bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-05-56: The clinical impact of preoperatively needle-aspiration biopsy for axillary lymph nodes in T1-T2 breast cancer patients with axillary lymph node metastasis
Authors: Ahn Jee Hyun , Lee Suk Jun , Go Jieon , Park Hyung Seok , Kim Jee Ye , Kim Seung Il , Park Byeong Woo , Park Seho
Published: March 2023

Introduction: More than half of the results of axillary lymph node dissection followed by metastasis in sentinel lymph node(SLN) biopsy are negative. For deescalating axillary surgery, it is necessary to predict the non-SLN metastasis state, where metastasis was confirmed in the SLN biopsy. Method: Breast cancer patients with T1 and T2 stage were retrospectively reviewed from January 2008 to December 2016. A total of 818 patients underwent surgery as the primary treatment and the result of SLN biopsy was positive for metastasis. Patients who skipped SLN biopsy procedure and were proven metastatic axillary lymph nodes by needle-aspiration biopsy (NAB) were excluded. SLN was defined as lymph nodes detected by the dual method with hot-uptake by radioisotope and dyed by blue dye, or lymph nodes with palpable or suspected metastatic findings during SLN biopsy. Clinicopathological factors including and extra-nodal invasiveness were analyzed. Result: The median follow-up period was 73 months. Non-SLN metastasis was significantly seen in patients with older than 50 years, positive node metastases by preoperative NAB, high T stage, and extra-nodal invasion. In subgroup analysis, patients who underwent total mastectomy had the similar patterns of the increased risk of having non-SLN. Poor overall survival was observed in the patients with the presence of non-SLN metastasis. Conclusion: We confirmed predictive factors with a high probability of non-SLN metastasis. Axillary lymph node dissection cannot be overlooked in the patients proven the metastatic result of preoperative NAB.

Citation Format: Jee Hyun Ahn, Suk Jun Lee, Jieon Go, Hyung Seok Park, Jee Ye Kim, Seung Il Kim, Byeong Woo Park, Seho Park. The clinical impact of preoperatively needle-aspiration biopsy for axillary lymph nodes in T1-T2 breast cancer patients with axillary lymph node metastasis [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 P3-05-56.
Abstract P3-07-02: Anti-tumor efficacy of GMF-1A3, an MMAE-based antibody drug conjugate targeting cell surface cleaved Amphiregulin in breast cancer
Authors: Lofgren Kristopher , Sreekumar Sreeja , Reker Nicolette , Ernzen Kyle , Kenny Paraic A.
Published: March 2023

The Epidermal Growth Factor Receptor ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently internalized. Here, we describe the development of an antibody drug conjugate, GMF-1A3-MMAE, targeting an AREG neo-epitope revealed following ADAM17-mediated cleavage. The antibody does not interact with uncleaved Amphiregulin, providing a novel means of targeting cells with high rates of Amphiregulin shedding. Using fluorescent dye conjugation, we demonstrated that the antibody is internalized by cancer cells in a manner dependent on the presence of cell surface cleaved Amphiregulin. Antibodies conjugated with monomethyl auristatin E (MMAE) were cytotoxic in vitro and induced rapid regression of established breast tumor xenografts in immunocompromised mice. We further demonstrate that these antibodies recognize the Amphiregulin neo-epitope in formalin fixed paraffin embedded tumor tissue, suggesting their utility as a companion diagnostic for patient selection. A pan-cancer tissue microarray analysis indicates that the target is commonly detected (> 50% of cases) in breast, prostate, liver and lung cancer.

Citation Format: Kristopher Lofgren, Sreeja Sreekumar, Nicolette Reker, Kyle Ernzen, Paraic A. Kenny. Anti-tumor efficacy of GMF-1A3, an MMAE-based antibody drug conjugate targeting cell surface cleaved Amphiregulin in breast cancer [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 P3-07-02.
Abstract P3-07-17: Nanosecond Electric Pulses Modify Breast Tumor Microenvironment to Promote Antitumor Immunity
Authors: Yang Lifang , Nanajian Anthony , Beebe Stephen , Guo Siqi
Published: March 2023

