bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-05-03: Prevalence of BRCA1/2 mutations in an underrepresented population of women with breast cancer: Observations from the City of Hope INSPIRE study
Authors: Mortimer Joanne , Lindsey Sidney S. , Solomon Ilana , Park Wai , Sturgeon Duveen , Blazer Kathleen , Gray Stacy , Bonner Joseph , Xia Xiaoyu , Gruber Stephen
Published: March 2023

Table 1. Incidence of BRCA 1 and 2 mutations by Race and Ethnicity BRCA1 BRCA2 BRCA1 or 2 VUS/Negative Native American 0 1 1 6 Asian 2 3 5 150 Black/African American 3 2 5 48 Native Hawaiian or Pacific Islander 0 0 0 5 Other 1 1 1* 26 White 25 17 42 688 Unknown 0 0 0 20 Declined 1 0 1 24 TOTAL 32 24 55 967 * Patient had both BRCA1 and BRCA2 mutations

Citation Format: Joanne Mortimer, Sidney S. Lindsey, Ilana Solomon, Wai Park, Duveen Sturgeon, Kathleen Blazer, Stacy Gray, Joseph Bonner, Xiaoyu Xia, Stephen Gruber. Prevalence of BRCA1/2 mutations in an underrepresented population of women with breast cancer: Observations from the City of Hope INSPIRE study [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 P1-05-03.
Abstract P1-07-07: Cross-talk of Four Types of RNA Modification Proteins with Adenosine Reveals the Landscape of Multivariate Prognostic Patterns in Breast Cancer
Authors: Wang Xuliren , Xiong Min , Xiu Bingqiu , Wu Jiong , Chi Yayun
Published: March 2023

Background: BRCA is the most common malignant tumour, and its heterogeneity is one of its major characteristics. m6A, m1A, APA, and A-to-I RNA editing constitute the four most common adenosine-associated RNA modifications and represent the most typical and critical forms of epigenetic regulation contributing to the immunoinflammatory response, tumorigenesis and tumour heterogeneity. However, the cross-talk and potential combined profiles of these RMPs in multivariate prognostic patterns of BRCA remain unknown. Methods: A total of 48 published RMPs were analysed and found to display significant expression alterations and genomic mutation rates between tumour and normal tissues in the TCGA-BRCA cohort. Data from 4188 BRCA patients with clinical outcomes were downloaded from the GEO, METABRIC and TCGA databases, normalized and merged into one cohort. The prognostic value and interconnections of these RMPs were also studied. The four PRGs with the greatest prognostic value were then selected to construct diverse RMP-associated prognostic models through uniCox, differential expression analysis, LASSO regression and multiCox. Alterations in biological functional pathways, genomic mutations, immune infiltrations, RNAss scores and drug sensitivities among different models, as well as their prognostic value, were then explored. Results: Utilizing a large number of samples and a comprehensive set of genes contributing to adenosine-associated RNA modification, our study revealed the joint potential bio-functions and underlying features of these diverse RMPs and provided effective models (PRG clusters, gene clusters and the risk model) for predicting the clinical outcomes of BRCA. The individuals with higher risk scores showed poor prognoses, cell cycle function enrichment, upregulation of stemness scores, higher TMBs, immune activation and specific drug resistance. This work highlights the significance of comprehensively examining post-transcriptional RNA modification genes. Conclusions: Here, we designed and verified an advanced forecasting model to reveal the underlying links between BRCA and RMPs and precisely predict the clinical outcomes of multivariate prognostic patterns for individuals.

Citation Format: Xuliren Wang, Min Xiong, Bingqiu Xiu, Jiong Wu, Yayun Chi. Cross-talk of Four Types of RNA Modification Proteins with Adenosine Reveals the Landscape of Multivariate Prognostic Patterns 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 P1-07-07.
Abstract P1-07-08: Prediction of breast cancer late recurrence according to Clinical Treatment Score post-five years (CTS5) and progesterone receptor in a wider patient population
Authors: Carvalho Giselle S. , BRETAS GUSTAVO O. , Musse Daniel , Gondim Victor , Bines José
Published: March 2023

Background The duration of adjuvant endocrine therapy remains a continuous challenge in hormone-receptor positive (HR+) early breast cancer. The Clinical Treatment Score post-five years (CTS5) is an online model used to predict late distant metastasis for women with HR+ breast cancer who are recurrence-free 5 years after endocrine therapy (ET). It incorporates patients age, tumor size, grade, and number of positive lymph nodes, and is an important tool to help in this treatment decision. There is a paucity of data in premenopausal women and whether other variables could add additional information. Methods A single-center retrospective analysis of patients that have received adjuvant ET for 5 years, between January 2007 and December 2008 at the Instituto Nacional de Cancer (INCA), Brazil. Disease-Free Survival (DFS) was compared between the low, intermediate, and high-risk subgroups. Data analysis was descriptive and exploratory. Kaplan-Meier estimates and Cox regression models were used. Results A total of 183 patients were enrolled, 26.5% being premenopausal. Median age at diagnosis was 66 years. Tumor stage: I (44%) and II (56%). ET consisted of tamoxifen (88%), anastrozol (6%), and a switch (6%). There were 39.5%, 39.5% and 21% of patients in the low, intermediate, and high-risk (L/I/H) subgroups, respectively. Progesterone-receptor was ≥ 20% in 71% of tumors and in 55%, 49% and 34% in the L/I/H subgroups, respectively. Median follow up was 88.9 months. After 5 years, the median DFS was 100%, 96.3% and 68.2% in L/I/H subgroups (p < 0,001). Progesterone-receptor was also an independent prognostic factor for late recurrence (p < 0,05). Conclusion CTS5 performed well in a wider patient population including premenopausal women. Progesterone-receptor was an independent prognostic factor for DFS and should be further considered into the model.

