ACS Chemical Health & Safety最新文献

{"title":"Abstract PO2-07-12: Analysis Of Malignity Rates Of Percutaneous Biopsy In Lymph Nodes Of Breast Cancer Patients","authors":"Marina Diógenes, A. Amorim, André Mattar, M. Antonini, L. Gebrim, R. C. Lopes, Luciana Damous","doi":"10.1158/1538-7445.sabcs23-po2-07-12","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po2-07-12","url":null,"abstract":"\u0000 BACKGROUND: The evaluation of regional lymph nodes in patients with breast cancer is one of the main predictive and prognostic factors for treatment. The methods of percutaneous biopsies of suspicious lymph nodes frequently used are fine-needle aspiration cytology (FNA) and core needle biopsy (CORE). According to the international literature, CORE and FNA are considered diagnostic methods with high specificity (98% vs. 99%), however, the FNA may present up to 21% of inconclusive results by insufficient material. Although CORE is well established as a percutaneous method for diagnostic evaluation of suspected breast lesions, the literature is scarce on the use of this technique for the evaluation of suspicious lymph nodes in breast cancer patients. OBJECTIVE: Analyze the positivity of FNA and CORE performed in suspicious lymph nodes for breast cancer metastasis according to the anatomical location of biopsies and the type of needle used, verifying which technique was preferred. METHODS: A retrospective study was conducted by evaluating the database of patients treated in a public hospital in São Paulo, Brazil. Women submitted to ultrasound-guided percutaneous biopsy of lymph nodes from May 2015 to November 2019 were included in the study. The data were analyzed using IBM-SPSS version 27 and Microsoft EXCEL version 2010. RESULTS: A total of 499 biopsies were performed and the mean age of the women was 54.2 years (SD± 11.9) in the CORE group and 53.4 years (SD± 11.8) in the FNA group (p=0.619). According to the anatomical location, 385 were axillary (77.2%), 62 supraclavicular (12.4%), 48 cervical (9.6%) and 4 infraclavicular (0.8%). Regarding the type of needle, 393 were CORE (78.8%) and 106 were FNA (21.2%). When analyzing the results of the FNA, 38 (35.8%) did not present enough material, 31 (29.2%) were positive, 32 (30.2%) were negative and 5 (4.8%) showed atypical cells. Among the 393 CORE performed, 255 (64.9%) were positive, 132 (33.6%) were negative, 1 (0.3%) showed atypical cells and 5 (1.3%) had no representative material. No complications were reported after the procedures. CONCLUSION: CORE was the preferred diagnostic technique in our center, being considered a feasible procedure to evaluate lymph nodes in different sites and with low rates of inconclusive results by insufficient material. In the future, studies evaluating indirect costs may confirm the feasibility of CORE in patients with suspicious lymph nodes in terms of obtaining greater agility and resolutive conducts in the public healthcare system.\u0000 Citation Format: Marina Diogenes, Andressa Amorim, ANDRE MATTAR, MARCELO ANTONINI, Luiz Henrique Gebrim, REGINALDO COELHO LOPES, Luciana Damous. Analysis Of Malignity Rates Of Percutaneous Biopsy In Lymph Nodes Of Breast Cancer Patients [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 PO2-07-12.","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"26 3","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141022687","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 PO1-06-09: Phase 2 Trial with Safety Run-In of Gedatolisib Plus Talazoparib in Advanced Triple Negative or BRCA1/2 Positive, HER2 Negative Breast CancersBig Ten Cancer Research Consortium BTCRC-BRE18-337","authors":"S. Phadke, Kari Wisinski, O. Danciu, Ami N. Shah, Menggang Yu, Yi Chen, Kathy Miller, Mark Burkard","doi":"10.1158/1538-7445.sabcs23-po1-06-09","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po1-06-09","url":null,"abstract":"\u0000 Up to 2/3 of triple negative breast cancers (TNBC) have acquired defects in homologous recombination (HR) DNA repair, yet poly (ADP-ribose) polymerase inhibitor (PARPi) monotherapy has been largely ineffective in the absence of a germline BRCA 1/2 mutation (gBRCA1/2). Phosphoinositide-3-kinase (PI3K)/mTOR pathway alterations are also common in breast cancers. Preclinical data suggest that PI3K/mTOR inhibition may disrupt normal function of the HR complex and increase dependency on