ACS Chemical Health & Safety最新文献

{"title":"Abstract PO1-05-01: Cyclin-dependent Kinase 4/6 Inhibitors Combined with Radiotherapy in the Management of Brain Metastases in HR-positive/HER2-negative Breast Cancer Patients","authors":"M. Kubeczko, Dorota Gabryś, A. Polakiewicz-Gilowska, A. Krzywon, Donata Gräupner, Barbara Łanoszka, M. Mianowska-Malec, A. Leśniak, K. Świderska, Konstanty Chomik, B. Grandys, Michał Jarząb","doi":"10.1158/1538-7445.sabcs23-po1-05-01","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po1-05-01","url":null,"abstract":"\u0000 Purpose: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy demonstrated overall survival benefits in advanced breast cancer patients (ABC), hormone receptor-positive, HER2-negative (HR+/HER2-) and remains the mainstay in the first and second-line treatment. Brain metastases are rare at the beginning of treatment in this group of patients and are found more often during subsequent lines of treatment and other subtypes of breast cancer. However, there is a paucity of data on the safety and efficacy of multimodality CDK4/6i and radiotherapy treatment in the management of brain metastases. Thus, we performed a retrospective analysis of ABC patients (pts) treated at our institution with radiation therapy to the brain and CDK4/6i. Pts who received radiotherapy before CDK4/6i initiation or concurrently with CDK4/6i (group 1) were compared to the patients who progressed in the brain during CDK4/6i treatment and then received radiotherapy (group 2). The primary endpoint was progression-free survival (PFS) in group 1 vs. group 2; the secondary endpoints were local control (LC) within the brain in group 1 vs. group 2 and severe toxicity. Materials/Methods: Among 379 pts who received CDK4/6i, 26 pts (6.9%) received radiotherapy to the brain. 17 pts received radiotherapy before or concurrent with CDK4/6i and were included in group 1. Nine pts received radiotherapy after CDK4/6i discontinuation due to disease progression and comprised group 2. Results: The median age was 51.5 years (IQR range 41-62). Six pts had de novo metastatic disease. The majority of patients were treated in the first-line setting (15 pts, 58%). 17 pts received ribociclib, 7 palbociclib, and 2 abemaciclib. 15 pts received letrozole as an endocrine compound and 11 pts fulvestrant. 19 pts (73%) received previous chemotherapy. Six pts had an ECOG performance status of 0, 15 pts ECOG 1, and 5 pts ECOG 2. The most common local treatment was whole-brain radiotherapy with a total dose of 20 Gy delivered in 5 fractions (fr) (11 pts: 4 pts VMAT, 2 pts IMRT, 3 pts 3D, and 2 pts 2D). Eight pts received stereotactic radiation therapy (6 pts with Linac: 2 pts 24 Gy/2 fr, 2 pts 24 Gy/3 fr, 2 pts 25 Gy/5 fr; 1 pt GammKnife 20 Gy/1 fr, 1 pt Cyberknife 15 Gy/3 fr). Six- and 12-month PFS in group 1 was 88.2% (95% CI74.1-100) and 58.8% (95% CI: 37.7- 91.8), respectively, whereas in group 2, six- and 12-month PFS was 55.6% (95%CI: 31- 99.7) and 44.4% (95% CI: 21- 92.2), respectively. Six- and 12-month LC in group 1 was 92.3% (95%CI: 78.9-100) and 83.9% (65.7-100), respectively. LC in group 2 was poor: 3-month LC was only 66.7 (30-100). At a median follow-up of 8.8 months, no unanticipated toxicity was reported. Conclusion: Multimodality treatment with CDK4/6i and radiotherapy to the brain is safe and effective. Patients who developed metastases during CDK4/6i treatment tend to have a worse prognosis in comparison to those who received prior radiotherapy. CDK4/6i following radiotherapy","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"59 4","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PO1-15-09: Vitamin A Metabolism Induces Ferroptosis to Enhance Immune Therapy Efficacy in HR+/HER2- Breast Cancer","authors":"Yi-Fan Zhou, Hu-Yun-Long Zhang, X. Jin, Yizhou Jiang, Zhiming Shao","doi":"10.1158/1538-7445.sabcs23-po1-15-09","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po1-15-09","url":null,"abstract":"\u0000 Background: Immune checkpoint blockade (ICB) has substantially improved patient overall and progression-free survival in triple-negative breast cancer (TNBC), but its efficacy remains to be elucidated in the hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, which is characterized by generally impotent lymphocytic infiltration. In the I-SPY2 trial (NCT01042379), pembrolizumab- or durvalumab-containing neoadjuvant therapy increased the pathologic complete response of HR+/HER2- patients. However, pembrolizumab-containing therapy failed to improve the survival of metastatic HR+/HER2- breast cancer patients (NCT03051659). These inconsistent results underscored the necessity of the investigation of predictive biomarkers to pinpoint potential ICB responders in HR+/HER2- breast cancer.