Citation Format: Giselle S. Carvalho, GUSTAVO O. BRETAS, Daniel Musse, Victor Gondim, José Bines. Prediction of breast cancer late recurrence according to Clinical Treatment Score post-five years (CTS5) and progesterone receptor in a wider patient population [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 P1-07-08.
Abstract P1-10-06: Carcinoma en Cuirasse Secondary to Locally Advanced Breast Carcinoma: a case report
Authors: Liu Chung-Tang , Lanier Keri
Published: March 2023

Introduction & Objective This report highlights an unusual presentation of skin metastasis of inflammatory breast cancer that resembles a rare condition called Carcinoma en Cuirasse (CeC). CeC was first described by anatomist Alfred Velpeau in 1838 when he observed how the coalescing nodules and diffuse sclerodermoid induration found on the chest and abdomen in CeC resembled the medieval steel breastplate or a cuirasse. Case Presentation A 62-year-old female presented to the emergency department for evaluation of a palpable left breast mass and concurrent skin lesions for the past 5 months. Based on the erosion of the nipple, chest CT, as well as core needle and skin biopsy, a diagnosis of stage IV (cT4d, cN3, cM1) ER+, PR-, HER2/neu- advanced/inflammatory breast carcinoma was made. The patient underwent a 20-week course of neoadjuvant chemotherapy followed by 25 treatments of neoadjuvant external beam radiotherapy (EBRT) with a total dose of 5000cGy to the left breast and the regional lymph node due to disease progression after 4 cycles of neoadjuvant chemotherapy. She proceeded to bilateral modified radical mastectomy and bilateral lymph node involvement was found, and later disease progressed with skin involvement outside the EBRT treatment field. Additional 25 treatment of palliative radiotherapy was utilized with another 5000cGy, followed by 2 months of chemotherapy to provide better palliation and quality of life. Upon completion of therapy, a unique skin metastasis pattern was noticed. Shortly afterward the patient passed away from severe sepsis secondary to multiple wounds infected by drug-resistant Pseudomonas aeruginosa followed by Clostridium difficile colitis. Conclusion This case shows clinical characteristics of Carcinoma en Cuirasse and provides important considerations for more research to be done to highlight the unique pattern of skin metastasis following radiation and the potential use for radiation to treat chemotherapy-resistant skin metastasis from recurrent invasive breast carcinoma.

Citation Format: Chung-Tang Liu, Keri Lanier. Carcinoma en Cuirasse Secondary to Locally Advanced Breast Carcinoma: a case report [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 P1-10-06.
Abstract P1-11-18: The efficacy and safety of trastuzumab and pertuzumab in combination with different chemotherapy regimens for neoadjuvant treatment of HER2-posotive breast cancer: a multi-center real-world study in China
Authors: Qi Xiaowei , Hu Hong , wenlin chen , yan xu , shu liu , yanman fang , Li Taolang , jia ming , sihai zhou , fan chai , yueyang liang , yuanming fan , Zhang Yi , Tang Peng , jun jiang , jianyun nie , Chen Li , Wang Shushu
Published: March 2023

Background: Dual HER2 targeted therapy with trastuzumab (H) and pertuzumab (P) has been approved as neoadjuvant therapy for patients with HER2-positive breast cancer in China in 2019 based on the results from NeoSphere and PEONY study. However, the real-world efficacy and safety data are currently lack of evidence in China. Therefore, this multi-center real-world study aims to retrospectively analyze the efficacy and safety of neoadjuvant trastuzumab and pertuzumab combined with different chemotherapy regimens of HER2-positive early breast cancer. Methods: Patients received trastuzumab and pertuzumab in combination with different chemotherapy regimens, including taxanes (T), cyclophosphamide (C), anthracyclines (A) were collected retrospectively from 12 centers. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate. Results: A total of 357 patients were enrolled, among which 204 (57.5%) recieved TCbHP, 92 (25.9%) recieved EC-THP, and 51 (14.4%) received THP as chemotherapy regimens. The median age was 48 years old (range, 22-76), 142 (39.8%) of patients were classified as hormone receptor (HR)-positive, and 215 (60.2%) were HR-negative. The overall tpCR rate was 58.5% (95%CI, 53.2%-63.7%). tpCR rate for HR-negative patients was significantly higher than HR-positive patients (65.6% vs. 47.9%, p=0.001) and there was not any statistical difference according to chemotherapy regimens (56.9% for TCbHP, 56.5% for EC-THP, and 66.7% for THP, p=0.445). The most common adverse events included anemia (40.1%), white blood cell count decreased (34.3%), ejection fraction decreased (19.5%), Alanine aminotransferase increased (18.9%), platelet count decreased (12.8%) and neutrophil count decreased (12.0%). There was not any toxicity leading to death. Conclusions: Multi-center real-world data show satisfactory tpCR rate and tolerable adverse events of trastuzumab and pertuzumab in combination with different chemotherapy regimens in China.

