bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-10-01: Deciphering the heterogeneity of cell cycle in breast cancer and relevance to clinical application of CDK inhibitors
Authors: Knudsen Erik S. , Kumarasamy Vishnu M. , Wang Jianxin , Witkiewicz Agnieszka 
Published: March 2023

Abstract
BACKGROUND: Deregulation of cellular proliferation represents a defining hallmark of cancer. The mechanisms driving aberrant cell cycle progression across different breast cancer subtypes is highly diverse and likely contributes to therapeutic resistance in a variety of contexts. The significance of cell cycle heterogeneity is most clear in the context of metastatic HR+/HER2- breast cancer, wherein acquired and intrinsic resistance to CDK4/6 inhibition represents a significant clinical challenge. However, aberrant cell cycle regulatory networks likely further confound the use of targeted therapies in the context of TNBC. METHODS AND RESULTS: We employed unbiased analyses of large number of breast cancer models to decipher the genetic requirements for different CDK and Cyclins which drive proliferation and the significance to response to CDK4/6 inhibitors. Breast cancer cells harbor heterogeneity in the requirement for a given G1/S regulatory CDK or Cyclin. These dependencies are conditioned by the expression of the respective CDK or Cyclin, as well as other gene expression or genetic features present within the tumor that could represent putative biomarkers. In general, conventional dependency for CDK4 and Cyclin D1 is strongest in HR+/HER2- breast cancer models, whereas TNBC exhibits dependency on a variety of different CDK or Cyclin genes. Resistance to CDK4/6 inhibitors in HR+/HER2- breast cancer models, while occurring through a number of different primary mechanisms, functionally deregulates the phosphorylation of RB. However, genetically enforcing RB activation is sufficient to block proliferation, underscoring the opportunity to ameliorate resistance to CDK inhibitory strategies. CRISPR screens in HR+/HER2- and TNBC models are identifying new mediators of sensitivity and resistance to CDK4/6 inhibitors. Inherently, elevated expression of Cyclin E and p16INK4A are associated with resistance to multiple therapeutic approaches, including CDK4/6 inhibitors, but denote a requirement for CDK2. The cell cycle conditions disparately dependent on CDK4/D1 vs. CDK2/E can be visualized by multispectral imaging and used to direct CDK inhibitor based strategies. CONCLUSIONS: Together these studies illustrate the complex nature of breast cancer cell cycles which can confound therapy. However, understanding of this heterogeneity can create new opportunities for precision approaches targeting CDK/Cyclin-dependence therapeutically.
Citation Format: Erik S. Knudsen, Vishnu M. Kumarasamy, Jianxin Wang, Agnieszka Witkiewicz. Deciphering the heterogeneity of cell cycle in breast cancer and relevance to clinical application of CDK inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-10-01.
Abstract P3-10-02: Cell cycle dysregulation in breast cancer: why the details matter
Authors: Seker Sinem , Oropeza Elena , Carrel Sabrina , Mazumder Aloran , Punturi Nindo , Lei Jonathan , Anurag Meenakshi , Lim Bora , Bainbridge Matthew , Haricharan Svasti 
Published: March 2023

Abstract
Cell cycle dysregulation is a prerequisite for cancer formation. However, whether the type of cell cycle dysregulation event a cell incurs during transformation to malignancy influences the type of cancer that evolves or clinical outcome is unknown. In a comprehensive analysis of cell cycle dysregulation in breast cancer patient tumors, we associate mutations in each of four cell cycle checkpoint kinase genes, ATM, CHEK2, ATR and CHEK1, with known tumor characteristics and clinical outcome, and test these associations experimentally using transgenic mice, patient-derived xenografts and breast cancer cell line model systems. Results of this work demonstrate that dysregulation of specific cell cycle checkpoint kinases differently impacts the type of breast cancer that evolves in patients and in experimental model systems, and influences treatment responsiveness and disease progression. For instance, CHEK2 mutations associate preferentially with the incidence of metastatic, premenopausal estrogen receptor (ER)+/HER2- breast cancer in patient data (p=0.001) that is resistant to standard frontline therapy (HR=6.15, p=0.01). These associations appear causal when tested in an immune-competent genetically-engineered mouse model of Chk2 loss, in patient-derived xenograft, and in cell line experiments. On the other hand, ATR mutation by itself is not frequent in ER+/HER2- breast cancer, but co-incident mutation of ATR and TP53 is 2-fold enriched (p=0.002) and associates with metastatic progression (HR=2.01, p=0.007). Concordantly, ATR dysregulation induces metastatic phenotypes in ER+/HER- TP53 mutant, but not in TP53 wildtype, cell lines. Together, these results systematize the impact of individual cell cycle checkpoint kinases on the evolution of cancer subtypes, and on disease progression. Statement of Significance These findings reframe the paradigm of breast cancer classification through the lens of early cell cycle dysregulation events by demonstrating that cell cycle decisions during malignant transformation can direct the type of breast cancer that evolves, how it will respond to treatment, and whether it will metastasize. This work provides rationale for streamlined testing of checkpoint kinase dysregulation to improve precision diagnostics for cancer patients.
