFS (10 vs 5 months, p<0.0001) as well as OS (33 vs 24months; p < 0.022), compared to controls.2. CONCLUSION: In this single center analysis, of a large cohort of metastatic HR+ HER2- BCpatients, palbociclib in combination with endocrine therapy was associated with improved PFSin both first- and second-line settings and OS in the second-line setting compared withendocrine therapy alone cohort.3

Citation Format: Akshara Singareeka Raghavendra, Min Jin Ha, Nicole M. Kettner, Senthil Damodaran, Rachel Layman, Kelly K Hunt, Yu Shen, Debu Tripathy, Khandan Keyomarsi. Palbociclib plus endocrine therapy significantly enhances overall survival of HR+/HER2- metastatic breast cancer patients compared to endocrine therapy alone - A large institutional study [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 P1-19-01.
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

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

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<0.001), have poorly differentiated tumors (grade 3; MRM 63.7%, no MRM 46.7%; p<0.001) and metastasis in only one organ site (MRM 69.8%, no MRM 52.2%; p<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

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

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 (< 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<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 <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 <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 <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

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 >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 >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 <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

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>25 achieve a 34% of pCR. Based on initial considered High risk Score (>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 > 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

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 >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

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.
Abstract P3-19-19: Intraoperative Radiation Therapy (IORT) : A large integrated healthcare system’s approach and outcomes
Authors: Tang Annie , Kelly Jason , Cureton Elizabeth , Svahn Jonathan , Thomas Eva , Lyon Liisa , Shim Veronica
Published: March 2022

Background: With TARGIT-R(Retrospective) showing a higher-than-expected ipsilateral breast tumor recurrence (IBTR) the community setting for intraoperative radiation therapy (IORT), we evaluated IORT outcomes in an integrated health care system.Methods: A retrospective review of early breast cancer patients who received IORT between February 2014-February 2020 was performed. IORT was offered at a single medical center within a large integrated healthcare system. Criteria for IORT included patients ≥50 years with T1, low to intermediate grade, endocrine-responsive HER2- invasive ductal carcinoma. All breast cancer patients were reviewed at weekly multidisciplinary breast conferences, and IORT was offered when patients met the eligibility criteria. Primary outcomes include IBTR, mortality, and complications. Results: Of 5,731 potentially eligible patients, 245 patients (4.3%) underwent IORT. Mean age was 65.4 ± 0.4 years with median follow-up 3.5 years ± 2.2 months. Based on American Society of Radiation Oncology guideline, 51% were suitable, 38.4% cautionary, and 10.6% unsuitable candidates based on the final pathology. The patients were reassigned to the cautionary group because of the margin width and/or extensive DCIS. Unintended boost (primary IORT followed by whole-breast radiation) was given in 6.5% of IORT patients. At median follow-up of 3.5 years, IBRT was 3.7% for all patients. There was one breast-cancer-related mortality (0.4%), and 7 mortality (2.9%) from other causes. Although not statistically significant, there was a trend towards higher recurrence in those not adherent with endocrine treatment than those who were (7.4% vs 1.9%, p=0.07). The overall complication rate was 14.7% with seroma as the most common.Conclusions: At 3.5-year follow-up, our IORT IBTR rate of 3.7%. Our protocol subsequently was modified to require all IORT patients to receive surgical shave margins, WBI for all cautionary patients on the final pathology, and requirement of endocrine treatment.

Citation Format: Annie Tang, Jason Kelly, Elizabeth Cureton, Jonathan Svahn, Eva Thomas, Liisa Lyon, Veronica Shim. Intraoperative Radiation Therapy (IORT) : A large integrated healthcare system’s approach and outcomes [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 P3-19-19.
Abstract P3-20-05: Trends of axillary treatment in sentinel node-positive breast cancer patients undergoing amputation
Authors: Verreck Eline EF , van Steenhoven Julia , Kuijer Anne , van Maaren Marissa , Siesling Sabine , van Dalen Thijs
Published: March 2022

Objectives: To evaluate patterns of care in axillary treatment of Dutch patients - who were diagnosed with stage I-IV primary invasive breast cancer, underwent amputation and were found positive by sentinel lymph node biopsy (SLNB) - in the years following the publication of the American College for Surgeons Oncology Group (ACOSOG)-Z0011 and After Mapping of the Axilla: Radiotherapy Or Surgery (AMAROS) trials. Methods: Data from females diagnosed between January 1st 2009 and December 31st 2018 were obtained from the Netherlands Cancer Registry (NKR). Trends in completion axillary lymph node dissection (cALND), administration of adjunctive radiotherapy and, inversely, of omission of any kind of axillary treatment, were revealed by descriptive analyses on SNL positive patients. Results: Of 28,070 cT1-4 breast cancer patients undergoing amputation with SLNB from 2009 up until 2018, 10,706 were diagnosed as SLN positive. In the latter, the frequency of subsequent cALND went down significantly from 78% in 2009 to 10% in 2018 (P < 0.001), while adjunctive radiotherapy increased from 4% to 49% (P < 0.001). Omission of any additional local treatment increased from 18% to 41% (P < 0.001). In N1 patients cALND decreased from 57% to 13% (P < 0.001) and was mostly replaced by radiotherapy, increasing from 2% to 70% (P < 0.001). In N1mi and N0i+ patients, cALND decreased to less than 1% of cases in 2018, while radiotherapy increased from 4% to 40% and 8% to 13% (P < 0.001), respectively. Conclusion: In SLN positive breast cancer patients undergoing breast amputation, cALND had become rare 10 years following the AMAROS and Z0011 trial results. While radiotherapy mostly replaced cALND in the vast majority of N1 patients, less than half of N1mi and only a tenth of N0i+ patients received radiotherapy as the only adjunctive axillary treatment by the end of 2018.

