bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nectin-4 expression in primary breast cancer and associated clinical outcomes.
Authors: Medford Arielle J , Niemierko Andrzej , Abelman Rachel Occhiogrosso , Haradhvala Nicholas , Knape Justine , Spring Laura , Getz Gad , Bardia Aditya 
Published: May 2024

570 Background: Antibody-drug conjugates (ADC) selectively deliver chemotherapy to tumor cells expressing a target antigen. Currently approved ADCs in breast cancer target HER2 or Trop-2. Enfortumab vedotin, an ADC targeting Nectin-4, a cell adhesion molecule, is approved in advanced/metastatic urothelial cancer. This study evaluated the expression landscape of Nectin-4 in breast cancer and its association with clinical outcomes. Methods: Processed mRNAseq data was assessed for expression of the gene encoding Nectin-4 in primary breast cancer tissue and adjacent normal breast tissue from The Cancer Genome Atlas (TCGA), and normal tissue from the Genotype-Tissue Expression (GTEx) Project. Low gene expression was determined as <100 transcripts per million (TPM). TCGA samples had been annotated for putative copy-number alterations using GISTIC 2.0; genes with a score of 2 were marked as amplified. Multivariable Cox regression analysis was used to analyze the association of low vs medium/high gene expression with disease-free survival (DFS) and overall survival (OS), adjusting for age, stage, and subtype. Results: RNA-Seq data was available for 1086 patients with primary breast cancer, including known hormone receptor positive (HR+)/HER2- (n=530), HER2+ (n=112), and triple negative breast cancer (TNBC) (n=120). NECTIN4was amplified in 15% of cases (n=165): 15% (n=78) in HR+, 15% (n=17) in HER2+ and 21% (n=25) in TNBC. NECTIN4 expression was medium/high in 356 (33%) patients: 149 (28%) HR+/HER2- (median 77.8 TPM, IQR 50.1-116.5), 32 (29%) HER2+ (median 73.7 TPM, IQR 51.9-107.8), and 59 (49%) TNBC (median 99.7 TPM, IQR 57.8-148.3). Median expression in normal breast tissue was 47 TPM (TCGA) & 16.74 TPM (GTEx), and highest in normal skin at 205 TPM. In multivariable analysis, medium/high NECTIN4 expression was associated with worse OS (HR 1.96, 95% CI 1.32-2.99, p<0.001). As a continuous variable, increasing NECTIN4 expression levels were associated with worse OS. After correcting for age, stage and subtype, for each 10-unit increase in NECTIN4TPM, the risk of death increased by 5% (HR 1.0050, 95% CI 1.0028 - 1.0072, p < 0.001). Conclusions: NECTIN4 expression was higher in TNBC and associated with worse overall survival. The high expression level in normal skin possibly contributes to the cutaneous toxicity associated with enfortumab vedotin approval and requires careful consideration as ADCs targeting Nectin-4 are developed to target breast cancer.
Artificial intelligence (AI) –powered H&E whole-slide image (WSI) analysis to predict recurrence in hormone receptor positive (HR+) early breast cancer (EBC).
