tbuckley/cabot-search huggingface dataset:
Abstract PO5-27-03: Mutational impact of APOBEC3A and APOBEC3B in a human cell line
Authors: Michael Carpenter, Nuri Temiz, Mahmoud Ibrahim, Matthew Jarvis, Margaret Brown, Prokopios Argyris, William Brown, Douglas Yee, Reuben Harris
Journal: Cancer Research (2024)

Abstract A major source of mutation in cancer is DNA cytosine deamination by APOBEC3 enzymes resulting in C-to-T and C-to-G mutations in TCA and TCT motifs. Here, we develop a selectable system to quantify genomic mutations and compare the mutagenic activities of three leading APOBEC3 candidates - APOBEC3A, APOBEC3B, and APOBEC3H. The human cell line, HAP1, is engineered to express the thymidine kinase (TK) gene of HSV-1, which confers sensitivity to ganciclovir. Expression of APOBEC3A and APOBEC3B, but not catalytic mutant controls or APOBEC3H, triggers increased frequencies of TK mutation and nearly indistinguishable TC-biased cytosine mutation profiles in the selectable TK reporter gene. Whole genome sequences from TK mutant clones enabled an analysis of thousands of single base substitution mutations and extraction of local sequence preferences with APOBEC3A preferring YTCW motifs over 70% of the time and APOBEC3B just under 50% of the time (Y=C/T; W=A/T). Signature comparisons with breast tumor whole genome sequences indicate that most malignancies manifest intermediate percentages of APOBEC3 signature mutations in YTCW motifs, mostly between 50 and 70%, suggesting that both enzymes are contributing in a combinatorial manner to the overall mutation landscape. These studies combine to help resolve a long-standing etiologic debate on the source of APOBEC3 signature mutations in cancer and indicate that future diagnostic and therapeutic efforts should focus on both enzymes. Citation Format: Michael Carpenter, Nuri Temiz, Mahmoud Ibrahim, Matthew Jarvis, Margaret Brown, Prokopios Argyris, William Brown, Douglas Yee, Reuben Harris. Mutational impact of APOBEC3A and APOBEC3B in a human cell line [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 PO5-27-03.
Abstract PO4-12-05: Immediate breast reconstruction is associated with reduced incidence of ipsilateral lymphedema in breast cancer patients undergoing mastectomy
Authors: Jin Young Byeon, Ik Beom Shin, Hawjeong Lee, Eunhye Kang, Ji-Jung Jung, Changjin Lim, Wonshik Han, Hong-Kyu Kim, Han-Byoel Lee, Hyeong-Gon Moon
Journal: Cancer Research (2024)

Abstract Purpose: The number of patients undergoing immediate breast reconstruction after mastectomy is increasing. A study of ipsilateral lymphedema after immediate breast reconstruction is also needed.This retrospective study aimed to identify the risk factors associated with lymphedema incidence after mastectomy in breast cancer patients, particularly focusing on the impact of the immediate breast reconstruction. Methods: A retrospective analysis was conducted on 6,105 patients who underwent mastectomy for breast cancer with or without immediate breast reconstruction from Jan 2012 to Dec 2022 at Seoul National University Hospital to identify the potential risk factors for developing ipsilateral lymphedema. Results: A total of 6,105 breast cancer patients with a mean age of 50.1 years were included in this study, with a median follow-up period of 52.0 months. In univariate analysis, the incidence of lymphedema was significantly lower in the immediate breast reconstruction group (4.47%) compared to the no reconstruction group (9.15%) (p &amp;lt; 0.001). Other significant risk factors included the number of dissected axillary lymph nodes, number of metastatic lymph nodes, body mass index (BMI) over 25 kg/m2, the use of neo-adjuvant chemotherapy or adjuvant radiation therapy, and older age at the time of operation. In multivariate analysis, the immediate breast reconstruction remained to be an independent predictor of developing lymphedema (OR: 0.71, 95% CI: 0.55-0.91, p = 0.008), along with the number of dissected lymph nodes (OR: 1.06, 95% CI: 1.05-1.08, p &amp;lt; 0.001), neoadjuvant chemotherapy (OR: 1.83, 95% CI: 1.44-2.33; p &amp;lt; 0.001), adjuvant radiation therapy (OR: 6.77, 95% CI: 5.16-8.96, p &amp;lt; 0.001), BMI &amp;gt;25 kg./m2 (OR: 1.58, 95% CI: 1.26–1.97, p &amp;lt; 0.001) and older age at surgery (OR: 1.01, 95% CI: 1.00-1.02, p = 0.007). Conclusion: Our data demonstrates significantly lower rates of ipsilateral lymphedema for the patients undergoing immediate reconstruction after mastectomy when compared to that of the mastectomy alone. While these observations require further validation, our study provides useful information for the surgical decision making in patients who are considering the option of immediate reconstruction after mastectomy. Citation Format: Jin Young Byeon, Ik Beom Shin, Hawjeong Lee, Eunhye Kang, Ji-Jung Jung, Changjin Lim, Wonshik Han, Hong-Kyu Kim, Han-Byoel Lee, Hyeong-Gon Moon. Immediate breast reconstruction is associated with reduced incidence of ipsilateral lymphedema in breast cancer patients undergoing mastectomy [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 PO4-12-05.
Abstract PO4-20-12: Case Report: Should core needle biopsy showing primary leiomyosarcoma of the breast warrant a second look for accurate diagnosis and management?
Authors: Amanda Ritter, Sergey Shimunov
Journal: Cancer Research (2024)