Citation Format: Eline EF Verreck, Julia van Steenhoven, Anne Kuijer, Marissa van Maaren, Sabine Siesling, Thijs van Dalen. Trends of axillary treatment in sentinel node-positive breast cancer patients undergoing amputation [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 P3-20-05.
Abstract P3-20-10: Local recurrences after mammary adenectomy with clear retroareolar margin for the treatment of early infiltrating breast carcinomas
Authors: Heinzen Rebeca Neves , de Barros Alfredo CarlosSimõesDornellas , Jacomo Alfredo , Cinquini Marcella
Published: March 2022

Introduction. Mammary adenectomy (MA) is an evolving surgical procedure for patients with breast cancer (BC). It entails the resection of all gross visible glandular tissue, while preserving the overlying breast skin envelope and the nipple-areolar complex (NAC). For achieving the best oncologic outcomes it is recommended the obtainance of clear surgical margins, mainly the retroareolar, and careful selection of the patients to be treated accordingly. Here, we performed a study aiming to assess the local recurrences rate in patients who underwent MA for BC therapy. Methods. A retrospective cross-sectional study was carried out at a private Service (Clínica Prof. Alfredo Barros). Patients with invasive BC measuring up to 3.0 cm and at least 2.0 cm far from the NAC by resonance magnetic imaging, were elegible, while others with more than 3 foci of neoplasia, nipple discharge or neoadjuvant chemotherapy were excluded. All of them were submitted to MA and selective axillary dissection and reconstruction by immediate prothesis implants, with clear retroareolar margin by intraoperative cytology and frozen section exams, and intra-nipple ducts excision. External radiotherapy was delivered when more than 3 affected axillary lymph nodes were involved. Results. A total of 18 cases were analysed. Patient’s mean age was 51.5 years. The histopathologic subtypes were: invasive carcinoma (NOS) 146 (80.7%), infiltrative lobular 26 (14.4%), micropapilar 3 (1.7%) and others 6 (3.3%). Mean tumor size was observed 1.8 cm (0.4-5.0). Multicentricity/multifocality was observed in 62 cases (34.2%) a total of 144 cases presented positivity for estrogen receptor (86.7%), 144 (79.6%) for progesterone receptor, and 29 were HER2 positive (16.0%). In 98 cases (54.1%) a small padge of skin covering the tumor area was removed. Irradiation was ministered to 50 patients (27.6%). After a mean follow up period of 39.9 months (6-178), ten cases of local recurrences were detected (5.5%). No one case of local relapse was detected in the sub-NAC area Conclusion. Our data indicated that the local recurrences rate after therapeutic MA for well selected BC patients is low and acceptable. 2

Citation Format: Rebeca Neves Heinzen, Alfredo CarlosSimõesDornellas de Barros, Alfredo Jacomo, Marcella Cinquini. Local recurrences after mammary adenectomy with clear retroareolar margin for the treatment of early infiltrating breast carcinomas [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 P3-20-10.
Abstract P4-01-18: Acquired sensitivity strategies in ER+ breast cancer progressing on CDK4/6 and mTOR inhibitors
Authors: Farmaki Eleni , Emond Rena , Cosgrove Patrick , Bild Andrea
Published: March 2022

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and mammalian target of rapamycin (mTOR) inhibitors have become important components of the clinical management of metastatic ER+ breast cancer. Despite the benefit of these treatments, progression and resistance will still develop in the majority of patients. Therefore, it is important to research strategies that can increase response durability and effectiveness of these therapies. The aim of our study is to use the identified acquired resistance targets in progressing patients for treatment approaches. Our previous studies on the evolution of resistance using transcriptomic analysis in earlier stage patients as they progress on therapy identified resistance pathways that include the MAPK, AKT, and survival signaling pathways. We used isogenic breast cancer cell lineages sensitive and resistant to CDK4/6 inhibitors, ribociclib and abemaciclib, and the mTOR inhibitor, everolimus, to determine the efficacy of drug combinations targeting the acquired resistance JNK, MAPK and AKT pathways. The effect of the pathways’ inhibition in the resistant cells was examined in vitro, in 2D drug response assays, and in 3D spheroid assays. Our results indicate increased potency in the resistant cells to the combination therapies with JNK and TIC10/ONC201 inhibitors which are currently seeing promise in clinical trials. These findings were validated in 2D and 3D in vitro studies with patient derived breast cancer cells under the same combination treatments, recapitulating the increased response to combination therapy and further supporting clinical relevance. In conclusion, our study leveraged our patient data cohorts as well as pre-clinical models to identify acquired sensitivity to JNK, MAPK and AKT inhibition. With the linking of both patient derived data with isogenic cell line driven experiments, our study provides validated findings in various settings strengthening the potential of clinical applications of these targetable pathways.

Citation Format: Eleni Farmaki, Rena Emond, Patrick Cosgrove, Andrea Bild. Acquired sensitivity strategies in ER+ breast cancer progressing on CDK4/6 and mTOR inhibitors [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 P4-01-18.