Authors: Moon Jimin , Lee Hyunwoo , Cho Yoon Ah , Park Gahee , Jung Wonkyung , Kim Seulki , Shin Jiwon , Park Jiyoung , Park Jongchan , Yoo Donggeun , Pereira Sergio , Ahn Chang Ho , Cho Eun Yoon 
Published: May 2024

571 Background: The recurrence risk (RS) based on transcriptomic profiles or Ki-67 level of HR+ EBC has been used for adjuvant treatment decisions and may also aid selecting patients who could benefit from novel treatments including CDK4/6 inhibitor or oral selective estrogen receptor degraders (SERDs). Artificial intelligence-powered H&E whole slide image (WSI) models can be a practical approach for this biomarker without the need of additional tissue samples. We developed ML-based models of histopathologic features from an H&E WSI to approximate RS of 21-gene assay (OncotypeDx) using various algorithms of different complexities. Methods: The development dataset was composed of 1,009 cases from TCGA-BRCA with gene expression profiles and 483 EBC cases from Samsung Medical Center with RS results. The prediction model was developed in two-stages. First, Lunit SCOPE, an AI-powered H&E WSI analyzer, detects various cell types and segments tissue areas resulting in various cell densities in tissue regions of interest. Next, four traditional ML models were applied on top of the first stage results. In addition, a deep learning model based on multiple instance learning (DL-MIL) was developed using three features: a supervised convolutional neural network, a supervised cell detection model, and an AI-based pathology profiling analyzer, for extracting semantic contents. The model performance was validated using two independent EBC test sets: 248 cases for comparison with the RS results (set 1), and 708 cases with DFS (set 2). Results: The cross-validation performance of the four traditional ML algorithms had area under the curve of receiver operating characteristics curve (AUROC) ranging from 0.728 to 0.779, where mitotic cell density, tumor cell density, and fibroblast density in cancer area were the variables with the highest importance for all four models. The DL-MIL model had cross validation performance of AUROC 0.831. In test set 1, DL-MIL model showed the highest discrimination with AUROC of 0.828 compared to traditional ML models where logistic regression showed the highest discrimination with AUROC of 0.786 (Table). The DL-MIL model showed the highest performance among the models to predict DFS with hazard ratio (HR) of 2.48 (1.47-4.18). Conclusions: Histopathomic models can accurately predict the RS of high risk as well as poor DFS from only H&E WSIs. These AI models can be a practical tool for treatment selection including emerging drugs such as SERDs. [Table: see text]
Memory mayhem: Hormone therapy causing brain fog in patients with DCIS.
Authors: Desai Devashish , Ashok Kumar Prashanth , Benjamin Sam 
Published: May 2024

575 Background: Long term hormonal therapy in ductal carcinoma in situ (DCIS) have been studied without consistent evidence to cause cognitive side effects. Here we evaluate the relation of using hormonal therapy (HT) in patients with DCIS with cognitive effects. Methods: TrinetX, a global federated research network that provides a dataset of electronic medical records from different healthcare organizations (HCOs), was utilized. Initial query was made to isolate patients who had an ER positive DCIS. Two groups were made based on the receipt of hormone therapy (exemestane, tamoxifen, letrozole, anastrozole). Further, propensity score matching (PSM) was carried out to match age, sex, race, development of malignant neoplasm of breast, chemotherapy at any point. Outcomes of cognitive impairment were identified using ICD 10 CM codes R41.3, R41.0, F05, F02.81, and Alzheimer’s dementia was identified using ICD 10 CM code G30. Compare outcome analytic function was utilized to map the co-relation of HT with cognitive impairment. Results: 64,266 patients were identified with ER positive DCIS, of whom 63.18% (n=40,601) received HT. Patients who received HT were older (61.4 ± 12.3 vs. 61 ± 12.9, p<0.0001), and predominantly Caucasian (70% vs 65%, p<0.0001). On looking further into racial distribution of population, it was seen that Caucasians were predominant in both groups, followed by African Americans (12% vs. 11%, p=0.0016) and Unknown race (11% vs. 17%, p<0.0001), then Asians (4% vs. 4%, p=0.0675). Before PSM, it was seen that 7.55% (n= 2,818) patients had cognitive side effects compared to only 5.044% (n= 1,139) in group that did not receive HT (OR 1.537 (1.432,1.65), p<0.0001). Log-Rank Test for Kaplan-Meier curve was significant for the difference with hazard ratio 1.315, (1.227,1.409). A similar association was seen with Alzheimer’s dementia (0.735% vs. 0.547%, OR 1.346 (1.094,1.656), p= 0.0048) but Kaplan-Meier survival analysis did not show any significant difference between the groups. After PSM, both groups had 15,801 cases. The odds of developing cognitive impairment was higher in HT group (6.582% vs. 5.589%, OR 1.19, (1.082,1.309), p=0.0003). But Log-Rank Test for Kaplan-Meier curve did not show any significant difference (HR 1.047 (95% CI 0.954-1.149)). There was no significant difference for Alzheimer’s dementia development in either group (0.769% vs. 0.591%, 1.303 (0.994,1.709), p = 0.0548). Conclusions: Our study shows that HT significantly increases the odds of developing cognitive impairment. The limitation of the study is the duration of follow up. Usually, patients with DCIS live much longer and can have cognitive effects beyond the window of this study; hence a prospective long-term follow-up study is required to ascertain the relation of HT and cognitive side effects. Patients when starting the treatment should be counselled about the risk of developing cognitive side effects in future.