Abstract A 68-year-old female with unknown medical history presented to the emergency department with an exceptionally large necrotic mass of the right breast. Initial core needle biopsy showed morphology consistent with the exceedingly rare leiomyosarcoma of the breast. This patient’s necrotic, fungating tumor with abscess warranted urgent surgical excision. The pathology report that followed revealed malignant phyllodes tumor as her final diagnosis. The patient did well after surgery with no sign of metastasis and continued to follow-up with oncology. Lack of clinical guidance for breast leiomyosarcoma begs the question as to when further workup is indicated since it is known to imitate the histological and radiological features of other breast lesions. We discuss the need for updated guidance from prospective future studies to change national guidelines. Citation Format: Amanda Ritter, Sergey Shimunov. Case Report: Should core needle biopsy showing primary leiomyosarcoma of the breast warrant a second look for accurate diagnosis and management? [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 PO4-20-12.
Abstract PO4-28-06: A Singleminded-2s/Sirtuin interac4on in the regula4on of mitochondrial dynamics across normal mammary development and ER+ BC progression
Authors: Hannah Carter
Journal: Cancer Research (2024)

Abstract Characterizing the mechanisms underlying the regulation of cellular differentiation and mitochondrial dynamics are critical to understanding normal development and breast cancer in the mammary gland. Our previous studies have highlighted the significance of Singleminded-2s (Sim2s), a member of the bHLH/PAS family, in regulating mitochondrial dynamics during mammary gland development and the progression of estrogen receptor-positive (ER+) breast cancer. Sim2s is temporally regulated, with maximal expression occurring during mid-lactation. Cross-fostered pups nursed by miceover-expressing Sim2s under the mouse mammary tumor virus (MMTV-Sim2s) display significantly higher weights by mid-lactation compared to pups nursed by control dams. Overexpression of Sim2s leads to alterations in mitochondrial morphology and dynamics, characterized by increased OPA1 expression and decreased DRP1 levels, resulting in enhanced mitochondrial fusion and elongation. Furthermore, we have extended our investigations to an ER+ breast cancer cell line (MCF7). We have identified SIM2s as a tumor suppressor expressed in mammary epithelial cells, known to inhibit epithelial-mesenchymal transition (EMT) and metastasis. In our previous studies, we discovered that loss of SIM2s expression in the MCF7 cell line promotes mitochondrial fragmentation, as evidenced by a decrease in OPA1 expression and an increase in DRP1 levels. In conjunction with these findings, literature suggests that sirtuins also play a role in the regulation of mitochondrial dynamics similar to Sim2s. Specifically, there is an upregulation of Sirtuin 1 in cancer when Sim2 is lost, while Sirtuin 3 increases during differentiation and normal development progression. Therefore, our aim is to elucidate the potential interaction between Singleminded-2s and sirtuins, a family of NAD+-dependent deacetylases, in the regulation of mitochondrial dynamics. We hypothesize that Sim2s may modulate mitochondrial function through its association with sirtuins, thereby influencing normal mammary gland development and breast cancer progression. Citation Format: Hannah Carter. A Singleminded-2s/Sirtuin interac4on in the regula4on of mitochondrial dynamics across normal mammary development and ER+ BC progression [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 PO4-28-06.
Abstract PO4-07-11: FDG-PET is superior to bone scintigraphy for the detection of bone metastases in breast cancer patients
Authors: Laura Kenny, Maisher Tin-U
Journal: Cancer Research (2024)