PARP enzymes for HR DNA repair. Thus, combining a PI3K/mTOR inhibitor with a PARPi may result in a synergistic anti-neoplastic effect. The run-in portion of this study evaluated the safety of weekly IV gedatolisib (PI3K/mTORi) and continuous daily talazoparib to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). A 3+3 design for dose escalation explored two dose levels. The phase II study began once the MTD and R2PD were confirmed. Eligibility required age ≥ 18, 1-2 prior lines of therapy (protocol later amended to allow up to 3 lines), and advanced TNBC or advanced HER2-negative BC with gBRCA1/2 mutation. The sample size for the phase II study was determined based on a 1-sided binomial test under the null and alternative ORR of 5% vs 20% with a type I error rate of 0.1 and power level of 80%. The primary endpoint was overall response rate (ORR) in TNBC without known gBRCA1/2 with secondary endpoints of progression-free survival (PFS) and overall survival (OS). Patients with a gBRCA1/2 mutation were not included in the primary endpoint analysis. Correlative studies are planned to evaluate HR deficiency mutations, PIK3CA mutations, and other exploratory genomics. A total of 33 patients were enrolled: 14 in the safety run-in phase of the trial and 19 in the phase II study (17 TNBC, 2 with gBRCA2 mutation). In the safety run-in, 6 patients were enrolled at dose level 1 (0.75 mg talazoparib po daily and 180 mg gedatolisib IV weekly) and 8 at dose level 2 (1 mg talazoparib po daily and 180 mg gedatolisib IV weekly). 42% of the cohort developed hyperglycemia, which was mostly grade 1. There was 1 DLT of grade 3 neutropenia at dose level 1. There were 3 patients who experienced grade 4 AEs, thrombocytopenia (2) and lymphopenia (1) which were outside of the DLT window. The MTD was 1 mg of talazoparib daily and 180 mg of gedatolisib weekly, and this was selected as the RP2D. A protocol amendment was made during the phase II portion to allow for a 3 week on/1 week off schedule for gedatolisib due to emerging data showing a more favorable safety profile and enhanced antitumor activity with this dosing schedule. In the 17 patients with TNBC and no gBRCA mutation in the phase II cohort, the ORR was 12%. Best response was partial response (PR) in 2 patients (12%), stable disease (SD) in 7 patients (41%), and progressive disease (PD) in 8 patients (47%). The clinical benefit rate (ORR+SD) at 16 weeks was 23.5%. The most common adverse events (AEs) in all","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"25 4","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141022698","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 PO1-18-06: Phase 1/2a Open-label Clinical Trial of BI-1607, an Fc Engineered Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Trastuzumab in Subjects with HER2-positive Advanced Solid Tumors – CONTRAST","authors":"Javier Cortés, Araceli Priego, Elena Garralda Cabanas, Katerin Rojas Lamito, Simon Lord, Thorsten Goetze, Sherko Küemmel, Simon Crabb, M. Borggren, Ingrid Karlsson, L. Mårtensson, Anna Ropenga, I. Teige, Johan E Wallin, B. Frendéus, Andres McAllister","doi":"10.1158/1538-7445.sabcs23-po1-18-06","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po1-18-06","url":null,"abstract":"\u0000 Background\u0000 The introduction of trastuzumab has dramatically changed outcomes in patients with human epidermal growth factor receptor 2 positive (HER2+) cancer. However, primary or acquired resistance to trastuzumab has been increasingly recognized as a major obstacle in the clinical management of this disease. Combination of anti-HER2 antibodies with other immunotherapies is likely to improve the quantity and quality of responses.\u0000 BI-1607 is a human monoclonal antibody (mAb) targeting FcRIIB (CD32b) with antagonistic function capable of blocking the inhibitory function of FcRIIB on immune effector cells. BI-1607 has been engineered to lack a glycan in position N297Q in the constant domain (Fc), and thus cannot interact with FcγRs through its Fc. Given its high specificity and affinity for FcγRIIB, BI-1607 blocks other antibodies’ binding to FcγRIIB. As a result, BI-1607 is expected to shift tumor cells coated antibodies (here anti-HER2) to selectively engage activating FcγRs, thus augmenting FcγR-dependent therapeutic activity (ADDC, ADCP).