\u0000 Method: In this study, we collected pretreatment tumor samples from 16 patients in two respective clinical trials (NCT: 04215003 and 04355858) and profiled droplet-based single-cell sequencing, bulk RNA-Seq. Patients were treated with camrelizumab (PD-1 inhibitor)-containing therapy, and five of them achieved partial relief after an 8-week course. We also leveraged the bulk RNA-Seq data from the I-SPY2 trial and Fudan University Shanghai Cancer Center (FUSCC) TNBC ICB trials (NCT04418154 and NCT04613674) for external validation. Another FUSCC transcriptome dataset consisting of 933 treatment-naïve HR+/HER2- or TNBC breast cancer patients was used to detect the abundance of cell types. In vitro and in vivo experiments were used to explore mechanisms of anti-tumor immune response.\u0000 Results: Based on the single-cell sequencing results, we comprehensively delineated the microenvironmental landscape of HR+/HER2- breast cancer. We discovered responders of immunotherapy showed a higher presence of CXCL9/10+ M1-like macrophages and exhibited enrichment of tumor cells with ferroptosis. We further identified the upregulation of vitamin A metabolism and the vitamin A metabolic gene CRABP1 in tumor cells with ferroptosis. We verified the vitamin A metabolism could induce ferroptosis in HR+/HER2- breast cancers rather than TNBC by CRABP1-ERK axis, which could further recruit CXCL9/10+ M1-like macrophages and promote anti-tumor immune response in HR+/HER2- breast cancer. Combining anti-PD1 with enhancing vitamin A metabolism via retinoid acid possessed greater therapeutic efficacy than monotherapy in HR+/HER2- breast cancers. Finally, we developed an immune therapy response score and validated its reliability in predicting the immunotherapy efficacy for HR+/HER2-breast cancers through both internal and external cohorts.\u0000 Conclusion: Our study represents the earliest efforts to decipher the microenvironmental landscape and the mechanisms underlying the response to ICB in HR+/HER2- breast cancer at single-cell resolution. We unraveled a HR+/HER2- breast cancer-specific Vitamin A-ferroptosis axis that mediated immunotherapy response","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"64 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PO2-08-07: Evaluating chemotherapy receipt and candidacy for PARP inhibitors in germline BRCA1/2 carriers with early and locally advanced breast cancer","authors":"Stephanie M. Wong, Carla Apostolova, Amina Ferroum, Basmah Alhassan, Ipshita Prakash, M. Basik, K. Martel, Sarkis Meterissian, David Fleiszer, Nora Wong, Talia Malagon, William Foulkes, J. Boileau","doi":"10.1158/1538-7445.sabcs23-po2-08-07","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po2-08-07","url":null,"abstract":"\u0000 Introduction: While enhanced breast screening of germline BRCA1/2 carriers results in earlier stage at diagnosis, the impact of tumour biology and BRCA mutation on chemotherapy receipt in early stage disease remains understudied. Methods: We retrospectively reviewed treatment administered following a first diagnosis of BRCA1/2-associated breast cancer between 2003-2023 at our institution. Chemotherapy receipt (neoadjuvant or adjuvant) was evaluated according to tumor size, biologic subtype, and BRCA mutation. Current guidelines for PARP inhibitor use were applied to estimate the proportion of affected BRCA1/2 carriers that would be deemed eligible for targeted therapy in the future. Results: Overall, 251 affected BRCA1/2 carriers were included; 137 (54.6%) BRCA1 (median age 40 years, range 19-72) and 114 (45.4%) BRCA2 (median age 43, range, 24-80 years). Chemotherapy was administered in 70.1% of index breast cancer cases and was significantly associated with clinical tumor size (36.7% T1a-T1b, 90.9% T1c, 95.2% T2, 95.3% T3-T4, p< 0.001), nodal status (71.8% cN0 vs. 100% cN1-2, p=0.004), and biologic subtype (90.0% TNBC vs. 75.0% ER+HER2-, p=0.02). BRCA1-associated breast cancers were less likely to present with DCIS or T1 tumours (%Tis/T1; 46.7% BRCA1 vs. 70.8% BRCA2, p< 0.001) and