Abstract Background: Bone is the commonest site for metastases in breast cancer patients, with up to 44% of patients having bone as their sole site of metastatic disease. Patients are at increased risk of morbidity from skeletal related events (SRE) from bone metastases due to pathological fractures and spinal cord compression. Early diagnosis is crucial so that bone modifying agents can be used to prevent SREs and other agents such as CDK4/6 inhibitors can be considered. Bone scintigraphy is the most widely performed first investigation for patients at high risk or symptomatic from bone metastases. Methods: We performed a meta-analysis comparing FDG-PET and bone scintigraphy using PubMed, Science Direct, and Embase for the literature search. 1009 patients were included in the study. Data for 2 × 2 contigency tables was selected and QUADAS-2 was used for quality assessment. Diagnostic accuracy was performed using Graph pad Prism 9.5.1 and R studio 2022. Pooled sensitivity and specificity of FDG-PET/CT was 96.6% (95% CI=91.5%-98.7%) and 96.8% (95% CI=82.1%-99.5%) respectively. Respective results for BS were 88.3% (95% CI=79.8%-93.5%) and 81.3% (95% CI=63.1%-91.7%). Sensitivity and specificity of FDG-PET/CT was significantly higher than BS (P=0.0063, P= 0.0068, respectively). The diagnostic odds ratio and area under ROC curve were significantly higher for FDG-PET/CT than BS (654.36 vs 35.24, and 0.980 vs 0.877, respectively). Conclusion: FDG-PET is superior to bone scinitigaphy for the detection of bone metastases in breast cancer.The benefits of replacing BS with FDG-PET/CT are evident. However othere technologies such as DW-MRI should be considered. Large multicentre prospective trials with strict FDG-PET/CT imaging protocols compared to DW-MRI both for disease detection and monitoring of response are required to strengthen the evidence in this field, to help inform imaging guidelines and best practices in the future. Newer technologies such as [18F]estradiol (FES)-PET and [18F]GE-226 for HER2 expression also warrant further investigation in ER positive and HER2 positive breast cancer. Citation Format: Laura Kenny, Maisher Tin-U. FDG-PET is superior to bone scintigraphy for the detection of bone metastases in 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 PO4-07-11.
Abstract PS12-04: Inhibition of GPX4 enhances CDK4/6 inhibitor activity in breast cancer
Authors: Maria Teresa Herrera Abreu, Uzma Khalid, Jian Ning, Rosalind Cutts, Gemma Wilson, Christopher Lord, Amanda Swain, Nicholas Turner
Journal: Cancer Research (2024)

