tbuckley/cabot-search huggingface dataset:
Abstract PO3-01-11: Clinical Significance of HER2-low Breast Cancer
Authors: Fadi Zaiem, Asem AbuJamea, Mira Kheil, Anna Numi, Omar Abbas, Sanaa Awada, Ragad Almsaddi, Saleh Al-Juburi, Lauren Larson, Deepti Jain, Maya AlSaghir, Hyejeong Jang, Seongho Kim, Sudeshna Bandyopadhyay, Sunil Jaiman, Rouba Ali-Fehmi
Journal: Cancer Research (2024)

Abstract Context: Breast cancers with a HER2 immunohistochemistry (IHC) result of 1+ or 2+ and a negative amplification test (FISH), previously treated as HER2 negative, are now termed HER2-low and are being targeted for treatment. We aim to explore the clinical significance of this group. Design: 394 breast cancer cases were included from our institution from 2010. Demographic and clinicopathological data on receptors status, recurrence/metastasis, treatment, and survival was collected. HER2 was re-evaluated according to the 2018 CAP ASCO guidelines and patients were treated according to standardized protocol. HER2 +2 with positive FISH and HER2 +3 were excluded. HER2-low was compared to HER2-0. Appropriate statistical analysis was performed. Results: 394 patients (76% IDC; 8% ILC; 16% others) were included, such that 91 (23%) were HER2-0 and 303 (77%) HER2-low. Median age was 58 years (range: 25-95). Median follow-up was 54 months (range: 0.5-259). Grade 3 tumors were significantly more frequent in HER2-0 than HER-2 low (52% vs. 33%; p=0.010). Grade 3 or ILC patients had higher risk of recurrence than Grade 1 (HR 2.55; p&amp;lt; 0.001) or IDC (HR 2.03; p=0.033). After adjusting for grade, HER2-low had a significantly worse RFS than HER2-0 (HR 1.58; p=0.043). In the ER negative subgroup, HER2-low had significantly worse RFS than HER2-0 (HR 2.02; p=0.023). No differences in overall survival were seen. Conclusions: Our data showed higher recurrence in HER2-low group compared to HER2-0. This suggests that breast cancer patients with HER2- low are a separate entity and might benefit from additional targeted therapy. Table 1 Hazard regression analysis of risk factors associated with recurrence Citation Format: Fadi Zaiem, Asem AbuJamea, Mira Kheil, Anna Numi, Omar Abbas, Sanaa Awada, Ragad Almsaddi, Saleh Al-Juburi, Lauren Larson, Deepti Jain, Maya AlSaghir, Hyejeong Jang, Seongho Kim, Sudeshna Bandyopadhyay, Sunil Jaiman, Rouba Ali-Fehmi. Clinical Significance of HER2-low 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 PO3-01-11.
Abstract PO2-02-01: Online Virtual Patient Simulation CME Improves Clinical Decision-Making In The Management Of Patients With HR+/HER2- Early Breast Cancer
Authors: Nabil Dorkhom, Urvi Patel, Stephanie Baumhover, Jacob Cohen
Journal: Cancer Research (2024)

Abstract Background: The goal of this study is to assess whether an online, virtual patient simulation (VPS) continuing medical educational (CME) activity, improved the performance of oncologists in ordering appropriate diagnostic tests and managing and counselling patients with HR+/HER2- early breast cancer (EBC) at high risk of recurrence. Methods: Two VPS educational activities were developed, the first VPS consisted of one patient case, focused on diagnosing patients with high risk of recurrence, while the other VPS consisted of 2 patient cases focused on the management and counselling of patients with HR+/HER2- EBC with high risk of recurrence. Physicians could make clinical decisions using complete open-field entries, based on the 3 performance based learning objectives. After each decision, learners received clinical guidance (CG) based on current evidence and expert recommendations. Pre- and post-CG clinical decisions were compared using a a McNemar's test to determine P values (P &amp;lt; .05 is significant). Rationales for clinical decisions were collected in real time. Data were collected between November 2021 and August 2022 and are reported here as % point change per performance learning objective, P value. Results: A total of 922 oncologists were included in the analysis. There was a significant improvement across the 3 performance learning objectives analysed. Please see table below for the results. Conclusions: This analysis demonstrated the educational impact of an immersive, online VPS education which allowed physicians to improve evidence-based clinical decisions regarding diagnosing patients with HR+/HER2- early breast cancer at high risk of recurrence and managing and counselling them regarding their treatment. Results Citation Format: Nabil Dorkhom, Urvi Patel, Stephanie Baumhover, Jacob Cohen. Online Virtual Patient Simulation CME Improves Clinical Decision-Making In The Management Of Patients With HR+/HER2- Early 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 PO2-02-01.
Abstract PO1-16-03: GDP-mannose enhances the efficacy of PARP inhibitors and immunotherapy in triple-negative breast cancer
Authors: Yi Xiao, Jiahan Ding, Yi-Zhou Jiang, Zhi-Ming Shao, Genhong Di, Fan Yang, Xiaoqing Song
Journal: Cancer Research (2024)