Citation Format: Xiaowei Qi, Hong Hu, chen wenlin, xu yan, liu shu, fang yanman, Taolang Li, ming jia, zhou sihai, chai fan, liang yueyang, fan yuanming, Yi Zhang, Peng Tang, jiang jun, nie jianyun, Li Chen, Shushu Wang. The efficacy and safety of trastuzumab and pertuzumab in combination with different chemotherapy regimens for neoadjuvant treatment of HER2-posotive breast cancer: a multi-center real-world study in China [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 P1-11-18.
Abstract P1-13-11: YES1 is a targetable vulnerability for improving taxane response in triple-negative breast cancer
Authors: Ingles Natasha , Piemonte Katrina , Singh Salendra , Weber-Bonk Kristen , Keri Ruth
Published: March 2023

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Due to the lack of receptor expression, there are limited targeted therapies available for TNBC. As a result, TNBC patients are primarily treated with chemotherapies such as taxanes. Although TNBCs initially regress in response to taxane treatment, resistance is common. One mechanism of taxol unresponsiveness/resistance is an increase in chromosomal instability (CIN). Increased CIN can confer survival advantages to cancer cells and increase their aggressiveness. However, CIN levels can be leveraged using drugs that inhibit proteins important for chromosomal stability. Combining CIN-inducing drugs, such as taxanes, can improve treatment efficacy or re-sensitize tumor cells to certain drugs by shifting cells towards a state of maladaptive CIN that is incompatible with cell viability. We have found that the non-receptor SRC family kinase YES1 is crucial for chromosomal stability. YES1 is important for cell division, motility, adhesion, and survival in both normal and TNBC cells. Since taxol and YES1 silencing independently increase chromosomal instability, I hypothesized that combining a YES1 inhibitor (YES1i) with taxanes would shift cells toward an irreversible state of maladaptive CIN, decreasing their survival. I found that YES1 mRNA and protein are upregulated in taxane-resistant cells and that YES1 protein expression correlates with the paclitaxel IC50 in a panel of TNBC cell lines, suggesting that YES1 may drive taxane resistance. Furthermore, I found that a selective YES1 inhibitor (CH6953755) synergizes with paclitaxel and improves taxane response in both in vitro and in vivo TNBC models. In addition, the combination of YES1i and paclitaxel treatment increases phenotypes associated with chromosomal instability more than either drug alone. These data suggest that YES1 inhibition in combination with taxanes represents an innovative and novel drug treatment regimen that improves TNBC patient outcomes.

Citation Format: Natasha Ingles, Katrina Piemonte, Salendra Singh, Kristen Weber-Bonk, Ruth Keri. YES1 is a targetable vulnerability for improving taxane response in triple-negative 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 P1-13-11.
Abstract P2-11-07: Association of PIK3CA mutations with efficacy in HER2-positive first-line metastatic breast cancer: a meta-analysis
Authors: Swain Sandra , Cortés Javier , Xu Binghe , Lambertini Chiara , Essioux Laurent , Knott Adam , Restuccia Eleonora , Madjar Katrin , De Haas Sanne Lysbet
Published: March 2023

BACKGROUND: PIK3CA mutations have been shown to be associated with poor prognosis in HER2-positive breast cancer (BC). We combined data from three completed Phase III Roche-sponsored randomized trials of HER2-targeted therapy for the first-line treatment of HER2-positive metastatic BC (MBC); this allowed for exploration of the prognostic impact of PIK3CA mutations observed in the three individual trials across subgroups of interest.

METHODS: Data from CLEOPATRA (pertuzumab + trastuzumab + docetaxel [PHD] vs. placebo [Pla] + HD; NCT00567190; N = 808), MARIANNE (HD vs. ado-trastuzumab emtansine [K] + Pla vs. K + P; NCT01120184; N = 1095), and PUFFIN (PHD vs. Pla + HD; NCT02896855; N = 243) were included. An individual patient data (IPD) meta-analysis was performed to test the association between PIK3CA mutation status in tumor tissue (mutated vs. wild type [WT]) and efficacy (progression-free and overall survival [PFS/OS]) in different biomarker and clinical subgroups. Confounder adjustment was conducted for age, Eastern Cooperative Oncology Group Performance Status, body mass index, treatment, disease type, and number of metastases (all at baseline). “Study” was included as a random effect in the IPD meta-analysis model to account for variability between studies.

A landmark analysis was conducted on fast and non-fast progressors (cutoff of >137 days [i.e., after six chemotherapy cycles]) from CLEOPATRA and PUFFIN only, since they include the current standard-of-care regimens (PHD), by using Day 137 as the landmark time with separate Cox proportional hazards models.

RESULTS: PIK3CA mutation data were available for 1905/2146 patients (89%; ~80% from primary tissue); mutation prevalence was 27% (n = 521). PIK3CA-mutated vs. WT in association with PFS in pooled treatment arms is shown in the table. OS data were consistent.

CONCLUSIONS: PIK3CA mutations were associated with a worse prognosis across subgroups of interest, including in fast and non-fast progressors, in the two PHD-containing studies as compared with the overall ITT population.

