bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract F2-3: Immunosuppressive macrophages and PARP inhibitor resistance
Authors: Guerriero Jennifer 
Published: March 2023

Abstract
Despite objective responses to poly(ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high-dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in breast cancer susceptibility (BRCA)-associated TNBC. Macrophages are an innate immune cell that play a critical role in host defense and maintaining tissue homeostasis, however their infiltration into tumors has been associated with disease progression and resistance to therapy. Tumor associated macrophages (TAMs) represent a significant proportion of solid tumors, including breast cancer. TAMs play a major role in tumorigenesis as they can enhance tumor cell growth, angiogenesis and metastasis. In addition, TAMs can inhibit anti-tumor responses of T cells. Our recent work has shown that removal or conversion of TAMs to an anti-tumor phenotype enhances chemo- and immuno-therapy establishing TAMs as targets for anti-cancer therapy. Through multi-omics profiling, we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming, driven by the sterol regulatory element-binding protein 1 (SREBF1, SREBP1) pathway. Combining PARP inhibitor therapy with colony-stimulating factor 1 receptor (CSF1R)-blocking antibodies significantly enhanced innate and adaptive antitumor immunity and extended survival in mice with BRCA-deficient tumors in vivo, and this was mediated by CD8+ T cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate that combined PARP inhibition and macrophage-targeting therapy induces a durable reprogramming of the tumor microenvironment (TME), thus constituting a promising therapeutic strategy for TNBC. Therefore, targeting TAMs offers great potential to enhance both chemo- and immuno-therapy. Deep analysis of TAMs in solid tumors has revealed the complexity of TAMs and revealed major gaps in our knowledge of the functional and phenotypic characterization of TAM subsets associated with cancer, before and after treatment. Here we will discuss the complexity of TAMs in solid tumors including characterizing TAM subsets, location, and crosstalk with neighboring cells, as well as novel TAM-modulating strategies and combinations that are likely to enhance current therapies and overcome chemo- and immuno-therapy resistance.
Citation Format: Jennifer Guerriero. Immunosuppressive macrophages and PARP inhibitor resistance [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 F2-3.
Abstract F4-1: CDK4/6 inhibitor resistance: Biological mechanisms and novel approaches
Authors: Hanker Ariella 
Published: March 2023

Abstract
CDK4/6 inhibitors (CDK4/6i) in combination with antiestrogens have revolutionized the treatment of ER+ metastatic breast cancer (MBC), significantly prolonging survival. However, this combination is not curative in MBC, and resistance to CDK4/6i represents a major challenge. A diverse array of mechanisms of CDK4/6i resistance have been described, including deregulation of the G1/S cell cycle checkpoint (i.e. Rb, Cyclin E/CDK2, CDK6, INK4s), activation of growth factor signaling pathways (receptor tyrosine kinases, Ras/MAPK pathway, PI3K/AKT pathway), and contributions from the tumor microenvironment. A detailed understanding of these mechanisms is critical for overcoming CDK4/6i resistance. In this presentation, I will discuss recent advances in defining novel biomarkers that are causally associated with CDK4/6i resistance, therapeutic vulnerabilities linked to distinct mechanisms of resistance, and potential strategies to improve clinical responses to CDK4/6i in ER+ MBC.
Citation Format: Ariella Hanker. CDK4/6 inhibitor resistance: Biological mechanisms and novel 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 F4-1.
Abstract MS2-3: Implications for clinical care
Authors: Thomas Alexandra 
Published: March 2023

Abstract
Late recurrence, commonly considered to be distant recurrence five or more years after initial diagnosis remains a formidable challenge in breast oncology. Current management focuses on slowing the growth of macroscopic recurrent disease which is generally considered incurable. Emerging tools to identify minimal residual disease or tumor dormancy hold great promise to transform the treatment landscape in this space. This mini-symposium discussion will review the scope of the clinical challenge, highlighting the numbers at risk and the timeframe for recurrence risk. Current and emerging tools to assess the risk in individual patients beyond 5 years from diagnosis will be discussed. Evidence and guidelines on the use of clinically available anatomic-based and genomic assay-based late risk assessment tools including Clinical Treatment Score post-5 years (CTS5) and the Breast Cancer Index (BCI) will be highlighted. Current data on the role of circulating biomarkers including ctDNA, to identify at risk patients will be discussed as will open questions on how this might impact treatment approach. Finally, possible therapeutic approaches following the identification minimal residual or dormant disease will be reviewed, as will trial design options in this rapidly evolving space in breast oncology.
Citation Format: Alexandra Thomas. Implications for clinical care [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 MS2-3.
Abstract P2-14-20: Comparison of robot-assisted nipple sparing mastectomy with conventional nipple sparing mastectomy: a single-center experience
Authors: You Ji Young , Lee Haemin , Lee Eun-Shin , Jung Seung Pil 
Published: March 2023