Abstract Background: Triple-negative breast cancer (TNBC) patients with high HRD scores benefit from poly (ADP-ribose) polymerase (PARP) inhibitors, while those with low HRD scores still lack therapeutic options. Homologous recombination deficiency (HRD) induction is an effective strategy to broaden the indications of PARP inhibitors. Metabolic reprogramming is a critical feature of TNBC. In this study, we aimed to explore novel metabolic biomarkers for HRD and new strategy for sensitizing PARP inhibitors. Methods: We utilized TNBC metabolomics to systematically evaluate metabolites that were correlated with HRD. A crucial metabolite, GDP-mannose (GDP-M), that impedes homologous recombination repair (HR) and sensitizes PARP inhibitors was identified and functionally validated. We further explored the detailed mechanism and proposed a potential treatment strategy utilizing GDP-M for TNBC in preclinical models. Results: Systematic metabolomic analysis revealed that GDP-mannose (GDP-M) was significantly enriched in basal-like tumors with HRD. GDP-M promoted cisplatin-induced DNA double-strand breaks by inducing HRD. Mechanistically, the low expression of the upstream enzyme GMPPA led to the endogenous upregulation of GDP-M, which further promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HR. GMPPA expression and GDP-M could serve as predictive biomarkers for HRD and the response to PARP inhibitors. Therapeutically, we validated that the combination of GDP-M and PARP inhibitors synergistically inhibit tumor growth in multiple preclinical models. Moreover, GDP-M supplementation plus PARP inhibition activated STING-dependent antitumor immunity and further augmented the efficacy of anti-PD-1 antibodies. Conclusions: GDP-M promotes the degradation of BRCA2 and thus enhances the sensitivity of PARP inhibitors in TNBC. The combination of GDP-M, PARP inhibitors and anti-PD-1 immunotherapy may be a potential treatment strategy for HRD-low TNBC. Citation Format: Yi Xiao, Jiahan Ding, Yi-Zhou Jiang, Zhi-Ming Shao, Genhong Di, Fan Yang, Xiaoqing Song. GDP-mannose enhances the efficacy of PARP inhibitors and immunotherapy in triple-negative 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 PO1-16-03.
Abstract PO1-24-02: Enhancement of TGF-β Receptor Inhibitor Efficacy through CD44 Suppression in Claudin-low Breast Cancer
Authors: Ryoichi Matsunuma, Sae Imada, Shoko Sato, Ryosuke Hayami, Michiko Tsuneizumi
Journal: Cancer Research (2024)

Abstract Introduction: Claudin-low breast cancer is mostly classified as triple-negative breast cancer and is known to possess cancer stem cell properties with high expression of epithelial-to-mesenchymal transition (EMT) markers. However, specific therapeutic targets for this subtype have not yet been identified. While reports suggest that inhibition of EMT using EMT inhibitors can suppress cell and tumor proliferation, monotherapy may not be sufficient. The expression of CD44, a surface marker of cancer stem cells, has been reported to be involved in multiple signaling pathways, promoting cancer growth and invasion. In this study, we focus on CD44 and the TGF-β receptor, which is involved in EMT, to investigate the effect of inhibiting TGF-β receptor through CD44 inhibition in Claudin-low breast cancer and validate its potential as an effective treatment. Methods: SUM159 and MDA-MB-231 cell lines were used as Claudin-low breast cancer cell models. CD44 knockdown cells were established to examine the effects of TGF-β receptor inhibition and downstream signaling. Results: CD44 knockdown did not affect the expression of TGF-β receptor. Both SUM159 and MDA-MB-231 cells showed comparable cell growth inhibition through CD44 knockdown and TGF-β receptor inhibition, with enhanced effects observed in CD44 knockdown cells in response to TGF-β receptor inhibition. Furthermore, CD44 knockdown combined with TGF-β receptor inhibition significantly reduced the expression of Smad2/3. Conclusion: In Claudin-low breast cancer cells, CD44 knockdown enhances the effectiveness of TGF-β receptor inhibition and significantly influences the expression level of Smad2/3. Citation Format: Ryoichi Matsunuma, Sae Imada, Shoko Sato, Ryosuke Hayami, Michiko Tsuneizumi. Enhancement of TGF-β Receptor Inhibitor Efficacy through CD44 Suppression in Claudin-low 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 PO1-24-02.
Abstract PO1-13-08: Comparative analysis of stearoyl-CoA desaturase 1 expression and activity index in model cell lines of breast cancer subclasses
Authors: Hamid-Reza Feizi, Amir Mehdizadeh, Zohreh Sanaat, Khadijeh Abbasi, Frank Gieseler, Masoud Darabi
Journal: Cancer Research (2024)