\u0000 Tumor-associated macrophages express high levels of FcγRIIB and are a major target of BI-1607 in the tumor microenvironment. This concept was demonstrated in preclinical in vivo models showing increased efficacy of the combination therapy with the murine surrogate of BI-1607 and an anti-HER2, an anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and an anti-CD20 (rituximab) as compared to monotherapy.\u0000 It important to note that BI-1607 will have no single-agent activity. Instead, its clinical use will be in combination with other immunotherapies and tumor-targeting antibodies such as trastuzumab.\u0000 The choice of trastuzumab as the combination agent in this trial was based on promising preclinical studies, a recognized need for additional options for those patients who fail to respond or stop responding to trastuzumab, and promising results from the newly approved Fc-engineered anti-HER2 mAb margetuximab. Ultimately, if shown to be safe and effective in combination with trastuzumab, BI-1607 can also be used in combination with other cytotoxic or immunomodulatory antibodies for cancer treatment.\u0000 Methods\u0000 This is a Phase 1/2a, first-in-human, open-label, multicenter, dose-escalation, consecutive-cohort study of BI-1607 in combination with trastuzumab in subjects with HER2+ advanced solid tumors. Phase 1 aims to assess safety and tolerability and to determine the RP2D of BI-1607 in combination with trastuzumab. Phase 2a will explore efficacy at RP2D of BI-1607 in combination with trastuzumab in two separate expansion cohorts, a) in subjects with locally advanced or metastatic HER2+ breast cancer and b) in subjects with HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma.\u0000 Eligible patents must have a HER2+ locally advanced unresectable or metastatic solid tumors and have received standard of care or be intolerant to standard of care antineoplastic therapy, with progressive disease a","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"17 2","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141022728","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 PO4-12-08: Changes in peripheral immune cell composition in women who do and do not develop breast cancer","authors":"Jacob K. Kresovich, Katie O'Brien, Zongli Xu, Clarice Weinberg, Dale Sandler, Jack Taylor","doi":"10.1158/1538-7445.sabcs23-po4-12-08","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po4-12-08","url":null,"abstract":"\u0000 Background: Breast cancer survivors have higher age-specific rates of hypertension and other chronic diseases than women without a history of breast cancer. We and others have shown that alterations to the immune system are associated with risk of these conditions in the general population, leading to the hypothesis that the increased chronic disease risk in breast cancer survivors may be driven, in part, by lasting changes in immunity. Peripheral immune cell composition appears to become altered years before a breast cancer diagnosis, but little is currently known about the influence of different breast cancer treatments on subsequent changes to leukocyte composition and the persistence of these associations over time.\u0000 Methods: Among 410 women enrolled in the Sister Study, paired blood samples collected an average of 7.6 years apart were analyzed for DNA methylation (DNAm). Deconvolution methods were applied to these DNAm data to estimate circulating percentages of 12 leukocyte subsets. Approximately half the women sampled were diagnosed and treated for breast cancer between the blood draws (n= 185) whereas the other half remained breast cancer-free (n= 225). Breast tumor characteristics and treatment information were abstracted from medical records. Mixed-effect linear regression models were used to estimate changes in leukocyte composition over time comparing women with breast cancer to those who remained breast cancer-free. A case-only analysis of breast cancer survivors was performed to examine the persistence of changes over time and to explore whether changes in leukocyte composition were associated with the types of therapies received (endocrine therapy, radiation therapy, chemotherapy). All models were adjusted for age and self-reported race. In the treatment analysis, because tumor characteristics can guide clinical decisions, tumor estrogen receptor status and stage at diagnosis were additionally included as model covariates.