Cancer immunotherapy has had a significant impact on the management of many types of solid tumors. While some patients respond favorably to it, a significant number of patients do not respond or initially respond but develop resistance later, highlighting an unmet need to improve the effectiveness of this treatment. Cancers with intrinsic resistance include breast cancer, not only respond poorly to single agent immunotherapy, but also often show no durable response. Tumor microenvironment (TME) plays a critical role in both pre-existing and acquired immune resistance which is responsible for the low immunogenicity of cancers. We previously reported that an electrical engineering technology generating nanosecond length electric pulses (nsEP) can greatly enhance the immunogenicity of poorly immunogenic cancers including 4T1 breast and Pan02 pancreatic in animal models. To understand how nsEPs overcome predominant immunosuppression in the TME to induce a strong immune response, we further investigated the effects of nsEPs on the breast TME by performing transcriptomic and immune profiling of 4T1 breast cancer cells treated with nsEP. RNAseq data and cell death signaling results demonstrated that nsEPs induced regulated necrotic cell death rather than apoptosis. NsEPs-treated cancer cells greatly decreased angiogenic factors and multiple chemoattracts for myeloid-derived suppressor cells (MDSCs) and macrophages. On the other hand, nsEP-treated cancer cells significantly upregulated chemoattracts for T lymphocytes and a number of proinflammatory/immunostimulatory cytokines. Flow cytometry analysis showed that the dynamic changes of TME following nsEP treatment included: (1) the significant reduction of immunosuppressive cells (MDSCs, Tregs and TAMs); (2) the preservation of cytotoxic CD8+ T cells and conventional CD4+ T cells; and (3) a persistent elevation in cytotoxic cells vs Treg ratio and tissue resident memory CD8+ T cells. Taken together, our results suggest nsEP is a TME modifier that can potentially overturn the immunosuppressive hurdle in the TME to promote antitumor immunity.

Citation Format: Lifang Yang, Anthony Nanajian, Stephen Beebe, Siqi Guo. Nanosecond Electric Pulses Modify Breast Tumor Microenvironment to Promote Antitumor Immunity [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 P3-07-17.
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

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

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

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 < 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

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

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 (>=10%) or low (< 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

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

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< 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

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, > 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.
Abstract P4-05-05: The Psycho-Social Factors Impacting Black Women Breast Cancer Survivors
Authors: Leach Virginia
Published: March 2023

Background: Breast Cancer (BC) mortality rates disproportionately affect African American (AA) women over any other racial or ethnic group in the United States. However, questions about how AA women who survive the disease navigate psychosocial factors such as body image, self-esteem, stigma and shame, thoughts and fears surrounding fertility, and romantic relationships remain unanswered. This study’s primary research question is, "How do AA women BC survivors create a new normal post-breast cancer while figuring out their own identity?" Methods: This qualitative study aims to address the psychosocial factors experienced by 20 AA women BC survivors in the U.S. The 20 women were recruited to participate in the IRB-approved study (University of Illinois at Urbana-Champaign) through the Tigerlily Foundation, a non-profit breast cancer advocacy organization. The total duration of the study lasted a maximum of 1 hour and 45 minutes with participants answering one pre-interview questionnaire for demographic purposes and one interview with a member of the research team. Results: Preliminary results from the data conclude that AA women BC survivors, and potentially all cancer survivors, mirror individuals in the postpartum phase. Being postpartum is not inherently harmful; however, if one begins to experience symptoms of depression, loss of appetite, irritability, and insomnia for an extended period, there is a high possibility they are experiencing Postpartum Depression (PPD). BC survivors experience numerous changes that can drastically impact their quality of life. AA women BC survivors struggle immensely with body image and self-confidence issues after experiencing breast cancer, various surgeries, and treatments. Conclusion: If BC survivors, particularly AA women BC survivors experiencing systemic and institutional racism, are treated with the same care postpartum individuals are given, there can be a shift in how oncologists work with BC survivors. Creating more personalized survivorship care plans between patients, oncologists, and hospital-based social workers can improve psychosocial factors experienced by AA women BC survivors.

Citation Format: Virginia Leach. The Psycho-Social Factors Impacting Black Women Breast Cancer Survivors [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 P4-05-05.
Abstract P4-07-61: Lymphedema, shoulder range of motion, pain, and presence of cords in patients undergoing breast cancer treatment with axillary web syndrome: Late follow-up
Authors: Figueira Patricia V. , Haddad Cinira , Rizzi Samantha K. Lopes de Almeida , Estevao Amanda , Elias Simone , Facina Gil , Nazário Afonso
Published: March 2023

Introduction: Axillary web syndrome (AWS) is a common complication in the immediate postoperative period in women after breast cancer surgery. The symptoms are defined as the presence of cords, pain, and limited shoulder range of motion (ROM). Pathophysiology has been described as lymphatic thrombosis, which could be a risk factor for the development of lymphedema. Considered by some to be self-limiting, it has been described as a chronic complication, persisting for years after initial onset. Objective: To determine the prevalence of AWS in a longitudinal cohort of women in a late follow-up after breast cancer surgery and to assess shoulder ROM, presence of pain, permanence of cords and correlation with lymphedema. Methods: A longitudinal cohort study was carried out at the Division of Breast Cancer Disease of the Universidade Federal de São Paulo. Twenty-five women were followed up and reassessed regarding the permanence of cords, pain, ROM, and presence of lymphedema. Results: Of the 25 patients analyzed, 64% (16 patients) showed prevalence of AWS. On recall, all cords were palpable and 87.5% were in the axilla. There was no correlation between AWS and lymphedema. Conclusions: AWS is an important complication in the immediate postoperative period, that persists for several years, without restrictions on function, pain or shoulder ROM limitations. We must therefore consider it as a complication that becomes chronic but has no impact on quality of life. The correlation with lymphedema was not significant in our study. Key words: breast neoplasms, axillary web syndrome, physical exercise, articular range of motion, pain, lymphedema.