Abstract Introduction Due to the unique conditions of the tumor microenvironment, such as hypoxia, poor angiogenesis, and mitochondrial dysfunction, cancer cells face challenges in obtaining nutrients and energy supply. However, monounsaturated fatty acids have been identified as preferred substrates for energy generation and maintenance of cellular structures in cancer cells. These fatty acids can be obtained through de novo fatty acid synthesis. Stearoyl-CoA desaturase 1 (SCD1) is the primary enzyme involved in the biosynthesis of monounsaturated fatty acids from saturated fatty acids and is known to be upregulated in various malignancies, including breast cancer. This study aimed to assess the expression and activity index of SCD1 in well-characterized MCF-7, SK-BR3, and MDA-MB231 breast cancer cell lines, representing luminal A/B, HER2-enriched, and triple-negative subtypes, respectively. Methods The breast cancer cell lines were cultured in RPMI-1640 medium with 10% fetal bovine serum at 37°C, 5% CO2, and 95% humidity for 72 hours. After harvesting the cells, SCD1 expression was analyzed using real-time quantitative PCR, and the activity index was determined by measuring the ratio of monounsaturated fatty acids to saturated fatty acids using capillary gas-liquid chromatography. Results MCF-7 cell line showed a significantly higher SCD1 expression compared to MDA-MB231 (250-fold, p&amp;lt; 0.0001) and SK-BR3 (83-fold, p&amp;lt; 0.0001) cell lines. The activity index of SCD1 was significantly higher in both MCF-7 and MDA-MB231 cell lines with fold changes of 2.6 and 2.5, respectively, compared to SK-BR3 cell line (p=0.004 for both). Conclusion Cell model assays demonstrated that the luminal A/B and triple-negative subtypes showed a higher capacity to convert saturated fatty acids to monounsaturated fatty acids through SCD1 enzyme activity, indicating a different lipid metabolism profile in the HER2-enriched subtype. These new findings reveal differences in SCD1 expression and activity among breast cancer subclasses. They highlight vulnerabilities in metabolism and identify potential therapeutic targets with clinical implications for managing breast cancer. Citation Format: Hamid-Reza Feizi, Amir Mehdizadeh, Zohreh Sanaat, Khadijeh Abbasi, Frank Gieseler, Masoud Darabi. Comparative analysis of stearoyl-CoA desaturase 1 expression and activity index in model cell lines of breast cancer subclasses [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 PO1-13-08.
Abstract PO1-23-07: The effect of intra-operative margin assessment during breast conserving surgery for breast cancer in a Dutch cohort
Authors: Sophie Wooldrik, Elles van de Voort, Taco Klem, Thijs van Dalen, Cornelis Verhoef, Gerson Struik, Erwin Birnie
Journal: Cancer Research (2024)