Citation Format: Sinem Seker, Elena Oropeza, Sabrina Carrel, Aloran Mazumder, Nindo Punturi, Jonathan Lei, Meenakshi Anurag, Bora Lim, Matthew Bainbridge, Svasti Haricharan. Cell cycle dysregulation in breast cancer: why the details matter [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-10-02.
Abstract P4-01-12: BAT8006, a novel FRα ADC with strong bystander effect, for the treatment of advanced solid tumor
Authors: mai siqi , Mei xingxing , Tang weijia , Zhou Xin , qi Xuekang , Zhong Zhi , Li Shuoxu , fan Jianjun , Gan Jirong , Tan Binghua , Qi Yao , Guo Yanling , li Shengfeng , Yu Jin-Chen 
Published: March 2023

Abstract
FRα is overexpressed in a number of cancers, including ovarian, breast, lung cancer, and endometrial carcinoma, yet limited expression in normal tissue. Efficacy of anti-FRα ADC have been demonstrated in clinical trials for high FRα expression ovarian cancer. These results validate FRα as a viable target for cancer treatment. We have developed a novel FRα ADC with strong bystander killing effect, BAT8006, which consists of a high-affinity antibody, an enzymatically cleavable linker and a topoisomerase I inhibitor as the payload, with DAR of 8. BAT8006 shows high affinity for the FRα antigen (KD &lt; 0.5 nM) and FRα-expressing tumor cells. Upon binding to FRα on cell surface, BAT8006 internalizes effectively and traffics to the lysosome where payload is proteolytically released. BAT8006 demonstrated potent in vitro cell growth inhibitory activity to FRα-positive cells with IC50 values of ~ 1 nM. In an in vitro bystander killing assay, proliferation of FRα-negative cells was potently inhibited by addition of culture medium of BAT8006-treated FRα-positive cells, but not that of BAT8006-treated FRα-negative cells, indicating the bystander killing effect of the released payload in the culture medium. Less than 0.03% of the payload was released from BAT8006 when incubated with human or monkey plasma for 4 days in 37oC, suggesting the stability of BAT8006 in blood circulation. BAT8006 led to potent and dose-dependent tumor regression in patient-derived xenograft (PDX) model of SCLC. Furthermore, single dose of 2.5 mg/kg of BAT8006 showed complete eradication of tumor in choriocarcinoma JeG-3 xenograft mice model. In PDX of ovarian cancer, 2.5 mg/kg of BAT8006 (DAR8) demonstrated superior tumor inhibition activity than 5 mg/kg of BAT8006 with DAR4, suggesting the high DAR approach of BAT8006 would be more effective. In addition, BAT8006 showed favorable pharmacokinetic and safety profiles in cynomolgus monkeys with the highest non-severely toxic dose (HNSTD) of 30 mg/kg when dosed once every three weeks for 3 times. Together these results indicate that BAT8006 could potentially provide a therapeutic benefit to treat FRα-positive tumors including breast cancer in clinical trial.
Citation Format: siqi mai, xingxing Mei, weijia Tang, Xin Zhou, Xuekang qi, Zhi Zhong, Shuoxu Li, Jianjun fan, Jirong Gan, Binghua Tan, Yao Qi, Yanling Guo, Shengfeng li, Jin-Chen Yu. BAT8006, a novel FRα ADC with strong bystander effect, for the treatment of advanced solid tumor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-12.