more likely to present with triple negative disease (71.4% BRCA1 vs. 24.6% BRCA2, p< 0.001). BRCA1 carriers were more likely to require chemotherapy for index breast cancer (81.8% BRCA1 vs. 56.1% BRCA2, p< 0.001). In subgroup analysis of early stage, T1N0 disease, chemotherapy was administered in 79.0% BRCA1 and 52.2% BRCA2 patients (p=0.03). If recent guidelines incorporating biologic subtype, nodal involvement, and response to neoadjuvant chemotherapy were retrospectively applied to the cohort, 33.6% would be deemed eligible for PARP inhibitors in the adjuvant setting, including 40.9% BRCA1 and 17.5% BRCA2 affected carriers (p < 0.001). Conclusion: Chemotherapy receipt is high in BRCA-associated breast cancers including in early stage, node-negative disease. Overall, one third of affected carriers are expected to be eligible for PARP inhibitors in the adjuvant setting. Future studies exploring how this information may impact decisions around risk-reducing mastectomy are warranted.\u0000 Citation Format: Stephanie Wong, Carla Apostolova, Amina Ferroum, Basmah Alhassan, Ipshita Prakash, Mark Basik, Karyne Martel, Sarkis Meterissian, David Fleiszer, Nora Wong, Talia Malagon, William Foulkes, Jean-Francois Boileau. Evaluating chemotherapy receipt and candidacy for PARP inhibitors in germline BRCA1/2 carriers with early and locally advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-07.","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"63 8","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PO5-24-02: Interferon-induced bone marrow stromal antigen 2 (BST2) is a functional tumor-initiating cell marker in triple-negative breast cancer","authors":"Eric Souto, Ping Gong, John D. Landua, Ram Srinivasan, L. Dobrolecki, Abhinaya Ganesan, Michael Lewis","doi":"10.1158/1538-7445.sabcs23-po5-24-02","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po5-24-02","url":null,"abstract":"\u0000 Background: A subpopulation of tumor cells known to have intrinsic resistance to therapies and contribute to metastasis function as “cancer stem”, or tumor-initiating, cells (TICs). TICs can be identified by various biomarkers, including fluorescent reporters for signaling pathways that regulate TIC function such as STAT signaling. However, standard TIC reporters have limitations. Their expression is unstable and there is no established method to follow TICs as they undergo cell state changes. Furthermore, we do not completely understand the transcriptional features of TICs. Improved methods of identifying TICs as well as the development of high-resolution transcriptional signatures are essential to understand TIC biology. An improved understanding of TIC biology can inform the development of novel therapeutics to selectively ablate the TIC compartment, thus improving response to standard cancer therapies.\u0000 Methods: We screened a panel of PDX models to determine whether a STAT reporter identifies TICs in patient-derived xenograft (PDX) models. To augment existing STAT TIC reporters, we developed a two-component STAT signaling-specific lineage-tracing (LT) system. The first component labels active STAT signaling cells by expression of enhanced green fluorescent protein (EGFP+), followed by a self-cleaving P2A peptide and a TAM-inducible Cre-recombinase (4M67-EGFP-P2A-CreERT2). The second component is a constitutively expressed dual-color switching Cre-dependent reporter vector (EFS-loxPdsRedloxP-mNeptune2). We determined which LT cell populations (EGFP+/mNeptune2+, EGFP+/dsRed+, EGFP−/mNeptune2+, and EGFP−/dsRed+) from SUM159 xenografts functioned as TICs. To probe TIC transcriptional features, we performed scRNA seq on the two tumor models with STAT TICs and a PDX model that did not have STAT TICs. We performed lineage trajectory analysis and differential gene expression analysis to characterize candidate TIC transcriptional signatures. To confirm whether these transcriptional features are associated with TICs, we identified a biomarker of this cell state (bone marrow stromal antigen 2 [BST2]) and explored the relationship between this biomarker and TICs.