Therapeutic response and outcomes with less common breast cancer subtypes in the I-SPY trial 2011-2022.
Authors: Thomas Alexandra , Wolf Denise M. , Balassanian Ronald , Chen Yunn-Yi , Ye Julia , Vohra Poonam , Gulbahce Evin H , Borowsky Alexander D. , Brown Swigart Lamorna , Hirst Gillian L. , Venters Sara , Nanda Rita , Shatsky Rebecca Arielle , D'Agostino Ralph , Mukhtar Rita A. , Hatcher Sarah , Yau Christina , DeMichele Angela , van 't Veer Laura , Esserman Laura 
Published: May 2024

582 Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients (1). We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized. EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCs. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. 1. Wolf et al, Cancer Cell 2022. Clinical trial information: NCT01042379 . [Table: see text]
An MRI-based multi-parameter clinical decision support system (NeoMDSS) for early prediction of pathological complete response after the first cycle of neoadjuvant therapy in breast cancer: A multi-center prospective observational cohort study.
Authors: Zhang Liulu , Zhu Zhaowen , Chen Yuanqi , Wu Yidan , Zhang Yongcheng , Ye Guolin , Li Wei , Wang Kun 
Published: May 2024

592 Background: Currently, there is no reliable and convenient way to predict response rates in early stages of neoadjuvant therapy (NAT) for breast cancer, which can affect the prognosis of non-responsive patients. Methods: In this prospective multi-center observational study, eligible participants who underwent NAT followed by radical surgery were recruited. All patients underwent magnetic resonance imaging (MRI) examination before and after the first cycle of NAT (1st-NAT). We analyzed the effects of clinicopathological features, such as histological grade, hormone receptor (HR) and HER2 status, Ki-67 expression, blood cell analysis, and MRI parameters including the reduction ratio of tumor diameter (ΔD%), apparent diffusion coefficient (ADC), and early enhancement ratio (EER) on NAT. By incorporating independent influencing factors, we developed a multiparametric clinical decision support system (NeoMDSS) model based on a retrospective cohort and validated its accuracy in both a prospective single-center internal cohort and a prospective multi-center external cohort. Relevant clinical trial details can be found under the identifier NCT04909554. Results: A total of 301 breast cancer patients were enrolled between January 2019 and December 2023, including 140 patients in the training cohort, 120 patients in the internal validation cohort, and 41 patients in the external validation cohort. The NeoMDSS model demonstrated excellent performance in predicting pathological complete response (pCR) at 1st-NAT, with an AUC of 0.874 (95% CI 0.813-0.935) in the training cohort, 0.845 (95% CI 0.771-0.919) in the internal validation cohort, and 0.867 (95% CI 0.742-0.992) in the external validation cohort. The NeoMDSS model exhibited a sensitivity, specificity, and accuracy of 80.0%, 81.3%, and 80.5%, respectively, in the internal validation cohort, and 87.0%, 83.3%, and 85.4%, respectively, in the external validation cohort. Calibration curves and decision curve analysis (DCA) further supported the clinical value of the NeoMDSS model. To facilitate the clinical application of the NeoMDSS model, a nomogram and an online website ( www.gdphneomdss.com ) were developed to calculate the probability of pCR, which the sensitivity, specificity, and accuracy of the NeoMDSS model were all 80.0% in the internal validation cohort and 80.0%, 81.3%, and 80.5% in the external validation cohort. Conclusions: The NeoMDSS model serves as a convenient tool in clinical practice at 1st-NAT to calculate and accurately predict the probability of pCR after NAT. This assists clinicians in determining whether to modify the treatment plan and improving personalized treatment for patients with poor response to NAT. Clinical trial information: NCT04909554 .
Real life comparison between doxorubicin and cyclophosphamide (AC) dose-dense (dd) and conventional dose AC in patients with triple negative breast cancer (TNBC) under neoadjuvant treatment.