Abstract Background: Cyclin D-dependent kinases 4 and 6 (CDK4/6) inhibitors (CDK4/6i) including palbociclib, ribociclib and abemaciclib in combination with endocrine therapy are the standard of care for patients with estrogen receptor-positive (ER+). Despite the success of these treatments, cytostasis is frequently observed, and novel strategies that enhance efficacy are required to eradicate residual cancer in the clinic. Methods: In the search of an effective drug combinations to enhance the efficacy of CDK4/6 inhibitors in breast cancer, we performed a whole genome CRISPR-Cas9 suppressor screen in MCF-7, an ER+ model. We also carried out transcriptomics, proteomics, and functional molecular biology analysis of breast cancer models treated with palbociclib to identify resistant mechanisms. Results: The whole genome CRISPR-Cas9 screen revealed that multiple genes involved in oxidative stress and ferroptosis modulated palbociclib sensitivity, being GPX4 the top sensitizing hit. GPX4 is a key glutathione peroxidase that protects again ferroptosis by catalysing the reduction of phospholipid and cholesterol hydroperoxides. CRISPR-depletion or drug inhibition of GPX4 increased sensitivity to palbociclib in ER+ breast cancer models, and in addition sensitised triple negative breast cancer models to palbociclib. Moreover, GPX4 null xenografts were highly sensitive to palbociclib in vivo. Transcriptomics and proteomics analysis showed that palbociclib upregulate pathways involved in oxidative stress and lipid metabolism promoting a redox-lipid imbalance. Palbociclib induced lipid peroxidation leading to a ferroptosis vulnerable state with GPX4 preventing cell death. Polyunsaturated fatty acids (PUFAs) are highly susceptible of lipid peroxidation, and pathways that regulate their abundance in membrane phospholipids were explored. Interestedly, in ER+ breast cancer models, lipid peroxidation relied on a peroxisome AGPAT3-dependent pathway rather than the classical ACSL4 pathway. Conclusion: Our studies demonstrate that quiescence induced by palbociclib results in a ferroptosis-vulnerable state that could be exploited through combination with GPX4 inhibitors to enhance sensitivity to CDK4/6 inhibition in breast cancer. Citation Format: Maria Teresa Herrera Abreu, Uzma Khalid, Jian Ning, Rosalind Cutts, Gemma Wilson, Christopher Lord, Amanda Swain, Nicholas Turner. Inhibition of GPX4 enhances CDK4/6 inhibitor activity 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 PS12-04.
Abstract PO4-14-04: Comprehensive genomic profiling results in patients with metastatic breast cancer due to germline BRCA1/2 status and their HER2-low status
Authors: Hiroshi Tada, Minoru Miyashita, Narumi Harada-Shoji, Yohei Hamanaka, Miku Sato, Mika Yanagaki, Satoko Tsunokake, Tokiwa Motonari, Tomomi Kon, Asumi Yamazaki, Takanori Ishida
Journal: Cancer Research (2024)

Abstract Objective: To determine the usefulness of comprehensive genomic profiling testing and the percentage of HER2-low in patients with germline BRCA1/2 (gBRCA1/2) variants metastatic breast cancer. Methods: We included 3404 patients with metastatic recurrent breast cancer who underwent CGP testing from June 2019 to June 2023 in Japan. We examined the proportion of patients with or without recommended therapy, the proportion of patients who received matched therapy, and the proportion of patients with HER2 low by gBRCA1/2 variant due to CGP testing. RESULTS.: Of the 3404 patients, 69 (2.0%) had gBRCA1, 136 (4.0%) had gBRCA 2, 5 (0.1%) had gBRCA1 &amp; gBRCA2, 1807 (53.1%) were negative, and 1388 (40.1%) were untested or unknown. The overall percentage of patients who recommended targeted therapy due to CGP testing was 37.4%(1272/3404), with gBRCA1 at 31.9%(22/69), gBRCA2 at 43.4%(59/136), and gBRCA1&amp;gBRCA2 at 50%(2/4). The percentage of matched therapy performed in the 1st line after the expert panel was 8.3% overall, 2.9% for gBRCA1, 14.0% for gBRCA2, and 0% for gBRCA1&amp;gBRCA2. The rate of tumor mutation burden (TMB) high was 7.4% overall, and gBRCA1 at 2 .9%, gBRCA2 at 9.6%, and gBRCA1&amp;gBRCA2 at 50%. On the other hand, the percentage of HER2-low was 38.3% overall, 29% for gBRCA1, 58.1% for gBRCA2, and 25% for gBRCA1 &amp; gBRCA2. Conclusion.: Germline BRCA2 variants had a higher rate of reaching matched therapy based on CGP test results. The higher rate of TMB high was suggested to be the reason for this. The high percentage of patients with HER2-low is also expected to improve the prognosis. Citation Format: Hiroshi Tada, Minoru Miyashita, Narumi Harada-Shoji, Yohei Hamanaka, Miku Sato, Mika Yanagaki, Satoko Tsunokake, Tokiwa Motonari, Tomomi Kon, Asumi Yamazaki, Takanori Ishida. Comprehensive genomic profiling results in patients with metastatic breast cancer due to germline BRCA1/2 status and their HER2-low status [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 PO4-14-04.
Abstract PO4-04-06: Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study
Authors: Yongmei Yin, Chunxiao Sun, Yijia Hua, Nan Jin, Wei Li, Xiang Huang
Journal: Cancer Research (2024)