Citation Format: Patricia V. Figueira, Cinira Haddad, Samantha K. Lopes de Almeida Rizzi, Amanda Estevao, Simone Elias, Gil Facina, Afonso Nazário. Lymphedema, shoulder range of motion, pain, and presence of cords in patients undergoing breast cancer treatment with axillary web syndrome: Late follow-up. [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 P4-07-61.
Abstract P4-08-11: AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution
Authors: Schade Amy , Perurena Naiara , Watanabe Marina , Rodriguez Carrie L. , Loi Patrick , Pilla Natalie , Davis Rachel A. , Mattioli Kaia , Xiang Dongxi , Zoeller Jason J. , Li Zhe , Garrido-Castro Ana C. , Tolaney Sara , Cichowski Karen
Published: March 2023

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy, however responses are typically short-lived. Thus, there is an urgent need to develop more effective treatments. PI3K pathway components represent plausible therapeutic targets, as approximately 40% of TNBCs have PIK3CA/AKT1/PTEN alterations. However, unlike hormone receptor-positive tumors, it is still unclear if or how PI3K pathway inhibitors will be effective in triple-negative disease. Here we identify a promising AKT inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors potently synergize with agents that suppress the histone methyltransferase, EZH2, and promote robust tumor regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. More importantly, once differentiated, these agents kill TNBCs by hijacking signals that normally drive mammary gland involution. Together these findings identify a promising therapeutic strategy for this highly aggressive tumor type and illustrate how deregulated epigenetic enzymes can insulate tumors from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.

Citation Format: Amy Schade, Naiara Perurena, Marina Watanabe, Carrie L. Rodriguez, Patrick Loi, Natalie Pilla, Rachel A. Davis, Kaia Mattioli, Dongxi Xiang, Jason J. Zoeller, Zhe Li, Ana C. Garrido-Castro, Sara Tolaney, Karen Cichowski. AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution [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 P4-08-11.
Abstract P4-08-24: Palmitoylation of Flotillin-1 contributes to Breast Cancer Metastasis
Authors: McClellan Bryan
Published: March 2023

BACKGROUND Breast Cancer metastasis results in the majority of cancer-related mortality. Flotillin-1 is overexpressed in numerous solid tumors and has been demonstrated to contribute to invasion and metastasis in breast cancer. Though its expression alone has been associated with metastasis, there has yet to be any investigation as to how certain post-translational modifications can affect its metastatic capabilities. Flotillin-1 is modified through palmitoylation, a post-translational modification essential for protein stability, processing, and localization. By generating a palmitoylation defective mutant of flotillin-1, we have demonstrated that flotillin-1 palmitoylation contributes to its stability and metastatic capabilities in both 3D and in vivo models of invasion and metastasis. MATERIALS AND METHODS Flotillin-1 wild type or palmitoylation defective C-34-A mutants were expressed in stable flotillin-1 knockdown MDA-MB-231 and SUM-159 triple negative breast cancer cells. These cells were subjected to 2D invasion chambers and 3D collagen invasion assays. Further, both wild type and C34A expressing cells were used for experimental lung metastases in mice by tail vein injection. 2-bromopalmtiate (50µM) was used as a chemical palmitoylation inhibitor and MG-132 (10µM) for proteasomal inhibition. RESULTS Invasion in stable knockdown cells was restored by re-expression of flotillin-1, but not by follitillin-1 C34A. We further observed a significant decrease in lung metastasis in flotillin-1 C34A cells compared to wild type flotillin-1. Flotillin-1 C34A expression led to a significant decrease in protein stability, which was restored by MG-132. CONCLUSION Flotillin-1 palmitoylation contributes to its stability and subsequent metastatic capabilities in breast cancer cells and experimental metastasis models. Thus, flotillin-1 palmitoylation could be a promising target for breast cancer metastasis.