Table: PIK3CA-mutated vs. WT in association with PFS in pooled treatment arms

Citation Format: Sandra Swain, Javier Cortés, Binghe Xu, Chiara Lambertini, Laurent Essioux, Adam Knott, Eleonora Restuccia, Katrin Madjar, Sanne Lysbet De Haas. Association of PIK3CA mutations with efficacy in HER2-positive first-line metastatic breast cancer: a meta-analysis [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 P2-11-07.
Abstract P2-11-09: Association of 21-gene recurrence score with overall survival in phase 3 TAILORx trial
Authors: Yang Sherry X. , Yu John , Wang Molin
Published: March 2023

Background: The 21-gene recurrence score (RS) assay is a prognostic measurement originally established for distant recurrence in estrogen receptor-positive and node-negative breast cancer. Retrospective studies and the Trial Assigning Individualized Options for Treatment (TAILORx; ClinicalTrials.gov NCT00310180) validated its significance besides testing chemotherapy benefit in patients with midrange RS (11-25). However, unclarity remains as to whether RS has comparable prognostic value for overall survival (OS) in the TAILORx trial population. Methods: Association between the recurrence scores (midrange or high-range 26-100 vs. low-range 0-10) and OS was evaluated in all eligible patients with clinicopathological and treatment information by multivariable Cox proportional hazards regression model including RS, tumor size, tumor grades, chemotherapy, endocrine regimens, surgery type, progesterone receptor and demographics. We also evaluated the association between RS and invasive disease-free survival (DFS), recurrence-free interval (RFI) or distant recurrence-free interval (dRFI) by multivariable Cox analysis. Results: Median follow-up was 95.5 (range 0.1 to 138.6) months for OS, 89.6 months (range 0 to 134.8) for DFS, 87.7 (range 0 to 134.8) months for RFI or 87.6 (range 0-134.8) months for dRFI. Compared with low score group, midrange and high-range scores were associated with RFI and dRFI, respectively (P≤0.01 each). However, midrange score was neither associated with OS (adjusted HR 1.15; 95% CI 0.87-1.52; P=0.33) nor associated with DFS (HR 1.16; 95% CI 0.97-1.38; P=0.11). High-range score was associated with DFS (HR 1.58; 95% CI 1.21-2.06; P< 0.01) and had a trend towards association with OS (HR 1.44; 95% CI 0.95-2.19; P=0.08). Conclusions: The data indicate that the recurrence scores provide independent prognosis for breast cancer recurrence at both distant and locoregional sites and for distant recurrence, respectively. High-range score is prognostic of disease-free survival, with the midrange score showing marginal association. Midrange and high-range recurrence scores do not provide independent prognostic information for overall survival in hormone receptor-positive, HER2-negative, node-negative breast cancer in the TAILORx trial population.

Citation Format: Sherry X. Yang, John Yu, Molin Wang. Association of 21-gene recurrence score with overall survival in phase 3 TAILORx trial [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 P2-11-09.
Abstract P2-14-09: Sensory Evaluation of Nipple-Areolar Complex after Nipple-Sparing Mastectomy: A Comparison of Incision Approaches
Authors: Kook Yoonwon , Jang Ji Soo , Baek Seung Ho , Bae Soong June , Ahn Sung Gwe , Jeong Joon
Published: March 2023

Background: Since nipple-sparing mastectomy (NSM) has been widely practiced, majority of previous studies have evaluated the effects of Nipple-areolar complex (NAC) preservation on body image adjustment. However, few have evaluated NAC sensation after NSM in a large sample size. This study aims to assess NAC sensation after NSM and compare the results according to different incisional approaches; specifically, inframammary fold (IMF) and peri-areolar.

Methods: Post NSM patients from Oct 2019 to Nov 2021 have been recruited prospectively. A total of 115 patients (IMF 69 and peri-areolar 36) were evaluated for NAC sensory at various time points during follow up within 1.5 to 4 years after surgery. NAC sensation was scored by pin-prick test in a scale of 0 to 2 (0: no sensation, 1: dull sensation, 2: sharp sensation), divided in 5 areas of the NAC and summed up to a total of 10.

Results: In all patients, a median of the pin-prick test total score on NAC was 3 (0-10). Pin-prick test of NAC showed numerically higher NAC sensory score in the IMF incision than in the peri-areolar group without a statistical significance (IMF: Median 4 Mean 3.83 ± 3.04, Peri-areolar Median 2 Mean 2.69 ± 3.64, p=0.062). When sensory scores were evaluated depending on NAC zones (A: Nipple, B: Upper outer, C: Upper inner, D: Lower outer, E: Lower inner) the IMF incision group showed better outcomes in zone B (p=0.015) and E (p=0.043). Simple linear regression analysis showed the possibility of incisional approach, diabetes mellitus (DM) history, previous radiotherapy of ipsilateral breast, post mastectomy radiotherapy (PMRT), adjuvant chemotherapy, tumor to nipple distance and laterality influencing NAC sensory with p< 0.2. When these factors were taken to multiple linear regression analysis, DM history (p=0.045), previous radiotherapy (p=0.001), postop radiotherapy (p=0.001), and adjuvant chemotherapy (p=0.001).

Conclusion: NAC sensory deteriorated postoperatively in general. Scores of NAC sensation were numerically higher in the patients with IMF incision, although the difference was not statistically significant. NAC sensation was negatively affected by DM history, previous ipsilateral breast radiotherapy and post-NSM treatments such as chemotherapy and PMRT. While incision type may improve aesthetic outcomes, additional efforts are necessary to ameliorate the post-NSM NAC desensitization.