\u0000 Results: At baseline, women who developed breast cancer between the blood draws had lower mean circulating percentages of CD8+ cytotoxic T cells than women who remained breast cancer-free (3.8% vs 4.6%; P-diff= 0.04). After accounting for differences in leukocyte composition at baseline, compared to women who remained breast cancer-free, women diagnosed and treated for breast cancer between the blood draws had decreases in total circulating CD4+ helper T cell percentage (adjusted mean difference [β]= -1.50, 95% CI: -2.56, -0.44, P= 0.006) and alterations to both naïve and memory B cell percentages (naïve B cells, β= 0.46, 95% CI: 0.17, 0.75, P= 0.002; memory B cells, β= -0.22, 95% CI: -0.34, -0.09, P= 0.001). Although associations did not vary by tumor characteristics or participant race, the changes in leukocyte composition appeared to persist over time as changes were not associated with time since diagnosis. In the case-only analysis of different breast cancer therapies, radiation was associated with decrea","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"24 2","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141022753","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 PO4-23-07: Impact of distance between tumor and nipple on locoregional recurrence in breast cancer","authors":"J. Cheun, E. Kang, Hong-Kyu Kim, Han-Byoel Lee, H. Moon, Wonshik Han, Ki-Tae Hwang","doi":"10.1158/1538-7445.sabcs23-po4-23-07","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po4-23-07","url":null,"abstract":"\u0000 Introduction: Mastectomy is usually recommended for centrally located tumors due to the risk of nipple invasion. While it is well known that there is no significant difference in survival outcomes according to tumor location, central tumors have a higher likelihood of main lactiferous duct invasion, which can result in the migration of tumor cells to the periphery. Therefore, we conducted an investigation specifically focusing on locoregional recurrence (LRR) rates based on the tumor-to-nipple distance (TND).\u0000 Method: We retrospectively collected the data of patients who underwent breast cancer surgery between 2004-2018 from two institutions. Patients who underwent neoadjuvant chemotherapy were excluded. TND information was obtained from preoperative MRI records.\u0000 Results: A total of 9,014 patients were included in the study, and the median tumor-to-nipple distance (TND) was 3.4 (0.0-15.0) cm. For all patients, the restricted cubic spline curve analysis showed that the hazard risk of LRR increased with shorter TND. The pattern was more pronounced in the breast-conserving surgery (BCS) group, whereas the mastectomy group showed a relatively constant risk regardless of TND. Thus, we conducted survival analysis for 5,455 patients who underwent BCS. We set the cutoff for TND as 2.5cm as it showed the lowest p-value for LRR rate. Compared to those with TND >2.5cm, patients with TND≤2.5cm showed significantly lower LRR (HR,1.83;95%CI,[1.37-2.46],p< 0.001) and distant metastasis(DM) (HR,1.53;95%CI,[1.16-2.02],p=0.002) rates. Overall survival was not different between two groups (p=0.405). Cox-regression analysis revealed that TND still impacts LRR (HR,1.52;95%CI,[1.11-2.09],p=0.010) but not DM. Importantly, TND still remained significant factor affecting LRR when analyzed as continuous variable (HR,1.04; 95%CI,[1.02-1.06],p< 0.001). The prognostic impact of TND was particularly evident in patients with high mammographic density.\u0000 Discussion: BCS can be performed for centrally located tumors, as it offers considerable oncologic safety compared to mastectomy. However, for patients who have a fear of recurrence and are reluctant to undergo re-operation, mastectomy would be a good choice.