Authors: Cavalcanti Balint Flavia , Tavares Monique Celeste , Sousa Isadora Martins de , Marin Comini Ana Carolina , Borges Italo Barradas e Silva , Coimbra Barroso Matheus , Martins Livia Alexandre , de Albuquerque e Rodrigues de Sousa Débora Guilherme 
Published: May 2024

e12662 Background: High-risk early triple-negative breast cancer (TNBC) is frequently associated with early recurrence and high mortality. Studies suggest a sustained clinical benefit in patients with TNBC who have a pathological complete response (PCR) after neoadjuvant chemotherapy (NACT). The dose-dense (dd) regimen demonstrated improved survival regardless of hormone receptor expression or HER2 status. The doxorubicin and cyclophosphamide (AC) regimen can be performed in (dd), therefore it must include granulocyte growth factors, which may increase costs and toxicities. The object of the study was to evaluate their clinical characteristics and treatment, patients with TNBC, stage I-III who received ACdd in neoadjuvant treatment versus patients who received AC dose conventional (dc). Methods: We performed a retrospective observational cohort study of patients with early TNBC, stage I-III who received neoadjuvant treatment with chemotherapy based on doxorubicin, cyclophosphamide, paclitaxel and carboplatin associated with pembrolizumab. Results: All 82 patients were women 57.3% received ACdd, 30.4% received AC dc. In group ACdd 59.5% had intercurrence related with chemotherapy, in which 17.8% were neutropenic fever and 21.4% had developed different types of infections (ex: diarrhea, pneumonia and others). In these 2 groups all of them had received antibiotic. About 50% of the patients had developed intercurrence because of treatment toxicity and just 3.5% had disease progression. The other group that we evaluated is composed by patients who ACdc, dose Regarding to these group 48% developed any intercurrence during the neoadjuvant treatment, in which 8.3% had neutropenic fever and 25% had different types of infections. All of them earned antibiotic. About clinical and pathological response, the group that earned ACdd 61.7% got complete clinical response and 8.5% had a disease progression during the treatment. In the other arm 68% got complete clinical response and 4% had a progression. Conclusions: AC dd was more prevalent in our series, despite the additional use of granulocyte growth factor, there were more complications in this group and it did not demonstrate better results than those who received conventional dose AC.
Trends and outcomes in patients receiving neoadjuvant chemotherapy for breast cancer in Ontario: A population-based study.
Authors: Castelo Matthew , Nguyen Lena , Roberts Amanda 
Published: May 2024

e12664 Background: Modern neoadjuvant chemotherapy (NAC) regimens in breast cancer offer higher rates of pathologic complete response, an ability to guide further adjuvant treatment, and may de-escalate surgery. However, the utilization of NAC has been heterogeneous in Ontario. This study aimed to describe trends in NAC use in Ontario, report survival outcomes, and explore factors associated with overall survival in these patients. Methods: This was a population-based cohort study using linked health administrative data in Ontario, Canada. From the Ontario Cancer Registry, we identified women ≥18 years who underwent neoadjuvant chemotherapy followed by surgery for operable (cT1N1, cT2-3N0, or cT2-3N1) breast cancer between 2012 and 2020. Patients were divided by receptor subtype (triple negative breast cancer [TNBC], ER+/HER2-, ER+/HER2+, ER-/HER2+) and characteristics were compared using standardized mean differences (SMDs). Five-year overall survival (OS) and breast cancer-specific survival (BCSS) were determined and reported for each subtype. Associations with OS and BCSS were calculated for patient and disease characteristics using univariate and multivariable Cox proportional hazards models and Fine and Gray models, respectively. Results: 3,804 women underwent NAC for cT1N1, cT2-3N0, or cT2-3N1 breast cancer in Ontario between 2012 and 2020. The largest contributing subtype was ER+/HER2- patients (39.3%) followed by those with HER2+ disease (ER-/HER2+ 13.8%, ER+/HER2+ 23.4%), and TNBC (23.5%). The median age was 50 years (IQR 42-59 years). Most patients were clinically node-positive (2,736; 71.9%), and underwent mastectomy (2,397; 63.0%). There was a significant increase in the number of patients receiving NAC in Ontario, from 217 in 2012 to 667 in 2019 ( p<0.001), with a greater increase among patients with TNBC or HER2+ disease. Compared to those with ER+/HER2- disease, TNBC patients were treated for smaller tumours (28.6% T3 vs. 39.8%; SMD = 0.24), and were more likely to be node-negative (39.1% N0 vs. 22.1%; SMD = 0.38). Similar trends for nodal status were found for patients with ER-/HER2+ (26.7% N0) and ER+/HER2+ cancer (27.9% N0). 