Abstract P4-01-36: Real World Data for Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases
Authors: Toler Andrew , Bobolts Laura R. , Mangurian Mark , Pozotrigo Melissa , Wise Corey , Solomon Hiywete , Hartung Nicole , Makielski Rory , Marur Shika , Ravindranathan Meera , Marur Shanthi 
Published: March 2023

Abstract
Background: Trastuzumab deruxtecan (T-DXd) improves outcomes in HER2-positive metastatic breast cancer (MBC) patients, including patients with previously treated stable brain metastases (BMs). Our objective was to examine the characteristics of HER2-positive MBC patients with BMs prior to T-DXd use. Methods: We performed a retrospective cross-sectional study of T-DXd prior authorization (PA) approvals by OncoHealth for HER2-positive MBC patients between 1/17/2020 – 6/21/2022. Using medical records and utilization management data, we assessed the characteristics of PA approvals for 145 patients requesting T-DXd in Stage 4, HER2-positive, female MBC with BMs. Results: Brain metastases were identified in 41/145 patients with HER2-positive MBC prior to T-DXd authorization. Among the 41 patients The mean age was within the range of 50-59 years, 72% were hormone receptor-positive, and all were HER2 positive. 19/41(46%) had symptomatic BMs, 5/41(12%) had asymptomatic BMs. Prior local therapies for the BMs included craniotomy in 19.5% and brain radiotherapy in 87.8% prior to T-DXd. The median number of prior MBC therapies was 2 (range: 0-8) and 73% (30/41) did not receive tucatinib-based therapy prior to T-DXd. Tucatinib-based therapy was the most common subsequent line of therapy among T-DXd patients with further therapy (5/8). For available data (13 metastatic patients), 8 metastatic patients received tucatinib for an average of 149 days before receiving T-DXd for an average of 238 days, compared to 5 metastatic patients who received T-DXd for an average of 295 days before receiving tucatinib for 240 days, implying improved disease management in the T-DXd-to-tucatinib sequence. Conclusions: In the real world, patients with symptomatic, progressing BMs are more likely to receive T-DXd prior to tucatinib or potential tucatinib-based therapy, with longer duration of stability and treatment. Appropriate sequencing of available treatments with activity on brain metastases such as T-DXd and tucatinib-based therapy needs to be further studied.
Citation Format: Andrew Toler, Laura R. Bobolts, Mark Mangurian, Melissa Pozotrigo, Corey Wise, Hiywete Solomon, Nicole Hartung, Rory Makielski, Shika Marur, Meera Ravindranathan, Shanthi Marur. Real World Data for Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-36.
Abstract P4-02-23: Integrating tumor-intrinsic and immunological factors to improve locoregional treatment individualization of high-risk breast tumors
Authors: Tullberg Axel Stenmark , Sjöström Martin , Niméus Emma , Killander Fredrika , Lundstedt Dan , Kovács Anikó , Holmberg Erik , Karlsson Per 
Published: March 2023

Abstract
Background: The influence of the local immune infiltrate on tumor progression is dependent on tumor-intrinsic characteristics. Among highly aggressive subtypes, an immune infiltrate is associated with a favorable prognostic effect. The aim was to investigate whether the integration of histological grade and degree of tumor-infiltrating lymphocytes (TILs) permits improved treatment individualization for clinically high-risk tumors. Methods: The SweBCG91RT trial included 1178 patients with stage I-IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median time of 15.2 years. In total, 8% were treated with systemic therapy. Histological grade and TILs were evaluated on whole-tissue sections by board-certified pathologists. Grade III tumors were compared to grade I and II tumors. TILs were classified as high (&gt;=10%) or low (&lt; 10%). The primary endpoint was ipsilateral breast tumor recurrence (IBTR) within 10 years. Results: In total, 134 (57%) of the 235 grade III tumors had high TIL levels compared to grade I/II tumors where 142 (19.7%) out of 721 tumors exhibited high TIL levels. Grade III tumors with high TILs had a reduced risk of IBTR (HR 0.49, CI 95% 0.26-0.91, p=0.025) compared to grade III tumors with low TILs (HR 1.0). Among grade I/II tumors, high TILs was not prognostic (HR 1.02, CI 95% 0.62-1.68, p=0.95) compared to grade I/II tumors with low TILs (HR 1.0). Grade III tumors with low TILs had a high risk of recurrence without RT (36.2%) and derived benefit from RT (HR 0.16, CI 95% 0.047-0.53, p=0.0029). In contrast, grade III tumors with high TILs had a lower risk of IBTR without RT (14.5%) and did not benefit significantly from RT (HR 0.71, CI 95% 0.26-1.90, p=0.50). Conclusion: Measurements of the local immune infiltrate may improve treatment individualization when integrated with tumor-intrinsic features of aggressivity, such as histological grade. High-risk tumors with an immune infiltrate may be candidates for RT de-escalation.