Table 1. Patient characteristics

Table 2. Linear regression analysis for clinical factors affecting NAC sensory

Citation Format: Yoonwon Kook, Ji Soo Jang, Seung Ho Baek, Soong June Bae, Sung Gwe Ahn, Joon Jeong. Sensory Evaluation of Nipple-Areolar Complex after Nipple-Sparing Mastectomy: A Comparison of Incision Approaches [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 P2-14-09.
Abstract P2-16-02: TXNIP-dependent tumor suppressive pathways in breast cancer growth and progression
Authors: Singh Jasvinder , sah Bindeshwar , Liu Liang
Published: March 2023

Thioredoxin-interacting protein (TXNIP) plays a critical role in glucose metabolism and redox signaling through negatively regulating thioredoxin activity. Over the past decade, TXNIP has emerged as a novel tumor suppressor in various cancer models. In search of the molecular targets mediating the anticancer effect of an epigenetic drug UNC0642, we found TXNIP to be consistently upregulated by UNC0642, which was coupled with significant suppression of MDA-MB-231 breast cancer cell proliferation in vitro and tumor growth in vivo. TXNIP knockdown increased MDA-MB-231 cell proliferation and in vivo tumor growth and metastasis. In contrast, TXNIP-reconstitution in TXNIP-deficient HCC1954 breast cancer cells suppressed cell proliferation and migration that is coupled with increases in reactive oxygen species, strongly supporting TXNIP’s potent antitumor function. TXNIP-reconstitution also decreased mitochondrial respiration and glycolysis in HCC-1954 cells as determined by using the Agilent Seahorse XF Cell Energy assays. To understand the molecular targets through which TXNIP exerted its antitumor activity, we performed co-immunoprecipitation studies and proteomic analyses to identify TXNIP-interacting proteins in UNC0642-treated MDA-MB-231 cells. Besides thioredoxin, we identified peroxiredoxin-6 (PRDX6), another modulator of cellular redox signaling, as a major TXNIP-interacting protein. While Prdx6-knockout mice develop normally, PRDX6 is frequently upregulated in breast cancer patients that is significantly associated with aggressive tumor subtypes and poor overall survival. The mechanism underlying the role of PRDX6 in breast oncogenesis remains elusive. Our findings suggest that TXNIP might exert its antitumor activity through binding and inhibiting PRDX6 activity in breast cancer cells to alter ROS signaling, thus providing novel therapeutic targets and potential prognostic biomarkers for breast cancer patients.

Citation Format: Jasvinder Singh, Bindeshwar sah, Liang Liu. TXNIP-dependent tumor suppressive pathways in breast cancer growth and progression [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 P2-16-02.
Abstract P2-18-01: Matched Single-Cell RNA-seq and Single-Cell ATAC-seq of Male Breast Cancers Nominate Salient Cancer-Specific Enhancers
Authors: Wisniewska Kamila , Kim Hyunsoo , Regner Matthew J. , Spanheimer Philip , Franco Hector L.
Published: March 2023

Although male breast cancer accounts for less than 1% of all breast cancer cases, overall survival is worse for men compared to women. This is due, in part, to the older age of patients at the time of diagnosis and the increased presence of comorbidities in the male population. While male breast cancer presents with similarities to certain female breast cancers, the paucity of data available on male breast cancer makes it difficult to establish targeted therapies, and to date, most male breast cancers are treated according to the standards in place for female breast cancer. Thus, investigating the transcriptional and epigenetic landscape of male breast cancer with improved resolution is crucial for understanding the tumor heterogeneity of this rare cancer type and can lead to the discovery of new therapeutic targets. In this study, we present matched transcriptional (scRNA-seq) and epigenetic (scATAC-seq) profiles of two male breast cancer tumors at single-cell resolution. Using scRNA-seq, we determine differentially expressed genes between male and female breast cancer tumors, specifically in the malignant cell populations, and highlight several genes that may have therapeutic implications within male breast cancer. We then leverage the scATAC-seq data to link variation in chromatin accessibility to changes in gene expression and show that certain highly expressed genes in the tumor-epithelial cells of male breast tumors are linked to highly active enhancer elements that drive their expression. Finally, we examine transcription factor motifs in the tumor-epithelial regulatory regions of male breast cancer tumors to further investigate the regulatory logic of these cell types. Overall, this dataset exposes clinically relevant regulatory networks in male breast tumors, providing a useful resource to the field of breast oncology that expands on the current knowledge of male breast cancer genetics.

Citation Format: Kamila Wisniewska, Hyunsoo Kim, Matthew J. Regner, Philip Spanheimer, Hector L. Franco. Matched Single-Cell RNA-seq and Single-Cell ATAC-seq of Male Breast Cancers Nominate Salient Cancer-Specific Enhancers [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 P2-18-01.
Abstract P2-20-11: Progesterone impacts the growth and immune cell infiltration of murine mammary gland tumors
Authors: Werner Lauryn R , Helm Dominika E. , Tinoco Julio , Chowanec Eilidh I , Holloran Sean M , Hastings Richard C , Wei Junping , Lei Gangjun , Yang Xiao-Yi , Markiewicz Mary A , Chalise Prabhakar , Balko Justin , Hartman Zachary C , Hagan Christy R
Published: March 2023