\u0000 Results: We identified four PDX models with STAT reporter activity, one of which had STAT TICs. We validated our LT system in several models both in vitro and in vivo, then demonstrated EGFP+/mNeptune2+ from SUM159 xenografts are enriched for TICs and that lineage-tagged cells (mNeptune2+) function as proliferative early progenitor cells. scRNA seq of three xenograft models uncovered a distinct antiviral cell state in all three models that represent a more highly enriched TIC subpopulation. Critically, transcriptional features were shared between the antiviral cell states across xenograft models. To determine whether cells in this antiviral state represent TICs, we FACS-enriched BST2 cells (an IFN-stimulated cell surface protein that was a marker of the antiviral cell state) and demonstrated ","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"63 S6","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PO1-15-12: Circulating tumor DNA (ctDNA) for prediction of pathologic complete response (pCR) after 12 weeks of pembrolizumab + trastuzumab + pertuzumab in HER2-enriched early breast cancer: WSG-Keyriched-1 trial","authors":"M. Graeser, S. Kuemmel, O. Gluz, Christopher Schroeder, Leon Schuetz, Olga Kelemen, Stephan Ossowski, K. Jóźwiak, M. Reinisch, A. Kostara, I. Scheffen, K. Lüdtke-Heckenkamp, Felix Hilpert, Angela Kentsch, Carsten Ziske, Reinhard Depenbusch, Michael Braun, J. Blohmer, M. Christgen, S. Bartels, H. Kreipe, E. Pelz, U. Nitz, Peter Schmid, Nadia Harbeck, A. Hartkopf","doi":"10.1158/1538-7445.sabcs23-po1-15-12","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po1-15-12","url":null,"abstract":"\u0000 Background\u0000 ctDNA testing is emerging as an important biomarker in early breast cancer (eBC). However, its value in prediction of tumor response to de-escalated, chemotherapy-free neoadjuvant therapy (NAT) remains underexplored. In WSG-Keyriched-1 (NCT03988036), a single-arm phase 2 trial, we investigated for the first time a chemotherapy-free NAT with dual HER2 blockade and pembrolizumab in HER2- enriched HER2+ eBC. In this pre-specified translational analysis, we evaluated whether ctDNA measurement could predict pCR.\u0000 Methods\u0000 48 patients (pts) with HER2 2+ (ISH+) or 3+ eBC (stage I-III) and HER2-enriched subtype by PAM50 were included. Pts received pembrolizumab (200 mg), trastuzumab biosimilar (loading dose (LD) 8 mg/kg bodyweight (BW), maintenance dose (MD) 6 mg/kg BW), and pertuzumab (LD 840 mg/kg BW, MD 420 mg/kg BW) q3w for 12 weeks. Primary objective was pCR (ypT0/is ypN0).\u0000 ctDNA was analyzed in 92 plasma samples collected from 31 pts at baseline (BL) and week 3 of NAT and 30 pts at end of treatment (EOT). Sequencing libraries with unique molecular identifiers were constructed from cell-free DNA and hybridization panels with ≤50 patient-specific somatic mutations from tumor sequencing were used for enrichment. Libraries were sequenced to an ultra-high depth of 100,000×. Sequencing data was analyzed using a combination of public pipelines (megSAP and umiVar2 for mapping and deduplication) and custom in-house scripts (to extract the allele counts for patient-specific variants). To reduce the error rate, only corrected reads with ≥4 duplicates were used. p-value for ctDNA detection was calculated using the total variant count, depth and sample-specific error.\u0000 Association between ctDNA with pCR and other clinical parameters were assessed with Chi-square or Fisher’s exact test and univariable logistic regression. Additionally, bivariable logistic regressions for pCR were performed with ctDNA and either cT, cN, or grade.\u0000 Results\u0000 ctDNA was detected (ctDNA+) in 58.0% (n=18/31) of pts at BL, 9.7% (n=3/31) at week 3, and 10% (n=3/30) at EOT. ctDNA was cleared by week 3 in 83.3% of pts (n=15/18).\u0000 Compared with ctDNA-negative cases (ctDNA-) at BL, those ctDNA+ more often had cT2-3 disease (94.4%, n=17/18, vs 38.5%, n=5/13; p=.001) and lymph node involvement (61.1%, n=11/18, vs 0%, n=0/13; p&lt; .001). 72.2% (n=13/18) of ctDNA+ and 61.5% (n=8/13) of ctDNA- cases at BL were grade 3 (p=.53). Each of the 3 pts who remained ctDNA+ at week 3 was node-positive; all pts remaining ctDNA- at week 3 were node-negative.\u0000 pCR rate was 38.9% (n=7/18) in ctDNA+ vs 76.9% (n=10/13) in ctDNA- pts at BL (p=.067), 0% (n=0/3) in ctDNA+ vs 60.7% (n=17/28) in ctDNA- at week 3 (p=.081), and 33.3% (n=1/3) in ctDNA+ vs 59.3% (n=16/27) in ctDNA- at EOT (p=.565). pCR rate was highest in pts who remained ctDNA- throughout week 3 (76.9%, n=10/13), compared to pts with ctDNA cleared by week 3 (46.7%, n=7/15), and pts remaining ctDNA+ (0%, n=0/3, p=.024).