\u0000 Citation Format: Jong-Ho Cheun, Eunhye Kang, Hong-Kyu Kim, Han-Byoel Lee, Hyeong-Gon Moon, Wonshik Han, Ki-Tae Hwang. Impact of distance between tumor and nipple on locoregional recurrence in 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 PO4-23-07.","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"32 5","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141022953","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 PO1-06-12: Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer","authors":"Lei Fan, Xi-Yu Liu, Ying Xu, Xinyi Sui, Wenjuan Zhang, Linxiaoxi Ma, X. Jin, Songyang Wu, Han Wang, Yi Xiao, Li Chen, Jiong Wu, Ke-Da Yu, Guangyu Liu, Xin Hu, Zhong-hua Wang, Yizhou Jiang, Zhiming Shao","doi":"10.1158/1538-7445.sabcs23-po1-06-12","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po1-06-12","url":null,"abstract":"\u0000 Background:\u0000 The combination of a PD-(L)1 inhibitor plus chemotherapy demonstrated promising anti-tumor activity as first-line therapy for patients (pts) with locally recurrent inoperable or metastatic PD-L1 positive triple-negative breast cancer (TNBC). However, for pts without PD-L1 expression and for those who have failed prior lines of treatment, therapeutic options are still limited. This multi-cohort, phase II trial aimed to evaluate the safety and antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination (70 mg sitravatinib plus tislelizumab) with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The efficacy of sitravatinib plus tislelizumab in cohort A and B has been reported with objective response rate (ORR) of 38.1% and 45.0%, respectively. Herein, the preliminary results of cohort C and updated results of cohort A and B were reported. Methods:\u0000 Pts with untreated locally inoperable or metastatic TNBC were included in cohort C and received 70 mg sitravatinib orally once daily plus 200 mg tislelizumab intravenously on day 1 and 100mg/m2 nab-paclitaxel on days 1 and 8 every three weeks until disease progression or intolerable toxicity. The primary endpoint was ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival (OS) rate and safety/tolerability. Based on Simon’s two-stage design, &gt; 9 responders were need in stage 1 (n=18) for the study to continue, and &gt;19 responders were needed by the end of study (n=35) to demonstrate statistical superiority with sitravatinib plus tislelizumab and nab-paclitaxel (assumed to be around 65%) to a historical control of 46% (1-sided alpha of 0.1, power of 80%). Updated analyses were provided for cohort A (Simon’s 2 stage design) and B (Bayesian optimal phase II design). Results:\u0000 Among the 18 pts in stage 1 of cohort C, 12 of them achieved confirmed response, and therefore the study proceeded to the enrollment in stage 2. As of April 30, 2023, a total of 32 pts were enrolled, with a median age of 51 years. Among the 23 efficacy evaluable pts, unconfirmed ORR was 87.0% (95% CI 66.4-97.2) (including 3 CRs and 17 PRs), with 7 pts not reaching next tumor assessment after reaching CR/PR, and confirmed ORR was 52.2% (95% CI 30.6-73.2). DCR was 95.7%. Any grade of treatment-related adverse events (TRAEs) occurred in 31 (96.9%) pts, and grade ≥3 TRAEs occurred in 5 (15.6%) pts. One (3.1%) patient experienced grade ≥3 immune-related adverse events. SAEs were reported in 3 (9.4%) pts. At the data cut-off date, the median follow-up duration for cohort A and B was 20.4 (range 1.3–24.3) months and 13.3 (range 5.1-19.1) months, respectively. The median PFS in cohort A was 8.2 (95% CI 2.8-12.4) months, and in cohort B was 5.4 (95% CI 4.2-10.9) months. Median OS was not reached in b","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"25 8","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141022972","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 PO3-02-12: Dalpiciclib combination with letrozole as neoadjuvant therapy for HR-positive HER2-negative breast cancer: a single-arm, prospective exploratory clinical study","authors":"Jingruo Li, Yuanting Gu, Chuang Du, Jianhua Zhang, Yingying Zhang, Lin-feng Zhang, Nan Wang, Lin Li, Fang Wang, P. Lv, Hong Zong, Xinhong Pei, Bingjian Xue, Yan Wang, Dongcheng Gao","doi":"10.1158/1538-7445.sabcs23-po3-02-12","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po3-02-12","url":null,"abstract":"\u0000 Background:\u0000 CDK4/6 inhibitors effectively block tumor cells from progressing from the G1 phase to the S phase, thereby interrupting the cell cycle progression and inhibiting tumor cell proliferation. Dalpiciclib is a novel CDK4/6 inhibitor developed independently in China, which has been approved for use in combination with fulvestrant for the treatment of HR-positive/HER2-negative recurrent or metastatic breast cancer in patients who have experienced disease progression after prior endocrine therapy, or in combination with aromatase inhibitors as initial treatment for HR-positive/HER2-negative locally advanced or metastatic breast cancer patients. This study aims to explore the efficacy and safety of dalpiciclib in combination with letrozole as neoadjuvant therapy for HR-positive, HER2-negative breast cancer.