Citation Format: Bryan McClellan. Palmitoylation of Flotillin-1 contributes to Breast Cancer Metastasis [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 P4-08-24.
Abstract P4-09-03: Survival differences between HER2-zero and HER2-low-expressing breast cancer—A meta-analysis of early breast cancer patient data from 12 studies including 39831 patients
Authors: Zhang Xiaoqi , Yang Ciqiu , Wang Kun
Published: March 2023

Background: HER2-low-expressing breast cancer takes up 40-50% in all breast cancer subtypes. Survival difference between HER2 low expression and HER2-zero breast cancer remains controversial. Therefore, the aim of this study was to compare the survival outcome of the two subtypes and to explore the impact of hormone receptor status.

Methods:A comprehensive medical literature search was performed by PubMed, EMBASE, and the Cochrane Library through June 2022. We included observational studies reporting hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). The results of individual studies were pooled by fixed-effects models. Twelve articles with a total of 39,831 breast cancer patients were included in the meta-analysis.

Results:We observed a statistically significant association between low HER2 expression levels and better breast cancer survival outcomes (OS: HR: 0.82; 95% confidence interval: 0.77, 0.88; DFS/RFS: HR: 0.88; 95% confidence interval: 0.83, 0.93). In a subgroup analysis, we found that HER2-low patients had better survival outcomes among hormone receptor-positive breast cancer patients (OS: HR: 0.85; 95% confidence interval: 0.78, 0.92; DFS/RFS: HR: 0.90; 95% confidence interval: 0.84, 0.96). Similarly, in triple-negative breast cancer patients, we also observed a positive association between HER2 low expression and better survival (OS: HR: 0.78; 95% confidence interval: 0.69, 0.87; DFS/RFS: HR: 0.86; 95% confidence interval: 0.77, 0.94).

Conclusions: Our study showed that HER2 low expressing breast cancer had better survival outcomes compared to HER2 negative breast cancer in patients with early stage breast cancer, regardless of hormone receptor status. The result has a positive effect on us to further explore the clinical features, molecular characteristics and better treatment strategies of HER2-low-expressing breast cancer.

Forest plot of HER2 low expression and overall survival in overall population

Forest plot of HER2 low expression and disease free survival or relapse free survival in overall population

Citation Format: Xiaoqi Zhang, Ciqiu Yang, Kun Wang. Survival differences between HER2-zero and HER2-low-expressing breast cancer—A meta-analysis of early breast cancer patient data from 12 studies including 39831 patients [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 P4-09-03.
Abstract P5-01-06: Single cell profile of tumor and immune cells in primary triple-negative breast cancer and different sites in the axillary lymph nodes
Authors: Liao Ning , Li Cheukfai , Cao Li , Chen Yanhua , Ren Chongyang , Chen Xiaoqing , Mok Hsiaopei , Wen Lingzhu , Li Kai , Wang Yulei , Zhang Yuchen , Li Yingzi , Lv Jiaoyi , Cao Fangrong , Luo Yuting , Li Hongrui , Wu Wendy , Balch Charles M. , Giuliano Armando E.
Published: March 2023

Purpose: Little is known about the host-tumor interaction in the lymph node basin at a single cell level. This study examines single cell sequences in breast cancer nodal metastasis of a patient with triple negative breast cancer. Methods: The primary breast tumor, sentinel lymph node, an adjacent lymph node with metastatic involvement and a clinically normal-appearing lymph node were collected during operation. Single-cell sequencing was performed on all specimens. Results: 14,016 cells were clustered as 6 cell populations. Cancer cells demonstrated the molecular characteristics of TNBC basal B subtype and highly expressed genes in the MAPK signaling cascade. Tumor associated macrophages regulated antigen processing and presentation and other immune-related pathways to promote tumor invasion. CD8+ and CD4+ T lymphocytes concentrated more in sentinel lymph node and mainly stratified as two transcriptional states. The immune cell amount variation among primary tumor, sentinel and normal lymph nodes showed the similar tendency between the scRNA-seq profile of TNBC samples and a previous reported bulk RNA-seq profile of a breast cancer cohort including all four breast cancer subtype samples. Discussion: Single-cell sequencing analysis suggested that the sentinel lymph node was the initial meeting site of tumor infiltration and immune response, where partial T lymphocytes perform anti-tumor activity while other T cells exhibit an exhaustion state. We proposed a molecular explanation to the well-established clinical principle that the 5-year and 10-year survival outcomes were noninferior between SLND and ALND.

Citation Format: Ning Liao, Cheukfai Li, Li Cao, Yanhua Chen, Chongyang Ren, Xiaoqing Chen, Hsiaopei Mok, Lingzhu Wen, Kai Li, Yulei Wang, Yuchen Zhang, Yingzi Li, Jiaoyi Lv, Fangrong Cao, Yuting Luo, Hongrui Li, Wendy Wu, Charles M. Balch, Armando E. Giuliano. Single cell profile of tumor and immune cells in primary triple-negative breast cancer and different sites in the axillary lymph nodes [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 P5-01-06.