\u0000 ctDNA at BL was pred","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"57 11","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PO3-24-04: Altered epigenetic modifications and genome architecture reshape lipid metabolism during secondary trastuzumab resistance formation of HER2-positive breast cancer","authors":"Ningjun Duan, Y. Hua, Yongmei Yin","doi":"10.1158/1538-7445.sabcs23-po3-24-04","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po3-24-04","url":null,"abstract":"\u0000 Title\u0000 Altered epigenetic modifications and genome architecture reshape lipid metabolism during secondary trastuzumab resistance formation of HER2-positive breast cancer\u0000 Background\u0000 Secondary trastuzumab resistance seriously affects the treatment of HER2-positive breast cancer. Although studies have demonstrated several key cellular properties that are closely accompanied with trastuzumab resistance formation, we still have poor knowledge on the genetic and epigenetic variations that promote such transformation. Here we suggested that the epigenetic modification changes on histone H3 together with altered chromatin architecture promote lipid metabolism reprogramming during secondary trastuzumab formation.\u0000 Materials and methods\u0000 Induced secondary trastuzumab-resistant SKBR3_HR cell line together with the original trastuzumab-sensitive SKBR3 cell line were applied in this study. Total RNA was collected for transcriptome analysis. Anti-H3K4me3 and K27me3 antibodies were chosen for CUT&Tag sequencing library preparation. Total genome DNA was prepared for Micro-C sequencing library preparation. Activity score of metabolism pathway was calculated as relative gene expression value averaged over all genes in this pathway in certain cell types.\u0000 Results\u0000 Upregulation of arachidonic acid metabolism and downregulation of unsaturated fatty acid synthesis, which are mainly characterized by the activation of PTGS1 and PTGES genes and the repression of FASN and SCD genes, respectively, were observed during the formation of secondary trastuzumab resistance from SKBR3 cell to SKBR3_HR cells.\u0000 Variations of H3k4me3 instead of H3k27me3 regulate the expression of these 4 genes. The accumulation of H3k4me3 was detected at the promoters of PTGS1 and PTGES genes while they were removed from the promoters of FASN and SCD genes in SKBR3_HR cells.\u0000 More intra-chromosomal interactions were constituted during resistance formation. In detail, 4626 and 4394 topological associated domains, 3125 and 5824 DNA loops were founded in SKBR3 and SKBR3_HR cells, respectively. Furthermore, the lost and gained DNA loops between SCD and PTGS1 genes and distant genome regions may indicate the weaken and strengthen interactions with transcriptional regulators located there.\u0000 Conclusions\u0000 During trastuzumab resistance formation, altered histone modifications as well as higher genome structure could regulate the expression of key genes in lipid metabolism pathways, which may further affect cell properties and interactions with cells in tumor microenvironment.\u0000 Citation Format: Ningjun Duan, Yijia Hua, Yongmei Yin. Altered epigenetic modifications and genome architecture reshape lipid metabolism during secondary trastuzumab resistance formation of HER2-positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-24-04.","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"49 11","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PO4-13-02: Molecular Expression Assays Improve the Prediction of Local and Invasive Local Recurrence after Breast Conserving Surgery for DCIS","authors":"Ezra Hahn, R. Sutradhar, L. Paszat, Lena Nguyen, Danielle Rodin, S. Nofech-Mozes, Sabina Trebinjac, Cindy Fong, E. Rakovitch","doi":"10.1158/1538-7445.sabcs23-po4-13-02","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po4-13-02","url":null,"abstract":"\u0000 Introduction\u0000 Ductal carcinoma in situ (DCIS) is routinely treated with adjuvant radiotherapy (RT) after breast conserving surgery (BCS) in order to reduce the risk of local recurrence (LR) and invasive LR. Nomograms based on clinicopathological features (CPF) and molecular expression assays have been developed in an effort to provide individualized risk estimates and personalize decision-making. However, molecular assays are costly and it remains unclear if they provide more accurate recurrence risk estimates compared to algorithms based on CPF alone. We examined the impact of the 12-Gene DCIS Score (DS) and the 21-Gene Recurrence Score (RS) molecular expression assays, in addition to CPF, on the accuracy of predicting 10-year LR and invasive LR risk compared to predicted estimates based on CPF alone. In addition, we examined if a model including the 21-Gene RS improves the 10-year predicted risks of invasive LR after BCS for DCIS compared to estimates based on the DS+CPF or CPF alone.