\u0000 Methods:\u0000 This is a single-arm, open-label study that enrolled female breast cancer patients with early or locally advanced HR-positive, HER2-negative tumors and an ECOG performance status of 0 to 1. After enrollment, patients first received 4 cycles of dalpiciclib (150mg po qd, d1-21, q4w) in combination with letrozole as neoadjuvant therapy. Breast MRI was performed every 2 cycles, and treatment response was evaluated according to the RECIST 1.1 criteria. If patients achieved a confirmed complete response (CR) or partial response (PR) after 4 cycles, they would continue to receive an additional 4 cycles of dalpiciclib in combination with letrozole treatment. If the treatment response was stable disease (SD) or disease progression (PD), the investigator might modify other treatment regimens based on the individual circumstances of the subjects. The primary endpoint was residual cancer burden (RCB 0/I), and the secondary study endpoints were objective response rate (ORR), complete cell cycle arrest (CCCA, C1D15 Ki67≤2.7%) rate and safety. This study is registered at the Chinese Clinical Trial Registry Centre (registration No. ChiCTR2200057104).\u0000 Results:\u0000 From April 2022 to June 2023, a total of 38 patients were screened and enrolled in the study. All patients had ER ≥ 50%, and 84% (32/38) had Ki67 ≥ 88%. Among the 21 patients who completed the assessment after 4 cycles, the overall response rate (ORR) was 81% (17/21). Additionally, among the 22 patients who underwent C1D15 biopsy and Ki67 analysis, 55% (12/22) had C1D15 Ki67 ≤ 2.7%. After completing 8 cycles of neoadjuvant treatment with the combination of dalpiciclib and letrozole,12 patients underwent surgery. The postoperative RCB scores were as follows: 1 patient had RCB (0-I), and 11 patients had RCB (II-III). The most common adverse event was decreased neutrophil count (25/38 [66%]). Among the 38 patients, 16 (42%) experienced grade 3 or worse treatment-related adverse events. There were no occurrences of grade 4 or worse adverse events.\u0000 Conclusions:\u0000 The combination of dalpiciclib and letrozole has shown efficacy in downstaging and shrinking tumors in patients with early or loc","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"2 s1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141023091","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 PO2-28-04: Pregnancy-associated relapse of triple-negative breast cancer","authors":"Vaidarshi Abbagoni","doi":"10.1158/1538-7445.sabcs23-po2-28-04","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po2-28-04","url":null,"abstract":"\u0000 Introduction: Pregnancy Triple-negative breast cancer(TNMC) is the absence of ER PR and HER2 receptor expression. It constitutes about 15-20% of all breast cancers and is known to be the aggressive form with a high relapse rate (1). Interestingly, it usually affects women aged &lt; 40 and has a low survival rate in African-American females. This case is a typical presentation of a 38-year-old young woman with PMH of T2NO right triple-negative breast cancer diagnosed in 2017 s/p right mastectomy with sentinel LN biopsy, received immunotherapy and chemotherapy, has been cancer-free for two years, and developed metastatic cancer during her pregnancy. In this case, we understand the diagnostic and therapeutic challenges of TNBC during pregnancy. Case: A 38-year-old African American woman, G0, T2NO triple negative invasive ductal carcinoma, underwent a right breast mastectomy and sentinel LN biopsy. She received treatment with (Anti-PD-L1 Antibody) concomitant with weekly paclitaxel and Doxorubicin/Cyclophosphamide (AC) chemotherapy. However, she had a residual 4cm tumor for which she was treated with adjuvant therapy with capecitabine for six months. A repeat Mammogram in 2019 showed no evidence of malignancy. In 2021, the patient was G2P2L1, admitted to the hospital after having a seizure. CT reported cystic/necrotic left parietal lesion mass effect with 8mm right-sided midline shift with metastasis to lungs and abdominal wall. She underwent L parietal craniectomy with resection of the tumor. At 32 weeks of gestation , chemotherapy with carboplatin and paclitaxel was given after