Abstract
Purpose: Robot-assisted nipple-sparing mastectomy (RANSM) improves cosmetic outcomes compared to conventional nipple-sparing mastectomy (CNSM) since RANSM is performed with minimal incisions. However, there are few studies on the feasibility and surgical outcome of RANSM. The aim of this study was to compare the surgical outcomes of RANSM and CNSM in breast cancer patients. Method: A retrospective observational study was conducted at our institution between January 2021 and December 2021. A total of 54 patients diagnosed with breast malignancy that underwent either a robotic-assisted or conventional nipple-sparing mastectomy were included. The demographics of the patient’s sex, age, body mass index (BMI), breast weight, and preoperative diagnosis were investigated. The surgical method, operation time (including docking time and console time in the case of robotic surgery), postoperative complications, length of hospital stay, pain score, and adjuvant therapy were analyzed. Result: A total of 57 breasts in 54 female patients were included in the study: 36 invasive ductal carcinoma patients, 11 ductal carcinoma cases, 6 invasive lobular carcinoma, 2 mucinous carcinoma, one solid papillary carcinoma and one lobular carcinoma in situ. A median age of 49(27-66), mean BMI of 22 (18.89-26.28), and mean breast weight was 246 g (120-305g). The mean operation time was 122 minutes (robotic 140 vs. conventional 118), and the average docking time was five minutes and console time 60 minutes in the robot-assisted surgery. There was only one postoperative complication in the robot group and ten cases in the conventional group. The mean hospital stay was 12.6 days (RANSM 10.75 vs. CNSM 12.92), and the average pain score was 3.53 (RANSM 3.50 vs. CNSM 3.54). None needed adjuvant therapy in the robot group. In the conventional surgical group, four patients underwent adjuvant radiotherapy and sixteen patients underwent chemotherapy including six neoadjuvant cases. Conclusion: Our results showed that RANSM had advantages of shorter hospitalization and lower pain scores although it had slightly longer operation time and could not applicable in relatively large breasts. In the near future, RANSM may be considered as the surgery of choice over CNSM in breast cancer patients.
Citation Format: Ji Young You, Haemin Lee, Eun-Shin Lee, Seung Pil Jung. Comparison of robot-assisted nipple sparing mastectomy with conventional nipple sparing mastectomy: a single-center experience. [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 P2-14-20.
Abstract P3-05-23: Pathological complete response rate and disease-free survival after neoadjuvant chemotherapy in patients with HER2-low and HER2-0 breast cancers
Authors: de Nonneville Alexandre , HOUVENAEGHEL Gilles , Cohen Monique , SABIANI Laura , BANNIER Marie , VIRET Frederic , Gonçalves Anthony , BERTUCCI François 
Published: March 2023