\u0000 Methods\u0000 We used a population-based cohort diagnosed with pure DCIS treated with BCS +/- RT from 1994-2003. All cases had expert pathology review providing contemporary assessment of diagnosis, margin status, margin width, multifocality, presence and extent of comedo necrosis, subtype, nuclear grade, and tumor size. For each case, a representative tissue block or unstained slide was sent to measure the 12-Gene DS and 21-Gene RS. Predictive models were developed using multivariable Cox regression analyses with backward selection and included all CPF, treatment with RT, and interactions. The performance of each model was evaluated based on c-statistic, -2log likelihood estimate (-2LLE), and Akaike information criterion (AIC). Calibration was performed using bootstrap resamples, with replacement. We compared the performance of the best model derived from CPF alone, the 12-Gene DS with CPF, and the 21-Gene RS with CPF on their ability to predict the 10 year risks of LR and invasive LR measured against outcomes observed in the cohort.\u0000 Results\u0000 The population-based cohort includes 1226 women, 514 were treated with BCS alone and 712 were treated with BCS + RT. Median age was 56 years. Median follow-up was 10 years. Fifty-two percent of tumors were between 1 and 2.5 cm, 35% were ≤1cm, and 13% were &gt;2.5 cm. Comedo necrosis was present in 68%, and nuclear grade was low, moderate, and high in 7%, 54%, and 39%, respectively. Margins were negative in 90.5% of cases (N=1109). The 12-Gene DS was low, intermediate, and high in 53.5%, 20.9%, and 25.6% and the 21-Gene RS was &gt;25 in 30% of patients. 194 women (15.8%) experienced ipsilateral LR as a first event; 112 were invasive LR.\u0000 Models including either the DS or RS expression assays performed better in predicting the 10-year risk of LR after BCS compared to the model based on CPFs alone, demonstrating higher c-statistics (0.705, 0.699, and 0.662, respectively), lower AIC and lower -2LLE. The two molecular-based predictive m","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"83 7","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PO5-05-09: Testing AI-Predicted Protein Motifs that Direct Constitutive Genomic AR Activity in Endocrine Resistant Breast Cancer","authors":"A. Khan, Anthony S Peidl, Shaymaa Bahnassy, Henry Vo, Micah Castillo, Sarah Herzog, S. Fuqua, Preethi H Gunaratne, Xiaolian Gao, Subash Pakhrin, Tasneem Bawa-Khalfe","doi":"10.1158/1538-7445.sabcs23-po5-05-09","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po5-05-09","url":null,"abstract":"\u0000 Testing AI-Predicted Protein Motifs that Direct Constitutive Genomic AR Activity in Endocrine-Resistant Breast Cancer Ashfia F. Khan 1,2, Anthony S. Peidl 1,2, Shaymaa Bahnassy 3, Henry Vo2, Micah B. Castillo 2, Sarah K Herzog4,5, Suzanne AW Fuqua4,6, Preethi Gunaratne 2, Xiaolian Gao 2, Subash C. Pakhrin7, Tasneem Bawa-Khalfe1,2 1 Center for Nuclear Receptors & Cell Signaling, University of Houston, Houston, TX 2 Department of Biology & Biochemistry, University of Houston, Houston, TX 3 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 4 Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 5 Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 6 Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 7 Department of Computer Science & Engineering Technology, University of Houston-Downtown, Houston, TX Background: Endocrine therapy (ET) remains the first-line treatment for hormone-receptor positive (HR+) breast cancer (BCa). Approximately 15–20% of HR+ BCa are intrinsically resistant to ET, and 30–40% of patients acquire resistance. Resistance to ET (ET-R) supports cancer progression with reduced disease-free survival and greater incidence of metastatic disease. Hence, therapeutic strategies for ET-R HR+ BCa remain an overarching challenge. The androgen receptor (AR) is emerging as an attractive alternative target for BCa subtypes, and elevated AR levels drive HR+ BCa progression. Targeting AR in