Abstract Background Pre-operative tumour localisation and intraoperative specimen radiography are necessary to perform adequate resection of non-palpable breast tumours. Intraoperative digital specimen mammography (IDSM), is an alternative to conventional specimen radiography (CSR) and has the benefit of providing immediate specimen evaluation and the potential of decreasing operation time. IDSM may also reduce positive margins and re-excision rates. IDSM was implemented in our hospital in 2018. The study objective was to evaluate the surgery time, radicality and re-excisions in IDSM and CSR. Methods A single centre retrospective cohort study with two cohorts: CSR (n=532) and IDSM (n=475). The primary outcome was duration of surgery. Secondary outcomes were margin status of the primary surgery, the perioperative cavity shave rate and the re-excision rate. Differences between cohorts were compared using univariate statistics and multiple regression to adjust for variables that were statistically significantly associated with duration of surgery. Results IDSM use was associated with 8 minutes shorter surgery time (B -8.242, p &amp;lt; 0.001). Treatment variables independently associated with the duration of surgery were use of IDSM, type of (axillary) surgery and the performance of cavity shaving. Cavity shaves were more often performed when IDSM was used (24% versus 14% in CSR group, p &amp;lt; 0.001), while the proportion of radical first surgeries (93% versus 96% respectively, p = 0.070) was comparable. Conclusion IDSM was associated with a modest reduction in duration of surgery. Surgeons performed more cavity shaves since IDSM but this was not reflected by a lower proportion of patients with positive margins. Table 1. Baseline characteristics of the CSR versus the IDSM cohort Table 2. Results of surgery in the CSR versus the IDSM cohort. Citation Format: Sophie Wooldrik, Elles van de Voort, Taco Klem, Thijs van Dalen, Cornelis Verhoef, Gerson Struik, Erwin Birnie. The effect of intra-operative margin assessment during breast conserving surgery for breast cancer in a Dutch cohort [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 PO1-23-07.
Abstract PO5-07-05: Deep learning can diagnose axillary lymph node metastases on optical virtual histologic images in breast cancer patients during surgery
Authors: Shuwei Zhang, Houpu Yang, Jin Zhao, Shu Wang
Journal: Cancer Research (2024)

Abstract Background: Reliable identification of axillary lymph node (ALN) involvement in patients with breast cancer allows for definitive axillary dissection at the time of the initial surgery, thus avoiding the need for a separate axillary surgery. However, conventional intraoperative ALN diagnostic methods are time-consuming and labor-intensive and can result in tissue destruction. Dynamic full field optical coherence tomography, also called dynamic cell imaging (DCI), has been developed and validated to offer rapid and label-free histologic approximations of metastatic and non-metastatic ALNs. In this study, we aim to optimize the diagnostic pipeline with an automated approach and present the results of using a deep learning (DL) algorithm with DCI to predict ALN status intraoperatively in patients with breast cancer. Methods: Breast cancer patients who required ALN staging were enrolled prospectively in this study. DCI was applied to bisected fresh lymph nodes in a non-destructive manner, and the specimens were subsequently sent for histopathological examination, regarded as the gold standard for comparison. A DL model was trained and fine-tuned on over 80,000 DCI images, and the results were mapped to slide level to predict ALN diagnosis. Results: Total 607 DCI slides of ALNs with 112,852 cropped patches were included in the study. The DL model was trained and validated on a dataset containing 481 slides and tested on an independent testing dataset with 126 slides. In the test set, the DL algorithm yielded accuracy for prediction of ALN status, with sensitivity and specificity of 91.9% and 95.5% and an area under the receiver operating characteristic curve (AUC) of 0.937 (95% confidence interval [CI]: 0.912-0.957) at slide level. Conclusion: These results demonstrate that the integration of DCI with DL is rapid, reduces labor requirements and minimizes tissue destruction. Meanwhile, this algorithm had high classification accuracy to predict the metastatic burden of ALNs for patients with breast cancer. Citation Format: Shuwei Zhang, Houpu Yang, Jin Zhao, Shu Wang. Deep learning can diagnose axillary lymph node metastases on optical virtual histologic images in breast cancer patients during surgery [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 PO5-07-05.
Abstract PO1-04-13: CARDIAC-STAR: Prevalence of Cardiovascular Comorbidities in Hormone Receptor Positive Human Epidermal Growth Factor Negative metaStatic breasT cAnceR
Authors: Susan Dent, Avirup Guha, Heather Moore, Rachael McCaleb, Irene Arias, Stella Stergiopoulos, Benjamin Li, Doris Makari, Michael Fradley
Journal: Cancer Research (2024)