Clinical studies have linked usage of progestins (synthetic progesterone) to breast cancer risk. However, little is understood regarding the role of native progesterone (P4), signaling through the progesterone receptor (PR), in breast tumor formation. Recently, we demonstrated that P4 treatment or PR overexpression can drive changes in immune cell populations in the murine mammary gland and that PR overexpression leads to increased development of mammary gland tumors in mice. Given these findings, we sought to investigate whether P4 impacts tumor growth and immune cell infiltration of mammary gland tumors. We utilized syngeneic mammary gland tumor models to evaluate the effect of P4 on PR+ mammary gland tumor growth, which revealed that P4 promoted tumor growth and impacted immune cell infiltration of PR+ mammary gland tumors. Of note, numbers of tumor-infiltrating dendritic cells were decreased and exhausted T cells and regulatory T cells were increased with P4 treatment in PR+ tumors. To determine if anti-progestin therapies could reverse the growth-promoting effect of P4 on mammary gland tumors, mice bearing PR+ mammary gland tumors were treated with the anti-progestin onapristone. Onapristone treatment led to significantly decreased tumor volumes in two syngeneic mammary gland tumor models and reversed the effect that P4 had on tumor-infiltrating regulatory T cells. To determine if inhibition of tumor growth by onapristone was immunologically mediated, SCID mice bearing PR+ mammary gland tumors were treated with onapristone. Results revealed a decreased ability of onapristone to inhibit tumor growth in SCID mice compared to immunocompetent mice, suggesting that inhibition of tumor growth is, in part, immunologically mediated. These findings offer a novel mechanism of P4-driven mammary gland tumor development and provide rationale in investigating the usage of anti-progestin therapies to promote immune-mediated elimination of mammary gland tumors.

Citation Format: Lauryn R Werner, Dominika E. Helm, Julio Tinoco, Eilidh I Chowanec, Sean M Holloran, Richard C Hastings, Junping Wei, Gangjun Lei, Xiao-Yi Yang, Mary A Markiewicz, Prabhakar Chalise, Justin Balko, Zachary C Hartman, Christy R Hagan. Progesterone impacts the growth and immune cell infiltration of murine mammary gland 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 P2-20-11.
Abstract P2-23-19: Interrogating multicellular signaling in breast cancer using a bio-orthogonal chemistry-based proteomics platform
Authors: Krajina Brad A. , Yamamoto Ami , Cheung Kevin J. , Madasu Samuel
Published: March 2023

Tumors are multicellular ecosystems that communicate through the exchange of extracellular signaling molecules. In breast cancer, this multicellular communication can enable tumor cells to cooperate in a range of contexts, including tumor invasion and the outgrowth of distal metastases. Illuminating the mechanisms by which tumor cells communicate may reveal new therapies. To this end, three-dimensional tumor organoid models have emerged as versatile platforms for modeling multicellular behavior ex vivo. However, organoid culture typically requires the use of poorly defined, animal-derived extracellular matrices, such as Matrigel. These exogenous matrices contain thousands of proteins that dominate over and conceal cell-secreted factors in conventional proteomics approaches. Revealing low abundance cell-secreted factors from this complex exogenous background presents a formidable challenge. To surmount this challenge, we develop a new method to isolate the pericellular proteome in 3D organotypic culture models. This technology harnesses biorthogonal click chemistry to bypass exogenous factors, infiltrate intercellular spaces, and retrieve the endogenous intercellular proteome. This approach requires no genetic manipulation, requires only 1 million cells, and can be adapted to diverse organotypic models. These capabilities enable isolation of intercellular signaling factors in models that yield precious amounts of material and that can sustain only limited manipulation ex vivo, which we demonstrate using organoids established from patient-derived xenografts. To establish the generalizability of our approach, we apply this technology to a panel of breast cancer and small-cell lung cancer organoid models. Furthermore, we demonstrate that this method can be readily adapted to different extracellular matrix environments that are widely employed in organoid research, including basement membrane matrices and collagen gels. Taken together, our results establish this technology as a scalable and generalizable platform that may open opportunities for researchers investigating diverse questions in organoid models of cancer. Moving forward, we are leveraging these capabilities to investigate changes in the intercellular proteome that emerge after the acquisition of therapy resistance. We hope to uncover new mechanisms of collective signaling that may be targeted to overcome therapy resistance.

Citation Format: Brad A. Krajina, Ami Yamamoto, Kevin J. Cheung, Samuel Madasu. Interrogating multicellular signaling in breast cancer using a bio-orthogonal chemistry-based proteomics platform [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 P2-23-19.
Abstract P2-24-02: Analyzing susceptibility to macrophage-activating immunotherapy bexmarilimab in breast cancer by using patient-derived tumor explants
Authors: Rannikko Jenna H. , Virtakoivu Reetta , Takeda Akira , Boström Pia , Koskivuo Ilkka , Bono Petri , Hollmén Maija
Published: March 2023

The immunosuppressive tumor microenvironment governed by tumor-associated macrophages (TAMs) remains a major obstacle to effective cancer immunotherapy. A novel humanized antibody bexmarilimab, targeting the scavenger receptor Clever-1 on TAMs, has shown clinical benefit in ~40% of patients with late-stage ER+ breast cancer (MATINS; NCT03733990). To increase response rates, a comprehensive understanding on how TAM phenotype and the tumor immune landscape affect bexmarilimab-induced immune activation is needed. Single-cell RNA sequencing analysis of breast tumor macrophages shows high phenotypic variation across pathological subtypes and Clever-1 mRNA (STAB1) expression on various immunosuppressive IL4I1+ and TREM2+ monocyte-derived TAMs. STAB1 expressing macrophages were located in both lymphocyte rich and excluded areas in the tumor stroma based on digital spatial profiling with GeoMx. Due to this diversity, we studied bexmarilimab mode-of-action in breast cancer patient-derived tumor explant cultures (PDEC) by RNA sequencing and cytokine profiling. Our results show that bexmarilimab induced TNFα and CXCL10 secretion in 30-40% of the treated explants. In depth analysis of the responsive PDECs revealed a lower baseline expression of interferon responsive genes in their tumor microenvironment. Correspondingly, in vitro assays with primary human macrophages showed that chronic IFNγ priming abolished bexmarilimab-induced immune activation, suggesting potential use of bexmarilimab in patients with immunologically cold breast tumors.