Abstract
ABSTRACT Background: Half of HER2-negative breast cancers (BC) show HER2-low expression. The strong efficacy of recent anti-HER2 antibody-drug conjugates (ADC) in HER2-low tumors has risen the interest of HER2-low as a proper BC subtype. Chemosensitivity and prognosis of this subtype are not clear when compared to HER2-0 tumors. We investigated the pathological complete response (pCR) and disease-free survival (DFS) rates in BC patients receiving neoadjuvant chemotherapy for HER2-low or HER2-0 tumors. Methods: Data were collected from the Institut Paoli-Calmettes European Comprehensive Cancer Center database. HER2-low tumors were defined by HER2 IHC score of 1+ or 2+ with negative FISH, and HER2-0 by IHC score of 0+. Clinicopathological characteristics, pCR (defined as [ypT0/ypTis] and [pN0sn or ypN0]) and DFS rates were compared between the two cohorts. Results: From Jan/2005 to Jun/2021, 1,111 patients receiving neoadjuvant chemotherapy were evaluable. The incidence of HER2-low was 41%, including 63% of hormone receptor (HR)-positive and 37% of HR-negative tumors (p&lt; 0.001). In the whole population, the pCR rate was lower in HER2-low (23%) versus HER2-0 (30%) tumors (p=0.013), but this association was lost in multivariate analysis. In HR-positive patients, HER2-low negatively impacted pCR rates when compared to HER2-0 (10% vs. 16%, p=0.046), but not in HR-negatives (46% vs. 42%), and this result was maintained in multivariate analysis (OR 0.60 [95CI 0.36-1.00]; p=0.049, and OR 1.15 [95CI 0.77-1.71]; p=0.490, respectively. No correlation existed between DFS and HER2-status. Conclusion: HER2-low is associated with HR positivity. HER2 status did not impact pCR in HR-negative patients, whereas HER2-low was associated with lower pCR rate in HR-positive patients, supporting the development of anti-HER2 ADC in this setting.
Citation Format: Alexandre de Nonneville, Gilles HOUVENAEGHEL, Monique Cohen, Laura SABIANI, Marie BANNIER, Frederic VIRET, Anthony Gonçalves, François BERTUCCI. Pathological complete response rate and disease-free survival after neoadjuvant chemotherapy in patients with HER2-low and HER2-0 breast cancers [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 P3-05-23.
Abstract P3-08-04: Discovery of cancer genes and pathways operative in PI3K-activated mammary cancer reveals clinically relevant genotype-phenotype correlations
Authors: Kurata Morito , Pope Emiily , Shu Jingmin , Yuan Wenlin , Hudson Wendy , Sokolowski Mark , Bagherzadeh Setareh , Modrusan Zora , Stawiski Eric , Durinck Steffen , Seshigiri Sekar , Sarver Aaron , Temiz Nuri , Largaespada David 
Published: March 2023

Abstract
Human breast cancer (BRCA) shows tremendous genomic, gene expression, clinical, and phenotypic heterogeneity. Known driver gene alterations can only explain a portion of this heterogeneity, some of which likely arise from variation in the target cell for transformation, in addition to incompletely understood gene copy number and epigenetic alterations. These factors are difficult to identify with certainty using human patient samples due to widely varying germline genetic backgrounds, thousands of gene copy and epigenetic changes per sample, and, unknown target cell transformation. Activating mutations in the p110α catalytic subunit of PI3K are one of the most common genetic alterations in human BRCA. Here, we report results from two Sleeping Beauty (SB) transposon-accelerated mouse models of Pik3ca-mutant mammary cancer showing how genotype-phenotype correlations can be drawn providing strong candidates for mediating tumor phenotypes, including estrogen-receptor (ER)-dependent gene expression, high cell cycle activity, and immune cell exclusion. We used SB transposon mutagenesis in mice on a Pik3caH1047R activated mutant background to model mammary cancer development in two different mammary epithelial compartments. Both the target cell for mutagenesis and the specific transposon-induced mutations correlated with specific tumor phenotypes, including whether the tumors were ER positive or negative. RNA sequencing of tumors revealed novel genotype-phenotype correlations implicating specific transposon-altered gene drivers of high cell cycle activity, ER-dependent gene expression, and white blood cell exclusion from the tumor. Many transposon-implicated genes are altered at the gene copy number or epigenetic/methylation level in human BRCA, and several were functionally validated. These models provide a source of genetically heterogenous mouse mammary tumors with a uniform initiating mutation, Pik3caH1047R, useful for identifying cooperating pathways and drivers of specific tumor phenotypes.
Citation Format: Morito Kurata, Emiily Pope, Jingmin Shu, Wenlin Yuan, Wendy Hudson, Mark Sokolowski, Setareh Bagherzadeh, Zora Modrusan, Eric Stawiski, Steffen Durinck, Sekar Seshigiri, Aaron Sarver, Nuri Temiz, David Largaespada. Discovery of cancer genes and pathways operative in PI3K-activated mammary cancer reveals clinically relevant genotype-phenotype correlations. [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 P3-08-04.
Abstract P3-11-11: Impaired Succinate Metabolism Supports Endocrine Therapy Resistance in ER Positive Breast Cancers
Authors: Yadav Anil , de Oliveira Karla Andrade , Jin Lu , Clarke Robert , Sengupta Surojeet 
Published: March 2023