Citation Format: Axel Stenmark Tullberg, Martin Sjöström, Emma Niméus, Fredrika Killander, Dan Lundstedt, Anikó Kovács, Erik Holmberg, Per Karlsson. Integrating tumor-intrinsic and immunological factors to improve locoregional treatment individualization of high-risk breast tumors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-23.
Abstract P4-03-03: Elevated Risk of Breast Cancer Diagnosis in Women with Dense Breasts reflects a similarly Elevated Risk of Breast Cancer Onset that is Robust to the Effect of Density on Mammography Sensitivity
Authors: Lange Jane M. , Gard Charlotte , O’meara Ellen , Etzioni Ruth 
Published: March 2023

Abstract
Dense breasts are associated with a higher risk of breast cancer diagnosis, which has impacted risk prediction tools and patient notification policies. However, given that mammography is less sensitive for women with dense breasts and these women may be subject to different confirmation testing pathways, the true association between breast density and cancer risk is unknown. We investigated the relationship between breast density and onset using a natural history model that accounts for differential sensitivity and rates of exams by breast density. Data consisted of Breast Cancer Surveillance Consortium mammogram and cancer outcomes among women aged 40-54 with a first digital mammogram between 2000-2018 (N=33,542). Of these, 15,092 had non-dense (almost entirely fatty or scattered fibroglandular densities) and18,450 had dense (heterogeneously dense or extremely dense) breasts. We estimated the empirical sensitivity of mammograms in dense and non-dense breasts (fraction of diagnosed cancers that were screen detected) and examined rates of mammograms by density. We estimated the relative risk of breast cancer diagnosis five years after the first exam using Kaplan Meier methods and the relative risk of breast cancer onset from a natural history model, assuming density-specific sensitivity was equal to the empirical sensitivity. Empirical sensitivity was .88 in women with non-dense and .78 in women with dense breasts. Mammogram utilization was somewhat higher in women with dense breasts (HR for subsequent mammograms 1.10 (95% CI [1.07, 1.12]). The relative risk of diagnosis for dense versus non-dense breasts was 1.80 (95% CI [1.46,2.57]); based on the natural history model the relative risk of onset was 1.73 [1.43,2.25]. The estimated relative risk of onset ranged from 1.67 to 2.03 under assumptions that the relative sensitivity of the screening episode for dense versus non-dense breasts was 1.0 to 0.4. In conclusion, the association of risk of breast cancer onset with breast density is robust to assumptions about the relative sensitivity in dense and non-dense breasts.
Citation Format: Jane M. Lange, Charlotte Gard, Ellen O’meara, Ruth Etzioni. Elevated Risk of Breast Cancer Diagnosis in Women with Dense Breasts reflects a similarly Elevated Risk of Breast Cancer Onset that is Robust to the Effect of Density on Mammography Sensitivity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-03.
Abstract P4-03-14: Proinflammatory Dietary Patterns and Risk of Total and Subtypes of Breast Cancer Among US Women
Authors: Romanos-Nanclares Andrea , Willett Walter C , Rosner Bernard A , Stover Daniel G , Asad Sarah , Sardesai Sagar , Holmes Michelle D , Chen Wendy Y , Tamimi Rulla M. , Tabung Fred K , Eliassen A Heather 
Published: March 2023

Abstract
Background: Dietary patterns promoting chronic inflammation, including the empirical dietary inflammatory pattern (EDIP), have been shown to strongly influence risk of weight gain, type 2 diabetes, cardiovascular disease, and colorectal cancer. However, it is unclear if this dietary pattern is associated with other tumors in which the mechanisms are not totally understood such as breast cancer. Methods: We prospectively followed 76,295 women from the Nurses’ Health Study (NHS, 1984-2016) and 91,078 women from the Nurses’ Health Study II (NHSII, 1991-2017). Diet was assessed by food frequency questionnaires (FFQs) every 4 years. The inflammatory potential of diet was evaluated using the previously established EDIP based on plasma C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha receptor 2 (TNF-αR2). Higher scores indicate higher inflammatory potential of the diet. Results: During 4,153,676 person-years of follow-up, we documented 10,632 invasive breast cancer cases (6,807 NHS; 3,825 NHSII). In the pooled multivariable-adjusted analyses, women in the highest, compared with the lowest, EDIP quintile were at higher breast cancer risk (HRQ5vsQ1=1.12; 95% CI 1.05, 1.20; P-trend&lt; 0.001). This association was attenuated after adjusting for weight change since age 18 y, although it remained significant (HRQ5vsQ1=1.07; 95% CI 1.00, 1.14; P-trend=0.01). In subtype analyses, we found evidence that the inflammatory potential of diet influenced breast cancer risk differentially by ER status (P-heterogeneity=0.038) and by molecular phenotype (P-heterogeneity=0.007), with the association between EDIP and breast cancer limited to ER-negative tumors (HRQ5vsQ1=1.31; 95% CI: 1.11, 1.55; P-trend=0.002; for ER-positive tumors, HR Q5vsQ1=1.03; 95% CI, 0.96, 1.12;P-trend=0.10) and basal-like tumors (HRQ5vsQ1=1.78; 95% CI: 1.19, 2.65; P-trend=0.004). Further adjustment for weight change since age 18 y did not materially alter the association for these subtypes. Conclusions: Dietary patterns with high potential to contribute to chronic systemic inflammation, based on higher EDIP scores, were associated with a modestly increased risk of breast cancer, which was more pronounced for ER-negative and basal-like breast tumors.