her C-section and Gamma knife radiosurgery for metastatic lesions. She developed super refractory seizures, was induced into a coma with therapeutically anesthetic agents, and passed eventually. Discussion: Little literature exists on pregnancy-associated relapse of triple-negative breast cancer and its deterioration. Our patient was in remission for two years and was diagnosed with metastatic cancer during her second pregnancy. John et al., (2018) discussed an interesting association between breastfeeding, parity, and occurrence of TNBC, that there is a two-fold increased risk of developing TNBC with high parity(3 full-term pregnancies) and short-term breastfeeding (&lt; 12 months) (2). Studies have also shown that cancers during or postpartum pregnancy are aggressive with more tumor burden and metastasize to the lungs, liver, and brain, which is consistent with our patient. (3) Conclusion: Pregnancy-associated breast cancer is diagnostically and therapeutically challenging during or in the postpartum period and with a high propensity of the triple-negative type. It requires a multidisciplinary team approach, awareness in the African American population, clinical suspicion of breast mass during pregnancy warrants imaging, and prolonged breastfeeding postpartum. Diagnosis is usually delayed due to pregnancy, and more research is needed on the diagnostic modalities during pregnan","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"27 5","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141023128","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 PO2-11-10: Can chemotherapy-induced peripheral neuropathy be predicted? Implications for future prevention and treatment of this side-effect","authors":"Alisha Maity, Nolan Metz, Kathryn Fleck, Zonera Ali, Aarthi Shevade, A. Ghaneie, Margaretha Wallon","doi":"10.1158/1538-7445.sabcs23-po2-11-10","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po2-11-10","url":null,"abstract":"\u0000 Background: The pain and sensory abnormalities associated with chemotherapy-induced peripheral neuropathy (CIPN) may persist for months or even years after chemotherapy. CIPN has a negative impact on routine activities, functions, and behaviors in the domestic, work, and social lives of cancer patients, adversely affecting the quality of their survivorship.\u0000 CIPN is a major adverse effect of taxanes and other agents, possibly requiring dose-reduction or early termination of treatment. Taxane-based regimens are first-line treatment in both early-stage and metastatic breast cancer and therefore place numerous women at risk for developing CIPN. Regrettably, taxane-induced neurotoxicity can be arduous to predict, and there are no preventive or curative treatments currently available.\u0000 Our work aims to assess a predictive tool for identification of patients at high risk of developing neuropathy and the progression of symptoms towards chronic CIPN.\u0000 We hypothesized that oxidative stress might be a triggering event for the development of CIPN and that changes in glutathione recycling can identify patients at high risk for developing prolonged and severe CIPN. This hypothesis is based on reports in the literature proposing that CIPN is triggered by damage to the myelin sheath, which protects nerves from damage, by drug-induced free radicals in and around the nerves. Damage to myelin, a lipid- and protein rich sheath, by lipid peroxidation can result in loss of signal transmission, false signaling, or signal overload. Prolonged exposure to elevated levels of free radicals might result in structural changes to the nerves.\u0000 Methods: Cancer patients seeking treatment at the Lankenau Medical Center Cancer center were asked to participate in our Institutional Review Board approved study of adverse effects. In this on-going study, the cohort (Ntotal =352) includes 104 breast cancer patients that are predominantly Caucasian with 14.9% African American. The median age is 56 (range 26 – 82) and 60.9% were treated with a taxane-based regimen. Nearly half the breast cancer group were diagnosed with Stage I disease. All consented patients donated a tube of blood prior to each treatment and filled out the Rotterdam Symptom Checklist (RSCL). Blood samples were analyzed for glutathione recycling using the ChemoTox assay (MNT™ Test, MYNARI Biomedical) and lipid peroxidation using a thiobarbituric acid reactive substances (TBARS) test (Cayman Chemical). All samples were analyzed in duplicate, and results analyzed using GraphPad Prism 8.4.3.