Abstract
Estrogen receptor positive (ER+) breast cancer is the most common subtype among all breast cancers and is responsible for most breast cancer related deaths. Endocrine therapies, such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI), often given in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, are initially effective but the majority of advanced ER+ breast cancers eventually become refractory to endocrine therapies. Therefore, understanding the underlying molecular mechanisms that enable or promote resistance to endocrine therapies may lead to novel therapeutic targets. Cancer cells consume greater quantities of glucose to meet their energy and anabolic demands to support cell growth and proliferation. In this study, we used breast cancer cell models that are endocrine therapy sensitive and resistant and investigated the metabolites by growing the cells in the presence of the stable glucose isotope, UC13-Glucose. We measured the C13-labelled metabolites of glycolysis and the TCA cycle. Glucose consumption was higher in endocrine therapy resistant MCF7/LCC9 (LCC9) cells compared with parental MCF7 (MCF7) and estrogen independent, endocrine therapy sensitive MCF7/LCC1 (LCC1) cells. Notably, in LCC9 cells the m+4 and m+6 isotopomer of C-13 labelled citrate was absent with a concurrent high succinate:fumarate ratio. Furthermore, in LCC9 cells, most of the fumarate was unlabeled suggesting that fumarate was not generated from glucose. These results suggest that the TCA cycle is impaired in LCC9 cells and the conversion of succinate to fumarate is dysregulated. Succinate dehydrogenase (SDH) enzyme is responsible for reversible catalytic conversion of succinate to fumarate. SDH is a multimeric protein comprised of four different subunits and SDH assembly factor 2 (SDHAF2), which is a tumor suppressor gene. Comparable SDH enzyme activity was observed in LCC9 and LCC1 cells. Intriguingly, when SDH activity was inhibited using dimethylmalonate, the LCC9 cells were re-sensitized to both Fulvestrant and 4-hydroxytamoxifen. Succinate accumulation was accompanied with HIF 1-alpha stabilization and SDH inhibition led to lower levels of HIF1-alpha. This indicated that SDH may function in the conversion of fumarate to succinate in LCC9 cells. Our study further investigates the source of fumarate in LCC9 cells. Overall, this study suggests that targeting succinate metabolism may help to restore sensitivity to Fulvestrant and tamoxifen in endocrine therapy resistance in ER+ breast cancer cells.
Citation Format: Anil Yadav, Karla Andrade de Oliveira, Lu Jin, Robert Clarke, Surojeet Sengupta. Impaired Succinate Metabolism Supports Endocrine Therapy Resistance in ER Positive Breast Cancers [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 P3-11-11.
Abstract P4-01-07: FS-1502, an anti-HER2 ADC, in Patients with HER2-Expressing Advanced Solid Tumors: A Phase 1a Dose-Escalation Study
Authors: Li Qiao , Wang Xian , Cheng Ying , Liu Yunjiang , Chang Jianhua , Wang Zhuo , Wu Chunjiao , Wang Mingxia , Hui Ai-Min , Wu Zhuli , Jin Yongli , Huang Xin , Zhong Liping , Diao Lei , Zhao Han , Xu Binghe 
Published: March 2023