HR+ BCa is proving difficult with preclinical studies showing conflicting results for AR antagonists. Yet clinical trials with several AR-targeting drugs are ongoing. Our recent report highlights a unique constitutively active modified AR population that drives HR+ BCa metastatic properties and is insensitive to AR inhibitors. Our current objectives are to 1) use a novel machine-learning model to predict AR modifications and 2) establish a strategy to identify patients with high modified AR levels. Methods: An advanced artificial intelligence (AI) tool and mid-throughput microfluidic peptide array technology were used to map modification domains on AR. SUMO post-translational modification of AR (SUMO-AR) was eliminated in HR+ BCa using CRISPR-Cas9 technology. RNA-seq was employed to identify a unique gene signature for SUMO-AR, and comparative bioinformatic analysis stratified patients with high versus low SUMO-AR. Results: A novel deep-learning AI platform SumoPred-PLM is trained to identify consensus, non-consensus, and SUMO2/3-specific motifs on AR. We verified SUMO2/3-specific sites on AR with a mid-throughput microfluidic peptide array. The identified SUMO2/3-acceptor site of AR is important for HR+ BCa cell pathophysiology; loss of this SUMO2/3-acceptor site impacts endogenous AR SUMOylation, cell morphology, and proliferation/apoptosis. Using both high and low SUMO-AR BCa lines, a unique SUMO-AR gene profi","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"64 9","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141018070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PO3-12-12: Axial Neuropathy in Two Breast Cancer Patients receiving Fam-trastuzumab deruxtecan: A Case Report","authors":"Lauren Botero, Katharine McNeill, Della Makower","doi":"10.1158/1538-7445.sabcs23-po3-12-12","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po3-12-12","url":null,"abstract":"\u0000 Introduction. Fam-trastuzumab deruxtecan (T-DXd) is FDA approved for metastatic HER2-positive (HER2+) and HER2-low breast cancer (BC). Peripheral neuropathy is a side effect of T-DXd, with an incidence of 13%. Here we discuss two BC patients (pts) who presented with paresthesias of the trunk after receiving T-DXd.\u0000 Case 1. A 51-year-old female with Stage IIIB cT4N2M0 left BC, estrogen receptor positive (ER+), progesterone receptor positive (PR+) and HER2+ was treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP), followed by mastectomy and axillary lymph node dissection, with downstaging to ypT3N2a disease. She was enrolled on a clinical trial comparing T-DXd with standard treatment for HER2+ BC with residual disease after neoadjuvant therapy, and was randomized to T-DXd arm. She also received adjuvant proton radiation therapy to the chest wall. One week after her third cycle of T-DXd she developed Grade 3 paresthesias on her trunk and proximal upper and lower extremities, stating she could not bend over or perform activities of daily living. She did not experience associated weakness or peripheral neuropathy. Symptoms improved to Grade 1 after initiation of gabapentin and delay of cycle 4 T-DXd by one week. She resumed T-DXd with dose reduction per protocol, and increase in gabapentin dose. She was seen by neurology who localized her sensory findings to T5-T9. She was recommended to undergo MRI spine, but was unable to do so, due to presence of tissue expander. Paresthesias have been controlled on dose reduced T-DXd and continued gabapentin.\u0000 Case 2. A 56-year-old female with ER+, PR+, HER2-negative BC initially diagnosed in 1990, with local recurrence in 2005, treated with mastectomy, adjuvant chemotherapy, and adjuvant endocrine therapy, followed by development of metastatic disease to lung, liver, bone and skin in 2017. She received multiple lines of endocrine therapy, including aromatase inhibitors and fulvestrant, with cdk4/6 inhibitors and everolimus, but either progressed or was intolerant to all treatments. Skin biopsy in 2022 confirmed metastatic BC, which was ER+, PR+, and HER2 low (IHC2+, FISH nonamplified). She then received T-DXd, with clinical and radiographic response to treatment. After cycle 8 T-DXd, the patient was hospitalized for severe burning pain of her trunk and skin. Radiologic evaluation, including CT chest, abdomen, pelvis, and MRI spine, did not show an etiology of her pain, and showed stable metastatic disease to liver and bones, without evidence of cord or nerve root compression. Symptoms improved on pregabalin. She received an additional cycle of T-DXd with dose reduction, but ultimately declined further treatment. Symptoms resolved within 5 months of discontinuation of T-DXd.