Citation Format: Andrea Romanos-Nanclares, Walter C Willett, Bernard A Rosner, Daniel G Stover, Sarah Asad, Sagar Sardesai, Michelle D Holmes, Wendy Y Chen, Rulla M. Tamimi, Fred K Tabung, A Heather Eliassen. Proinflammatory Dietary Patterns and Risk of Total and Subtypes of Breast Cancer Among US Women [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-14.
Abstract P4-03-32: Association between androgen receptor expression and recurrence free survival among locally advanced triple negative breast. Real world data from a single Institution in Mexico City
Authors: Alvarado Eder Araiza , Salinas Claudia Haydee Arce 
Published: March 2023

Abstract
Background The androgen receptor (AR) is expressed in 12-41% of the TNBC, contributes with differentiation, proliferation, apoptosis, and angiogenesis; its expression is associated with better recurrence free survival (RFS) and overall survival (OS). Objective The aim is to determine the association between AR and pathologic complete response (PCR), recurrence free survival (RFS) in TNBC patients treated with neoadjuvant chemotherapy (neoCT). Patients and methods Cross-sectional, retrospective cohort trial. Adult women with stage II-III TNBC, treated with neoCT from 2014 to 2021 were included. Incomplete medical record, AR not-determined, secondary malignant neoplasm were excluded. AR was determined with the VENTANA assay system, &gt; 1% were considered as positive. Statistical analyses included frequencies and range, comparison was done with X2, cox regression model was made for the prognostic association with a two-sided significance level of 0.05 95% CI. RFS were evaluated with Kaplan Meier method and log-rank test. Results 309 patients were analyzed; AR prevalence was 14.6%. Median age was 49 years (21-87), tumor size was 6.3 cm (0.1-22), ductal histology (95.1%) and nuclear-grade 3 (79%), these findings were not different between the AR+ vs AR-. Median Ki67 was 52% within AR+ vs 65% AR- (p=0.05). All patients were treated with neoCT, 14.9% had disease progression, PCR rates were similar among two groups (48.5% vs 42.2%) p=0.78. At a mean follow up of 19 months, 7 recurrences presented in AR+ (15.5%) vs 67 in the AR- (25.4%) p=NS. Median RFS was 54.9 (IC 95% 45.2-64-6) and 65.5 months (IC 95% 60.4-70.7), p=0.3. We analyze the prognostic factors, for RFS we found statistically significant the locally advanced stage OR 5.6 (1.4-22.9), residual cancer burden (RCB) OR 2.8 (2.1-3.9), N stage OR 1.4 (1.1-1.8) and progression during neoCT OR 2.8 (1.5-5.1); and for OS the RCB OR 2.8 (1.9-4.1) and progression during neoCT OR 3.1 (1.5-6.9). Conclusions In this trial the AR expression did not show significant association neither with PCR and RFS; main reasons are the low prevalence of AR expression, high rate of disease progression and high residual cancer burden after neoCT. We found association with other known factors (RCB, N stage, progression during neoCT and locally advanced stage), which are more important factors that determine the bad prognosis of TNBC.
Citation Format: Eder Araiza Alvarado, Claudia Haydee Arce Salinas. Association between androgen receptor expression and recurrence free survival among locally advanced triple negative breast. Real world data from a single Institution in Mexico City [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-32.