Citation Format: Jenna H. Rannikko, Reetta Virtakoivu, Akira Takeda, Pia Boström, Ilkka Koskivuo, Petri Bono, Maija Hollmén. Analyzing susceptibility to macrophage-activating immunotherapy bexmarilimab in breast cancer by using patient-derived tumor explants [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 P2-24-02.
Abstract P2-24-05: TAVO412 - A Novel Trispecific cMet x EGFR x VEGF Antibody for Triple Negative Breast Cancer
Authors: Chiu Mark
Published: March 2023

Novel Multispecific Antibody with Superior Activity in TNBC INTRO: TNBC (Triple Negative Breast Cancer) has a diverse etiology and high unmet need. We created a novel multispecific antibody with unique 2:1:1 ratio of EGFR:cMet:VEGF binding arms with excellent activity against TNBC. METHOD: Multiple in vitro EGFR & cMet signaling pathway inhibition, proliferation inhibition, and ADCC, ADCP, and CDC were conducted. Various in vivo studies using the TNBC cell lines (MDA-MB-468, MDA-MB-231, HCC70, BT20) with diverse levels of EGFR and cMet receptor density levels were tested. RESULTS: Strong tumor growth inhibition was found in multiple TNBC animal models (56% tumor growth inhibition (TGI) in BT20, 26% TGI in HCC70, 62% TGI in MDA-MB-231). Tavo412 demonstrated better activity than comparator molecules in several in vivo models using lung, gastric, and pancreatic cancer cell lines (data not shown). A one month GLP toxicity study in cynomolgus monkeys has been completed with well-expected tolerability and pharmacokinetic profiles. Besides shutting down three important cancer pathways, TAVO412 showed high potency because it also has strong EGFR and VEGF binding at pH 6 in the tumor microenvironment. Moreover, Tavo412 has exemplary Fc effector function engaging the innate immune responses that include ADCC, ADCP, and CDC. There is also a synergistic tumor growth inhibition in the presence of a standard of care molecule such as doxorubicin (61% in HCC70 with TAVO412 + doxorubicin, 66% TGI in BT20 with TAVO412 + doxorubicin, 71% TGI in MDA-MB-231 with TAVO412 + doxorubicin). In addition, gastric, pancreatic, and lung cancer in vivo models showed excellent TGI profiles. CONCLUSIONS: Tavo412 has the potential activity to be a superior multispecific antibody to treat patients with triple negative breast cancer. Phase 1 clinical testing in patients is anticipated in early 2023.

Citation Format: Mark Chiu. TAVO412 - A Novel Trispecific cMet x EGFR x VEGF Antibody for Triple Negative 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 P2-24-05.
Abstract P2-25-04: Granzyme B expression in tumor microenvironment as a biomarker for prognosis of triple-negative breast cancer
Authors: Mizoguchi Kimihisa , Nakamura Masafumi
Published: March 2023

Background: Many analyzes on tumor microenvironment has made it clear that tumor infiltrating lymphocytes (TILs) plays an important role in treating cancers with high tumor mutation burden such as triple-negative breast cancer (TNBC). We reported that the relationship between TILs and PD-L1 expression (Oncotarget 2017) and revealed that high-TILs/positive-PD-L1 expression population in TNBC was associated with better prognosis. However, its molecular mechanism is still unclear. Meanwhile, it was well-known that activated T-cells work as antitumor lymphocytes by enhancing the apoptosis by granzyme B (GZMB) and perforin, and then production of cytokines such as INFγ. We focused on GZMB and examined the function of activated T-cells. Patients and Methods: This study included 230 patients with primary TNBC who underwent resection without neoadjuvant chemotherapy at our three hospitals between January 2004 and December 2014. The immunohistochemistry (IHC) scoring for GZMB expression on TILs was defined as 1 or 5%. PD-L1 positivity was defined as ≥ 10 Combined Positive Score (CPS) based on tumor and immune cells staining positive for PD-L1. Results: Of the 230 TNBC, GZMB on TILs was expressed as more than 1% and 5% positive in 181 (79%) and 50 (22%) tumors, respectively, and PD-L1 and CD8 on TILs was expressed as positive in 99 (43%) and 127 (55%) tumors, respectively. GZMB expression (more than 5%) was significantly correlated with PD-L1 expression (P=0.0048) and CD8 expression (P=0.0156). There was no significant difference in recurrence free survival (RFS) and overall survival (OS) regardless of CD8 or PD-L1expression level. Meanwhile, the patients with GZMB-positive tumors had a longer OS, compared to the patients with GZMB-negative tumors (P = 0.0155 in RFS and P = 0.0202 in OS) when PD-L1 expression on TILs was high, but not when it was low. Conclusion: OS was significantly longer among patients with high GZMB expressing TNBC. These results may validate the significance of GZMB as a biomarker for various immunotherapies in TNBC.