\u0000 Discussion. These cases represent unusual events of axial neuropathy in two BC patients receiving T-DXd. Given the similarity of their symptoms, these findings may represent an unusual adverse effect of T-DXd.","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"33 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141018137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PO1-09-12: Cancer health disparities among patients with early-stage estrogen receptor-positive (ER+) breast cancer treated in public or private practices in Brazil","authors":"R. Barroso-Sousa, Daniele Assad-Suzuki, D. Santos, Fernanda Moura, S. Oliveira, Anna Luiza Galvão, Bruno Souza, Amanda Castro, Monalisa Andrade, Andrea Shimada, Yuri Beckedorff, M. C. Magalhães, C. Souza, Carlos Paiva, Heloísa Resende, Daniela Pereira, Angelica Rodrigues, Daniela Rosa","doi":"10.1158/1538-7445.sabcs23-po1-09-12","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po1-09-12","url":null,"abstract":"\u0000 Background Cancer registries in Brazil are deficient and data about patients’ profiles and cancer treatment patterns are scarce in the country. Moreover, while 30% of population has access to private insurance, almost 70% of population uses publicly health services. The objective of this work was to describe the sociodemographic and clinicopathological characteristics of women with early-stage ER+ breast cancer on adjuvant ET in different regions of Brazil, and to describe treatment patterns for this disease according public and private institutions. Methodology: We performed a real-world data analysis in different institution regions of Brazil. Women with a history of early-stage ER+ invasive carcinoma of the breast on adjuvant endocrine therapy for at least 6 months were invited to participate of this study in 12 centers in four different regions in Brazil. Demographic and clinicopathologic information was retrieved from medical records. In order to compare healthcare insurance type, we considered patients who were treated under the Brazilian public health system as publicly insured, and women who had private insurance or paid for their treatment as privately insured. High education level was defined by completed high school. Data collection was done with RedCap software. Qualitative variables were compared between groups using the Chi-square or exact Chi-square test and for quantitative variables the non-parametric Mann-Whitney test was used. P &lt; 0.05 was considered significant. Analyzes were performed in SAS 9.4; Results: From June 2021 to May 2023, a total of 461 women with ER+, early BC, were included in this analysis. A total of 233 (50.6%) came from private institutions, the mean age was 56.02 years (range 22-93), 47.69% were non-white, 61.3% were post-menopause, 61.7% lived with a partner, and 76.2% were highly educated and 66.81% had comorbidities. Tumor staging at diagnosis was classified as III, II and I respectively in 21.26%, 43.17% and 35.57% of all cases. Regarding treatment received, 62.4% of patients underwent lumpectomy, 32.2% had axillary dissection, 67.6% received (neo)adjuvant chemotherapy, 45.2% were on aromatase inhibitors and 14.19% were on ovarian function suppression plus ET . Median duration of ET use was 2.78 years (range 6 months- 9.61 years). Publicly health insurance was associated significantly associated with younger age at diagnosis (&lt; 60 yo), premenopausal status, to live alone, lower educational level, more advanced tumors, prior mastectomy, prior axillary dissection, prior neo-adjuvant chemotherapy, prior radiotherapy, lower use of aromatase inhibitors, ovarian function suppression plus ET, and CDK4/6 inhibitors, while higher use of concomitant medications. Conclusion: The study shows significant health disparities among women with early-stage ER+ breast cancer treated in private versus public institutions in Brazil. Importantly, despite having more advanced tumors, women in public institution had less acce","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"15 3","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141018367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}