\u0000 Results: Preliminary results from the first 83 breast cancer patients showed African American patients reported a higher rate of NCCN grade 2 and 3 CIPN while Caucasians reported a higher rate of severe, long-lasting CIPN. Our results showed that patients who reported CIPN at later cycles had diminished glutathione recycling capacity already after the first treatment. Drop in recycling capacity had an inverse relationship with lipid","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"70 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017673","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 PO4-28-08: Unraveling the Role of BRCA1-BARD1 E3 Ubiquitin Ligase in DNA Repair: A Promise for Enhanced Chemotherapy Outcomes","authors":"Wenjing Li, Meiling Wang, N. Tomimatsu, Jae-Hoon Ji, S. Alejo, Gangadhara R. Sareddy, Sandeep Burma, Rachel Klevit, Weixing Zhao","doi":"10.1158/1538-7445.sabcs23-po4-28-08","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs23-po4-28-08","url":null,"abstract":"\u0000 BACKGROUND: BRCA1, a central player in gynecological cancers, collaborates with BARD1 to shape a potent complex pivotal for DNA binding and ubiquitin E3 ligase activities. This complex impacts a myriad of biological pathways. Notably, BRCA1-BARD1’s role in tumor suppression and homology-directed DNA repair (HDR) has been spotlighted. Our innovative approach used RING-domain mutations to craft ligase-dead BRCA1-BARD1 mutants, hypothesizing that these mutants would offer fresh insights into the DNA repair dynamics of BRCA1-BARD1. METHODS: Full length BRCA1-BARD1 or truncated mutants, and histones were purified from E. coli. or insect cells. Nucleosomes were assembled for in vitro ubiquitylation reaction and binding assays. Stable mammalian cell lines HeLa and MDA-MB-436 that express wild type or mutant forms of BRCA1 and BARD1 were established for a host of analyses, including cellular fractionation, foci analysis, Proximity ligation assay (PLA), comet assays and clonogenic survival assays with various DNA damage agents. RESULTS: By systematic biochemical screening and a series of in vitro assays, we generated a truly BRCA1-BARD1 E3 dead mutant, BRCA1I26A, L63A, K65A-BARD1 (BRCA1-E3d), which lacks E3 ligase activity but possesses all other known attributes such as retention of BRCA1-BARD1 heterodimeric structure formation, DNA binding, and intact RAD51-mediated recombinase activity. To our surprise, we discovered that previously described BRCA1-BARD1 RING-domain mutant (BRCA1-I26A) still possessed ubiquitylation activity not found in BRCA1-E3d. To determine the biological significance of these mutants, cells stably expressing BRCA1-E3d were treated with various DNA-damaging agents and shown to more sensitive than WT or previously identified mutants. DNA repair pathway reporter assays determined these cells were deficient in various repair pathways compared to their BRCA1-WT counterparts. Further studies demonstrate that BRCA1-BARD1 E3 ligase is required for DNA resection during HDR, as evidenced in reduced levels of DNA repair-related foci formation such as RPA, RAD51 and CtIP in BRCA1-E3d cells. Furthermore, compared to BRCA1-WT cells, BRCA1-E3d cells were more sensitive to DNA damage reagents after depletion of 53BP1, which indicates BRCA1-BARD1 E3 ligase function also contributes to later stages of DNA repair completion. CONCLUSIONS: Our work dispels prevailing ambiguities surrounding BRCA1-BARD1 E3 ligase functions, underscoring its paramountcy in genome repair. This trailblazing research not only enriches our understanding but also beckons therapeutic interventions targeting tumor suppression. The unveiling of BRCA1-BARD1 E3 ligase's intricate regulatory dynamics combined with our novel mutants paves the way for an exciting new era in cancer therapeutics, hinting at superior treatments to enhance patient recovery.\u0000 Citation Format: Wenjing Li, Meiling Wang, Nozomi Tomimatsu, Jae-Hoon Ji, Salvador Alejo, Gangadhara R. Sareddy, Sandeep Burma, ","PeriodicalId":12,"journal":{"name":"ACS Chemical Health & Safety","volume":"52 5","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017715","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}