5-year OS for the entire cohort was 88.1% (95% CI 87.1 – 89.2%). Survival was highest for ER+/HER2+ patients (94.2%, 95% CI 92.6 – 95.8%) and lowest for TNBC patients (80.1%, 95% CI 77.5 – 82.8%). Similar patterns were seen for BCSS. Factors associated with OS in a multivariable model included older age (increase in 5 years HR 1.1, 95% CI 1.07 – 1.14), N1 status (HR 1.99, 95% CI 1.61 – 2.47), larger tumour size (T3 HR 1.83, 95% CI 1.34 – 2.5), mastectomy (HR 1.45, 95% CI 1.2 – 1.75), and TNBC (versus ER+/HER2- HR 1.9, 95% CI 1.56 – 2.32). Conclusions: The use of NAC has increased in Ontario, particularly among TNBC and HER2+ patients. Women with TNBC have worse outcomes compared to those with ER+/HER2- disease, despite being treated for less advanced disease.
FIT as a population-based and financially viable method to screen underserved patients for colorectal cancer.
Authors: Grivas Christopher , Ifrah Abraham , Dahake Nikita , Vallabhaneni Manasa , McNeilly Shelby , Graham Brianna , Gillow Gabrielle , Khatri Rishabh , Raab Claire 
Published: May 2024

e13516 Background: Temple University Hospital (TUH) created an initiative to increase colorectal cancer (CRC) screening by administering fecal immunochemical tests (FIT) to the underserved population of Philadelphia. We hypothesize that this will increase the percentage of diagnostic colonoscopies performed compared to baseline in our fixed capacity colonoscopy suite and ultimately generate a higher reimbursement per colonoscopy. This potential revenue increase can help fund the infrastructure to administer a large quantity of FIT tests to the community and create a truly equitable population-based approach to CRC screening. Methods: 27,169 colonoscopies and their associated CPT codes from 2017-2022 performed at TUH were analyzed. 16 individual CPT codes were identified and categorized as either screening or diagnostic CPT codes. Reimbursement for each of the CPT codes was determined by the Medicare reimbursement per CPT code and used to determine the average reimbursement per screening CPT code and average reimbursement per diagnostic CPT code. A Monte Carolo simulation model was created using Palisades @Risk software to compare the reimbursements of FIT test prompted vs. non-FIT test prompted colonoscopies over a range of possible distributions of diagnostic CPT codes. Monte Carlo simulations model scenarios that incorporate uncertainties with the objective of providing a distribution of outcomes from the least likely to most likely outcomes. Results: The historical distribution of screening vs. diagnostic CPT codes at TUH is 31% and 69%, respectively, with an average Medicare reimbursement of $2,668 per colonoscopy. We have distributed 292 FIT tests, and 5 FIT test prompted colonoscopies have been completed with 7 associated CPT codes. The preliminary distribution of screening CPT codes vs diagnostic CPT codes is 29% and 71%, respectively, with an average reimbursement of $2,691. Lastly, we used a Monte Carlo simulation to run 10 separate simulations with 5000 iterations each to show the most likely reimbursement rates over a possible distribution of diagnostic colonoscopies (Table). Conclusions: Our preliminary data suggests FIT testing can offer three main benefits: 1) Expansion of the number of patients receiving CRC screening; 2) triage optimization of the fixed capacity colonoscopy suite by performing more diagnostic colonoscopies than screening colonoscopies to diagnose more colorectal pathologies; and 3) funding for a population based FIT testing campaign by utilizing the Medicare reimbursement delta from screening to diagnostic colonoscopies. [Table: see text]