Citation Format: Kimihisa Mizoguchi, Masafumi Nakamura. Granzyme B expression in tumor microenvironment as a biomarker for prognosis of triple-negative 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 P2-25-04.
Abstract P2-26-21: The Principal Factors Associated with Engraftment Success of Patient-Derived Xenograft of Breast Cancer
Authors: Lee Jongwon , Lee Uk , Lee Hee Jin , Gong Gyungyub
Published: March 2023

Background: Patient-derived xenografts (PDXs) are increasingly used in cancer research as tools for studying cancer biology and personalized immunotherapy response. However, a comprehensive evaluation of patient-derived breast cancer xenograft generation rates in various settings is understudied. Methods: We conducted a prospective study of breast cancer patients treated with surgery to generate PDXs. PDXs were characterized by molecular subtypes, specific diagnostic entities, modified Bloom-Richardson system nuclear and histologic grades, treatment with neoadjuvant chemotherapy (NAC), Miller Payne grade, residual caner burden class, invasive tumor size, lymphovascular invasion status, number of positive lymph nodes, and the percentage of tumor infiltrating lymphocytes in the implanted tumors. Results: Three hundred and seventy-two (157 post-chemotherapy, 215 chemo-naïve) patient-derived tumors were implanted and 63 PDXs were established (17.0%). PDX engraftment was higher in the patients with higher nuclear and histologic grades using the modified Bloom-Richardson system (27.6% vs. 3.2%, p = 0.003) and triple negative breast cancer (TNBC) than in those with hormone receptor-positive cancer (36.4% vs. 3.2%, p = 0.02). Tumors from patients who received NAC (30.0% vs. 7.4%, p = 0.05) were also close to being statistically significant for successful PDX generation. Conclusions: PDXs can be established from clinically aggressive breast cancers, especially in patients with high nuclear and histologic grade TNBC treated with NAC. The prediction of engraftment success using these factors would establish cost-effective immunotherapy trials employing PDXs.

Citation Format: Jongwon Lee, Uk Lee, Hee Jin Lee, Gyungyub Gong. The Principal Factors Associated with Engraftment Success of Patient-Derived Xenograft of 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 P2-26-21.
Abstract P3-03-29: SMARTphone-Based Cardiovascular Risk Reduction in Breast Cancer Patients [SMART-BREAST]: A Randomized Controlled Trial
Authors: Murphy Alexandra C. , Farouque Omar , Koshy Anoop N. , Yeo Belinda , Dick Ron , Nadurata Voltaire , Roccisano Laura , Reid Christopher , Yudi Matias
Published: March 2023

Introduction Breast cancer survivors are at greater risk for cardiovascular-related mortality compared to women without breast cancer. Accordingly, attention to reducing the risk of cardiovascular disease must be a priority in the long-term management of these patients. Objective To assess the efficacy of a smartphone-based model of care for exercise promotion, cardiovascular risk reduction and psychological wellbeing in women undergoing treatment for breast cancer. Methods Female patients with breast cancer across four tertiary Australian hospitals were screened for inclusion in this randomized controlled trial. Patients were randomized to standard care (SC), with or without an adjunctive smartphone application ‘BreastMate’ (SP) at time of diagnosis. The primary endpoint was change in exercise capacity, measured by the change in six-minute walk test (6MWT) distance at 12-months when compared to baseline, between groups. Secondary endpoints included changes in cardiovascular risk factors, psychological wellbeing, and major adverse cardiovascular events (MACE). Results Of the 103 patients recruited, complete follow-up data was available in 80 (77.7%) patients (age 60±12 years, SP=41, SC=39). At 12-months follow-up, the SP group had a statistically and clinically significant improvement in 6MWT distance (Median Δ46 (IQR 28 to 63) metres vs. Δ8 (-10 to 35) metres; p< 0.001). Compared to SC, patients in the SP group had a greater reduction in systolic blood pressure (Δ-5.1 (-10 to 0) vs 0 (-10 to 7) mmHg; p=0.03) and waist circumference (Δ-1 (-4 to 0) vs 0 (-1.5 to 1) centimetres; p=0.003) as well as a greater improvement in vitality as measured by the sf-36 questionnaire (48.1 ± 18.4 to 63.3±19.2 vs 48.3 ± 24.2 to 59.6±18.8; p=0.04). There was no significant difference in cholesterol levels, diabetes control, smoking cessation or incidence of MACE between groups (p-value for all=NS). Conclusion In patients with breast cancer, a smartphone-based cardiovascular risk reduction program, as an adjunct to standard care, improved exercise capacity, systolic blood pressure, waist circumference and patient-reported vitality at 12-months. This innovative model of care could be implemented to improve the cardiovascular risk profile of breast cancer survivors. Australia and New Zealand Clinical Trials Registry (ANZCTR12620000007932).

Citation Format: Alexandra C. Murphy, Omar Farouque, Anoop N. Koshy, Belinda Yeo, Ron Dick, Voltaire Nadurata, Laura Roccisano, Christopher Reid, Matias Yudi. SMARTphone-Based Cardiovascular Risk Reduction in Breast Cancer Patients [SMART-BREAST]: A Randomized Controlled Trial [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 P3-03-29.