Abstract BACKGROUND: Baseline cardiovascular (CV) comorbidities can impact treatment decisions for patients (pts) with metastatic breast cancer (mBC). There is limited data on the prevalence of CV comorbidities at the time of hormone receptor positive human epidermal growth factor negative (HR+/HER2-) mBC diagnosis. The primary objective of this study is to describe the prevalence of pre-existing CV comorbidities in women and men with newly diagnosed HR+/HER2- mBC. A secondary objective is to describe the first documented cancer treatment for patients with or without CV comorbidities. METHODS: Women and men ≥18 years of age with newly diagnosed HR+/HER2- mBC from 01/2016 to 12/2021 were included in this retrospective, observational study using the Merative™ Marketscan® Commercial and Medicare Databases which is nationally representative. Evidence of mBC was defined as having two or more claims containing one or more diagnosis code for BC at least 30 days apart and at least two secondary malignancy diagnosis codes. Previously published claims-based algorithms were used to identify the HR+/HER2- molecular subtype. The index date is defined as the date of first mBC diagnosis. Patients had a 1-year pre-index period for observation of CV comorbidities and a 6-month post-index period for first documented cancer treatmen RESULTS: We identified 5,452 pts with HR+/HER2- mBC, 99% of whom were female, with a median age of 58 years (yrs) (IQR 13), and 83% having a health plan from an employer; i.e., are still employed. At mBC diagnosis, 3,335 pts (61.2%) had at least one pre-existing CV comorbidity (see Table). The most reported CV comorbidities were hypertension (50.7%), hyperlipidemia (33.7%), and diabetes (19.2%). The median age of pts with or without a CV comorbidity was 61 and 52 yrs, respectively; 16.2% with CV comorbidities were ≥75 yrs. Additional data, including first documented treatment, will be presented at the meeting. CONCLUSIONS: The prevalence of CV comorbidities in pts with HR+/HER2- mBC is often underrecognized. In this analysis, more than half of pts had at least one CV comorbidity by mBC diagnosis. CV comorbidities may impact treatment decisions in the HR+/HER2- mBC population, particularly in older pts. Table Citation Format: Susan Dent, Avirup Guha, Heather Moore, Rachael McCaleb, Irene Arias, Stella Stergiopoulos, Benjamin Li, Doris Makari, Michael Fradley. CARDIAC-STAR: Prevalence of Cardiovascular Comorbidities in Hormone Receptor Positive Human Epidermal Growth Factor Negative metaStatic 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 PO1-04-13.
Abstract PO5-14-06: Transcriptomics-based drug screening in 3D ex vivo patient-drived breast cancer model and patient biopsy for personalized therapy
Authors: Yueyun Zhang, Carlos Henrique Venturi Ronchi, Giovanna Ambrosini, Yuanlong Liu, Patrick Aouad, Daria Matvienko, Christoph Merten, Cathrin Brisken
Journal: Cancer Research (2024)

Abstract Breast cancer is a leading cause of cancer-related mortality for women worldwide. Hormone receptor-positive (HR+) breast tumors, which represent 70% of all breast cancer cases, are treated with endocrine therapy. However, not all patients benefit from this treatment regimen because of patient-to-patient variation. Therefore, high throughput drug screening system is warranted to enable personalized medicine. Patient-derived organoids, which serve as a screening platform, lose their hormone receptors and response upon ex vivo culturing, and may not be adequate models for HR+ breast tumors. Moreover, unidentified biological components in the widely-used basement membrane matrix, Matrigel, result in high batch-to-batch variations and poor reproducibility in organoid cultures. Here, we propose a hydrogel-based 3D ex vivo model with defined structural and chemical properties to test hormone and drug sensitivity of HR+ breast tumors from patient-derived xenografts (PDXs) and patient tumor biopsies using microfluidics. Our data demonstrate the feasibility of this model to preserve cell proliferation and hormone receptor expression over 7 days. We also demonstrate that responses to hormones and FDA-approved drugs are faithfully maintained in this model. Finally, to establish a high throughput hormone and drug testing workflow with transcriptomic readout, we multiplexed barcoded- and drug-treated tumor samples in a single experiment with bulk RNA-sequencing. Our preliminary data demonstrate patient-specific responses to hormones and drugs that correspond to patient genetic mutation profiles, treatment history, disease stages and subtypes. This platform also enables testing of drugs in clinical trials that shows promising therapeutic outcomes for breast cancer, such as CDK4/6i, AKTi, PARPi, mTORi and their combination with endocrine therapy, thanks to the high throughput of the screening system and the low consumption of patient-derived or patient tissue. Given the capability of combining this physiologically-relevant 3D ex vivo model with RNA-seq for HR+ breast tumors, this platform holds potential for high throughput compound testing and transcriptomic profiling of patient biopsies for personalized medicine. Citation Format: Yueyun Zhang, Carlos Henrique Venturi Ronchi, Giovanna Ambrosini, Yuanlong Liu, Patrick Aouad, Daria Matvienko, Christoph Merten, Cathrin Brisken. Transcriptomics-based drug screening in 3D ex vivo patient-derived breast cancer model and patient biopsy for personalized therapy [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 PO5-14-06.