Abstract Background Trastuzumab emtansine (T-DM1) is the established standard second-line treatment for HER2-positive metastatic breast cancer (MBC) patients who have previously received trastuzumab. However, there is ongoing debate regarding the subsequent therapeutic options following T-DM1 failure. This study aimed to evaluate the efficacy and safety of tyrosine kinase inhibitors (TKIs)-based therapy in HER2-positive MBC patients with resistance to T-DM1. Methods During the period from September 2018 to October 2021, a multicenter real-world study was conducted, enrolling a total of 53 patients diagnosed with HER2-positive metastatic breast cancer (MBC). These patients underwent TKIs-based therapy following the failure of T-DM1 treatment. The primary focus of the study was on evaluating progression-free survival (PFS) as the main endpoint. Secondary endpoints encompassed objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and safety assessments. Results A total of 53 patients received TKIs-based therapy as a second-line or later treatment. The median progression-free survival (PFS) for TKIs-based therapy was 11.9 months (95% CI 7.9-15.9). The objective response rate (ORR) and clinical benefit rate (CBR) were found to be 19.6% and 72.5%, respectively. Among patients with brain metastasis (n=12), a median PFS of 10.5 months (95% CI 7.5-13.5) and an intracranial ORR of 33.3% were observed. Patients treated with pyrotinib (n=21) showed improved PFS compared to those treated with lapatinib (n=30), as well as patients who had derived favorable benefit from T-DM1 (PFS ≥ 6 months). Hormone receptor status (HR) and response to T-DM1 were identified as independent factors affecting the effectiveness of TKIs-based therapy. The most frequently reported adverse events included thrombocytopenia (23.6%), diarrhea (15.7%), leucopenia (15.7%), and hand-foot syndrome (15.7%). Conclusion TKIs-based therapy demonstrated favorable effectiveness and safety in HER2-positive metastatic breast cancer (MBC) patients who had previously received T-DM1 but experienced treatment failure. This includes patients with brain metastases. Notably, individuals who derived favorable benefits from prior T-DM1 treatment displayed significantly prolonged progression-free survival (PFS) when undergoing subsequent TKIs-based therapy. Citation Format: Yongmei Yin, Chunxiao Sun, Yijia Hua, Nan Jin, Wei Li, Xiang Huang. Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study [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 PO4-04-06.
Abstract PO4-17-09: Epidemiological Analysis and Overall Survival of Male Breast Cancer in a Developing Middle Eastern Country Over 18 Years
Authors: Zaid Abdulelah, Ahmed Abdulelah, Abdulrahman Alhajahjeh, Ahmad Ghazzawi, Layla El-Amayreh, Hikmat Abdel-Razeq
Journal: Cancer Research (2024)

Abstract Background: despite the profound rarity of breast cancer in males, it remains of importance given the associated morbidity and mortality, including the association with worse prognosis than female patients. Nonetheless, male breast cancer epidemiology remains poorly studied in middle eastern populations. Methodology: This retrospective cohort study examined male patients aged 15 to 85 years who were diagnosed with breast cancer between 2000 and 2018, using data from the Jordan Cancer Registry. Kaplan-Meier analysis was performed to assess the 5-year overall survival of the patients over time. Results: A total of 22,600 patients were diagnosed with breast cancer since 2000 in Jordan, of which 362 (1.6%) patients were males. 39.8% of male breast cancer cases occurred in the right breast, while the left breast was affected in 43.4% of the cases, and 3.3% of the cases were bilateral. Meanwhile, laterality was not mentioned in 13.5% of registry records. All male breast cancer cases were malignant in origin with the breast being the primary cancer. Most male patients had grade II (N=112, 30.9%) followed by grade III breast cancer (N=88, 24.3%). Among the male breast cancer cohort, 224 (62.2%) were treated with surgical intervention, 103 (28.8%) patients were given chemotherapy, 84 (23.4%) patients had radiotherapy and 24 (6.70%) patients had hormonal therapy. 27 patients died during the follow up period. The 5-year overall survival rate for the patients was 92.5% (95% CI, 89.9% to 95.3%). Conclusion: Breast cancer in middle eastern males tends to more commonly present in the left breast, and at a more advanced stage in comparison to females. Citation Format: Zaid Abdulelah, Ahmed Abdulelah, Abdulrahman Alhajahjeh, Ahmad Ghazzawi, Layla El-Amayreh, Hikmat Abdel-Razeq. Epidemiological Analysis and Overall Survival of Male Breast Cancer in a Developing Middle Eastern Country Over 18 Years [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 PO4-17-09.