Abstract
Background: FS-1502 is a HER2-targeting antibody drug-conjugate with a cleavable β-glucuronide linker and an antimitotic agent (monomethyl auristatin F) which showed promising antitumor activity in preclinical studies. We are evaluating the safety and tolerability of FS-1502 in patients with HER2-expressing advanced solid tumors (NCT03944499). Methods: Patients with HER2-expresssing advanced solid tumors who had failed prior standard of care therapies were enrolled in a single-arm, open-label, dose-escalation phase Ia study in China. FS-1502 was given IV once in 21-day or 28-day cycles. The primary endpoint was incidence of dose-limiting toxicity (DLT). Adverse events (AEs), objective response rate (ORR) and duration of response (DoR) were also assessed. Data cutoff was December 30, 2021. Results: A total of 67 patients, 64 with breast cancer and 3 with other solid tumors, with median 3 prior therapies (range 1-10), were enrolled in 5 sites and treated with FS-1502 at doses of 0.1-3.5 mg/kg. Two DLTs, as defined by the protocol, were observed, with one G2 decrease in creatinine clearance at 3.0 mg/kg and one G3 thrombocytopenia with hemorrhage at 3.5 mg/kg. No Grade 4/5 events were observed. Grade 3 TRAEs were observed in 24 (35.8%) patients with the most common AEs of hypokalemia (14.9%) and decreased platelet count (9.0%). ORRs were observed at doses at or above 1.0 mg/kg with an ORR of 66.7% (4/6) at the recommended phase 2 dose (RP2D) of 2.3 mg/kg. Median duration of response (DoR) across all dose levels was 9.2 months (95%CI 5.6-NR). ORR for HER2-low patients was 42.9% (3/7). Plasma concentration and exposure (AUC) based on total ADC and total antibody increased dose proportionally at ≥1.0 mg/kg, with a T1/2 of 2.4-4.9 days. The incidence and magnitude of immunogenicity were low. While no MTD was determined, the 2.3mg/kg dose once in a 21-day cycle was selected as the RP2D based on safety, antitumor activity and PK data. Conclusions: FS-1502 was well-tolerated and demonstrated encouraging antitumor activity in both HER2-high and -low patients. Phase Ib and phase II clinical trials with FS-1502 are currently ongoing in various solid tumor indications including breast, gastric, and colorectal cancer.
Citation Format: Qiao Li, Xian Wang, Ying Cheng, Yunjiang Liu, Jianhua Chang, Zhuo Wang, Chunjiao Wu, Mingxia Wang, Ai-Min Hui, Zhuli Wu, Yongli Jin, Xin Huang, Liping Zhong, Lei Diao, Han Zhao, Binghe Xu. FS-1502, an anti-HER2 ADC, in Patients with HER2-Expressing Advanced Solid Tumors: A Phase 1a Dose-Escalation 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 P4-01-07.
Abstract P4-08-09: Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2-deficiency
Authors: Guantay María L. , Garro Cintia A. , Siri Sebastian , Pansa María , Ghidelli-Disse Sonja , Paviolo Natalia , Racca Ana , Nicotra Viviana , Radu Caius , Bocco José L. , Felice Rosana , Gloger Israel , Muelbaier Marcel , Drewes Gerard , Madauss Kevin , García Manuela , Gottifredi Vanesa , Soria Gastón 
Published: March 2023

Abstract
BRCA2 is a well-established cancer driver in several human malignancies. While the remarkable success of PARP inhibitors proved the clinical potential of targeting BRCA deficiencies, the emergence of resistance mechanisms underscores the importance of seeking novel Synthetic Lethal (SL) targets for future drug development efforts. In this work, we performed a BRCA2-centric SL screen with a collection of plant-derived compounds from South America. We identified the steroidal alkaloid Solanocapsine as a selective SL inducer, and we were able to substantially increase its potency by deriving multiple analogs. The use of two complementary chemoproteomic approaches led to the identification of the nucleotide salvage pathway enzyme deoxycytidine kinase (dCK) as Solanocapsine’s target responsible for its BRCA2-liked SL induction. Additional confirmatory evidence was obtained by using a highly specific dCK inhibitor (DI-87), which induces SL in multiple BRCA2-deficient and KO contexts. Interestingly, dCK-induced SL is mechanistically different from the one induced by PARP inhibitors. dCK inhibition generates substantially lower levels of DNA damage, and cytotoxic phenotypes are associated exclusively with mitosis, thus suggesting that the fine-tuning of nucleotide supply in mitosis is critical for the survival of BRCA2-deficient cells. Moreover, by using a xenograft model of contralateral tumors, we show that dCK impairment suffices to trigger SL in-vivo. Taken together, our findings unveil dCK as a promising new target for BRCA2-deficient cancers, which provides future therapeutic alternatives to PARP inhibitors.
Citation Format: María L. Guantay, Cintia A. Garro, Sebastian Siri, María Pansa, Sonja Ghidelli-Disse, Natalia Paviolo, Ana Racca, Viviana Nicotra, Caius Radu, José L. Bocco, Rosana Felice, Israel Gloger, Marcel Muelbaier, Gerard Drewes, Kevin Madauss, Manuela García, Vanesa Gottifredi, Gastón Soria. Deoxycytidine kinase (dCK) inhibition is synthetic lethal with BRCA2-deficiency [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 P4-08-09.